Linda-Gail Bekker

A Phase IIA Randomized Clinical Trial of a Multiclade HIV-1 DNA Prime Followed by a Multiclade rAd5 HIV-1 Vaccine Boost in Healthy Adults (HVTN204)

Background The safety and immunogenicity of a vaccine regimen consisting of a 6-plasmid HIV-1 DNA prime (envA, envB, envC, gagB, polB, nefB) boosted by a recombinant adenovirus serotype-5 (rAd5) HIV-1 with matching inserts was evaluated in HIV-seronegative participants from South Africa, United States, Latin America and the Caribbean. Methods 480 participants were evenly randomized to receive either: DNA (4 mg IM by Biojector) at 0, 1 and 2 months, followed by rAd5 (1010 PU IM by needle/syringe) at 6 months; or placebo. Participants were monitored for reactogenicity and adverse events throughout the 12-month study. Peak and duration of HIV-specific humoral and cellular immune responses were evaluated after the prime and boost. Results The vaccine was well tolerated and safe. T-cell responses, detected by interferon-γ (IFN-γ) ELISpot to global potential T-cell epitopes (PTEs) were observed in 70.8% (136/192) of vaccine recipients overall, most frequently to Gag (54.7%) and to Env (54.2%). In U.S. vaccine recipients T-cell responses were less frequent in Ad5 sero-positive versus sero-negative vaccine recipients (62.5% versus 85.7% respectively, p = 0.035). The frequency of HIV-specific CD4+ and CD8+ T-cell responses detected by intracellular cytokine staining were similar (41.8% and 47.2% respectively) and most secreted ≥2 cytokines. The vaccine induced a high frequency (83.7%–94.6%) of binding antibody responses to consensus Group M, and Clades A, B and C gp140 Env oligomers. Antibody responses to Gag were elicited in 46% of vaccine recipients. Conclusion The vaccine regimen was well-tolerated and induced polyfunctional CD4+ and CD8+ T-cells and multi-clade anti-Env binding antibodies. Trial Registration: ClinicalTrials.gov NCT00125970

Recombinant adenovirus type 5 HIV gag/pol/nef vaccine in South Africa: unblinded, long-term follow-up of the phase 2b HVTN 503/Phambili study

Background The Phambili study, conducted in South Africa amongst a predominantly heterosexual population, evaluated the efficacy of the MRK Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine. Enrollment and vaccinations were stopped, participants unblinded, and follow-up extended when the Step study evaluating the same vaccine in the Americas, Caribbean and Australia was unblinded for non-efficacy with more HIV infections amongst vaccinee than placebo recipients [ZM1]. Extensive analyses over the complete follow-up period, most of which was unblinded, are reported.BACKGROUND The HVTN 503/Phambili study, which assessed the efficacy of the Merck Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine in South Africa, was stopped when futility criteria in the Step study (assessing the same vaccine in the Americas, Caribbean, and Australia) were met. Here we report long-term follow-up data. METHODS HVTN 503/Phambili was a double-blind, placebo-controlled, randomised trial that recruited HIV-1 uninfected, sexually active adults aged 18-35 years from five sites in South Africa. Eligible participants were randomly assigned (1:1) by computer-generated random numbers to either vaccine or placebo, stratified by site and sex. Cox proportional hazards models were used to estimate HIV-1 infection in the modified intention-to-treat cohort, all of whom were unmasked early in follow-up. The trial is registered with ClinicalTrials.gov, number NCT00413725 and the South African National Health Research Database, number DOH-27-0207-1539. FINDINGS Between Jan 24, 2007, and Sept 19, 2007, 801 participants (26·7%) of a planned 3000 were randomly assigned (400 to vaccine, 401 to placebo); 216 (27%) received only one injection, 529 (66%) received only two injections, and 56 (7%) received three injections. At a median follow-up of 42 months (IQR 31-42), 63 vaccine recipients (16%) had HIV-1 infection compared with 37 placebo recipients (9%; adjusted HR 1·70, 95% CI 1·13-2·55; p=0·01). Risk for HIV-1 infection did not differ according to the number of vaccinations received, sex, circumcision, or adenovirus type 5 (Ad5) serostatus. Differences in risk behaviour at baseline or during the study, or annualised dropout rate (7·7% [95% CI 6·2-9·5] for vaccine recipients vs 8·8% [7·1-10·7] for placebo recipients; p=0·40) are unlikely explanations for the increased rate of HIV-1 infections seen in vaccine recipients. INTERPRETATION The increased risk of HIV-1 acquisition in vaccine recipients, irrespective of number of doses received, warrants further investigation to understand the biological mechanism. We caution against further use of the Ad5 vector for HIV vaccines. FUNDING National Institute of Allergy and Infectious Diseases, Merck, and South African Medical Research Council.

