Treatment

There is an urgent need to reduce the unacceptably high mortality rate among people with HIV (PWH) hospitalized with tuberculosis (TB), particularly those with advanced HIV disease and disseminated TB. Two large, randomized clinical trials presented at the 2026 Conference on Retroviruses and Opportunistic Infections (CROI) addressed this crucial gap.

Blanc and colleagues (Abstract 123) presented results from the DATURA ANRS 12424 (Determination of Adequate Tuberculosis Regimen in Patients Hospitalized With HIV-Associated Severe Immune Suppression) trial, a phase III, randomized, open-label superiority trial conducted in Cambodia, Cameroon, Guinea, Mozambique, Uganda, and Zambia. PWH aged 15 years and older who were hospitalized for TB with a CD4+ count of 100 cells/μL or less were randomly assigned to receive intensified TB treatment of high-dose rifampicin (RIF; 35 mg/kg/d) and isoniazid (INH; 10 mg/kg/d) with standard-dose ethambutol and pyrazinamide (PZA) for the first 8 weeks, along with oral corticosteroids for 6 weeks and albendazole 400 mg daily for 3 days, or standard TB treatment. Antiretroviral therapy (ART) with tenofovir/lamivudine plus twice-daily dolutegravir (DTG) was initiated at week 2 in both arms. Among 908 participants in the modified intention-to-treat (mITT) group (44% women; median age, 37 years; median CD4+ count, 44 cells/μL; 88% with disseminated TB; 70% ART naive), the cumulative mortality rate at 48 weeks was 29.4% in the intensified arm and 26.8% in the standard arm (adjusted hazard ratio [aHR], 1.13; 95% CI, 0.88–1.45; P = 0.4), with a similar trend among those with a CD4+ count of 50 cells/μL or less (aHR, 1.28; 95% CI, 0.94–1.75). Overall, grade 3 or 4 adverse event (AE) rates were similar between arms (adjusted relative risk [aRR], 0.98; 95% CI, 0.90–1.06), although drug-induced liver injury was significantly more common in the intensified arm (13.4% vs 5.3%; aRR, 2.7; 95% CI, 1.8–4.2), and paradoxical TB-associated immune reconstitution inflammatory syndrome (IRIS) was lower (2.8% vs 6.4%; aRR, 0.5; 95% CI, 0.3–0.8). Intensification of TB treatment did not improve survival among hospitalized people with advanced HIV.

Namale and colleagues (Abstract 124) reported results from the prednisone vs placebo comparison of the NEW-STRAT TB (Testing New Strategies for Patients Hospitalised With HIV-associated Disseminated Tuberculosis) trial, a 2×2 factorial randomized clinical trial at 3 hospitals in CapeTown, South Africa. This trial also evaluated intensified TB treatment (high-dose RIF + levofloxacin). The intensified arm was stopped early after the 14-day mortality rate was significantly higher (10.9% vs 5.0%; P=.008), as previously reported at CROI 2025.¹ In the prednisone comparison, eligible adults had HIV-associated disseminated TB (positive blood Xpert Ultra, urine Xpert Ultra, or urine lipoarabinomannan [LAM] testing) and were randomly assigned to prednisone 1.5 mg/kg/d or placebo for 14 days. Among 712 participants in the mITT population (55% female; median age, 36 years; median CD4+ count, 43 cells/μL; median HIV viral load, log 5.4 copies/mL), 12-week mortality rate was 17.6% (95% CI, 14.0–22.0) in the prednisone arm and 19.2% (95% CI, 15.5–23.7) in the placebo arm (difference, −1.6%; 95% CI, −7.5 to 4.2; P=.6). At 14 days, the mortality rate was 6.8% vs 9.5% (difference, −2.8%; 95% CI, −6.9 to 1.3; P=.2). Grade 3 and grade 4 AEs and nonfatal serious AEs occurred at similar frequencies in the study arms. Subgroup analyses suggested possible heterogeneity by hemoglobin level (<7 g/dL vs >7 g/dL; interaction P = .01) and creatinine clearance rate (<50 mL/min vs >50 mL/min; interaction P = .045), with a trend toward harm among those with lower hemoglobin level and renal impairment. There was no statistically significant interaction between the prednisone and intensified TB treatment factorial randomizations. Although well tolerated, a 14-day course of adjunctive prednisone did not reduce the mortality rate in patients hospitalized with disseminated HIV-associated TB. Together with the DATURA trial findings, these results underscore that TB treatment intensification and adjunctive corticosteroids fail to improve outcomes in this severely ill population, reinforcing the need for novel approaches to address the persistently high mortality rate among hospitalized people with advanced HIV and TB.

Four-month rifapentine (RPT)-based TB regimens are now a US Food and Drug Administration (FDA)-approved shortened treatment option, but their pharmacokinetic (PK) interactions with DTG-based ART are not well characterized. Wasserman and colleagues (Abstract 146) presented results from A5406 (Pharmacokinetics and Safety of Double-Dose Dolutegravir When Used With Rifapentine for HIV-Associated Tuberculosis), a phase II, open-label, single-arm PK study conducted at 4 sites in South Africa and Thailand that evaluated the safety and adequacy of DTG exposure during coadministration with RPT. Adults with HIV not currently on ART with drug-susceptible TB received twice-daily DTG 50 mg plus 2 nucleoside reverse transcriptase inhibitors (nRTIs) with a 4-month RPT-based TB treatment regimen (2 months of daily RPT 1200 mg, INH, PZA, and moxifloxacin [MFX] followed by 2 months of daily RPT, INH, and MFX), switching to once-daily DTG 2 weeks after RPT discontinuation. Among 30 participants enrolled (43% female; median age, 35 years; median CD4+ count, 185 cells/μL), DTG area under the curve from 0 to 24 hours (AUC0-24) was 34.2 μg·h/mL with twice-daily dosing during RPT coadministration and 48.8 μg·h/mL with once-daily dosing after RPT discontinuation (geometric mean ratio, 0.70; 90% CI, 0.61–0.80), with DTG clearance increasing 2.2-fold (95% CI, 1.9–2.5). In simulations, 98.8% of individuals were predicted to remain above the efficacy threshold of 0.158 μg/mL with twice-daily DTG during RPT compared with only 29.8% with once-daily dosing. All participants on treatment achieved virologic suppression by week 21, with no hepatotoxicity attributed to the study regimen. These findings provide reassurance that twice-daily DTG achieves adequate drug exposures during RPT coadministration and support the use of DTG-based ART during shorter RPT-based TB regimens.

