Abstracts

Note: The data in these abstracts were current at the time they were submitted, which may have been months before the start of CROI. For the most up-to-date data, please view the posters and oral abstract presentations.

To search for specific keywords, presenters, or authors on this document, hold the “Ctrl” and press the “F” keys on your keyboard (or "Command" and "F" keys for some Apple devices) to prompt a word search.

CROI conference materials (including, but not limited to, the CROI Program Guide, Abstract eBook, electronic posters, CROI logo, etc) are protected by copyright. Permission to replicate or reproduce any part of CROI materials (such as an abstract as formatted in the CROI Abstract eBook) must be obtained from the CROI Conference Manager, the International Antiviral Society–USA (IAS–USA). However, study data are the property of the author(s) and study sponsors as relevant. For more information, please email CROIabstracts@iasusa.org.

Background

Over the past four decades, remarkable progress has been made in understanding HIV epidemiology, pathogenesis, treatment, and prevention from the combined efforts of community members, clinicians, investigators, and funding agencies worldwide. Yet more work and new approaches are needed to achieve the ambitious goal of ending the epidemic and ensuring optimal quality of life for those living with HIV. To encourage and stimulate the next generation of investigators, the CROI Program Committee organizes the Scott M. Hammer Workshop for New Investigators and Trainees comprised of expert and comprehensible talks to introduce key topics in basic, clinical, and public health investigation into HIV and related infections and to highlight relevant work to be presented over the ensuing days at CROI. This year, each presentation is preceded by a “Hearing Community Voices” testimonial focused on how the type of work impacts the community and how the community can impact the research. In the first talk, Stuart J. D. Neil will provide an accessible updated on Virology, and Lishomwa Ndhlovu will follow with a talk on Immunology. Susan P. Buchbinder will focus on the Prevention of HIV and STIs, followed by Judith S. Currier on Cardiovascular Complications of HIV. The session will end with a talk on HIV Cure Research by Joseph J. Eron, Jr. By completing the workshop, attendees will have achieved a head start toward maximizing the knowledge gained and research ideas as they navigate CROI 2025.

Background

The genetic material of HIV-1 is packaged inside a cone shaped container that is called the viral core. To infect a cell, the viral core must pass through the cell’s nuclear pore. Using atomic force microscopy, a technique that uses a tiny needle to feel the surface of things at the microscopic level, and molecular dynamic simulations, we discovered that wild-type HIV-1 cores quickly revert to their normal shape after compression, while capsid mutants with impaired nuclear entry are brittle. Restoring elasticity in these mutants recovered their ability to infect. Treatment with capsid-targeting drugs also reduced core elasticity. These findings suggest that capsid elasticity is essential for HIV-1 nuclear entry and infection, offering new insights into HIV-1 mechanics and potential antiviral strategies.

Background

We use the power of CRISPR-based gene editing technologies to decode and rewrite DNA programs that govern cells in the human immune system. Human immune cells, especially T cells, can be genetically engineered to target various cancers. Despite their utility for the treatment of hematological malignancies, chimeric antigen receptor (CAR) T cells have significant limitations, which are especially clear in the context of solid tumors. Mounting evidence suggests that for many clinical applications, engineering the T cell to recognize the target cancer cells will not be sufficient to cure disease. Major challenges to the utility of immunotherapy in cancer include overcoming immunosuppressive tumor microenvironments and maintaining the therapeutic cells’ functionality in the tumor over time. We are working to accelerate the design of genome modifications and synthetic DNA sequences that can be introduced into human T cells to program the enhanced functionality necessary to overcome these challenges.

Background

Humanized mouse models, immunodeficient mice transplanted with human cells/tissues, have been used by HIV researchers for over 30 years to study aspects of HIV infection (e.g. transmission, pathogenesis, and persistence) and to perform efficacy testing of novel prevention, treatment, and cure approaches. This presentation will introduce the most commonly used humanized mouse models for HIV research providing details on their construction, reconstitution with different human cell types, susceptibility to different routes of HIV transmission, and parameters of infection. The application of humanized mice for testing novel antivirals, biologics, and cell and gene therapy approaches will also be discussed as will practical considerations for working with these models. This presentation will highlight strengths of using humanized mouse models for HIV research, challenges, and areas for further refinement. A future outlook on the use of humanized mice for HIV research will also be provided.

Background

This case-based session will address the most common cause of liver disease namely metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and the overlapping entity MetALD. The audience will become familiar with the new nomenclature, epidemiology, clinical diagnosis, and risk-stratification using non-invasive tests. In addition, practical approaches to MASLD treatment including newly approved medications will be discussed. Join this session to: (1) gain insights into the spectrum of steatotic liver disease and (2) enhance knowledge of MASLD diagnostic and new therapeutic strategies in clinical practice.

Background

Hepatitis B remains a significant cause of liver disease and remains the leading cause of hepatocellular carcinoma worldwide. Effective therapy for hepatitis B is available, and nucleos(t)ide analogs (NAs) suppress hepatitis B DNA levels and normalize ALT levels. Long-term treatment can lead to reduction in necroinflammatory activity, with potential improvement in fibrosis or reduction in fibrosis progression, as well as a reduction in the risk of hepatocellular carcinoma. Treatment recommendations are guided by the degree of inflammation as reflected by ALT levels, HBV DNA levels and the degree of fibrosis. Current societal guidelines have recommended treatment during certain phases of hepatitis B infection in those who are HBeAg+ or HBeAg- with elevated HBV DNA levels and intermittently or persistently elevated ALT levels. However, approximately 30% of individuals with chronic hepatitis B remain in the gray zone including both HBeAg+ and HBeAg – infected individuals where HBV DNA and ALT levels do not fit into these well-described phases. Recent cohort studies have suggested that patients within the gray zone remain at risk for significant fibrosis and development of hepatocellular carcinoma. One limitation of gray zone patients has been the lack of histologic assessment of inflammation and fibrosis, rather relying on ALT and non-invasive measures of fibrosis. One recent study identified 242 individuals with chronic HBV infection in the gray zone, of whom 73% had significant histological disease. More recent treatment recommendations have suggested lower thresholds for treatment. Given the effectiveness of NA therapy and the recent data demonstrating improved functional cure rates with emerging therapies, patients in the gray zone should be assessed for treatment to reduce the incidence of advanced fibrosis, disease progression, and hepatocellular carcinoma in this highly prevalent disease. New biomarkers and risk models are needed to more accurately identify patients with significant inflammation and fibrosis who reside in the gray zones and would benefit from antiviral treatment and surveillance for hepatocellular cancer. Regardless, close follow-up of hepatitis B patients is required, given the highly dynamic interplay between the virus and the host.

Background

Most liver cancer (also called hepatocellular cancer, or HCC) cases occur in patients with established risk factors for chronic liver disease, including hepatitis C virus (HCV) infection, heavy alcohol drinking, hepatitis B virus (HBV) infection, and metabolic dysfunction associated steatotic liver disease (MASLD). These HCC risk factors lead to cirrhosis, which is present in 90% of patients with HCC in the Western world. Two large randomized controlled trials in patients with HBV and several observational cohort studies in patients with cirrhosis have shown that patients who undergo HCC surveillance have earlier-stage HCC, are more likely to receive potentially curative treatment, and have improved survival than those who presented symptomatically or had HCC detected incidentally. Based on these data, professional societies recommend HCC surveillance every 6 months in at-risk individuals, including all patients with cirrhosis from any etiology and subgroups of patients with HBV in the absence of cirrhosis. Surveillance is not recommended in patients with Child–Pugh class C cirrhosis unless they are awaiting liver transplantation, given the low probability of treatment eligibility and limited benefits. Liver ultrasound has been long regarded as a standard surveillance test for HCC. Ultrasound is non-invasive and relatively inexpensive. However, the performance of ultrasound can be impacted by several patient-level factors, with particularly suboptimal performance in obese patients (such as those with MASLD) and those with more advanced cirrhosis. Addition of blood-based biomarkers to ultrasound increases the sensitivity of surveillance, particularly for early tumor detection. The best-studied biomarker to date is AFP, with a level of 20 ng/mL being the most used cutoff to trigger further evaluation in clinical practice. The pooled sensitivities of ultrasound with and without AFP for early-stage HCC are 63% (95% CI, 48%–75%) and 45% (95% CI, 30%–62%), respectively (P = .002).

HCC surveillance should be performed every 6 months. Once initiated, there is no consensus about when to stop surveillance. In general, surveillance can be stopped in patients who develop child C cirrhosis and who are not liver transplant candidates. Despite demonstrated benefits, including early tumor detection, <20% of patients with cirrhosis undergo surveillance.

Background

This session explores the transformative impact of artificial intelligence (AI) across the HIV research continuum, from basic science to public health. Key highlights include AI's role in accelerating drug discovery, optimizing clinical trials, and enhancing HIV care and prevention strategies. Emphasis is placed on ethical considerations, community engagement, and implementation science to ensure equitable and effective integration of AI-driven innovations. The discussion aligns with the Ending the HIV Epidemic initiative, showcasing AI as a catalyst for precision medicine and public health advancements in the fight against HIV.

Background

I will overview the state of the art in HIV prevention efficacy trial design and articulate lessons learned from recently conducted trials.

Background

A pharmacokinetic (PK) target is a specific drug concentration range in the body that ensures maximum efficacy while minimizing toxicity. In HIV clinical trials, selecting the correct PK target is crucial for the success of the study and the interpretation of its results. This issue is particularly relevant when evaluating the treatment of understudied populations like pregnant women, children, or patients on treatments with potential drug-drug interactions, such as those for tuberculosis (TB). These studies are generally too small to assess efficacy and toxicity, but they rather aim to show that target concentrations are successfully achieved. This makes the choice of a suitable PK target even more crucial. This presentation emphasizes the importance of accurate and critical selection PK targets, highlighting the risks of relying on widely accepted values from literature, which are often based on surprisingly limited evidence.

Background

In this session, Drs. Pedro Cahn and Jenny Hoy will present cases to an expert faculty panel from around the world to highlight cutting-edge issues in the care of people with HIV. Topics will include the management of weight gain in the setting of ART, the approach to cardiovascular events in people with HIV, whether people who are elite controllers should be treated with ART, and ART considerations for people with drug-resistant HIV and adherence challenges. This stimulating interactive session will illustrate the current evidence-based approaches to managing people with HIV from different parts of the world.

Background

Studies of HIV DNA integration provide a rich example of how basic research can inform new therapies, and how findings from translational implementation in turn can pose new questions. To replicate, a retrovirus such as HIV must integrate a DNA copy of the viral RNA genome into host cells. Establishing methods for analyzing HIV DNA integration in vitro helped launch the development of the integrase inhibitors, a pivotal class of antiretroviral drugs. Coming from another direction, studies of HIV integration target site selection have provided additional insights into mechanisms of replication and control of viral replication. Early studies showed that HIV favors integration in active transcription units, which makes sense for facilitating efficient HIV gene expression after integration. Further studies showed that tethering to cellular chromatin binding proteins contributed to targeting. Recent studies in people with HIV who effectively control virus show that distributions may be enriched in regions where the virus is poorly expressed due to aggressive selection by CD8+ T cells. These results have been recapitulated in various cell culture and animal models, allowing detailed mechanistic analysis. Studies of integration targeting also inform monitoring of human gene therapy, where insertional mutagenesis by gene transfer vectors is a concern. Recent studies suggest that HIV and retroviral vectors can carry out insertional mutagenesis in humans via four different mechanisms: enhancer insertion, promoter insertion, gene inactivation, and gene activation by mRNA 3’ end substitution. Stepping back, these mechanistic studies provide an overview of how basic research advances treatment of HIV, and contribute to the conceptual foundation for addressing many other disorders.

Background

We are gathering in a moment of tremendous challenges and opportunities. We have developed biomedical tools to prevent HIV transmission and support the wellbeing of over 38 million individuals living with HIV, yet a truly healthy world eludes us. Stigma, discrimination, preventable deaths, and inequitable access to resources and health care persist. Human rights that have progressed in some places are under attack in others. Across the U.S., and perhaps the world, we are more connected yet more lonely than ever before. Our greatest achievements in evidence-based science are undermined by misunderstandings and deliberate disinformation. While many young people in the U.S. have never heard of HIV, and many of their parents think “AIDS is over,” the internet offers newly diagnosed people a firehose of information at the expense of their privacy. Meanwhile, their elders — long-term and lifetime survivors — bear the weight of trauma, gratitude, and persistence in a world unprepared to meet the needs of people aging with HIV. The challenges we face call for creativity, collaboration, and courage. Please join 42-year HIV survivor Rebecca Denison — Bay Area writer, founder of WORLD, co-founder of ICW, and clinical research participant since 1985 — as she reflects on lessons from the past, challenges in the present, and opportunities for the future.

Background

From the beginning of the pandemic, people who inject drugs (PWID) were identified as a key population at significant risk of HIV infection. However, despite evidence of the effectiveness of harm reduction, many countries failed to respond adequately or in a timely manner. Embedded in prohibition and punitive approaches, Malaysia’s initial resistance to harm reduction led to a large, concentrated epidemic amongst PWID. Although now more widely adopted, to date very few countries have achieved targets for opioid agonist therapy or met the recommended number of needles and syringes distributed per year. With less than 1% of total HIV spending allocated to programs for PWID globally, it is no surprise that PWID continue to be left behind in access to prevention and treatment programs. Far from its intended aim of protecting individuals and society from the harm of drug use, punitive drug laws and prohibition continue to result in diseases, deaths from drug overdoses, prison overcrowding, violence and a cycle of poverty. Drug use is often seen through a moral lens, with users stigmatized as criminals or morally deficient rather than individuals in need of help. This stigma makes it challenging to build public support for harm-reduction policies and programmes. Many fear that alternative approaches, such as legalization or decriminalization, could lead to unintended consequences, including increased drug use or addiction, despite evidence from countries like Portugal demonstrating otherwise. The “War on Drugs” relied on fear-based narratives and racialized rhetoric that continue to shape public opinion. This is compounded by global treaties, such as the 1961 Single Convention on Narcotic Drugs, which tie nations to prohibitionist policies and make reform on an international scale more difficult. Despite these challenges, there is a growing recognition of the failure of prohibition and increasing momentum for reform. The success of alternative approaches, such as decriminalization and harm reduction, highlights the potential for treating drug use as a public health issue rather than a criminal one. However, overcoming the entrenched political, economic, and cultural barriers to change requires sustained effort, evidence-based policymaking, and a shift in public perception toward compassion and practicality over punishment. By leveraging evidence, building partnerships, and engaging in public discourse, the scientific community can challenge outdated drug policies and push for reforms grounded in science, equity, and compassion.

Background

Antiretroviral therapy (ART) has transformed HIV-1 infection from a fatal disease into a manageable chronic condition. However, longitudinal studies reveal that the decay rate of the HIV-1 reservoir is so slow that ART alone cannot eliminate the reservoir within the lifetime of people living with HIV-1 (PLWH). This underscores the urgent need for safe and scalable strategies to achieve an HIV-1 cure. Most HIV-1 cure strategies fall into two main categories: (1) approaches aimed at eradicating or inactivating the reservoir and (2) approaches designed to induce immune-mediated control of the virus. Hematopoietic stem cell transplantation (HSCT) has demonstrated the potential to completely eradicate the HIV-1 reservoir, as seen in case reports of PLWH receiving HSCT for hematologic conditions. However, due to its inherent risks, HSCT is not a feasible cure strategy for otherwise healthy individuals. Consequently, most research has shifted toward strategies focused on immune-mediated control of HIV-1. Cytotoxic CD8+ T cells are strongly associated with spontaneous HIV-1 control, making the enhancement of CD8+ T cell immunity a promising avenue for clearing infected cells and achieving long-term viral suppression. Despite these prospects, therapeutic HIV-1 vaccines have so far failed to produce the desired results in clinical trials. Nevertheless, a range of other compounds - both those specifically designed for HIV-1 cure and repurposed drugs from fields such as oncology and hematology - have been investigated for their potential to impact HIV-1 persistence. While many of these interventions have not succeeded in significantly reducing the reservoir or inducing robust adaptive immune responses, recent trials have reported encouraging outcomes, with some individuals achieving partial or complete long-term control of HIV-1 after discontinuing ART. These findings raise the possibility that a functional cure for HIV-1 is achievable. In this talk, I will provide an overview of the most promising therapeutic strategies in the pursuit of an HIV-1 cure, including the use of broadly neutralizing antibodies. I will also discuss key populations that may have a higher likelihood of achieving a cure and address the critical barriers that remain in developing effective interventions. Additionally, I will review findings from in-depth studies of the biological mechanisms underlying sustained HIV-1 suppression in individuals who maintain control for years after stopping ART.

Background

This "state of the pandemic plenary will review the current status of the global pandemic; interrogate recent available data on HIV incidence from placebo arms of RCT and PURPOSE trials; review data on mortality; elucidate the challenges of primary prevention in high HIV burden and lower HIV burden populations; explore the challenges of late diagnoses and advanced HIV disease; and suggest ways forward for an invigorated response using new prevention tools which could achieve epidemic control. The key themes and messages, supported by current evidence are that:

Background

Current ART has the capacity to drastically suppress but not abolish previously infected cells which can persist for the life of the host. This persistent rebound competent virus is the primary barrier to HIV cure. This long-term stable virus resides in multiple subsets of CD4+ T cells, particularly CD4+ memory T cells, and possibly macrophages that are widely distributed throughout the body. To mediate post-ART viral rebound, viruses must be genetically intact and replication competent, but viral rebound is not a wholesale resumption of viral replication from all replication-competent genomes but rather reflects an initial oligofocal outgrowth of virus from a limited subset of the total infected cell population that subsequently spreads throughout the body. Despite the importance of understanding the clonal origins of post-ART viral rebound, virtually nothing is known about these early local dynamic events, due to challenges with sampling, variability in time to rebound, and limited genetic diversity between individual rebounding lineages with previous work studying viral rebound only at later viremic stages or in limited numbers of tissues. To overcome these challenges, we developed and validated a barcoded virus model (SIVmac239M) that contains a short, unique nucleotide insert allowing for genetic discrimination of over 10,000 viral lineages. We used viral barcode analysis from a comprehensive collection of tissue samples in a large cohort of SIV-infected, ART suppressed rhesus macaque during both on-ART and post-ART cessation, to identify the initial sites of rebound and patterns of subsequent viral spread. Our results indicate that it is possible to identify the earliest stages of local tissue-level post-ART rebound and that this early rebound preferentially occurs in gut and gut-draining lymph nodes. Pinpointing the anatomic sites of viral rebound can facilitate the identification of the mechanisms that specifically mediate these reactivation events in these specific tissues. Together, these observations may have potential therapeutic implications for interventions designed to prevent or control viral rebound.

Background

Cellular and tissue sources of viral rebound primarily originate from long-lived reservoirs of HIV in individuals under antiretroviral therapy (ART). Key cellular reservoirs include CD4+ T cells, particularly memory subsets like central memory (Tcm), which harbor latent provirus. Tissue-specific sources include lymphoid tissues (lymph nodes, spleen, and gut-associated lymphoid tissue), where virus can persist despite ART. The central nervous system (CNS) acts as a sanctuary probably also due to limited drug penetration. Additionally, myeloid cells like macrophages and microglia may contribute to viral rebound. Gut tissue plays a significant role as it harbors high numbers of infected cells and provides a pro-inflammatory environment conducive to viral reactivation. In this presentation, we will explore methods used to characterize the persistent HIV reservoir across various cell subsets and tissues, highlighting their successes and limitations in identifying the viruses responsible for systemic rebound upon treatment interruption. Additionally, we will discuss how emerging technologies and multi-omics platforms can enhance our understanding of the viral reservoir and provide new insights into its dynamics and reactivation potential.

Background

The objectives of this talk are to: (1) define different patterns of HIV rebound (i.e., categories of post-ART control), (2) review examples of effective immune responses against HIV, focusing on immune mechanisms that have been implicated in post-ART control, and (3) discuss lessons learned about immune responses to rebound from recent ATI trials, including the UCSF-amfAR combination immunotherapy trial.

Background

In 2025, late diagnosis of HIV in children continues to be a significant global concern, with many presenting with advanced HIV disease (AHD). This issue contributes to a considerable number of hospital admissions, particularly among infants, due to acute conditions such as pneumonia, sepsis, and diarrhea. These acute illnesses are frequently accompanied by important by sometimes subtler health issues, including malnutrition, anemia, and HIV-related encephalopathy. As a result, there is an alarming mortality rate during hospital stays, coupled with notably high post-discharge mortality rates in the year that follows. The WHO STOP AIDS technical brief provides a vital framework of care for children with AHD, outlining clear intervention strategies; however, its implementation remains inadequate worldwide, especially in Sub-Saharan Africa. Furthermore, there is an urgent need for additional research to combat these unacceptably high mortality rates. Areas requiring investigation include the benefits of rapid PCR diagnostic confirmation in critically ill infants, enhanced strategies for both the prevention and treatment of malnutrition, clarification of the role of cytomegalovirus (CMV) in severe pneumonia and its management, and the formulation of effective prophylactic approaches for serious bacterial infections in the context of rising antibiotic resistance.

Background

Children aged 0-15 years lag behind adults in achieving HIV treatment goals across HIV testing, initiation of antiretroviral therapy and viral suppression. While early diagnosis of pediatric HIV has scaled up significantly, children continue to slip through the cracks and remain undiagnosed and untreated. For children living with HIV, challenges in adherence to treatment is hampered by family and caregiving structures leaving children prone to poor viral suppression. Recent advances in treatment including newer dolutegravir based regimens and easy to use treatment formulations have improved adherence and viral suppression in children but gaps remain in achieving optimal viral suppression. This talk will focus on the state of the HIV care continuum for children aged 0-15 years, focusing on current trends, gaps and advances to improve the cascade of care in children.

Background

Since 1990 an estimated 11 million children have been born with HIV and with the successful global role out of paediatric antiretroviral therapy (ART) increasing numbers of young people are transitioning through adolescence and entering adult care. In resourced settings with earlier access to ART the oldest survivors are now entering their 5th decade of life but with a legacy of years of unsuppressed viraemia and/or exposure to older more toxic ART agents. However survivor bias means they represent a unique cohort who survived childhood without access to ART, with slower disease progression and likely favourable host genetics and immune responses. In contrast many of those born in more recent decades started ART in early childhood and are more likely reflective of the emerging adolescent perinatal cohorts globally, important in identifying the consequences of lifelong HIV and ART exposure throughout postnatal, childhood and adolescent development in the ART era. This talk will follow the journey of a young person living with perinatal HIV through the unique challenges of adolescence, a period of life encompassing complex biological and psychosocial changes that include sexual maturation, development of sexual identity and the onset of sexual activity, through to pregnancy and parenthood. We will examine existing data on sexual and reproductive health for this unique cohort, born into a family living with HIV and the challenges of negotiating adolescence with a potentially sexually transmissible infection for the first and every subsequent sexual encounter and that sharing your status potentially discloses the status of other family members. We will focus on biomedical prevention strategies including sexual health education, vaccination, contraception and screening for sexually transmitted infections and for anogenital cancers. Increasing numbers of young people born with HIV are choosing to start families with pregnancy data emerging, including the early infant outcomes for a unique cohort of “3rd Generation” HIV exposed uninfected infants born to people who themselves have lived with HIV their entire lives. Finally we will identify data gaps in sexual, reproductive and pregnancy health for this cohort, highlighting future research questions and the importance of the meaningful inclusion of youth in setting the research agenda to support them in fulfilling their potential as adults, partners and parents.

Background

Over the past 25 years, the global HIV response has made remarkable progress at controlling HIV epidemics, including reducing new infections and ensuring healthy lives for people living with HIV. However, progress has not been equal across epidemic settings or populations affected by HIV, and overall remains off track to achieve targeted 90% reductions in new infections and AIDS-related deaths by 2030. This presentation will review immediate challenges impeding attaingment of these goals, including sustaining high coverage of effective programmes in high HIV burden settings, regions and epidemiologic settings with lagging in progress, and population groups with distinct unmet needs. Moreover, whilst there are opportunities to accelerate progress toward Ending AIDS as a Public Health Threat by 2030, even with a successful response the global community will continue to live with HIV for decades to come. We will discuss long-term goals in responding to HIV and needs and priorities to sustain effective HIV responses that safeguard and continue epidemiologic gains.

Background

This presentation will delve into the complexities of sustaining the global HIV commitment amidst evolving health priorities and funding landscapes. This session will explore the opportunities and risks of integrating HIV care and prevention into broader health services. From innovative service delivery models to community-driven solutions, we will highlight how integration can enhance health system efficiency, reduce patient burden, and improve access to services. Participants will gain insights from global examples of successful integration strategies, and the challenges of maintaining focus on HIV in the face of competing priorities and declining donor funding. This presentation will discuss the dual imperatives of sustaining HIV-specific commitments and leveraging integration to achieve broader health goals. Discover how a people-centered, multisectoral approach can navigate risks such as weakened prevention efforts, service quality compromises, and fragmented systems. By addressing these challenges, we can seize the opportunities of integration to build resilient health systems and accelerate progress toward ending AIDS as a public health threat by 2030.

Background

Over the last 40 years, remarkable achievements have been recorded in the HIV response, with service delivery models that have increased access to HIV testing, expansion of the HIV prevention toolbox, availability of newer and less toxic antiretroviral therapy resulting in fewer people acquiring HIV in 2023 than at any point since the late 1980’s and almost 31 million people on treatment. Despite advances in science, individuals and communities continue to not access HIV prevention, care and treatment services. This session explores HIV service delivery innovations to bridge the gap and reach individuals and communities left behind.

Background

This presentation will discuss HIV incidence during pregnancy and breastfeeding as well as factors (hormonal, immunological, behavioural, sexual and genital infections, and low male participation in antenatal care and HIV testing) that increase risk of HIV acquisition this period. In addition, we will look at the contribution of acute HIV infection to vertical HIV infection and underlying factors driving the increased risk of transmission. I will highlight existing HIV prevention interventions with focus on behavioural and biomedical interventions. Behavioural interventions discussed will include enhanced HIV counseling, use of lay community based workers to provide HIV prevention counselling and male partner referral for circumcision, sexually transmitted infections or HIV treatment implemented in several sub-Saharan African countries. The role of oral antiretroviral pre-exposure prophylaxis (PrEP) during pregnancy and breastfeeding, maternal and infant outcomes following PrEP use, importance of integrating PrEP delivery within maternal and child health clinics and whether a risk based approach is better compared to universal PrEP delivery model will be discussed. Barriers to oral PrEP uptake and continuation and perspectives of health providers on determinants that impact ability to deliver PrEP will be described. Strategies to promote PrEP use among pregnant and breastfeeding women including differentiated service delivery models will be discussed. The talk will also cover use of use of currently available long‐acting formulations that is carbotegravir, six-month injectable lenacapavir and dapivirine ring during pregnancy and breast feeding including efficacy, maternal and infant outcomes as well as effect of added choice of biomedical interventions on HIV prevention coverage. Potential challenges during implementation at scale and the role of all stakeholders including governments, donors, civil society, or manufacturers among others to ensure seamless and impactful rollout will be highlighted. There will be focus on requirements for provision of lenacapavir regarded as 2024 Breakthrough of the year by the Science Magazine. Lenacapavir represents a transformative opportunity to dramatically reduce the number of new HIV infections. Finally, we will deliberate on how to protect women through and NOT from research in order to reduce evidence gaps regarding safety and efficacy of new antiretroviral formulations during pregnancy and breastfeeding.

Background

Although the development of effective vaccines has saved countless lives from infectious diseases, the basic workings of the human immune system are complex and have required the development of animal models, such as inbred mice, to define mechanisms of immunity. However, past results are not necessarily a reliable guide to the future, and a notable limitation of animal models has been their failure to accurately model some human diseases and their inability to predict human immune responses in many cases. In the past decade there has been an explosion of new approaches and technologies to explore the human immune system with unprecedented precision. Insights into the human immune response to vaccination, cancers, and viral infections such as COVID-19 have come from high-throughput “omics” technologies that measure the behavior of genes, mRNA, proteins, metabolites, cells, and epigenetic modifications, coupled with computational approaches. I will discuss how these “Systems Vaccinology” approaches are advancing our mechanistic understanding of the human system and its response to vaccines and infections and facilitating the development of vaccines against HIV and other infectious diseases.