Men who have sex with men sensitivity training reduces homoprejudice and increases knowledge among Kenyan healthcare providers in coastal Kenya

Healthcare workers (HCWs) in Africa typically receive little or no training in the healthcare needs of men who have sex with men (MSM), limiting the effectiveness and reach of population‐based HIV control measures among this group. We assessed the effect of a web‐based, self‐directed sensitivity training on MSM for HCWs (www.marps‐africa.org), combined with facilitated group discussions on knowledge and homophobic attitudes among HCWs in four districts of coastal Kenya.

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

Continued Follow-Up of Phambili Phase 2b Randomized HIV-1 Vaccine Trial Participants Supports Increased HIV-1 Acquisition among Vaccinated Men.

Background The Phase 2b double-blinded, randomized Phambili/HVTN 503 trial evaluated safety and efficacy of the MRK Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine vs placebo in sexually active HIV-1 seronegative participants in South Africa. Enrollment and vaccinations stopped and participants were unblinded but continued follow-up when the Step study evaluating the same vaccine in the Americas, Caribbean, and Australia was unblinded for non-efficacy. Final Phambili analyses found more HIV-1 infections amongst vaccine than placebo recipients, impelling the HVTN 503-S recall study. Methods HVTN 503-S sought to enroll all 695 HIV-1 uninfected Phambili participants, provide HIV testing, risk reduction counseling, physical examination, risk behavior assessment and treatment assignment recall. After adding HVTN 503-S data, HIV-1 infection hazard ratios (HR vaccine vs. placebo) were estimated by Cox models. Results Of the 695 eligible, 465 (67%) enrolled with 230 from the vaccine group and 235 from the placebo group. 38% of the 184 Phambili dropouts were enrolled. Enrollment did not differ by treatment group, gender, or baseline HSV-2. With the additional 1286 person years of 503-S follow-up, the estimated HR over Phambili and HVTN 503-S follow-up was 1.52 (95% CI 1.08–2.15, p = 0.02, 82 vaccine/54 placebo infections). The HR was significant for men (HR = 2.75, 95% CI 1.49, 5.06, p = 0.001) but not for women (HR = 1.12, 95% CI 0.73, 1.72, p = 0.62). Conclusion The additional follow-up from HVTN 503-S supported the Phambili finding of increased HIV-1 acquisition among vaccinated men and strengthened the evidence of lack of vaccine effect among women. Trial Registration clinicaltrials.gov NCT00413725 SA National Health Research Database DOH-27-0207-1539

Characteristics of Women Enrolled into a Randomized Clinical Trial of Dapivirine Vaginal Ring for HIV-1 Prevention.

Introduction Women in sub-Saharan Africa are a priority population for evaluation of new biomedical HIV-1 prevention strategies. Antiretroviral pre-exposure prophylaxis is a promising prevention approach; however, clinical trials among young women using daily or coitally-dependent products have found low adherence. Antiretroviral-containing vaginal microbicide rings, which release medication over a month or longer, may reduce these adherence challenges. Methods ASPIRE (A Study to Prevent Infection with a Ring for Extended Use) is a phase III, randomized, double-blind, placebo-controlled trial testing the safety and effectiveness of a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine for prevention of HIV-1 infection. We describe the baseline characteristics of African women enrolled in the ASPIRE trial. Results Between August 2012 and June 2014, 5516 women were screened and 2629 HIV-1 seronegative women between 18–45 years of age were enrolled from 15 research sites in Malawi, South Africa, Uganda, and Zimbabwe. The median age was 26 years (IQR 22–31) and the majority (59%) were unmarried. Nearly 100% of participants reported having a primary sex partner in the prior three months but 43% did not know the HIV-1 status of their primary partner; 17% reported additional concurrent partners. Nearly two-thirds (64%) reported having disclosed to primary partners about planned vaginal ring use in the trial. Sexually transmitted infections were prevalent: 12% had Chlamydia trachomatis, 7% Trichomonas vaginalis, 4% Neisseria gonorrhoeae, and 1% syphilis. Conclusions African HIV-1 seronegative women at risk of HIV -1 infection were successfully enrolled into a phase III trial of dapivirine vaginal ring for HIV-1 prevention.