Diabetes is an important TB risk factor, but the PK impact of metformin, a commonly used diabetes treatment, on first-line TB drugs has not been well characterized. Rossouw and colleagues (Abstract 785) conducted a PK substudy nested within the METHOD (Safety and Tolerability of Metformin in People With Tuberculosis [TB] and Human Immunodeficiency Virus [HIV]) trial, a phase IIa randomized clinical trial of adjunctive metformin (500 mg once daily for 1 week, then 500 mg twice daily through week 12) in 78 adults with HIV-associated pulmonary TB, performing population PK modeling from samples collected at week 5. Metformin coadministration reduced modeled INH bioavailability by 15.6% (95% CI, 4.45–26.4%; P = .009) and RIF bioavailability by 24.1% (95% CI, 7.8336.3%; P <.001); PZA exposure was unaffected. It is unclear whether these represent clinically significant reductions, but given the crucial role of RIF and INH in TB treatment and existing concerns about subtherapeutic drug concentrations, these findings may warrant further investigation.

Drug-Resistant Tuberculosis

Optimizing linezolid (LZD) dosing in drug-resistant TB regimens remains a high priority, as LZD toxicity — particularly myelosuppression and peripheral neuropathy — substantially limits tolerability and treatment completion. Benson and colleagues (Abstract 149) presented results from ACTG (AIDS Clinical Trials Group) A5356 (A Phase II, Prospective, Randomized, Multicenter Trial to Evaluate the Efficacy and Safety/Tolerability of 2 Linezolid Dosing Strategies in Combination With a Short Course Regimen for the Treatment of Drug-Resistant Tuberculosis), a phase IIb, randomized, open-label, multicenter trial in 7 countries comparing 26 weeks of standard-dose LZD 600 mg daily with an investigational higher-dose strategy of LZD 1200 mg daily for 4 weeks followed by 1200 mg thrice weekly, each combined with bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ). Among 138 adults with newly diagnosed pulmonary drug-resistant TB (median age, 36 years; 37% female; 20% PWH; 66% multidrug-resistant TB), sputum liquid culture conversion by week 26 was similar in both arms (97% vs 94%), although time to conversion was longer in the higher-dose arm (aHR, 0.63; 95% CI, 0.42–0.95; P = .03). Favorable TB outcomes at week 26 were higher with standard-dose LZD than higher-dose LZD (65% vs 53%, respectively), with lower premature treatment discontinuation (8% vs 16%, respectively). Although overall rates of grade 2 or higher AEs were similar between arms, the profiles differed, ie, Fridericia-corrected QT interval prolongation was more common with higher-dose LZD than standard-dose LZD (41% vs 23%, respectively), whereas peripheral neuropathy (16% vs 9%, respectively) and increased alanine aminotransferase levels (14% vs 4%, respectively) were more frequent with standard-dose LZD than higher-dose LZD, possibly reflecting higher cumulative exposure with uninterrupted daily dosing over 26 weeks. Dose reductions for toxicity occurred in approximately one-quarter of participants (26% in the standard-dose arm vs 29% in the higher-dose arm), although time to first dose reduction was earlier in the higher-dose arm.

Companion PK analyses (Abstract 788) confirmed that at week 4, 80% to 100% of participants achieved pharmacodynamic targets for LZD (80% in the standard-dose arm vs 100% in the higher-dose arm) and 90% for DLM across both arms, with LZD exposure 2.5-fold higher in the higher-dose arm and DLM exposure similar between arms. These data support the continued use of the currently recommended LZD 600 mg daily dose in DR-TB regimens, as a novel higher LZD dosing strategy did not improve outcomes and was associated with more treatment discontinuations.

Surveillance of drug resistance in the era of BDQ-based and pretomanid (PTM)-based regimens is essential to ensure their long-term durability. Cardenas-Alvarez and colleagues (Abstract 780) evaluated baseline and emergent resistance among 129 PWH with culture-positive RIF-resistant or multi-DR (MDR)-TB enrolled in the ADAPTIV (An Adaptive Randomized Controlled Trial) study in KwaZulu-Natal, South Africa. Baseline phenotypic resistance to BDQ and PTM was observed in 5.5% and 2.7%, respectively, including in 1 participant with resistance to both agents. Emergent resistance to BDQ and PTM occurred in 2.7% and 0.9%, respectively, with no emergent LZD resistance detected. These findings highlight a concerning prevalence of baseline and emergent resistance to the core components of BDQ, PTM, and LZD (BPaL)-based regimens in this high-burden setting, potentially raising important questions about their long-term durability as these regimens are scaled more broadly.

