Introduction

In 1992, when San Francisco's HIV/AIDS crisis peaked, the early success of a local “curbside” HIV telephone consultation operation for practitioners supported the idea of implementing a similar program nationally. With support from the Health Resources and Services Administration (HRSA) and the Centers for Disease Control and Prevention (CDC), Dr Ronald Goldschmidt and others at San Francisco General Hospital founded the National Clinician Consultation Center (NCCC) as a resource to support clinicians through direct, “on-demand” expert consultation. Housed within the University of California San Francisco Department of Family and Community Medicine, the NCCC began providing free, distance-based teleconsultations on all aspects of HIV care to any US-based clinician, with a mission to improve health outcomes and build capacity through expert consultation and education.

Over the years, the NCCC has expanded to operate 6 distinct services, including the HIV Warmline, Post-exposure Prophylaxis line (“PEPline”), Perinatal HIV Hotline, Preexposure Prophylaxis line (“PrEPline”), Substance Use Warmline, and Hepatitis C Warmline (Table 1). The NCCC has responded to more than 340,000 calls since its inception, and the program maintains a multidisciplinary roster including HIV and viral hepatitis-experienced physicians, clinical pharmacists, advanced practice nurses, and additional backup subspecialists.

Consultants have responded to questions from a wide range of clinicians, representing different geographic locations, practice types, and levels of HIV experience. For example, nearly 60% of HIV Warmline callers have been in practice for less than 10 years, and more than 60% are at clinics delivering “high-volume” HIV care (ie, ≥20 persons with HIV followed per clinician). By contrast, PrEPline callers are relatively new to HIV care, with almost 40% staffing clinics with low-volume HIV care. As new prevention and treatment options have become available, clinical challenges and paradigms in HIV care have evolved. This article describes the 10 most common questions received by the NCCC over recent years, reflecting areas of ongoing clinical uncertainty or emerging conundrums.

Question 1: “PEP or no PEP?”

Different algorithms, protocols, and guidelines for occupational and nonoccupational blood-borne pathogen (BBP) exposure management often make it difficult for clinicians to feel confident in the management of potential BBP exposures. If initial assessments are not conducted in a timely manner, it can result in delays in accessing medications and initiating the first dose of PEP, which should ideally be started within a few hours of the exposure.

The rationale for emphasizing timely PEP initiation is based on the concept that PEP works by blocking the initial steps of local viral replication in tissue macrophages and dendritic cells, which begin shortly after exposure.^1,2 New York State guidelines highlight that after a percutaneous or mucosal exposure to HIV, there is local replication of the virus, and then within 48 to 72 hours there is replication within regional lymph nodes. Systemic viremia follows within 3 to 5 days of virus inoculation.³ The 72- hour outer limit, which has been maintained in CDC guidelines, is based on early animal studies, and no human studies have definitively established the outer limit of PEP effectiveness. Therefore, PEP regimens with the most rapid activity onset, various sites of action, and greatest potency are likely the most effective. Convenience is also important for supporting medication adherence, and single-tablet PEP options such as bictegravir (BIC) coformulated with tenofovir alafenamide (TAF) plus emtricitabine (FTC) may be well tolerated with low discontinuation rates. The source and exposed persons should also be screened for hepatitis B virus (HBV) and hepatitis C virus (HCV) as part of the standard PEP evaluation. All persons with newly diagnosed HBV or HCV should be linked to care for further evaluation and treatment.

Practitioners evaluating exposed persons should conduct an expeditious but complete evaluation to determine whether to initiate PEP, remembering that transmission requires a potentially infectious material and a clear portal of entry (eg, blood contact with intact skin does not confer any risk for transmission). Saliva, sputum, tears, urine, and feces are not considered infectious for BBPs unless visibly bloody.⁴ By contrast, other fluids, such as blood, semen, vaginal fluid, amniotic fluid, breast milk, and cerebrospinal fluid can potentially transmit BBPs. Table 2 summarizes the relative risk of transmission from different exposure routes when the source is a person with HIV with a detectable viral load. Similar to HIV, the probability of HBV transmission depends on the amount of infectious material involved and the route of inoculation: the risk of transmission after a needlestick involving a nonimmune exposed person is as high as 30% if a hepatitis B surface antigen (HBsAg)-positive source is also HBeAg positive.⁴ For HCV, evidence suggests the overall risk of transmission is lower: approximately 0.2% to 0.8% for percutaneous exposures and negligible for mucocutaneous exposures.⁴

