Vaccine Efficacy of ALVAC-HIV and Bivalent Subtype C gp120-MF59 in Adults.

BACKGROUND: A safe, effective vaccine is essential to eradicating human immunodeficiency virus (HIV) infection. A canarypox-protein HIV vaccine regimen (ALVAC-HIV plus AIDSVAX B/E) showed modest efficacy in reducing infection in Thailand. An analogous regimen using HIV-1 subtype C virus showed potent humoral and cellular responses in a phase 1-2a trial in South Africa. Efficacy data and additional safety data were needed for this regimen in a larger population in South Africa. METHODS: In this phase 2b-3 trial, we randomly assigned 5404 adults without HIV-1 infection to receive the vaccine (2704 participants) or placebo (2700 participants). The vaccine regimen consisted of injections of ALVAC-HIV at months 0 and 1, followed by four booster injections of ALVAC-HIV plus bivalent subtype C gp120-MF59 adjuvant at months 3, 6, 12, and 18. The primary efficacy outcome was the occurrence of HIV-1 infection from randomization to 24 months. RESULTS: In January 2020, prespecified criteria for nonefficacy were met at an interim analysis; further vaccinations were subsequently halted. The median age of the trial participants was 24 years; 70% of the participants were women. The incidence of adverse events was similar in the vaccine and placebo groups. During the 24-month follow-up, HIV-1 infection was diagnosed in 138 participants in the vaccine group and in 133 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.81 to 1.30; P = 0.84). CONCLUSIONS: The ALVAC-gp120 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence of immunogenicity. (HVTN 702 ClinicalTrials.gov number, NCT02968849.).

Analysis of the HIV Vaccine Trials Network 702 Phase 2b-3 HIV-1 Vaccine Trial in South Africa Assessing RV144 Antibody and T-Cell Correlates of HIV-1 Acquisition Risk.

BACKGROUND: The ALVAC/gp120 + MF59 vaccines in the HIV Vaccine Trials Network (HVTN) 702 efficacy trial did not prevent human immunodeficiency virus-1 (HIV-1) acquisition. Vaccine-matched immunological endpoints that were correlates of HIV-1 acquisition risk in RV144 were measured in HVTN 702 and evaluated as correlates of HIV-1 acquisition. METHODS: Among 1893 HVTN 702 female vaccinees, 60 HIV-1-seropositive cases and 60 matched seronegative noncases were sampled. HIV-specific CD4+ T-cell and binding antibody responses were measured 2 weeks after fourth and fifth immunizations. Cox proportional hazards models assessed prespecified responses as predictors of HIV-1 acquisition. RESULTS: The HVTN 702 Env-specific CD4+ T-cell response rate was significantly higher than in RV144 (63% vs 40%, P = .03) with significantly lower IgG binding antibody response rate and magnitude to 1086.C V1V2 (67% vs 100%, P < .001; Pmag < .001). Although no significant univariate associations were observed between any T-cell or binding antibody response and HIV-1 acquisition, significant interactions were observed (multiplicity-adjusted P ≤.03). Among vaccinees with high IgG A244 V1V2 binding antibody responses, vaccine-matched CD4+ T-cell endpoints associated with decreased HIV-1 acquisition (estimated hazard ratios = 0.40-0.49 per 1-SD increase in CD4+ T-cell endpoint). CONCLUSIONS: HVTN 702 and RV144 had distinct immunogenicity profiles. However, both identified significant correlations (univariate or interaction) for IgG V1V2 and polyfunctional CD4+ T cells with HIV-1 acquisition. Clinical Trials Registration . NCT02968849.

High Asymptomatic Carriage With the Omicron Variant in South Africa.

We report a 23% asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) Omicron carriage rate in participants being enrolled into a clinical trial in South Africa, 15-fold higher than in trials before Omicron. We also found lower CD4 + T-cell counts in persons with human immunodeficiency virus (HIV) strongly correlated with increased odds of being SARS-CoV-2 polymerase chain reaction (PCR) positive.

Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women.

BACKGROUND: The incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda. METHODS: In this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks for up to 24 months. The primary efficacy end point was the rate of HIV type 1 (HIV-1) seroconversion. RESULTS: A total of 77 participants in the dapivirine group underwent HIV-1 seroconversion during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years), as compared with 56 in the placebo group who underwent HIV-1 seroconversion during 917 person-years of follow-up (6.1 seroconversions per 100 person-years). The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P=0.04). There was no significant difference in efficacy of the dapivirine ring among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI, 0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45 to 1.60; P=0.43 for treatment-by-age interaction). Among participants with HIV-1 infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56 (16.1%) in the placebo group. Serious adverse events occurred more often in the dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]). However, no clear pattern was identified. CONCLUSIONS: Among women in sub-Saharan Africa, the dapivirine ring was not associated with any safety concerns and was associated with a rate of acquisition of HIV-1 infection that was lower than the rate with placebo. (Funded by the International Partnership for Microbicides; ClinicalTrials.gov number, NCT01539226 .).

