Development of a checklist of quality indicators for clinical trials in resource-limited countries: the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) experience.

BACKGROUND: Since 1994, the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) has funded research sites in resource-limited countries (RLCs). These sites implement research on human immunodeficiency virus (HIV) infection and Hepatitis C. In parallel, international regulations and recommendations for clinical trials have evolved and proliferated. However, little guidance exists on how these should be interpreted and applied within academic trials and in the context of RLCs. After developing a specific Ethical Charter for research in developing countries in 2002, ANRS developed a set of quality indicators (QIs) as a monitoring tool for assessing compliance to international guidelines. PURPOSE: We describe here the development process, QIs adopted, and areas for improvement. METHODS: In 2008, a group of experts was convened that included a researcher representing each ANRS site (Cote d'Ivoire, Senegal, Cameroun, Burkina Faso, Egypt, and Cambodia). Our structuring interaction development process combined evidence and expert opinion in two nominal group meetings to identify (1) clinical trial processes involved, (2) issues specific to RLCs in terms of Good Clinical Practice (GCP) and the application of ethical recommendations, and (3) checklists of QIs adapted to clinical trials conducted in RLCs. RESULTS: The trial process reviewed and proposed for RLCs was mostly similar to the one produced in wealthier countries. The scheme generated by our work group added two further processes: 'drug management' and 'biological investigations'. Specific issues regarding trial management in RLCs were therefore described for eight trial steps (1) protocol conception and seeking authorizations, (2) participant enrollment and follow-up, (3) site monitoring, (4) drug management, (5) biological investigations, (6) record management, (7) data management, and (8) site closeout. A total of 58 indicators were identified with at least one indicator for each trial process. LIMITATIONS: Some trial activities require further consideration, that is, in the case of vulnerable participants (children, pregnant women). Proposed indicators are the result of expert consensus and reflect their experience in the HIV field. Relevance to existing trials and extrapolation to other fields must be assessed. CONCLUSIONS: This innovative program allowed ANRS sites located in RLCs to share their GCP implementation experiences in order to build a list of relevant indicators for clinical trials. The next step is to collect data from ongoing HIV and hepatitis C trials in these settings and will assess the relevance of these indicators to document current quality of performance among trials in resource-limited settings.

Universal test and treat and the HIV epidemic in rural South Africa: a phase 4, open-label, community cluster randomised trial.

BACKGROUND: Universal antiretroviral therapy (ART), as per the 2015 WHO recommendations, might reduce population HIV incidence. We investigated the effect of universal test and treat on HIV acquisition at population level in a high prevalence rural region of South Africa. METHODS: We did a phase 4, open-label, cluster randomised trial of 22 communities in rural KwaZulu-Natal, South Africa. We included individuals residing in the communities who were aged 16 years or older. The clusters were composed of aggregated local areas (neighbourhoods) that had been identified in a previous study in the Hlabisa subdistrict. The study statisticians randomly assigned clusters (1:1) with MapInfo Pro (version 11.0) to either the control or intervention communities, stratified on the basis of antenatal HIV prevalence. We offered residents repeated rapid HIV testing during home-based visits every 6 months for about 4 years in four clusters, 3 years in six clusters, and 2 years in 12 clusters (58 cluster-years) and referred HIV-positive participants to trial clinics for ART (fixed-dose combination of tenofovir, emtricitabine, and efavirenz) regardless of CD4 cell count (intervention) or according to national guidelines (initially ≤350 cells per µL and <500 cells per µL from January, 2015; control). Participants and investigators were not masked to treatment allocation. We used dried blood spots once every 6 months provided by participants who were HIV negative at baseline to estimate the primary outcome of HIV incidence with cluster-adjusted Poisson generalised estimated equations in the intention-to-treat population after 58 cluster-years of follow-up. This study is registered with ClinicalTrials.gov, number NCT01509508, and the South African National Clinical Trials Register, number DOH-27-0512-3974. FINDINGS: Between March 9, 2012, and June 30, 2016, we contacted 26 518 (93%) of 28 419 eligible individuals. Of 17 808 (67%) individuals with a first negative dried blood spot test, 14 223 (80%) had subsequent dried blood spot tests, of whom 503 seroconverted after follow-up of 22 891 person-years. Estimated HIV incidence was 2·11 per 100 person-years (95% CI 1·84-2·39) in the intervention group and 2·27 per 100 person-years (2·00-2·54) in the control group (adjusted hazard ratio 1·01, 95% CI 0·87-1·17; p=0·89). We documented one case of suicidal attempt in a woman following HIV seroconversion. 128 patients on ART had 189 life-threatening or grade 4 clinical events: 69 (4%) of 1652 in the control group and 59 (4%) of 1367 in the intervention group (p=0·83). INTERPRETATION: The absence of a lowering of HIV incidence in universal test and treat clusters most likely resulted from poor linkage to care. Policy change to HIV universal test and treat without innovation to improve health access is unlikely to reduce HIV incidence. FUNDING: ANRS, GiZ, and 3ie.

[Ethical constraints of clinical trials in developing countries: experience of the French National Agency for AIDS Research (ANRS)]. / Contraintes éthiques des essais cliniques dans les pays en développement: experience de l'Agence Nationale de Recherches sur le Sida (ANRS) française.

