Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition.

BACKGROUND: Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear. METHODS: We enrolled at-risk cisgender men and transgender persons in the Americas and Europe in the HVTN 704/HPTN 085 trial and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081 trial. Participants were randomly assigned to receive, every 8 weeks, infusions of a bnAb (VRC01) at a dose of either 10 or 30 mg per kilogram (low-dose group and high-dose group, respectively) or placebo, for 10 infusions in total. HIV-1 testing was performed every 4 weeks. The VRC01 80% inhibitory concentration (IC80) of acquired isolates was measured with the TZM-bl assay. RESULTS: Adverse events were similar in number and severity among the treatment groups within each trial. Among the 2699 participants in HVTN 704/HPTN 085, HIV-1 infection occurred in 32 in the low-dose group, 28 in the high-dose group, and 38 in the placebo group. Among the 1924 participants in HVTN 703/HPTN 081, infection occurred in 28 in the low-dose group, 19 in the high-dose group, and 29 in the placebo group. The incidence of HIV-1 infection per 100 person-years in HVTN 704/HPTN 085 was 2.35 in the pooled VRC01 groups and 2.98 in the placebo group (estimated prevention efficacy, 26.6%; 95% confidence interval [CI], -11.7 to 51.8; P = 0.15), and the incidence per 100 person-years in HVTN 703/HPTN 081 was 2.49 in the pooled VRC01 groups and 3.10 in the placebo group (estimated prevention efficacy, 8.8%; 95% CI, -45.1 to 42.6; P = 0.70). In prespecified analyses pooling data across the trials, the incidence of infection with VRC01-sensitive isolates (IC80 <1 µg per milliliter) per 100 person-years was 0.20 among VRC01 recipients and 0.86 among placebo recipients (estimated prevention efficacy, 75.4%; 95% CI, 45.5 to 88.9). The prevention efficacy against sensitive isolates was similar for each VRC01 dose and trial; VRC01 did not prevent acquisition of other HIV-1 isolates. CONCLUSIONS: VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that bnAb prophylaxis can be effective. (Supported by the National Institute of Allergy and Infectious Diseases; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 ClinicalTrials.gov numbers, NCT02716675 and NCT02568215.).

Negative clinic experiences as a barrier to care for people with HIV and their impact on patient preferences for intervention support: a qualitative study in Cape Town, South Africa.

We conducted qualitative research among people with HIV (PWH) and care providers in Cape Town, South Africa to understand the impact of negative clinic experiences on adherence and support preferences. In-depth interviews were conducted with 41 patients with an unsuppressed viral load or a treatment gap, and focus group discussions with physicians, nurses, counselors, and community health workers. Questions addressed treatment history and adherence barriers, then participants evaluated evidence-based adherence interventions for potential scale up. Inductive analysis examined care experiences and corresponding preference for intervention options. More than half of PWH described negative experiences during clinic visits, including mistreatment by staff and clinic administration issues, and these statements were corroborated by providers. Those with negative experiences in care stated that fear of mistreatment led to nonadherence. Most patients with negative experiences preferred peer support groups or check-in texts to clinic-based interventions. We found that PWH's negative clinic experiences were a primary reason behind nonadherence and influenced preferences for support mechanisms. These findings emphasize the importance of HIV treatment adherence interventions at multiple levels both in and outside of the clinic, and providing more comprehensive training to providers to better serve PWH in adherence counseling, especially those who are most vulnerable..

Acceptability and Feasibility of Providing Adherence Feedback Based on Tenofovir Diphosphate in Dried Blood Spots: Results from a Pilot Study Among Patients and Providers in Cape Town, South Africa.

Tenofovir diphosphate (TFV-DP) concentrations in dried blood spots (DBS) predict viral breakthrough, but their use remains understudied in real-world clinic settings. This pilot study examined acceptability, feasibility, and initial adherence outcomes of providing adherence feedback using TFV-DP concentrations on patient- and provider-levels in Cape Town, South Africa. We enrolled 60 persons with HIV (PWH) receiving tenofovir-containing ART attending a primary health clinic. They were randomized 1:1 to an intervention receiving TFV-DP concentration feedback by research staff vs. no feedback at monthly visits for 4 months. Acceptability among medical providers and level of clinical follow-up of TFV-DP results was examined. Patient acceptability was assessed descriptively. Mean electronic adherence (EA), as measured by WisePill device, and TFV-DP in DBS were compared between the two arms. All participants in the intervention group (100%) reported finding TFV-DP feedback helpful and 86% reported changing adherence behaviors. Medical providers indicated high acceptability of incorporating TFV-DP concentration feedback into the clinic, yet among 29 results < 1000 fmol/punch, only 2 were reviewed with no follow-up actions performed. In the intervention arm, mean TFV-DP concentrations were significantly higher (t = 2.5, p < .01) during follow-up and EA in upper quartile (96-100%) was greater compared to controls (x2 = 7.8, p ≤ .05). This study found high acceptability among patients for receiving adherence feedback based on TFV-DP concentrations. TFV-DP and EA data demonstrated greater adherence in the intervention group. Providers indicated high acceptability of incorporating TFV-DP feedback into the clinic, but few providers reviewed results, which could impact clinic-level feasibility.

