Efficacy dilution in randomized placebo-controlled vaginal microbicide trials

For four individual sources of dilution, we describe the dilution mechanisms and quantify the expected effectiveness. An overall expected effectiveness that combines all sources of dilution in a trial is derived as well.Under conditions that have been observed in recent microbicide trials, the overall expected effectiveness assuming an active gel with true efficacy of 50% and 75% are in the range of [16%; 33%] and [28%; 50%], respectively, when considering the four major sources of dilution. In contrast the diluting effect due to adherence alone (assuming an adherence of 80%) leads to higher expected effectiveness, 40% and 60% assuming an active gel with true efficacy of 50% and 75%, respectively. Individual sources of dilution may demonstrate a small effect when evaluated independently, but the overall dilution effect in a trial with several sources of dilution can be quite substantial.Currently planned phase 2b/3 microbicide trials of new candidate vaginal microbicides are not immune from these shortcomings. A good understanding of dilution effects is necessary to properly interpret microbicide trial results and to identify products worthy of further development and evaluation. Greater attention should be devoted to reducing and assessing the impact of efficacy dilution and to carefully selecting the effect size in the design of future trials.The development of female initiated HIV prevention methods is a high priority. For this reason, several different vaginal gel microbicides have been evaluated in phase 2b/3 efficacy trials, but to date none have demonstrated effectiveness while several have suggested evidence of harm. Table S1 reviews the findings of phase 2b/3 microbicide trials completed to date (see Table S1 in additional file 1). For instance, the cellulose sulfate gel (Ushercell, Polydex Pharmaceuticals, Toronto, ON, Canada and Topical Prevention of Conception and Disease [TOPCAD], Chicago, IL, USA) was found to be ineffective in preventing HIV infection