Background

As a lentivirus, HIV is capable of infecting non-dividing cells. For decades it has been understood that HIV must be able to deliver its genetic material across the nuclear envelope in order to establish infection. As the gatekeeper between the cytoplasm and the nucleus, the nuclear pore complex (NPC) represents an obvious entry point. During normal cellular function, the NPC controls nucleocytoplasmic transport by establishing a ‘diffusion barrier’ at the centre of the pore. Often described as a ‘mesh’ or ‘filter’, the diffusion barrier is formed by intrinsically-disordered nucleoporin domains which project into the central pore. Critically, these domains are enriched for phenylalanine-glycine (FG) dipeptide motifs that cause them to form a liquid-liquid phase separation which typically prevents the passive diffusion of molecules greater than ~25 kDa. Larger cargoes can be escorted across the nuclear pore by the action of karyopherins – chaperone proteins which can cross the diffusion barrier by virtue of their weak, multivalent, and specific interactions with the FG motifs. Recent studies have shown that the HIV capsid also possesses a conserved FG-binding pocket on it surface. Indeed, it is this same site that is targeted so successfully by the first-in-class anticapsid drug, lenacapavir. This ‘FG-pocket’ grants the capsid similar biophysical properties to the karyopherins, thereby licensing the capsid for nuclear entry without the need of chaperones. The karyopherin mimicry model explains how a structure as large as the HIV core can penetrate the nucleus despite being greater than 10,000 times the diffusion limit of the nuclear pore.

Background

The HIV Preintegration Complex (PIC) mediates the integration of the viral reverse transcript into host cell chromosomes. The HIV core is composed of a shell of capsid protein that encases the viral RNA together with reverse transcriptase and integrase enzymes. Reverse transcription occurs within the viral core, and nicking of the viral DNA ends by integrase converts the reverse transcription complex into the integration-competent PIC. After circumventing the nuclear pore complex, the core traffics to interior regions of the nucleus for uncoating and integration. Integration into host chromosomes is non-random, and interactions between the capsid and integrase proteins with cognate host factors guides the core to transcriptionally active chromatin. The interaction of capsid with alternative polyadenylation host protein CPSF6 is required for cores to move beyond the nuclear rim, where they eventually congregate with nuclear speckles for integration into nearby speckle-associated domains (SPADs) of chromatin. Interactions between integrase and transcriptional coactivator LEDGF/p75 direct integration into the mid-regions of active genes. Recent work has clarified that both CPSF6 and LEDGF/p75 possess liquid-liquid phase separation activity and that these activities can impact their roles as integration cofactors. Completion of reverse transcription can aid core dissolution or uncoating to reveal chromatin to the PIC for integrase-mediated integration of viral DNA.

Background

Recent research underscored that HIV transcription remains a critical step in the viral life cycle. Especially the transition between active and latent infection is critically regulated by viral factors such as Tat and many host factors that either control the transcriptional activity of the virus directly or the epigenetic landscape around it. It has become apparent that during antiretroviral therapy 81% of the viral reservoir remains transcriptionally active while “true” latency mainly exists in viruses embedded in a very repressive chromatin environment especially near repetitive genomic elements. Reactivation of HIV transcription from latency involves a shift to a permissive chromatin state, driven by histone acetylation, recruitment of bromodomain-containing proteins, and the viral protein Tat, which recruits the positive transcription elongation factor b to release RNA polymerase II from pausing. Therapeutically, modalities targeting epigenetic proteins such as histone deacetylases, bromodomains, or histone methyltransferases as well as Tat are being studied to either reactivate latent proviruses for eradication or reinforce latency to suppress reactivation. Successfully suppressing transcriptional activity in the reservoir during antiretroviral therapy is promising as it decreases the chances of viral reactivation and is critical to alleviate chronic immune activation, which otherwise fuels early appearance of chronic diseases of aging. We speculate that suppressing transcription will also change the epigenetic landscape of the integrated proviruses in a durable way to long-term tune down reactivation potential. We will discuss the mechanisms of HIV transcription in the context of chromatin and our ongoing efforts to inhibit the transcriptionally active reservoir.

Background

HIV-1 persists in a mostly latent state within blood and tissues during suppressive ART. Proviral integration sites may play a critical role in the establishment and maintenance of this latent reservoir. Understanding the landscape of proviral integration is essential for deciphering the mechanisms behind HIV-1 latency and reactivation. Recent studies have shed light on the factors that regulate proviral latency, including host cell type, epigenetic modifications, and the influence of host immune responses. The interplay between viral and host factors in proviral integration and latency is complex, with integration site-specific transcriptional activity influencing the susceptibility to latency reversal agents. Continued exploration of this landscape offers promising avenues for therapeutic strategies aimed at eradicating HIV-1 through targeted interventions that either enhance immune responses or directly disrupt latent proviral genomes. Ultimately, a comprehensive understanding of proviral integration patterns is essential for designing therapies that could effectively eliminate the HIV-1 reservoir and achieve sustained viral remission without ongoing ART.

Background

This presentation will explore the lived experience of women living with HIV (WLWH) as they navigate menopause and the intersections with HIV and aging stigma. As a woman living with HIV, I also intend to briefly touch on the clinical care experience from the patient perspective and its impact on engagement in care. WLWH have the double stigma that surrounds both HIV and aging. Feelings of shame, reduced sense of worth, loss of vitality, and reduction in sexual attractiveness and desire are common, and multiplied in both populations. The desired outcome of this talk is the intentional investment of clinicians and researchers in exploring the quality of life of the women they serve as it relates to menopause. There must be research in all aspects of women’s health as it relates to HIV and the transitions that women experience aging with the disease process. Quality of life can only be achieved when women are given the tools and information to make informed decisions about their health. Shared decision making which is a critical component of quality care can only be effective when comfortability and willingness to engage exist.

Background

Menopause represents a highly vulnerable time for women physically, mentally, and socially. The growing body of menopause research among women living with HIV (WLWH) demonstrates that this vulnerable population experiences greater mood and vasomotor symptom burden, which adversely impacts adherence to clinic visits and antiretroviral therapy. Estrogen loss associated with menopause may further enhance the risk for cardiometabolic, cognitive, and bone comorbidities in WLWH. Although there are still more questions than answers in the context of the clinical management of menopause in WLWH, research in this field is evolving, and clinical prevention along with clinician and patient education on this topic can enhance clinical outcomes and quality of life in WLWH globally.

Background

Disentangling the unique impacts of aging and reproductive aging through menopause may identify novel features of the pathogenesis of HIV that will inform strategies to manage longterm complications and achieve an HIV cure. Early data indicate that menopause and declining levels of estradiol are associated with increased inflammation and changes in HIV viral dynamics. Further work is needed to define the mechanisms of estradiol impacts on both HIV and the immune system.

Background

Long-acting injectable formulations are revolutionizing HIV treatment and prevention and have similar potential to improve the treatment and prevention of tuberculosis, including simpler, shorter regimens and expanded treatment options. This presentation will describe how long-acting injectable formulations could address important obstacles to ending the world’s oldest pandemic, review recent progress in the development of long-acting tuberculosis drugs, and discuss future research needs and priorities.

Background

This talk will highlight the burden and spectrum of post-tuberculosis disease, focusing on the complexities of clinical presentation and pitfalls in assessment. We will give an overview of pathogenesis, and an update of recent work in post-tuberculosis lung disease (PTLD). We will highlight important knowledge gaps in the field, and will discuss ongoing work and needed efforts for both the future prevention and management of PTLD.

Background

We are at the dawn of a new era of long-acting antiretroviral (ARV) agents that promises to revolutionize the prevention of HIV infection. The HPTN083 and 084 studies first demonstrated the promise of cabotegravir for HIV pre-exposure prophylaxis (PrEP), but its use needs to be balanced with frequent injections, risks of drug resistance and challenges in diagnosing breakthrough infections. Lenacapavir represents the next leap forward for HIV PrEP with every 6 month dosing and impressive efficacy in recently completed clinical trials that led to its designation as Science’s 2024 Breakthrough of the Year. We will review the promise and challenges of these and other long-acting ARV options, including dapivirine ring and other novel approaches in development.

Background

Is testing the key to unlocking PrEP scale-up? The use of antiretroviral drugs (ARVs) to prevent new HIV infections has been well-established for decades, particularly in the context of pre-exposure prophylaxis (PrEP). Yet, only an estimated 2.5 million people are currently using PrEP—far fewer than the 10 million needed to meet global HIV prevention goals by the end of 2025. A key barrier to PrEP scale-up is the challenge of HIV testing, which often requires frequent facility visits and relies on complex and costly testing technologies and algorithms. This session will present the latest evidence and best practices to ensure safe, accurate, and effective HIV testing, including self-testing, as part of PrEP delivery across various agents and service delivery models. It will also address emerging data on Long-acting Early Viral Inhibition (LEVI) with long-acting PrEP agents and propose a public health approach to testing that can support the implementation of these evolving PrEP tools.

Background

In the past 12 years, 6.2 million individuals globally have been prescribed PrEP since its initial approval by the US FDA. The majority of these prescriptions, 1.4 million, have been issued in the past two years. However, oral PrEP's effectiveness is contingent on high adherence, posing challenges for certain high-risk groups. Research indicates that long-acting injectable PrEP (cabotegravir and Lenacapavir) surpasses oral PrEP in efficacy. LA PrEP offers a broader range of effective and acceptable prevention choices, overcoming oral tablet use challenges and enhancing prevention uptake. Despite LA Cabotegravir (CAB) being approved by the US FDA in 2021 and by the WHO in 2022, its rollout has been sluggish. Only approximately 11,000 prescriptions for CAB LA have been issued in the US since approval, compared to an estimated 382,000 annual PrEP users. Globally, especially in the global South, CAB-LA has seen limited uptake, primarily through implementation science projects in Africa and Asia. In the United States and high-income countries, the high cost of cabotegravir the intricate medication acquisition pathways for health centres delay national implementation. Healthcare organizations face intense staffing requirements for medication acquisition, insurance paperwork, process documentation, billing, injection administration, appointment scheduling, and client follow-up. Low- and middle-income countries (LMICs) face limited availability and access to cabotegravir. The production of generic medication is a lengthy process, with the first generic dose expected by 2027 for LMICs. PEPFAR's potential aggressive rollout in Africa, which involved purchasing and distributing the medication, faces setbacks. Global Fund, PEPFAR, and the Bill and Melinda Gates Foundation (BMGF) announced efforts to ensure two million people have equitable access to affordable Lenacapavir for three years. Recent termination of several PEPFAR grants further complicates these efforts. Overcoming the implementation challenges of cabotegravir, the first long-acting agent to market, will offer valuable lessons for future agents like Lenacapavir, administered every six months.The potential for LA PrEP to revolutionize HIV prevention is immense, but scaling it effectively requires addressing the aforementioned barriers and ensuring equitable access across different regions.

Background

Long Covid is a disabling post-viral disease state that impacts over 400 million people worldwide, with no effective treatment currently available. Despite incomplete mechanistic understanding, lack of clinically actionable biomarkers, and insufficient policymaker recognition, significant progress has been made in recent years, revealing a clear histological and pathophysiological basis for the condition. SARS-CoV-2 infection prompts a complex immune response involving both innate and adaptive responses and immunothrombosis mechanisms. The virus infects multiple cell types and tissues, primarily those expressing ACE-2, including enterocytes, cardiomyocytes, and vasculature. Tissues with lower ACE-2 expression, like the brain, might be affected indirectly via immune-mediated and microthrombotic events. ACE-2 expression varies with disease severity and immune activation, including macrophage infiltration and microthrombi. Following acute infection, viral antigens may persist in tissues for years, continuously modulating the immune system, although they are inconsistently found in plasma. Acute systemic tissue injury releases host cell antigens which trigger autoimmunity. Enterocyte infection, inflammation, and antibiotic therapy during early Covid-19 cause gut microbial dysbiosis, which parallels the disease course. Microvascular damage and thrombosis result from endothelial damage, platelet infection, and activation of complement and coagulation cascades, leading to tissular hypoxemia, apoptosis, necrosis, and organ dysfunction. Mitochondrial respiratory chain changes and altered glucose and tryptophan metabolism worsen tissue damage, contributing to exercise intolerance and muscle necrosis post-exercise. All these and additional factors, like cranial nerve, suprarenal, or pancreatic dysfunction, contribute to long Covid's diverse clinical presentation. Host tissue susceptibility, predisposition, and functional reserve, but also stochastic phenomena, influence individual clinical presentations. Long Covid affects individuals with over 150 potential symptoms impacting various organs and systems, often with a remitting-relapsing course. However, 10 to 15 core symptoms help identify symptom clusters, aiding targeted mechanistic studies and clinical trials. Despite its complexity, Long Covid is being understood at a pace never seen before. The recent NIH Recover-TLC initiative represents a unique opportunity to advance towards finding a cure for this disease.

Background

People with HIV (PWH) are facing multiple challenges in the battle against weight gain, including the growing, worldwide obesity epidemic and its drivers, normal aging and HIV- and antiretroviral therapy (ART)-associated contributors. The worldwide obesity epidemic is beyond the scope of this talk but must be considered when assessing individual patient risk and treatment options. HIV itself appears to promote fat gain and lean mass loss greater than expected for age, creating additional challenges. Finally, while ART initiation is universally associated with generalized weight gain, some PWH experience excessive (>10%) weight gain following initiation of or switch to newer agents, particularly bictegravir, dolutegravir and tenofovir alafenamide. This presentation will review the available evidence on weight gain in PWH, discuss potential treatment options and highlight research questions important to optimizing weight for PWH.

Background

HIV persists in the central nervous system (CNS), and a subset of PWH develop neurocognitive issues despite virally suppression. With a diverse set of infected cells comprising the CNS reservoir, along with the impact of both acute and chronic infection on local inflammation and blood brain barrier integrity, the CNS presents an important and unique challenge, not only for ongoing management, but importantly for cure strategies. Studies have demonstrated the CNS reservoir resides predominantly in resident microglia, the role of astrocytes, resident and circulating T cells is less clear. HIV genomes in the CNS are transcriptionally/translationally active despite viral suppression with transcriptional products and viral proteins detected. As reported for peripheral reservoirs, defective proviral genomes predominate in the CNS in both virally suppressed and viremic PWH. The function of these defective genomes remains unclear, but likely contribute to ongoing neuroinflammation. The frequency of infected cells within the brain is reported to be very low, however, in the cerebrospinal fluid (CSF), levels of cell free virus and HIV+ T cells have been associated with adverse neurological outcomes in PWH. The source of cell free CSF virus remains unclear.

With the advent of cure strategies involving activation of virus either by removal of ART or by the administration of latency reversal agents (LRAs) the ability of these strategies to access and impact the CNS is critical. Some LRAs can cross the blood brain barrier (BBB) with little toxicity observed and are capable of activating brain derived HIV in vitro, however, the impact of activating the brain reservoir on local inflammation is less clear. The restrictive nature of BBB may impact other current strategies including immunotherapy and gene therapy approaches; therefore, effectiveness and adverse CNS effects needs consideration. Currently, the development of cure strategies focuses primarily on effectiveness and impacts on the peripheral blood and tissue reservoirs. Clinical trials in both non-human primates (NHPs) and PWH have largely failed to include consideration and analysis of impacts on the CNS. It is critical that future cure strategies consider the CNS and include PWH with a greater predisposition for poor HIV associated neurological outcomes. In this presentation we will discuss the nature and impact of the CNS reservoir, its role in ongoing neuropathology and the potential impact of cure strategies.

Background

This presentation will address how T cell and specific T cell subsets are revealing new insights in neuroHIV pathogenesis, specifically in HIV neuroinvasion, persistence, and neuroprotection. Recent data will show the establishment and maintenance of infected CD4 T cells in the brain from acute infection to ART-suppression, discuss the role of CD8 T cells in neuropathogenesis and mechanisms T cells play in both controlling HIV infection and the effects that lead to pathological consequences in the brain. Additional data will address the role of T cells during viral rebound after ART interruption and discuss how to harness T cells therapeutically to manage the consequences of HIV persistence in the brain.

Background

Today's ART paradigm is characterized by the availability of potent drugs for HIV prevention and treatment, including second-generation integrase strand transfer inhibitors (INSTIs) like dolutegravir (DTG). INSTIs block the integration of viral DNA into the host genome, a critical step in HIV's life cycle. The integrase (IN) gene, a highly conserved region of the HIV genome, plays a key role in the virus's integration process and is targeted by INSTIs. Dolutegravir stands out for its superior efficacy, potency, high resistance barrier, and widespread use, particularly in resource-limited settings, making it a cornerstone of modern HIV treatment and a key contributor to achieving global epidemic control goals by 2030. The wide-scale adoption of DTG-based ART in RLS, coupled with limited treatment options in case of failure, highlights the need to closely monitor the emergence and spread of DTG resistance to ensure long-term and sustained efficacy. Furthermore, as the selection mechanism of drug resistance mutations (DRMs) is subtype-dependent, HIV-1 integrase resistance patterns as well as natural polymorphisms might display distinct pathways in the frame of a broad diversity of HIV-1 clades. We conducted a rapid review of recent literature (2023–2024) on global DTG resistance, analyzing 23 studies, including systematic reviews, scoping reviews, clinical trials, cohort studies, cross-sectional studies, and case reports. Overall, DTG resistance prevalence remains low: 0–1.9% in clinical trials, 0–14% in cohorts, and 0–27% in cross-sectional studies. Key mutations identified include R263K, G118R, N155H, and Q148H/R/K, with resistance influenced by prior treatment history and current formulations.

Six scenarios were associated with DTG resistance:

Special considerations include (i) perinatally HIV-infected infants at risk of drug resistance from maternal ARVs or sub-therapeutic prophylaxis; and (ii) HIV/TB coinfected patients requiring careful regimen selection. DTG remains highly effective with a strong barrier to resistance. While resistance rates are encouragingly low, ongoing surveillance is crucial.

Background

DTG-based regimens have simplified management for providers: 1. Resistance to 1st-line DTG-based regimens is still incredibly rare. Therefore limited role for resistance testing in this scenario; can mostly assume non-adherence if viral load elevated. Fewer resistance tests required; less unnecessary switching drug classes, esp. in LMIC. 2. “Blind” switching to DTG-based regimens without requiring a resistance test has also been feasible in many cases. This has allowed regimen simplification & better outcomes.

Implications for monitoring 1. More frequent resistance testing will be required. A. Will show an example from WHO/SA context of how thinking is changing. B. Cost implications (will show an estimate) 2. Could baseline InSTI test required if transmitted DR to DTG becomes more prevalent? A. Also relevant: problem of ART “initiators” actually being re-initiators, esp. in LMIC. This would further increase the prevalence of “pretreatment” resistance.

Implications for management algorithms 1. In most settings, DTG resistance will necessitate PI (DRV)-based therapy for the foreseeable future, which is: A. Not coformulated with full regimen as a single tablet B. More expensive C. More prone to side effects D. Associated with a worse metabolic profile and more drug-drug interactions 2. Paradoxical reduction in treatment options compared to situation before 1st line DTG rollout. Previously started with NNRTIs 1st, then had PIs and DTG (3 backbone class options in total), but if starting with InSTI, can really only move to PIs currently (i.e. 2 backbone class options in total) – most NNRTIs don’t do well with concomitant NRTI resistance, unlike PIs/DTG. 3. Potential to derail CAB injectable options via cross-resistance: G118R, Q148H/K/R, etc. [BIC almost always cross-resistant also] 4. Also derails oral dual therapy options: 3TC+DTG, DTG+RPV. 5. Accelerated need for other options: (doravirine), lenacapavir, islatravir, CAB/ RPV, VH-184. A. Huge problems with access in many settings though (cost, availability, coformulation, logistics). Not nearly as well studied either.

Conclusion

We’ve been here before! DTG-era was atypical – this is a return to business as usual for HIV community. Parallels to antimicrobial resistance problems/solutions.

Background

Long-acting injectables (LAI) represents one of the most significant advances in antiretroviral therapy in recent years, offering durable suppression for PLWH who find daily oral medications challenging. Confirmed virological failure (CVF) is a low-incidence (1.4% over 152 weeks) but high-consequence event, with almost all developing drug-resistant mutations. This is in contrast to daily oral INSTI-based regimens. Risk factors for CVF with LAI therapy are well-characterised and include having 2 or more of the following risk factors: i) prior rilpivirine resistance associated mutations, ii) HIV subtype A1/A6 and iii) BMI ≥30kg/m2. In real-world deployment, CVF can be minimised through careful selection of patients for LAI. However this could exclude significant numbers of people for whom LAI would have the greatest benefit, since stigma, the need for treatment concealment and the psychological challenges of daily oral medications affects so many people. In combined analyses, 82% (18/22) of participants with CVF had low predicted plasma trough concentrations of cabotegravir or rilpivine (lowest quartile). LAIs are associated with considerable inter- and intra-patient variability. In the latter case, injection-to-injection variability is likely to be a dominant contributory factor. This pharmacokinetic variability has led to some calls for therapeutic drug monitoring but its availability, feasibility and the scope of actions that should follow are some of the many barriers to uptake. Is LAI therapy incremental or transformative ? In public health terms, pragmatic limits to delivery (based on current service models) and careful case-selection (to limit CVF) lean to the former, making this a valuable addition to the existing armamentarium of drugs. To be transformative, LAIs need to reach those who would not otherwise be treated, and to suppress those who would otherwise fail. These are generally populations explicitly excluded from pivotal trials. Recent clinical studies in these challenging populations provide important evidence that LAIs could be transformational, and this work will be reviewed.

Background

Private-sector pharmacies are ubiquitous in many African countries yet underutilized for delivery of HIV prevention services, including pre- and post-exposure prophylaxis (PrEP and PEP). This is a missed opportunity, as pharmacies are staffed by medical professionals (e.g., pharmacists, pharmaceutical technologists); are frequently accessed for sexual and reproductive health products (e.g., contraception, treatment for sexually transmitted infections); and—unlike many healthcare facilities—are open evenings and weekends. Additionally, research evidence suggests that some individuals prefer accessing PrEP/PEP at private pharmacies over public clinics because of their convenience, privacy, and lack of HIV stigma. Key barriers to pharmacy-delivered PrEP/PEP services, however, include gaps in enabling policy and guidelines (e.g., limitations to pharmacy providers’ scope of practice) and private pharmacies’ exclusions from pooled PrEP/PEP procurement mechanisms that are critical to keeping the cost of PrEP/PEP affordable to clients. In collaboration with the Kenya Ministry of Health, our research team developed a care pathway for pharmacy-delivered PrEP/PEP that enables trained pharmacy providers (working under remote clinician oversight) to deliver drugs procured from government stock to eligible clients. Pilot studies have found this delivery approach reaches demographics underrepresented in clinic-based PrEP/PEP programs (e.g., men, unmarried individuals) and is highly acceptable and feasible to pharmacy clients and providers. Implementation challenges, however, include heavy burden on provider time (particularly for conducting the requisite HIV testing and counseling) and evidence gaps around how government might subsidize pharmacy PrEP/PEP delivery in ways that incentivize pharmacy providers and keep services affordable for clients. To fill these gaps, our research team is conducting hybrid cluster-randomized controlled trials to test different pharmacy PrEP/PEP delivery models that vary client cost and cadre of staff involved in delivery. In this presentation, we will present key implementation insights from these trials to date and potential paths forward.

Background

In Mexico, stigma and inequality limit access to HIV prevention tools like PrEP and PEP. Alain Pinzón of VIHve Libre has developed a peer-based, technology-supported program to overcome these barriers. Participants connect via social media, enroll through a digital platform, and access testing and medication either in person or via courier services. Personalized counseling ensures informed use of PrEP (daily or on-demand), while PEP is made accessible even in underserved regions across the country. This model highlights the power of community-driven approaches to dismantle stigma, promote adherence, and scale equitable HIV prevention solutions while establishing a permanent community network nationwide.

Background

Effective HIV prevention requires well-designed and well-targeted services tailored according to client characteristics and needs. PrEP biomedical product choice allows young people to select a formulation that works for them and their lifestyle, while HIV prevention impact may be even greater if PrEP service delivery models also match young people’s diverse lifestyles and unique needs. During this presentation, we will discuss how to link PrEP-interested young people to PrEP products (oral, dapivirine vaginal ring, and injectable cabotegravir) and services (including community-based models) most appropriate for their lifestyles and prevention needs. The talk will highlight effective PrEP choice frameworks for adolescents and young people; provide a detailed description of community-based mobile clinic delivery of a range of PrEP products (oral, dapivirine vaginal ring, and injectable cabotegravir) integrated into other sexual and reproductive health services; and describe how young people accessing PrEP from mobile clinics may be different than those seeking traditional healthcare.

Background

Residual viremia (RV) persists despite years of effective ART due to the daily activation of latently infected cells. Some people on long-term ART develop nonsuppressible viremia (NSV), characterized by persistently detectable HIV RNA that complicates clinical care, raising concerns for virological failure and HIV transmission. Recent work from our group and others showed that proviruses with defects in the 5’Leader (5’L) can also cause NSV. However, their overall contribution to persistent viremia remains unknown.

Methods

We enrolled 30 participants with intermittent or persistent plasma HIV RNA above the limit of quantification by clinical assays (20-1500 copies/ mL) despite no history of adherence issues. We isolated virus-associated RNA by plasma centrifugation and performed single genome sequencing covering the U5-gag and protease-reverse transcriptase (P6-RT) regions. Sequences were analyzed for drug-resistance mutations, clonality, and 5’L defects. To benchmark the frequency of major splicing donor (MSD) mutations pre-ART, we used 2238 5’L RNA sequences from the LANL HIV database. The impact of 5’L defects on viral infectivity was tested by site-directed mutagenesis of pNL4-3.

Results

We obtained 376 U5-gag and 358 P6-RT HIV RNA sequences from 29 participants with a median of 28 sequences per participant. No drug-resistance mutations relevant for current ART were detected. On average, 90% of sequences were identical, with a median of 2 unique variants per participant. Estimates of clonality by U5-gag and P6-RT strongly correlated (Spearman r=0.77, P<0.0001). We detected HIV RNA with 5’L defects in 27/29 participants, contributing to an average of 78% (sd±34%) of defective sequences per participant. Among 65 unique 5’L variants recovered, 22 were intact, 18 had deletions of 2-98 nucleotides involving the MSD, and 25 had single mutations in three conserved positions (HXB2 G744, T745, G748) necessary for MSD-spliceosome binding. These mutations abolished viral replication in vitro and were significantly enriched in participants with NSV compared to the pre-ART sequences (Chi-square, p<0.00001). Conversely, the polymorphic T742C substitution showed no significant difference in frequency (p=0.35).

Conclusions

HIV RNA contributing to NSV is highly clonal and enriched in narrowly focused 5’L defects that prevent de novo invention events. These findings can inform the clinical management of NSV and support the development of assays to distinguish intact from defective HIV RNA in plasma.

Background

Tissue resident memory T cells (TRMs) protect the gut mucosal barrier against microbial invasion by exerting rapid and localized effector functions while restraining excessive inflammation. Yet, pathogens can evade immune clearance and persist. The gut is a major HIV-1 reservoir in people living with HIV-1 (PLWH). However, given the rarity of HIV-1-infected cells (<0.1%) and the lack of selection markers, how HIV-1-infected cells survive and evade immune clearance in the gut remain unknown.

Methods

To determine mechanisms of HIV-1 persistence in the gut, we coupled single-cell DOGMA-seq and TREK-seq to simultaneously capture chromatin accessibility, transcriptome, 156 surface proteins, T cell receptor, HIV-1 DNA and HIV-1 RNA in the same cells from colon biopsy samples of ten PLWH under antiretroviral therapy (ART) and five uninfected donors.

Results

We identified 49,205 CD4+ T cells, including 99 HIV-1-infected cells, and 51,539 CD8+ T cells in the gut. Gene regulatory network analysis and multiomic profiling revealed BACH2 as the leading transcription factor that shaped gut T cell programs. While IRF drove effector T cell responses and clonal proliferation, BACH2 restrained effector programs and increased cytokine receptor expression to maintain long-term survival of tissue resident memory T cells (TRMs). TRMs accounted for half (55.1%) of gut CD4+ T cells, but the majority (80.81%) of HIV-1-infected CD4+ T cells were TRMs. HIV-1-infected cells had increased BACH2 and RORC transcription factor activity, TRM (CD49a, CD69, CD103) surface protein expression, Th17 (CCR6), and long-lived memory (IL7R) gene expression (q < 0.05, Wilcoxon rank-sum test). In vitro validation revealed HIV-1 preferential infection and persistence in CCR6+CD4+ TRMs (q < 0.05, Wilcoxon rank-sum test).

Conclusions

Overall, BACH2-driven TRM program restrained effector T cell functions and maintained long-lived TRMs. The long-lived nature of CD4+ TRMs allowed HIV-1-infected cells to upregulate survival cytokine receptors, escape activation-induced cell death, and persist in the gut. Our work identified BACH2-driven TRM program as a new therapeutic target for HIV-1 eradication strategies.

Background

Recent studies suggest that HIV-1 reservoir cells are subject to immune selection pressure, but the host immune responses that are able to engage and target viral reservoir cells are unknown. To infer mechanisms underlying immune selection activity against viral reservoir cells, we conducted a parallel, longitudinal phenotypic evaluation of HIV-1 reservoir cells and antiviral immune cells.