Perspectives of people living with HIV and health workers about a point-of-care adherence assay: a qualitative study on acceptability.

Current antiretroviral therapy (ART) adherence monitoring is premised on patients' self-reported adherence behaviour (prone to recall error) and verified by blood viral load measurement (which can delay results). A newly developed Urine Tenofovir Rapid Assay (UTRA) assesses tenofovir in urine at point-of-care and is a novel tool to test and immediately respond to adherence levels of people living with HIV (PLHIV). We explored PLHIV and health workers' initial perceptions about integrating the UTRA into routine medical care for adherence support. We conducted a series of once-off in-depth qualitative interviews with PLHIV (n = 25) and health workers (n = 5) at a primary care health facility in Cape Town, South Africa. Data analysis involved descriptive summaries of key emergent themes with illustrative case examples. We applied a deductive, outcomes-driven analytic approach to the summaries using the Implementation Outcomes Framework proffered by Proctor et al. (2011). The three relevant concepts from this framework that guided our evaluation were: acceptability, appropriateness, and feasibility. We found positive perceptions about the UTRA from many PLHIV and health worker participants. Many PLHIV reported that the immediate results offered by the UTRA could enable them to have constructive discussions with health workers on how to resolve adherence challenges in real-time. Few PLHIV reported concerns that drinking alcohol could affect their UTRA results. Many health workers reported that the UTRA could help them identify patients at risk of treatment failure and immediately intervene through counselling, though some relayed that they would support the UTRA's implementation if more staff members could be added in their busy facility. Overall, these findings show that the UTRA was widely perceived to be acceptable and actionable by many PLHIV and health workers in the study.

Conceptualising engagement with HIV care for people on treatment: the Indicators of HIV Care and AntiRetroviral Engagement (InCARE) Framework.

BACKGROUND: As the crisis-based approach to HIV care evolves to chronic disease management, supporting ongoing engagement with HIV care is increasingly important to achieve long-term treatment success. However, 'engagement' is a complex concept and ambiguous definitions limit its evaluation. To guide engagement evaluation and development of interventions to improve HIV outcomes, we sought to identify critical, measurable dimensions of engagement with HIV care for people on treatment from a health service-delivery perspective. METHODS: We used a pragmatic, iterative approach to develop a framework, combining insights from researcher experience, a narrative literature review, framework mapping, expert stakeholder input and a formal scoping review of engagement measures. These inputs helped to refine the inclusion and definition of important elements of engagement behaviour that could be evaluated by the health system. RESULTS: The final framework presents engagement with HIV care as a dynamic behaviour that people practice rather than an individual characteristic or permanent state, so that people can be variably engaged at different points in their treatment journey. Engagement with HIV care for those on treatment is represented by three measurable dimensions: 'retention' (interaction with health services), 'adherence' (pill-taking behaviour), and 'active self-management' (ownership and self-management of care). Engagement is the product of wider contextual, health system and personal factors, and engagement in all dimensions facilitates successful treatment outcomes, such as virologic suppression and good health. While retention and adherence together may lead to treatment success at a particular point, this framework hypothesises that active self-management sustains treatment success over time. Thus, evaluation of all three core dimensions is crucial to realise the individual, societal and public health benefits of antiretroviral treatment programmes. CONCLUSIONS: This framework distils a complex concept into three core, measurable dimensions critical for the maintenance of engagement. It characterises elements that the system might assess to evaluate engagement more comprehensively at individual and programmatic levels, and suggests that active self-management is an important consideration to support lifelong optimal engagement. This framework could be helpful in practice to guide the development of more nuanced interventions that improve long-term treatment success and help maintain momentum in controlling a changing epidemic.