Prevention

Shorter TB preventive therapy (TPT) regimens improve treatment completion and reduce the burden of HIV-associated TB compared with longer INH-based regimens. Regimens comprising 12 weekly doses of INH plus weight-based RPT (3HP) or 28 daily doses of INH plus weight-based RPT (1HP) are recommended by the World Health Organization (WHO) for PWH. The 3HP regimen is also recommended in US guidelines, whereas 1HP has not been universally adopted. Despite both regimens being available options, they had not previously been directly compared. Two randomized clinical trials presented at CROI 2026 addressed this important gap.

Avihingsanon and colleagues (Abstract 145) conducted a randomized, open-label, phase III, noninferiority trial comparing 1HP and 3HP in 1500 PWH on efavirenz-based (58%) or once-daily DTG-based ART (42%) across 14 sites in Thailand. Most participants were male (82%), with a median age of 32 years and a median CD4+ count of 348 cells/μL. Over a median follow-up time of 3.7 years, there were 3 confirmed active TB cases (2 of 748 participants in the 1HP arm [0.27%] vs 1 of 752 in the 3HP arm [0.13%]), with a corresponding incidence difference of 0.13% (95% CI, −0.32 to 0.58) that met the prespecified noninferiority criterion (upper 95% CI, below 2.5%). Notably, all TB cases occurred after 3 years of follow-up. Grade 2 to 4 hepatotoxicity was similar between arms (7.7% vs 6.9%; P = .18) and grade 3 to 4 AEs (<3% across arms) and treatment discontinuations due to AEs (<3% across arms) were low and did not differ by arm or ART backbone. HIV-1 RNA suppression at 144 weeks exceeded 93% in each arm regardless of ART backbone.

The One-to-Three trial, presented by Moodley and colleagues (Abstract 148), was a phase IV randomized clinical trial comparing 1HP and 3HP in virally suppressed PWH on DTG-based or efavirenz-based ART in South Africa and India. The primary endpoint was treatment completion, assessed by a prespecified composite endpoint that required concordance across self-report, pill count, and electronic monitoring device (EMD) data. Among 500 participants (median age, 42 years; 68% female; median CD4+ count, ∼800 cells/μL), treatment completion was significantly lower in the 1HP arm than in the 3HP arm (75.6% vs 87.6%, respectively; difference, 12.1%; 95% CI, 5.7–18.5; P <.001), driven largely by lower EMD-confirmed adherence (79.2% vs 96.4%, respectively; P <.001), although self-reported and pill count adherence exceeded 90% in each arm. The investigators noted that EMD box openings may have underestimated true adherence in the daily 1HP arm. Notably, treatment-limiting AEs were more frequent with 1HP (3.2% vs 0% with 3HP; P = .002), although targeted grade 2 or higher AEs and virologic failure rates were similar between arms.

Collectively, these data support both regimens as safe and effective options for TB prevention in PWH, with 3HP demonstrating more favorable completion and tolerability in the One-to-Three trial, an important finding to monitor if 1HP is scaled up in real-world settings.

Pregnant women with HIV face heightened TB risk but have been largely excluded from TPT trials. The DOLPHIN-Moms (Safety and Tolerability of 1 Month Daily [1HP] and 3 Months Weekly [3HP] Isoniazid and Rifapentine With Pharmacokinetics of Dolutegravir [DTG] in Pregnant People With HIV) trial (Abstract 147) is a phase II, randomized clinical trial evaluating the safety and PK data of DTG-based ART with 1HP or 3HP in pregnant women at 20 to 34 weeks’ gestation in South Africa. At CROI 2025, data demonstrated that twice-daily DTG maintained adequate trough concentrations and viral suppression with either 1HP or 3HP; however, simulation models of once-daily DTG suggested that trough levels would fall below the acceptable threshold with 1HP but remain adequate with 3HP — a finding that required confirmation with observed data.² At CROI 2026, Mathad and colleagues reported new PK data from 38 participants receiving 3HP with an ART regimen that included standard once-daily DTG. Median DTG trough concentrations remained above the 158 ng/mL target threshold at 97% to 100% of assessments across all timepoints, consistent with data from nonpregnant adults, and viral suppression exceeded 90% during TPT. These findings provide PK data and clinical evidence for the use of 3HP in pregnant women with HIV on standard once-daily DTG-based ART.

Prior data have confirmed that 3HP can be coadministered with once-daily DTG-based ART in adults without dose adjustment, but because RPT is a potent inducer of the primary enzymes responsible for DTG metabolism and children clear DTG more rapidly than adults, standard DTG dosing may not achieve adequate exposure during 3HP coadministration. Salazar-Austin and colleagues (Abstract 150) presented results from the DOLPHIN-Kids (Rifapentine and Isoniazid TB Preventive Therapy [3HP] for Children Taking Dolutegravir-Based Antiretroviral Treatment) trial, a phase I/II PK and safety study evaluating once-daily DTG-based ART coadministered with 3HP in 41 children with HIV weighing 10 kg or more who were virally suppressed at entry (median age, 5.5 years; 46% female; all Black African). DTG trough concentrations were significantly reduced during 3HP coadministration and formal PK criteria were not met, ie, the fifth percentile fell below the 158 ng/mL threshold and 2 participants had trough levels below the protein-adjusted 90% inhibitory concentration of 64 ng/mL — 1 individual remained virally suppressed throughout and the other resuppressed with adherence counseling. No grade 3 or higher drug-related AEs occurred, no participants discontinued due to AEs, and 95% were virally suppressed at study completion. Although formal PK criteria were not met, the absence of drug-related AEs and high rates of viral suppression at study completion suggest that 3HP may be coadministered with once-daily DTG-based ART in children weighing 10 kg or more, with strong adherence support and close monitoring.