Methods

Longitudinal peripheral blood samples collected at ~1 year on ART (T1), at ~10 years on ART (T2), and at ~20 years on ART (T3) of 5 long-term ART-treated individuals were studied. Phenotypic and proviral sequencing (PheP-Seq) was used for the analysis of 73 markers on HIV-1 reservoir cells and CITE-seq was conducted for profiling of 177 markers on host immune cells.

Results

Using PheP-seq, we analyzed a total of 1,075,240 individual memory CD4 (mCD4) T cells from all three timepoints combined (2433 represented HIV-infected cells; 265 cells harbored genome-intact HIV-1 and 356 included clonally-expanded reservoir cells). Cells harboring clonal intact proviruses integrated into heterochromatin regions increased from 2.5% at T1 to 25% at T3. At the earliest timepoint, reservoir cells harboring intact proviruses showed few phenotypic alterations relative to HIV-uninfected cells. After 20 years of ART, the following markers were significantly (FDR-adjusted p<0.01) upregulated on mCD4 T cells containing intact HIV-1: CD127, HLA-G, 2B4, CD161, HLA-E, KLRG1, CD28, and CD48; all of these markers can be associated with reservoir persistence and resistance to immune-mediated killing. Correspondingly, CITE-Seq demonstrated statistically significant (FDR-adjusted p<0.01) downregulation of the activating markers Siglec-7, CD161, NKG2D, NKp46, DNAM1, NKp30 on NK cells on T3 relative to T1, while the inhibitory receptors KIR2DL2/3 were upregulated. Phenotypic changes in CD8 T cells over two decades of ART were more limited and included significant upregulation of activation (CD38, CD151) and immune inhibition (CD39, CD93) markers.

Conclusions

These data suggest a longitudinal evolution of viral reservoir cells with phenotypic features of resistance to immune-mediated killing, paired with a progressive increase of NK cells and, to a lesser extent, CD8 T cells with signs of immune inhibition and dysfunction. Phenotypic changes in reservoir cells and effector cells may jointly contribute to an immune microenvironment conducive to viral persistence.

Background

We explored the potential of combining the cIAP inhibitor AZD5582 with the BCL-2 inhibitor Venetoclax (VTX) to reverse latency and clear reactivated infected CD4+ T cells in a nonhuman primate model of HIV.

Methods

Thirty SIVmac239M-infected rhesus macaques (RMs), 18 males and 12 female, began antiretroviral therapy (ART) at 4 weeks post-infection (wpi). At 68 wpi, they were divided equally into three groups: A) ART-only, B) ART + VTX, and C) ART + VTX + AZD5582. VTX was given either intramuscularly (15 mg/ kg) or orally (300 mg) in 3 cycles of 4 daily doses to Groups B and C. Group C also received weekly intravenous AZD5582 (0.1 mg/kg) for 10 weeks, followed by an analytical treatment interruption (ATI) 4 weeks after the final AZD5582 infusion. Additionally, plasma concentrations for AZD5582 and VTX were measured by HPLC MS/MS in a subset of RMs in groups B and C (N=5 RMs per group).

Results

AZD5582 effectively reversed latency, with on-ART viremia exceeding 60 copies/ml in 6/10 RMs in the ART + VTX + AZD5582 group. The level of intact SIV proviruses in mononuclear cells isolated from peripheral blood and bone marrow was significantly lower after intervention with ART + VTX + AZD5582 (p<0.0001 for both sites), while levels remained stable in ART-only controls. Despite this impact on the intact reservoir, RMs from all groups experienced viral rebound after ATI within a similar timeframe. Area under the curve of on-ART viremia in the ART + VTX + AZD5582 group was not associated with post-intervention reservoir size, suggesting that the decline in intact proviral DNA was due more to VTX than to AZD5582. Indeed, AUC of VTX concentrations was positively correlated with the fold decline in intact reservoir size in PBMCs (Spearman r=0.9, p=0.08). A weak negative association between VTX AUC and post-ATI rebound viremia AUC (Spearman r= -0.60, p=0.350) was also observed.

Conclusions

The combination of AZD5582 and VTX reduced the intact SIV reservoir in peripheral blood and bone marrow but did not delay viral rebound after ATI. These findings highlight the intricate relationship between latency reversal, reservoir size, and viral rebound.

The figure, table, or graphic for this abstract has been removed.

Background

ImmTAV® are soluble bispecific T cell engagers that kill virus-infected cells presenting extremely low target peptide-HLA levels. IMC-M113V (GAGxCD3) is the first HIV ImmTAV in the clinic; a single dose study demonstrated safety and biological activity in antiretroviral therapy (ART)-suppressed PLWH. We investigated the effect of multiple ascending doses of IMC-M113V on HIV reservoir size and post-treatment viral control off ART.

Methods

HLA-A*02:01 positive PLWH on ART ≤7 years were enrolled in this open-label Phase 1/2 trial (EudraCT: 2021-002008-11). After step dosing during weeks (W) 1-2, escalating target IMC-M113V doses were administered IV Q1W to sequential cohorts during W3-12. Participants paused ART (analytical therapy interruption, ATI) during W13-W24. ART was resumed at W24 or earlier if plasma viral load (pVL) copies/ml exceeded 103 for >4 weeks or 105 x2 weeks, or CD4 count fell <350 cells/μl. Primary objectives were safety and tolerability; secondary and exploratory analyses include quantification of serum cytokines and cell-associated HIV RNA (CA-RNA), duration of pVL <103 during ATI and time to ART resumption. Change in CA-RNA from baseline to W13 was analysed by mixed effects models.

Results

Sixteen males were enrolled to 3 target dose cohorts of IMC-M113V: 60 μg, n=5; 120 μg, n=5; 300 μg, n=6. Doses were well tolerated and there were no serious adverse events or treatment-related discontinuations. Transient (<24 h duration) fever ≥38 °C was observed in 5/6 PLWH only after the first 300 μg dose, in tandem with a rise in serum IL-6, IFN-γ and CXCL10 (peak 16-, 4- and 264-fold respectively). At W13, IMC-M113V was not detectable in serum. During ATI (n = 13), post-rebound viremia control was observed in 3/13 PLWH: 0 at 60 µg; 1 at 120 μg (pVL <10³ x7/12 weeks); 2 at 300 μg (1 with pVL <10³ x10 weeks, enabling ATI extension to W28; 1 with rebound at W17, followed by a 3-log decline in pVL at W18-21). Of the remaining 3 at 300 mcg dose, 2 are due to start ATI and 1 withdrew prior to ATI. HIV CA-RNA (mean ±SD copies/10⁶ TBP) was significantly reduced from baseline (2374 ±2733) to W13 (1175 ±1809), p = 0.019.

Conclusions

IMC-M113V was well tolerated with initial evidence of post-rebound viral control off-ART. We observed a reduction in the active reservoir (CA-RNA) during treatment, the most substantial reported to date. This study provides the first evidence of antiviral efficacy for this novel mechanism of action. Doses >300 μg and longer ATI duration will be evaluated.

The figure, table, or graphic for this abstract has been removed.

Background

Antiretroviral therapy (ART) can reduce morbidity and mortality but does not eradicate HIV. Developing new therapies that induce HIV remission is crucial to end the epidemic. African women bear a disproportionate burden of the global epidemic yet are rarely included in clinical trials. We conducted a phase 2a HIV cure study to evaluate the safety of a regimen of 2 broadly neutralizing antibodies (bNAbs), VRC07-523LS and CAP256V2LS, and a TLR7 agonist, vesatolimod (VES), in acutely treated women with HIV-1 in South Africa (NCT05281510).

Methods

Twenty women from the Females Rising through Education, Support, and Health (FRESH) acute HIV infection cohort, who were suppressed on ART for ≥12 months and sensitive to at least 1 bNAb, were enrolled. Participants received up to 10 oral doses of VES (6 mg, dose escalation to 8 mg) every 2 weeks starting on day 0 and IV infusions of VRC07-523LS (20 mg/kg) and CAP256V2LS (20 mg/kg) on day 7. Participants began an analytical treatment interruption (ATI) on day 35 and remained off ART until day 336 or until they met ART restart criteria (HIV-1 RNA ≥1000 copies/mL for 8 consecutive weeks and without a drop of 0.3log₁₀; or confirmed HIV-1 RNA >100,000 copies/mL; or confirmed CD4 count <350 cells/µL). The primary endpoint was safety. Secondary endpoints included time to viral rebound (HIV-1 RNA >200 copies/mL), time to ART restart, and pharmacokinetics.

Results

As of September 18, 2024, all 20 participants had received study treatment and started ATI. There were no treatment-related serious adverse events. One participant experienced grade 1 cytokine release syndrome that led to discontinuation of VES. Eighteen experienced infusion-related reactions (16 grade 1; 2 grade 2); all resolved within 2 days. Five participants completed the 43-week ATI without meeting ART restart criteria, 2 of whom were completely suppressed (HIV-1 RNA <50 copies/mL); 14 met ART restart criteria; and 1 remained in ATI. Eight participants had evidence of partial virologic control with oscillating rebound, characterized by fluctuating levels of viremia with periods of undetectable viral load.

Conclusions

This first-in-Africa HIV cure trial demonstrates that complex cure studies can be successfully conducted in resource-limited settings with great unmet need. VES, VRC07-523LS, and CAP256V2LS were safe and well tolerated in acutely treated South African women. Potential mechanisms for the variable patterns of virologic control observed in this novel study are under investigation.

Background

ART suppresses HIV replication but fails to eliminate the virus, necessitating innovative strategies for curing HIV. CCR5-/- CD4+ T cells from CCR5Δ32 HSCT have eliminated HIV but are invasive and induce toxicity. Autologous CCR5 knockout (CCR5-/-) CD4 T cell therapy trials offer a safer alternative. We have shown that the persistence of CCR5-/- stem-like CD4 T (Tscm) cells post-infusion of CCR5 edited memory T cells was associated with reduced latent HIV and control of viremia upon Analytical Treatment Interruption (ATI). Here, we used a SIV-infection model to assess whether CCR5-/- CD4 Tscm can control viremia upon ATI.

Methods

20 non-human primates (NHPs) were infected with the stringent SIV SIV-mac239 for 4 weeks before being put on ART. 40 weeks post-ART, a single infusion of autologous CCR5-/- Tscm product (5M cells/kg) was infused after mild chemotherapy, along with B cell depletion using an anti-CD20 antibody (n = 10). Bi-allelic knockout of CCR5 in ~80% of the cells within the product was attained using CRISPR-Cas9 editing and Tscm phenotype was obtained using a cytokine mix. ATI was started 16 weeks after infusion and rebound was tracked for 12 weeks.

Results

Nine NHPs infused showed significant control of viremia at 4 weeks post-ATI and maintained control of viremia (<5000 copies/mL) at 12 weeks; anti-CD20 did not impact this virological outcome. The enrichment of CD28+CD95+TCF1+CD27+CCR7+ Tscm cells that were Ki67- in the infused product was associated with the control of viremia at the 4th week post-ATI (p-val=0.06). While high viremia at 4 weeks of ATI was correlated with plasma levels of IL-15 and IL-17 (p-val<0.05) before product infusion; this cytokine milieu likely promotes persistence of effector CD4 T cells that are permissive to infection. Importantly, an enrichment of CD4 Tscm phenotype was detected 6-days post-product infusion in the controllers, where sustained viral control was observed 12 weeks post-ATI.

Conclusions

We show that a single infusion of autologous CCR5 edited CD4 Tscm cells leads to sustained control of viremia for up to 12 weeks post-ATI. The efficacy of these cells is dampened if an effector cytokine milieu in the host, that promotes survival of virally permissive effector CD4 T cells, precedes the infusion of the product. These data show that the success of cell-based therapies depends on the stemness of infused product and an antiviral host environment that promotes innate and adaptive immune responses to control SIV dissemination.

Background

The extent to which LS-broadly neutralizing antibodies (LS-bNAbs) maintain viral control off ART remains unknown. RIO tested the frequency and durability of viral control of LS-bNAbs compared with placebo in people with treated early HIV.

Methods

RIO is a double-blind randomised 1:1 placebo-controlled trial designed to investigate viral control in the absence of ART. Virally-suppressed participants (aged 18-60) who started ART during early HIV received up to two intravenous infusions >20 weeks apart of bNAbs (3BNC117-LS & 10-1074-LS) (Arm A) or placebo (Arm B), and undertook analytical treatment interruption (ATI). Participants were screened for resistance to 10-1074 based on HIV DNA env sequences. Viral rebound confirmed by an independent committee was based on the first date of 6 consecutive plasma HIV RNA >1,000 or two >100,000 copies/ ml. Primary outcome was time to viral rebound at Week 20 after stopping ART, assessed using a Cox proportional hazards model. Secondary outcomes included adverse events, longer term viral suppression, bNAb pharmacokinetics, anti-drug antibody levels, predicted bNAb resistance and T-cell immunity.

Results

Of 145 participants screened, 68 were enrolled. 63/68 had no predicted significant baseline 10-1074 resistance; 5 failed to amplify. By Week 20, 25/68 had not rebounded: 22/34 in Arm A and 3/34 in Arm B. Arm A participants were 91% less likely to rebound over 20 weeks compared to Arm B (HR: 0.09; 95% CI: 0.04, 0.21, p<0.0001). In Arm A 13/34 and 7/34 had not rebounded out to 48 weeks and 72 weeks respectively after ATI, compared to 2/34 and 2/34 in Arm B. Nine SAEs were reported including one death, all unrelated to study drugs, ATI or protocol. There was no evidence of anti-drug antibodies or ART in plasma during the ATIs. Modelled 10-1074-LS and 3BNC117-LS levels remained above 10 µg/ ml for 48 (±13 2SD) and 47 (±12 2SD) weeks after last bNAb dose, respectively; 6 participants in Arm A remained virally suppressed off ART beyond week 48 after last bNAb dose. HIV Gag-specific T-cell responses were enhanced following bNAb dosing in those remaining suppressed.

Conclusions

Two LS-bNAbs were safe and significantly improved viral control off ART compared to placebo. Sustained viral suppression after bNAb dosing associated with enhanced T cell immunity is consistent with an immunologically-driven post-bNAb effect.

Figure 1.

Background

Hepatitis C virus (HCV) incidence is high among people with HIV (PWH) and people who inject drugs (PWID). Sexual transmission may also contribute to a higher HCV incidence in PWH, mainly among men who have sex with men (MSM). We report epidemiologic trends of incident HCV infection among PWH engaged in care in the US, stratified by HIV acquisition risk factors.

Methods

This retrospective cohort study used data from the CFAR Network of Integrated Clinical Systems from 1995-2023. Included PWH had a negative HCV antibody at first measurement (baseline) and any HCV test (HCV antibody or RNA) at least 12 months later. Incident HCV infection was defined as newly reactive HCV antibody or plasma HCV RNA. Follow up time was censored at first positive HCV test, or last observed negative HCV test. Crude incidence rates (IR) with 95% CI stratified by HIV risk group were calculated using survival methods. Calendar time trends were analyzed in three periods: 1995-2005 (interferon era), 2006-2014 (early direct-acting antiviral [DAA] era), and 2015-2023 (highly active DAA era). We calculated adjusted incidence rate ratios (aIRR) using Poisson regression to estimate the association of baseline sociodemographic factors and detectable HIV RNA with incident HCV.

Results

In sum, 20,917 PWH met study criteria, with median age 37 years, 81% male sex assigned at birth, 41% Black, 61% MSM, and 6.4% with PWID/MSM-PWID. There were 1,276 (6.1%) incident cases of HCV infection, overall IR 7.1 (CI 6.7-7.5) per 1000 person-years (py). Crude IR was highest among persons with PWID (IR 28.2 per 1000 py, CI 23.4-34.1) and MSM-PWID (IR 20.4 per 1000 py, CI 17.3-24.0), but stable across calendar periods. Crude IR was higher among MSM without IDU history (6.7 per 1000 py, CI 6.2-7.2) than heterosexual PWH (4.8 per 1000 py, CI 4.2-5.4). The crude IR increased from 3.5 (CI 2.7-4.6) per 1000 py in 1995-2005 to 7.6 (CI 6.9-8.3) per 1000 py in 2015-2023 among MSM without IDU. Calendar periods 2006-2014 (aIRR 1.3, CI 1.1-1.7) and 2015-2023 (aIRR 1.9, CI 1.4-2.6) and HIV risk category MSM without IDU (aIRR 1.3, CI 1.1-1.6) were independent risk factors for incident HCV.

Conclusions

HCV incidence increased more than two-fold in MSM without IDU history from 1995-2005 to 2015-2023; rates in PWID/MSM-PWID were stable over this period. Further study of time-varying covariates such as substance use, incident STIs, and HCV testing frequency that may account for the rising HCV incidence among MSM in the highly active DAA era is needed.

Table 1.

Background

HIV increases the risk of hepatitis B virus (HBV) reactivation after spontaneous HBV control (SC), which we hypothesized was due to differences in HBV-specific antibody responses between people with HIV (PWH) and people without HIV (PWoH).

Methods

We studied stored sera from 136 males (98 PWH, 38 PWoH) in the MACS/WIHS Combined Cohort Study with documented incident HBV and SC at their first HBsAg negative visit (v1), six months after v1 (v2), and 24 months after v2 (v3). Sera were assessed for (i) anti-HBs titer (EIA) and (ii) neutralization capacity using HepG2-NTCP HBV infection system. Neutralizing antibody (NAb) responses were quantified by area under the neutralization curve (AUC). Correlations were assessed using Spearman’s rank correlation. Comparisons were made using Generalized Estimating Equations model in R (geepack). Statistical significance p< 0.05.

Results

Age was similar in PWH and PWoH (median (yr); IQR) 31 (26-39) and 35 (30-43), respectively). Baseline CD4 count (cells/mm³) (median; IQR) was 506 (400-679) for PWH and 958 (766-1,210) for PWoH (P=2.2e-08). HIV viral load (VL) (copies/ml) (median; IQR) at v1 was 11,235 (1,386 -25,278) with 4 receiving ART. At v1, anti-HBs titers were similar between PWoH and PWH. However, at v2 and v3, titers were significantly higher in PWoH compared to PWH (p ≤ 0.001). In PWoH, titers increased from v1 to v2 and v3 (p = 1.6e-06) (mean increase of 0.31 units/yr) whereas titers in PWH declined (0.11 units/yr) (P comparing trends in PWH and PWoH = 5.1e-07). A cutoff of 10,000 HIV copies/ml was used to stratify PWH into high (H) and low (L) VL groups. Anti-HBs titers were significantly higher at v1 in the L vs H VL group (p < 0.001). Over time, a significant mean decrease in anti-HBs titers was only seen in the H VL (0.1 units/year (p = 0.04)) (Figure). In general, NAb AUC correlated with anti-HBs titers in PWH and PWoH with strongest correlation at v1 in both groups (PWoH rs = 0.79, PWH rs = 0.81, p < 0.001). The NAb AUC was significantly higher in PWoH than PWH at v1 (p < 0.01), v2 (p < 0.001), and v3 (p < 0.001). Amongst PWH, CD4 count and ART use did not affect titer or NAbs.

Conclusions

Over the first 30 months after HBV SC, PWoH have a stronger anti-HBs and HBV NAb response than PWH, which may explain the increased risk of HBV reactivation in PWH. Notably, rising anti-HBs titers in PWoH suggest ongoing sAg stimulation. The mechanism underlying the association of high HIV VL with declining anti-HBs requires further study.

Figure 1.

Background

The global burden of viral hepatitis B (HBV) is substantial, and monitoring progress across the care cascade is essential to plan elimination strategies. In Sub-Saharan Africa, data on the HBV care cascade are limited. We examined the HBV care cascade in Rwanda from 2016 to 2023.

Methods

In this population-based retrospective cohort study, we used routinely collected data from the District Health Information System 2, which included over 4.6 million people screened for HBV from January 2016 to June 2023. During this period, individuals were included if they were >2 years old. The HBV care cascade was analyzed across six stages: (1) lifetime prevalence, (2) diagnosis, (3) enrolled in care, (4) eligible to treatment, (5) treatment initiation, and (6) treatment continuation. Infection was defined as presence of at least one reactive hepatitis B surface antigen (HBsAg). Lifetime prevalence was estimated as the sum of diagnosed and estimated undiagnosed cases. Hierarchical logistic regression was used to identify progression-related factors through the different cascade stages.

Results

Among 4,604,468 individuals screened, 57,520 tested positive for HBsAg, of which 52,827 (91.8%) had HBV mono-infection and 4,693 (8.2%) were co-infected with HIV. Of those diagnosed, 21,247 (37.0%) were enrolled in care, and 6,429 (30.3%) of the enrolled individuals were eligible for treatment. Of those eligible, 4,893 (76.1%) initiated treatment, and 4,839 (98.9%) were retained on treatment at one-year post-initiation. Individuals aged 35–54 were more likely to engage in care (adjusted odds ratio [aOR], 1.19; 95% CI: 1.12–1.27), initiate treatment (aOR, 1.45; 95% CI: 1.14–1.86), and be retained on treatment (aOR, 2.88; 95% CI: 1.09–7.63) compared to those under 35. Individuals living 30 minutes to 1 hour from a health facility were less likely to engage in care or remain on treatment compared to those living closer to a facility.

Conclusions

Overall, engagement with care was low, which highlights the need to strengthen awareness among general population regarding HBV prevention and control. Younger individuals and those living farther from health facilities are less likely to engage in care and remain on treatment. Strengthening lower-level health facilities by expanding the number of trained healthcare providers and improving infrastructure is critical to enhance HBV prevention and treatment at the community level.

Figure 1.

Background

Liver disease due to viral hepatitis is a leading cause of mortality in PWH. Elucidating host genes that affect HBV transcription may accelerate hepatitis B virus (HBV) cure discovery. We hypothesized that host genes modulate HBV transcription during nucleos(t)ide analogue (NUC) therapy.

Methods

We used mRNA-capture slides (10X Genomics) on liver biopsies from 14 people with HIV and CHB (PWHHB) to sequence 100-250 million read-pairs per sample (Illumina NovaSeq 6000). Reads were mapped to a custom human+HBV reference. After quality control, we applied robust cell-type decomposition within gene expression spots to identify hepatocytes where HBV replicates and immune cell populations. We applied linear mixed-effects regression (LMER) using HBV RNA as a covariate to identify host genes associated with HBV transcription. Pathway analysis was performed.

Results

Among 7 HBeAg-positive (EP) PWHHB, median values were: HBV DNA (Log₁₀ IU/ml) 4.1, HIV RNA <20 cp/ml, duration of NUCs 7 years (0.1 - 12.5); 1 participant was treatment-naïve and 1 underwent rapid HBeAg seroconversion (HBeSC) post-biopsy. Among 7 HBeAg-negative (EN) PWHHB, all but one had undetectable HBV DNA, all had HIV RNA <20 cp/ml, and NUC duration was 8.1 years (7.0 - 9.1). We analyzed 54,250 genes across 25,109 cell spots. LMER on HBV+ hepatocytes (spots) among EP identified 727 upregulated and 76 downregulated host genes (mean fixed effect + 6SD, adjusted p-value < 0.05). The expression pattern of the top 50 significant genes varied with NUC duration, showing higher expression in hepatocytes from EP with long-term NUC. These genes comprised several enriched pathways crucial to liver function, such as the lipid metabolic process (adjusted p-value = 1.6e-05, fold enrichment = 10.64). Furthermore, immune response pathways to viral infection were enriched, highlighted by 15 upregulated genes (e.g., C3, APOA1). Enriched lymphocyte markers surrounding HBV-transcribing hepatocytes were identified in EP with the longest antiviral treatment and in most EN compared to those EP with short-term treatment. Notably, the post-biopsy HBeSC EP with short-term NUC exhibited pronounced expression of these markers around HBV+ hepatocytes.

Conclusions

Spatial transcriptomics of liver from PWHHB reveals that HBV transcription was closely associated with host metabolic processes and immune responses. These findings underscore intricate dynamics between HBV and host cellular machinery, yielding putative genes and pathways affecting HBV transcription.

Figure 1.

Background

A5379 primary analysis demonstrated that 2- and 3-dose HepB-CpG (2-CpG, 3-CpG) achieved superior seroprotective response (SPR defined as anti-HBs ≥10 mIU/mL) compared to 3-dose HepB-alum (3-alum) in PWH with prior HBV vaccine non-response (Group A), and 100% SPR was achieved with 3-CpG in vaccine-naïve PWH (Group B). SPR durability is now evaluated.

Methods

A5379 evaluated immunogenicity of HepB-CpG in PWH on ART with CD4 ≥100 cells/mm³ and HIV-1 RNA <1000 copies/mL. Group A was randomized 1:1:1 to: 2-CpG intramuscularly (IM) (20 mcg recombinant HBsAg, 3000 mcg CpG 1018® adjuvant) at Wks 0 and 4; 3-CpG IM at Wks 0, 4, 24; or 3-alum IM (20 mcg recombinant HBsAg) at Wks 0, 4, 24. All Group B participants received 3-CpG. End of study anti-HBs was assessed at Wk72 (48 wks after 3-dose, 68 wks after 2-dose) regardless of visit window. SPR proportion differences in Group A were estimated with two-sided 97.5% Newcombe CI, stratified by sex at birth and diabetes status. Otherwise, 95% Wilson CIs were used.

Results

Group A included 561 participants at 41 sites in 10 countries and Group B 74 participants at 13 sites in 3 countries. 95% of Group A and 100% of Group B completed study follow-up to Wk72. Group A: At end of study, 86.1% of 2-CpG (n=173), 97.2% of 3-CpG (n=177), and 57.5% of 3-alum (n=174) had SPR. SPR% difference was 28.6% (18.0%,38.4%) for 2-CPG v. 3-alum, 39.2% (30.0%,47.9%) for 3-CpG v. 3-alum, and 11.0% (4.3%,18.1%) for 3-CpG v. 2-CpG. The proportion who achieved SPR at any time on study but had anti-HBs <10 mIU/mL by study end was 2.1% for 3-CpG, 10.7% for 2-CpG and 22.0% in 3-alum. Among those with anti-HBs >1000 mIU/mL at the primary vaccine response time (Wk28 for 3-dose arms and Wk12 for 2-dose), 100% in all arms had SPR at study end. Overall, 73.3% (66.5%,79.1%), 77.7% (71.2%,83.0%), and 73.7% (66.9%,79.5%) of participants in 2-CpG, 3-CpG, and 3-alum reported AEs; two deaths unrelated to vaccines (TB, Wk43 2-CpG; and cardiac arrest, Wk36 3-CpG). Group B: At the end of study, 97.3% (90.7%,99.3%) of 74 participants had SPR. The 2 participants with anti-HBs <10 mIU/mL were among those with the lowest anti-HBs titers at time of primary vaccine response time. 87.8% (78.5%, 93.5%) reported AEs; no deaths.

Conclusions

In PWH, higher end of study seroprotection was achieved with HepB-CpG over HepB-alum, and 3 doses of HepB-CpG over 2 doses. HepB-CpG achieved durable seroprotection in both vaccine-naïve and prior vaccine non-response groups.

Figure 1.

Background

In a recent pilot study (ACTG A5371, SLIM LIVER: NCT04216589), 24 weeks of low-dose semaglutide (1 mg sc weekly) reduced metabolic dysfunction-associated steatotic liver disease (MASLD) in people with HIV (PWH), with 58% having improved MRI-proton-derived fat fraction-quantified intrahepatic triglycerides (IHTG). Although trends suggested greater IHTG improvements in women and older participants, the role of biological age indicators was not assessed. We investigated whether epigenetic indicators incorporating physical fitness were associated with IHTG changes on semaglutide.

Methods

The SLIM LIVER study enrolled PWH ≥18 years on suppressive ART with central adiposity and MASLD. All participants received semaglutide for 24 weeks and PBMCs were available at weeks 0 and 24. Genome-wide DNA methylation profiles were analyzed in 41 participants with available PBMCs and used to calculate DNAm-based aging biomarkers, DNAmFitAge, that provides an estimate of biological age using DNAm-based estimates of three physical fitness measurements: maximal oxygen uptake (DNAmVO2max), maximal gripping force (DNAmGripmax), and gait speed (DNAmGaitspeed). R code was used calculate DNAm fitness biomarkers available at GitHub repository at https://github.com/ kristenmcgreevy/DNAmFitAge. Linear regression models evaluated relationships between relative percent (%) change in IHTG (PCHG) and DNAm indicators, controlling for sex at birth and age.

Results

At entry, the mean age of participants (n=41) was 49 years (39% female), CD4+ T cell count was 776 cells/mm³ and absolute IHTG was 12.7%. Relative IHTG decrease was -29% (95% CI: -37, -20). The mean epigenetic age estimate at entry for DNAmFitAge was 59.2 years (mean epigenetic age acceleration of 10.2 years). A less accelerated DNAmFitAge at entry was associated with greater IHTG improvements (β=-1.6, p=0.10) when controlling for sex and chronological age. Weaker DNAmGripmax was also associated with greater improvements in IHTG over 24 weeks (β=4.68, p=0.009) when controlling for sex and chronological age.

