Safety and immunogenicity of a subtype C ALVAC-HIV (vCP2438) vaccine prime plus bivalent subtype C gp120 vaccine boost adjuvanted with MF59 or alum in healthy adults without HIV (HVTN 107): A phase 1/2a randomized trial.

BACKGROUND: Adjuvants are widely used to enhance and/or direct vaccine-induced immune responses yet rarely evaluated head-to-head. Our trial directly compared immune responses elicited by MF59 versus alum adjuvants in the RV144-like HIV vaccine regimen modified for the Southern African region. The RV144 trial of a recombinant canarypox vaccine vector expressing HIV env subtype B (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost adjuvanted with alum is the only trial to have shown modest HIV vaccine efficacy. Data generated after RV144 suggested that use of MF59 adjuvant might allow lower protein doses to be used while maintaining robust immune responses. We evaluated safety and immunogenicity of an HIV recombinant canarypox vaccine vector expressing HIV env subtype C (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost (gp120) adjuvanted with alum (ALVAC-HIV+gp120/alum) or MF59 (ALVAC-HIV+gp120/MF59) or unadjuvanted (ALVAC-HIV+gp120/no-adjuvant) and a regimen where ALVAC-HIV+gp120 adjuvanted with MF59 was used for the prime and boost (ALVAC-HIV+gp120/MF59 coadministration). METHODS AND FINDINGS: Between June 19, 2017 and June 14, 2018, 132 healthy adults without HIV in South Africa, Zimbabwe, and Mozambique were randomized to receive intramuscularly: (1) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/MF59 (months 3, 6, and 12), n = 36; (2) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/alum (months 3, 6, and 12), n = 36; (3) 4 doses of ALVAC-HIV+gp120/MF59 coadministered (months 0, 1, 6, and 12), n = 36; or (4) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/no adjuvant (months 3, 6, and 12), n = 24. Primary outcomes were safety and occurrence and mean fluorescence intensity (MFI) of vaccine-induced gp120-specific IgG and IgA binding antibodies at month 6.5. All vaccinations were safe and well-tolerated; increased alanine aminotransferase was the most frequent related adverse event, occurring in 2 (1.5%) participants (1 severe, 1 mild). At month 6.5, vaccine-specific gp120 IgG binding antibodies were detected in 100% of vaccinees for all 4 vaccine groups. No significant differences were seen in the occurrence and net MFI of vaccine-specific IgA responses between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/alum-prime-boost groups or between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/MF59 coadministration groups. Limitations were the relatively small sample size per group and lack of evaluation of higher gp120 doses. CONCLUSIONS: Although MF59 was expected to enhance immune responses, alum induced similar responses to MF59, suggesting that the choice between these adjuvants may not be critical for the ALVAC+gp120 regimen. TRIAL REGISTRATION: HVTN 107 was registered with the South African National Clinical Trials Registry (DOH-27-0715-4894) and ClinicalTrials.gov (NCT03284710).

Pharmacokinetics and predicted neutralisation coverage of VRC01 in HIV-uninfected participants of the Antibody Mediated Prevention (AMP) trials.

The phase 2b AMP trials are testing whether the broadly neutralising antibody VRC01 prevents HIV-1 infection in two cohorts: women in sub-Saharan Africa, and men and transgender persons who have sex with men (MSM/TG) in the Americas and Switzerland. We used nonlinear mixed effects modelling of longitudinal serum VRC01 concentrations to characterise pharmacokinetics and predict HIV-1 neutralisation coverage. We found that body weight significantly influenced clearance, and that the mean peripheral volume of distribution, steady state volume of distribution, elimination half-life, and accumulation ratio were significantly higher in MSM/TG than in women. Neutralisation coverage was predicted to be higher in the first (versus second) half of a given 8-week infusion interval, and appeared to be higher in MSM/TG than in women overall. Study cohort differences in pharmacokinetics and neutralisation coverage provide insights for interpreting the AMP results and for investigating how VRC01 concentration and neutralisation correlate with HIV incidence.

Safety and immune responses after a 12-month booster in healthy HIV-uninfected adults in HVTN 100 in South Africa: A randomized double-blind placebo-controlled trial of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 vaccines.