After the initial evaluation has been conducted, additional details can help guide HIV PEP continuation or completion. This may include direct testing of the source person and information that helps guide clinical assessment of whether the source may have acquired HIV within 1 to 2 weeks before the exposure (eg, needle/equipment-sharing, condomless sex with numerous partners, or signs or symptoms of acute HIV infection [eg, fever, myalgia, lymphadenopathy]). For exposed persons on PEP, clinicians should offer brief counseling to help address concerns about the medications, which are generally very safe for most individuals. Counseling points include: (1) the potential benefit of antiemetics to relieve early adverse effects (eg, nausea has been reported in up to 20% of individuals on tenofovir disoproxil fumarate [TDF] and up to 10% on TAF); (2) the potential for drug-drug interactions between integrase strand transfer inhibitors (InSTIs; eg, raltegravir [RAL], dolutegravir [DTG], BIC) and polyvalent cations (eg, calcium, magnesium, aluminum, iron), which may be present in chewable antacids or other supplements; and (3) the importance of reporting any adverse effects. Exposed persons should have a followup soon after PEP initiation to identify and resolve any pharmacy- or insurance-related challenges, assess tolerability, and address any questions. For some people taking nonoccupational PEP (nPEP), follow-up interactions are valuable opportunities to share information on PrEP and explore options for transitioning to PrEP after nPEP completion. Furthermore, since maintaining daily adherence to a 4-week course of oral PEP may be challenging for some people, shorter-course regimens or long-acting injectable (LAI) antiretroviral (ARV) PEP regimens merit further investigation.

Question 2: “Which PrEP option should I prescribe?”

Available toolkits that review PrEP medications include the “PrEP Action Kit” from the National LGBTQIA+ Health Education Center and the “HIV PrEP Tools for Clinicians” by the National HIV PrEP Curriculum. Guidelines and PrEP experts agree that the best option for each person is the one they are most comfortable with and are able and willing to take. PrEP use is dynamic, and people may stop, restart, or change their selected option for various reasons, such as changes in relationship status, other life circumstances, and health concerns. People may also desire to stop or change PrEP due to adverse effects. Supportive interventions can help mitigate common medication initiation-related symptoms (eg, antiemetics for people starting oral PrEP or cold/warm compresses plus analgesics for injection-site reactions related to LAI PrEP). HIV practitioners can also share information on best practices for cultivating trusting patient-clinician relationships and a welcoming environment where shared decision-making can be practiced and sustained.

For individuals who can take daily oral medications, TDF/FTC or TAF/FTC are potential options (Table 3). More than 2 decades of data support TDF/FTC as a safe and effective option, regardless of sex or risk factor. Additionally, a low-cost generic version is available. TAF/FTC is a safe and effective option approved for men who have sex with men (MSM) and transgender women that may have less impact on bone or renal function among people with risk factors for bone or renal conditions. TAF/FTC has been associated with increased weight and cholesterol level, although the long-term clinical impact of these observations is unclear.

Event-based dosing of TDF/FTC, also known as 2-1-1 dosing, is an option for MSM and transgender women who are HBsAg negative and have an estimated creatinine clearance rate above 60 mL/min (Figure 1). It consists of a loading dose of 2 TDF/FTC tablets 2 to 24 hours before sex, followed by a third tablet 24 hours and a fourth tablet 48 hours after the first double dose. This approach requires planned sex and some level of organization to adhere to the dosing strategy. Event-based dosing for female genital tract exposures is under investigation. There are data showing that protective drug concentrations of TDF/FTC persist for about 5 days longer in rectal tissues than female genital tract tissues; therefore, TDF/FTC may be needed to be continued for 7 days postexposure to maintain protective vaginal (or front-hole) drug concentrations. As such, an event-driven PrEP regimen consisting of a double dose followed by 7 days of dosing after sexual exposure (ie, 2-1-1-1-1-1-1-1) might be required for protection during vaginal sex.⁵ Modeling data were recently presented showing that 2-1-1 dosing of TDF/FTC resulted in 85% protection for 5 days after sex, and adding a fourth day of dosing (ie, 2-2-2-2, 2-1-1-1, or 2-2-1-1) achieved more than 90% protection for 7 days.⁶

Figure 1.

Examples of on-demand preexposure prophylaxis (PrEP). Adapted from Saberi et al.³⁷

Abbreviation: tab, tablet.

LAI cabotegravir (CAB-LA), administered in a clinical setting, was the first long-acting PrEP option to receive regulatory approval. CAB-LA is an option for those willing to attend clinic visits every 2 months to receive ventrogluteal injections. In June 2025, the US Food and Drug Administration (FDA) approved the LAI capsid inhibitor lenacapavir (LEN), given subcutaneously twice yearly as PrEP. Studies indicate that it reduces the risk of acquiring HIV by 96% or more.⁷

For people on tenofovir-containing products who experience a decline in renal function, close laboratory monitoring is recommended. Potential management strategies include a temporary medication pause with early reassessment, a trial of event-based dosing (if it would result in fewer than daily doses), a review and discontinuation of supplements or comedications that can adversely impact kidney function, or a transition to another PrEP medication. Although viral hepatitis screening is recommended at the initial PrEP assessment (with HBV vaccination for susceptible individuals), liver function testing is not required for ongoing monitoring. Elevated transaminase levels have been observed in some people on PrEP; however, these are generally minor, transient, and often unrelated to ARV use.⁸ People with HBV or HCV infection should be offered treatment as indicated, and people who are not yet fully immunized for hepatitis A and B should be counseled on effective prevention strategies.

