Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women.

BACKGROUND: There are gaps in uptake of, adherence to, and persistence in the use of preexposure prophylaxis for human immunodeficiency virus (HIV) prevention among cisgender women. METHODS: We conducted a phase 3, double-blind, randomized, controlled trial involving adolescent girls and young women in South Africa and Uganda. Participants were assigned in a 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine-tenofovir alafenamide (F/TAF), or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF; active control); all participants also received the alternate subcutaneous or oral placebo. We assessed the efficacy of lenacapavir and F/TAF by comparing the incidence of HIV infection with the estimated background incidence in the screened population and evaluated relative efficacy as compared with F/TDF. RESULTS: Among 5338 participants who were initially HIV-negative, 55 incident HIV infections were observed: 0 infections among 2134 participants in the lenacapavir group (0 per 100 person-years; 95% confidence interval [CI], 0.00 to 0.19), 39 infections among 2136 participants in the F/TAF group (2.02 per 100 person-years; 95% CI, 1.44 to 2.76), and 16 infections among 1068 participants in the F/TDF group (1.69 per 100 person-years; 95% CI, 0.96 to 2.74). Background HIV incidence in the screened population (8094 participants) was 2.41 per 100 person-years (95% CI, 1.82 to 3.19). HIV incidence with lenacapavir was significantly lower than background HIV incidence (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.04; P<0.001) and than HIV incidence with F/TDF (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001). HIV incidence with F/TAF did not differ significantly from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P = 0.21), and no evidence of a meaningful difference in HIV incidence was observed between F/TAF and F/TDF (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14). Adherence to F/TAF and F/TDF was low. No safety concerns were found. Injection-site reactions were more common in the lenacapavir group (68.8%) than in the placebo injection group (F/TAF and F/TDF combined) (34.9%); 4 participants in the lenacapavir group (0.2%) discontinued the trial regimen owing to injection-site reactions. CONCLUSIONS: No participants receiving twice-yearly lenacapavir acquired HIV infection. HIV incidence with lenacapavir was significantly lower than background HIV incidence and HIV incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 1 ClinicalTrials.gov number, NCT04994509.).

Interest in Oral Pre-exposure Prophylaxis Among Men Who Have Sex with Men and Transfeminine Persons in HPTN 075, a Multi-center HIV Prevention Study in Sub-Saharan Africa (2015-2017).

Use of oral pre-exposure prophylaxis (O-PrEP) for HIV prevention has not been fully utilized in sub-Saharan Africa, especially among key populations with high HIV incidence and prevalence, including men who have sex with men (MSM) and transgender women (TGW). We examined correlates of interest in O-PrEP among participants in the HIV Prevention Trials Network (HPTN) Study 075, a prospective cohort study, conducted between 2015 and 2017, across 4 sites in Kenya, Malawi, and South Africa. The study included persons assigned male sex at birth, between 18 and 44 years of age, who reported anal intercourse with a man in the past 3 months. Interest in O-PrEP and potential correlates were assessed among 297 participants who were HIV negative. 52% of the participants reported being aware of PrEP and 73% indicated interest in PrEP once informed about it. PrEP interest was not significantly associated with any of the surveyed demographic or psychosocial variables except study site. Our findings suggest a broad and general interest in O-PrEP among MSM and TGW in sub-Saharan Africa, despite relatively low awareness. While the situation around PrEP will have changed in the included countries, major questions about successful implementation still need to be addressed.

RESUMEN: El uso de la profilaxis oral previa a la exposición (O-PrEP) para la prevención del VIH no se ha utilizado plenamente en el África subsahariana, especialmente entre poblaciones clave como los hombres que tienen sexo con hombres (HSH) y las mujeres transgénero (TGW), que demuestran alta Incidencia y prevalencia del VIH. Examinamos los correlatos de interés en O-PrEP entre los participantes en el Estudio 075 de la Red de Ensayos de Prevención del VIH (HPTN), un estudio de cohorte prospectivo, realizado entre 2015 y 2017, en 4 localidades en Kenia, Malawi y Sudáfrica. El estudio involucró a personas asignadas al sexo masculino al nacer que tenían entre 18 y 44 años de edad y que manifestaron haber tenido relaciones anales con un hombre en los últimos 3 meses. Se evaluó el interés en la O-PrEP y sus posibles correlatos entre 297 participantes que eran VIH negativos. El cincuenta y dos por ciento de los participantes reportaron tener conciencia de la existencia de PrEP y el 73% indicó interés en utilizar PrEP una vez informados sobre su existencia. El interés por la PrEP no se asoció significativamente con ninguna de las variables demográficas o psicosociales encuestadas, excepto el lugar del estudio. Nuestros hallazgos sugieren un interés amplio y general en la O-PrEP entre HSH y TGW en el África subsahariana, a pesar de un conocimiento relativamente bajo. Si bien la situación en torno a la PrEP habrá cambiado en los países incluidos, aún quedan importantes cuestiones por abordar sobre su implementación exitosa.

