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Beating the placebo in HIV prevention efficacy trials: the role of the minimal efficacy bound.

ABSTRACT: OBJECTIVES:To produce an effect on the HIV epidemic, preventive interventions need to achieve a minimum level of efficacy to offset potential indirect effects such as an increase in risky behavior. The current generation of HIV prevention trials on oral preexposure prophylaxis and on vaginal microbicides were designed using different set points for minimum individual-level efficacy (MIE). Some trials were designed not only to show superiority over placebo but also to rule out lower efficacies. The MIE has a substantial impact on the size and cost of a trial. Ideally, the MIE should be chosen to reduce uncertainty in the estimation of population-level effects. In this article, we investigate the effect of MIE on estimates of population-level impact to better inform trial design. METHODS:We used mathematical model simulations assuming various rates of efficacy obtained from trials and different MIEs to study the impact of wide-scale interventions on 2 public health indicators. RESULTS:Implementation factors were the main drivers of uncertainty in public health indicators for an intervention, although MIE also contributed. The level of uncertainty introduced by the MIE was substantially lower than that of the other factors. CONCLUSIONS:Investigators in clinical trials have set the MIE solely on the basis of potential public health impact. However, the substantial increase in trial costs associated with a large MIE is unlikely to be justified. These additional funds would be better spent in evaluating more critical implementation factors that cannot be assessed in clinical trials.

SUBMITTER: Dimitrov DT

PROVIDER: S-EPMC3529808 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Beating the placebo in HIV prevention efficacy trials: the role of the minimal efficacy bound.

Dimitrov Dobromir T DT Mâsse Benoît R BR Boily Marie-Claude MC

Journal of acquired immune deficiency syndromes (1999) 20130101 1

<h4>Objectives</h4>To produce an effect on the HIV epidemic, preventive interventions need to achieve a minimum level of efficacy to offset potential indirect effects such as an increase in risky behavior. The current generation of HIV prevention trials on oral preexposure prophylaxis and on vaginal microbicides were designed using different set points for minimum individual-level efficacy (MIE). Some trials were designed not only to show superiority over placebo but also to rule out lower effic ...[more]

PMID: 23075921

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Project description:Four randomized placebo-controlled efficacy trials of a candidate vaccine or passively infused monoclonal antibody for prevention of HIV-1 infection are underway (HVTN 702 in South African men and women; HVTN 705 in sub-Saharan African women; HVTN 703/HPTN 081 in sub-Saharan African women; HVTN 704/HPTN 085 in U.S., Peruvian, Brazilian, and Swiss men or transgender persons who have sex with men). Several challenges are posed to the optimal design of the sequel efficacy trials, including: (1) how to account for the evolving mosaic of effective prevention interventions that may be part of the trial design or standard of prevention; (2) how to define viable and optimal sequel trial designs depending on the primary efficacy results and secondary "correlates of protection" results of each of the ongoing trials; and (3) how to define the primary objective of sequel efficacy trials if HIV-1 incidence is expected to be very low in all study arms such that a standard trial design has a steep opportunity cost. After summarizing the ongoing trials, I discuss statistical science considerations for sequel efficacy trial designs, both generally and specifically to each trial listed above. One conclusion is that the results of "correlates of protection" analyses, which ascertain how different host immunological markers and HIV-1 viral features impact HIV-1 risk and prevention efficacy, have an important influence on sequel trial design. This influence is especially relevant for the monoclonal antibody trials because of the focused pre-trial hypothesis that potency and coverage of serum neutralization constitutes a surrogate endpoint for HIV-1 infection. Another conclusion is that while assessing prevention efficacy against a counterfactual placebo group is fraught with risks for bias, such analysis is nonetheless important and study designs coupled with analysis methods should be developed to optimize such inferences. I draw a parallel with non-inferiority designs, which are fraught with risks given the necessity of making unverifiable assumptions for interpreting results, but nevertheless have been accepted when a superiority design is not possible and a rigorous/conservative non-inferiority margin is used. In a similar way, counterfactual placebo group efficacy analysis should use rigorous/conservative inference techniques that formally build in a rigorous/conservative margin to potential biases that could occur due to departures from unverifiable assumptions. Because reliability of this approach would require new techniques for verifying that the study cohort experienced substantial exposure to HIV-1, currently it may be appropriate as a secondary objective but not as a primary objective.