Use of Tenofovir Diphosphate Levels to Predict Viremia During the Postpartum Period in Women Living With Human Immunodeficiency Virus (HIV): A Nested Case-Control Study.

BACKGROUND: There are few data on the utility of tenofovir diphosphate (TFV-DP) in dried blood spots (DBSs) to predict future viral load (VL) in postpartum women with HIV on antiretroviral therapy (ART). METHODS: We conducted a nested case-control study within a trial of postpartum ART delivery strategies. Participants started ART containing tenofovir disoproxil fumarate (TDF) in pregnancy, were <10 weeks postpartum, and had a VL <400 copies/mL. VL and TFV-DP samples were taken every 3-6 months over 24 months. Cases had ≥1 VL ≥20 copies/mL; controls were randomly sampled from women with persistent viral suppression (VS; VL <20 copies/mL). Generalized estimating equations were used to calculate likelihood odds ratios (LORs) for future VL ≥20 copies/mL by TFV-DP concentration at the preceding visit. RESULTS: 61 cases and 20 controls contributed 365 DBS-VL pairs (median ART duration, 16 months). Sensitivity and specificity of TFV-DP <700 fmol/punch to detect future viremia were 62.9% (95% CI, 54.7-70.6%) and 89.7% (84.9-93.4%), respectively. Adjusting for age, ART duration, previous VL, and duration between the TFV-DP and VL measures, LORs of viremia for TFV-DP concentrations 350-699 and <350 fmol/punch versus TFV-DP ≥1850 fmol/punch were 3.5 (95% CI, 1.1-10.8; P = .033) and 12.9 (3.6-46.6; P < .0001), respectively. Including only samples taken during VS, the LOR of future viremia for TFV-DP concentration <350 fmol/punch versus TFV-DP ≥1850 fmol/punch was 9.5 (1.9-47.0). CONCLUSIONS: TFV-DP concentrations in DBSs were strongly associated with future viremia and appear useful to identify nonadherence and predict future elevated VL.

Adherence Measured Using Electronic Dose Monitoring is Associated with Emergent Antiretroviral Resistance and Poor Outcomes in People with Human Immunodeficiency Virus/AIDS and Multidrug-Resistant Tuberculosis.

BACKGROUND: Medication adherence is known to challenge treatment of human immunodeficiency virus (HIV)/AIDS and multidrug-resistant tuberculosis (MDR-TB). We hypothesized that adherence using electronic dose monitoring (EDM) would identify an antiretroviral therapy (ART) adherence threshold for emergent ART resistance and predict treatment outcomes in patients with MDR-TB and HIV on ART and bedaquiline-containing TB regimens. METHODS: A prospective cohort of adults with MDR-TB and HIV on ART and initiating MDR-TB treatment with bedaquiline were enrolled at a public hospital in KwaZulu-Natal, South Africa (PRAXIS Study). Participants received separate EDM devices that measure adherence to bedaquiline and ART (nevirapine or lopinavir/ritonavir). Adherence was calculated cumulatively over 6 months. Participants were followed through completion of MDR-TB treatment. HIV genome sequencing was performed at baseline and 2 and 6 months on samples with HIV RNA ≥1000 copies/mL. RESULTS: From November 2016 through February 2018, 198 persons with MDR-TB and HIV were enrolled and followed (median, 17.2 months; interquartile range, 12.2-19.6). Eleven percent had baseline ART resistance mutations, and 7.5% developed emergent ART resistance at 6 months. ART adherence was independently associated with ART resistance and mortality. Modeling identified a significant (P < .001), linear association between ART adherence and emergent resistance, suggesting a strong association without a specific threshold. CONCLUSIONS: Our findings highlight the need for ART resistance testing, especially in patients with MDR-TB and HIV, which is currently not the standard of care in resource-limited settings. Despite short follow-up duration, reduced ART adherence was significantly associated with emergent resistance and increased mortality. CLINICAL TRIALS REGISTRATION: NCT03162107.

The Effect of Rifampicin on Darunavir, Ritonavir, and Dolutegravir Exposure within Peripheral Blood Mononuclear Cells: a Dose Escalation Study.