Another HIV prevention modality garnering interest is the concept of “PEP-in-pocket” (PIP). PIP is a safe, feasible, and highly acceptable option that has been integrated into some PrEP/sexual health programs.⁹ It involves a clinician proactively prescribing a 28-day course of nPEP for individuals who then self-initiate it as instructed after an exposure. PIP may be a good option for people who may have a low frequency of (often unanticipated) HIV exposures (eg, 4 or fewer per year) and individuals living in areas with barriers to PrEP and PEP access.

Question 3: “Is this a false-positive HIV test result, or is something else going on?”

Falsely reactive HIV screening and testing results have been described for many reasons, including interfering antibodies, specimen handling or laboratory errors, vaccinations, and other scenarios. Overall, the prevalence of false-reactive results remains relatively low (varying by assay and population), and most reactive HIV screening tests in the US are eventually resolved to be HIV-1 infection.¹⁰

With increased screening and rapid antiretroviral therapy (ART) and PrEP delivery across various practice settings, including street-based programs, sexual health clinics, emergency departments, and hospitals, HIV practitioners should remain current on key screening and testing concepts so that results can be interpreted and applied appropriately. A deeper understanding of the technical aspects of testing, assay variability and performance characteristics, and common reasons for false-reactive results may help guide clinical decision making in some circumstances of diagnostic uncertainty. Delayed or suppressed antibody responses and seroreversion can occur with early ART or PrEP, and “sero-waffling” (ie, a reactive result followed by a nonreactive and then by a reactive result) has also been described.¹¹ “Elite controllers” remain a population of substantial interest, with traditional estimates indicating that less than 1% of people with HIV (PWH) demonstrate durable control of viremia in the absence of ART.¹² Challenges related to laboratory monitoring for people on LAI PrEP, timely HIV screening and ART initiation during pregnancy, and urgent maternal-infant management during labor and delivery after a reactive rapid test result (for mothers with previously unknown status) persist, underscoring the importance of testing as a cornerstone of HIV care.

The 2014 CDC/Association of Public Health Laboratories (APHL) testing algorithm¹³ (Figure 2) recommends that specimens with reactive results on initial HIV-1/2 antigen (Ag)/antibody (Ab) (“fourth-generation” assays) and subsequent nonreactive/indeterminate differentiation tests be followed with HIV-1 nucleic acid testing (NAT) to help identify acute HIV infection. However, the 2023 CDC/APHL technical update highlights alternative testing algorithms that have been adopted, incorporating HIV NATs that have received FDA approval for diagnostic use.¹⁰ This update includes considerations for when HIV NATs with diagnostic claims might be performed as the second step in an alternative testing sequence (Figure 3).¹⁰ Practitioners should note that interpretations and caveats of using a diagnostic NAT as the second step will differ based on which assay is used.

Figure 2.

Recommended laboratory HIV testing algorithm. Adapted from Branson et al.¹³

Abbreviations: Ag, antigen; NAT, nucleic acid test.

Figure 3.

(A, B) Alternative HIV screening/testing sequences when nucleic acid tests (NATs) with diagnostic claim are used as the second step in the algorithm. Adapted from the Centers for Disease Control and Prevention.¹⁰

^aHIV differentiation NATs that have a diagnostic claim.

^bNATs that have a diagnostic claim.

^cDoes not distinguish between established and recent infection.

^dConsider individual's history in deciding whether follow-up testing is warranted.

Although HIV immunoassays are designed to detect a variety of markers specific to HIV infection, there are subtle differences across tests (Table 4). Instrumented assays involve automated reader/software systems and proprietary algorithms based on the presence or absence (and levels) of detected markers. Furthermore, the time from HIV acquisition to reactivity for a particular assay depends on which target is being detected, when it can be detected after infection, the concentration of the target in the specimen, the volume of the specimen tested, and the test's analytical sensitivity.¹³ The ability to detect p24 antigen during acute infection is directly related to the degree of viremia, generally requiring HIV RNA levels of at least 10,000 to 20,000 copies/mL.¹⁴

HIV false-positive reactivity occurs commonly; therefore, when reviewing cases of unclear or ambiguous testing results, clinicians should inquire about recent potential HIV exposures and assess for infections or conditions that might affect results (eg, COVID-19, parasitic infections, autoimmune disorders, recent vaccination, pregnancy), and strongly consider reaching out to a medical affairs or scientific liaison or director from the clinical or reference laboratory. It can be helpful to obtain additional details from the laboratory, such as the signal-to-cut-off ratio and band patterns detected by immunoassay. For NATs, laboratories may be able to repeat testing if the sample is still available and in suitable condition. In some circumstances, additional sample collection and repeat testing may be necessary. Even if clinical suspicion favors a provisional interpretation as a falsely reactive result, clinicians should maintain a low threshold to retest and consider using a different laboratory or assay. In the current “test and treat” era of widespread rapid ART, HIV experts will be relied on to review cases of unclear screening and testing results, and offer guidance on whether to initiate, continue, or discontinue ARVs (either as HIV treatment or PrEP).