Project description:Obtaining the definitive data necessary to determine the safety and efficacy of using antiretroviral treatment (ART) to reduce the sexual transmission of HIV in heterosexual couples encountered an array of ethical challenges that threatened to compromise HIV Prevention Trials Network (HPTN) 052, the multinational clinical trial addressing this issue that has profound public health implications.To describe and analyze the major ethical challenges faced in HPTN 052.The ethical issues and modifications of HPTN 052 in response to these issues were cataloged by the principal investigator, the lead coordinator, and the ethicist working on the trial. The major ethical issues that were unique to the trial were then described and analyzed in light of the published literature as well as guidances and policies. The ethical challenges that must be addressed in many clinical trials, such as those related to obtaining informed consent and making provisions for ancillary care, are not described.When HPTN 052 was being designed, ethical questions emerged related to the relevance of the research question itself given data from observational research and a range of beliefs about the appropriate means of preventing and treating HIV infection and AIDS. Furthermore, ethical challenges were faced regarding site selection since there was a scientific need to conduct the research in settings where HIV incidence was high, but alternatives to study participation should be available. As in most HIV-prevention research, ethical questions surrounded the determination of the appropriate prevention package for all of those enrolled. During the course of the trial, guidance documents and policies emerged that were of direct relevance to the research questions, calling for a balancing of concerns for the research subjects and trial integrity. When the study results were made public, there was a need to ensure access to the treatment shown to be effective that in some cases differed from the guidelines used at the sites where the research was being conducted. In addition, questions were raised about whether there was an obligation to notify subjects about 'unlinked' transmissions of HIV, that is, infections acquired from someone other than the designated sexual partner enrolled in the study.The ethical issues described are limited to those discerned by the authors and not those of other stakeholders who may have identified additional issues or had a different perspective in analyzing them.Understanding the ethical challenges faced in HPTN 052 promises to inform the design and conduct of future complex, long-term clinical trials aimed at addressing critical scientific and public health questions, where data and practice patterns emerge over the course of the trial.

Project description:Anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been developed as potential agents for prevention of HIV-1 infection. The HIV Vaccine Trials Network and the HIV Prevention Trials Network are conducting the Antibody Mediated Prevention (AMP) trials to assess whether, and how, intravenous infusion of the anti-CD4 binding site bnAb, VRC01, prevents HIV-1 infection. These are the first test-of-concept studies to assess HIV-1 bnAb prevention efficacy in humans. The AMP trials are two parallel phase 2b HIV-1 prevention efficacy trials conducted in two cohorts: 2700 HIV-uninfected men and transgender persons who have sex with men in the United States, Peru, Brazil, and Switzerland; and 1500 HIV-uninfected sexually active women in seven countries in sub-Saharan Africa. Participants are randomized 1:1:1 to receive an intravenous infusion of 10 mg/kg VRC01, 30 mg/kg VRC01, or a control preparation every 8 weeks for a total of 10 infusions. Each trial is designed (1) to assess overall prevention efficacy (PE) pooled over the two VRC01 dose groups vs. control and (2) to assess VRC01 dose and laboratory markers as correlates of protection (CoPs) against overall and genotype- and phenotype-specific infection. Each AMP trial is designed to have 90% power to detect PE > 0% if PE is ≥ 60%. The AMP trials are also designed to identify VRC01 properties (i.e., concentration and effector functions) that correlate with protection and to provide insight into mechanistic CoPs. CoPs are assessed using data from breakthrough HIV-1 infections, including genetic sequences and sensitivities to VRC01-mediated neutralization and Fc effector functions. The AMP trials test whether VRC01 can prevent HIV-1 infection in two study populations. If affirmative, they will provide information for estimating the optimal dosage of VRC01 (or subsequent derivatives) and identify threshold levels of neutralization and Fc effector functions associated with high-level protection, setting a benchmark for future vaccine evaluation and constituting a bridge to other bnAb approaches for HIV-1 prevention.

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Beating the placebo in HIV prevention efficacy trials: the role of the minimal efficacy bound.

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Beating the placebo in HIV prevention efficacy trials: the role of the minimal efficacy bound.

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