Pre-Exposure Prophylaxis for HIV Infection as a Public Health Tool

The efficacy of pre-exposure prophylaxis, PrEP, with antiviral agents for prevention of HIV infection has been demonstrated in multiple randomized controlled trials and demonstration projects. These trials have studied prevention at the individual level. The effectiveness of PrEP as a public health intervention to reduce HIV incidence at community and population levels is being actively evaluated but is less well described. In reviewing the available data on PrEP as a public health intervention, three significant examples have demonstrated success, and all have been among communities of gay, bisexual and other men who have sex with men (MSM)

Licenced doses of approved COVID-19 vaccines may not be optimal: A review of the early-phase, dose-finding trials

Although over 13 billion COVID-19 vaccine doses have been administered globally, the issue of whether the optimal doses are being used has received little attention. To address this question we reviewed the reports of early-phase dose-finding trials of the nine COVID-19 vaccines approved by World Health Organization, extracting information on study design and findings on reactogenicity and early humoral immune response. The number of different doses evaluated for each vaccine varied widely (range 1-7), as did the number of subjects studied per dose (range 15-190). As expected, the frequency and severity of adverse reactions generally increased at higher doses, although most were clinically tolerable. Higher doses also tended to elicit better immune responses, but differences between the highest dose and the second-highest dose evaluated were small, typically less than 1.6-fold for both binding antibody concentration and neutralising antibody titre. All of the trials had at least one important design limitation - few doses evaluated, large gaps between adjacent doses, or an inadequate sample size - although this is not a criticism of the study investigators, who were working under intense time pressures at the start of the epidemic. It is therefore open to question whether the single dose taken into clinical efficacy trials, and subsequently authorised by regulatory agencies, was optimal. In particular, our analysis indicates that the recommended doses for some vaccines appear to be unnecessarily high. Although reduced dosing for booster injections is an active area of research, the priming dose also merits study. We conclude by suggesting improvements in the design of future vaccine trials, for both next-generation COVID-19 vaccines and for vaccines against other pathogens

Interpretation of active-control randomised trials: the case for a new analytical perspective involving averted events

Active-control trials, where an experimental treatment is compared with an established treatment, are performed when the inclusion of a placebo control group is deemed to be unethical. For time-to-event outcomes, the primary estimand is usually the rate ratio, or the closely-related hazard ratio, comparing the experimental group with the control group. In this article we describe major problems in the interpretation of this estimand, using examples from COVID-19 vaccine and HIV pre-exposure prophylaxis trials. In particular, when the control treatment is highly effective, the rate ratio may indicate that the experimental treatment is clearly statistically inferior even when it is worthwhile from a public health perspective. We argue that it is crucially important to consider averted events as well as observed events in the interpretation of active-control trials. An alternative metric that incorporates this information, the averted events ratio, is proposed and exemplified. Its interpretation is simple and conceptually appealing, namely the proportion of events that would be averted by using the experimental treatment rather than the control treatment. The averted events ratio cannot be directly estimated from the active-control trial, and requires an additional assumption about either: (a) the incidence that would have been observed in a hypothetical placebo arm (the counterfactual incidence) or (b) the efficacy of the control treatment (relative to no treatment) that pertained in the active-control trial. Although estimation of these parameters is not straightforward, this must be attempted in order to draw rational inferences. To date, this method has been applied only within HIV prevention research, but has wider applicability to treatment trials and other disease areas

Microbicides development programme: engaging the community in the standard of care debate in a vaginal microbicide trial in Mwanza, Tanzania.