Ritonavir-boosted darunavir (DRV/r) and dolutegravir (DTG) are affected by induction of metabolizing enzymes and efflux transporters caused by rifampicin (RIF). This complicates the treatment of people living with HIV (PLWH) diagnosed with tuberculosis. Recent data showed that doubling DRV/r dose did not compensate for this effect, and hepatic safety was unsatisfactory. We aimed to evaluate the pharmacokinetics of DRV, ritonavir (RTV), and DTG in the presence and absence of RIF in peripheral blood mononuclear cells (PBMCs). PLWH were enrolled in a dose-escalation crossover study with 6 treatment periods of 7 days. Participants started with DRV/r 800/100 mg once daily (QD), RIF and DTG were added before the RTV dose was doubled, and then they received DRV/r 800/100 twice daily (BD) and then 1,600/200 QD or vice versa. Finally, RIF was withdrawn. Plasma and intra-PBMC drug concentrations were measured through validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Seventeen participants were enrolled but only 4 completed all study phases due to high incidence of liver toxicity. Intra-PBMC DRV trough serum concentration (Ctrough) after the addition of RIF dropped from a median (interquartile range [IQR]) starting value of 261 ng/mL (158 to 577) to 112 ng/mL (18 to 820) and 31 ng/mL (12 to 331) for 800/100 BD and 1,600/200 QD DRV/r doses, respectively. The DRV intra-PBMC/plasma ratio increased significantly (P = 0.003). DTG and RIF intra-PBMC concentrations were in accordance with previous reports in the absence of RIF or DRV/r. This study showed a differential impact of enzyme and/or transporter induction on DRV/r concentrations in plasma and PBMCs, highlighting the usefulness of studying intra-PBMC pharmacokinetics with drug-drug interactions. (This study has been registered at ClinicalTrials.gov under registration no. NCT03892161.).

Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study.

BACKGROUND: Phase 3 clinical studies showed non-inferiority of long-acting intramuscular cabotegravir and rilpivirine dosed every 4 weeks to oral antiretroviral therapy. Important phase 2 results of every 8 weeks dosing, and supportive modelling, underpin further evaluation of every 8 weeks dosing in this trial, which has the potential to offer greater convenience. Our objective was to compare the week 48 antiviral efficacy of cabotegravir plus rilpivirine long-acting dosed every 8 weeks with that of every 4 weeks dosing. METHODS: ATLAS-2M is an ongoing, randomised, multicentre (13 countries; Australia, Argentina, Canada, France, Germany, Italy, Mexico, Russia, South Africa, South Korea, Spain, Sweden, and the USA), open-label, phase 3b, non-inferiority study of cabotegravir plus rilpivirine long-acting maintenance therapy administered intramuscularly every 8 weeks (cabotegravir 600 mg plus rilpivirine 900 mg) or every 4 weeks (cabotegravir 400 mg plus rilpivirine 600 mg) to treatment-experienced adults living with HIV-1. Eligible newly recruited individuals must have received an uninterrupted first or second oral standard-of-care regimen for at least 6 months without virological failure and be aged 18 years or older. Eligible participants from the ATLAS trial, from both the oral standard-of-care and long-acting groups, must have completed the 52-week comparative phase with an ATLAS-2M screening plasma HIV-1 RNA less than 50 copies per mL. Participants were randomly assigned 1:1 to receive cabotegravir plus rilpivirine long-acting every 8 weeks or every 4 weeks. The randomisation schedule was generated by means of the GlaxoSmithKline validated randomisation software RANDALL NG. The primary endpoint at week 48 was HIV-1 RNA ≥50 copies per mL (Snapshot, intention-to-treat exposed), with a non-inferiority margin of 4%. The trial is registered at ClinicalTrials.gov, NCT03299049 and is ongoing. FINDINGS: Screening occurred between Oct 27, 2017, and May 31, 2018. Of 1149 individuals screened, 1045 participants were randomised to the every 8 weeks (n=522) or every 4 weeks (n=523) groups; 37% (n=391) transitioned from every 4 weeks cabotegravir plus rilpivirine long-acting in ATLAS. Median participant age was 42 years (IQR 34-50); 27% (n=280) female at birth; 73% (n=763) white race. Cabotegravir plus rilpivirine long-acting every 8 weeks was non-inferior to dosing every 4 weeks (HIV-1 RNA ≥50 copies per mL; 2% vs 1%) with an adjusted treatment difference of 0·8 (95% CI -0·6-2·2). There were eight (2%, every 8 weeks group) and two (<1%, every 4 weeks group) confirmed virological failures (two sequential measures ≥200 copies per mL). For the every 8 weeks group, five (63%) of eight had archived non-nucleoside reverse transcriptase inhibitor resistance-associated mutations to rilpivirine at baseline. The safety profile was similar between dosing groups, with 844 (81%) of 1045 participants having adverse events (excluding injection site reactions); no treatment-related deaths occurred. INTERPRETATION: The efficacy and safety profiles of dosing every 8 weeks and dosing every 4 weeks were similar. These results support the use of cabotegravir plus rilpivirine long-acting administered every 2 months as a therapeutic option for people living with HIV-1. FUNDING: ViiV Healthcare and Janssen.