Large-scale real-world effectiveness data on TPT across diverse programmatic settings remain limited. Shah and colleagues (Abstract 771) used a target trial emulation framework applied to individual-level electronic health records from Haiti, Kenya, Nigeria, Uganda, Ukraine, and Zimbabwe to estimate the programmatic effectiveness of TPT among 235,424 PWH initiating ART from 2018 to 2021. Initiating TPT within 8 weeks of HIV care entry was associated with a 61% reduction in TB incidence (pooled HR, 0.39; 95% CI, 0.34–0.43) and a 45% reduction in mortality (pooled HR, 0.55; 95% CI, 0.51–0.58) across the 6 countries. These findings provide large-scale real-world evidence reinforcing the effectiveness of TPT in reducing TB incidence and mortality among PWH, further supporting TPT as an essential component of HIV care in high TB burden settings.

Kalema and colleagues (Abstract 770) evaluated TB incidence among 130,954 adult PWH enrolled in HIV care across Kenya, Uganda, and Tanzania before (2012–2016) and after (2017–2020) implementation of the WHO test and treat strategy (TTS), using data from the East Africa International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium. TB incidence declined significantly following TTS implementation, from 19.3 to 12.9 per 1000 person-years (aHR, 0.55; 95% CI, 0.42–0.73), but disparities persisted. Males experienced higher TB incidence than females (HR, 1.74; 95% CI, 1.61–1.87) and adults aged 25 to 34 years (HR, 1.31; 95% CI, 1.14–1.51) and 35 to 44 years (HR, 1.39; 95% CI, 1.19–1.61) had higher TB hazard than the reference group comprising individuals aged 18 to 24 years. Notably, the frequency of TPT use was not reported, limiting the ability to disentangle the effects during the post-TTS period. These findings add further real-world evidence of the importance of expanding access to timely HIV diagnosis and ART, highlighting the need for targeted interventions in higher-risk subgroups, including men.

Diagnosis and Case Finding

Asymptomatic TB is an increasingly recognized challenge in high-burden settings, but its prevalence among PWH enrolled in clinical trials has not been well characterized. Tapley and colleagues (Abstract 774) conducted a cross-sectional TB substudy nested within CoVPN 3008 (Multicenter, Randomized, Efficacy Study of COVID-19 mRNA Vaccine in Regions With SARS-CoV-2 Variants of Concern), a COVID-19 vaccine trial among predominantly PWH in Botswana, Kenya, Malawi, South Africa, Uganda, and Zambia. All participants underwent comprehensive TB screening regardless of symptoms, including chest radiography, sputum smear, Xpert Ultra, and culture; asymptomatic TB was defined as microbiologically confirmed TB in the absence of a current cough, fever, night sweats, or unintentional weight loss. Among 5694 participants, 88% were PWH (median CD4+ count, 724 cells/μL) and microbiologically confirmed TB was identified in 108 participants (1.9%), of whom 82 (76%) were asymptomatic. TB prevalence did not differ significantly by HIV status (2.1% in PWH vs 3.3% in people without HIV [PWoH]; P=0.4) and was significantly higher in males (4.0% vs 1.7% in females), those with prior TB (4.2% vs 1.7% in those without prior TB), smokers (3.4% vs 1.8% in nonsmokers), and in those with at-risk drinking (3.0% vs 1.7% in those without at-risk drinking). These findings underscore the limitations of symptom-based TB screening and highlight the need for improved screening approaches to detect all forms of HIV-associated TB in clinical trials and in other contexts in high TB burden settings.

TB meningitis remains a frequently missed diagnosis associated with poor outcomes in high TB and HIV prevalence settings. Milburn and colleagues (Abstract 775) integrated routine cerebrospinal fluid (CSF) Xpert MTB/ RIF Ultra testing into the evaluation of adults (defined as age >16 years) with a suspected central nervous system infection at hospitals in Botswana and Zimbabwe, identifying microbiologically confirmed TB meningitis in 7.1% of 1131 patients undergoing lumbar puncture (LP), with inpatient mortality of 56% among confirmed cases. Only 21 (39%) received empiric anti-TB treatment prior to microbiologic confirmation. These findings suggest that empiric anti-TB treatment is likely underutilized while awaiting microbiologic confirmation, and routine rather than targeted CSF Xpert testing may be warranted in high TB burden settings where feasible.

Diagnosing TB in children remains challenging due to the paucibacillary nature of pediatric TB and the difficulty of obtaining respiratory samples. Bollore and colleagues (Abstract 776) compared the diagnostic performance of 3 urine-based assays (PathFast LAM, Determine LAM, and IS6110 polymerase chain reaction [PCR]) in 591 hospitalized children with suspected TB in Zambia. Overall, 53 had microbiologically confirmed TB, and the overall sensitivity of PathFast LAM was 76%, increasing to 83% (95% CI, 0.65–0.94) among children with HIV, outperforming both Determine LAM and IS6110 PCR in sensitivity and exceeding the 75% minimum performance target set by the WHO for a near point of care (POC) test. Specificity exceeded 89% across all subgroups, which is likely an underestimate based on clinical data. Although these initial data are promising for the PathFast LAM test using urine samples, prospective validation in larger and more diverse pediatric populations is needed.

Tuberculosis Pathogenesis and Outcomes

Early mortality in HIV-associated TB remains poorly understood. Boloko and colleagues (Abstract 778) investigated whether inflammasome activation and secondary hemophagocytic lymphohistiocytosis (HLH) contribute to the high early mortality rate seen in hospitalized PWH with TB. Among 355 adults with confirmed HIV-associated TB (median CD4+ count, 57 cells/μL), 22% had died by 12 weeks. HLH prevalence ranged from 19% to 50% depending on the criteria used and was associated with mortality by all criteria. Mycobacterial load correlated with ferritin (R = 0.61; P <.001) and caspase-1 (R = 0.43; P <.001), and caspase-1 was independently associated with increased mortality risk (HR, 4.9/log₁₀ increase; 95% CI, 2.5–9.6; P <.001). These findings suggest that inflammasome-driven hyperinflammation along the HLH spectrum plays a prominent role in HIV-associated TB pathogenesis and mortality, and may represent a target for adjunctive therapeutic strategies.