BACKGROUND: HIV prevention research in resource-limited countries is associated with a variety of ethical dilemmas. Key amongst these is the question of what constitutes an appropriate standard of health care (SoC) for participants in HIV prevention trials. This paper describes a community-focused approach to develop a locally-appropriate SoC in the context of a phase III vaginal microbicide trial in Mwanza City, northwest Tanzania. METHODS: A mobile community-based sexual and reproductive health service for women working as informal food vendors or in traditional and modern bars, restaurants, hotels and guesthouses has been established in 10 city wards. Wards were divided into geographical clusters and community representatives elected at cluster and ward level. A city-level Community Advisory Committee (CAC) with representatives from each ward has been established. Workshops and community meetings at ward and city-level have explored project-related concerns using tools adapted from participatory learning and action techniques e.g. chapati diagrams, pair-wise ranking. Secondary stakeholders representing local public-sector and non-governmental health and social care providers have formed a trial Stakeholders' Advisory Group (SAG), which includes two CAC representatives. RESULTS: Key recommendations from participatory community workshops, CAC and SAG meetings conducted in the first year of the trial relate to the quality and range of clinic services provided at study clinics as well as broader standard of care issues. Recommendations have included streamlining clinic services to reduce waiting times, expanding services to include the children and spouses of participants and providing care for common local conditions such as malaria. Participants, community representatives and stakeholders felt there was an ethical obligation to ensure effective access to antiretroviral drugs and to provide supportive community-based care for women identified as HIV positive during the trial. This obligation includes ensuring sustainable, post-trial access to these services. Post-trial access to an effective vaginal microbicide was also felt to be a moral imperative. CONCLUSION: Participatory methodologies enabled effective partnerships between researchers, participant representatives and community stakeholders to be developed and facilitated local dialogue and consensus on what constitutes a locally-appropriate standard of care in the context of a vaginal microbicide trial in this setting. TRIAL REGISTRATION: Current Controlled Trials ISRCTN64716212

Apples and oranges? Interpreting success in HIV prevention trials.

BACKGROUND: In the last decade, several large-scale, clinical trials evaluating the efficacy of novel HIV prevention products have been completed, and eight are currently underway or about to be reported. Little attention has been given in the literature to the level of protection sufficient to warrant introduction, and there is concern that using the term "efficacy" to describe the effect of user-controlled methods such as microbicides may mislead policymakers. DESIGN: We review how the fields of family planning, vaccine science and mathematical modelling understand and use the terms efficacy and effectiveness, and explore with simple mathematical models how trial results of user-controlled products relate to common understandings of these terms. RESULTS: Each field brings different assumptions, a different evidence base and different expectations to interpretations of efficacy and effectiveness - a reality that could cloud informed assessment of emerging data. CONCLUSION: When making judgments on the utility of new health technologies, it is important to use standards that yield appropriate comparisons for the innovation and that take into account the local epidemic and available alternatives

Uptake of hormonal contraceptives and correlates of uptake in a phase III clinical trial in rural South Western Uganda.

BACKGROUND: Use of a reliable contraception method has become an inclusion criterion in prevention trials to minimize time off product. We report on hormonal contraceptive prevalence, uptake, sustained use and correlates of use in the Microbicides Development Programme (MDP 301) trial at the Masaka Centre in Uganda. METHODS: HIV negative women in sero-discordant relationships were enrolled and followed-up for 52 to 104 weeks from 2005 to 2009. Contraceptive use data was collected through self-report at baseline and dispensing records during follow-up. Hormonal contraceptives were promoted and provided to women that were not using a reliable method at enrolment. Baseline contraceptive prevalence, uptake and sustained use were calculated. Uptake was defined as a participant who reported not using a reliable method at enrolment and started using a hormonal method at any time after. Logistic regression models were fitted to investigate predictors of hormonal contraceptive uptake. RESULTS: A total of 840 women were enrolled of whom 21 aged ≥50 years and 12 without follow-up data were excluded; leaving 807 (median age 31 IQR 26-38) in this analysis. At baseline, 228 (28%) reported using a reliable contraceptive; 197 hormonal, 28 female-sterilisation, two IUCD and one hysterectomy. As such 579 were not using a reliable contraceptive at enrolment, of whom 296 (51%) subsequently started using a hormonal contraceptive method; 253 DMPA, four oral pills, and two norplant. Overall 193 (98%) existing users and 262 (88%) new users sustained use throughout follow-up. Independent correlates of hormonal contraceptive uptake were: younger women ≤30 years, aOR = 2.5, 95% CI: 1.7-3.6 and reporting not using contraceptives at baseline due to lack of access or money, breastfeeding or other reasons, in comparison to women who reported using unreliable method. CONCLUSION: Promotion and provision of hormonal contraception doubled the proportion of women using a reliable method of contraception. Uptake was pronounced among younger women and those not previously using a reliable method because of lack of access or money, and breastfeeding. Promotion and provision of hormonal contraceptives in trials that require the interruption or discontinuation of investigational products during pregnancy is important to reduce the time off product. TRIAL REGISTRATION: Protocol Number ISRCTN64716212