High residual inflammation despite HIV viral suppression: Lessons learned from real-time adherence monitoring among people with HIV in Africa.

BACKGROUND: Lower antiretroviral therapy (ART) adherence is associated with higher systemic inflammation in virally suppressed people with HIV (PWH); however, previous studies have mostly relied on subjective adherence measures and have not assessed this association by disease stage upon ART initiation. METHODS: In the Monitoring Early Treatment Adherence study, adherence was monitored electronically in real time among adult, treatment-naïve PWH in Uganda and South Africa who initiated tenofovir disoproxil fumarate/emtricitabine/efavirenz during early-stage (CD4 > 350 cells/µL) or late-stage (CD4 < 200 cells/µL) disease. Participants who achieved viral suppression (< 400 copies/mL) at 6 months and remained suppressed after 12 months were analysed. The association between average ART adherence and plasma concentrations of interleukin 6 (IL-6), soluble CD14 (sCD14) and D-dimer was evaluated using adjusted multivariable linear regression, stratified by disease stage. RESULTS: In all, 488 PWH (61% women, mean age 35 years) were included in the analysis. Median ART adherence overall was 87%. In adjusted models, every 10% increase in average adherence was associated with a 3.0% decrease in IL-6 [95% confidence interval (CI): -5.9 to -0.01, p = 0.05] at 12 months. This relationship was observed in PWH with both early-stage (5.9%, 95% CI: -10.1 to -1.6, p = 0.009) and late-stage disease (3.7%, 95% CI: -7.2 to -0.2, p = 0.039). No significant associations were found with sCD14 or D-dimer. CONCLUSIONS: Objective ART adherence measurement was inversely associated with systemic inflammation in PWH who achieved viral suppression after ART initiation in sub-Saharan Africa, with a greater association in those with early-stage HIV. This finding underscores the importance of ART adherence beyond establishing viral suppression.

Gender Moderates Results of a Randomized Clinical Trial for the Khanya Intervention for Substance Use and ART Adherence in HIV Care in South Africa.

Little is known about gender effects of alcohol and drug use (AOD) among people living with HIV (PLWH) in resource-limited settings. Using multilevel models, we tested whether gender moderated the effect of Khanya, a cognitive-behavioral therapy-based intervention addressing antiretroviral (ART) adherence and AOD reduction. We enrolled 61 participants from HIV care and examined outcomes at 3- and 6-months compared to enhanced treatment as usual (ETAU). Gender significantly moderated the effect of Khanya on ART adherence (measured using electronically-monitored and biomarker-confirmed adherence), such that women in Khanya had significantly lower ART adherence compared to men in Khanya; no gender differences were found for AOD outcomes. Exploratory trajectory analyses showed men in Khanya and both genders in ETAU had significant reductions in at least one AOD outcome; women in Khanya did not. More research is needed to understand whether a gender lens can support behavioral interventions for PLWH with AOD.Trial registry ClinicalTrials.gov identifier: NCT03529409. Trial registered on May 18, 2018.

Patients' and Providers' Views on Optimal Evidence-Based and Scalable Interventions for Individuals at High Risk of HIV Treatment Failure: Sequential Explorations Among Key Stakeholders in Cape Town, South Africa.

To support translation of evidence-based interventions into practice for HIV patients at high risk of treatment failure, we conducted qualitative research in Cape Town, South Africa. After local health officials vetted interventions as potentially scalable, we held 41 in-depth interviews with patients with elevated viral load or a 3-month treatment gap at community clinics, followed by focus group discussions (FGDs) with 20 providers (physicians/nurses, counselors, and community health care workers). Interviews queried treatment barriers, solutions, and specific intervention options, including motivational text messages, data-informed counseling, individual counseling, peer support groups, check-in texts, and treatment buddies. Based on patients' preferences, motivational texts and treatment buddies were removed from consideration in subsequent FGDs. Patients most preferred peer support groups and check-in texts while individual counseling garnered the broadest support among providers. Check-in texts, peer support groups, and data-informed counseling were also endorsed by provider sub-groups. These strategies warrant attention for scale-up in South Africa and other resource-constrained settings.

