Efficacy dilution in randomized placebo-controlled vaginal microbicide trials.
Efficacy dilution in randomized placebo-controlled vaginal microbicide trials.
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DOI：
10.1186/1742-7622-6-5
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发表时间：
2009-10-09
影响因子：
2.3
通讯作者：
Desai K
中科院分区：
文献类型：
--
作者：
Mâsse BR;Boily MC;Dimitrov D;Desai K
到目前为止，不同的阴道凝胶杀微生物剂已在2b/3期试验中进行了评估，但没有一个显示出预防HIV感染的有效性。然而，未能证明有效性并不一定表明产品确实无效，因为几种有效性稀释的来源可能会损害我们识别可能真正有效的产品的能力。对于四个单独的稀释源，我们描述了稀释机制，并量化了预期的效果。还得出了在试验中结合所有稀释来源的总体预期有效性。在最近的杀微生物剂试验中观察到的条件下，当考虑到四种主要稀释来源时，假设活性凝胶的真实功效为50%和75%，则总体预期有效性分别在[16%; 33%]和[28%; 50%]范围内。相比之下，仅由于粘附（假设粘附率为80%）导致的稀释效应导致更高的预期有效性，假设活性凝胶的真实有效性分别为50%和75%，则为40%和60%。当独立评价时，单个稀释源可能表现出较小的影响，但在具有几个稀释源的试验中，总体稀释效应可能相当大。目前计划的新候选阴道杀微生物剂的2b/3期杀微生物剂试验也未能幸免于这些缺点。要正确解释杀微生物剂试验结果并确定值得进一步开发和评价的产品，就必须充分了解稀释效应。应更加注意减少和评估疗效稀释的影响，并在未来试验的设计中仔细选择效应量。
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. 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.