Conclusions

Epigenetic age indicators incorporating physical fitness, specifically worse DNAmGripmax and younger DNAmFitAge were associated with greater improvements in IHTG following 24 weeks of low-dose semaglutide treatment in PWH, suggesting a potential role for epigenetic biomarkers in predicting treatment responses.

Figure 1.

Background

Disseminated TB is a common cause of hospitalisation for people with HIV and has high early mortality.

Methods

The NEW STRAT-TB trial, conducted at 3 hospitals in Cape Town, South Africa, has a 2x2 factorial randomization to standard TB treatment versus intensified TB treatment (standard TB treatment with rifampicin dose increased to 35mg/kg/d plus levofloxacin) and prednisone (1.5mg/kg/d) versus identical placebo, for the initial 14 days, followed by standard TB treatment. Adults admitted to hospital with HIV-associated disseminated TB (one or more of urine Alere LAM, urine Xpert Ultra or blood Xpert Ultra positive) are eligible. The primary endpoint is 12-week mortality. The absolute difference between arms was estimated using the Kaplan-Meier method with bootstrapping to obtain 95% confidence intervals and associated p-values.

Results

On 6 June 2024, the intensified TB treatment arm was stopped by the DSMB due to higher 2-week mortality. Investigators remain blinded to prednisone versus placebo allocation. 580 participants (of planned 732) had been enrolled with 563 in mITT population. Median age was 36 years (interquartile range, IQR=30-43), 299 (53%) were female with median CD4 count 42 cells/μL (IQR=18-92), Hb 8.2 g/dL (IQR=6.9-9.6), venous lactate 2.1 mmol/L (IQR=1.6-2.9) and creatinine 70μmol/L (IQR=52-102). 113 (20%) had eGFR < 50mL/min. 83%, 67% and 31% were positive by urine Xpert Ultra, urine Alere LAM and blood Xpert Ultra, respectively. 55/548 participants (10%) had HIV RNA < 50 copies/mL. 14-day mortality was 31/283 (11.0%) in the intensified arm and 14/280 (5.0%) in the standard arm (difference 6.0%; 95%CI 1.6% - 10.4%; p=0.008). Mortality at 12 weeks was 55/283 (19.4%) in the intensified arm and 43/280 (15.4%) in the standard arm (difference 4.1%; 95%CI -2.2% - 10.4%; p=0.204). None of the early deaths were attributed to drug-induced liver injury. Clinical hepatitis events within 14 days occurred in 15 participants in the intensified arm and 21 in the standard arm.

Conclusions

Intensified TB treatment was associated with higher 2-week mortality, which has not been observed in prior trials of higher dose rifamycins and fluoroquinolones in TB. Reasons for higher 2-week mortality are currently unclear. Interaction with prednisone will be explored when that randomization is unblinded. Strategies involving higher dose rifamycins and fluoroquinolones should be used with caution in critically ill inpatients with HIV and disseminated TB.

Figure 1.

Background

Transmission is the primary driver of drug-resistant (DR) TB epidemics; however, where and between whom spread occurs is poorly understood. Although TB is transmitted through shared air between individuals, numerous studies have demonstrated that <30% of genomically clustered individuals were household or other close contacts. We evaluated the role of casual contact in DR-TB transmission in the Durban metropolitan area in South Africa.

Methods

We conducted a prospective study of all XDR and pre-XDR TB patients diagnosed in 2019-2022. Participants were interviewed about homes, hospitals, clinics, and community locations visited regularly, in the 2 years before TB diagnosis. GPS coordinates were collected at all locations. TB isolates underwent whole genome sequencing; a SNP difference of ≤12 was considered genomically clustered. Person-to-person links and overlapping hospital admissions were defined as close contact. Casual contact was based on clinics or community locations named in common or proximate to each other (≤500 meters). Genomic, social network, and spatial analyses were performed to determine the proportion of transmission due to close versus casual contact.

Results

We enrolled 305 (80%) of 383 patients diagnosed with pre-XDR or XDR TB. Median age was 36 years (IQR 30-44), 137 (45%) were female, and 216 (73%) were HIV-positive. TB isolates were sequenced for 253 (83%) participants; 141 (56%) were genotypically linked. Only 13 (9%) genomically clustered participants were linked by close contact. An additional 81 (57%) were linked through casual contact, and 47 (33%) had no identifiable epi link. Casual contact links were found through same named outpatient clinics (n=56, 40%), proximate home or community locations (≤500 meters) (n=39, 28%), or a same named community location (n=10, 7.0%). Inclusion of casual contact in network analysis increased the median degree from 1 (IQR 0-2) to 10 (IQR 5-19) and reduced median shortest path length to 3 (IQR 2-3) among clustered participants.

Conclusions

Although a majority of participants were genomically clustered, close contact explained only 9% of links. Casual contact in community locations, including clinics and proximate locations, explained an additional 57% of potential transmission. Future efforts to curb TB transmission will require a greater understanding of unrecognized infectiousness and social mixing in community settings.

Background

The World Health Organization endorses 3 months of weekly isoniazid and rifapentine (3HP) as TB preventive therapy (TPT) in people with HIV (PWH) on once-daily dolutegravir (DTG)-based antiretroviral treatment (ART). Optimal dosing of DTG to maintain HIV viral suppression in pregnancy while taking 3HP or 1 month of daily isoniazid and rifapentine (1HP) has not been studied.

Methods

DOLPHIN-Moms (NCT95122026) is an open-label phase II trial in South Africa investigating the safety and pharmacokinetics of DTG in pregnant PWH initiated on 1HP or 3HP. Pregnant PWH at 20-34 weeks’ gestation with HIV viral suppression on DTG-based ART were randomized 1:1 to receive 1HP or 3HP. All initiated twice-daily DTG prior to starting 1HP or 3HP on day 1. Twenty-five participants in each arm had sparse DTG PK sampling on days 1 (pre-HP) and 17 (11h and 12h post DTG dose). DTG dosing was considered acceptable if 5th percentile DTG troughs were >158 ng/mL. HIV viral load was measured at screening, delivery, and TPT completion (1HP: week 4, 3HP: week 12). We estimated population PK of DTG using non-linear mixed effects modeling and performed Monte Carlo simulations of daily DTG dosing with 1HP and 3HP.

Results

Among 50 pregnant PWH, at entry, the median age was 33 years (IQR 31–37), gestational age 26.8 weeks (IQR 23–30), and CD4 696 cells/mm³ (IQR 459–864). All had HIV viral suppression. On day 1, there were no significant differences in median DTG troughs between 1HP and 3HP (2730 vs 2890 ng/ mL, p=0.91). On day 17, median (5th-95th percentile) troughs were 871 ng/mL (391–1754) in the 1HP arm and 1890 ng/mL (843–4764) with 3HP (p<0.01). At day 17, one participant per arm had DTG troughs <64ng/mL (Fig 1A): both had documented nonadherence and received counseling; one had detectable viral load at delivery (6697 copies/mL) and viral suppression at 12 weeks postpartum (3HP arm); the other remained virally suppressed throughout. Excluding these two participants, simulations of once-daily DTG predicted median (5th–95th percentile) DTG troughs of 88ng/mL (28–212) with 1HP and 436ng/mL (209–781) with 3HP.

Conclusions

In pregnant PWH, 1HP and 3HP administered with twice-daily DTG yields therapeutic DTG troughs and viral suppression among participants with adherence. Simulations predict once-daily dosing will achieve target DTG concentrations with 3HP but not 1HP. The next phase of the trial (confirming PK and virologic outcomes of once-daily DTG with 3HP in pregnant PWH) is ongoing.

Figure 1.

Background

Hepatitis B (HB) vaccination starting with a birth dose and HB immune globulin (HBIg) are given to prevent HB in infants, but HBIg is not available in many settings. This trial aimed to assess whether the risk of infection is below 2% in infants born to HBeAg positive mothers prescribed tenofovir disoproxil fumarate (TDF) prophylaxis, with the infants receiving HB vaccination according to national guidelines without HBIg. This is the regimen recommended by the 2024 WHO Guidelines.

Methods

This prospective, single arm clinical trial was designed to enroll 499 pregnant women with positive HBsAg and HBeAg tests at 28 weeks gestational age (GA), no contraindications to TDF, and no HIV infection in 8 public hospitals in Laos and 12 in Thailand (NICHD R01 HD092527) . An HBV DNA load measurement was scheduled during pregnancy to assess adherence and consider infant HBIg if needed. The primary outcome was infant HBV infection (positive HBsAg test confirmed by HBV DNA PCR at 6 months of age). The primary analysis was performed in infants who had an HBsAg test at 6 months of age, who did not receive HBIg, and whose mothers had no evidence of an unsatisfactory virologic response after initiating TDF, defined as HBV DNA load measurement between 20 days after starting TDF and 36 weeks GA that had not decreased by >10-fold in IU/mL from baseline and was >200,000 IU/mL. The proportion of pregnancies with HBV infection at 6 months was estimated along with a two-sided 90% Clopper-Pearson confidence interval (CI).

Results

Baseline and follow up data are summarized in the Table. No safety concerns were identified. There were 6 infant deaths, none deemed related to TDF exposure. In the primary analysis, 4 singleton infants of 423 pregnancies were infected at 6 months, yielding an infection risk of 0.95% (90% CI: 0.32%-2.15%), with the upper limit above the 2% hypothesized. In addition, one infant had a first HBsAg positive test (confirmed by HBV DNA PCR) at 4 months but was then lost to follow up, and another was infected but with an unsatisfactory maternal response: both cases were part of those excluded from the primary analysis. Sensitivity analyses confirmed the findings.

Conclusions

Maternal TDF prophylaxis and active immunization was efficacious in preventing HBV infection but the risk of infection was not demonstrably below 2%. These findings highlight the level of efficacy achievable when adhering to the 2024 WHO guidelines in South East Asia.

Table 1.

Background

Facilitating engagement from both partners of a pregnant couple has the potential to improve joint decision-making, healthcare utilization, and health outcomes. We tested the efficacy of a home-based couples intervention for improving Couples HIV Testing and Counseling (CHTC) and family health during pregnancy and postpartum.

Methods

In a 3-arm randomized controlled trial in southwestern Kenya (2019-2024), we recruited women attending antenatal care (2/3 with HIV), subsequently contacting the male partner. A total of 800 pregnant couples were randomized to the home visit intervention (HV, n=267), HIV self-test kits (HIVST, n=266), or standard care (SC, n=267). In the HV arm, lay health worker pairs (one female, one male) conducted 5 couple home visits during pregnancy and postpartum, including health education and couple relationship skills, with CHTC offered at home. Even when women knew their HIV status, CHCT was used to facilitate mutual HIV-status disclosure. In the HIVST arm, pairs of self-test kits were given to the woman to use independently with her partner. Interviews with both partners were conducted in pregnancy and at months 3 and 12 postpartum. Viral loads were abstracted from medical records. Outcomes were analyzed using general estimating equation models, adjusted for previous couple testing, education, wealth, couple age disparity, and length of relationship.

Results

Couples in the HV arm had a higher likelihood of engaging in CHTC compared to SC counterparts (adjusted risk ratio (aRR)=4.22, 95% confidence interval (CI)=2.88-6.18), as did those in HIVST arm (aRR=3.69, 95% CI=2.50-5.45). Home visits were associated with a greater number of male HIV+ diagnoses and identification of discordant couples. Measures of positive relationship dynamics (relationship satisfaction, trust, communication) were significantly higher in HV arm compared to HIVST and SC arms. Utilization of maternal and child health services was equally high across the three arms. Only 2 infant HIV infections were detected in the cohort. Women with HIV in HV arm had a significantly higher probability of achieving viral suppression at 18 months (aRR=1.07, 95%CI=1.03-1.12).

Conclusions

A home-based couples intervention led to measurable improvements in maternal viral suppression and was associated with increased couple HIV testing and better couple relationships. Addressing both members of a couple around the time of pregnancy is a highly promising strategy for achieving HIV prevention and family health.

Figure 1.

Background

Drug-drug interactions (DDIs) between contraceptives and antiretroviral therapy (ART) may increase the risk of unintended pregnancy and side effects. The levonorgestrel (LNG) implant and depot medroxyprogesterone acetate (DMPA) injectable are commonly used contraceptives in women living with HIV (WLWH), but pharmacokinetic (PK) data evaluating DDIs between dolutegravir (DTG) and LNG or MPA are lacking.

Methods

We conducted a phase 4 non-randomised, parallel-arm, open-label PK study among non-pregnant WLWH on DTG-based ART and HIV-negative, ART-naïve women in Botswana, who chose to initiate the LNG implant or DMPA injectable (n=140; 70 LNG, 70 DMPA; 35 WLWH per arm). Blood was sampled before contraceptive initiation and at 2-4 weekly intervals. A pregnancy test and data on safety and tolerability were collected each visit. Area under the concentration-time curves of LNG over 24 weeks (LNG AUC_24weeks) and MPA over 12 weeks (MPA AUC_12weeks) were compared between WLWH on DTG-based ART and HIV-negative, ART-naïve women using geometric mean ratios (GMR).

Results

Median (range) LNG AUC_24weeks was 13732 (6252-46797) pg.week/ mL and 10157 (3922-36311) pg.week/mL in WLWH on DTG-based ART and HIV-negative women respectively; GMR 1.30, 95% CI 0.99-1.68. Median (range) MPA AUC_12weeks was 10770 (4665-20005) pg.week/mL and 10212 (3018-18122) pg.week/mL in WLWH on DTG-based ART and HIV-negative women respectively; GMR 1.09, 95% CI 0.91-1.32. LNG C_max was higher in WLWH on DTG compared to HIV-negative women (GMR 1.71, 95% CI 1.01-2.89), while MPA C_max was similar between groups (GMR 1.16, 95% CI 0.92-1.47). There was no difference in median DTG concentrations before and after LNG (2155 vs. 2774pg/ml, p=0.09) or MPA (3358 vs. 3244pg/ml, p=0.46). Both contraceptive methods were well-tolerated, with no unintended pregnancies or serious adverse events. Endogenous progesterone was suppressed (<0.7 nmol/L) in 93% of WLWH on DTG vs. 78% HIV-negative women using LNG implant at 24 weeks, p=0.09; and 94% of WLWH on DTG vs. 87% HIV-negative women using DMPA injectable at 12 weeks, p=0.35.

Conclusions

There are no clinically significant DDIs between DTG-based ART and the LNG implant or DMPA injectable. DTG does not reduce LNG or MPA concentrations; and the LNG implant and DMPA injectable do not reduce DTG levels in WLWH. The LNG implant and DMPA injectable are both highly effective, safe and well-tolerated contraceptive options for WLWH on DTG-based ART.

Figure 1.

Background

Despite having high HIV incidence, adolescents have historically been excluded from Phase 3 HIV trials; separate trials of ~25–50 adolescents are required, resulting in prolonged delays in access to pre-exposure prophylaxis (PrEP). The PURPOSE program is the first to intentionally include adolescents aged 16 and 17 years. PURPOSE 1 found twice-yearly lenacapavir (LEN) was highly efficacious in people aged 16–25 years. We describe our approach to adolescent inclusion and a comparison of the pharmacokinetics (PK), safety, and efficacy of LEN in adolescents vs adults.

Methods

The study team engaged with key stakeholders, such as adolescent medicine experts and community advocates, to ethically and responsibly include adolescents. Consistent with standard practice, most adolescents provided assent and parents/guardians provided consent for trial inclusion. Innovations for adolescent inclusion included a community consent process led by a site community advisory board, after which waivers for parental consent were issued and adolescents could consent for themselves at that site. In other locales, adolescents who had ever been pregnant were considered emancipated and could consent for themselves. Further, an independent data monitoring committee reviewed safety data from the first 300 adult participants prior to adolescent enrollment. We compared LEN PK at Weeks 4, 8, 13, 26, and every 13 weeks thereafter, adverse events (AEs), laboratory abnormalities, and HIV infections between adolescents and adults.

Results

We enrolled 124 adolescents; 56 were assigned to the LEN group. Preliminary observed LEN plasma concentrations were comparable between adolescents and adults; LEN C_trough at Week 26 is shown (Fig). In both adolescents and adults in the LEN group, the most common AEs (excluding injection-site reactions [ISRs]) were headache, genitourinary chlamydia, and urinary tract infection; the most common ISRs were low-grade nodules, pain, and swelling. Laboratory abnormalities were mostly low grade and similar between adolescents and adults. There were no incident HIV infections among adolescents or adults receiving LEN.

Conclusions

LEN was safe and well-tolerated, with similar PK in adolescents aged 16 and 17 years versus adults, supporting extrapolation of efficacy in younger people. The intentional efforts to include adolescents resulted in robust enrollment ~2.5 to 5-fold higher than typical adolescent-dedicated studies, potentially accelerating access for adolescents who need or want PrEP.

Figure 1.

Background

Despite accounting for 3% of all people living with HIV, children (<15 yo) represented 12% of all AIDS-related deaths globally in 2023. Interruptions in HIV treatment (IIT) have been associated with higher mortality among children living with HIV (CLHIV). To explore this association further, we analyzed IIT and mortality data among CLHIV in PEPFAR-supported countries in the last 4 fiscal years, FY21 – FY24.

Methods

We analyzed PEPFAR Monitoring, Evaluation, and Reporting data for all CLHIV <15 yo on ART with IIT between October 2020 and June 2024 (FY21-FY24) from 32 PEPFAR-supported country and regional programs. IIT was defined as having no clinical contact or ART pick-up for >28 days since the last clinical encounter. IIT data was disaggregated based on cause and included transferred out, refused treatment, unknown IIT after <3 months, 3-5 months, or 6+ months on ART, or died. Mortality data was further disaggregated by cause of death including HIV disease resulting in tuberculosis (TB), cancer, infectious or parasitic disease, or other HIV disease; other natural causes; non-natural causes; and not reported cause. Prevalence of these outcomes were calculated across quarters and by five-year age bands.

Results

Among 490,000 CLHIV on ART in PEPFAR-supported countries, 22,329 experienced IIT in FY24. IIT occurred most frequently after 6+ months on ART among all CLHIV, except for those <1 (Figure 1). Among CLHIV on ART, IIT due to death was highest among children <5 yo, ranging from 0.47% to 1.88% (Figure 1). In FY24, HIV-related mortality accounted for 43% of all reported causes. This proportion remained relatively unchanged across the analysis period, but TB-related deaths increased from 6% in FY21 to 9% in FY24 (Figure 2). Data completeness improved as 80% of deaths in FY24 included an identified reported cause compared to 65% in FY21.

Conclusions

CLHIV experienced notable rates of IIT and mortality, with CLHIV <5yo experiencing a disproportionate share of these outcomes, underscoring the importance of targeted interventions such as early diagnosis of HIV and differentiated service delivery models that support retention in care. Further analyses are needed to better understand the drivers of IIT and causes of mortality among CLHIV on ART. Improving pediatric data reporting is crucial to accurately determine HIV-related deaths (i.e. death audits), identify programmatic gaps and focus resources on reducing preventable deaths.

Figure 1.

Figure 2.

Background

Dolutegravir (DTG) is not recommended for neonates due to absence of dosing guidelines and safety information. We are evaluating the multi-dose pharmacokinetics (PK) and safety of two pediatric DTG formulations in neonates: a dispersible scored tablet (DTG-DT, 10 mg) and a novel oral dispersible film (DTG-OF, 5 mg).

Methods

PETITE-DTG is an ongoing phase I/II, open-label, single center, two-stage trial in South Africa for term neonates exposed to HIV (N=56, birth weights ≥2kg). Stage 1 single dose DTG data (n=16) informed the multi-dose strategy for Stage 2: 5 mg DTG every 48 hours (q48) from Day 1 to 14 of life, followed by 5 mg daily (q24) until Day 28. In Stage 2, neonates born to mothers on DTG-based ART are randomized to receive either DTG-DT or DTG-OF with zidovudine postnatal prophylaxis. Three PK visits are performed: sparse on Day 1, intensive after ≥3 DTG doses, and sparse during week 4. Safety assessments are performed through week 6 of life. We report the interim PK/safety analysis after the first 20 neonates completed Stage 2. Target DTG criteria: geometric mean (GM) C_tau>0.67 µg/mL, and C_max<17.0 µg/mL in the majority of neonates; proportion of neonates with C_tau <0.5 μg/mL (EC95) was also assessed.

Results

Ten neonates on DTG-DT and 10 on DTG-OF were included. Overall median (range) birth weight was 3.2 (2.6-4.1) kg and 1st DTG dose given at 48 (28-60) hours of life. Median age at PK sampling visits were 3, 7, and 23 days of life. DTG GM concentrations prior to the 1st dose (placenta washout) was 0.98 μg/mL. Intensive DTG PK profiles were similar between DTG-DT and DTG-OF, with both formulations achieving a DTG GM C_tau >0.67 µg/mL (Figure 1a). Two neonates, one on DTG-DT and one on DTG-ODF, had an C_tau <0.5 µg/mL, but both remained >0.22 µg/mL (>3-fold higher than DTG IC₉₀ of 0.064 µg/mL). All neonates had a DTG C_max<17.0 µg/mL across PK visits. Our prior neonatal DTG population PK model was updated with the multi-dose data and adequately predicted DTG concentrations (Figure 1b). No grade ≥3 adverse events (AEs) were related to DTG. Two grade 3 AEs unrelated to DTG were observed in one neonate with pneumonia. All neonates were HIV negative at study exit.

Conclusions

The multi-dose strategy of 5 mg DTG q48 from Day 1 to 14 of life, followed by 5 mg DTG q24 through day 28, was safe and achieved target concentrations for both DTG-DT and DTG-OF. This is the first evidence in neonates supporting the extension of DTG dosing recommendations from birth through week 4 of life.

The figure, table, or graphic for this abstract has been removed.

Background

In the CHAPAS-4 trial of second-line antiretroviral therapy following NNRTI-based first-line, 96-week efficacy was superior for tenofovir alafenamide (TAF) vs standard-of-care (SOC: abacavir (ABC)/zidovudine (ZDV)), and for dolutegravir (DTG) vs ritonavir-boosted lopinavir (LPV/r)/atazanavir (ATV/r). We present data on emergent resistance and associations between baseline resistance and virological failure at week 96 (W96).

Methods

Randomisation was simultaneously to TAF vs ABC/ZDV, and DTG vs darunavir (DRV/r) vs LPV/r vs ATV/r. Baseline samples and those with viral load (VL)≥400c/ml at W96 were sequenced for resistance, defined using Stanford Algorithm (v9.6) with scores categorised into susceptible/low-/intermediate-/ high-level resistance.

Results

Of 919 children, age 10 (range:3-15) years, 5.6 (IQR:3.3-7.8) years on first-line, 713 (78%) had baseline sequencing: 665 (93%) had M184V/I; intermediate/high-level resistance to allocated NRTI was present in 30% ABC, 10% ZDV, and 15% TAF. At W96, 14% (124/908) had VL≥400c/ml: 17% SOC (12% ABC; 21% ZDV) vs 11% TAF and 19% LPV/r, 16% ATV/r, 12% DRV/r, and 8% DTG (Table). At W96, 0/17 ABC, 14% (5/36) ZDV, 9% (3/33) TAF had intermediate/high-level resistance to NRTI initiated; 59% ABC, 78% ZDV, 36% TAF, to FTC/3TC. Intermediate/high-level resistance to anchor was: 0/29 LPV/r, 4% (1/26) ATV/r (1 TAF/FTC), 0/18 DRV/r and 22% (2/9) DTG (2 ZDV/3TC). 54% (67/124) children with VL≥400c/ mL at W96 had reverse transcriptase sequencing at baseline and W96; resistance categorisation to allocated NRTI remained the same in all, although score worsened in 16. Three children on ZDV/3TC (2 DTG,1 LPV/r) developed new high-level emtricitabine/lamivudine (FTC/3TC) resistance (M184V). Odds ratios (95% confidence interval) of VL≥400c/ml at W96 in those with intermediate/high vs low/susceptible baseline resistance to allocated NRTI were 0.23 (0.05-1.03) on ABC, 1.61 (0.53-4.92) on ZDV, and 1.01 (0.37-2.76) on TAF.

Conclusions

TAF resistance at baseline was less common than ABC resistance, supporting TAF in second-line. No new intermediate/high-level resistance to allocated NRTI occurred. W96 intermediate/high-level anchor drug resistance was uncommon, and as in second-line adult and paediatric trials, resistance to DTG only occurred in children taking ZDV. These results will inform second-line treatment guidelines for children.

Table 1.

Background

Kaposi sarcoma (KS), caused by KS herpesvirus (KSHV), is a multicentric angioproliferative tumor seen in people with and without HIV. Abemaciclib (Abema) is an oral cyclin-dependent kinase (CDK) inhibitor that targets CDK4 (cyclin D1) and CDK6 (cyclin D3) that is FDA-approved for breast cancer. In vitro studies of KSHV-infected cells have shown that CDK4/6 inhibitors enhance T-cell activation and host immune cell surface expression, hindering immune evasion. Here, we investigate the safety and activity of Abema in participants (pts) with KS.

Methods

This is a Phase 1/2 study of Abema in pts with KS. Phase 1 evaluated safety and tolerability of Abema using a 3+3 dose de-escalation design to identify a maximum tolerated dose (MTD). Pts were treated at dose level 1 of 200mg twice daily in 28-day cycles. Phase 2 assessed overall response rate of Abema of all pts and stratified by previously treated (Arm 1) or untreated KS (Arm 2). Eligibility criteria included adherence to antiretroviral therapy in people with HIV (PWH) for > 8 weeks prior to enrollment and no concomitant strong CYP3A4 inhibitors. Dose de-escalation was permitted for pts who experienced toxicities. KS response was evaluated using the modified AIDS Clinical Trials Group criteria.

Results

Twenty-five cisgender men (18 PWH), median age of 47 years are enrolled in this ongoing study. Twenty pts had stage T1 KS. In Phase 1, 6 pts were enrolled at 200mg BID with no dose-limiting toxicities. In Phase 2, 12 pts (10 PWH) were enrolled to Arm 1, and 7 pts (4 PWH) enrolled to Arm 2. The most common grade 1/2 adverse events were anemia and diarrhea. Twelve pts had dose reductions for grade 3/4 neutropenia. Among 23 evaluable pts receiving >2 cycles, 18 pts had a partial response (PR) (78% [95% confidence interval: 56-93%]), 4 pts had stable disease and 1 pt had progressive disease. All 7 pts in Arm 2 with previously untreated KS had a PR. The median HIV viral load among PWH was <20 copies/ml. Among PWH, the median CD4 T-cell count was 279 cells/µL (interquartile range: 176-435 cells/µl) without significant changes prior to cycle 3 (P=0.23) or at the end-of-treatment (P=0.39, Figure 1).

Conclusions

Abema is a novel therapeutic option in KS, with notable activity among pts with previously untreated KS. Adverse events were managed with dose reduction and supportive measures. Unlike chemotherapies for KS, there was no impact on CD4 T-cell counts among PWH.

Figure 1.

Background

People with HIV (PWH) are at increased risk of oropharynx cancer (OPC) compared with people without HIV (PWoH). PWH and OPC also have poorer survival compared to PWoH and OPC. However, prior studies have not evaluated OPC treatment initiation and survival among cohorts of PWH and PWoH matched on demographic variables, stage, and HPV tumor status.

Methods

We conducted a matched retrospective cohort study of PWH and PWoH diagnosed with OPC between 2008-2019 utilizing data from the Veterans Affairs and Kaiser Permanente health systems. PWH and PWoH with OPC were matched 1:1 on sex, age (+ 1 year), race, year of OPC diagnosis (+ 1 year), stage, and HPV status. Patients were followed from OPC diagnosis until death, loss-to-follow-up, or December, 31, 2021. Treatment initiation (chemotherapy, radiation, or surgery) within 180 days, and HPV tumor status were assessed through chart review. Kaplan-Meier curves by HIV and HPV status were conducted. Cox regression was used to assess the association of HIV infection with overall survival adjusting for matching variables, co-morbidity score, alcohol and tobacco use, and time-dependent chemotherapy and radiation initiation within 180 days of diagnosis.

Results

Our analysis included 130 PWH and 130 PWoH OPC patients. There were no significant differences between PWH and PWoH on matched variables. Overall median age at OPC diagnosis was 57.8 years; 32.3% were non-Hispanic Black, 59% were non-Hispanic White, and 9% were Hispanic. The cohort included 20% diagnosed at stage 1 or 2, and 79.6% were stage 3 or 4a/b; 61.5 % were HPV positive. There was no significant difference in smoking history (82% vs 79% among PWH and PWoH, respectively). PWH and PWoH had comparable rates of chemotherapy and radiation uptake within 180 days (65.2% vs 72%, p= 0.166) and median time to treatment initiation (57 days vs 60 days, p=0.76). PWH had shorter restricted Mean Survival Time to PWoH (3.4 vs 3.9 years, p=0.04); HPV status was the largest predictor of survival regardless of HPV status (figure 1). In adjusted multivariable Cox survival analyses, HIV infection was associated with non-significant increase in mortality (HR 1.48, 95%CI: 1.00 to 2.28, p=0.063).