Epidemiology and Outbreak Dynamics

Silent and unrecognized transmission emerged as a consistent theme across various settings. Abdullahi and colleagues (Abstract 325) found 13.6% baseline mpox seropositivity among healthy Nigerian adults, with 3% showing evidence of recent asymptomatic exposure over 9 months, suggesting substantial unrecognized transmission. Co and colleagues (Abstract 500) similarly identified 24.8% m pox virus (MPXV) immunoglobulin G (IgG) seropositivity among men who have sex with men (MSM) with sexual risk factors in the Philippines, with serologic evidence of transmission predating the first official case by approximately 3 months. Together, these studies suggest that case counts substantially underestimate true infection burden, especially in settings without robust surveillance, highlighting the need for expanded genomic and serologic monitoring.

Additional studies underscored the importance of genomic surveillance and health system preparedness to detect and contain spread before it escalates. Lautner and colleagues (Abstract 208) reported that clade IIb lineages E and F dominated MPXV samples in Berlin from 2022 through 2025, with emerging clade Ib detections increasing since late 2025. Phylogenetic analysis indicated that these represent numerous independent introductions rather than local viral evolution or vaccine evasion, suggesting that the virus is repeatedly imported across borders. This kind of genomic surveillance can be useful when health systems are able to respond rapidly, as illustrated by Eleeza and colleagues (Abstract 957), who found that facilities supported by the Epidemic-Ready Primary Health Care initiative in Sierra Leone substantially outperformed standard facilities on case-detection speed and infection prevention and control measures, demonstrating that structured investment in facility-level preparedness can meaningfully improve outbreak response in resourcelimited settings.

Diagnostics

As mpox cases become less frequent and clinical suspicion wanes, the risk of missed diagnosis grows, making syndromic molecular testing increasingly important. Da Silva and colleagues (Abstract 497) developed a multiplex PCR test that simultaneously detects MPXV, herpes simplex virus (HSV)-1, HSV-2, and Treponema pallidum from a single swab. Rizzo and colleagues (Abstract 1034) extended this approach to a broader genital ulcer panel, adding Chlamydia trachomatis lymphogranuloma venereum (LGV) serovars, Haemophilus ducreyi, and varicella zoster virus (VZV), achieving concordance with routine diagnostics and potentially identifying coinfections missed by single-pathogen testing.

Nsawotebba and colleagues (Abstract 498) further showed that using saliva achieved diagnostic performance similar to lesion swabs during a 2025 outbreak in Uganda. Anal swabs showed high sensitivity, whereas urine, although highly specific, had the lowest sensitivity and should not be used as a primary specimen.

Clinical Manifestations and Impact of Treatment

When MPXV infection occurs, HIV coinfection and structural vulnerabilities consistently amplify its severity and mortality rate. Banai and colleagues (Abstract 499) demonstrated that integrated HIV, syphilis, and mpox screening across 11 high-burden health zones in Kinshasa is feasible and has high impact; 80.5% of suspected mpox cases received dual HIV/syphilis rapid testing alongside MPXV PCR evaluation, identifying HIV coinfection in 12.3% of confirmed cases (more than 12 times the national prevalence) and syphilis in 9.0%, underscoring that mpox response programs represent a crucial and often missed opportunity for HIV and sexually transmitted infection detection. The consequences of missed coinfection were stark, with a case fatality rate of 28% among individuals with HIV/MPXV-coinfection at tertiary hospitals. This was further supported by Namusoosa and colleagues (Abstract 955), who reported that HIV coinfection was present in 50% of the 46 deaths across the national outbreak in Uganda.

The central role of HIV immune status in mpox outcomes is further illustrated by treatment response data. Grinsztejn and colleagues (Abstract 501) analyzed predictors of lesion resolution in 106 participants with severe mpox in the UNITY (Assessment of the Efficacy and Safety of Tecovirimat in Patients With Monkeypox Virus Disease) open-label arm. Faster lesion resolution was associated with younger age, earlier presentation, and controlled or absent HIV infection, with uncontrolled HIV viremia being the strongest predictor of prolonged healing.

Greninger and colleagues (Abstract 502) reported that acquired tecovirimat resistance emerged in 6.5% of participants in the ACTG A5418/STOMP (A Randomized, Placebo-Controlled, Double-Blinded Trial of the Safety and Efficacy of Tecovirimat for the Treatment of Human Mpox Disease) open-label arm, predominantly in those with advanced HIV and CD4+ counts below 80 cells/μL. This finding suggests that profound immunosuppression permits sustained viral replication, which, in turn, creates selective pressure for resistance mutations to emerge under drug exposure. Clinical resolution by day 57 occurred in only 28.6% of resistant cases and 94.7% of nonresistant cases, underscoring that in the most immunocompromised patients, prolonged viral replication drives resistance and limits the prospects for recovery.

At a mechanistic level, Yazici and colleagues (Abstract 496) used human in vitro models to characterize cell-type-dependent MPXV replication, finding that THP-1 macrophages support progressively increasing viral replication, peaking at 4 days post infection, whereas epithelial cells are least permissive. This is particularly relevant in the context of advanced HIV, where macrophage function is impaired, and their susceptibility to MPXV replication may help explain the sustained viral loads observed by Greninger and colleagues.