BACKGROUND: HVTN 100 evaluated the safety and immunogenicity of an HIV subtype C pox-protein vaccine regimen, investigating a 12-month booster to extend vaccine-induced immune responses. METHODS AND FINDINGS: A phase 1-2 randomized double-blind placebo-controlled trial enrolled 252 participants (210 vaccine/42 placebo; median age 23 years; 43% female) between 9 February 2015 and 26 May 2015. Vaccine recipients received ALVAC-HIV (vCP2438) alone at months 0 and 1 and with bivalent subtype C gp120/MF59 at months 3, 6, and 12. Antibody (IgG, IgG3 binding, and neutralizing) and CD4+ T-cell (expressing interferon-gamma, interleukin-2, and CD40 ligand) responses were evaluated at month 6.5 for all participants and at months 12, 12.5, and 18 for a randomly selected subset. The primary analysis compared IgG binding antibody (bAb) responses and CD4+ T-cell responses to 3 vaccine-matched antigens at peak (month 6.5 versus 12.5) and durability (month 12 versus 18) timepoints; IgG responses to CaseA2_gp70_V1V2.B, a primary correlate of risk in RV144, were also compared at these same timepoints. Secondary and exploratory analyses compared IgG3 bAb responses, IgG bAb breadth scores, neutralizing antibody (nAb) responses, antibody-dependent cellular phagocytosis, CD4+ polyfunctionality responses, and CD4+ memory sub-population responses at the same timepoints. Vaccines were generally safe and well tolerated. During the study, there were 2 deaths (both in the vaccine group and both unrelated to study products). Ten participants became HIV-infected during the trial, 7% (3/42) of placebo recipients and 3% (7/210) of vaccine recipients. All 8 serious adverse events were unrelated to study products. Less waning of immune responses was seen after the fifth vaccination than after the fourth, with higher antibody and cellular response rates at month 18 than at month 12: IgG bAb response rates to 1086.C V1V2, 21.0% versus 9.7% (difference = 11.3%, 95% CI = 0.6%-22.0%, P = 0.039), and ZM96.C V1V2, 21.0% versus 6.5% (difference = 14.5%, 95% CI = 4.1%-24.9%, P = 0.004). IgG bAb response rates to all 4 primary V1V2 antigens were higher 2 weeks after the fifth vaccination than 2 weeks after the fourth vaccination: 87.7% versus 75.4% (difference = 12.3%, 95% CI = 1.7%-22.9%, P = 0.022) for 1086.C V1V2, 86.0% versus 63.2% (difference = 22.8%, 95% CI = 9.1%-36.5%, P = 0.001) for TV1c8.2.C V1V2, 67.7% versus 44.6% (difference = 23.1%, 95% CI = 10.4%-35.7%, P < 0.001) for ZM96.C V1V2, and 81.5% versus 60.0% (difference = 21.5%, 95% CI = 7.6%-35.5%, P = 0.002) for CaseA2_gp70_V1V2.B. IgG bAb response rates to the 3 primary vaccine-matched gp120 antigens were all above 90% at both peak timepoints, with no significant differences seen, except a higher response rate to ZM96.C gp120 at month 18 versus month 12: 64.5% versus 1.6% (difference = 62.9%, 95% CI = 49.3%-76.5%, P < 0.001). CD4+ T-cell response rates were higher at month 18 than month 12 for all 3 primary vaccine-matched antigens: 47.3% versus 29.1% (difference = 18.2%, 95% CI = 2.9%-33.4%, P = 0.021) for 1086.C, 61.8% versus 38.2% (difference = 23.6%, 95% CI = 9.5%-37.8%, P = 0.001) for TV1.C, and 63.6% versus 41.8% (difference = 21.8%, 95% CI = 5.1%-38.5%, P = 0.007) for ZM96.C, with no significant differences seen at the peak timepoints. Limitations were that higher doses of gp120 were not evaluated, this study was not designed to investigate HIV prevention efficacy, and the clinical significance of the observed immunological effects is uncertain. CONCLUSIONS: In this study, a 12-month booster of subtype C pox-protein vaccines restored immune responses, and slowed response decay compared to the 6-month vaccination. TRIAL REGISTRATION: ClinicalTrials.gov NCT02404311. South African National Clinical Trials Registry (SANCTR number: DOH--27-0215-4796).

