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.

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).

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.

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.

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.

HIV Incidence Among Pregnant and Nonpregnant Women in the FACTS-001 Trial: Implications for HIV Prevention, Especially PrEP Use.

BACKGROUND: During pregnancy and postpartum period, the sexual behaviors of women and their partners change in ways that may either increase or reduce HIV risks. Pregnant women are a priority population for reducing both horizontal and vertical HIV transmission. SETTING: Nine sites in 4 South African provinces. METHODS: Women aged 18-30 years were randomized to receive pericoital tenofovir 1% gel or placebo gel and required to use reliable modern contraception. We compared HIV incidence in women before, during, and after pregnancy and used multivariate Cox Proportional hazards models to compare HIV incidence by pregnancy status. RESULTS: Rates of pregnancy were 7.1 per 100 woman-years (95% confidence interval [CI]: 6.3 to 8.1) and highest in those who reported oral contraceptive use (25.1 per 100 woman-years; adjusted hazard ratio 22.97 higher than other women; 95% CI: 5.0 to 105.4) or had 2 children. Birth outcomes were similar between trial arms, with 59.8% having full-term live births. No difference was detected in incident HIV during pregnancy compared with nonpregnant women (2.1 versus 4.3%; hazard ratio = 0.56, 95% CI: 0.14 to 2.26). Sexual activity was low in pregnancy and the early postpartum period, as was consistent condom use. CONCLUSIONS: Pregnancy incidence was high despite trial participation being contingent on contraceptive use. We found no evidence that rates of HIV acquisition were elevated in pregnancy when compared with those in nonpregnant women. Risks from reductions in condom use may be offset by reduced sexual activity. Nevertheless, high HIV incidence in both pregnant and nonpregnant women supports consideration of introducing antiretroviral-containing pre-exposure prophylaxis for pregnant and nonpregnant women in high HIV prevalence settings.

Sexually transmitted infections among HIV serodiscordant partners: A secondary analysis of HIV Prevention Trial Network 052.

Sexually transmitted infections (STIs) remain a public health concern because of their interaction(s) with HIV. In the HPTN 052 study, STIs were evaluated in both HIV-positive index cases and their HIV-negative partners at enrollment and at yearly follow-up visits. Our definition for STI was based on any infection with Chlamydia trachomatis, Neisseria gonorrhoeae, syphilis, or Trichomonas vaginalis. We used log-binomial regression models to identify factors associated with prevalent STIs. Generalized estimating equation models with the Poisson distribution were used to compare STI incidence between HIV-positive index cases and HIV-negative partners. 8.1% of the participants had STIs at enrollment. The prevalence of STIs (8.9 vs. 7.2) was higher in HIV-positive index cases than HIV-negative partners. Being female (prevalence ratio (PR) = 1.61; 95% CI: 1.20-2.16) or unmarried (PR = 1.92; 95% CI: 1.17-3.14) was associated with prevalent STIs. Compared to HIV-negative male partners, HIV-positive female index cases had a higher risk of STI acquisition (incidence rate ratio (IRR) = 2.25; 95% CI: 1.70-2.97). While we are implementing HIV prevention interventions for HIV-negative people, we should also intensify targeted STI prevention interventions, especially among HIV-positive women.

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.

HIV incidence in a multinational cohort of men and transgender women who have sex with men in sub-Saharan Africa: Findings from HPTN 075.

Few studies have assessed HIV incidence in men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa (SSA). We assessed HIV incidence and its correlates among MSM and TGW in SSA enrolled in the prospective, multi-country HIV Prevention Trials Network (HPTN) 075 study, conducted from 2015 to 2017. Participants were enrolled at four sites in SSA (Kisumu, Kenya; Blantyre, Malawi; Cape Town and Soweto, South Africa). Eligible participants reported male sex assignment at birth, were 18 to 44 years of age, and had engaged in anal intercourse with a man in the preceding three months. Participation involved five study visits over 12 months. Visits included behavioral assessments and testing for HIV and sexually transmitted infections. Twenty-one of 329 persons acquired HIV during the study [incidence rate: 6.96/100 person-years (PY) (95% CI: 4.3, 10.6)]. Among TGW, HIV incidence was estimated to be 8.4/100 PY (95% CI: 2.3, 21.5). Four participants were found to have acute HIV infection at their first HIV-positive visit. HIV incidence varied among the four study sites, ranging from 1.3/100 PY to 14.4/100 PY. In multivariate longitudinal analysis, factors significantly associated with HIV acquisition were engagement in unprotected receptive anal intercourse [adjusted hazard ratio (AHR) 5.8, 95% confidence interval (CI): 2.4, 14.4] and incident rectal gonorrhea and/or chlamydia (AHR: 2.7, 95% CI: 1.1, 6.8). The higher HIV incidence in Cape Town compared to Blantyre could be explained by the higher prevalence of several risk factors for HIV infection among participants in Cape Town. Annual HIV incidence observed in this study is substantially higher than reported HIV incidence in the general populations in the respective countries and among MSM in the United States. Intensification of HIV prevention efforts for MSM and TGW in SSA is urgently needed.