Question 4: “Is this a breakthrough infection on PrEP?”

Long-acting early viral inhibition (LEVI) was initially described by HPTN (HIV Prevention and Treatment Network) 083 and 084 study investigators who had identified baseline and incident cases of HIV infection among a small group of participants who seroconverted during their recent exposure to CAB-LA as PrEP.¹⁵ The phenomenon typically involves minimal or no clinical symptoms and is characterized by “smoldering” levels of HIV viral replication, which may persist for months even after CAB-LA discontinuation.¹⁵ During this time, HIV antibody development may be reduced or delayed, and reversions in HIV assay results (Ab, Ag, RNA, or DNA) may also occur. Timely and accurate identification of HIV infection is necessary to support prompt clinical evaluation, including initiation of suppressive ART, which also then reduces the risk of viral “escape,” emergence of HIV drug resistance, and forward HIV transmission. However, there are currently no standardized clinical guidelines for evaluating and managing unconfirmed HIV infection in the setting of PrEP use. Thus, LEVI has further highlighted crucial diagnostic and implementation challenges to address as PrEP is further scaled up, especially in resource-limited settings. Additionally, although LEVI was initially recognized as a new PrEP paradigm that occurred in the setting of CAB-LA, cases of dampened and delayed HIV antibody responses continue to be observed among people on oral PrEP.

Figure 4A illustrates the 6 Fiebig stages that have been used to describe and classify the stages involved in early HIV infection in non-PrEP users based on the different times that various viral markers and host antibody responses generally appear. After HIV acquisition, no virologic or immunologic markers are detected by routine clinical testing during the initial “eclipse period.” Thereafter, the appearance of HIV RNA in plasma appears around day 8 to 10 following infection (Stage I), with p24 antigen appearing 4 to 5 days later (Stage II), and finally, various HIV-specific antibodies with detectable seroconversion on immunoassays and Western blot (Stages III-V). The p31 band in Western blot testing usually appears 90 to 100 days after infection, signaling completion of the seroconversion period. In contrast, in some cases of HIV acquisition among people on oral PrEP, delays in reaching the various Fiebig stages and delayed seroconversion have been observed, along with lower viral load peaks and lower viral “set points” (Figure 4B). In these scenarios, clinical presentation and HIV laboratory detection were thought to be modified based on the level of PrEP adherence or PrEP initiation in the setting of an undiagnosed primary infection. To date, few cases of oral PrEP “failure” have been reported among individuals with high levels of medication adherence, with most cases attributed to the transmission of a strain of HIV that harbored TDF, FTC, or TDF/FTC drug resistance.

Figure 4.

Comparison of Fiebig Stages for primary HIV infection among (A) people who have not used preexposure prophylaxis (PrEP) versus (B) changes that may be observed in primary HIV infection among people who have used PrEP. In these scenarios, clinical presentation and HIV laboratory detection were thought to be modified based on the level of PrEP adherence or PrEP initiation in the setting of an undiagnosed primary infection. Adapted from Ambrosioni et al.³⁸

Abbreviation: IgM, immunoglobulin M.

As highlighted in the 2021 CDC Clinical Practice Guideline for PrEP update, the clinical management of ambiguous HIV test results in the context of PrEP use is not straightforward, and there is no universally favored approach at this time. Close clinical follow-up with additional laboratory testing (occasionally over several weeks to months) is typically required, and decisions regarding PrEP continuation, temporary PrEP interruption, or presumptive ART initiation should be highly individualized for each patient. Furthermore, the anticipated time for clinical laboratory detection of “occult” HIV infection among people on PrEP remains largely undefined, given how challenging it has been to identify these rare cases (especially for people on CAB-LA). Clinical research studies are underway to better understand why some individuals acquire HIV despite adherence to oral PrEP and on-time CAB-LA doses.¹⁶

Importantly, although the FDA package insert and CDC guidelines for CAB-LA use currently indicate that individuals should be assessed for acute/early HIV-1 infection with an RNA test prior to CAB-LA initiation and with or prior to each subsequent dose, this approach differs from recommendations outlined by the World Health Organization.¹⁷ Given the high efficacy and acceptability of CAB-LA as an additional PrEP option, further investigation is needed to understand the role of NAT for ongoing monitoring of people on PrEP and resolving discrepant HIV screening or testing results across various clinical scenarios.

Question 5: “What ART medications should I start for this infant?”