Integrated provision of topical pre-exposure prophylaxis in routine family planning services in South Africa: a non-inferiority randomized controlled trial.

INTRODUCTION: Tenofovir-containing oral pre-exposure prophylaxis (PrEP) is recommended for those at substantial risk as part of combination HIV prevention. However, there are limited data, beyond clinical trial settings, to guide the introduction of PrEP in healthcare services with adequate levels of adherence. Since young women in Africa are at high risk of HIV and likely to utilize family planning (FP) services, the feasibility, acceptability and effectiveness of integrating topical PrEP provision into routine FP services was assessed. METHODS: This two-arm, randomized controlled, non-inferiority, open-label extension trial was undertaken in urban and rural KwaZulu-Natal, South Africa. HIV-negative eligible women (n = 372) from the parent trial (Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004) were randomized to receive tenofovir gel either through intervention (FP clinics, n = 189) or control clinics (CAPRISA research clinics, n = 183). Non-inferiority was predefined as gel use in the intervention clinics would be no more than 20% lower than in the control clinics. Adherence, retention and HIV incidence rates were assessed. RESULTS: Women were enrolled between November 2012 and October 2014, and followed up for 682.3 women-years (mean = 22 months). Baseline characteristics of women in intervention and control clinics were comparable and retention rates were 92.1% and 92.3% respectively. Women in intervention clinics and control clinics returned on average 5.2 (95% confidence interval (CI): 4.7 to 5.7) and 5.7 (CI: 5.2 to 6.2) used gel applicators per month respectively, with a mean difference of -0.47 (CI: -1.16 to 0.21). Per-protocol estimates were on average 5.5 (CI: 5.0 to 6.1) and 5.8 (CI: 5.3 to 6.3) respectively, with a mean difference of -0.25 (CI: -0.98 to 0.48), meeting the non-inferiority criteria. Adherence, based on proportion of reported sex acts covered by two gel doses, was 79.9% (CI: 76.7 to 83.2) in intervention compared with 73.9% (CI: 70.7 to 77.1) in control clinics; mean difference:6.0% (CI: 1.5 to 10.6) (p = 0.009). HIV incidence rates were 3.5 (CI: 1.8 to 6.0) and 3.6 (CI: 1.9 to 6.3) per 100 women-years in intervention and control clinics respectively. Both these incidence rates were lower than the age-standardized rate of 6.2 per 100 women-years (n = 444) in the placebo arm of the parent trial (p = 0.019). CONCLUSIONS: Provision of topical PrEP as part of an integrated FP service achieved higher adherence, and was as feasible, acceptable and effective in preventing HIV as provision through a research setting. This provides useful evidence for scale-up of oral PrEP in urban and rural high burden communities.

Using Mobile Technology (pMOTAR) to Assess Reactogenicity: Protocol for a Pilot Randomized Controlled Trial.

BACKGROUND: Accurate safety monitoring in HIV vaccine trials is vital to eventual licensure and consequent uptake of products. Current practice in preventive vaccine trials, under the HIV Vaccine Trials Network (HVTN), is to capture related side effects in a hardcopy tool. The reconciliation of this tool, 2 weeks after vaccination at the safety visit, is time consuming, laborious, and fraught with error. Unstructured Supplementary Service Data (USSD), commonly used to purchase airtime, has been suggested for collection of safety data in vaccine trials. With saturated access to mobile phones in South Africa, this cheap, accessible tool may improve accuracy and completeness of collected data and prove feasible and acceptable over the hardcopy tool. OBJECTIVE: The objective of our study is to develop and implement a USSD tool for real-time safety data collection that is feasible and acceptable to participants and staff, allowing for a comparison with the hardcopy tool in terms of completeness and accuracy. METHODS: This feasibility study is being conducted at a single study site, the Centre for the AIDS Programme of Research in South Africa eThekwini Clinical Research site, in South Africa. The feasibility study is nested within a parent phase 1/2a preventive HIV vaccine trial (HVTN 108) as an open-label, randomized controlled trial, open to all consenting parent trial participants. Participants are randomly assigned in a 1:1 ratio to the hardcopy or USSD tool, with data collection targeted to the third and fourth injection time points in the parent trial. Online feasibility and acceptability surveys will be completed by staff and participants at the safety visit. We will itemize and compare error rates between the hardcopy tool and the USSD printout and associated source documentation. We hypothesize that the USSD tool will be shown to be feasible and acceptable to staff and participants and to have superior quality and completion rates to the hardcopy tool. RESULTS: The study has received regulatory approval. We have designed and developed the USSD tool to include all the data fields required for reactogenicity reporting. Online feasibility and accessibility surveys in both English and isiZulu have been successfully installed on a tablet. Data collection is complete, but analysis is pending. CONCLUSIONS: Several HIV preventive vaccine trials are active in Southern Africa, making tools to improve efficiencies and minimize error necessary. Our results will help to determine whether the USSD tool can be used in future vaccine studies and can eventually be rolled out. TRIAL REGISTRATION: ClincalTrials.gov NCT02915016; https://clinicaltrials.gov/ct2/show/NCT02915016 (Archived by WebCite at http://www.webcitation.org/71h0cztDM). REGISTERED REPORT IDENTIFIER: RR1-10.2196/9396.