Conclusions

In a matched cohort of PWH and PWoH with OPC, the two groups had similar treatment rates and timing of treatment initiation. When adjusted for receipt of treatment, there was a trend for poorer survival among PWH compared to PWoH.

Figure 1.

Background

UNAIDS estimates, derived by fitting mathematical models to national surveillance data, indicate that HIV incidence in sub-Saharan Africa has declined substantially since 2000. We assessed whether the level and age distribution of HIV incidence from mathematical-model derived estimates, which are critical to guide epidemic response strategies, are consistent with empirical HIV incidence observations.

Methods

We matched empirical HIV incidence observations from cohort studies, control arms of intervention trials, and Population-Based HIV Impact Assessment household surveys in sub-Saharan Africa conducted 1990-2022 to UNAIDS HIV incidence estimates by study area, gender, age group, and year. Using two Bayesian mixed-effect Poisson regression models we estimated (1) incidence rate ratios (IRR) between all empirical observations and matched modelled incidence estimates with covariates for gender, year, and study type/population; and (2) temporal patterns in age-specific incidence from population-based cohort studies alone.

Results

Incidence data were included from 3479 observations from 148 studies conducted in 21 countries, comprising 20,000 infections and 2.3 million person-years. Across population cohorts in South Africa, Uganda, Zimbabwe, and Kenya, HIV incidence among adults aged 15-49 declined by 75-90% between 2010-2023, and declined 3% (95%CI 2-4%) faster per year among young adults 15-24 compared to age 25+ years. Modelled incidence declined similarly to cohort data, but did not reflect the different rates of decline by age group. Relative to matched modelled estimates, incidence observations from representative household surveys (IRR 1.15 95%CI 0.86, 1.54) and population-based cohorts/Universal Testing and Treatment trials (IRR 0.91 95%CI 0.52-1.60) were not significantly different. Studies among pregnant women (IRR 2.83 95%CI 1.56, 5.13) and control arms of intervention trials (IRR 2.54 95%CI 1.64, 3.96) had significantly higher incidence than modelled incidence estimates.

Conclusions

Incidence from modelled estimates were consistent for level and trend with population-representative studies, but significantly lower than studies with non-representative inclusion criteria, including those among pregnant women and most HIV prevention/vaccine efficacy trials. Incidence has declined steeply among population cohort studies and modelled estimates. The age pattern of incidence in modelled estimates should be revised to capture the aging of the epidemic indicated by cohort studies.

Table 1.

Background

Comparing cause-specific mortality among people with HIV (PWH) and people without HIV (PWOH) is important for tracking improved survival following increased antiretroviral therapy (ART) access. However, comprehensive data on cause-specific mortality rates in Sub-Saharan Africa remains inadequate. We estimated mortality trends in Tanzania.

Methods

Data were collected in a health and demographic surveillance system (HDSS) in Magu, rural Tanzania from 1994-2023, among individuals aged ≥15 years. For people who died, a verbal autopsy was conducted and the InSilicoVA statistical algorithm was used to ascertain the main cause of death. The duration of residency within the HDSS was utilized to estimate follow-up time in this open cohort. People could leave and re-enter the HDSS in this analysis and follow-up ended at the earliest of death date, out-migration or administrative censoring. To calculate cause-specific mortality rates, follow-up was censored for the other causes of death. Causes of death were grouped as: HIV/AIDS/tuberculosis, infectious diseases, non-communicable diseases (NCD), external causes, direct obstetric-related deaths, and missing. Standardized mortality ratios (SMRs) were calculated from the indirect standardization method by dividing observed by expected deaths with PWOH being the standard population.

Results

Among 99,380 adults contributing 425,004 person-years, median age at follow-up start was 27 years (interquartile range: 21-38) and 55% were women. During follow-up, 4,120 died, with 68% of deaths assigned a cause. Among PWH and those with unknown HIV status, crude all-cause mortality declined over the years, whilst for PWOH, crude mortality was relatively constant post-2000 (Figure). Compared to PWOH, overall mortality was 6 times higher among PWH. SMRs comparing PWH with PWOH for all-cause mortality decreased from 16.4 (95% confidence interval [CI]: 15.2-17.7) in 1994-1999 to 4.7 (95% CI: 4.1-5.3) in 2020-2023. The highest SMR, 109.2 (95% CI: 98.8-119.6), was of mortality due to HIV/AIDS/tuberculosis between 2015 and 2019. SMRs for mortality due to infectious diseases, external causes, and direct obstetrics declined in later years, while SMRs for mortality due to HIV/AIDS/tuberculosis and NCD increased.

Conclusions

There is continuing elevated mortality among PWH, compared with PWOH, with HIV/AIDS/tuberculosis remaining the leading cause of death, highlighting the need to address barriers to HIV treatment to capitalize on the benefits of increased ART coverage.

The figure, table, or graphic for this abstract has been removed.

Figure 1.

Background

Viral suppression estimates are essential for monitoring progress towards the UNAIDS 95-95-95 targets. We sought to generate updated estimates of viral suppression rates in South African adults on antiretroviral treatment (ART) to understand changes in viral suppression following the introduction of dolutegravir and the COVID-19 epidemic.

Methods

This retrospective cohort study included adults (15 years or older) starting ART between 2005 and 2023 from seven South African sites of the International epidemiology Databases to Evaluate AIDS collaboration. We excluded those with no recorded baseline CD4 count or who were virologically suppressed before starting ART. Participants were censored at the earliest of death, transfer to another facility, 180 days after the last recorded visit (“lost to follow-up”), or 31 December 2023. After starting ART, viral load testing was scheduled at 6 months, 1 year, and yearly thereafter. Missing viral loads were imputed using multivariate imputation by chained equations. Viral suppression was defined as less than 1000 copies/ml. Multivariable logistic regression was used to estimate associations with viral suppression.

Results

187 624 participants contributed 986 348 person-years of observation. The proportion virologically suppressed reached a low of 86.4% in the 2011 calendar year, and then increased steadily to 94.8% in 2022. Virological failure was less likely amongst those starting ART on dolutegravir-based regimens than those starting on other regimens (adjusted odds ratio [aOR] 0.45, 95% CI 0.42-0.50). The odds of virological failure was lower amongst females (aOR 0.80, 95% CI 0.78-0.82), and decreased with increasing baseline CD4 count, duration on ART, and age (Figure 1). The odds of virological failure during the height of the COVID-19 pandemic (2020-2021) did not differ from other years (aOR 1.03, 95% CI 0.99-1.07). Those with a history of previous care interruptions, defined as gaps in contact longer than 180 days, were more likely to be virally unsuppressed (aOR 1.88, 95% CI 1.82-1.95).

Conclusions

Viral suppression rates in South Africa are on a promising trajectory toward the 95% UNAIDS target. The introduction of dolutegravir has likely contributed positively to the ongoing success of the national HIV programme. Viral suppression was not adversely affected by the COVID-19 pandemic, highlighting the resilience of the health system.

Figure 1.

Background

As the global response to HIV intensifies toward the goal of ending the epidemic by 2030, accurate estimates of mortality among people with HIV are needed to appropriately allocate limited resources. Standard patient monitoring approaches frequently lead to misclassification of patient outcomes, including vital status. In South Africa, the national HIV electronic health record system, TIER.net, fails to link patient-level outcomes across clinics, further complicating estimation of true patient outcomes. To address this, we used a multistage sampling strategy to systematically capture and verify vital status of people with HIV in KwaZulu-Natal Province (KZN).

Methods

We employed a stratified, multi-stage sampling approach to obtain representative estimates of vital status across all 11 districts in KZN. Clinics were selected from among all government-funded clinics providing HIV treatment services in KZN using probability proportional to size sampling. Random sampling was then employed to select up to 125 patients who had accessed HIV care in the prior two years but were 90+ days late for their most recent scheduled clinic visit using TIER.net. Trained teams conducted phone-based and in-person tracing to verify patient vital status. Inverse-probability weighting was used to obtain a provincial estimate of mortality among people with HIV with a current clinical lapse.

Results

Across 36 sampled clinics, a total of 4,482 individuals were randomly selected from 33,581 individuals who had at least one clinic visit in the prior two years but were 90+ days late for their most recent scheduled visit. Of the 33,581 individuals eligible for sampling,~4% had a documented death in TIER.net. Of sampled individuals, 3,156 (70.4%) were successfully traced; 2,737 (61.1%) were alive and 419 (9.3%) had died. Clinic-level estimates of mortality ranged from 5.0% to 19.3%. After weighting, an estimated 11.0% of the 33,581 individuals seeking HIV care in KZN who were late for their most recent scheduled clinic visit had died.

Conclusions

These findings indicate that relying solely on national health record data substantially underestimates mortality in people with HIV, emphasizing the importance of tracking efforts to obtain accurate estimates of HIV-related deaths. Moreover, our results underscore the potential of sampling-based approaches to refine mortality and other HIV care estimates, thereby informing strategies that bolster re-engagement pathways and mitigate overall mortality.

Background

The Africa CDC and the WHO declared Mpox a Public Health Emergency of Continental Security and of International Concern respectively. The first Mpox-positive cases in Uganda were reported in July 2024 from Kasese District, Bwera Hospital by the Uganda Virus Research Institute (UVRI) and MRC/ UVRI & LSHTM Uganda Research Unit. In light of ongoing Mpox virus (MPXV) transmission and an increasing number of cases reported in the neighboring DRC, we heightened surveillance for MPXV infections in Uganda to mitigate against the increased public health risk of cross-border spillover.

Methods

In this cross-sectional study, we tested samples collected from suspected Mpox cases on real-time PCR using different platforms to increase accuracy. All Mpox-positive samples were subsequently genotyped using targeted enrichment next-generation sequencing (NGS) while unbiased metagenomic NGS was performed on the Mpox-negative samples from clinically suspected cases to characterize other pathogens. Phylogenetic analysis was performed using IQTREE.

Results

As of 24-09-2024, 24 specimens tested positive for Mpox virus (MPXV) on real-time PCR out of the 597 samples collected from clinically suspected cases. Twenty of the 24 positives (83%) were detected at UVRI and near full-length Mpox genomes were generated for 8 samples with a genome coverage of >99%. Phylogenetic analysis showed that Ugandan sequences were closely genetically related to clade Ib sequences from the DRC suggesting a close link to the Sudan-Kivu Mpox outbreaks (Figure 1). Differential testing using unbiased deep sequencing of suspected Mpox cases that tested PCR-negative (n=73) detected human herpesvirus 3 as the top viral hit present in the samples (genome coverage of 90-100%) (Figure 1).

Conclusions

The Mpox outbreak in Uganda suggests an epidemiologic link to clade Ib MPXV associated with recent South Kivu Mpox outbreaks in the Democratic Republic of Congo (DRC). An increase in Mpox positivity is likely due to increasing community transmissions and findings from differential testing of Mpox-negative samples suggests co-circulation of Mpox and Chickenpox viruses, highlighting the need for routine surveillance of other emerging and re-emerging infections.

The figure, table, or graphic for this abstract has been removed.

Background

Mpox, a zoonotic disease caused by the Monkeypox virus (MPXV) within the Orthopoxvirus family, includes two major clades: Clade I, associated with severe disease and higher mortality, and Clade II. On August 14, 2024, the World Health Organization (WHO) declared Mpox a public health emergency of international concern following multi-country outbreaks since May 2022. Uganda declared a Mpox outbreak on August 2, 2024. With increasing case counts, sexually mediated clusters, and sustained human-to-human transmission, this study aimed to characterize the epidemiology, clinical presentations, and genetic diversity of Mpox cases confirmed in Uganda from July to October 2024.

Methods

This cross-sectional study analyzed data from the national Results Dispatch System (RDS) for Mpox cases reported between July 22 and October 31, 2024. Extracted data included patient demographics, symptom onset dates, symptoms, sample collection dates, sample types, test results, epidemiological exposure links, and whole-genome sequencing results.

Results

A total of 323 Mpox cases were confirmed from 1,991 samples tested (positivity rate: 16%) across 35 districts (24% of Uganda’s 146 districts), with Kampala reporting the highest case burden (41%). The median age was 24 years (IQR: 17), and 28% of cases involved children (0–17 years). Males accounted for 55% of cases. Symptom onset began on July 12, 2024, with a median delay of 4 days (IQR: 6) to sample collection. Common symptoms included rash (92%), fever (85%), and lymphadenopathy (78%). Atypical genital lesions were observed in 25% of cases within sexually mediated clusters. Close contact with infected individuals was reported in 60% of cases. Genomic analysis classified all positive samples as Clade 1b, with five distinct subclades, and no APOBEC3-like mutations were identified. No associations were found between clustering and variables such as district, gender, and collection batch.

Conclusions

The Mpox outbreak in Uganda was primarily driven by behavioral and environmental factors, emphasizing the importance of targeted interventions to address sexual transmission dynamics and protect vulnerable populations. While viral evolution resulted in five subclades, transmission was not linked to specific demographic or geographic factors, indicating widespread dissemination.

Background

Persistence of the HIV reservoir during antiretroviral therapy is a major obstacle to curing the infection. This reservoir can be established in the hyperacute stage of the infection, and lymphoid tissue analysis of this stage revealed HIV infection of resting T cells. Given that the HIV reservoir resides in resting CD4 T cells, we investigated whether direct infection of resting CD4 T cells could be involved in its establishment.

Methods

We infected primary resting CD4 T cells with a CCR5-tropic replication competent GFP reporter virus. We co-measured GFP expression with activation and proliferation markers by flow cytometry over five days. We performed bulk and single-cell RNAseq of sorted GFP+ cells to measure host and virus mRNAs. We bioinformatically analyzed cellular dNTP pathways for HIV reverse transcription and read-through HIV transcripts for HIV integration. Lastly, we cross-validated our findings with peripheral and lymphoid tissue samples from people living with HIV (PLWH).

Results

We detected resting GFP+ cells 3 to 5 days after infection. These GFP+ cells lacked CD69, CD25, HLA-DR, and CD154 expression. They also did not express the proliferation markers Ki-67 and phospho-H3.3. Transcriptome analysis of resting GFP+ cells revealed that infected cells expressed a cell-cycle independent pathway for dNTP synthesis. This pathway lacked expression of the genes required to convert deoxyuracil (dU) to thymidine (dT), which resulted in incorporation of dU into the provirus. We observed that dU-containing (dU+) proviruses were integrated into the host genome. We designed and ran a qPCR assay that differentiated between proviruses with dU or dT on samples from PLWH. dU+ proviruses and dT+ proviruses were detected in different CD4 T cell populations in all donors tested. Finally, after performing viral outgrowth assays, we found that cell subsets with dU+ proviruses had replication-competent virus.

Conclusions

We conclude that HIV can directly infect primary resting CD4 T cells and establish the reservoir in these cells. A key feature of HIV infection of resting cells is dU incorporation during reverse transcription due to the absence of enzymes required for dT synthesis. Therefore, the HIV reservoir comprises integrated, replication-competent, deoxyuracil-containing proviruses.

Background

The CARD8 inflammasome is a key driver of innate immune responses to HIV-1. CARD8, containing HIV-1 protease (PR) cleavage sites, responds to PR upon enforced NNRTI-induced dimerization of the viral Gag-Pol polyprotein and premature PR activation. In the absence of antiretrovirals, the apparent lack of CARD8 activation during HIV-1 assembly along with the observation that PR activation is precisely timed during virus release strongly suggests the existence of HIV-1 encoded mechanisms that prevent premature PR activation and CARD8-mediated cell death. In this study, we determined how structural domains of Gag coordinate the timing of PR activity to evade cleavage of CARD8 and facilitate innate immune escape.

Methods

We established an overexpression system in HEK293T cells using transient transfection to assay CARD8 cleavage by wildtype HIV-1 (WT) or mutants with selective inactivation of MA (Δ6-125), CA oligomerization (VK181-2/P224A), NC (zinc-finger deletion, Δ15-49) or p6 (ΔPTAP) domains of Gag. We infected PMA-differentiated THP-1 cells (PMA/THP1) and primary monocyte-derived macrophages (MDM) with WT or Gag-mutant viruses and determined CARD8 inflammasome activation by measuring IL-1β secretion and LDH release. We also infected primary CD4+ T cells (CD4T) with WT or Gag-mutant viruses in the presence or absence of lopinavir (PR inhibitor) to assess efficiency of PR-mediated cell killing.

Results

We found that alteration of HIV-1 assembly site (MA/Δ6-125) or arrest of virus particle release (p6/ΔPTAP) but not RNA binding (NC/Δ15-49) dramatically induced CARD8 inflammasome by de novo assembling Gag in HEK293T, PMA/THP1, and MDM. In the context of MA-mutant infection, CARD8 activation was dependent on CA-CA interactions and MA myristoylation, consistent with a model where CARD8 is cleaved late in the viral life cycle if the assembly process is altered. In CD4T, NC deletion did cause enhanced PR-mediated cell death, but the effect remained less significant than infection with the MA or p6 mutants. Interestingly, replacement of the NC domain with a nonspecific RNA-binding leucine zipper domain (GagZip) was sufficient to abolish PR-mediated activation of CARD8 in CD4T.

Conclusions

This work reveals important structural regulators of PR activation during the assembly of HIV-1 particles, and identifies the MA and p6 domains of Gag as potential targets to pharmaceutically enact killing of myeloid and lymphoid cells productively infected with HIV-1.

Background

The nuclear import of HIV-1 into the host nucleus marks a milestone of the viral infection, making it a potential drug target for effective prophylaxis and treatment. However, understanding this process has been challenged by its dynamic nature and the scarcity of HIV-1 cores in infected cells.

Methods

To elucidate the mechanisms underlying the translocation of HIV-1 capsids into the nucleus and their interactions with nuclear pore complexes (NPCs), we developed a robust system that recapitulates the nuclear import of HIV-1 cores into intact nuclei using mechanically lysed or detergent permeabilized T cells with purified HIV-1 cores. We employed cryo-focused ion beam (cryo-FIB) milling and planar lift-out, guided by cryogenic correlative fluorescence light and electron microscopy (cryo-CLEM), to prepare thin lamellae of T-cell nuclei containing HIV-1 cores. These developments enabled the following correlative cryo-electron tomography (cryo-ET) analysis of HIV-1 core nuclear import in situ.

Results

By utilizing these technologies, we achieved a productive capture of HIV-1 cores at different stages of nuclear import, with an unprecedented correlation efficiency of over 52%. Among the 510 HIV-1 cores identified in our tomograms, 87% of cores were specifically associated with nuclei. Statistical analyses of core morphology and size revealed, intriguingly, that tube-shaped and small HIV-1 cores were more advantageous in nuclear import compared to larger cone-shaped cores. Moreover, some large HIV-1 cores appeared to undergo deformation during the passage. Interestingly, NPCs, on the other end, were observed to dilate and occasionally crack, upon the entry of HIV-1 cores. We further observed the surface of capsid is coated with distinct densities, potentially corresponding to FG meshes, when passing through the NPCs.

Conclusions

This work introduces a robust in situ system with a highly efficient correlative cryo-ET workflow and provides novel insights into the nuclear import of HIV-1, which not only advances HIV-1 research but also opens a new avenue for studies on nuclear import mechanisms.

Background

Studies using the Jurkat T-cell model have identified numerous factors crucial for initiating HIV-1 transcription. However, a significant limitation of transformed cells is their inability to replicate the transitions between active effector cells and quiescent memory T cells, which are the key drivers of HIV latency in vivo.

Methods

We use refined primary cell models for HIV latency that accurately replicate the transitions between active effector cells and quiescent memory T cells. Our approach combines an HIV Cas-FISH immunofluorescence assay to trace changes in HIV DNA localization and immunofluorescence to identify key transcription factors. In parallel, the cells were analyzed by single-cell (sc) RNA-Seq, snRNA-Seq, AB-Seq, and ATAC-Seq, ensuring a comprehensive understanding of the process.

Results

As activated effector cells transition quiescence, HIV proviral DNA moves from the nuclear Intermediate Euchromatic Compartment (IEC) to the perinucleolar compartment (PNC). Strikingly, the localization of proviruses to the PNC was blocked by integrase inhibitor raltegravir, which showed that this was due to spatial genome rearrangements. Dramatic changes in histone methylation, cellular metabolism, and transcriptome changes accompany the transition into quiescence. snRNA-Seq and scATAC-Seq show that the subset of genes that are known HIV integration sites become more inaccessible when cells enter quiescence. During the reactivation of latently infected cells through the T-cell receptor, nascent viral mRNA transcripts emanating from proviruses in the PNC were detected. There was the rapid accumulation of the viral trans-activator Tat and its proviral reactivation regulatory partners, P-TEFb and 7SK snRNA, and RNA processing factors in large interchromatin granule clusters, which assembled near the provirus, and a shift of the proviruses away from the nucleolus. For all latency reversing agens (LRAs), there is a strong correlation between the extent of P-TEFb biogenesis and their potency. HIV proviruses in latently infected memory T cells from patients also accumulated in the PNC and showed identical patterns of nuclear rearrangements after cellular reactivation.

Conclusions

In contrast to transformed cells where proviruses are found primarily at the nuclear periphery, in primary memory T cells, P-TEFb highly restricts HIV transcription, and the nuclear architecture undergoes rearrangements that shape the transcriptional silencing and reactivation of proviral HIV.

Figure 1.

Background

How HIV reservoir is established in lymphoid tissues remain elusive.

Methods

We obtained frozen lymph nodes from 2 viremic donors and 2 virally suppressed donors from the Last Gift Cohort. Lymph nodes from 2 uninfected donors served as negative controls. We performed single-cell spatial transcriptomic profiling (475 immune genes) of 11 tissue sections using 10x Genomics Xenium, which uses cell segmentation to identify bona fide single cells. To distinguish intact vs non-intact HIV RNA, we designed 5 sets of HIV probes targeting packaging signal, Rev-response element (RRE), unspliced HIV (gag-pol), splice junctions, and all HIV. A threshold of >2 HIV RNA reads/probe defines HIV RNA+ cells. Detection of both packaging signal and RRE defines cells having intact HIV. An adjusted P<0.05 with a log2 fold change >2 is considered significant.

Results

We found that nonspecific RNA detection was a major caveat of this platform. We identified 791,108 cells (162,326 from viremic, 129,754 from virally suppressed, and 499,028 from uninfected donors). In viremic samples, we identified 1,967 HIV+ cells (1.21%, 12,117.6/million), including 17 cells having intact HIV RNA (104.7/million). Comparing non-intact HIV+ cells vs HIV– cells in viremic samples showed no differentially expressed genes, indicating the robustness of intact HIV detection. Of note, HIV– cells in viremic (vs virally suppressed) samples already showed upregulated type I IFN response (IFI44L, MX1, IFIT1, IFIT2, IFIT3, ISG15, APOBEC3G), Th1 (EOMES, IFNG, TNF), cytotoxic (NKG7, CD8B, GZMH, GZMK, GZMB), and exhaustion (LAG3, TIGIT) genes, indicating immune responses to HIV in the tissues in uninfected cells. In viremic sample, HIV+ cells having intact HIV (vs uninfected cells) had higher levels of type I IFN response (ISG20, IRF8), cytotoxic (PRF1, GZMK, GZMH, NKG7), memory (SELL, CCR7, TCF7), activation (TNFRSF9, ICOS, CD40, CD74), exhaustion (TOX, PDCD1), Th1 (TBX21), Th17 (CCR6), homing (CD69, ITGB7), and HIV coreceptor (CCR5, CXCR4) genes. Of note, we found upregulation of BACH2 and BCL2A1 in intact HIV+ cells which may promote long-term survival. In contrast, in virally suppressed (vs uninfected donor) samples, IFITM3 and IL1B were the only upregulated type I IFN response genes, indicating minimal but detectable viral sensor expression.

Conclusions

We identified immune profiles of cells having intact HIV in lymph nodes and the lymph node microenvironment during viremia and viral suppression.

Figure 1.

Background

Due to its high binding affinity to HIV capsid (p24), the first-in-class capsid inhibitor Lenacapavir (LEN) might display a post-integration effect on capsid production. However, this effect and its underlying mechanism, as well as its clinical impact on LEN-treated individuals, have yet to be characterized.

Methods

The post-integration effect of increasing concentrations of LEN was measured in vitro (8E5, ACH2, U1, transfected 293T cells) and ex vivo (PBMCs from n=12 viremic HIV-infected participants enrolled in the APRIL study [NCT05752318]) by analysing HIV transcripts and proteins expression by flow cytometry and p24 and HIV RNA levels in supernatants.

Results

LEN induces a rapid dose-dependent decrease of intracellular p24 detection at therapeutic concentrations in HIV-1 infected cell lines (reaching top plateau within 15 minutes exposure of 50nM LEN), whereas HIV-2 infected cell line was less sensitive. The latently-infected cell line also displayed a p24 decrease on LEN independently of the activation pathway targeted. The intracellular matrix (p17), but not the envelope (Env), detection decreased with the same magnitude as p24, suggesting that LEN targets the Gag polyprotein (Pr55). These decreases further translated in lower levels of viral particle release in supernatants on LEN. Intracellular HIV Gag and Nef transcripts levels were unchanged, and maturation inhibition did not affect the LEN-induced p24 decrease, suggesting a post-transcription but pre-maturation effect. The p24 detection in oligomerization mutants (W184D+M185D, P38E+A42E+E45R) and LEN-resistant mutants (N74D and Q67H+N74D) was less affected by LEN, suggesting that LEN binding requires specific capsid oligomers and residues. Proteasome inhibition by bortezomib partially constrained the LEN-induced p24 decrease, suggesting a proteasome-mediated p24 degradation. LEN also impaired p24 detection ex vivo in productively-infected CD4+ T cells from viremic HIV-infected individuals (decreased intracellular p24 [but not envelope] detection associated with decreased viral particle release).

Conclusions

Altogether, LEN appears to be causing a rapid and specific proteasome-mediated degradation of not only the capsid but also other gag proteins in vitro and ex vivo, which echoes in virions production. Reduced Gag proteins expression by infected cells in LEN-treated individuals could impact recognition of these cells by the immune system and thus the dynamics of HIV reservoirs and should be further studied.

Background

Cytomegalovirus (CMV) is a prevalent beta-herpesvirus that persists asymptomatically in immunocompetent hosts. More than 90% of people with HIV are co-infected with CMV. During long-term ART, HIV-1/CMV-coinfection is associated with inflammatory-related co-morbidities and persistence of the HIV-1 reservoir, yet the precise degree to which CMV contributes to these pathologies remains unclear.

Methods

We utilized specific pathogen-free rhesus macaques (RMs) that are seronegative for rhesus CMV (RhCMV) throughout life. Adult RhCMV- RMs (n=8) were age and gender matched to animals that naturally acquired RhCMV in early life (n=10) through co-housing. Animals were infected intravenously with 5000IU SIVmac239M and after 28 days received daily suppressive ART for 2 years. Plasma RNA and cell-associated SIV DNA were quantitated by PCR, and immunophenotype by flow cytometry was assessed in blood, lymph node (LN), and gut tissues at baseline and acute SIV (14dpi).

Results

Overall, natural coinfection with RhCMV led to a more severe SIV burden. RhCMV+ RMs had higher peak viremia (p=0.016), and near log-fold increases in seeding of SIV DNA at 14dpi in the colon and duodenum (p<0.0001, p=0.0008, respectively; Fig. A). RhCMV+SIV+ RMs took significantly longer to fully suppress viremia following ART initiation (p=0.031). At 14dpi, RhCMV+SIV+ animals exhibited higher frequencies of activated (CD169+) monocytes in blood (p=0.003) and HLA-DR+CD4+ T-cells in LNs (p=0.033). Prior to SIV, RhCMV+ RMs had higher percentages of CCR5+CD4+ memory T-cells in the blood (p=0.012), LN (p=0.0014), and colon (p=0.01), suggesting that RhCMV systemically increases SIV target cells (Fig. B). At baseline, target cell frequencies in LNs, but not other anatomical sites, were associated with higher peak viremia (p=0.0016, R=0.673). Notably, in RhCMV+ RMs, most CCR5+CD4+ T-cells did not respond to an RhCMV lysate ex vivo (p=0.002), suggesting target cell expansion by antigen-independent mechanisms. We also observed that HIV-CMV+ human donors (n=6) exhibited higher CCR5 expression on terminal effector memory CD4+ T-cells when compared to those of HIV-CMV- donors (n=6; p=0.041).