High Levels of Pretreatment HIV-1 Drug Resistance Mutations Among South African Women Who Acquired HIV During a Prospective Study.

BACKGROUND: Pretreatment HIV drug resistance (PDR) undermines individual treatment success and threatens the achievement of UNAIDS 95-95-95 targets. In many African countries, limited data are available on PDR as detection of recent HIV infection is uncommon and access to resistance testing is limited. We describe the prevalence of PDR among South African women with recent HIV infection from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. METHODS: HIV-uninfected, sexually active women, aged 18-35 years, and seeking contraception were enrolled in the ECHO Trial at sites in South Africa, from 2015 to 2018. HIV testing was done at trial entry and repeated quarterly. We tested stored plasma samples collected at HIV diagnosis from women who seroconverted during follow-up and had a viral load >1000 copies/mL for antiretroviral resistant mutations using a validated laboratory-developed population genotyping assay, which sequences the full protease and reverse transcriptase regions. Mutation profiles were determined using the Stanford Drug Resistance Database. RESULTS: We sequenced 275 samples. The median age was 23 years, and majority (98.9%, n = 272) were infected with HIV-1 subtype C. The prevalence of surveillance drug resistance mutations (SDRMs) was 13.5% (n = 37). Nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations were found in 12.4% of women (n = 34). Few women had NRTI (1.8%, n = 5) and protease inhibitor (1.1%, n = 3) mutations. Five women had multiple NRTI and NNRTI SDRMs. CONCLUSIONS: The high levels of PDR, particularly to NNRTIs, strongly support the recent change to the South African national HIV treatment guidelines to transition to a first-line drug regimen that excludes NNRTIs.

Brief Report: Quantifiable Plasma Tenofovir Among South African Women Using Daily Oral Pre-exposure Prophylaxis During the ECHO Trial.

BACKGROUND: HIV endpoint-driven clinical trials provide oral pre-exposure prophylaxis (PrEP) as HIV prevention standard of care. We evaluated quantifiable plasma tenofovir among South African women who used oral PrEP during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. METHODS: ECHO, a randomized trial conducted in 4 African countries between 2015 and 2018, assessed HIV incidence among HIV-uninfected women, aged 16-35 years, randomized to 1 of 3 contraceptives. Oral PrEP was offered onsite as part of the HIV prevention package at the South African trial sites. We measured tenofovir in plasma samples collected at the final trial visit among women reporting ongoing PrEP use. We used bivariate and multivariate logistical regression to assess demographic and sexual risk factors associated with plasma tenofovir quantification. RESULTS: Of 260 women included, 52% were ≤24 years and 22% had Chlamydia trachomatis at enrollment. At PrEP initiation, 68% reported inconsistent/nonuse of condoms. The median duration of PrEP use was 90 days (IQR: 83-104). Tenofovir was quantified in 36% (n = 94) of samples. Women >24 years had twice the odds of having tenofovir quantified vs younger women (OR = 2.12; 95% confidence interval = 1.27 to 3.56). Women who reported inconsistent/nonuse of condoms had lower odds of tenofovir quantification (age-adjusted OR = 0.47; 95% confidence interval = 0.26 to 0.83). CONCLUSIONS: Over a third of women initiating PrEP and reporting ongoing use at the final trial visit had evidence of recent drug exposure. Clinical trials may serve as an entry point for PrEP initiation among women at substantial risk for HIV infection with referral to local facilities for ongoing access at trial end. CLINICAL TRIAL NUMBER: NCT02550067.

Safety, adherence, and HIV-1 seroconversion among women using the dapivirine vaginal ring (DREAM): an open-label, extension study.