Interest in I-PrEP and Willingness to Participate in Clinical Trials Among Men and Transfeminine Persons Who have Sex with Men in Sub-Saharan Africa: Quantitative and Qualitative Findings from HPTN 075.

This study explored interest in injectable PrEP (I-PrEP) and willingness to participate in clinical trials testing new biomedical HIV prevention strategies among men and transfeminine persons who have sex with men (MSM & TGP), using data collected in the HIV Prevention Trials Network (HPTN) 075 study, which took place at sites in Kenya, Malawi, and South Africa. Data result from a survey among 267 18-44 years old HIV negative participants, complemented with semi-structured interviews with 80 purposively recruited persons. Correlations coefficients were calculated to identify demographic and psychosocial factors associated with interest in I-PrEP. Qualitative interviews were analyzed using concept-driven and subsequent data-driven coding. Most surveyed participants expressed an interest in I-PrEP. Quantitatively, only being interested in other HIV prevention measures was associated with interest in I-PrEP. Qualitatively, most participants preferred I-PrEP to O-PrEP and remained interested in I-PrEP despite barriers such as the somewhat invasive nature of the procedure and potential side effects of I-PrEP. Interest in I-PrEP was driven by the possibility of avoiding sexual or HIV stigma. Access to healthcare and altruism-such as assisting in the development of new HIV prevention methods-positively impacted willingness to participate in clinical trials. With I-PrEP favored by most participants, it is potentially a critical tool to prevent HIV infection among MSM & TGP in sub-Saharan Africa, with the mitigation of stigma as a major advance. Recruitment of MSM & TGP in biobehavioral clinical trials seems feasible, with altruistic reasons and receiving I-PrEP and free medical care as major motivators.

RESUMEN: Este estudio exploró el interés en la PrEP inyectable (I-PrEP) y la voluntad de participar en ensayos clínicos que prueban nuevas estrategias biomédicas de prevención del VIH entre hombres y personas transfemeninas que tienen sexo con hombres (HSH y TGP), utilizando datos recopilados en la Red de Ensayos de Prevención del VIH. (HPTN) 075, que se llevó a cabo en sitios de Kenia, Malawi y Sudáfrica. Los datos son el resultado de una encuesta entre 267 participantes VIH negativos de entre 18 y 44 años, complementada con entrevistas semiestructuradas con 80 personas reclutadas intencionalmente. Se calcularon coeficientes de correlación para identificar factores demográficos y psicosociales asociados con el interés en la I-PrEP. Las entrevistas cualitativas se analizaron mediante codificación basada en conceptos y, posteriormente, basada en datos. La mayoría de los participantes encuestados expresaron interés en la I-PrEP. Cuantitativamente, sólo estar interesado en otras medidas de prevención del VIH se asoció con el interés en la I-PrEP. Cualitativamente, la mayoría de los participantes prefirieron la I-PrEP a la O-PrEP y siguieron interesados en la I-PrEP a pesar de barreras como la naturaleza algo invasiva del procedimiento y los posibles efectos secundarios de la I-PrEP. El interés en la I-PrEP fue impulsado por la posibilidad de evitar el estigma sexual o del VIH. El acceso a la atención sanitaria y el altruismo (como la asistencia en el desarrollo de nuevos métodos de prevención del VIH) tuvieron un impacto positivo en la voluntad de participar en ensayos clínicos. Dado que la mayoría de los participantes prefieren la I-PrEP, es potencialmente una herramienta crítica para prevenir la infección por VIH entre HSH y TGP en el África subsahariana, con la mitigación del estigma como un avance importante. El reclutamiento de HSH y TGP en ensayos clínicos bioconductuales parece factible, con razones altruistas y recibir I-PrEP y atención médica gratuita como principales motivadores.

Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial.