The US Panel on Treatment of HIV During Pregnancy and Prevention of Perinatal Transmission coordinated closely with the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV to extensively revise guidelines regarding ARV management of infants with in utero or intrapartum exposures to HIV-1, and develop new ARV recommendations for breastfeeding exposures.¹⁸ For infants with in utero or intrapartum exposures, guidelines continue to recommend the timely initiation of one or more ARVs during the immediate neonatal period, with medication selection and duration guided by the level of perinatal transmission risk, infant gestational age, and weight. For “low-risk” scenarios, zidovudine is usually administered for 2 weeks; for “high-risk” scenarios, a 3-drug regimen of zidovudine plus lamivudine plus either nevirapine or RAL is usually initiated. Given increasing use of highly effective second-generation integrase inhibitor-based therapies among people who are pregnant/breast-feeding or considering pregnancy, newer approaches to infant prophylaxis are also being evaluated. The primary medications currently used for exposed infants (eg, zidovudine, nevirapine) were first studied for this purpose in the 1990s, and are limited by side effects and concerns regarding potency. Recent studies have established safe, multidose approaches involving novel formulations of pediatric dolutegravir (eg, dispersible scored tablet, oral dispersible film): findings are informing updated global strategies for perinatal and postnatal HIV transmission prevention.^19-21

Perinatal HIV transmission and transmission during breastfeeding can be effectively prevented by ensuring use of suppressive ART before, during, and after pregnancy. Maternal viral load is the most important factor for determining HIV transmission risk, and viremia during pregnancy, particularly in the last month prior to delivery, confers elevated risk for infant HIV acquisition. To develop an appropriate care plan for exposed infants, clinicians, therefore, need complete information regarding maternal treatment and virologic response during the pregnancy, including the last few weeks prior to delivery. For women with known, established HIV infection prior to pregnancy, details should be obtained regarding which ART regimen was taken and viral load monitoring, including dates and timing of testing and exact results. For women diagnosed with HIV during pregnancy, practitioners should confirm when ART was started and when virologic suppression was achieved and maintained. In the context of maternal viremia, in utero transmission is thought to be “rare in the first trimester, uncommon but possible in the second trimester, and most common in the third trimester.”¹⁸

Figure 5 depicts the Panel's algorithm for ARV management of infants with in utero or intrapartum HIV exposure.¹⁸ The initial management of infants born to people with unconfirmed status who have at least 1 positive HIV test result at delivery (or postpartum) should follow the “high-risk” pathway. If supplemental testing confirms the mother does not have HIV, infant ARV medications can be discontinued.

Figure 5.

Algorithm for antiretroviral management of infants with in utero or intrapartum HIV exposure by risk of transmission. Adapted from clinicalinfo.hiv.gov.¹⁸

^aEarly (acute or recent) HIV infection in pregnancy may result in a scenario where viremia occurs early in gestation but is suppressed after 20 weeks and through the remainder of pregnancy until delivery. In these situations, decision-making guided by the clinical scenario is recommended.

Abbreviations: ARV, antiretroviral; NAT, nucleic acid test; PCR, polymerase chain reaction; ZDV, zidovudine.

Some observational studies describe an association between ART during pregnancy and preterm birth; mechanisms for this remain unclear. Data suggest there may be differences by ARV class; for example, the use of ritonavir-boosted protease inhibitors may be associated with an increased risk of preterm birth compared with nonboosted combinations. Given the importance of virologic suppression during pregnancy for transmission prevention, ART should not be withheld before conception or during pregnancy due to concern for preterm birth. However, hospitals should be well prepared and ensure that commonly used medications for both pregnant PWH and exposed fetuses are in stock or readily available. Currently, US guidelines do not have established dosing for lamivudine or nevirapine for infants under 32 weeks’ gestation (and RAL dosing is only available for infants ≥37 weeks and weighing ≥2 kg). Therefore, early maternal screening and treatment during pregnancy are paramount, and obstetric teams should be well prepared and supported to deliver person-centered care for birthing parents and infants.

Question 6: “My patient is interested in breastfeeding. Is that okay?”

In 2023, US guidelines for PWH shifted substantially, stating that “people with HIV should receive patient-centered, evidence-based counseling to support shared decision-making about infant feeding.”¹⁸ In 2024, the American Academy of Pediatrics updated its policy for PWH, stating that although avoidance of breastfeeding is the only option with zero transmission risk, PWH may express interest in breastfeeding, and pediatricians “should be prepared to offer a family-centered, nonjudgmental, harm-reduction approach to support PWH on ART with sustained viral suppression … who desire to breastfeed.”²² Increasing awareness of these changes and operationalization efforts across health systems is reflected in NCCC calls, with more than 40% of inquiries to the Perinatal HIV Hotline involving infant feeding discussions.

In December 2024, guidelines on infant feeding for PWH were further modified to include additional details and specific recommendations for clinical management of detectable viremia in the breastfeeding parent and ARV prophylaxis dosing for breastfed infants.¹⁸ As this area of HIV care continues to move forward, many questions remain, including: (1) How can breastfeeding PWH and their care teams prevent and respond to breastfeeding interruptions (eg, mastitis) or delayed lactation? (2) Does “mixed” feeding increase transmission risk if the breastfeeding parent remains virologically suppressed on ART? (3) Should decisions about infant feeding differ for preterm infants? (4) What do we know regarding newer ARVs (such as LAIs), HIV drug resistance, and ARV exposures via breastmilk? and (5) What is the optimal approach to transitions in feeding plans, including difficulties with weaning? Regular care coordination between health care teams supporting breastfeeding parents and infants is paramount. Guidelines continue to emphasize that engaging Child Protective Services or similar agencies is not an appropriate response to infant feeding choices of PWH.