Subtype C ALVAC-HIV and bivalent subtype C gp120/MF59 HIV-1 vaccine in low-risk, HIV-uninfected, South African adults: a phase 1/2 trial.

BACKGROUND: Modest efficacy was reported for the HIV vaccine tested in the RV144 trial, which comprised a canarypox vector (ALVAC) and envelope (env) glycoprotein (gp120). These vaccine components were adapted to express HIV-1 antigens from strains circulating in South Africa, and the adjuvant was changed to increase immunogenicity. Furthermore, 12-month immunisation was added to improve durability. In the HIV Vaccine Trials Network (HVTN) 100 trial, we aimed to assess this new regionally adapted regimen for advancement to efficacy testing. METHODS: HVTN 100 is a phase 1/2, randomised controlled, double-blind trial at six community research sites in South Africa. We randomly allocated adults (aged 18-40 years) without HIV infection and at low risk of HIV infection to either the vaccine regimen (intramuscular injection of ALVAC-HIV vector [vCP2438] at 0, 1, 3, 6, and 12 months plus bivalent subtype C gp120 and MF59 adjuvant at 3, 6, and 12 months) or placebo, in a 5:1 ratio. Randomisation was done by computer-generated list. Participants, investigators, and those assessing outcomes were masked to random assignments. Primary outcomes included safety and immune responses associated with correlates of HIV risk in RV144, 2 weeks after vaccination at 6 months (month 6·5). We compared per-protocol participants (ie, those who completed the first four vaccinations and provided samples at month 6·5) from HVTN 100 with stored RV144 samples assayed contemporaneously. This trial is registered with the South African National Clinical Trials Registry (DOH-27-0215-4796) and ClinicalTrials.gov (NCT02404311). FINDINGS: Between Feb 9, 2015, and May 26, 2015, 252 participants were enrolled, of whom 210 were assigned vaccine and 42 placebo. 222 participants were included in the per-protocol analysis (185 vaccine and 37 placebo). 185 (100%) vaccine recipients developed IgG binding antibodies to all three vaccine-matched gp120 antigens with significantly higher titres (3·6-8·8 fold; all p<0·0001) than the corresponding vaccine-matched responses of RV144. The CD4+ T-cell response to the ZM96.C env protein in HVTN 100 was 56·4% (n=102 responders), compared with a response of 41·4% (n=79 responders) to 92TH023.AE in RV144 (p=0·0050). The IgG response to the 1086.C variable loops 1 and 2 (V1V2) env antigen in HVTN 100 was 70·5% (95% CI 63·5-76·6; n=129 responders), lower than the response to V1V2 in RV144 (99·0%, 95% CI 96·4-99·7; n=199 responders). INTERPRETATION: Although the IgG response to the HVTN 100 vaccine was lower than that reported in RV144, it exceeded the predicted 63% threshold needed for 50% vaccine efficacy using a V1V2 correlate of protection model. Thus, the subtype C HIV vaccine regimen qualified for phase 2b/3 efficacy testing, a critical next step of vaccine development. FUNDING: US National Institute of Allergy and Infectious Diseases (NIAID), and Bill & Melinda Gates Foundation.

