Peebles Kathryn, Matrajt Laura, Baeten Jared M, Palanee-Phillips Thesla, Brown Elizabeth R
Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA.
Int J STD AIDS. 2025 Mar;36(3):195-204. doi: 10.1177/09564624241300199. Epub 2024 Nov 26.
Women-initiated HIV - 1 prevention products are key to reducing women's HIV-1 risk. Clinical trials of vaginal microbicides have shown limited to no efficacy in intention-to-treat (ITT) analyses. It is hypothesized that these negative results are partly due to efficacy dilution.
We developed a microsimulation model of MTN-020/ASPIRE, a phase 3 trial that evaluated monthly use of a dapivirine vaginal ring for HIV-1 prevention. We evaluated four sources of efficacy dilution: trial-level factors: (i) an imbalance in the number of monthly sex acts between study arms and (ii) heterogeneity in risk emergent over time; and individual-level factors: (iii) product non-adherence and (iv) receptive anal intercourse.
Assuming 70% per-vaginal exposure efficacy (consistent with the ITT estimate of 27%), heterogeneity in risk accounted for the largest proportion of efficacy dilution, at 42% (90% CrI: 38, 45), followed by non-adherence (33%; 90% CrI: 27, 39), an imbalance in arms (18%; 90% CrI: 16, 21) and lastly, anal intercourse with less than 10% of efficacy dilution.
Our results suggest that heterogeneity in risk was the most important source of efficacy dilution in the ASPIRE trial. Future trials of HIV-1 prevention products for women should consider alternative trial designs and analytic approaches that minimize bias introduced by heterogeneity in risk.
女性主导的HIV-1预防产品是降低女性感染HIV-1风险的关键。阴道杀菌剂的临床试验在意向性分析（ITT）中显示疗效有限或无疗效。据推测，这些阴性结果部分归因于疗效稀释。
我们开发了MTN-020/ASPIRE的微观模拟模型，这是一项3期试验，评估每月使用达匹韦林阴道环预防HIV-1的效果。我们评估了四个疗效稀释来源：试验水平因素：（i）研究组之间每月性行为次数的不平衡，以及（ii）随时间出现的风险异质性；以及个体水平因素：（iii）产品不依从性和（iv）接受性肛交。
假设每次阴道暴露的疗效为70%（与ITT估计的27%一致），风险异质性占疗效稀释的比例最大，为42%（90%CrI：38,45），其次是不依从性（33%；90%CrI：27,39）、组间不平衡（18%；90%CrI：16,21），最后是肛交，疗效稀释低于10%。
我们的结果表明，风险异质性是ASPIRE试验中疗效稀释的最重要来源。未来针对女性的HIV-1预防产品试验应考虑替代试验设计和分析方法，以尽量减少风险异质性带来的偏差。