We neglect primary HIV prevention at our peril

Inspired by a steady decline in new HIV infections and AIDS-related deaths, the sustainable development goals call for ending the AIDS epidemic as a public health threat by 2030. However, the world is not on track to end the epidemic. In particular, the pace at which new HIV infections are declining is substantially slower than the fall in AIDS-related deaths, and epidemic control remains out of reach. In 2015, the estimated number of new HIV infections in adults (1·9 million worldwide) was no fewer than in 2010. Unless the decline in new HIV infections is accelerated, a rebound of the epidemic is likely, with potentially catastrophic consequences for the communities most vulnerable to HIV. Although antiretroviral therapy (ART) is powerfully eff ective in reducing the risk of HIV transmission, HIV transmission will persist even with achievement of the ambitious UNAIDS 90-90-90 target for ART. Only by combining scaled up ART with substantially more eff ective prevention of HIV acquisition will the decline in the global HIV burden accelerate. The urgency of strengthening HIV prevention is emphasised by demographic realities, as the proportion of the population younger than age 15 exceeds 40% in all but eight countries in sub-Saharan Africa. In the coming years, as this especially large cohort of young people enters young adolescence and young adulthood, when HIV acquisition risks are greatest, failing to strengthen primary HIV prevention will undermine the benefi ts of treatment. In the high-burden countries of eastern and southern Africa, this demographic bulge poses particular risks of HIV acquisition for adolescent girls and young women. Eff orts to prevent new HIV infections early in the epidemic were stymied by a shortage of validated data on the sources of new infections and scaleable prevention approaches, but this is no longer the case. Scientifi c fi ndings over the past decade have greatly expanded the evidence base for HIV prevention. As Krishnaratne and colleagues observe, clear evidence exists of effi cacy for voluntary medical male circumcision (VMMC), pre-exposure antiretroviral prophylaxis (PrEP), HIV treatment as prevention, and other biomedical approaches, as well as strong evidentiary support for interventions to increase the supply of condoms, clean needles, and other prevention measures. Evidence strongly indicates that the most eff ective approach to reducing the number of new HIV infections is a combination of biomedical, behavioural, and structural interventions that both reduces vulnerability to HIV acquisition and accelerates uptake of key prevention methods. Despite improvements in HIV prevention science over the past decade, we have yet to see a suffi cient decline in new HIV infections. As Dehne and coauthors explain, current prevention eff orts suff er from several weaknesses, including chronic underfunding, variable quality of programme design, the failure to bring interventions to scale, and poor or non-existent monitoring of outcomes. A much stronger, more rigorous approach to HIV prevention, with clearer monitoring and accountability, focused on a single agreed target for reducing new infections, is needed to accelerate the decline in the global HIV burden. Modelling by Smith and co-workers indicate that scale-up of existing interventions would strongly accelerate the decline in HIV incidence, but that the public health impact of existing approaches would be magnifi ed by the development and complementary use of newer, easier-to-use technologies that rely less on individual adherence. Synergistic combination of diverse approaches, including structural interventions, is likely to optimise prevention outcomes. Where HIV services have succeeded, programme designers, implementers, and evaluators have used service cascades to clarify key programmatic elements, highlight areas where gaps, or leaks, in the cascade occur, and inform eff orts to adapt programmatic design and approaches to improve performance and outcomes. For example, eff orts to prevent new HIV infections among children have long benefi ted from the routine use of data-based service cascades. As the coverage and performance of services to prevent mother-to-child HIV transmission (PMTCT) have improved, the health benefi ts for children have increased, with 45% fewer children newly infected in 2014 compared with 2009. Indeed, PMTCT eff orts, informed by strong data collection and programme monitoring, represent what is arguably the single most important prevention achievement in the history of the epidemic. See Articles pages e289, e297, and e307

Sibanye Methods for Prevention Packages Program Project Protocol: Pilot Study of HIV Prevention Interventions for Men Who Have Sex With Men in South Africa

