Efficacy dilution in randomized placebo-controlled vaginal microbicide trials

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

The future role of rectal and vaginal microbicides to prevent HIV infection in heterosexual populations: implications for product development and prevention.

Objectives. To compare the potential impact of rectal (RMB), vaginal (VMB) and bi-compartment (RVMB) (applied vaginally and protective during vaginal and anal intercourse) microbicides to prevent HIV in various heterosexual populations. To understand when a RMB is as useful than a VMB for women practicing anal intercourse (AI). Methods. Mathematical model was used to assess the population-level impact (cumulative fraction of new HIV infections prevented (CFP)) of the three different microbicides in various intervention scenarios and prevalence settings. We derived the break-even RMB efficacy required to reduce a female’s cumulative risk of HIV infection by the same amount than a VMB. Results. Under optimistic coverage (fast roll-out, 100% uptake), a 50% efficacious VMB used in 75% of sex acts in population without AI may prevent -33% (27, 42%) new total (men and women combined) HIV infections over 25 years. The 25-year CFP reduces to -25% (20, 32%) and 17% (13, 23%) if uptake decreases to 75% and 50%, respectively. Similar loss of impact (by 25% - 50%) is observed if the same VMB is introduced in populations with 5% - 10% AI and for RRRAI=4-20. A RMB is as useful as a VMB (ie, break-even) in populations with 5% AI if RRRAI=20 and in populations with 15% - 20% AI if RRRAI=4, independently of adherence as long as it is the same with both products. The 10-year CFP with a RVMB is twofold larger than for a VMB or RMB when AI=10% and RRRAI=10. Conclusions. Even low AI frequency can compromise the impact of VMB interventions. RMB and RVMB will be important prevention tools for heterosexual populations

Impact of High-Risk Sex and Focused Interventions in Heterosexual HIV Epidemics: A Systematic Review of Mathematical Models

Background: The core-group theory of sexually transmitted infections suggests that targeting prevention to high-risk groups (HRG) could be very effective. We aimed to quantify the contribution of heterosexual HRGs and the potential impact of focused interventions to HIV transmission in the wider community. Methods: We systematically identified studies published between 1980 and 2011. Studies were included if they used dynamical models of heterosexual HIV transmission, incorporated behavioural heterogeneity in risk, and provided at least one of the following primary estimates in the wider community (a) the population attributable fraction (PAF) of HIV infections due to HRGs, or (b) the number per capita or fraction of HIV infections averted, or change in HIV prevalence/incidence due to focused interventions. Findings: Of 267 selected articles, 22 were included. Four studies measured the PAF, and 20 studies measured intervention impact across 265 scenarios. In low-prevalence epidemics (≤5% HIV prevalen