Bbosa and colleagues (Abstract 954) applied deep metagenomic sequencing to samples from 22 fatal mpox cases in Uganda and found VZV coinfection in the majority of fatalities among PWH and PWoH. Staphylococcus aureus, Klebsiella pneumoniae, and Acinetobacter baumannii were also identified among these fatal cases, suggesting that coinfections may have contributed to mortality.

Alongside coinfections, structural barriers present a challenge to the management of mpox; in New York, New York, Castellano and colleagues (Abstract 956) demonstrated that being uninsured or on Medicaid was independently associated with greater mpox severity, as was HIV with CD4+ count below 200 cells/μL, underscoring that biologic and structural factors impact outcomes.

Vaccination and Immunity

Vaccine coverage remains inadequate in many populations. Atkins and colleagues (Abstract 1124) identified a striking gap: among transfeminine persons in the US with a clear vaccination indication, only 25% had received at least 1 dose despite 83% having recently seen a clinician, underscoring that closing immunization gaps remains the most urgent priority.

Among those who are vaccinated, questions about durability persist, and the data are inconsistent. Liu and colleagues (Abstract 319) found that mpox-specific antibodies waned substantially by 2 years post vaccination in smallpox-naive MSM; notably, most breakthrough infections occurred in those who had not mounted an initial antibody response, suggesting that clinical risk is concentrated in primary vaccine nonresponders and raising the question of whether postvaccination serology has a role in identifying this population.

The Mazzotta group confirmed and extended this picture across 3 abstracts. By 3 years post vaccination, antibody titers were largely undetectable in smallpoxnaive individuals (Abstract 323), T-cell responses were significantly reduced in PWH with CD4+ count below 350 cells/μL despite similar antibody levels (Abstract 322), and a booster dose administered at least 2 years after the primary cycle rapidly restored humoral and cellular immunity, with intradermal administration eliciting higher neutralizing antibody titers than subcutaneous administration and supporting a dose-sparing strategy (Abstract 324).

The key tension in these data is between immunologic waning and clinical protection. Despite the serologic decline documented above, Zucker and colleagues (Abstract 320) reported that prior immunity continued to confer meaningful protection against severe disease and hospitalization in a 2025 multicenter cohort, even years after vaccination, suggesting that antibody titers alone do not fully capture immune response. Meana and colleagues (Abstract 321) add a counterpoint, finding that those vaccinated more than 2 years prior in Washington state showed a trend toward higher severity scores using a modified severity scoring tool, a finding more consistent with the immunologic waning data. Overall, these studies do not yet resolve whether or when boosters are warranted for the general vaccinated population, but converge on PWH with low CD4+ cell counts as being at greatest risk and most likely to benefit.

Cryptococcal Meningitis

In 2022, the WHO recommended a single high-dose liposomal amphotericin B (L-AmB) regimen with fluconazole and flucytosine as induction therapy for cryptococcal meningitis (CM), based on the AMBITION (AMBITION-cm: AMBIsome Therapy Induction OptimizatioN - Intermittent High-Dose AmBisome on a High Dose Fluconazole Backbone for Cryptococcal Meningitis Induction Therapy in Sub-Saharan Africa) trial results. Falconer and colleagues (Abstract 769) conducted a prospective cohort study (2023–2025) evaluating this regimen as part of routine care in Médecins Sans Frontières-supported hospitals in the Democratic Republic of Congo, Guinea, and Mozambique. Among 174 adult PWH with CM (median CD4+ count, 50 cells/μL), 2-week and 10-week mortality rates were 22% (95% CI, 17–30) and 43% (95% CI, 36–51), respectively, with a favorable safety profile including grade III/IV renal impairment in only 2% and hypokalemia in 3%. Notably, 37% of survivors were discharged before day 7. Fidelity to recommended care was variable, eg, 85% received L-AmB within 4 hours of admission, 79% had at least 1 follow-up LP, and only 34% completed WHO-recommended laboratory monitoring. These data suggest that although single-dose L-AmB is largely feasible in low-resource settings, a persistently high mortality rate shows that current regimens and strategies are inadequate.

POC diagnostics are central to the WHO advanced HIV disease care package and detection of CM, but cascading implementation gaps can substantially reduce their effectiveness. Falconer and colleagues (Abstract 1097) leveraged pre-and postimplementation programmatic data from 3 Médecins Sans Frontières-supported programs in Guinea, Democratic Republic of Congo, and Mozambique, using sequential loss modeling to estimate that the cumulative effects of suboptimal performance across POC CD4+ cell count testing, POC serum cryptococcal antigen screening, and LP linkage could result in up to 66% of true CM cases being missed, but that this could be reduced to 25% with optimized implementation support. These findings underscore that novel POC diagnostics must be accompanied by robust implementation strategies, including structured supervision and quality assurance, to realize their potential in advanced HIV disease care in resource-limited settings.

Histoplasmosis

TB and histoplasmosis are leading opportunistic infections among people with advanced HIV disease in Latin America and the Caribbean, but the prevalence and outcomes associated with coinfection are not well described. To address this, Camiro-Zuñiga and colleagues (Abstract 768) pooled data from 4 prospective implementation studies evaluating rapid opportunistic infection diagnostics in 1282 individuals with advanced HIV disease. Among these, 325 (25.3%) had TB, 108 (8.4%) had histoplasmosis, and 46 of the 325 TB cases (14.1%) had histoplasmosis coinfection. Mortality rate was dramatically higher among patients with coinfection than in those with TB alone (34.6% vs 7.8%, respectively, at 90 days and 41.9% vs 9.3%, respectively, at 365 days; P <.001). These data highlight that TB-histoplasmosis coinfection is common in endemic settings and carries a markedly higher mortality rate than TB alone, underscoring the importance of maintaining a low threshold for histoplasmosis testing in PWH presenting with TB in compatible clinical settings.