Conclusions

RhCMV exacerbates SIV burden, and this is associated with body-wide expansion of CCR5+ target cells, most of which do not react to RhCMV peptides. RhCMV may promote seeding of the SIV reservoir in a diverse array of CD4+ clonotypes. Targeting CMV may be therapeutic during periods of active reservoir seeding.

The figure, table, or graphic for this abstract has been removed.

Background

Monkeypox virus (MPXV) is a zoonotic virus endemic to Africa that has recently spread globally, becoming the first human orthopoxvirus (OPXV) since smallpox eradication. The MPXV global outbreak strain (Clade IIb, lineage B) derives from Clade IIb lineage A strains that circulate and remain endemic to Africa with limited human-to-human transmission. Clinically, lineage A-infected individuals exhibit more severe disease including substantial viral dissemination (>100 lesions per individual) relative to lineage B patients (<10 localised anogenital lesions). Lineages A and B differ by 51 nucleotides, most of which are compatible with host APOBEC3-mediated mutation. The consequences of these mutations to the biology of the virus remain unclear.

Methods

Here we used comparative virology to determine the phenotypic properties of MPXV lineage B relative to the closest ancestral lineage A and related OPXV.

Results

We found that both global and endemic MPXV replicated to the same extent in multiple cell types, but the global lineage B virus produced lower extracellular virus titres and showed defects in long-range spread. Both viruses had extensive capacity to suppress human innate antiviral responses, with a major role for the viral cGAMP nuclease (poxin). Consistent with this, RNAseq in infected fibroblasts and macrophages showed no significant induction of interferon (IFN) or antiviral-related KEGG pathways with either MPXV strain. Both viruses however induced strong inflammatory cytokine responses that have also been observed in patients and, interestingly, were absent with other OPXV. Importantly, comparative transcriptomics revealed defects in innate immune control by global MPXV, including IFNβ induction, increased innate immune signalling gene expression and enhanced MAP kinase activation. Furthermore, global MPXV had reduced capacity to suppress interleukin-1β-mediated immune responses. Consistent with the above, the global strain had reduced virulence in a mouse model of MPXV infection relative to the ancestral endemic strain.

Conclusions

Our findings reveal phenotypic differences between these two clade IIb viruses and demonstrate attenuation of globally circulating MPXV concomitant with human transmission. Our data may help explain clinical observations that lineage B is associated with milder disease. Finally, our work reveals that the APOBEC3-like mutational footprint is not only a signature of MPXV transmission amongst humans but also drives phenotypic changes.

Background

HIV-1 replication is associated with the generation of various nucleic acid products that may act as ligands for cytosolic innate immune sensors including RIG-like receptors (RLRs). However, to induce an effective innate immune response, RLRs need to be primed by actin disturbances, sensed by R12C (Acharya et al., Cell 2022). While mounting evidence suggests that HIV-1 is sensed by RLRs, whether HIV-1 is capable of antagonizing this sensing mechanism is currently unclear.

Methods

Using wild-type and mutant clade B and C HIV-1 constructs, we quantified the impact of Nef-dependent actin remodeling on viral replication and the induction of antiviral and pro-inflammatory responses in macrophages, dendritic cells and CD4+T cells. The impact of immune sensing on viral replication was further examined by blocking IFN signaling. To define the key sensors and underlying mechanisms, we knocked-out MAVS in human primary macrophages (MDMs) and treated cells with HIV-1 inhibitors.

Results

We found that a single R191A or F191A mutation in the C-terminus of Nef, which specifically prevents Pak2-mediated phosphorylation of the actin modulator cofilin, doubled the level of MX1, CXCL10 and CCL5 induction in primary MDMs and dendritic cells (DCs) upon HIV-1 infection. Strikingly, infection of DCs with this mutant is also associated with an up to 10-fold increase in production of pro-inflammatory cytokines such as IP-10, IL-6 and IL-8. Using HIV inhibitors, we show that this response is dependent on integration. Furthermore, CRISPR-Cas9 KO of MAVS in primary human macrophages abrogated innate immune activation. We also support a role for the sensor MDA-5 as it is activated and ISGylated upon infection with the mutant virus. Finally, we show that Nef prevents recruitment of R12C to RLRs and thus maintains both MDA-5 and RIG-I in a phosphorylated, inactive state, similar to that of uninfected cells.

Conclusions

Our results present HIV-1 Nef as the first viral counter-mechanism of actin disturbances critical for effective immune sensing.

Background

Generating robust virus-specific CD8+ T cell responses is the major objective of most HIV therapeutic vaccines. However, standard T cell assays fail to distinguish whether vaccine-expanded T cell populations are boosted pre-existing responses and/or newly-recruited clonotypes. Here, we utilized two single cell T cell receptor (TCR) sequencing approaches to characterize CD8+ T cell clonotypes expanded in the peripheral blood of five people living with HIV two weeks after receiving a multiclade consensus HIV gag/pol ± env DNA vaccine/IL-12 regimen (n=3) versus placebo (n=2) in the PENNVAX trial (NCT03606213).

Methods

First, we sequenced single paired TCR alpha and beta chains from enriched CD8+ T cells using the high-throughput Omniscope OS-T assay (per sample sequenced: median 1.3e6 [1.7e5-1.9e6] cells and 1.1e5 [6.1e4-1.6e5] unique clonotypes, defined as matching CDR3b amino acid [aa] sequence plus V/J usage). To investigate clonal dynamics between pre- and post-vaccination, expanded clones were defined as having a log2 fold change of ≥2 post- vs pre-vaccination (FDR adj. p-value <0.05, Fisher’s exact test). Clusters of clonotypes with similar CDR3 beta sequences were identified using TCRdist3. Additionally, we performed 10X single cell (sc)RNA/TCR sequencing from sorted MHC class I multimer+ HIV-specific CD8+ T cells from the same participants and timepoints.

Results

Among the three vaccinated individuals, we observed a significant expansion of 133 (15% newly detected), 415 (49% new), and 445 (12.5% new) CD8+ T cell clonotypes. Network graphs of the expanded clonotypes revealed hubs containing both boosted and newly detected clonotypes. The CDR3 beta aa sequence of 3.4% of boosted and 6.4% of newly detected clonotypes matched publicly available sequences reported to be HIV-specific. Expansion dynamics of clonotypes sequenced by 10X from multimer+ HIV-specific CD8+ T cells matched their expansion dynamics in the high-throughput assay.

Conclusions

By performing scTCRseq on approximately 1 million CD8+ T cells per sample, we successfully identified coordinated expansion following an HIV therapeutic vaccine of both boosted clonotypes as well as what appear to be newly expanded clonotypes with similar TCRs. Our data provide a benchmark for understanding how scTCRseq assays can be used to study vaccine-elicited HIV-specific T cells and lay the groundwork for future studies aimed at optimizing therapeutic strategies for HIV.

Background

Prospective trials have not previously compared the efficacy of boosting with the ancestral/monovalent mRNA vaccine (WA-1) versus a bivalent ancestral plus BA.4/BA.5-targeted vaccine in African countries, with high HIV and SARS-CoV-2 seroprevalence.

Methods

The second phase of CoVPN 3008 (Ubuntu trial) was a double-blind randomized trial in 7 countries, among people with HIV (PWH) or another comorbidity linked to severe Covid-19. It activated during the BA.4/5 omicron wave, progressing through to XBB.1. At month 6 (M6), previously-vaccinated volunteers received 100 mcg of either a monovalent or bivalent boost (1:1), then monthly PCR testing until M18. We compared the risk of symptomatic Covid-19 between arms using cumulative incidences and Cox regression overall and by HIV status, SARS-CoV-2 serology (SARS+/SARS-), CD4 count and HIV viremia. We assessed neutralizing anti-Spike antibody ID50 titers against BA.4/5 and XBB.1.5 (dominant strain during the trial) before boost and 1-month after, in 100 PWH per arm.

Results

From 10/2022-03/2023, 3988 participants (3086 PWH; 3491 SARS+) received the monovalent (n=1976) or bivalent (n=2012) boost and were followed until 05/2024. At M6, characteristics were balanced by arm with 68% born female and median age 37 years overall; among PWH, median CD4 count was 653 cells/mm³, 18% had HIV viremia and 95.8% were on antiretroviral therapy. At M12 (6 months after boosting), we observed 113 Covid-19 cases (all Omicron) including 1 non-hospitalized severe case. Incidence was 5.58 per 100 person-years, with no difference in efficacy overall (HR=1.00, 95% CI [0.69,1.45], Fig 1); by HIV status (PWH HR=0.99 [0.64,1.51]; PWoH HR=1.03 [0.50,2.14]); by prior SARS-CoV-2 infection (SARS+ HR=0.98 [0.66,1.46]; SARS- HR=1.17 [0.42,3.47]); or by CD4 count or HIV viremia (not shown). HRs were similar at M18. Geometric mean titers to BA.4/5 increased from 835 at M6 to 2544 at M7 in the monovalent arm vs. 773 to 3639 in the bivalent; and to XBB.1.5 from 135 to 559 in the monovalent arm vs. 156 to 1191 in the bivalent (Fig 1). The <2 fold higher titers among bivalent recipients were not associated with discernable clinical benefit. Severe disease was rare based on daily O₂ readings, temperatures and symptom checks following each positive PCR.

Conclusions

Among PWH, despite modestly higher neutralizing titers to circulating strains of Omicron after bivalent boosting, the bivalent boost provided no added protection against symptomatic Covid-19 over the monovalent boost.

The figure, table, or graphic for this abstract has been removed.

Figure 1.

Background

Vaccination to enhance HIV-specific T-cell immunity may be important for HIV cure strategies. GS-1966+GS-1144 is a novel heterologous vaccine regimen comprising GS-1966 (chimpanzee adenovirus vector) and GS-1144 (self-amplifying mRNA-lipid nanoparticle), both encoding a novel conserved HIV-1 immunogen that spans Gag, Pol, and Nef. This regimen was safe and well tolerated in a phase 1b study in virologically suppressed people with HIV on antiretroviral therapy (ART). To better understand the impact of GS-1966+GS-1144 on antigen-specific T-cell quality, we assessed changes in breadth, T-cell phenotype, and polyfunctionality.

Methods

The study included 3 cohorts randomized 2:1 to receive GS-1966+GS-1144 or placebo. Two doses of GS-1966+GS-1144 were evaluated. Cohorts 1 (low dose) and 2 (high dose) received a monovalent HIV-1 immunogen; cohort 3 (high dose) received a bivalent version. Participants maintained ART. T-cell breadth was evaluated by interferon-γ ELISpot assay using 16 peptide mini-pools covering vaccine epitopes. Polyfunctionality was assessed by intracellular cytokine staining and cells were analyzed via LSR flow cytometer and CellEngine software. Antigen-specific polyfunctionality was evaluated for each participant at days 1 and 183 using COMPASS.

Results

Although no significant increase in breadth of the vaccine-specific T-cell response was observed over time or between cohorts, the median number of mini-pool responses was numerically highest for cohort 3 at day 183 (median of 3 for cohort 3 compared with 1.5, 1.0, and 2.0 for placebo, cohort 1, and cohort 2, respectively). GS-1966+GS-1144 induced a CD8+ T-cell dominant response; vaccine-specific CD4+ T cells were also detected. No changes in the frequency of effector memory subsets were observed. COMPASS analysis revealed an increase in polyfunctionality of Gag-specific CD4+ T cells in cohorts 2 and 3, and in Gag-specific CD8+ T cells in cohort 3 at day 183 compared with baseline.

Conclusions

Breadth of the vaccine-specific T-cell response was not significantly different over time or between cohorts. Significant differences in Gag-specific T-cell polyfunctionality were noted for both CD4+ and CD8+ T-cell responses in cohort 3, suggesting that GS-1966+GS-1144 is able to induce highly functional T-cell responses to a key vaccine region. These results expand our understanding of T-cell response quality induced by GS-1966+GS-1144, a novel vaccine regimen for HIV cure.

The figure, table, or graphic for this abstract has been removed.

Background

Depletion studies in non-human primates demonstrated the crucial role of CD8 T cells in controlling SIV replication. However, the precise mechanisms underlying the control of HIV replication remain elusive. Lymph nodes (LN) are a primary site of HIV replication, and studying the CD8 T cell response at this level may provide additional insights.

Methods

We performed an in-depth characterization of HIV-specific CD8 T cells of matched blood and LN samples from 5 chronic HIV infected individuals (CHI) and 4 HIV controllers by scRNA-seq and scTCR-Seq. In addition, longitudinal blood samples collected from 3 HIV controllers were also evaluated over-time (median interval years=11).

Results

A total of 63’881 and 32’922 HIV-specific CD8 T cells were sequenced from blood and LN, respectively. Consistently with previous studies, HIV-specific CD8 T cells showing canonical cytotoxic functions (granzyme B, perforin) were rare ex vivo in LN of both CHI and controllers. However, blood and, to a greater extent, LN HIV-specific CD8 T cells of controllers were enriched (p<2^-16) in cells characterized by stemness markers (i.e. TCF7, IL7R, BACH2). This population, representing up to 63% of HIV-specific CD8 T cells in controllers, expressed the receptor GPR183 (EBI2), responsible for cell positioning at the T:B border in LN, and the effector molecule granzyme K. Interestingly, follicular-homing CXCR5+ HIV specific CD8 T cells in LN of controllers were also enriched in stem-like markers such as IL7R and CCR7 (p<10^-18), while LN CXCR5+ HIV specific CD8 T cells of CHI expressed more exhaustion markers (TIGIT, CD160, p<10^-5). Finally, TCR repertoire analysis revealed that HIV-specific CD8 T cells of CHI were more oligoclonal (blood, p=0.03; LN, p=0.25), suggesting the selection and/or elimination of some clonotypes during chronic infection. Of note, longitudinal analyses revealed that the clonotypic distribution of HIV-specific T cells may evolve in controllers, with expansion of subdominant clonotypes associated with transcriptomic traces of recent TCR engagement.

Conclusions

This study suggests that LN HIV-specific CD8 T cells in controllers harbor a distinct “stem-like” transcriptomic profile, possibly underlying an enhanced proliferative potential, associated with an optimal positioning in the LN microenvironment. Interestingly, both the transcriptomic profile and the TCR repertoire of HIV-specific CD8 T cells of HIV controllers can evolve with time, suggesting a dynamic adaptation of the immune response.

Background

Durable post-intervention control of viremia (PIC) occurs in a subset of people with HIV (PWH) after broadly-neutralizing antibody (bNAb) therapy and analytical treatment interruption (ATI). While prior studies support a role for CD8+ T cells in PIC, precise determinants remain unclear. We hypothesized that CD8+ T cell stemness against autologous proviral epitopes may determine PIC.

Methods

We obtained longitudinal peripheral blood before and 6-12 weeks following ATI, prior to viral rebound, from post-intervention controllers (PICs, n=7) and non-controllers (PINCs, n=5) from the MCA-906, MCA-965, TITAN, and eCLEAR trials, in which participants received infusions of bNAbs 3BNC117 and/ or 10-1074 and underwent ATI. We mapped HLA-optimal HIV epitope-specific CD8+ T cell responses by interferon (IFN)-γ ELIspot using peptides matching participants’ autologous proviruses. We measured the proliferative capacities of detected responses by CFSE dilution and assessed HIV-specific CD8+ T cell phenotypes via flow cytometry.

Results

HIV-specific CD8+ T cells were significantly more proliferative at baseline in PICs than PINCs (p<0.001) despite similar epitope-specific breadth and IFN-γ production between groups and over time. HIV-specific CD8+ T cell proliferative capacities increased modestly after bNAb infusion in both PICs (p<0.01) and PINCs (p<0.05). Ex vivo HIV epitope-specific CD8+ T cells in PICs were enriched for a CD45RA+CD62L+ stem cell-like memory (TSCM) phenotype both at baseline (p<0.05) and after bNAb therapy (p<0.01), which was associated with proliferative capacity (Spearman ρ=0.67, p=0.001). In contrast, PINCs were enriched for a CD45RA–CD62L– effector-memory phenotype (p<0.01). T_SCM frequency increased after bNAb infusion in PICs (p<0.01) without significant changes in ex vivo frequency or markers of activation, proliferation, or cytotoxicity.

Conclusions

The proliferative capacity and stem cell-like memory phenotype of pre-existing CD8+ T cell responses targeting autologous HIV epitopes were associated with subsequent PIC. Although PIC was not associated with the emergence of new responses or the in vivo activation or expansion of memory responses, modest increases in proliferative capacity and T_SCM frequency after bNAb therapy were consistent with a potential vaccinal effect. These results identify functional determinants of PIC that may guide the development of effective immunotherapies to elicit durable ART-free control of viremia in a larger proportion of PWH.

Background

The anti-apoptotic molecule BCL-2 promotes the establishment, maintenance, and expansion of the CD4 T cell reservoir. In SIV-infected rhesus macaque (RMs), we found that BCL-2 inhibition at antiretroviral therapy (ART) initiation (ARTi) promotes a rapid and sustained reduction of the SIV reservoir in blood CD4 T cells. To determine mechanisms for reservoir decrease, we assess the immunological impact of a BCL-2 inhibitor, venetoclax (vtx), in SIV-infected RMs.

Methods

24 RMs were infected with barcoded SIVmac239M and initiated ART at 14 days post-infection (p.i.). 8 RMs received ART alone; 8 RMs received 10 daily doses of vtx starting at ARTi; and 8 RMs received vtx in combination with a single dose of the anti-CD8a depleting antibody MT807R1 at ARTi. RMs were followed until d294 p.i. Immunological signatures in purified CD4 T cells were assessed at the end of vtx treatment (d25 p.i.) and of the follow-up period (d294 p.i.) by flow cytometry and RNA-seq.

Results

At d25 p.i., we found a reduction of central and effector memory CD4 T cells in RMs treated with vtx alone or with MT807R1. The remaining CD4 T cells showed significant enrichment of the 'Regulation of apoptosis' gene set, consistent with BCL-2 inhibition. Additionally, pathways such as 'inflammasomes' and 'NOD signaling' were enriched, with upregulation of CARD9, PYCARD, caspase-1, and caspase-4—key mediators of pyroptosis, an alternative cell death process. Notably, there was also increased expression of anti-apoptotic molecules like clusterin, NOL-3 and BCL-2, which counteract pro-apoptotic Bax, indicating activation of pathways promoting resistance to cell death following BCL-2 inhibition in the remaining cells. Consistently, genes associated with vtx resistance in cancer patients, such as BCL-XL, CLEC7A, and CD14, were upregulated in blood CD4 T cells. At d294 p.i., gene and pathway expression had normalized, except for the T-cell receptor beta chain variable region, which remained suppressed, suggesting vtx may reduce clonotype diversity during ART.

Conclusions

BCL-2 inhibition via vtx promotes rapid changes in gene expression within CD4+ T cells, associated with reduced size of the SIV reservoirs. While key cell death mediators were upregulated, anti-apoptotic mechanisms also emerged, suggesting resistance to BCL-2 inhibition. These findings provide a rationale for targeting BCL-2 in people with HIV and identifying additional anti-apoptotic molecules to target in a combination approach to eradicate the SIV reservoir.

Background

Non-human primate (NHP) and human clinical studies highlight the utility of broadly neutralizing antibodies (bNAbs) for immunoprophylaxis against HIV-1. Passively delivered bNAbs protect against viral strains susceptible to antibody-mediated neutralization. To protect against HIV-1 strains resistant to individual antibodies, endeavors to improve bNAb breadth are required. A key strategy to enhance the neutralization breadth of individual bNAbs is to generate designer bispecific bNAbs.

Methods

We implemented CrossMAb technology to generate a bispecific anti-HIV-1 Env bNAb with antigen-binding arms derived from the VRC07 and PGT121 bNAbs. We screened the antibody for viral neutralization in a pseudovirus neutralization assay and assessed for in vivo anti-viral activity in humanized NSG mice infected with HIV-1_JRCSF (n=8). We then implemented an NHP high-dose intravenous viral exposure model to assess antibody-mediated immunoprophylaxis. This model mimics exposure via a large unscreened blood transfusion but is also relevant to lower-dose intravenous exposures such as through sharing drug injection equipment. Experimental (n=8) and control (n=8) Indian-origin rhesus macaques were infused with VRC07/PGT121 (30 mg/kg) or an equivalent volume of saline, respectively, one hour before intravenous challenge with SHIV-BG505 (40 X 10⁶ viral RNA copies). Plasma bNAb concentration was monitored by ELISA. Starting at week eight post-challenge, anti-CD8 alpha antibody (45 mg/kg) was administered in animals lacking evidence of plasma viremia and with VRC07/PGT121 plasma concentrations <1 µg/ml for at least two weeks to reveal possible subclinical infections.

Results

The VRC07/PGT121 bispecific bNAb neutralized >90% of a panel of 64 global HIV-1 strains (geometric mean IC₅₀=0.64 µg/ml) and reduced viremia in HIV-1-infected humanized mice (average viral load decline ~1.0-1.5 log₁₀ for three weeks). The high-dose intravenous SHIV-BG505 challenge infected all eight control animals (peak log₁₀ viral load range: 6.3-7.3 copies/ml). We have yet to observe evidence of viral replication in animals pre-treated with VRC07/PGT121 before SHIV-BG505 exposure, including during the post-CD8 depletion period (animals are currently between one- and five-weeks post-depletion).

Conclusions

Bispecific anti-HIV-1 bNAbs are potentially valuable biomedical interventions for ongoing efforts to achieve HIV-1 immunoprophylaxis, as evidenced in this very stringent IV challenge model.

Background

Many HIV cure trials use time-to-rebound during an analytic treatment interruption (ATI) as a primary outcome measurement. In a previously described ATI study with no intervention, the fraction of replication-competent outgrowth viruses neutralized by contemporaneous autologous neutralizing antibodies (aNAbs) prior to ART interruption correlated with time to rebound. Therefore, aNAbs may also contribute to delayed rebound in trials that include a broadly neutralizing antibody (bNAb) intervention or other interventions. Participants in the NCT03588715 (BEAT2) clinical trial received six infusions of the bNAbs 3BNC117 and 10-1074, and thirty doses of IFNa2b. Following cessation of all immunotherapies, BEAT2 participants had variable times to rebound (4-25 weeks), and we hypothesized that aNAbs may be a critical contributing factor.

Methods

Inhibition of viral outgrowth by aNAbs was assessed at baseline using a modified quantitative viral outgrowth assay in which resting CD4+ T cells were activated by PHA and cultured in the presence of contemporaneous autologous IgG, HIV-negative donor IgG, or no IgG for 14 days. Viral outgrowth was measured by HIV-1 p24 ELISA and env genes sequenced.

Results

The fraction of replication-competent outgrowth viruses neutralized by contemporaneous aNAbs at baseline varied widely (0 to 100%) among participants and correlated significantly (p=0.0342) with time-to-rebound following cessation of all immunotherapies. HIV-1 env sequencing and phylogenetic analyses revealed critical differences between aNAb-sensitive and aNAb-resistant outgrowth virus. aNAb-resistant reservoir variants detected prior to the ATI may be genetically similar or identical to rebound virus.

Conclusions

The study participants had a variable fraction of inducible, replication-competent reservoir viruses neutralized by contemporaneous aNAbs prior to receiving immunotherapy (bNAbs and IFNa2b) and undergoing ART interruption. Higher proportions of replication-competent outgrowth viruses neutralized by aNAbs was associated with a more delayed time-to-rebound following cessation of all immunotherapies. ATI studies must consider the role of pre-existing aNAbs in potentially confounding time-to-rebound measurements.

Background

Broadly neutralizing antibodies (bnAbs) targeting the V2-apex of the HIV-1 envelope glycoprotein (Env) are among the most potent, with potential utility for prevention and therapy. However, V2 bnAbs have low activity against Envs lacking K/R169, as in 88% of subtype B and 26% of recent subtype C Envs (Mkhize et al, 2023). Furthermore, subtype B infections rarely trigger prototypic V2 bnAbs (Rusert et al, 2016), suggesting K/R169 may be a key regulator of V2 bnAb induction. Increasing the coverage of resistance mutations at K169 is crucial to leverage the potential of V2 bnAbs.

Methods

The bnAb SHCS-0170 was isolated from the XbnAb cohort, comprising 304 bnAb inducers from the Swiss HIV Cohort Study (SHCS) (Pasin et al, biorxiv 2024). Neutralization activities of V2 bnAbs (N=28) and XbnAb plasmas (N=304) were assessed against a multi-clade Env pseudovirus panel (N=41). Epitope mapping included binding antibody multiplex assays with 16 Env targets, Env mutant neutralization and Cryo-EM structure analysis.

Results

Isolated from a subtype B donor with multispecific bnAb activity, SHCS-0170 had 80% breadth at a geometric mean IC50 0.43 µg/mL. Intriguingly, given the rarity of V2 bnAbs in subtype B, SHCS-0170 neutralization correlated strongly with V2 bnAb PGT145 (Spearman’s rho=0.72). SHCS-0170 neutralized 86% of subtype B viruses, outperforming other V2 bnAbs. Epitope mapping showed N160-dependent neutralization and binding but, consistent with its high breadth, SHCS-0170 tolerated variation at Env positions 164, 166, 167, 169 and 171. A 2.9Å structure in complex with BG505.SOSIP trimer confirmed that SHCS-0170 did not interact with K169. The long beta-hairpin CDRH3 reached an extreme trimer penetration depth of 24.6Å inserting a sulfated tyrosine residue between protomers that interacts with Env residues K121 (97% conserved across subtypes) and Q315 (Q315R/K in 84% of subtype B). Thus, SHCS-0170 reached K169-independence by targeting positive charges at positions 121 and 315. Clustering of Spearman correlations between neutralization fingerprints of XbnAb plasmas and V2 bnAbs suggested that K169-independent classes may be more commonly elicited by subtype B Envs than other prototype V2 bnAbs (mixed effects model p<0.001).

Conclusions

SHCS-0170 represents a novel K169-independent V2 bnAb that may be prevalent in subtype B infection. The complementarity of its epitope, relative to other V2 bnAbs, provides opportunities for combination bnAb therapy and vaccines across subtypes.

Background

In a non-comparative pilot Phase 1b study (NCT04811040), the long-acting HIV-1 capsid inhibitor lenacapavir (LEN) in combination with broadly neutralizing antibodies (bNAbs) teropavimab (TAB, GS-5423) and zinlirvimab (ZAB, GS-2872) maintained virologic suppression (VS; HIV-1 RNA <50 copies/mL) for 6 months after dosing in 18/20 people with HIV-1 (PWH) highly susceptible to both bNAbs. In this Phase 2 study (NCT05729568), efficacy and safety of switching to LEN+TAB+ZAB (LTZ) every 6 months (Q6M) versus staying on stable baseline oral antiretroviral regimen (SBR) is being evaluated.

Methods

This open-label study enrolled virologically suppressed PWH (≥12 months on ART) with HIV-1 highly susceptible to both bNAbs (IC₉₀ ≤2 µg/ mL [Monogram PhenoSense mAb DNA assay] at screening). Participants were randomized 2:1 to switch to subcutaneous (SC) LEN 927 mg Q6M (+ oral 600 mg on Days 1+2), plus intravenous (IV) TAB 2550 mg Q6M and IV ZAB 2550 mg Q6M, or SBR. Primary endpoint was the proportion of participants with HIV-1 RNA ≥50 copies/mL at Week (W) 26 per FDA snapshot algorithm. Secondary endpoints included change from baseline in CD4 cell count at W26 and adverse events (AEs).

Results

Fifty-three participants received LTZ and 27 SBR. Median (range) age was 51 (20–65) years, 15% were female, 36% were Black, and mean (SD) CD4 count was 749/μL (245). At W26, 1 of 53 (2%) receiving LTZ and none in the SBR arm had HIV-1 RNA ≥50 copies/mL in the analysis window; 51 (96%) and 26 (96%) remained virologically suppressed, respectively (Table). One participant in each arm withdrew; both had HIV-1 RNA <50 copies/mL. CD4 count increased from baseline to W26; mean change (SD): +23/μL (143) with LTZ; +69/μL (203) with SBR. Treatment-emergent AEs (TEAEs) were observed in 45 (85%) and 17 (63%) of participants in the LTZ and SBR arms, respectively. The most common TEAEs in the LTZ arm were Grade 1 (mild) injection site reactions related to SC LEN. No infusion-related reactions to TAB or ZAB, study drug-related Grade ≥3 TEAEs, serious TEAEs, or TEAEs leading to study drug or study discontinuation occurred in the LTZ arm. One participant in the SBR arm discontinued the study due to a serious TEAE.

Conclusions

Efficacy of Q6M LTZ was similar to that of daily oral ART through W26. LTZ was well tolerated. These results demonstrate high efficacy of LTZ through W26 and support further investigation of LTZ as the first Q6M combination treatment for PWH.

Table 1.

