Weighing the gold in the gold standard: challenges in HIV prevention research

Sexual transmission

Weighing the gold in the gold standard: challenges in HIV prevention research

Few HIV prevention interventions have been evaluated in randomized controlled trials. Padian and colleagues examined design, implementation, and contextual considerations that may limit detection of a positive or adverse effect in HIV prevention trials. They conducted a systematic review of late phase randomized controlled trials for prevention of sexual transmission of HIV that: randomly allocated intervention and comparison groups; evaluated interventions to prevent sexual transmission in nonpregnant populations; and reported HIV incidence as the primary or secondary outcome. PubMed/MEDLINE, other electronic databases, and electronic conference proceedings of recent HIV/AIDS-related conferences were searched to identify published or unpublished trials meeting the inclusion criteria. Descriptive, methodological, and contextual factors were abstracted from each trial. The review included 37 HIV prevention randomized controlled trials reporting on 39 unique interventions. Only six randomized controlled trials, all evaluating biomedical interventions, demonstrated definitive effects on HIV incidence. Five of the six randomized controlled trials significantly reduced HIV infection: all three male circumcision trials, one trial of sexually transmitted infection treatment and care, and one vaccine trial. One microbicide trial of nonoxynol-9 gel produced adverse results. Lack of statistical power, poor adherence, and diluted versions of the intervention in comparison groups may have been important issues for the other trials that demonstrated 'flat' results. Almost 90% of HIV prevention trials had 'flat' results, which may be attributable to trial design and/or implementation. The HIV prevention community must not only examine evidence from significant RCTs, but must also examine flat trials and address design and implementation issues that limit detection of an effect.

Editors’ note: Randomised controlled trials (RCTs) in HIV prevention can have positive results (they demonstrate efficacy or effectiveness), negative results (increased HIV risk), or flat results (unable to demonstrate a positive or adverse effect). This review, which examined 37 individual and community trials evaluating behavioural interventions, microfinance, STI treatment, diaphragm, microbicides, pre-exposure prophylaxis (PrEP), male circumcision, and vaccines, was published before the exciting results of CAPRISA 004 – 1% tenofovir gel. However, the fact that more than 90% of the trials described here had flat results has led to serious questioning about whether RCTs should remain the gold standard in an era of combination prevention. When there is good reason to believe that an approach should work, flat results may result from a variety of causes. These include exceptional or enhanced standard of prevention offered to both the active and control arms, declining HIV incidence in the community, poor adherence in the intervention arm, a Hawthorne effect (changes in behaviour simply from being in a trial), all of which can reduce the power of a trial to detect a difference. In addition to moving rapidly now to confirm the tenofovir gel results in women, we need to think more about ways of evaluating combination prevention strategies that combine partially protective prevention measures to break the trajectory of the HIV epidemic.