Understanding Repeat Positive HIV Testing in South Africa Under Changing Treatment Guidelines.

Some people with HIV (PWH) test positive multiple times without initiating antiretroviral therapy (ART). We surveyed 496 ART-eligible PWH following routine HIV testing at three clinics in Soweto and Gugulethu, South Africa in 2014-2015. Among repeat positive testers (RPTs) in this cohort, we compared rates of treatment initiation by prior treatment eligibility and assessed psychosocial predictors of treatment initiation in logistic regression models. RPTs represented 33.8% of PWH in this cohort. Less than half of those who reported eligibility for ART on prior testing started treatment upon retesting, in contrast to two thirds of RPTs who were previously ineligible for treatment who started treatment once they learned of their eligibility. Those who reported coping through substance use were more likely to decline treatment versus those not using substances. PWH who test repeatedly represent a vulnerable population at risk for ART non-initiation who may benefit from interventions addressing individualized coping strategies.

Accuracy of measures for antiretroviral adherence in people living with HIV.

BACKGROUND: Good patient adherence to antiretroviral (ART) medication determines effective HIV viral suppression, and thus reduces the risk of progression and transmission of HIV. With accurate methods to monitor treatment adherence, we could use simple triage to target adherence support interventions that could help in the community or at health centres in resource-limited settings. OBJECTIVES: To determine the accuracy of simple measures of ART adherence (including patient self-report, tablet counts, pharmacy records, electronic monitoring, or composite methods) for detecting non-suppressed viral load in people living with HIV and receiving ART treatment. SEARCH METHODS: The Cochrane Infectious Diseases Group Information Specialists searched CENTRAL, MEDLINE, Embase, LILACS, CINAHL, African-Wide information, and Web of Science up to 22 April 2021. They also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for ongoing studies. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included studies of all designs that evaluated a simple measure of adherence (index test) such as self-report, tablet counts, pharmacy records or secondary database analysis, or both, electronic monitoring or composite measures of any of those tests, in people living with HIV and receiving ART treatment. We used a viral load assay with a limit of detection ranging from 10 copies/mL to 400 copies/mL as the reference standard. We created 2 × 2 tables to calculate sensitivity and specificity. DATA COLLECTION AND ANALYSIS: We screened studies, extracted data, and assessed risk of bias using QUADAS-2 independently and in duplicate. We assessed the certainty of evidence using the GRADE method. The results of estimated sensitivity and specificity were presented using paired forest plots and tabulated summaries. We encountered a high level of variation among studies which precluded a meaningful meta-analysis or comparison of adherence measures. We explored heterogeneity using pre-defined subgroup analysis. MAIN RESULTS: We included 51 studies involving children and adults with HIV, mostly living in low- and middle-income settings, conducted between 2003 and 2021. Several studies assessed more than one index test, and the most common measure of adherence to ART was self-report. - Self-report questionnaires (25 studies, 9211 participants; very low-certainty): sensitivity ranged from 10% to 85% and specificity ranged from 10% to 99%. - Self-report using a visual analogue scale (VAS) (11 studies, 4235 participants; very low-certainty): sensitivity ranged from 0% to 58% and specificity ranged from 55% to 100%. - Tablet counts (12 studies, 3466 participants; very low-certainty): sensitivity ranged from 0% to 100% and specificity ranged from 5% to 99%. - Electronic monitoring devices (3 studies, 186 participants; very low-certainty): sensitivity ranged from 60% to 88% and the specificity ranged from 27% to 67%. - Pharmacy records or secondary databases (6 studies, 2254 participants; very low-certainty): sensitivity ranged from 17% to 88% and the specificity ranged from 9% to 95%. - Composite measures (9 studies, 1513 participants; very low-certainty): sensitivity ranged from 10% to 100% and specificity ranged from 49% to 100%. Across all included studies, the ability of adherence measures to detect viral non-suppression showed a large variation in both sensitivity and specificity that could not be explained by subgroup analysis. We assessed the overall certainty of the evidence as very low due to risk of bias, indirectness, inconsistency, and imprecision. The risk of bias and the applicability concerns for patient selection, index test, and reference standard domains were generally low or unclear due to unclear reporting. The main methodological issues identified were related to flow and timing due to high numbers of missing data. For all index tests, we assessed the certainty of the evidence as very low due to limitations in the design and conduct of the studies, applicability concerns and inconsistency of results. AUTHORS' CONCLUSIONS: We encountered high variability for all index tests, and the overall certainty of evidence in all areas was very low. No measure consistently offered either a sufficiently high sensitivity or specificity to detect viral non-suppression. These concerns limit their value in triaging patients for viral load monitoring or enhanced adherence support interventions.