Question 7: “Is this patient a candidate for long-acting ART?”

Although CAB/rilpivirine (RPV) LA was initially licensed for use in people with virologic suppression on a stable ART regimen with no history of treatment failure and no known or suspected resistance to its components, advocates highlighted the need to expand its use to other populations. The International Antiviral Society-USA (IAS-USA) treatment recommendations were updated in 2024,²³ stating that CAB/RPV LA may be considered when no other options are effective due to persistent inability to take oral ART, there is a high risk of HIV disease progression, intensive follow-up and case management support are incorporated, and the person's virus is susceptible to CAB and RPV.²⁴ The Panel on Antiretroviral Guidelines for Adults and Adolescents further noted that practitioners “need to be aware of the significant risk of developing resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs), and particularly InSTIs, if virologic failure occurs.”²⁵ When assessing eligibility for CAB/RPV LA initiation or continuation, several questions regarding HIV drug resistance remain, namely, whether peripheral blood mononuclear cell (PBMC) DNA genotype testing, sometimes referred to as “proviral” resistance testing, might be useful if plasma RNA resistance testing results are not available or cannot be performed.

Much remains unknown about PBMC genotyping and its application in practice, and the interpretation requires a nuanced understanding of the clinical context in which testing was performed (ie, whether specimens were obtained during a period of virologic suppression or viremia and the individual's prior ART history and virologic responses). An international working group of HIV drug resistance experts recently published guidance that details specific limitations and concerns that should be carefully considered by clinicians who utilize such tests in routine clinical practice.²⁶ Figure 6 depicts the anticipated sensitivity of PBMC testing for a treatment-experienced person with current virologic suppression on ART.²⁷ In scenario A, prior episodes of virologic failure were prolonged and associated with high plasma HIV-1 RNA levels; therefore, the likelihood of detecting mutations in PBMC DNA is higher than for scenario B, where previous episodes of virologic failure were short and associated with lower plasma HIV-1 RNA levels. As ongoing research aims to elucidate the potential utility of PBMC resistance assays and testing technologies are refined and standardized, the current best practice is still to obtain a complete clinical and laboratory testing history regarding previous ART use, virologic response, and prior genotypes to develop a cumulative list of resistance mutations.

Figure 6.

Sensitivity of peripheral blood mononuclear cell (PBMC) genotype resistance testing. (A) When past episodes of virologic failure are prolonged and the patient has high plasma HIV-1 RNA levels, the likelihood of detecting drug-resistant mutations (DRMs) in proviral DNA is high. (B) When past episodes of virologic failure are short and the patient has low plasma HIV-1 RNA levels, the likelihood of detecting DRMs in proviral DNA is low. Proviral DNA containing DRMs are indicated by red double-helixes in the boxes at the right side of the figure. Adapted from Chu et al.²⁷

Approaches vary regarding which mutations should be considered an absolute or relative contraindication to CAB/RPV LA use. The 2025 IAS-USA Drug Resistance Mutations Group update includes major and minor mutations in the reverse transcriptase and integrase genes that have been associated with CAB and RPV resistance.²⁸ These are generally identified based on in vitro studies, susceptibility testing of laboratory or clinical isolates, sequencing of viruses from people experiencing drug failure, or association studies between baseline genotype and virologic response in persons with drug exposure. San Francisco General Hospital's Ward 86 Long-Acting Injectable Antiretroviral Protocol, updated in May 2024,²⁹ includes a mutation list based on which resistance-associated mutations were observed with breakthrough viremia or infections in initial CAB/RPV LA trials. Table 5 includes a comprehensive list of these mutations.