Cytomegalovirus

Cytomegalovirus (CMV) pneumonia is a major but often unrecognized cause of death in infants with HIV, yet empiric treatment is not currently the standard of care. Rojo and colleagues (Abstract 151) presented results from EMPIRICAL (Empirical Treatment Against Cytomegalovirus and Tuberculosis in HIV-Infected Infants With Severe Pneumonia), a phase II/III, randomized, open-label factorial trial evaluating empiric valganciclovir and empiric TB treatment independently in 558 infants with HIV aged 28 to 365 days hospitalized with severe pneumonia across 19 hospitals in 6 African countries; the TB treatment arm results are reported separately. CMV viremia was detected in 84.3% of participants at baseline and 51.3% had viral loads above 4.1 log copies/mL, consistent with CMV-attributable pneumonia. Valganciclovir was associated with a significant reduction in early mortality (23.2% vs 27.0% at 15 days; HR, 0.60; 95% CI, 0.41–0.87), but this benefit diminished over time. Overall 1-year mortality rate, although lower in the valganciclovir arm, remained high in the trial arms (43.1% vs 47.5%; HR, 0.79; 95% CI, 0.62–1.01; P=.07). Valganciclovir was associated with higher rates of neutropenia (16.7% vs 9.2%; P=.013) and anemia (36.6% vs 27.7%; P=.030) during the first 15 days, although grade 3 or 4 neutropenia did not differ significantly. The high burden of CMV-attributable pneumonia in this population, combined with a modest but borderline significant mortality benefit and largely reassuring safety profile, suggest that empiric valganciclovir warrants serious consideration as a strategy to reduce early mortality in infants with HIV and severe pneumonia.

Kaposi Sarcoma

Understanding why Kaposi sarcoma (KS) persists requires a clearer picture of human herpesvirus-8 (HHV-8) biology and immune control. Kibanga and colleagues (Abstract 627) found HHV-8 DNA in various organs in 30% of serologically negative individuals at autopsy, demonstrating that standard serology substantially underestimates true HHV-8 prevalence, a finding with direct implications for transplant safety. Isnard and colleagues (Abstract 628) found that higher anti-HHV-8 IgG binding capacity was inversely correlated with circulating HHV-8 viremia in PWH and in MSM who are HIV negative, a relationship not observed for CMV or Epstein-Barr virus, suggesting a specific and potentially protective role for humoral immunity in controlling HHV-8 replication.

These biologic insights point to the need for better clinical tools to identify who is at risk and to monitor KS. Dittmer and colleagues (Abstract 122) demonstrated in 169 participants from the ACTG A5264/AMC067 REACT-KS (Antiretroviral Therapy (ART) Alone or With Delayed Chemo Versus ART With Immediate Chemo for Limited AIDS-Related Kaposi Sarcoma) trial that detectable plasma HHV-8 DNA at entry was the strongest predictor of treatment failure at 48 weeks, outperforming interleukin-6, tumor necrosis factor receptor type 2, and c-reactive protein, and was associated with worse progression-free survival and higher rates of KS-IRIS. Flores-Andrade and colleagues (Abstract 630) provided additional insight, showing that an HHV-8 viral load above 3.0 log₁₀ copies/mL independently predicted visceral KS involvement with high specificity, suggesting a decisive rule to identify which patients with cutaneous KS warrant aggressive visceral work-up, which is particularly relevant given that more than 40% of KS cases develop visceral disease.

Borok and colleagues (Abstract 629) showed that HHV-8 DNA concentrations were similar in paired oral and cutaneous KS tumors within the same individual, with intraindividual variability substantially lower than interindividual variability, raising questions about the biologic and clinical significance of between-person differences in tumor viral load that warrant further investigation. Together, these studies make a case for routine HHV-8 viral load measurement as a standard part of KS clinical assessment.

Clinical data from CROI 2026 help to define those at greatest risk once KS is established. Volkow-Fernández and colleagues (Abstract 625) compared 218 PWH with disseminated KS, finding that those with pulmonary involvement had higher rates of IRIS, more chemotherapy cycles, and a substantially greater burden of concurrent AIDS infectious events including CMV end-organ disease and syphilis. Importantly, after adjustment, the mortality rate did not differ between pulmonary and nonpulmonary groups, and nearly 75% of the cohort was alive and in complete remission at 4 years. This underscores the importance of aggressive evaluation and treatment of coinfections alongside chemotherapy, which is central to improved outcomes regardless of disease extent.

Mercado Matos and colleagues (Abstract 626) found that among patients with HHV-8-associated diseases, survival was driven by disease phenotype rather than viral subtype, with concurrent primary effusion lymphoma conferring the worst prognosis. KS and multicentric Castleman disease alone were not independently associated with mortality; however, HHV-8 subtype A was associated with worse outcomes in the setting of primary effusion lymphoma, a finding that warrants confirmation in larger cohorts.

Human Papillomavirus and Associated Malignancies

High-risk strains of human papillomavirus (HR-HPV) are prevalent among key populations at risk for anal cancer, yet vaccination coverage remains low. Füllekrug and colleagues (Abstract 1007) found anal HR-HPV in 68% of MSM using HIV preexposure prophylaxis (PrEP) and in 34% of PrEP-naive peers in a German-Austrian cohort, with HPV-16 and HPV-18 more prevalent among PrEP users. Despite this elevated burden, vaccination rates were low in each group (22% and 15%, respectively), underscoring a primary prevention gap that is addressable through the integration of HPV vaccination into PrEP programs. In the ANRS PrevHPV-TG (HPV Infection, Sexually Transmitted Infections and Anal Dysplasia in the Transgender Population) cohort of transgender women, Ferré and colleagues (Abstract 1012) found anal HR-HPV in 70%, with concomitant oral and anal infections occurring together in 12% of cases. Modeling indicated that 9-valent vaccination would have prevented infection in at least 1 anatomic site in 72% of participants, with low vaccination coverage and high rates of engagement in transactional sex highlighting the magnitude of unmet prevention need in this highrisk population.

