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. 2009 Oct 9:6:5.
doi: 10.1186/1742-7622-6-5.

Efficacy dilution in randomized placebo-controlled vaginal microbicide trials

Benoît R Mâsse  1 , Marie-Claude Boily, Dobromir Dimitrov, Kamal Desai
Affiliations

Efficacy dilution in randomized placebo-controlled vaginal microbicide trials

Benoît R Mâsse et al. Emerg Themes Epidemiol. .

Abstract

Background: To date different vaginal gel microbicides have been evaluated in phase 2b/3 trials, but none have demonstrated effectiveness for preventing HIV infection. Failure to demonstrate effectiveness however does not necessarily indicate that a product is truly inefficacious, as several sources of efficacy dilution may compromise our ability to identify products that may have been truly efficacious.

Methods: 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.

Results: 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.

Conclusion: 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.

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Figures

Figure 1
Figure 1
Expected effectiveness for different source of dilution. For different level of true efficacy of a candidate microbicide; ET = 25%, 50%, and 75%; Panel A shows the results for the dilution due to adherence (Ea), Panel B shows the results for the dilution due to HIV infections from anal intercourse (Es), Panel C shows the results for the dilution from time off-product due to pregnancy (Eo), and Panel D shows the results for the dilution due to the efficacy of the placebo gel (Eb).
Figure 2
Figure 2
Overall expected effectiveness and total dilution effect. For the four different scenarios described in Table S3 (see Table S3 in additional file 3) and as a function of the true efficacy of a candidate microbicide (ET), Panel A shows the results for the overall expected effectiveness (Eall) and Panel B shows the results for the total dilution effect (D).
See this image and copyright information in PMC

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