Determinants and reasons for switching anti-retroviral regimen among HIV-infected youth in a large township of South Africa (2002-2019).

BACKGROUND: There are limited data exploring antiretroviral therapy (ART) changes and time to change among South Africa young people living with HIV/AIDS. OBJECTIVE: We describe the time to first drug switch, which includes ART regimen change (three drug switch) and substitutions (single drug switch). We describe common reasons for ART switch among young people aged 10 to 24 years in South Africa. METHODS: We conducted a retrospective cohort study at a primary health care clinic in Cape Town, South Africa, providing ART to HIV-infected adolescents and adults since 2002. Those aged 10 to 24 years at ART initiation, who accessed care clinic between September 2002 and April 2019. Data was retrieved from electronic information systems: ART regimens, ART changes, dates for initiation or stop of each drug/regimen, laboratory results (viral loads, haemoglobin, liver enzyme results, and creatinine to support the reason for ART switch. From written records, we abstracted reason for single drug switch or regimen change, as well as socio demographic and clinical data. We fitted cox regression models to determine factors associated with ART switch (Having a change in one or more drugs in ART combination) and the rate of occurrence. RESULTS: Of 2601 adolescents included, 605 (24.9%) adolescents switched ART over 5090.5 person years at risk (PYAR), a rate of 11.9 /100PYAR. Median follow-up time was 4.4 (± 3.2) years. At multivariable analysis, the older age group was protective of the risk of ART switch: adjusted Hazard Ratio [aHR] 0.78, 95% CI 0.62-0.98, transfer status [transferred out 1.42 [1.11-1.82]. The hazard of ART switch increased with more severe HIV-disease at ART start, as observed by increasing WHO clinical stage or reduced CD4 count at baseline. The primary reasons for ART switch were side effects (20.0%), virological failure (17.9%) and formulation switch (27.8%). Others reasons included pregnancy, Hepatitis B, tuberculosis and psychosis. CONCLUSION: ART switches are frequent and occur at a consistent rate across 7.5 years from initiation. The main reasons for ART switch were virological failure and drug side effects.

Infant Exposure to Dolutegravir Through Placental and Breast Milk Transfer: A Population Pharmacokinetic Analysis of DolPHIN-1.

BACKGROUND: Rapid reduction in human immunodeficiency virus (HIV) load is paramount to prevent peripartum transmission in women diagnosed late in pregnancy. We investigated dolutegravir population pharmacokinetics in maternal plasma, umbilical cord, breast milk, and infant plasma samples from DolPHIN-1 participants (NCT02245022) presenting with untreated HIV late in pregnancy (28-36 weeks gestation). METHODS: Pregnant women from Uganda and South Africa were randomized (1:1) to daily dolutegravir (50 mg/d) or efavirenz-based therapy. Dolutegravir pharmacokinetic sampling (0-24 hours) was undertaken 14 days after treatment initiation and within 1-3 weeks after delivery, with matched maternal and cord samples at delivery. Mothers were switched to efavirenz, and maternal and infant plasma and breast milk samples were obtained 24, 48, or 72 hours after the switch. Nonlinear mixed-effects modeling was used to describe dolutegravir in all matrices and to evaluate covariates. RESULTS: A total of 28 women and 22 infants were included. Maternal dolutegravir was described by a 2-compartment model linked to a fetal and breast milk compartment. Cord and breast milk to maternal plasma ratios were 1.279 (1.209-1.281) and 0.033 (0.021-0.050), respectively. Infant dolutegravir was described by breast milk-to-infant and infant elimination rate constants. No covariate effects were observed. The median predicted infant dolutegravir half-life and median time to protein-adjusted 90% inhibitory concentration (0.064 mg/L) for those above this threshold were 37.9 (range, 22.1-63.5) hours and 108.9 (18.6-129.6) hours (4.5 [0.8-5.4] days) (n = 13), respectively. CONCLUSIONS: Breastfeeding contributed relatively little to infant plasma exposure, but a median of 4.5 days of additional prophylaxis to some of the breastfed infants was observed after cessation of maternal dolutegravir (3-15 days postpartum), which waned with time postpartum as transplacental dolutegravir cleared.