BACKGROUND: Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women. METHODS: HPTN 084 was a phase 3, randomised, double-blind, double-dummy, active-controlled, superiority trial in 20 clinical research sites in seven countries in sub-Saharan Africa. Participants were eligible for enrolment if they were assigned female sex at birth, were aged 18-45 years, reported at least two episodes of vaginal intercourse in the previous 30 days, were at risk of HIV infection based on an HIV risk score, and agreed to use a long-acting reversible contraceptive method. Participants were randomly assigned (1:1) to either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Study staff and participants were masked to study group allocation, with the exception of the site pharmacist who was responsible for study product preparation. Participants were prescribed 5 weeks of daily oral product followed by intramuscular injections every 8 weeks after an initial 4-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF-FTC for 48 weeks. The primary endpoints of the study were incident HIV infection in the intention-to-treat population, and clinical and laboratory events that were grade 2 or higher in all women who had received at least one dose of study product. This study is registered with ClinicalTrials.gov, NCT03164564. FINDINGS: From Nov 27, 2017, to Nov 4, 2020, we enrolled 3224 participants (1614 in the cabotegravir group and 1610 in the TDF-FTC group). Median age was 25 years (IQR 22-30); 1755 (54·7%) of 3209 had two or more partners in the preceding month. 40 incident infections were observed over 3898 person-years (HIV incidence 1·0% [95% CI 0·73-1·40]); four in the cabotegravir group (HIV incidence 0·2 cases per 100 person-years [0·06-0·52]) and 36 in the TDF-FTC group (1·85 cases per 100 person-years [1·3-2·57]; hazard ratio 0·12 [0·05-0·31]; p<0·0001; risk difference -1·6% [-1·0% to -2·3%]. In a random subset of 405 TDF-FTC participants, 812 (42·1%) of 1929 plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of the total number of person-years. Adverse event rates were similar across both groups, apart from injection site reactions, which were more frequent in the cabotegravir group than in the TDF-FTC group (577 [38·0%] of 1519 vs 162 [10·7%] of 1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1·3 per 100 person-years (0·9-1·7); no congenital birth anomalies were reported. INTERPRETATION: Although both products for HIV prevention were generally safe, well tolerated, and effective, cabotegravir was superior to TDF-FTC in preventing HIV infection in women. FUNDING: National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and the Bill & Melinda Gates Foundation. Additional support was provided through the National Institute of Mental Health, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. ViiV Healthcare and Gilead Sciences provided pharmaceutical support.

Human Immunodeficiency Virus (HIV) Drug Resistance, Phylogenetic Analysis, and Superinfection Among Men Who Have Sex with Men and Transgender Women in Sub-Saharan Africa: HIV Prevention Trials Network (HPTN) 075 Study.

BACKGROUND: The HIV Prevention Trials Network (HPTN) 075 study evaluated the feasibility of enrolling and retaining men who have sex with men (MSM) and transgender women (TGW) from Kenya, Malawi, and South Africa. During the study follow-up, 21 participants acquired human immunodeficiency virus (HIV) (seroconverters). We analyzed HIV subtype diversity, drug resistance, transmission dynamics, and HIV superinfection data among MSM and TGW enrolled in HPTN 075. METHODS: HIV genotyping and drug resistance testing were performed for participants living with HIV who had viral loads >400 copies/mL at screening (prevalent cases, n = 124) and seroconverters (n = 21). HIV pol clusters were identified using Cluster Picker. Superinfection was assessed by a longitudinal analysis of env and pol sequences generated by next-generation sequencing. RESULTS: HIV genotyping was successful for 123/124 prevalent cases and all 21 seroconverters. The major HIV subtypes were A1 (Kenya) and C (Malawi and South Africa). Major drug resistance mutations were detected in samples from 21 (14.6%) of 144 participants; the most frequent mutations were K103N and M184V/I. Phylogenetic analyses identified 11 clusters (2-6 individuals). Clusters included seroconverters only (n = 1), prevalent cases and seroconverters (n = 4), and prevalent cases only (n = 6). Superinfections were identified in 1 prevalent case and 2 seroconverters. The annual incidence of superinfection was higher among seroconverters than among prevalent cases, and was higher than the rate of primary HIV infection in the cohort. CONCLUSIONS: This report provides important insights into HIV genetic diversity, drug resistance, and superinfection among MSM and TGW in sub-Saharan Africa. These findings may help to inform future HIV prevention interventions in these high-risk groups.

Cabotegravir Is Not Associated With Weight Gain in Human Immunodeficiency Virus-uninfected Individuals in HPTN 077.