Communication About Microbicide Use Between Couples in KwaZulu-Natal, South Africa

The ways in which couples communicate about microbicides is likely to influence microbicide uptake and usage. We collected quantitative data about whether women in a microbicide trial discussed microbicides with their partners and explored communication about microbicides during 79 in-depth-interviews with women enrolled in the trial and 17 focus-group discussions with community members. After 4 weeks in the trial, 60 % of 1092 women had discussed microbicides with their partners; in multivariate analysis, this was associated with younger age, clinic of enrolment and not living in households that owned cattle. After 52 weeks, 84 % of women had discussed microbicides; in multivariate analysis, this was associated with not living in households that owned cattle, not living in a household that relied on the cheapest water source, allocation to 0.5 % PRO2000 gel and consistent gel adherence. Qualitative findings highlighted that women in committed relationships were expected to discuss microbicides with their partners and preferred to use microbicides with their partner's knowledge. Women had different reasons for, and ways of, discussing microbicides and these were influenced by the couple's decision-making roles. Although there was tolerance for the use of microbicides without a partner's knowledge, the women who used microbicides secretly appeared to be women who were least able to discuss microbicides. In KwaZulu-Natal, socio-cultural norms informing sexual communication are amenable to microbicide introduction

Psychological and Behavioural Within-participant Predictors of Adherence to Oral HIV Pre-Exposure Prophylaxis (PrEP)

Oral PrEP's effectiveness relies on adequate adherence during periods of substantial HIV risk. Since most PrEP users will miss doses, understanding predictors within participants can help to explain adherence. We used a cross-sectional, within-participant design with 67 gay, bisexual, and other men who have sex with men taking PrEP daily. Using a questionnaire, informed by the Information Motivation Behavioral Skills Model, participants were asked about an adherent and a non-adherent episode. PrEP non-adherence was associated with non-normality of the day (p < .001), being out of the home (p < .001), weekend days (p = .01), having company (p = .02), using substances (p = .2), not using reminders (p = .03), lower PrEP information (p = .04), lower behavioural skills (p < .001) and less positive affect (p = .002). PrEP adherence assessment could focus on situational variations, supporting the construction of alternative strategies to facilitate adherence in these situations

Biomedical prevention: state of the science.

Preexposure prophylaxis (PrEP) and treatment as prevention (TasP) involve the use of antiretroviral (ARV) drugs by human immunodeficiency virus (HIV)-negative and -positive individuals to reduce HIV acquisition and transmission, respectively. Clinical science has delivered a consistently high effect size for TasP and a range from 0%-73% reduction in incidence across placebo-controlled PrEP trials. However, the quality of evidence for PrEP compares favorably with evidence for postexposure prophylaxis (PEP). It is clear from treatment programs and PrEP trials that daily adherence presents challenges to a large proportion of the population. Although there are factors associated with inconsistent use (ie, younger age), they do not assist clinicians at the point of care. There are additional provider concerns about PrEP (covering cost of drug and delivery, undermining condom promotion, and facilitating resistant strains) that have delayed widespread acceptance. These issues need to be addressed in order to realize the full public health potential of antiretrovirals