The ethical principles of clinical research in the developing countries have recently been revised in most international guidelines. Their implementation leads to practical difficulties in the field. As an institutional sponsor, the French National Agency for AIDS Research (ANRS), responsible for research on AIDS and hepatitis in France and in the developing countries, released an Ethical Charter. It represents a commitment for the ANRS partners from the North and the South. The most important principles of the Charter are as follows: an early integration of research in the national programmes of public health; a strong partnership between North and South at any step of the research; a clear definition of rules concerning evaluation and ethical follow-up of the research; enrolment of the subjects; healthcare; care for the patients; and management of the post-study.

Evaluation of the impact of immediate versus WHO recommendations-guided antiretroviral therapy initiation on HIV incidence: the ANRS 12249 TasP (Treatment as Prevention) trial in Hlabisa sub-district, KwaZulu-Natal, South Africa: study protocol for a cluster randomised controlled trial.

BACKGROUND: Antiretroviral therapy (ART) suppresses HIV viral load in all body compartments and so limits the risk of HIV transmission. It has been suggested that ART not only contributes to preventing transmission at individual but potentially also at population level. This trial aims to evaluate the effect of ART initiated immediately after identification/diagnosis of HIV-infected individuals, regardless of CD4 count, on HIV incidence in the surrounding population. The primary outcome of the overall trial will be HIV incidence over two years. Secondary outcomes will include i) socio-behavioural outcomes (acceptability of repeat HIV counselling and testing, treatment acceptance and linkage to care, sexual partnerships and quality of life); ii) clinical outcomes (mortality and morbidity, retention into care, adherence to ART, virologic failure and acquired HIV drug resistance), iii) cost-effectiveness of the intervention. The first phase will specifically focus on the trial's secondary outcomes. METHODS/DESIGN: A cluster-randomised trial in 34 (2 × 17) clusters within a rural area of northern KwaZulu-Natal (South Africa), covering a total population of 34,000 inhabitants aged 16 years and above, of whom an estimated 27,200 would be HIV-uninfected at start of the trial. The first phase of the trial will include ten (2 × 5) clusters. Consecutive rounds of home-based HIV testing will be carried out. HIV-infected participants will be followed in dedicated trial clinics: in intervention clusters, they will be offered immediate ART initiation regardless of CD4 count and clinical stage; in control clusters they will be offered ART according to national treatment eligibility guidelines (CD4 <350 cells/µL, World Health Organisation stage 3 or 4 disease or multidrug-resistant/extensively drug-resistant tuberculosis). Following proof of acceptability and feasibility from the first phase, the trial will be rolled out to further clusters. DISCUSSION: We aim to provide proof-of-principle evidence regarding the effectiveness of Treatment-as-Prevention in reducing HIV incidence at the population level. Data collected from the participants at home and in the clinics will inform understanding of socio-behavioural, economic and clinical impacts of the intervention as well as feasibility and generalizability. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01509508; South African Trial Register: DOH-27-0512-3974.

Antiretroviral therapy in prevention of HIV and TB: update on current research efforts.

There is considerable scientific evidence supporting the use of antiretroviral therapy (ART) in prevention of human immunodeficiency virus (HIV) and tuberculosis (TB) infections. The complex nature of the HIV and TB prevention responses, resource constraints, remaining questions about cost and feasibility, and the need to use a solid evidence base to make policy decisions, and the implementation challenges to translating trial data to operational settings require a well-organised and coordinated response to research in this area. To this end, we aimed to catalogue the ongoing and planned research activities that evaluate the impact of ART plus other interventions on HIV- and/or TB-related morbidity, mortality, risk behaviour, HIV incidence and transmission. Using a limited search methodology, 50 projects were identified examining ART as prevention, representing 5 regions and 52 countries with a global distribution. There are 24 randomised controlled clinical trials with at least 12 large randomised individual or community cluster trials in resource-constrained settings that are in the planning or early implementation stages. There is considerable heterogeneity between studies in terms of methodology, interventions and geographical location. While the identified studies will undoubtedly advance our understanding of the efficacy and effectiveness of ART for prevention, some key questions may remain unanswered or only partially answered. The large number and wide variety of research projects emphasise the importance of this research issue and clearly demonstrate the potential for synergies, partnerships and coordination across funding agencies.

Development of resistance mutations in women receiving standard antiretroviral therapy who received intrapartum nevirapine to prevent perinatal human immunodeficiency virus type 1 transmission: a substudy of pediatric AIDS clinical trials group protocol 316.

Pediatric AIDS Clinical Trials Group protocol 316 was an international, multicenter, placebo-controlled trial comparing single-dose oral nevirapine (200 mg to mother and 2 mg/kg to infant) with placebo in human immunodeficiency virus (HIV)-infected pregnant women receiving standard antiretroviral therapy. This substudy evaluated the emergence of nevirapine-resistance mutations at 6 weeks postpartum in a subgroup of participants. Maternal risk factors for the emergence of nevirapine-resistance mutations were evaluated. Mutations associated with nevirapine resistance were detectable at delivery, prior to receipt of study drug, in 5 (2.3%) of 217 women. Fourteen (15%; 95% confidence interval, 8%-23%) of 95 women who received intrapartum nevirapine developed a nevirapine-resistance mutation 6 weeks postpartum. The most common mutation was K103N, which was present in 10 women. The risk for development of a new nevirapine-resistance mutation did not correlate with CD4 cell count or HIV-1 RNA load at delivery or with type of antepartum antiretroviral therapy. The risk of nevirapine resistance should be considered when determining the risks or benefits of intrapartum nevirapine in women receiving antepartum antiretroviral therapy.