Pooled clinical trial data identified RPV resistance-associated mutations, HIV-1 subtype A6, and body mass index above 30 kg/m² as specific baseline factors that may increase the risk of CAB/RPV LA virologic failure.^28,30 There is no consensus on how to manage low-level viremia (LLV), and data are beginning to emerge on the prevalence and outcomes of LLV among people on CAB/RPV LA. In the registrational trials, viral “blips” (ie, RNA measurements ≥50 but <200 copies/mL) were observed in 3% to 13% of participants and did not predict week 48 virologic nonresponse.^31,32 In a recent retrospective single-center analysis (n = 144, all with HIV RNA level <200 copies/mL at the time of the switch to CAB/RPV LA and followed up for a median of 287 days), 34.7%, 15.3%, and 2.8% experienced 1 or more viral load measurement of 20 copies/mL or more, 50 copies/mL or more, and 200 or more copies/mL, respectively, after starting CAB/RPV LA. Persistent LLV before the switch was associated with detectable viremia post switch. By contrast, late injections (defined as 1-28 days outside the ±7-day dosing window), dosing schedule (ie, monthly vs bi-monthly), body mass index, and preswitch minor RPV mutations (V106I, V179D, V179E) were not associated with postswitch LLV. In this cohort, among 4 individuals with viral load above 200 copies/mL on CAB/RPV LA, 3 had resuppression without intervention.³¹ A separate, prospective single-center study (n = 173, all with HIV RNA level <200 copies/mL at time of switch to bimonthly CAB/RPV LA and followed up for a median of 11.1 months) found that 31.2% had low-range intermittent viremia (defined as a single viral load between 20 and 199 copies/mL with adjacent values <20 copies/mL), and 4.0% had persistent LLV (defined as at least 2 consecutive measurements of 20-199 copies/mL). Among this cohort, higher viral load at HIV diagnosis, episodes of detectable viremia during oral ART, and level of viral suppression at the time of transition to CAB/RPV LA were associated with a higher risk of nonsustained viral suppression. Pharmacokinetic covariates measured (ie, CAB and RPV trough concentrations) did not appear to impact viral suppression outcomes.³² However, understanding the causes of nonsustained viral suppression and their potential relationship with suboptimal pharmacokinetic parameters may help prevent CAB/RPV LA failures and emergent resistance.

Question 8: “How do I screen and manage HBV for someone on 2-drug HIV therapy?”

With continued interest in the use of 2-drug combinations for HIV treatment, HBV screening and vaccination remain important interventions to prevent the development and progression of co-occurring liver disease. All people with newly diagnosed HIV infection should be screened for viral hepatitis A, B, and C. Treatment should be offered for people with HBV and/or HCV coinfection, and vaccination(s) for HAV and HBV should be offered to people without demonstrated immunity. Currently, available 2-drug ART regimens are insufficient for preventing or treating HBV coinfection, and guidelines indicate that people with coinfection who are being considered for ART simplification or switch should continue tenofovir (either as TDF or TAF) for HBV treatment as part of the individual's new ART regimen. If TAF or TDF cannot be used, entecavir should be used along with fully suppressive ART.²⁵ Without the use of effective anti-HBV agents, people who are HBV susceptible may acquire new infections, and people with chronic or prior (resolved) infections may be at increased risk for HBV reactivation. Furthermore, some PWH do not develop sufficient immunity after a primary, standard 3-dose vaccine series (ie, nonresponse), and revaccination is recommended, preferably using newer adjuvant formulations, which have demonstrated improved immunogenicity. Although some experts recommend annual HBV surveillance for PWH, especially individuals with ongoing exposures to HBV who are not on tenofovir, this may not be common practice among most HIV practitioners.

One suggested approach to this dilemma involves: (1) HBV serology reassessment (HBsAg, hepatitis B core antibody [HBcAb], hepatitis B surface antibody [HBsAb]) prior to switching to a 2-drug ART regimen; (2) vaccination and confirmation of immunity before switch, per current guidelines;²⁵ (3) annual serologies post switch to ensure sustained immunity and absence of new HBV infection; and (4) counseling about HBV reactivation potential for people with HBcAb or concern for occult HBV (with liver enzyme and HBV DNA surveillance every 1-3 months after switch, continued for 1 year or the duration of concurrent immunosuppression).³³ This strategy was adopted by a large network of urban HIV primary care clinics using an electronic health record-based quality improvement intervention and led to improved rates of complete HBV serology assessment performed within one year before switch as well as fewer switches among people at increased risk for HBV-related events (ie, HBV infection, relapse, or reactivation). A recent meta-analysis evaluating HBV reactivation after switches to HBV-inactive ART found a low but notable risk of reactivation: investigators concluded that thorough evaluation of HIV-related and other HBV reactivation risk factors “is essential before switching and should continue post switch… standardization of pre- and postswitch HBV monitoring practices remains a critical need.”³⁴

Question 9: “How do I manage hepatitis C treatment interruptions?”

Treatment interruptions during hepatitis C therapy are common and may occur for reasons such as adverse effects, gaps in medication access or insurance challenges, lapses in clinician-patient communication and coordination, acute illness, and loss to follow-up. Current guidance acknowledges that there are minimal data regarding outcomes among people who have incomplete adherence to direct-acting antiviral (DAA) therapy, and uncertainty regarding the threshold level of adherence that impacts the sustained viral response 12 weeks after completing treatment (SVR12).³⁵ Limited information is available to guide management when DAAs have been discontinued for several days to weeks, and therefore, the recommended approach to DAA interruptions for individuals who are treatment naive (without cirrhosis or with compensated cirrhosis) receiving either initial therapy with pangenotypic glecaprevir/pibrentasvir or sofosbuvir/velpatasvir may not be applicable in some cases. Furthermore, current guidance recommends the use of HCV RNA testing to help guide decisions regarding treatment extension or retreatment in some scenarios.³⁵ Although many practitioners may be able to request expedited HCV RNA results, some low-barrier HCV treatment programs may not have robust access to this type of testing.