Undue inducement: a case study in CAPRISA 008.

: Participant safety and data integrity, critical in trials of new investigational drugs, are achieved through honest participant report and precision in the conduct of procedures. HIV prevention post-trial access studies in middle-income countries potentially offer participants many benefits including access to proven efficacious but unlicensed technologies, ancillary care that often exceeds local standards-of-care, financial reimbursement for participation and possibly unintended benefits if participants choose to share or sell investigational drugs. This case study examines the possibility that this combination of benefits may constitute an undue inducement for some participants in middle-income countries, where economic challenges are prevalent. A case study is presented of a single participant in a cohort of 382 participants who used concealment, fabrication and deception to ensure eligibility for a post-trial access study of an unlicensed HIV prevention technology at potential risk to her health and that of her fetus. A root cause analysis revealed her desire to access HIV prevention during an unplanned pregnancy with a partner whose faithfulness was in question. Researchers should consider implementation of systems to efficiently identify similar cases without inconveniencing the majority of participants TRIAL REGISTRATION NUMBER: NCT01691768.

Challenges with participant reimbursement: experiences from a post-trial access study.

Reimbursement of trial participants remains a frequently debated issue, with specific guidance lacking. Trials combining post-trial access and implementation science may necessitate new strategies and models. CAPRISA 008, a post-trial access study testing the feasibility of using family planning services to rollout a prelicensure HIV prevention intervention, tried to balance the real-life scenario of no reimbursement for attendance at public sector clinics with that of a trial including some visits that focused on research procedures and others that focused on standard of care procedures. A reduced reimbursement was offered for 'standard of care' visits, meant primarily to cover transport costs to and from the clinic only. This impacted negatively on accrual, retention and participant morale, primarily due to the protracted delay in regulatory approval, during which time, the costs of living, including travel costs had increased. Relevant guidelines were reviewed and institutional policy was updated to incorporate the South African National Health Research Ethics Committee guidelines on reimbursement (taking into account participant time, travel and inconvenience). The reimbursement amount for 'standard of care' visits was increased accordingly. The question remains whether a trial that combines post-trial access with implementation science, with clear benefits for the participants and the provision of above standard medical care, should have reimbursement rates that approach those of a proof-of-concept trial, for 'standard of care' visits.

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.

Assessing the implementation effectiveness and safety of 1% tenofovir gel provision through family planning services in KwaZulu-Natal, South Africa: study protocol for an open-label randomized controlled trial.

BACKGROUND: The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial demonstrated a 39% reduction in HIV infection, with a 54% HIV reduction in women who used tenofovir gel consistently. A confirmatory trial is expected to report results in early 2015. In the interim, we have a unique window of opportunity to prepare for and devise effective strategies for the future policy and programmatic scale-up of tenofovir gel provision. One approach is to integrate tenofovir gel provision into family planning (FP) services. The CAPRISA 008 implementation trial provides an opportunity to provide post-trial access to tenofovir gel while generating empiric evidence to assess whether integrating tenofovir gel provision into routine FP services can achieve similar levels of adherence as the CAPRISA 004 trial. METHODS/DESIGN: This is a two-arm, open-label, randomized controlled non-inferiority trial. A maximum of 700 sexually active, HIV-uninfected women aged 18 years and older who previously participated in an antiretroviral prevention study will be enrolled from an urban and rural site in KwaZulu-Natal, South Africa. The anticipated study duration is 30 months, with active accrual requiring approximately 12 months (following which an open cohort will be maintained) and follow-up continuing for approximately 18 months. At each of the two sites, eligible participants will be randomly assigned to receive tenofovir gel through either FP services (intervention arm) or through the CAPRISA research clinics (control arm). As part of the study intervention, a quality improvement approach will be used to assist the FP services to expand their current services to include tenofovir gel provision. DISCUSSION: This protocol aims to address an important implementation question on whether FP services are able to effectively incorporate tenofovir gel provision for this at-risk group of women in South Africa. Provision of tenofovir gel to the women from the CAPRISA 004 trial meets the ethical obligation for post-trial access, and helps identify a potential avenue for future scale-up of microbicides within the public health system of South Africa. TRIAL REGISTRATION: This trial was registered with the South Africa Department of Health (reference: DOH-27-0812-4129) and ClinicalTrials.gov (reference: NCT01691768) on 05 July 2012.