Studies in human immunodeficiency virus (HIV)-infected individuals suggest excess weight gain with integrase inhibitor-based antiretroviral therapy. The HIV Prevention Trials Network Study 077 evaluated changes in weight and fasting metabolic parameters in HIV-uninfected individuals randomized to cabotegravir or a placebo. No differences between arms were found for change in weight or fasting metabolic parameters overall or for subgroups.

Acceptability of Long-Acting Injectable Cabotegravir (CAB LA) in HIV-Uninfected Individuals: HPTN 077.

Long-acting injectable PrEP could offer an alternative to daily oral PrEP, improve adherence and protection, if found acceptable, safe and effective. HPTN 077 evaluated injectable cabotegravir safety, tolerability and pharmacokinetics among HIV-uninfected males and females in sequentially-enrolled cohorts of two dosing strategies. We compared acceptability of product attributes, prevention preferences and future interest in injectable PrEP (FIIP) by region, sex-at-birth, arm and cohort and used multivariable analysis to identify FIIP determinants. Baseline injectable PrEP preferences were higher in non-U.S. sites and increased in both regions over time. In multivariable models, FIIP was most strongly associated with acceptability of product attributes, was higher in non-U.S. sites and more altruistic participants. Treatment arm and report of pain were not associated with FIIP. Injectable acceptability was highest in non-U.S. sites. Preferences for injectable versus other PrEP methods were higher among U.S. males than females, but higher among males and females in non-U.S. settings.

Healthcare-related stigma among men who have sex with men and transgender women in sub-Saharan Africa participating in HIV Prevention Trials Network (HPTN) 075 study.

ABSTRACT The inability to access health services when needed is a critical barrier to HIV prevention, treatment and care among men who have sex with men (MSM) and transgender women (TGW). Using data collected in HPTN 075, we explored factors associated with any experienced healthcare-related stigma. HPTN 075 was a cohort study to assess the feasibility of recruiting and retaining MSM and TGW in clinical trials in sub-Saharan Africa. Of 401 MSM and TGW enrolled at four sites (Kisumu, Kenya; Blantyre, Malawi; Cape Town, Soweto, South Africa) 397 contributed to the analysis (79.9% cis-gender and 20.1% TGW). Of these, (45.3%; 180/397) reported one or more of healthcare-related stigma experiences. Most frequently reported experiences included fear to seek healthcare services (36.3%) and avoiding seeking such services because of the discovery of MSM status (29.2%). Few men and TGW (2.5%) reported having been denied health services because of having sex with men. In multivariable analysis, more participants in Soweto [adjusted odds ratio (AOR) = 2.60] and fewer participants in Blantyre (AOR = 0.27) reported any healthcare-related stigma experiences, in comparison to participants in Kisumu. MSM and TGW that did not have a supportive gay community to rely on were more likely to report any healthcare-related stigma experiences (AOR = 1.46), whereas MSM and TGW who reported high social support and who never had engaged in transactional sex were less likely to report such experiences (AOR = 0.76 and AOR = 0.43, respectively). Our results suggest that encouraging support groups for MSM and TGW as well as training and sensitizing healthcare staff, and the general community, on MSM and TGW health issues and cultural competence may reduce stigma, improve access to healthcare, which could ultimately reduce HIV transmission.

Antiretroviral Therapy for the Prevention of HIV-1 Transmission.

BACKGROUND: An interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission. METHODS: We randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked HIV-1 infection in the previously HIV-1-negative partner in an intention-to-treat analysis. RESULTS: Index participants were followed for 10,031 person-years; partners were followed for 8509 person-years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant. CONCLUSIONS: The early initiation of ART led to a sustained decrease in genetically linked HIV-1 infections in sexual partners. (Funded by the National Institute of Allergy and Infectious Diseases; HPTN 052 ClinicalTrials.gov number, NCT00074581 .).

Accuracy of Self-Reported HIV Status Among African Men and Transgender Women Who Have Sex with Men Who were Screened for Participation in a Research Study: HPTN 075.