Background

New long-acting antiretroviral therapy (ART) regimens are needed to expand treatment choices for people living with HIV-1. VH4524184 (VH-184) is a third-generation integrase strand transfer inhibitor (INSTI) with an enhanced in vitro resistance profile compared with second-generation INSTIs being developed as a long-acting antiretroviral agent for the treatment of HIV-1. Here, we present data for VH-184 from a proof-of-concept, phase 2a trial in people living with HIV-1.

Methods

This randomized, double-blind, placebo-controlled trial evaluated oral VH-184 monotherapy in adults naive to ART with HIV-1 RNA ≥3000 c/mL. In the 10-day monotherapy period, participants received oral VH-184 10, 50, or 300 mg or placebo on Days 1 (baseline), 4, and 7. After monotherapy, participants initiated standard-of-care ART. The primary endpoint was maximum change from baseline in plasma HIV-1 RNA through Day 10. Secondary endpoints included safety, tolerability, exposure-response relationships, immunologic effects, and treatment-emergent resistance.

Results

Of 22 participants enrolled (VH-184, n=19; placebo, n=3), 86% were assigned male at birth, 68% identified as White, and 59% identified as Hispanic or Latin American; mean age was 34.1 years. Plasma HIV-1 RNA levels declined from baseline through Day 10 with all VH-184 doses (Figure). Mean maximum change from baseline in plasma HIV-1 RNA was −1.17, −2.15, and −2.31 log10 c/mL for VH-184 at 10, 50, and 300 mg, respectively. An exposure-response relationship was observed for plasma HIV-1 RNA decrease. During monotherapy, the only adverse event (AE) reported in >1 participant was vomiting (VH-184, n=2 [11%]). Each drug-related AE was reported in 1 participant. All AEs were grade 1 or 2 in severity. No AEs leading to withdrawal, serious AEs, or deaths were reported during monotherapy or follow-up. There were no clinically relevant changes in clinical laboratory parameters, electrocardiograms, or vital signs. No VH-184 genotypic or phenotypic resistance was detected at Day 10, the end of monotherapy.

Conclusions

VH-184 monotherapy demonstrated rapid and highly potent antiviral activity, with HIV-1 RNA declines of >2 log₁₀ c/mL at the highest doses, and was well tolerated, with a favorable safety and tolerability profile. An exposure-response relationship was established comparable to the maximum effect with other INSTIs. These results support further development of VH-184 as the core agent in a complete long-acting regimen for the treatment of HIV-1.

Figure 1.

Background

New long-acting antiretroviral therapy (ART) regimens are needed to expand treatment choices for people living with HIV-1. VH4011499 (VH-499) is a new HIV-1 capsid inhibitor in development as a long-acting antiretroviral agent for the treatment and prevention of HIV-1. Here, we present antiviral effect, pharmacokinetics, safety, and tolerability data for VH-499 from a proof-of-concept, phase 2a trial in people living with HIV-1.

Methods

This randomized, double-blind, placebo-controlled trial evaluated oral VH-499 monotherapy in adults naive to ART with HIV-1 RNA ≥3000 c/mL. In the 10-day monotherapy period, participants received oral VH-499 25, 100, or 250 mg or placebo on Day 1 (baseline) and Day 6. After the monotherapy period, participants initiated locally sourced, standard-of-care ART. The primary endpoint was maximum change from baseline in plasma HIV-1 RNA through Day 11. Secondary endpoints included pharmacokinetics, exposure-response relationships, safety, and tolerability.

Results

A total of 23 participants were enrolled (VH-499, n=20; placebo, n=3), 83% were assigned male at birth, 65% identified as White, and 65% identified as Hispanic or Latin American; median (range) age was 31 (18-62) years. Plasma HIV-1 RNA levels for all VH-499 dose groups declined from baseline through Day 11 (Figure). The 250 mg dose group had a greater mean (SD) maximum change in HIV-1 RNA (−2.2 [0.43] log₁₀ c/mL) than the 25 mg (−1.8 [0.51] log₁₀ c/mL) and 100 mg dose groups (−1.8 [0.45] log₁₀ c/mL). Increasing VH-499 exposures were associated with higher viral load declines. All adverse events (AEs) were grade 1 or 2 in severity, with no trends observed in types of AEs. Each drug-related AE was only reported once. No AEs leading to withdrawal, serious AEs, or deaths were reported. There were no clinically relevant changes in clinical laboratory parameters, electrocardiograms, or vital signs.

Conclusions

VH-499 monotherapy was well tolerated, had a favorable safety profile, and demonstrated highly potent antiviral activity in people living with HIV-1, with up to a mean maximum 2.2 log₁₀ c/mL reduction in HIV-1 RNA over 10 days. A VH-499 exposure-response relationship was established. These results support further development of VH-499 as part of a complete long-acting regimen for the treatment of HIV-1.

Figure 1.

Background

Long-acting injectables may address barriers to HIV pre-exposure prophylaxis (PrEP), such as stigma and pill burden. In a Phase 3 trial in cisgender women, twice-yearly (Q6M) subcutaneous (SC) lenacapavir (LEN) (927 mg, in two 1.5 mL injections) was safe and 100% efficacious as PrEP, with high adherence among participants. We assessed the pharmacokinetics (PK) and safety of two once-yearly (Q12M) LEN formulations.

Methods

This ongoing, open-label study in healthy participants (n=20/cohort) evaluated the PK, safety, and tolerability of two intramuscular (IM) single-dose 500 mg/mL LEN free acid formulations: formulations 1 and 2. Intensive PK sampling occurred from Days 1–15, and single anytime PK samples were collected at prespecified times through Day 449. LEN plasma concentrations were quantified using a validated liquid chromatography–tandem mass spectrometry method. LEN PK parameters (maximum observed concentration [C_max], trough concentration [C_trough]) were estimated using non-compartmental analysis. Safety and tolerability, including participant-reported pain scores, were assessed throughout.

Results

Peak concentrations of LEN formulation 1 were achieved ~12 weeks (W) post dose with mean (coefficient of variation [CV]) C_max of 290 ng/mL (61.4%) (Fig). After 12 months (M) (52W, n=13), mean (CV) C_trough was 62.2 ng/mL (42.8%), and its lower bound 90% CI was 49.1 ng/mL, which were above the target concentration (mean C_trough following Q6M SC LEN: 21.1 ng/mL [Jogiraju et al, AIDS 2022]). Preliminary PK data for LEN formulation 2 (40W) showed similar LEN concentrations; mean C_trough and the lower bound 90% CI are expected to remain above target concentration after 12M. Adverse events (AEs), including injection-site reactions (ISRs), were similar between the two cohorts; most were mild or moderate in severity. The most common ISR was pain (75%); pain scores were similar between cohorts. Most reported mild pain, which resolved within 1 week of injection. Pretreatment for approximately 3-5 minutes with an ice pack substantially reduced pain.

Conclusions

Following administration of IM LEN formulation 1, mean C_trough after 12M was above mean SC LEN Q6M C_trough, confirming the potential of Q12M dosing. Comparison with LEN Q6M Phase 3 PrEP will be conducted as PK data become available. Both formulations of Q12M LEN were safe and well tolerated. These data support future development of IM Q12M LEN for HIV PrEP, which has the potential to significantly improve PrEP uptake and persistence.

Figure 1.

Background

People living with HIV (PLWH) receiving HIV integrase (IN) strand transfer inhibitors (INSTIs) have been reported to experience virological failure (VF) in the absence of resistance mutations in IN. To elucidate INSTI resistance mechanisms and pathways, we performed long-term (~ one year) passaging of several viral isolates with an escalating concentration of the INSTI dolutegravir (DTG). Independent of viral strain and cell type, HIV-1 became resistant to DTG by sequentially acquiring mutations in Env, nucleocapsid (NC), and, in some cases, IN. This study aims to elucidate the role of NC in HIV-1 resistance to INSTIs.

Methods

We evaluated the impacts of the selected NC mutations on DTG sensitivity and viral infectivity. qPCR and time-of-addition (TOA) assays were conducted to examine the impacts of mutations on post-entry events in the virus replication cycle.

Results

The NC mutations selected in the presence of DTG confer modest (3-5-fold) resistance to INSTIs, a level of resistance comparable to that observed with clinically relevant IN mutations. These NC mutations do not appreciably affect viral RNA packaging, viral assembly, virus release, or infectivity. qPCR and TOA analyses with RT inhibitors and INSTIs revealed that the NC mutations accelerate the kinetics of integration. Notably, the shortened time frame between reverse transcription and integration correlates with reduced sensitivity to DTG, suggesting that NC mutations limit the window of opportunity for INSTIs to bind intasomes and block integration. Examination of the sequence at 2-LTR junctions showed no significant difference, suggesting that NC mutants preserve viral DNA ends, which are important for integration and INSTI binding. During DTG selection in primary PBMCs, we identified NC-N27I and IN-S153Y, which conferred 2.5-fold and 3.4-fold resistance to DTG, respectively. We observed that mutations in NC and IN acted in concert to confer 8.5-fold resistance to DTG, suggesting that NC mutations engage in epistatic interactions with IN resistance mutations. Significantly, we identified some of the in vitro-selected NC mutations in PLWH who experienced VF with DTG-containing regimens.

Conclusions

These findings demonstrate that mutations in multiple regions in the HIV-1 genome – Env, NC, and IN – collectively contribute to INSTI resistance. These results further our understanding of INSTI resistance and support the need for genotypic analysis outside of IN in individuals failing INSTI-containing regimens.

Background

Tenofovir-lamuvidine-dolutegravir (TLD) is highly effective as ART but the causes of virologic failure (VF) in individuals on TLD without integrase (IN) resistance mutations are not well understood. Off-target mutations in nucleocapsid (NC) have been selected in vitro and are associated with decreased DTG susceptibility in vitro. Samples from ACTG study A5381 were examined to assess the potential contribution of NC mutations to VF in individuals on TLD.

Methods

A5381 was an observational cohort study enrolling individuals aged >10y with viral load >1000 c/ml at start of TLD as 1st, 2nd or 3rd-line ART. Paired study entry and VF samples from 57 participants with confirmed VF on ≥6 months of TLD were sequenced by whole genome Illumina MiSeq. Mutations were identified with HyDRA Web (IN) and a pipeline using reference alignment to HXB2 RefSeq (NC_001802.1) with BWA v0.7.17, LoFreq 2.1.5 and SNPeff 5.0 for putative variant calling (NC) with a mutation threshold of 20% frequency. Site directed NC and integrase (IN) mutants were phenotyped for DTG sensitivity with TZM-bl assays.

Results

Mutations in NC at a frequency of ≥20% of the virus population at VF but not before TLD start were detected in 10 of 57 (17%) participants (Table). Of these 10, two participants had both NC and IN mutations at VF but not at study entry, suggesting dual selection. Participant 1 selected A30T (57% frequency) and M46I (69% frequency) in NC and the accessory mutation H51Y (9% frequency) in IN. Participant 2 selected N27I (77% frequency) in NC and the major mutation R263K (100% frequency) and polymorphism M50I (100% frequency) in IN. Laboratory-generated infectious mutant clones of NC-N27I and IN-M50I/R263K show 1.8- and 2.4-fold resistance to DTG, respectively. When they are combined, the triple mutant showed 5.8-fold resistance. IN-M50I/R263K mutants show lower infectivity than wild-type (WT), but NC-N27I did not further affect viral infectivity in the context of IN-WT and or IN-M50I/R263K.

Conclusions

This work provides the first clinical evidence of selection of NC mutations with TLD failure and of decreased DTG susceptibility from the combination of NC and IN mutations. Our findings support further investigation of the potential contributions of mutations outside of IN to VF of TLD.

Table 1.

Background

Despite availability of long-acting products for HIV pre-exposure prophylaxis (PrEP), some women may prefer on-demand oral PrEP. Using an existing PK/PD model (Cottrell JID 2016), we previously predicted protective drug exposure would be sustained in the female genital tract (FGT) for 5 days after sex for >80% of the population using the 2-1-1 IPERGAY regimen (#2 tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) tablets pre-sex then #1 tablet 24 and 48 hours after), and >90% of the population regularly taking 4 tablets/week on Tuesday, Thursday, Saturday, and Sunday. Here, we sought to identify the optimal on-demand TDF/FTC regimen to achieve protective drug exposure in the FGT over 5-10 days post-sex.

Methods

TDF/FTC tissue PK/PD predictions were generated via the aforementioned published in vivo/in vitro model with the EC₉₀ derived from an in vitro synergy model of TDF/FTC’s active metabolites vs competing endogenous nucleotides. The proportions of 1000 predicted profiles achieving EC₉₀ in the FGT at 5, 7, and 10 days post-sex were calculated for all simulated dosing scenarios. These were extensions of the 2-1-1 regimen and included: 2-2-1, 2-2-2, 2-1-1-1, 2-2-1-1, 2-2-2-1, and 2-2-2-2. PK modeling/simulation was performed in NONMEM v7.2, and R was used for synergy modeling and data management/ visualization.

Results

Table 1 shows proportion achieving EC₉₀ in the FGT over time following sex. All regimens demonstrate >80% achievement of EC₉₀ at 5 days. A 2nd double-dose increases the proportion achieving EC₉₀ at 7 days by 20-30% compared to the IPERGAY regimen. Extending to 4 days of dosing increases the proportion achieving EC₉₀ >80% at 7 days post-sex. No regimen sustained this high proportion achieving EC₉₀ for 10 days post sex.

Conclusions

Our model suggests prevention of HIV acquisition via the FGT using on-demand TDF/FTC dosing with an initial double-dose is likely, with high (>80%) protection for 5 days after sex. Adding a 4th day of dosing is required to achieve >80% protection for 7 days, with 2-2-2-2 at 95% and 2-1-1-1 at 84% protection. While limited data suggest 2-2-2-2 dosing is safe for short-term use, the 2-1-1-1 regimen may better balance safety, efficacy, and tolerability while maintaining effectiveness comparable to 4 daily doses/week reported by recent analyses of PrEP clinical trial data. The 2-2-2, 2-1-1-1, and 2-2-1-1 regimens could be considered in future clinical studies of on-demand PrEP in cisgender women.

Table 1.

Background

The rapid emergence of immune-evasive SARS-CoV-2 variants poses a significant challenge, as current therapies and vaccines struggle to keep pace. SNS812, an aerosolized broad-spectrum antiviral siRNA, targets a conserved region of the RNA-dependent RNA polymerase gene, unchanged since the 2003 SARS outbreak, offering potential efficacy against diverse variants. In a 2023 Phase I trial (NCT05677893) in the U.S., SNS812 showed excellent safety. Here we present the Phase II trial results which shows SNS812 is safe and effective in treating COVID-19.

Methods

This double-blind, randomized, placebo-controlled Phase II trial (NCT05941793) involved 135 symptomatic, PCR-confirmed COVID-19 patients, all vaccinated at least three months prior. Participants were randomly assigned to receive either 100mg SNS812, 200mg SNS812, or placebo. The primary endpoint was the incidence of treatment-emergent adverse events; efficacy endpoints included viral variant analysis, time to viral clearance, viral load reduction, and symptoms improvement.

Results

Baseline characteristics showed no significant differences between the groups. No drug-related adverse events were observed in the SNS812 treatment groups. All 135 participants had their viral sequence confirmed and identified which revealed that 90% of patients were infected with highly immune-evasive variants, with the majority being JN.1 (49.6%), LB.1 (17.1%), and KP.2 (11.1%). Viral load analysis showed that in the SNS812 treatment groups, viral load significantly decreased by 0.4 log within one day of SNS812 200mg administration (P=0.029). Additionally, the median time to viral clearance was reduced from 3.6 days (control group) to 2.9 days (200mg group)(P=0.007). For clinically meaningful symptoms, 12 out of 14 COVID-19 symptoms showed improvements, with key symptoms such as shortness of breath (P=0.007), loss of smell (P=0.028), and loss of taste (P=0.006) achieving statistical significance. Furthermore, a dose-dependent relationship was noted, with more significant improvement in 200mg group compared to the 100mg.

Conclusions

The Phase II study demonstrates that SNS812 is a safe and effective treatment for COVID-19, especially in the context of immune-evasive variants. Its ability to significantly reduce viral load within one day, accelerate viral clearance, and improve symptoms positions SNS812 as a promising pan-coronavirus therapeutic solution, capable of addressing ongoing viral mutations.

Table 1.

Background

ACTG A5418/STOMP is a phase 3 randomized placebo-controlled double-blind trial evaluating the efficacy of tecovirimat in people with mpox. It includes an open-label arm for people <18 years, pregnant or breastfeeding, with severe immune suppression, or protocol-defined severe disease. We analyzed host and disease factors associated with clinical mpox resolution and mpox DNA clearance from skin lesions in individuals receiving open-label tecovirimat for 14 days.

Methods

Time to clinical resolution was the time from treatment initiation until all skin lesions were scabbed, desquamated, or healed and all visible mucosal lesions were healed through 28 days. An index skin lesion chosen at enrollment was swabbed weekly; mpox DNA levels were measured by PCR. Associations between baseline characteristics and time to clinical resolution were explored using Kaplan-Meier plots and Cox proportional hazards models.

Results

Of 233 enrolled in the open-label arm, 107 had lab-confirmed clade II mpox (skin, oral or rectal swabs) who enrolled early enough to have completed 28-day follow-up and had baseline skin lesion mpox DNA available were included. Ninety-six (90%) were cisgender male, 3 (3%) were transgender female, median age was 34 years, 45 (42%) are living with HIV, including 11 with CD4 <200 cells/mm³ or HIV-1 RNA >1000 copies/ml, and 12 (11%) had previously received ≥1 dose of the smallpox/mpox vaccine. At enrollment, median skin lesion count was 26 (IQR: 13, 49), 78 (73%) had >5 days of symptoms at time of enrollment, and 11 (10%) had undetectable skin lesion mpox DNA. By Days 8 and 15, 47% (of 76) and 82% (of 77) had undetectable skin lesion mpox DNA. The cumulative probability of clinical resolution by 28 days was 86% (95% CI: 79, 92); median days to clinical resolution was 14 (Q1, Q3: 8, 22). While there were trends between faster clinical resolution, lower levels of mpox DNA, and younger age, no associations were found in multivariable modeling (Table 1). Similarly, there were no factors significantly associated with clearance of mpox DNA at day 8. Clearance of mpox DNA at Day 8 was not associated with faster clinical resolution.

Conclusions

This interim exploratory analysis of participants receiving open-label tecovirimat did not identify predictors of clinical mpox resolution. Compared to PALM007 participants with Clade 1 mpox, we found lower lesion counts and slower clinical resolution. Further investigation is needed.

Figure 1.

Background

As syphilis rates rise, emergency department (ED) screening has been proposed as an important opportunity for early diagnosis and treatment of syphilis, especially for communities with limited access to care, for whom the ED visit may represent their primary contact with the healthcare system. Given potential increased costs and resources needed for universal screening, models targeted to certain high priority groups have been proposed. However, it is unknown if these targeted screening models successfully detect the majority of syphilis cases.

Methods

In May 2019, a routine, opt-out, syphilis screening program for all ED patients under age 65 was implemented at a large, urban, tertiary care hospital in Chicago. This study retrospectively reviewed all ED encounters that included syphilis screening for the two-year period after implementation of the screening program. Syphilis cases were defined by a combination of positive serology, rapid plasma regain (RPR) titers, and clinical history derived from chart review. Descriptive statistics were used to evaluate the hypothetical sensitivity of screening models targeted to 1) only persons tested for gonorrhea or chlamydia, 2) women of reproductive age, 3) anyone receiving a blood draw, or 4) anyone receiving a complete blood count (CBC), compared to the cases detected with universal screening.

Results

A total of 37,289 individuals were screened for syphilis during the two-year study period, of whom 624 (1.7%) were considered active syphilis cases. Had syphilis screening been performed only in patients receiving testing for gonorrhea or chlamydia, only 147 cases would have been identified (23.6% sensitivity). Screening only women of reproductive age would have identified 142 cases (22.8% sensitivity). Notably, screening only patients undergoing an unrelated blood draw would have identified 516 cases (82.7% sensitivity), and screening only those receiving a CBC would have identified 472 cases (75.6% sensitivity).

Conclusions

This study found that targeted models of syphilis screening would miss a large proportion of syphilis cases. While implementation of universal ED screening may require additional resources and infrastructure, it may be the most effective strategy to address the syphilis epidemic in high prevalence communities facing major health care disparities.

Background

Congenital syphilis (CS) is an urgent threat; cases are at their highest rate (102.5/100,000 live births) since 1991. The only treatment (tx) for late latent syphilis (LLS) in pregnancy is 3 doses of benzathine penicillin G (BPGx3), given at 7-day (d) intervals. If intervals exceed 9d, US guidelines recommend restarting the full tx series, implying intervals up to 9d are acceptable. We previously demonstrated CS is not more likely with prenatal BPGx3 at 6-8d vs strict 7d intervals (OR 1.0, 95%CI 0.4-3.0), but there are no studies of 9d.

Methods

Using California surveillance data, we leveraged an existing cohort of all mother/infant dyads wherein the parent had LLS in pregnancy from 1/1/16-6/30/19. Since only 5 dyads in this cohort received BPGx3 with a 9d interval, we enriched the study population with additional dyads who received BPGx3 with at least one 9d interval (and no intervals outside 6-9d), from a later period (7/1/19-12/31/23). We divided all dyads into 3 groups: adequate tx (Atx: BPGx3 at strict 7 or 6-8d intervals, started 30+d before delivery); BPGx3 at 6-9d (at least one 9d interval, no intervals outside 6-9d, started 30+d before delivery), and no/inadequate tx (NAtx). We compared clinical/demographic characteristics and infant CS incidence proportions via chi-squared/Wilcoxon rank sum, then estimated odds of CS by group via logistic regression.

Results

We analyzed 1109 dyads: 677 Atx, 22 BPGx3 at 6-9d, and 410 NAtx. Comparing Atx vs 6-9d dyads, there were no differences (p>0.05) in maternal HIV (0.5 vs 0% positive), maternal RPRs 1:32+ (45.1 vs 40.9%), prenatal care (97.3 vs 95.5% received care), or gestational age at syphilis tx (median 16 vs 21 weeks). CS incidence proportions were 5.6% (38/677) for Atx, 18.2% (4/22) for 6-9d, and 36.8% (151/410) for NAtx (p=0.01 for 6-9d vs Atx). With Atx as reference, odds of CS were 3.7 (95%CI 1.2-11.6) for 6-9d and 9.8 (95%CI 6.7-14.4) for NAtx (Table 1).

Conclusions

Compared to Atx, odds of CS approached 4-fold higher among dyads who received BPGx3 with 9d interval(s). These findings question current guidelines, suggesting CS may be more likely when BPG intervals are extended to 9d. Limitations include small numbers (preventing controlling for confounders) and the fact that most 6-9d dyads were from a later period than the comparator dyads. Still, given lack of data otherwise and while awaiting larger studies with higher statistical power, clinicians should consider erring on the side of caution, avoiding intervals outside 6-8d.

Table 1.

Background

Doxycycline post-exposure prophylaxis (DoxyPEP) use can significantly reduce the incidence of bacterial sexually transmitted infections (STIs), yet uptake has been low among people with HIV (PWH). In Washington, DC, high rates of STIs have been observed among PWH. We assessed STI diagnosis rates, DoxyPEP eligibility, use, and the potential impact of DoxyPEP prescribing on STI incidence among a large cohort of PWH in Washington, DC.

Methods

DC Cohort longitudinal HIV cohort participants were considered DoxyPEP eligible per the CDC guidelines if they were men who have sex with men (MSM) or transwomen (TW) diagnosed with gonorrhea, chlamydia, and/or syphilis in a calendar year during the observation period (1/1/2019-12/31/2023). We assessed the number of DoxyPEP eligible PWH and DoxyPEP prescriptions. We conducted descriptive statistics on demographics, sexual behaviors, and HIV viral loads (VL). We calculated STI diagnosis rates and estimated the potential impact of DoxyPEP prescribing by assessing the proportion of diagnoses potentially averted based on efficacy trial results. Using the number needed to treat (NNT) with DoxyPEP for one year to avert one STI diagnosis, we estimated the efficiency of three prescribing strategies for PWH with 1) any STI, 2) a concurrent STI, or 3) ≥2 STIs in the past 12 months.

Results

From 2019 to 2023, among 1,403 participants with ≥1 STI diagnosis, only 13 (0.93%) were prescribed DoxyPEP (85% male, median age 43, 85% MSM HIV risk factor, 92% had a rectal STI, and 46% had ≥2 STIs within a 12-month period). In any given year 50%-56% of STI cases were DoxyPEP eligible. Overall, there were 3,581 STI diagnoses, of which 2,890 were among MSM/TW (63.4 STI diagnoses/100 person-years). Among the 1,077 MSM or TW who had ≥1 bacterial STI diagnosis, 10% had a VL >200 copies/mL, 68% reported >1 sexual partner in the prior 3 months. Strategies with the lowest NNT were prescribing DoxyPEP for 12 months to PWH with a concurrent STI diagnosis (NNT=2.99 for any STI); with ≥2 STIs (NNT=3.22 for any STI); and to PWH with any STI (NNT=3.89 for concurrent STI diagnoses)(Figure).

Conclusions

Among a large clinical cohort of PWH, despite high STI rates, early uptake of DoxyPEP was minimal, yet a majority of PWH were DoxyPEP eligible.

While the NNT varied based on the strategy, widespread DoxyPEP uptake could result in significant decreases in STI incidence among PWH. As DoxyPEP use rolls out, greater awareness of its use and prescribing efforts should be emphasized among PWH.

Figure 1.

Background

Doxycycline for post-exposure prophylaxis (DPEP) is highly effective for preventing bacterial sexually transmitted infections (STIs) in clinical trials; however recent real-world data suggests lack of effectiveness for gonorrhea. We examined the impact of DPEP on STIs (syphilis, chlamydia, and gonorrhea) in clients at a large sexual health clinic in San Francisco, CA, US.

Methods

Starting in 11/30/2022 DPEP was offered to all clients receiving sexual health services. For clients who were prescribed DPEP (Users) for >90 days, we evaluated up to 5 quarters before and after the initial DPEP prescription through 09/24/2024. For clients who were never prescribed DPEP (Non-DPEP users), we evaluated up to 5 quarters before and after 4/2023 – the midpoint (median) quarter for the DPEP initiations across the evaluation period. We fit an interrupted time series (ITS) analysis in which STI rates, overall and by individual STI, were predicted by a three-way interaction between DPEP use, time (in quarters), and DPEP initiation (pre-post DPEP prescription for the DPEP Users, and pre-post median time for the non-DPEP users).

Results

Overall, 4,149 clients (2,419 DPEP users and 1,730 non-DPEP users) were included in the analyses with an average of 3.13 (SD=1.70) quarters of follow-up. The median age range was 30-39 years and most (89%) were cisgender men. Race/ethnicity included 33% White, 24% Hispanic/Latinx, 17% Asian, 13% multiracial, and 4% Black. Almost all (98.7%) were also prescribed HIV pre-exposure prophylaxis. Before initiating DPEP, the DPEP users had significantly higher risk of an STI than non-DPEP users [Odds Ratio (OR)=5.33, 95% Confidence Interval (CI) 4.11-6.90, p<.001); however, after initiation STI rates were similar (OR=1.21, 95%CI 0.86-1.68, p=.280). In a pre-post analysis among DPEP users, STI incidence declined significantly overall (OR=0.28, 95%CI 0.24-0.35, p<.001) and for each STI: chlamydia (OR=0.05; 95%CI 0.11-0.20, p<.001), gonorrhea (OR=0.45; 95%CI 0.39-0.53, p<.001), and syphilis (OR=0.16; 95%CI 0.12-0.21, p<.001). The ITS revealed a significant three-way interaction between DPEP use, time, and DPEP initiation, p<.001.

Conclusions

DPEP uptake continues to increase and bacterial STI incidence among DPEP users declined significantly overall and for each STI including gonorrhea demonstrating sustained high impact of this intervention in a real-world setting. Continued evaluation of DPEP uptake, use, and adherence will be essential as implementation expands.

Figure 1.

Background

In 2024, San Francisco Department of Public Health released updated recommendations for prescribing doxycycline post-exposure prophylaxis (doxy-PEP). These matched CDC guidance and additionally encouraged shared decision-making between providers and patients with at least 2 sex partners in the last year who were assigned male sex at birth. San Francisco AIDS Foundation’s Magnet Clinic, a large, community-based clinic in San Francisco’s Castro neighborhood, provides doxy-PEP in line with these recommendations. We used Magnet Clinic patient data to define and produce population estimates for a doxy-PEP continuum among patients with indication for doxy-PEP overall and stratified by select demographics. At each stage of the continuum, we assessed whether characteristics were associated with drop-off.