Background Human immunodeficiency virus (HIV) prevention intervention programs and related research for men who have sex with men (MSM) in the southern African region remain limited, despite the emergence of a severe epidemic among this group. With a lack of understanding of their social and sexual lives and HIV risks, and with MSM being a hidden and stigmatized group in the region, optimized HIV prevention packages for southern African MSM are an urgent public health and research priority. Objective The objective of the Sibanye Health Project is to develop and evaluate a combination package of biomedical, behavioral, and community-level HIV prevention interventions and services for MSM in South Africa. Methods The project consists of three phases: (1) a comprehensive literature review and summary of current HIV prevention interventions (Phase I), (2) agent-based mathematical modeling of HIV transmission in southern African MSM (Phase II), and (3) formative and stigma-related qualitative research, community engagement, training on providing health care to MSM, and the pilot study (Phase III). The pilot study is a prospective one-year study of 200 men in Cape Town and Port Elizabeth, South Africa. The study will assess a package of HIV prevention services, including condom and condom-compatible lubricant choices, risk-reduction counseling, couples HIV testing and counseling, pre-exposure prophylaxis (PrEP) for eligible men, and non-occupational post-exposure prophylaxis for men with a high risk exposure. The pilot study will begin in October 2014. Results Preliminary results from all components but the pilot study are available. We developed a literature review database with meta-data extracted from 3800 documents from 67 countries. Modeling results indicate that regular HIV testing and promotion of condom use can significantly impact new HIV infections among South African MSM, even in the context of high coverage of early treatment of HIV-positive men and high coverage of PrEP for at-risk HIV-negative men. Formative qualitative research consisted of 79 in-depth interviews, and six focus group discussions in Cape Town and Port Elizabeth. Analysis of these data has informed pilot study protocol development and has been documented in peer-reviewed manuscripts. Qualitative work regarding stigma faced by South African MSM resulted in finalized scales for use in the pilot study questionnaire. A total of 37 health care providers completed training designed to facilitate clinically and culturally competent care for MSM in the Eastern Cape. Conclusions The design of a future, larger study of the HIV prevention package will be conducted at the end of the pilot study, powered to detect efficacy of the prevention package. Data from the updated mathematical model, results of the pilot study, acceptability data, and advancements in HIV prevention sciences will be considered in developing the final proposed package and study design. Trial Registration ClinicalTrials.gov NCT02043015; http://clinicaltrials.gov/show/NCT02043015 (Archived by WebCite at http://www.webcitation.org/6THvp7rAj).

High Rate of Multiple Concurrent Human Papillomavirus Infections among HIV-Uninfected South African Adolescents

BACKGROUND The epidemiology and impact of multiple concurrent Human papillomavirus (HPV) infections on the natural history of cervical disease is uncertain, but could have significant implications for cervical cancer prevention and HPV vaccination strategies. METHODS A cross-sectional prevalence study was conducted to determine the overall prevalence of HPV and the rate of multiple concurrent HPV infections, in a cohort of sexually active HIV-uninfected South African adolescents. HPV genotyping was performed using the polymerase chain reaction. RESULTS Overall prevalence of HPV was 64.1%. Multiple concurrent HPV infections were found in 43.6% of participants and 68% of HPV-infected participants. Non-vaccine high-risk HPV (HR-HPV) genotypes were found much more often than vaccine types (HPV16 and HPV18). CONCLUSIONS Our cohort of young South African females was found to have a high overall prevalence of HPV and multiple concurrent HPV infections. Most HR-HPV infections found were genotypes other than HPV16 or HPV18.

Exploring repeat HIV testing among men who have sex with men in Cape Town and Port Elizabeth, South Africa

Despite the high prevalence of HIV among men who have sex with men (MSM) – and the general adult population – in South Africa, there is little data regarding the extent to which MSM seek repeat testing for HIV. This study explores reported histories of HIV testing, and the rationales for test seeking, among a purposive sample of 34 MSM in two urban areas of South Africa. MSM participated in activity-based in-depth interviews that included a timeline element to facilitate discussion. Repeat HIV testing was limited among participants, with three-quarters having two or fewer lifetime HIV tests, and over one-third of the sample having one or fewer lifetime tests. For most repeat testers, the time gap between their HIV tests was greater than the one-year interval recommended by national guidelines. Analysis of the reasons for seeking HIV testing revealed several types of rationale. The reasons for a first HIV test were frequently one-time occurrences, such as a requirement prior to circumcision, or motivations likely satisfied by a single HIV test. For MSM who reported repeat testing at more timely intervals, the most common rationale was seeking test results with a sex partner. Results indicate a need to shift HIV test promotion messaging and programming for MSM in South Africa away from a one-off model to one that frames HIV testing as a repeated, routine health maintenance behavior.