Currently, more than 10% of calls to the NCCC Hepatitis C Warmline involve questions about evaluating and managing lapses in DAA therapy, and NCCC data suggest 2 primary patterns: (1) cases involving interruptions during the first course of therapy for individuals who are treatment-naive, typically lasting days to weeks; and (2) cases involving people who reported incomplete treatment with 1 or more courses of therapy in the remote past who are reengaging in care (in this group, interruptions may have occurred over months to years, and therefore practitioners must determine whether to consider the person treatment naive or experienced). As viral hepatitis elimination initiatives continue expanding screening and testing and treatment access in resource-rich and resource-limited settings, more data on treatment interruptions are needed to refine clinical recommendations.

Question 10: “How do I start buprenorphine?”

Buprenorphine is currently the most widely prescribed medication to treat opioid use disorder. It has several advantages, including a well-established safety profile and relative ease of use. Despite this availability, buprenorphine remains substantially underused, and several professional organizations and clinician groups have highlighted the importance of increasing buprenorphine comfort and capacity among infectious disease specialists and other HIV practitioners, given established connections between HIV and substance use. With an evolving illicit drug supply including prevalent high-potency synthetic opioids such as fentanyl, traditional buprenorphine initiation strategies have been adjusted, and induction options now include “macrodosing” and “micro (low)-dosing” approaches across various settings, including emergency departments/hospitals, outreach/low-barrier settings, and ambulatory practices (Table 6).³⁶

Table 6.

Induction Options for Microdosing, Traditional Dosing, and Macrodosing Approaches for Buprenorphine

	Microdosing		Traditional dosing	Macrodosing
	Difficulty tolerating withdrawal			Able to tolerate withdrawal
	Stop drug of choice more slowly			Stop drug of choice quickly
Protocol	7 day Day 1, 0.5 mg once Day 2, 0.5 mg BID Day 3, 1 mg QAM, 0.5 mg Q noon 1 mg QHS Day 4, 2 mg BID Day 5, 3 mg BID Day 6, 4 mg BID Day 7, option to do 4 or 8 mg tab or films Q 1-4 hr NTE 32 mg/d	4 day Day 1, 0.5 mg QID Day 2, 1 mg QID Day 3, 2 mg QID Day 4, option to do 4 or 8 mg tab or films Q 1-4 hr NTE 32 mg/d	In withdrawal with ≥2 signs, take 4 mg SL, then 4 mg Q 1-2 hr PRN withdrawal NTE final dose after 2-3 d of 32 mg/d	Day 1 16 mg SL PRN withdrawal with ≥2 signs, then 8 mg Q 1-2 hr PRN withdrawal symptoms NTE 32 mg Days 2-7 8 mg TID (in some scenarios may be up to 32 mg/d)
What to do if it goes wrong	If withdrawal during overlap period, use other opioid and ancillary meds		If worsening withdrawal after first dose, take additional 16 mg SL ASAP or other opioid	If worsening withdrawal after first dose, take an additional 16 mg SL ASAP or other opioid
Notes	4-day protocol requires Q 6 hr dosing; adherence can be difficult. Bubble packing can assist with adherence (best to use SL tablets for ease of dividing pills but films can also work)	Works well with heroin For fentanyl, due to lipophilicity, moderate-to-severe withdrawal (12-48 hr) may be needed to avoid precipitated withdrawal; use ancillary meds for comfort	Works well with heroin For fentanyl, due to lipophilicity, moderate-to-severe withdrawal (12-48 hr) may be needed to avoid precipitated withdrawal; use ancillary meds for comfort	Moderate-to-severe withdrawal (12-48 hr) may be needed to avoid precipitated withdrawal; use ancillary meds for comfort; avoid other street drugs

[i] Adapted from Coffin et al.³⁶

[ii] Abbreviations: ASAP, as soon as possible; NTE, not to exceed; PRN, as needed; SL, sublingual.

As with sharing information about HIV prevention and treatment options, practitioners considering buprenorphine can engage in shared decision-making with patients about their prior experiences with buprenorphine and offer information on various dosing strategies to develop an individualized care plan responsive to patient questions and concerns. People with recent exposure to high potency or long-acting opioids or challenges tolerating withdrawal may be more comfortable with microdosing strategies than people who are able and willing to tolerate a substantial degree of withdrawal.

Conclusion

The NCCC is a longstanding, readily available resource that supports the delivery of high-quality HIV services across the US. Calls to the NCCC reflect the dynamic nature of HIV-related science and care, as evolving approaches to prevention and treatment stimulate new clinical challenges and dialogue. In line with its mission and vision, the NCCC will continue its goal of supporting clinicians with the aim of ending the HIV epidemic.

Funding

The NCCC is supported by the HRSA of the US Department of Health and Human Services (HHS), in partnership with the CDC, via award U1OHA30039 issued to the University of California San Francisco. Dr Parya Saberi's time is also funded by the National Institute of Mental Health (award number P30MH062246).