Some HIV-infected individuals in research studies may choose not to disclose knowledge of their HIV status to study staff. We evaluated the accuracy of self-reported HIV status among African men and transgender women who have sex with men and who were screened for a research study. Sixty-seven of 183 HIV-infected participants reported a prior HIV diagnosis. Samples from the remaining 116 participants were tested for antiretroviral (ARV) drugs. Thirty-six of the 116 participants had ARV drugs detected, indicating that they were on antiretroviral treatment; these participants were classified as previously diagnosed based on ARV drug testing. Among participants classified as previously diagnosed, disclosure of a prior HIV diagnosis varied among study sites (p = 0.006) and was more common among those who reported having sex with men only (p = 0.002). ARV drug testing in addition to self-report improves the accuracy for identifying individuals with a prior HIV diagnosis.

Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial.

BACKGROUND: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. METHODS AND FINDINGS: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18-65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. CONCLUSIONS: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. TRIAL REGISTRATION: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800.

Cost-effectiveness of HIV treatment as prevention in serodiscordant couples.

BACKGROUND: The cost-effectiveness of early antiretroviral therapy (ART) in persons infected with human immunodeficiency virus (HIV) in serodiscordant couples is not known. Using a computer simulation of the progression of HIV infection and data from the HIV Prevention Trials Network 052 study, we projected the cost-effectiveness of early ART for such persons. METHODS: For HIV-infected partners in serodiscordant couples in South Africa and India, we compared the early initiation of ART with delayed ART. Five-year and lifetime outcomes included cumulative HIV transmissions, life-years, costs, and cost-effectiveness. We classified early ART as very cost-effective if its incremental cost-effectiveness ratio was less than the annual per capita gross domestic product (GDP; $8,100 in South Africa and $1,500 in India), as cost-effective if the ratio was less than three times the GDP, and as cost-saving if it resulted in a decrease in total costs and an increase in life-years, as compared with delayed ART. RESULTS: In South Africa, early ART prevented opportunistic diseases and was cost-saving over a 5-year period; over a lifetime, it was very cost-effective ($590 per life-year saved). In India, early ART was cost-effective ($1,800 per life-year saved) over a 5-year period and very cost-effective ($530 per life-year saved) over a lifetime. In both countries, early ART prevented HIV transmission over short periods, but longer survival attenuated this effect; the main driver of life-years saved was a clinical benefit for treated patients. Early ART remained very cost-effective over a lifetime under most modeled assumptions in the two countries. CONCLUSIONS: In South Africa, early ART was cost-saving over a 5-year period. In both South Africa and India, early ART was projected to be very cost-effective over a lifetime. With individual, public health, and economic benefits, there is a compelling case for early ART for serodiscordant couples in resource-limited settings. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results from the children with HIV early antiretroviral (CHER) randomised trial.

BACKGROUND: Interim results from the children with HIV early antiretroviral (CHER) trial showed that early antiretroviral therapy (ART) was life-saving for infants infected with HIV. In view of the few treatment options and the potential toxicity associated with lifelong ART, in the CHER trial we compared early time-limited ART with deferred ART. METHODS: CHER was an open-label randomised controlled trial of HIV-infected asymptomatic infants younger than 12 weeks in two South African trial sites with a percentage of CD4-positive T lymphocytes (CD4%) of 25% or higher. 377 infants were randomly allocated to one of three groups: deferred ART (ART-Def), immediate ART for 40 weeks (ART-40W), or immediate ART for 96 weeks (ART-96W), with subsequent treatment interruption. The randomisation schedule was stratified by clinical site with permuted blocks of random sizes to balance the numbers of infants allocated to each group. Criteria for ART initiation in the ART-Def group and re-initiation after interruption in the other groups were CD4% less than 25% in infancy; otherwise, the criteria were CD4% less than 20% or Centers for Disease Control and Prevention severe stage B or stage C disease. Combination therapy of lopinavir-ritonavir, zidovudine, and lamivudine was the first-line treatment regimen at ART initiation and re-initiation. The primary endpoint was time to failure of first-line ART (immunological, clinical, or virological) or death. Comparisons were done by intention-to-treat analysis, with use of time-to-event methods. This trial is registered with ClinicalTrials.gov, number NCT00102960. FINDINGS: 377 infants were enrolled, with a median age of 7·4 weeks, CD4% of 35%, and HIV RNA log 5·7 copies per mL. Median follow-up was 4·8 years; 34 infants (9%) were lost to follow-up. Median time to ART initiation in the ART-Def group was 20 weeks (IQR 16-25). Time to restarting of ART after interruption was 33 weeks (26-45) in ART-40W and 70 weeks (35-109) in ART-96W; at the end of the trial, 19% of patients in ART-40W and 32% of patients in ART-96W remained off ART. Proportions of follow-up time spent on ART were 81% in the ART-Def group, 70% in the ART-40W group, and 69% in the ART-96W group. 48 (38%) of 125 children in the ART-Def group, 32 (25%) of 126 in the ART-40W group, and 26 (21%) of 126 in the ART-96W group reached the primary endpoint. The hazard ratio, relative to ART-Def, was 0·59 (95% CI 0·38-0·93, p=0·02) for ART-40W and 0·47 (0·27-0·76, p=0·002) for ART-96W. Three children in ART-Def, three in ART-40W, and one in ART-96W switched to second-line ART. INTERPRETATION: Early time-limited ART had better clinical and immunological outcomes than deferred ART, with no evidence of excess disease progression during subsequent treatment interruption and less overall ART exposure than deferred ART. Longer time on primary ART permits longer subsequent interruption, with marginally better outcomes. FUNDING: US National Institutes of Health.