Across populations with HIV, HPV persistence after treatment and through cooccurring infections represents a central challenge for cancer prevention. Diwan and colleagues (Abstract 1008) followed 400 women with HIV in Kenya for a decade after random assignment to cryotherapy or loop electrosurgical excision procedure for grade 2 cervical intraepithelial neoplasia, finding that HPV prevalence remained at 54% after 10 years with no difference between treatment arms, and that nearly half of genotypes detected were already present in the first 2 years, highlighting that ablative and excisional treatments remove lesions but do not reliably clear underlying infection. Harfouch and colleagues (Abstract 1009) conducted a longitudinal cohort study in transgender women and MSM and found that baseline HPV-16 and abnormal anal cytology both tended to persist at 1 year, with HIV status and sex-hormone levels not significantly associated with persistence, suggesting that anal cancer screening remains a priority for all transgender women regardless of HIV status.

Euzen and colleagues (Abstract 1011) examined anal microbiome dynamics in MSM from the DEPIST-H (Prevalence and Longitudinal Follow-up of Anal Lesions, HPV Infection, and Associated Sexually Transmitted Infections Among Men Who Have Sex With Men in Togo) cohort and determined that primary HSV infection was associated with shifts in microbial composition over time, whereas HR-HPV persistence aligned with proinflammatory dysbiosis signatures characterized by the depletion of protective genera and enrichment of inflammation-linked taxa. This study points to a potential role for virus-microbiome interactions in sustaining HPV persistence.

Immune status shapes not only susceptibility to HPV but the response to vaccination against it, as 2 studies from CROI 2026 demonstrated. Nuwagaba-Biribonwoha and colleagues (Abstract 157) compared 2-dose 9-valent HPV vaccine regimens in children, adolescents, and young women with HIV against the standard 3-dose regimen in adolescent girls and young women without HIV in Eswatini, finding noninferior immunogenicity for nearly all subtypes across cohorts with HIV, with the exception of HPV-45 in older adolescent girls and young women. Crucially, those with unsuppressed viral load had lower titers and did not meet noninferiority thresholds, supporting 2-dose regimens for PWH only in the context of maintained viral suppression. Supporting those findings, Ansaldo and colleagues (Abstract 1010) found that a baseline CD4+ count above 500 cells/μL was associated with stronger early cellular immune responses to HPV vaccination, including larger increases in CD4+ and CD8+ polyfunctional T cells, suggesting that tailored vaccination schedules may be warranted for those with lower CD4+ cell counts to ensure durable protection.

Implementation of anal cancer screening programs revealed their feasibility in real-world settings and persistent challenges. Andrews and colleagues (Abstract 638) analyzed 2223 anal cytology samples at a large Ryan White HIV/AIDS Program-funded clinic in Dallas, Texas, and found that 79% of patients opted for self-collection, with no difference in unsatisfactory rates or cytology results compared with clinician collection. However, a 24% unsatisfactory rate overall highlighted the crucial importance of the collection technique as programs scale up.

Hessamfar and colleagues (Abstract 641) reported 2-year outcomes following the implementation of French national screening recommendations at Bordeaux University Hospital, where self-sampling for HPV-16 during routine HIV visits identified positivity in 23% of MSM, with severe dysplasia in 36% of those undergoing highresolution anoscopy (HRA) and biopsy. However, it also identified key implementation gaps, including underreferral of women, high invalid sample rates, and markedly limited HRA access, with only 1 capable center serving a region of 6 million people. Geba and Thomas (Abstract 640) mapped HRA clinics and practitioners nationally, finding that 23 US states lacked a single HRA clinic and that PWH in the South and Midwest face the greatest barriers to access, which is an important reminder that any guideline recommendations will not be realized without investment in infrastructure.

Refining who should be screened, and how intensively, is a central challenge as anal and oropharyngeal cancer prevention programs expand. Bandala-Jacques and colleagues (Abstract 121) analyzed oropharyngeal squamous cell carcinoma incidence across 21 NA-ACCORD (The North American AIDS Cohort Collaboration on Research and Design) cohorts spanning from 2000 to 2020, finding that rates tripled over this period and that risk was independently higher in men, in those aged 50 years and older, in those who have ever smoked, and in those with a CD4+ count nadir below 200 cells/μL. Notably, heterosexual men had the highest incidence, a finding that challenges screening frameworks focused primarily on MSM and suggests that immunosuppression and smoking history need to inform broader surveillance. Aradan and colleagues (Abstract 639) developed and validated an artificial intelligence (AI) model using immune parameters including the CD4+/CD8+ cell ratio and immune health grade to predict anal dysplasia among PWH. Multivariable models outperformed CD4+ cell count alone and the nadir CD4+/CD8+ cell ratio was the strongest individual predictor, with the approach offering the potential to reduce unnecessary HRAs and better identifying individuals who could benefit.

Aceiton and colleagues (Abstract 642) developed a machine-learning-based risk stratification score using routine clinical variables from 157,725 PWH across the ART-CC (Antiretroviral Therapy Cohort Collaboration) cohort, finding that an extreme gradient boosting model achieved higher sensitivity than current clinical guidelines and reduced the proportion classified as screening eligible, with nadir CD4+ cell count, age, and years in HIV care emerging as the strongest predictors; this provides a potential approach to improve screening efficiency in settings where HRA capacity remains severely constrained.