Identification of Novel UGT1A1 Variants Including UGT1A1 454C>A through the Genotyping of Healthy Participants of the HPTN 077 Study.

Cabotegravir (CAB) is an integrase strand-transfer inhibitor of HIV that has proven effective for HIV treatment and prevention in a long-acting injectable formulation, typically preceded by an oral formulation lead-in phase. Previous in vitro studies have demonstrated that CAB is primarily metabolized via glucuronidation by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A9. In this study, we performed next-generation sequencing of genomic DNA isolated from the HPTN 077 participants to explore the variants within UGT1A1 and UGT1A9. Additionally, to enable correlation of UGT1A1 and UGT1A9 genotypes with plasma CAB-glucuronide levels, we quantified glucuronidated CAB following both oral administration of CAB and intramuscular injection of long-acting CAB. From these studies, 48 previously unreported variants of UGT1A1 and UGT1A9 were detected. Notably, 5/68 individuals carried a UGT1A1 454C>A variant that resulted in amino acid substitution P152T, and the use of in silico tools predicted a deleterious effect of the P152T substitution. Thus, the impact of this mutant on a range of UGT1A1 substrates was tested using a COS-7 cell-based assay. The glucuronide conjugates of CAB, dolutegravir, and raltegravir, were not formed in the COS-7 cells expressing the UGT1A1 P152T mutant. Further, formation of glucuronides of raloxifene and 7-ethyl-10-hydroxycamptothecin were reduced in the cells expressing the UGT1A1 P152T mutant. Using the same approach, we tested the activities of two UGT1A9 mutants, UGT1A9 H217Y and UGT1A9 R464G, and found that these mutations were tolerated and decreased function, respectively. These data provide insight into previously unreported genetic variants of UGT1A1 and UGT1A9.

Uptake of antiretroviral treatment and viral suppression among men who have sex with men and transgender women in sub-Saharan Africa in an observational cohort study: HPTN 075.

OBJECTIVES: HPTN 075 enrolled men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa. Persons in HIV care or on antiretroviral treatment (ART) were not eligible to enroll. We evaluated antiretroviral (ARV) drug use, viral suppression, and drug resistance in this cohort over a 12-month follow-up period. METHODS: Assessments included 64 participants with HIV (39 MSM, 24 TGW, and one gender not specified). ARV drugs were detected using a qualitative assay. Viral load (VL) and drug resistance testing were performed using commercial assays. RESULTS: Over 12 months, the proportion of participants using ARV drugs increased from 28.1% to 59.4% and the proportion with VLs <400 copies/mL increased from 21.9% to 57.8%. The rate of ART failure (detection of drugs without viral suppression) was similar at screening and 12 months (12.0% and 11.1%, respectively) and was similar among MSM and TGW. Two participants developed HIV drug resistance during follow-up. CONCLUSIONS: Over 12 months, ARV drug use in the cohort more than doubled and viral suppression increased nearly threefold without a significant increase in ART failure or drug resistance. These results suggest that ART can be successfully scaled up for HIV prevention and treatment in this high-risk population.

Correction to "Identification of Novel UGT1A1 Variants Including UGT1A1 454C>A through the Genotyping of Healthy Participants of the HPTN 077 Study".

[This corrects the article DOI: 10.1021/acsptsci.0c00181.].

Prevalence and Incidence of Sexually Transmitted Infection in Injectable Progestin Contraception Users in South Africa.