Electronic Dose Monitoring Identifies a High-Risk Subpopulation in the Treatment of Drug-resistant Tuberculosis and Human Immunodeficiency Virus.

BACKGROUND: In generalized drug-resistant tuberculosis (DR-TB) human immunodeficiency virus (HIV) epidemics, identifying subpopulations at high risk for treatment failure and loss to care is critically important to improve treatment outcomes and prevent amplification of drug resistance. We hypothesized that an electronic dose-monitoring (EDM) device could empirically identify adherence-challenged patients and that a mixed-methods approach would characterize treatment challenges. METHODS: A prospective study of patients with DR-TB HIV on antiretroviral therapy (ART) initiating bedaquiline-containing regimens in KwaZulu-Natal, South Africa. Separate EDM devices measured adherence for bedaquiline and ART. Patients with low adherence (<85%) to both bedaquiline and ART were identified as high risk for poor outcomes. Baseline survey, study visit notes, and focus group discussions characterized treatment challenges. RESULTS: From December 2016-February 2018, 32 of 198 (16%) enrolled patients with DR-TB HIV were identified as dual-adherence challenged. In a multivariate model including baseline characteristics, only receiving a disability grant was significantly associated with dual nonadherence at 6 months. Mixed-methods identified treatment barriers including alcohol abuse, family conflicts, and mental health issues. Compared with adherent patients, dual-adherence-challenged patients struggled to prioritize treatment and lacked support, and dual-adherence-challenged patients experienced higher rates of detectable HIV viral load and mortality than more adherent patients. CONCLUSIONS: EDM empirically identified a subpopulation of patients with DR-TB HIV with dual-adherence challenges early in treatment. Mixed-methods revealed intense psychosocial, behavioral, and structural barriers to care in this subpopulation. Our data support developing differential, patient-centered, adherence support interventions focused on psychosocial and structural challenges for subpopulations of at-risk DR-TB HIV patients.

Association between obesity and combination antiretroviral therapy (cART) adherence among persons with early-stage HIV infection initiating cART.

BACKGROUND: Obesity is common among people living with HIV (PLWH) and early-stage infection, yet associations with combination antiretroviral (cART) adherence are unclear. METHODS: Among PLWH initiating cART in Uganda and South Africa, body mass index (BMI) was assessed at cART initiation, and cART adherence was monitored in real-time over 12 months. The association of obesity (BMI ≥ 30 kg/m2) with adherence was assessed among nonpregnant participants with CD4 > 350 cells/mm3 using fractional regression modeling. RESULTS: Among 322 participants, median age was 32 years, 70% were female, and 54% were from Uganda. Prevalence of obesity was 12% in Uganda and 28% in South Africa. Mean overall cART adherence was 83% in Uganda and 66% in South Africa. Participants with obesity had higher adherence than those without obesity: +3.6% (p = 0.44) in Uganda and +11.4% (p = 0.02) in South Africa. CONCLUSION: Obesity at cART initiation was common and associated with higher adherence, although only significantly in South Africa.

The Treatment Ambassador Program: A Highly Acceptable and Feasible Community-Based Peer Intervention for South Africans Living with HIV Who Delay or Discontinue Antiretroviral Therapy.

We conducted a novel pilot randomized controlled trial of the Treatment Ambassador Program (TAP), an 8-session, peer-based, behavioral intervention for people with HIV (PWH) in South Africa not on antiretroviral therapy (ART). PWH (43 intervention, 41 controls) completed baseline, 3- and 6-month assessments. TAP was highly feasible (90% completion), with peer counselors demonstrating good intervention fidelity. Post-intervention interviews showed high acceptability of TAP and counselors, who supported autonomy, assisted with clinical navigation, and provided psychosocial support. Intention-to-treat analyses indicated increased ART initiation by 3 months in the intervention vs. control arm (12.2% [5/41] vs. 2.3% [1/43], Fisher exact p-value = 0.105; Cohen's h = 0.41). Among those previously on ART (off for > 6 months), 33.3% initiated ART by 3 months in the intervention vs. 14.3% in the control arm (Cohen's h = 0.45). Results suggest that TAP was highly acceptable and feasible among PWH not on ART.

Emerging priorities for HIV service delivery.

Nathan Ford and co-authors discuss global priorities in the provision of HIV prevention and treatment services.