Undisclosed antiretroviral drug use in a multinational clinical trial (HIV Prevention Trials Network 052).

The HIV Prevention Trials Network 052 study enrolled serodiscordant couples. Index participants infected with human immunodeficiency virus reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45 of 96 participants (46.9%) with an undetectable viral load, 2 of 48 (4.2%) with a low viral load, and 1 of 65 (1.5%) with a high viral load (P < .0001); they were also detected in follow-up samples from participants who were not receiving study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings.

Safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or BNT162b2 in Ad26.COV2.S-vaccinated participants.

We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. A total of 286 adults (with or without HIV) were enrolled >4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Overall, in the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: The study has been registered to the South African National Clinical Trial Registry (SANCTR): DOH-27-012022-7841. The approval letter from SANCTR has been provided in the up-loaded documents.

Safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or BNT162b2 in Ad26.COV2.S-vaccinated participants.

Background: We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. Methods: A total of 286 adults (with or without HIV) were enrolled >4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. Results: No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Conclusion: In the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: South African National Clinical Trial Registry (SANCR): DOH-27-012022-7841. Funding: South African Medical Research Council (SAMRC) and South African Department of Health (SA DoH).

HIV risk perception and sexual behavior among HIV-uninfected men and transgender women who have sex with men in sub-Saharan Africa: Findings from the HPTN 075 qualitative sub-study.

There remains a limited understanding of how men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa (SSA) perceive their risk for HIV and how risk influences behavior during sexual interactions. We performed thematic analysis on in-depth interviews from the qualitative sub-study of HPTN 075 in Kenya, Malawi, and South Africa. Using the Integrated Behavioral Model (IBM) constructs, we found that most MSM and TGW perceived themselves to be at risk for HIV, leading them to regularly engage in safer sexual behaviors. Notably, even though these MSM and TGW perceived themselves to be at risk for HIV, some of them reported engaging in transactional sex, sex under the influence of alcohol, and intentional non-use of condoms. This indicates that HIV risk perception was not always associated with safer sexual behaviors or a reduction in risk behaviors. Attitudes (negative attitudes toward condom use), perceived norms (social pressures), and environment constraints (contextual barriers) were related to MSM and TGW not engaging in safe sexual behavior. Hearing the perspectives of MSM and TGW on their sexual behavior continues to be important for the development and implementation of effective prevention policies and interventions. Eliminating structural barriers such as stigma, discrimination, and criminalization of same-sex sexuality is a crucial prerequisite for the success of interventions to promote sexual health among MSM and TGW in SSA.

Prevalent human papillomavirus infection increases the risk of HIV acquisition in African women: advancing the argument for human papillomavirus immunization.