Introduction: Whether intramuscular depot medroxyprogesterone acetate (DMPA-IM) and norethisterone enanthate (NET-EN) have a differential impact on the incidence of sexually transmitted infection (STI) remains unclear. In the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, HIV-1 acquisition was higher for DMPA-IM users vs. NET-EN users. We compared DMPA-IM and NET-EN users with regard to chlamydia, gonorrhea, trichomoniasis, syphilis, and herpes simplex virus type 2 (HSV-2) infection. Materials and Methods: Prospective data were analyzed from VOICE, a randomized trial of HIV-1 chemoprophylaxis. Participants were evaluated annually and as indicated for chlamydia, gonorrhea, trichomoniasis, and syphilis. Stored specimens were tested for HSV-2. Proportional hazards models compared the risk of STI between DMPA-IM and NET-EN users. Results: Among 2,911 injectable contraception users in South Africa, 1,800 (61.8%) used DMPA-IM and 1,111 used NET-EN (38.2%). DMPA-IM and NET-EN users did not differ in baseline chlamydia: 15.1 vs. 14.3%, p= 0.54; gonorrhea: 3.4 vs. 3.7%, p= 0.70; trichomoniasis: 5.7 vs.5.0%, p= 0.40; or syphilis: 1.5 vs. 0.7%, p= 0.08; but differed for baseline HSV-2: (51.3 vs. 38.6%, p < 0.001). Four hundred forty-eight incident chlamydia, 103 gonorrhea, 150 trichomonas, 17 syphilis, and 48 HSV-2 infections were detected over 2,742, 2,742, 2,783, 2,945, and 756 person-years (py), respectively (chlamydia 16.3/100 py; gonorrhea 3.8/100 py; trichomoniasis 5.4/100 py; syphilis 0.6/100 py; HSV-2 6.4/100 py). Comparing DMPA-IM with NET-EN users, no difference was noted in the incidence of chlamydia, gonorrhea, trichomoniasis, syphilis, or HSV2 infections, including when adjusted for confounders [chlamydia (aHR 1.03, 95% CI 0.85-1.25), gonorrhea (aHR 0.88, 95% CI 0.60-1.31), trichomoniasis (aHR 1.07, 95% CI 0.74-1.54), syphilis (aHR 0.41, 95% CI 0.15-1.10), and HSV-2 (aHR 0.83, 95% CI 0.45-1.54, p= 0.56)]. Discussion: Among South African participants enrolled in VOICE, DMPA-IM and NETEN users differed in prevalence of HSV-2 at baseline but did not differ in the incidence of chlamydia, gonorrhea, trichomoniasis, syphilis, or HSV-2 infection. Differential HIV-1 acquisition, previously demonstrated in this cohort, does not appear to be explained by differential STI acquisition. However, the high incidence of multiple STIs reinforces the need to accelerate access to comprehensive sexual and reproductive health services.

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.

The feasibility of recruiting and retaining men who have sex with men and transgender women in a multinational prospective HIV prevention research cohort study in sub-Saharan Africa (HPTN 075).

INTRODUCTION: Men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa (SSA) are profoundly affected by HIV with high HIV prevalence and incidence. This population also faces strong social stigma and legal barriers, potentially impeding participation in research. To date, few multi-country longitudinal HIV research studies with MSM/TGW have been conducted in SSA. Primary objective of the HIV Prevention Trials Network (HPTN) 075 study was to assess feasibility of recruiting and retaining a multinational prospective cohort of MSM/TGW in SSA for HIV prevention research. METHODS: HPTN 075, conducted from 2015 to 2017, was designed to enroll 400 MSM/TGW at four sites in SSA (100 per site: Kisumu, Kenya; Blantyre, Malawi; Cape Town, South Africa; and Soweto, South Africa). The number of HIV-positive persons was capped at 20 per site; HIV-positive persons already in care were excluded from participation. The one-year study included five biobehavioural assessments. Community-based input and risk mitigation protocols were included in study design and conduct. RESULTS: Of 624 persons screened, 401 were enrolled. One in five participants was classified as transgender. Main reasons for ineligibility included: (a) being HIV positive after the cap was reached (29.6%); (b) not reporting anal intercourse with a man in the preceding three months (20.6%); and (c) being HIV positive and already in care (17.5%). Five (1.2%) participants died during the study (unrelated to study participation). 92.9% of the eligible participants (368/396) completed the final study visit and 86.1% participated in all visits. The main, overlapping reasons for early termination included being (a) unable to adhere to the visit schedule, predominantly because of relocation (46.4%), and (b) unable to contact the participant (32.1%). Participants reported strong motivation to participate and few participation barriers. Four participants reported social harms (loss of confidentiality and sexual harassment by study staff) that were successfully addressed. CONCLUSIONS: HPTN 075 successfully enrolled a multinational sample of MSM/TGW in SSA in a prospective HIV prevention research study with a high retention rate and few documented social harms. This supports the feasibility of conducting large-scale research trials in this population to address its urgent, unmet HIV prevention needs.

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.

Tail-phase safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in HIV-uninfected adults: a secondary analysis of the HPTN 077 trial.

BACKGROUND: Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial. METHODS: HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18-65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t1/2app) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52-76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov, NCT02178800. FINDINGS: Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p<0·0001). At 52-60 weeks after final injection, nine (23%) of 40 male participants had detectable cabotegravir concentrations and at week 76, four (13%) of 30 male participants had detectable cabotegravir concentrations compared with 52 (63%) of 82 female participants and 27 (42%) of 64 female participants at the same timepoints. The median time from the last injection to the time when cabotegravir concentration decreased below the LLOQ was 43·7 weeks (IQR 31·1-66·6; range 20·4-152·5) for male participants and 67·3 weeks (29·1-89·6; 17·7-225·5) for female participants (p=0·0003). t1/2app was longer for female participants than male participants (geometric mean fold-change 1·33, 95% CI 1·06-1·68; p=0·014), and longer for participants with a high body-mass index (BMI) than those with a low BMI (1·31, 1·06-1·63; p=0·015). INTERPRETATION: The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials. FUNDING: National Institute of Allergy and Infectious Diseases.

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.

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.