Disclosure of microbicide gel use to sexual partners: influence on adherence in the CAPRISA 004 trial.

Young women in sub-Saharan Africa are disproportionately affected by HIV, making the development of women initiated and controlled methods of prevention, including microbicides, a priority. Adherence is pivotal to microbicide efficacy and partner related factors are known to impact adherence. An analysis of disclosure of gel use to sexual partners and adherence in CAPRISA 004 women was conducted to better understand this relationship. Partner disclosure was significantly associated with a modest 4.2 % increased adherence (71.0 vs. 66.8 %, p = 0.03). Most women rated the experience of disclosure as positive, despite 6.7 % of partners expressing a negative reaction.Participants who disclosed were more likely to reside with their regular partner (14.4 vs. 8.4 %; p = 0.01) and reported consistent condom use at baseline (32.9 vs. 20.9 %; p < 0.01). Partner disclosure needs to be better understood as a potential facilitator or barrier to microbicide adherence.

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 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.

Adverse events with isoniazid preventive therapy: experience from a large trial.

OBJECTIVES: We describe isoniazid-related adverse events in Thibela TB, a cluster-randomized study of community-wide isoniazid preventive therapy (IPT) among gold miners in South Africa, where HIV prevalence is estimated at 30%. METHODS: Consenting employees were screened prior to IPT for active tuberculosis and increased risk of isoniazid toxicity using a questionnaire and chest radiograph. Study-defined IPT-related adverse events were sought at each study visit: liver function tests were only performed if clinically indicated. In a substudy, we questioned consecutive participants at baseline and months 1, 3, and 6 concerning minor IPT-related adverse events. RESULTS: Among 24,221 participants (95.2% men, median age 40 years), 130 individuals had 132 study-defined adverse events (0.54%); 61 (0.25%) possible hypersensitivity rash, 50 (0.21%) peripheral neuropathy, 17 (0.07%) clinical hepatotoxicity, and four (0.02%) convulsions. Four events (two hepatotoxicity, one fatal, and two convulsions) fulfilled criteria for seriousness. Clinical hepatotoxicity was associated with consumption of alcohol [0.11 vs. 0.03% if no alcohol consumed, odds ratio 3.9 (95% confidence interval 1.2-12.1)], but not with sex, age, weight, or concurrent antiretroviral therapy. In the substudy, 324 of 498 (65.1%) participants reported better health since starting IPT; 180 of 324 (55.6%) reported that this was because of increased appetite. The frequency of specific minor symptoms was low among those taking IPT, and all symptoms were reported less often than at baseline. CONCLUSION: The risk of adverse events, particularly hepatotoxicity, was very low in this population. Our data suggest that clinical criteria can safely be used for screening prior to and monitoring during IPT.

'Team up against TB': promoting involvement in Thibela TB, a trial of community-wide tuberculosis preventive therapy.

OBJECTIVE: To describe a programme of community education and mobilization to promote uptake in a cluster-randomized trial of tuberculosis preventive therapy offered to all members of intervention clusters. SETTING AND PARTICIPANTS: Gold mines in South Africa, where tuberculosis incidence is extremely high, despite conventional control measures. All employees in intervention clusters (mine shaft and associated hostel) were invited to enrol. MAIN OUTCOME MEASURE: Cumulative enrolment in the study in intervention clusters. RESULTS: Key steps in communicating information relevant to the study included extensive consultation with key stakeholders; working with a communication company to develop a project 'brand'; developing a communication strategy tailored to each intervention site; and involving actors from a popular television comedy series to help inform communities about the study. One-to-one communications used peer educators along with study staff, and participant advisory groups facilitated two-way communication between study staff and participants. By contrast, treatment 'buddies' and text messaging to promote adherence proved less successful. Mean cumulative enrolment in the first four intervention clusters was 61.9%, increasing to 83.0% in the final four clusters. CONCLUSION: A tailored communication strategy can facilitate a high level of enrolment in a community health intervention.