OBJECTIVE: Vaccine-preventable human papillomavirus (HPV) infection is common, especially in sub-Saharan Africa where HIV risk is also high. However, unlike other sexually transmitted infections (STIs), HPV's role in HIV acquisition is unclear. We evaluated this relationship using data from MTN-003, a clinical trial of HIV chemoprophylaxis among cisgender women in sub-Saharan Africa. DESIGN: A case-control study. METHODS: We matched 138 women who acquired HIV (cases) to 412 HIV-negative controls. Cervicovaginal swabs collected within 6 months before HIV seroconversion were tested for HPV DNA. We estimated the associations between carcinogenic (high-risk) and low-risk HPV types and types targeted by HPV vaccines and HIV acquisition, using conditional logistic regression models adjusted for time-varying sexual behaviors and other STIs. RESULTS: Mean age was 23 (±4) years. Any, high-risk and low-risk HPV was detected in 84, 74 and 66% of cases, and 65, 55 and 48% of controls. Infection with at least two HPV types was common in cases (67%) and controls (49%), as was infection with nonavalent vaccine-targeted types (60 and 42%). HIV acquisition increased with any [adjusted odds ratio (aOR) 2.5, 95% confidence interval (95% CI) 1.3-4.7], high-risk (aOR 2.6, 95% CI 1.5-4.6) and low-risk (aOR 1.8, 95% CI 1.1-2.9) HPV. Each additional type detected increased HIV risk by 20% (aOR 1.2, 95% CI 1.1-1.4). HIV acquisition was associated with HPV types targeted by the nonavalent (aOR 2.1, 95% CI 1.3-3.6) and quadrivalent vaccines (aOR 1.9, 95% CI 1.1-3.2). CONCLUSION: HPV infection is associated with HIV acquisition in sub-Saharan African women. In addition to preventing HPV-associated cancers, increasing HPV vaccination coverage could potentially reduce HIV incidence.

Nurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomised non-inferiority trial.

BACKGROUND: Expanded access to combination antiretroviral therapy (ART) in resource-poor settings is dependent on task shifting from doctors to other health-care providers. We compared outcomes of nurse versus doctor management of ART care for HIV-infected patients. METHODS: This randomised non-inferiority trial was undertaken at two South African primary-care clinics. HIV-positive individuals with a CD4 cell count of less than 350 cells per microL or WHO stage 3 or 4 disease were randomly assigned to nurse-monitored or doctor-monitored ART care. Patients were randomly assigned by stratified permuted block randomisation, and neither the patients nor those analysing the data were masked to assignment. The primary objective was a composite endpoint of treatment-limiting events, incorporating mortality, viral failure, treatment-limiting toxic effects, and adherence to visit schedule. Analysis was by intention to treat. Non-inferiority of the nurse versus doctor group for cumulative treatment failure was prespecified as an upper 95% CI for the hazard ratio that was less than 1.40. This study is registered with ClinicalTrials.gov, number NCT00255840. FINDINGS: 408 patients were assigned to doctor-monitored ART care and 404 to nurse-monitored ART care; all participants were analysed. 371 (46%) patients reached an endpoint of treatment failure: 192 (48%) in the nurse group and 179 (44%) in the doctor group. The hazard ratio for composite failure was 1.09 (95% CI 0.89-1.33), which was within the limits for non-inferiority. After a median follow-up of 120 weeks (IQR 60-144), deaths (ten vs 11), virological failures (44 vs 39), toxicity failures (68 vs 66), and programme losses (70 vs 63) were similar in nurse and doctor groups, respectively. INTERPRETATION: Nurse-monitored ART is non-inferior to doctor-monitored therapy. Findings from this study lend support to task shifting to appropriately trained nurses for monitoring of ART. FUNDING: National Institutes of Health; United States Agency for International Development; National Institute of Allergy and Infectious Diseases.

Likely clinical depression and HIV-related decline in antiretroviral therapy untreated women who seroconverted during participation in microbicide trials in sub-Saharan Africa.

Depression worsens HIV outcomes in populations treated with antiretroviral therapy (ART) medications. Data are limited on the relationship between depression and HIV in untreated populations in sub-Saharan Africa. We aimed to identify associations between likely clinical depression, alcohol use, social support by partners, and HIV viral load (VL) among ART untreated women who recently became HIV positive and enrolled in the Microbicide Trials Network (MTN)-015 study. Analyses used cross-sectional data collected at baseline in MTN-015. Participants in this analysis (N = 190) enrolled from other MTN trials were not receiving ART and provided data on their HIV disclosure status to their husband or male partner and alcohol use behavior. The dependent variable, VL, was categorized as: low (≤400 RNA copies/mL; 9.1% of participants), medium (401-20,000 RNA copies/mL; 48.8%), and high (>20,000 RNA copies/mL; 42.0%). Depression was assessed using eight items from Hopkins Symptom Checklist; a cutoff of ≥1.75 indicated likely clinical depression. Independent variables with a significance of p ≤ 0.05 in unadjusted regressions were included in a regression adjusted for age, education, and time since seroconversion. Depressive symptoms were positively associated with high VL, in the adjusted regression (OR = 1.80; 95% CI = 1.07-3.01). Results suggest that likely having clinical depression may have a biological relationship with HIV disease progression.