Methods

Among patients seen from December 2022-December 2024, we restricted to those with (1) a doxy-PEP indication. We then estimated the proportion who (2) received a doxy-PEP prescription; (3) initiated (i.e. self-reported ever taking) doxy-PEP; and (4) adhered to doxy-PEP (i.e. self-reported consistent use within 72 hours after sexual exposures since their last clinic visit). We stratified these analyses by several sociodemographic and health characteristics. We conducted one-tailed tests of equal proportions in each stratified analysis, where the referent was the group most likely to reach a given stage in the continuum conditional on reaching the prior stage.

Results

In the study period, 7,436 patients with indication for doxy-PEP were seen at the Magnet Clinic. Among them, 4,369 (60%) were prescribed doxy-PEP. Among those prescribed, 2,651 (61%) reported using it at least once. Among those who used doxy-PEP, 1,627 (61%) reported high adherence at their most recent clinic visit (Figure). Among patients with indications, transgender women were more likely to be prescribed doxy-PEP compared with other gender identities. At each stage of the continuum, patients living with HIV had higher drop-off rates compared to HIV-negative patients.

Conclusions

Although doxy-PEP is a safe, low-cost biomedical intervention for bacterial sexually transmitted infections, only 36% of Magnet Clinic patients with indication ever used it, and less than 25% were adherent. To maximize the impact of doxy-PEP, clinicians should encourage increased uptake and adherence among those with indication.

Figure 1.

Background

HIV infection significantly increases carcinogenesis following HPV infection. The impact of this relationship on the cervical cancer burden is well documented. Less is known on HPV non-cervical cancers including anal, oropharyngeal, vaginal, vulvar and penile cancers. The World Health Organisation (WHO) aims to vaccinate 90% of girls under 15 against HPV, yet global vaccine coverage is low at 21% for girls and 7% for boys. Coverage is especially low in countries with a high HIV prevalence. We aimed to evaluate the burden of HPV non-cervical cancers in people living with HIV (PLWHIV) and model the potential impact of improved gender-neutral HPV vaccine coverage worldwide.

Methods

We collected epidemiological data on cancer incidence in 185 countries from the GLOBOCAN 2022 database. HIV prevalence was collected from UNAIDS 2022, which analyses country-specific rates using the SPECTRUM model. The number of cancer cases was combined with relative risks of developing each cancer and HIV prevalence data to generate a population attributable fraction, which estimates the number of cancers ‘attributable’ to HIV. Lastly, we modelled the impact of improved vaccine coverage using point vaccine efficacy estimates and country-specific HPV vaccine coverage levels from the WHO.

Results

Globally, this burden exhibited significant geographical variation; 29% of all HPV-related non-cervical cancer cases in Africa may be HIV-attributable, compared to 5% worldwide. For anal cancer, an estimated 35,719 cases occurred worldwide in 2022 and 12.4% of these may have been attributable to HIV. This attributable fraction ranged from 1.5% in Southeast Asia, to 10.6% in the Americas, to more than 41.8% in Africa. We show that out of the ten countries with the highest number of HIV-attributable cancers, only two had vaccine coverage rates over 50%. Globally, our model shows that if gender-neutral vaccine coverage increases to the WHO’s 90% target, we could prevent 6854 cancer cases in PLWHIV; reflecting more than double the number currently prevented.

Conclusions

This analysis adds to the consensus that PLWHIV warrant special consideration in HPV prevention. More research is needed on vaccine efficacy in PLWHIV to inform future analyses. HPV vaccination is particularly important in Southern Africa where a large concurrent burden of HIV-attributable cancers exists. Ultimately, in countries with high HIV/HPV coinfection rates, integrating these services could minimise disparities in the global HPV cancer burden.

Figure 1.

Background

Non-adherence to oral TDF/FTC PrEP reduces efficacy for HIV prevention, including in pregnant and postpartum women (PPW). Urine tenofovir (TFV) testing detects dosing in past 72 hours in people taking oral PrEP, but there are few insights into whether providing PPW with feedback on urine TFV test results can support PrEP adherence. We examined this as the primary outcome of Step 1 of the Stepped Care to Optimize PrEP Effectiveness in PPW trial (NCT05322629).

Methods

We enrolled pregnant women attending primary care antenatal services in Cape Town without HIV who were >15 years old, >20 weeks’ gestation, and initiating or taking PrEP in pregnancy. We block randomized women 1:1 to the intervention (Int; biofeedback counseling based on urine TFV test result) vs. standard of care control (SOC; PrEP counseling without biofeedback; urine collected and TFV testing performed without the participant). PrEP was delivered to all women through standard public health services. The primary outcome was the impact of the urine TFV biofeedback intervention on objective PrEP adherence measured at 6m (based on urine TFV test results in both arms). Primary analyses were via intention to treat and assumed that women who did not attend the 6m study follow-up visit were non-adherent to PrEP. Results are presented at risk ratios (RR) with 95% Confidence Intervals (CI).

Results

Among 750 HIV- women on or initiating PrEP in pregnancy randomised (375 Int; 375 SOC), median age was 26 years (IQR:22-32); median gestational age was 29 weeks (IQR:23-35); 38% were married or cohabiting. Overall, 54% of women attended the 6m primary outcome visit (Int=58%; SOC=51%) of whom 66% self-reported PrEP in the past week (Int=68%, SOC=64%). For the primary outcome, 32% of Int participants had urine TFV+ (n=120 of 372) vs. 25% in SOC (n=91 of 365) (RR=1.29; 95% CI=1.03-1.63; Table). Findings persisted after adjustment for socio-demographic and HIV risk factors and were consistent across subgroups of PPW age, timing of enrollment and follow-up, and HIV risk markers.

Conclusions

In this setting a large proportion of women initiating PrEP in pregnancy do not persist through 6m; however, biofeedback using urine TFV testing was associated with small but significant increases in PrEP adherence. These findings point to the urgent need for long-acting PrEP modalities for PPW, and among women who use oral TDF/FTC, the potential impact of biofeedback interventions to enhance adherence.

Table 1.

Background

Previous studies on brain volumes in people with HIV (PWH) who initiated antiretroviral therapy (ART) during acute HIV infection (AHI) were limited by the absence of a control group or brief follow-up periods. A recent cross-sectional analysis revealed larger volumes in regions vulnerable to HIV during AHI. Here, we compared longitudinal brain volume changes over 96 weeks between RV254 AHI cohort participants and people without HIV (PWoH).

Methods

The study included 119 RV254 AHI cohort participants and 45 demographically matched PWoH from Thailand, all of whom underwent two 3T brain MRI approximately 96 weeks apart. RV254 participants underwent the 1st MRI and completed the Patient Health Questionnaire (PHQ-9) for depressive symptoms, and a 4-test cognitive battery during AHI and prior to ART initiation at week 0. AHI participants achieved HIV suppression by week 24, and underwent the 2nd MRI at approximately 96 weeks post-ART. Brain volumes were quantified using voxel-based morphometry and summed across hemispheres. Repeated measures compared volumes within and between the groups. Correlations examined associations between brain volumes with cognitive performance (NPZ-4) and the PHQ-9 score at week 0 for the PWH group, with adjustments for multiple comparisons.

Results

Both groups were similar in age, education, and comorbidities. All RV254 participants were male, with a median age of 28, median CD4+ T-cell count of 412 (IQR 277-664) cells/mm³, and median plasma HIV RNA of 6.66 (IQR 5.73-6.90) log₁₀ cps/ml at week 0. Both groups exhibited smaller brain volumes in most regions at week 96 compared to week 0 with no evidence of accelerated volume loss among PWH. At week 0, larger volumes were observed among PWH compared to PWoH in the hippocampus and thalamus with no differences between groups at week 96, consistent with normalization after ART. Amygdala and nucleus accumbens volumes were lower among PWH at week 0 without progressive volume loss. Among the AHI participants, larger hippocampal and caudate volumes at week 0 correlated with worse depressive symptoms and lower NPZ-4 score (p<.05).

Conclusions

We observed no evidence of more rapid brain atrophy in these young, healthy AHI individuals who initiated ART during acute infection compared to healthy PWoH. Larger brain volumes in select regions at week 0 (pre-ART) correlated with worse neurobehavioral indices, with normalization in brain volumes following sustained viral control.

The figure, table, or graphic for this abstract has been removed.

Background

The HIV reservoir in the central nervous system (CNS) poses a significant challenge to cure efforts, mostly by our limited understanding and access to this compartment.

Methods

Tissue samples across 9 CNS regions, including 5 spinal cord (SC) segments (pons, medulla, cervical, lumbosacral, and thoracic spinal cord [TSC], frontal motor cortex [FC], basal ganglia [BG], hippocampus [HP], and occipital cortex [OC]), and peripheral blood mononuclear cells (PBMCs) were collected during rapid autopsies (≤6 hour from death) from people with HIV enrolled in the Last Gift cohort. For each tissue, we measured cell-associated HIV DNA and RNA by ddPCR. Adjusted mixed-effects models compared the HIV reservoir measures across tissues. Single genome HIV-1 env sequencing (SGS, Illumina) and T cell receptor repertoire (TCR) sequencing were performed in a subset of participants. Bayesian phylodynamic and generalized linear models evaluated viral dispersal and associated factors. Tree- and distance-based methods evaluated compartmentalization.

Results

Twenty participants were evaluated: mean age 63±13 years, 85% males, median current CD4+ T cells 193/µL, 85% with plasma HIV RNA <40 cp/ mL. While HIV DNA levels in all the SC segments were lower compared to those in PBMCs (p<0.0001), they did not differ from the other CNS regions, except for higher HIV DNA in TSC compared to OC (p=0.039). HIV RNA levels were also similar across the CNS, except for BG that had higher HIV transcriptional activity compared to all the other CNS tissues and PBMCs (p<0.05 all). HIV-1 env diversity (entropy) in TSC was higher compared to that in FC and HP (p<0.05 both). In the 8 participants with SGS and TCR sequencing (≥4 CNS regions including TSC), phylodynamic models revealed viral migration between the SC segments and across the other CNS regions in all participants (e.g., Fig.A). Viral diversity, divergence, and TCR overlap (Morisita index) between CNS locations were not associated with HIV migration. Clear evidence of compartmentalization of HIV in the SC compared to the virus in the rest of the CNS and in PBMCs was supported in 2 and 3 participants, respectively (e.g., Fig.B).

Conclusions

This study provides a comprehensive characterization of the HIV reservoir and its dynamics within the human SC. The SC contributes to HIV persistence and replenishment of brain reservoirs and can be a distinct site of compartmentalization within the CNS. Larger studies are needed to fully understand the SC's role in reseeding peripheral tissues.

Figure 1.

Background

The central nervous system (CNS) reservoir for HIV during ART has implications for both HIV cure and clinical outcomes. HIV DNA has been cross-sectionally detected in cerebrospinal fluid (CSF) cells but the longitudinal dynamics of HIV DNA in CSF during long-term suppressive ART are unknown.

Methods

16 participants in ACTG A5321/A5341s who started ART during chronic infection and had documented long-term suppression of plasma HIV RNA underwent 4-5 serial lumbar punctures (LP) over a span of 2.4-4.4 years. Cell pellets from ~13mL of CSF were assayed for total HIV DNA and cell-associated HIV RNA; cell-free HIV RNA by single copy assay was measured from CSF supernatant. Geometric means of longitudinal measurements were calculated using censored-data methods, analyzing both quantifiable and below assay limit values, and used for Spearman correlation analyses.

Results

The participants (100% male) had a median (IQR) age of 56 (50, 59) years, and were on ART for median 9 (range 6-16) years at their first LP. All participants had HIV DNA detected in CSF at one or more time points, and in total, 48/79 samples assayed had detectable HIV DNA. 11/16 participants (69%) had detectable HIV DNA in CSF at ≥ 3 timepoints, based on a median of 4,400 cells assayed. There was no evidence for a decay in CSF HIV DNA over time (Figure 1; p=0.8 from a censored-data model). The geometric mean of each participant’s CSF HIV DNA across time points correlated with the amount of HIV DNA in blood measured near the time of the first LP (r=0.45, p=0.09) but no correlations were evident with pre-ART plasma HIV RNA, pre-ART CD4 cell count, or duration of ART. Cell-free HIV RNA in CSF was only detectable in 2 participants, at 1 or 2 time points (3 of 77 assays performed, with levels 1-4 copies/mL). Cell-associated HIV RNA in CSF was detectable in 3 participants, each at a single time point.

Conclusions

In a longitudinal study in which 4-5 serial LP were obtained over 2-4 years in people on ART for 6-19 years, HIV DNA was found to persist in CSF in most participants with no evidence of decay. These findings highlight the ongoing exposure of the CNS to infected cells during long-term ART, and the need to further understand the characteristics and pathobiological relevance of cells harboring HIV DNA in the CSF compartment.

Figure 1.

Background

Neurologic consequences of HIV linger even after viral suppression, suggesting a molecular “scar” that persists despite antiretroviral therapy (ART). However, whether innate immune cells in the cerebrospinal fluid (CSF) are altered during HIV and how they contribute to neuropathogenesis are poorly understood, owing in part to difficulties in isolating these rare populations of cells before the advent of single cell technologies.

Methods

We enrolled 12 neurologically asymptomatic people with HIV (PWH) on suppressive ART and 11 demographically matched people without HIV (PWoH) for cross-sectional CSF single immune cell epigenome and transcriptome analyses. We utilized the 10X Genomics single nucleus multiome platform (ATAC-Seq + RNA-Seq), modified for low-cellular CSF, for 6 PWH and 5 PWoH (33,353 total nuclei). ATAC-seq data was used to identify open chromatin regions (peaks). We validated the single-nucleus transcriptomic data with additional data previously collected utilizing 10X 5’ single cell RNA-Seq from CSF of 7 PWH also on ART with features similar to the multiome participants and 6 PWoH (102,313 total cells).

Results

CSF of both PWH and PWoH consisted primarily of T cells (median=89.5%; IQR=6.2%), and secondarily of myeloid cells (median=5.9%; IQR=6.5%), including a small percentage of dendritic cells (DCs) (median=2.4%; IQR=1.7%). We identified 555 differentially accessible chromatin regions (DARs) across all cell types between PWH and PWoH. Despite comprising only a minority of CSF cells, DCs contained 32.8% of DARs, most of which were more open (more accessible) in PWH (130/182) (Fig. 1A). By annotating these DARs of DCs to their nearest genes, we identified 145 genes, including interferon-related genes IFI6 and GBP4, both of which exhibit differential RNA expression between PWH and PWoH in DCs. In our validation dataset of 5’ single cell RNA-Seq CSF transcriptomes, we observed a DC transcriptomic signature in CSF of PWH compared to PWoH (Fig.1B). Pathway analysis identified downregulation of antigen processing and presentation, and cytokine (mainly IL-1 and IL-12) signaling in DCs in PWH. Lastly, we detected extremely rare HIV RNA and chromatin-accessible provirus DNA in CSF cells.

Conclusions

Single-cell epigenome and transcriptome profiling of CSF suggests dysregulation of DCs in virally suppressed PWH. Further studies are needed to determine if these changes impair antigen presentation and antiviral responses, contributing to HIV persistence and neuropathogenesis.

The figure, table, or graphic for this abstract has been removed.

Background

Alzheimer’s disease (AD) is the leading cause of dementia worldwide, and accurate diagnosis is crucial, including for people with HIV (PWH). Blood-based biomarkers for AD offer a promising, low-cost, non-invasive diagnostic alternative, but data are limited in PWH. Our study measured phosphorylated tau 217 (p-tau217)–the only blood-based biomarker currently recommended for diagnosing AD–and assessed its potential in predicting cognitive decline among virologically suppressed older Thai PWH.

Methods

Blood samples were collected at baseline from virologically suppressed PWH aged 50 years and older, who completed the Thai-validated Montreal Cognitive Assessment (MoCA) at baseline (2015–2017) and a follow-up visit (2021–2024). Cognitive impairment was defined as a MoCA score of less than 25. P-tau217 levels were measured and categorized by quartiles, with a binary comparison between quartile 4 (Q4) and quartile 1–3 (Q1–3). A multivariate linear mixed-effects model, adjusted for sex, education level, baseline MoCA score, HIV duration, nadir CD4 levels (<200 and ≥ 200 cells/ mm³), and exposure to efavirenz, with an interaction term for baseline p-tau217 quartile and age, was used to estimate the effect of baseline p-tau217 levels on the changes in cognitive performance overtime.

Results

A total of 255 PWH, with a median interval between MoCA of 5.9 years (IQR: 5.6–6.8), were included: 63.1% were male, median age was 54.3 years (IQR: 51.8–59.1), 76.1% had more than six years of education, median HIV duration was 18.7 years (IQR: 15.3–21.0), and 61.2% had cognitive impairment. There was no significant difference in the proportion of PWH with cognitive impairment at baseline between those in Q4 and those in Q1–3 of p-tau217. However, PWH in Q4 were significantly more likely to have a reduction in MoCA score at follow-up visit than those in Q1–3 (62.5% vs. 49.2%, P=0.01). In the adjusted model, PWH in Q4 showed a significantly greater decline in cognitive performance, with a MoCA score decrease of -4.3 (95% CI -5.8 to -2.7) compared to -1.7 (95% CI -2.6 to -0.8) for Q1–Q3 from age 50 to 80 years (Figure). The association between higher p-tau217 levels (Q4 vs. Q1-Q3) and greater decline in MoCA scores become more pronounced with increasing age (P-interaction=0.02).

Conclusions

Older virologically suppressed Thai PWH with higher baseline p-tau217 levels showed a greater cognitive decline. Measurements of biomarkers for staging and prognostication of AD are ongoing.

Figure 1.

Background

People with HIV (PWH) are at higher risk for visceral adiposity and enhanced inflammation, and lower neurocognitive function when compared to controls without HIV. In a recent randomized placebo-controlled clinical trial of the GLP1 receptor agonist semaglutide, we demonstrated that PWH with lipohypertrophy had a decrease in weight, visceral adipose tissue, and in several inflammatory markers including high sensitivity C-reactive protein (hs-CRP). This study aims to investigate the effect of semaglutide on neurocognitive function and the mediation of this effect by changes in adiposity and inflammatory markers in PWH.

Methods

This study is a randomized, double-blind, placebo-controlled phase 2b clinical trial conducted at University Hospitals of Cleveland, Ohio. We included adult PWH on ART with controlled HIV, BMI of ≥25 Kg/m², and increased waist-to-hip ratio. Participants were randomized 1:1 to receive 32 weeks of subcutaneous Semaglutide or placebo. The Cognivue®, an FDA-approved computer-based test, was used to evaluate cognitive function at baseline and at 32 weeks. This comprehensive assessment encompassed multiple subdomains, including memory, visuospatial ability, attention, and executive function. Furthermore, a whole-body DEXA scan and a non-contrast helical CT scan were used to assess for changes in body composition, alongside the evaluation of inflammatory markers. We performed causal mediation analysis in examining association among various direct and indirect effects of semaglutide on the cognitive scores.

Results

108 participants were included (54 per arm); 62% non-white, 40% female, and median age of 53 years. Compared to placebo, PWH on semaglutide had a significant increase in visuospatial, naming/language, and delayed recall scores at 32 weeks (p = 0.01, 0.05, and 0.04, respectively). After adjusting for sex and CD4 count, only the visuospatial score remained statistically significant (p=0.05). The total natural direct effect (TNDE) of semaglutide maintained a positive effect on the visuospatial score while accounting for potential changes in hs-CRP levels (p=0.04). No correlations were observed between changes in cognitive scores on semaglutide and changes in total or central adiposity.

Conclusions

Semaglutide has shown a beneficial impact on cognitive function in people with HIV, particularly in relation to visuospatial cognitive function. This effect appears to be mediated by the effect of the drug on inflammation.

Figure 1.

Background

Cognitive dysfunction is a common symptom of Long COVID (LC), but its underlying pathobiology is unclear. We hypothesized that multimodal structural brain MRI imaging in people with cognitive LC (c-LC) would demonstrate grey and white matter alterations in brain regions relevant to c-LC symptoms compared to no LC (n-LC) controls.

Methods

Individuals with c-LC (new self-reported cognitive symptoms >3 months after COVID) and n-LC (COVID >3 months prior and no LC) were prospectively enrolled for studies on a single Siemens 3T scanner. Sequences included 3D T1 MPRAGE (1mm) for cortical gray matter (CGM) volume, 3D FLAIR (1.2mm) for white matter hyperintensity (WMH) volume, and Diffusion Tensor Imaging (DTI) (2mm) for white matter integrity measures fractional anisotropy (FA) and mean diffusivity (MD). Post-processing used Icometrix AI-based software and Bioimage Suite. The Johns Hopkins atlas was used to generate FA and MD for regions of interest (ROI). Analyses used parametric statistics and FDR to correct for multiple comparisons.

Results

23 c-LC (median age 45 years [IQR 41–59], 73% female, 630 days [IQR 365–829] after COVID-19) and 19 n-LC (median age 38 [33 – 44], 73% female, 516 days [IQR 410-797]) were enrolled. The groups differed in age (p=0.03) but were similar in gender, race, and cardiovascular risk factors which were low in prevalence. CGM volumes were lower in the c-LC group in three key regions: right parietal lobe and supramarginal region (SM), right ventrolateral prefrontal cortex (VLPFC), and left posterior cingulate (for statistics, see Table). WMH lesion volume was similar between groups (c-LC: 0.65 mL n-LC: 0.65 p:0.90). In the fornix, FA and MD were both altered in the c-LC group compared to n-LC. In the c-LC group, MD was lower in the left posterior corona radiata and transverse pontine fibers compared to n-LC (Table). There was no difference between groups in the remaining ROIs.

Conclusions

Our finding of specific regional grey and white matter alterations aligns closely with c-LC symptomatology. The SM is intimately connected to the VLPFC and is involved in articulatory sequencing and language and executive processing; VLPFC is involved in speech production and emotional associations and regulation. Altered CGM in the left cingulate and left corona radiata and DTI measures in the fornix aligns with dysfunction of key memory circuits. These structural 3T brain MRI findings may serve as biomarkers for diagnostic and mechanistic understanding of c-LC.

Table 1.

Background

Healthy individuals who contract SARS-CoV-2 exhibit structural brain changes after infection. To assess whether SARS-CoV-2 is associated with unique or additive brain effects among people with HIV (PWH), we capitalized on systematic longitudinal 3T MRIs captured in the RV254 acute HIV (AHI) Thai cohort to compare changes between PWH who did or did not acquire SARS-CoV-2 infection.

Methods

RV254 participants are enrolled and offered antiretroviral therapy (ART) during AHI. This analysis included PWH who underwent longitudinal 3T MRI, with the first scan acquired ≥5 months after ART initiation. Participants who then acquired SARS-CoV-2 (COVID+ PWH) between 2 scans were compared to those who completed >2 scans prior to 2020 and thus were SARS-CoV-2 naïve (COVID- PWH). Selected regions included those susceptible to SARS-CoV-2 (olfactory cortex, superior frontal gyrus, orbital gyrus, gyrus rectus, hippocampus, and amygdala), and HIV (caudate, pallidum, putamen, thalamus, nucleus accumbens). Volumes were summed across hemispheres and corrected for head size. Longitudinal differences were assessed using a repeated-measures MANOVA with a false discovery rate (FDR) correction for multiple comparisons.

Results

Fifty RV254 COVID+ PWH (pre-COVID scan at median=5.6 years after ART initiation) were compared to 16 COVID- PWH. Subgroups did not differ by age, CD4 count, or HIV RNA detection rate (overall median [IQR] baseline 27 [23-31] years, 632 [476-859] CD4+ cells/µL, 1.5% detectable); baseline CD4/ CD8 ratio was lower in COVID+ PWH (p=.031). Volumetric trajectories differed significantly by group in the superior frontal (p<.001), anterior orbital (p=.014), and medial orbitofrontal (p=.043) gyri, and nucleus accumbens (p=.037). Only the change between groups in the superior frontal gyrus remained significant after FDR correction (p=.002), where COVID+ PWH had volumetric decreases (-339 mm3) while COVID- PWH exhibited increases (+393 mm³).

Conclusions

In the longitudinal RV254 study, participants acquiring SARS-CoV-2 demonstrated evidence of structural brain changes over time compared to those followed prior to the COVID pandemic in regions susceptible to both conditions despite well-controlled HIV viremia. This implicates frontal gray matter in as a potential locus of SARS-CoV-2 impacts among PWH. Additional work will more fully evaluate temporal profiles and mechanisms of brain change relative to both conditions independently as well as their potential synergistic effect on brain integrity.

Figure 1.

Background

Antiretroviral therapy (ART) has transformed HIV from a life-threatening infection into a manageable chronic condition, allowing people living with HIV (PLWH) to have a significantly longer lifespan. However, as this population ages, they become increasingly susceptible to non-AIDS-related comorbidities typically associated with aging. Understanding the evolving patterns of these age-related conditions is essential to optimize care for this group. In this study, we analyzed trends in severe non-AIDS events (SNAEs) over different time periods to provide insights into how advances in HIV management have impacted the onset and frequency of these comorbidities.

Methods

Using CoRIS, a Spanish multicenter prospective cohort with more than 20,000 PLWH, we defined three six-year periods: 2006–2011, 2012–2017, and 2018–2023. The primary outcome was a diagnosis of a severe non-AIDS event (SNAE) during follow-up. SNAE was defined as a composite event, including major adverse cardiovascular events (MACE), non-AIDS-defining malignancies, and non-accidental deaths. MACE included nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. We used the Kaplan-Meier method to plot the cumulative probabilities of events for each defined period. We used Cox proportional hazard models to assess the hazard ratios (HR) of events by period adjusted for age, sex, educational level, risk practice, geographic origin, CD4 nadir, baseline CD4/CD8, and baseline VL. We used linear regression to predict the mean age at first event in each period, using the same covariates.

Results

A total of 18,659 ART-naïve participants were enrolled in the cohort between 2006 and 2023. The incidence of SNAEs in each period was 1.44 (95%CI 1.29-1.61), 0.95 (95%CI 0.83-1.08), and 0.67 (95%CI 0.57-0.79) per 1000 person-years, respectively (p<0.001; Figure 1A). The adjusted HR for SNAEs compared to period 1 was 0.81 (95%CI 0.66-0.99) in period 2 and 0.58 (95%CI 0.45-0.73) in period 3. The adjusted predicted age for the first event was 42.2 (95%CI 39.8-44.6), 45.6 (95%CI 43.5-47.8), and 48.3 (95%CI 45.4-51.3) years, respectively (Figure 1B).

Conclusions

The incidence of severe non-AIDS events among PLWH has decreased significantly over time, with a notable delay in the age of onset of these events. This could indicate that improvements in HIV treatment and care contribute to healthier aging in this population.

Figure 1.

Background

Cardiovascular disease (CVD) risk is higher in people with HIV (PWH) than people without HIV. However, whether this elevated risk of CVD is present in antiretroviral therapy (ART)-naïve PWH with high CD4+ counts, and whether delayed initiation of ART worsens CVD outcomes is unknown.

Methods

The Strategic Timing of Antiretroviral Treatment (START) study randomized ART-naïve adults with HIV and CD4+ counts>500 cells/µL to immediate vs. deferred (until CD4 count <350/µL or AIDS developed) ART initiation. We report CVD event rates (composite of MI, stroke, coronary revascularization, or death from CVD) between treatment arms in three time periods: (i) pre-2016 (ART use differed by treatment arm); (ii) post-2016 (study was unblinded and continuous ART use was recommended for both groups, 2016-2021); and (iii) over the entire study. Subgroup analyses were performed according to baseline demographic, clinical characteristics and CVD risk factors. Time-to-event methods compared event rates between study arms.

Results

Overall, 4,684 participants were randomized (median age 36 yrs, 27% female, 30% Black race); 4436 (95%) had data available after 2016. At baseline, 32% were smokers, 17% had a BMI≥30 kg/m², and the median Framingham 10-yr risk score was 1.9%. Comorbidities included hypertension (19%), dyslipidemia (8%), and diabetes (3%); 0.8% had prior CVD. Composite CVD event rates were similar between treatment arms during the pre- and post-2016 periods: 0.18 and 0.17 per 100 person yrs (PY) pre-2016 in the immediate and deferred arms, respectively, and 0.16 and 0.17 per 100 PY post-2016 in the immediate and deferred arms, respectively (Figure 1). Over the entire study (median follow-up of 9.3 yrs), 71 participants (35 immediate, 36 deferred) had a CVD event. There was no difference in events between arms (immediate/ deferred hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.61-1.56) for the composite CVD outcome or its components. Immediate vs. deferred ART was associated with a reduced risk of CVD in women (HR 0.19; CI 0.04-0.86) but not in men (HR 1.33; CI 0.79-2.24), p-value for interaction=0.014; interpretation is limited by low numbers of events.

Conclusions

While immediate ART is known to reduce the risk of many clinical comorbidities and adverse outcomes among PWH, we did not find an effect of early ART initiation for reduction of CVD events among individuals at low CVD risk and moderate to high CD4 counts in the START study. The benefit found among women warrants further evaluation.

Figure 1.