BACKGROUND: The Ring Study, a phase 3 trial in 1959 sexually active women (randomised 2:1), showed a favourable safety profile and a 31% HIV-1 infection risk reduction for a vaginal ring containing 25 mg of dapivirine, compared with a placebo ring. We report here the DREAM study, which aimed to evaluate safety, adherence, and HIV-1 incidence in those using the dapivirine vaginal ring (DVR) in open-label use. METHODS: The DREAM study is an open-label extension of The Ring Study, done at five research centres in South Africa and one research centre in Uganda. Former participants from The Ring Study, who remained HIV-negative and who did not discontinue the study due to an adverse event or safety concern that was considered to be related to the investigational product, were eligible. Women who were pregnant, planning to become pregnant, or breastfeeding at screening for DREAM were excluded. All participants received the DVR for insertion at the enrolment visit. Participants attended a 1-month follow-up visit and could either proceed with visits once every 3 months or attend monthly visits up to month 3 and then continue with visits once every 3 months. At each visit, HIV testing and safety evaluations were done, and residual dapivirine measured in used rings (approximately 4 mg is released from the DVR over 28 days of consistent use). HIV-1 incidence was compared descriptively with the simulated incidence rate obtained from bootstrap sampling of participants in the placebo group of The Ring Study, matched for research centre, age, and presence of sexually transmitted infections at enrolment. This study is registered with ClinicalTrials.gov, NCT02862171. FINDINGS: Between July 12, 2016, and Jan 11, 2019, 1034 former participants from The Ring Study were screened, 941 were enrolled and 848 completed the trial. 616 (65·5%) of 941 participants reported treatment-emergent adverse events. Of these, six (0·6%) had events considered to be treatment-related. No treatment-related serious adverse events were reported. Measurements of monthly ring residual amounts in participants enrolled in both trials showed consistently lower mean values in DREAM than in The Ring Study. Arithmetic mean ring residual amounts of participants in The Ring Study DVR group who enrolled in DREAM were 0·25 mg lower (95% CI 0·03-0·47; p=0·027) than the mean ring residual amounts of these participants in The Ring Study. 18 (1·9%) HIV-1 infections were confirmed during DVR use, resulting in an incidence of 1·8 (95% CI 1·1-2·6) per 100 person-years, 62% lower than the simulated placebo rate. INTERPRETATION: Although efficacy estimation is limited by the absence of a placebo group, the observed low HIV-1 incidence and improved adherence observed in DREAM support the hypothesis that increased efficacy due to improved adherence occurs when women know the demonstrated safety and efficacy of the DVR. The feasibility of a visit schedule of once every 3 months was shown, indicating that the DVR can be used in a real-world situation in usual clinical practice. FUNDING: The Ministry of Foreign Affairs (MFA) Denmark, Flanders MFA, Irish Aid, Dutch MFA, UK Aid from the UK Government's Foreign, Commonwealth and Development Office, and the US President's Emergency Plan for AIDS Relief through the US Agency for International Development.

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.

Age-Specific Risk Scores Do Not Improve HIV-1 Prediction Among Women in South Africa.

BACKGROUND: HIV-1 risk scoring tools could help target provision of prevention modalities such as pre-exposure prophylaxis. Recent research suggests that risk scores for women aged 18-45 may not predict risk well among young women aged 18-24. We evaluated the predictive performance of age-specific risk scores compared with the existing non-age-specific VOICE risk score, developed for women aged 18-45. METHODS: We conducted a secondary analysis of the Evidence for Contraceptive Options and HIV Outcomes Trial to develop and internally validate HIV-1 risk scores for women aged 18-24 and 25-35 in South Africa. Candidate predictors included baseline demographic, clinical, behavioral, and contextual characteristics readily available in clinical settings. The VOICE risk score was applied to women aged 18-35. We evaluated predictive performance of each risk score by area under the receiver operating characteristic curve (AUC). RESULTS: Predictive performance of all risk scores was moderate, with AUC (95% confidence interval) of 0.64 (0.60 to 0.67) among women aged 18-24, 0.68 (0.62 to 0.73) among those aged 25-35, and 0.61 (0.58 to 0.65) for the VOICE risk score applied to women aged 18-35; The AUC was similar in internal validation. Among women aged 18-24, HIV-1 incidence was high even at low risk scores, at 3.9 per 100 person-years (95% confidence interval: 3.2 to 4.7). CONCLUSIONS: All risk scores were moderately predictive of HIV-1 acquisition, and age-specific risk scores performed only marginally better than the VOICE non-age-specific risk score. Approaches for targeted pre-exposure prophylaxis provision to women in South Africa may require more extensive data than are currently available to improve prediction.

Optimizing adherence in HIV prevention product trials: Development and psychometric evaluation of simple tools for screening and adherence counseling.

BACKGROUND: Low adherence in recent HIV prevention clinical trials highlights the need to better understand, measure, and support product use within clinical trials. Conventional self-reported adherence instruments within HIV prevention trials, often relying on single-item questions, have proven ineffective. While objective adherence measures are desirable, none currently exist that apply to both active and placebo arms. Scales are composed of multiple items in the form of questions or statements that, when combined, measure a more complex construct that may not be directly observable. When psychometrically validated, such measures may better assess the multiple factors contributing to adherence/non-adherence. This study aimed to develop and psychometrically evaluate tools to screen and monitor trial participants' adherence to HIV prevention products within the context of clinical trial research. METHODS AND FINDINGS: Based on an extensive literature review and conceptual framework, we identified and refined 86 items assessing potential predictors of adherence and 48 items assessing adherence experience. A structured survey, including adherence items and other variables, was administered to former ASPIRE and Ring Study participants and similar non-trial participants (n = 709). We conducted exploratory factor analyses (EFA) to identify a reduced set of constructs and items that could be used at screening to predict potential adherence, and at follow-up to monitor and intervene on adherence. We examined associations with other variables to assess content and construct validity. The EFA of screener items resulted in a 6-factor solution with acceptable to very good internal reliability (α: .62-.84). Similar to our conceptual framework, factors represent trial-related commitment (Distrust of Research and Commitment to Research); alignment with trial requirements (Visit Adherence and Trial Incompatibility); Belief in Trial Benefits and Partner Disclosure. The EFA on monitoring items resulted in 4 Product-specific factors that represent Vaginal Ring Doubts, Vaginal Ring Benefits, Ring Removal, and Side Effects with good to very good internal reliability (α = .71-.82). Evidence of content and construct validity was found; relationship to social desirability bias was examined. CONCLUSIONS: These scales are easy and inexpensive to administer, available in several languages, and are applicable regardless of randomization. Once validated prospectively, they could (1) screen for propensity to adhere, (2) target adherence support/counselling, and (3) complement biomarker measures in determining true efficacy of the experimental product.

