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.

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.

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.

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.