Safety, Acceptability and Adherence of Dapivirine Vaginal Ring in a Microbicide Clinical Trial Conducted in Multiple Countries in Sub-Saharan Africa.

BACKGROUND: This was the first microbicide trial conducted in Africa to evaluate an antiretroviral-containing vaginal ring as an HIV prevention technology for women. OBJECTIVES: The trial assessed and compared the safety, acceptability and adherence to product use of a 4-weekly administered vaginal ring containing the antiretroviral microbicide, dapivirine, with a matching placebo ring among women from four countries in sub-Saharan Africa. METHODS: 280 Healthy, sexually active, HIV-negative women, aged 18 to 40 years were enrolled with 140 women randomised to a dapivirine vaginal ring (25 mg) and 140 women to a matching placebo ring, inserted 4-weekly and used over a 12-week period. Safety was evaluated by pelvic examination, colposcopy, clinical laboratory assessments, and adverse events. Blood samples for determination of plasma concentrations of dapivirine were collected at Weeks 0, 4 and 12. Residual dapivirine levels in returned rings from dapivirine ring users were determined post-trial. Participant acceptability and adherence to ring use were assessed by self-reports. RESULTS: No safety concerns or clinically relevant differences were observed between the dapivirine and placebo ring groups. Plasma dapivirine concentrations immediately prior to ring removal were similar after removal of the first and third ring, suggesting consistent ring use over the 12-week period. No clear relationship was observed between the residual amount of dapivirine in used rings and corresponding plasma concentrations. Self-reported adherence to daily use of the vaginal rings over the 12-week trial period was very high. At the end of the trial, 96% of participants reported that the ring was usually comfortable to wear, and 97% reported that they would be willing to use it in the future if proven effective. CONCLUSIONS: The dapivirine vaginal ring has a favourable safety and acceptability profile. If proven safe and effective in large-scale trials, it will be an important component of combination HIV prevention approaches for women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01071174.

HIV incidence remains high in KwaZulu-Natal, South Africa: evidence from three districts.

BACKGROUND: HIV prevalence and incidence among sexually active women in peri-urban areas of Ladysmith, Edendale, and Pinetown, KwaZulu-Natal, South Africa, were assessed between October 2007 and February 2010 in preparation for vaginal microbicide trials. METHODOLOGY/PRINCIPAL FINDINGS: Sexually active women 18-35 years, not known to be HIV-positive or pregnant were tested cross-sectionally to determine HIV and pregnancy prevalence (798 in Ladysmith, 1,084 in Edendale, and 891 in Pinetown). Out of these, approximately 300 confirmed non-pregnant, HIV-negative women were subsequently enrolled at each clinical research center (CRC) in a 12-month cohort study with quarterly study visits. Women in the cohort studies were required to use a condom plus a hormonal contraceptive method. HIV prevalence rates in the baseline cross-sectional surveys were high: 42% in Ladysmith, 46% in Edendale and 41% in Pinetown. Around 90% of study participants at each CRC reported one sex partner in the last 3 months, but only 14-30% stated that they were sure that none of their sex partners were HIV-positive. HIV incidence rates based on seroconversions over 12 months were 14.8/100 person-years (PY) (95% CI 9.7, 19.8) in Ladysmith, 6.3/100 PY (95% CI 3.2, 9.4) in Edendale, and 7.2/100 PY (95% CI 3.7, 10.7) in Pinetown. The 12-month pregnancy incidence rates (in the context of high reported contraceptive use) were: 5.7/100 PY (95% CI 2.6, 8.7) in Ladysmith, 3.1/100 PY (95% CI 0.9, 5.2) in Edendale and 6.3/100 PY (95% CI 3.0, 9.6) in Pinetown. CONCLUSIONS/SIGNIFICANCE: HIV prevalence and incidence remain high in peri-urban areas of KwaZulu-Natal.