The HPTN 035 trial showed that 0.5% PRO2000 Gel was safe and, compared to the Placebo Gel, reduced the incidence of HIV infection by a modest 30%, although this finding was not statistically significant (p=0.10). The consistent presence of the 0.5% PRO2000 effect on HIV infection against each of the two comparator arms and in almost all study sites, the greater protection observed in self-reported high PRO2000 Gel users compared to low gel users, and the biological plausibility from animal challenge studies [24
] suggested a potentially promising signal on PRO2000. However, these data alone were insufficient to conclude that 0.5% PRO2000 Gel protected against HIV infection. Subsequently, our trial’s initial encouraging signal was superseded by the finding of no protection against HIV infection in the phase III MDP301 trial [21
The HEC Placebo Gel [26
] was found to be safe and had no demonstrable effect on HIV infection when compared to the No Gel arm, even after adjusting for baseline characteristics, including condom use. This addressed a key concern in microbicide research and makes HEC a suitable “universal” placebo for future microbicide gel trials [26
The results of microbicide effectiveness trials are impacted by several inherent design and implementation challenges [27
], including lengthy periods off-product (mainly due to pregnancy), adherence, other sexually transmitted infections, unprotected and unreported anal sex, use of intravaginal substances which may interfere with the study gel, and difficulties in applying study gel as prescribed.
The 6.1% of follow-up time that was off-product, mainly due to the 11.3% pregnancy rate, had little, if any, effect in the Placebo Gel comparisons. However, it had a small but important impact in the comparisons with the No Gel arm where the effect of PRO2000 changed from 33% (p=0.06) in the intent to treat analysis to 36% (p=0.04) in the per-protocol analysis, highlighting the potential impact of even relatively modest pregnancy rates on microbicide trial outcomes.
Adherence is a major challenge in microbicide trials [28
]. In the recent Carraguard trial an applicator dye test revealed a much lower estimate of use compared to self-reported adherence (42.1% vs 96.1%) [13
]. Our trial did not have such an objective measure of adherence because the dye test performed poorly on the applicator used in this trial [29
]. To increase their chances of success, future microbicides trials will need to enrol a higher proportion of women who will maintain high adherence for both study gel and reliable contraception during the trial.
While interpretation of microbicide trial results can be complicated by the indirect effect of other sexually transmitted infections on HIV infection, this did not apply to this trial as the three study gels did not alter the risk of other sexually transmitted infections. Self-reported unprotected anal sex, intravaginal substance use and concerns about the one hour pre-sex insertion requirement were low and therefore unlikely to have had an impact on the trial result. However, these may have been under-reported, making it difficult to estimate their full potential impact on the study outcome.
BufferGel was found to be safe but did not alter the risk of HIV infection. This could be due to the differential effect of acidity and BufferGel on cell-free [30
] compared to cell-associated viruses [31
]. Moreover, the duration of action of BufferGel is brief [32
]. It was posited that BufferGel would reduce HIV susceptibility by reducing the prevalence of bacterial vaginosis, as observed in a phase I trial [19
]; however, no effect on bacterial vaginosis was observed in this trial, possibly due to lower gel use here compared to twice daily use in the phase I trial.
The pregnancy rates in all arms were similar. While HPTN 035 was not specifically designed to assess contraceptive efficacy due to the high background rates of effective contraception use in the study population, 0.5% PRO2000 Gel and BufferGel did not demonstrate a contraceptive effect in this study.
Viewed jointly, the HPTN 035 and MDP 301 trials suggest that 0.5% PRO2000 gel may have little or no effect on reducing a woman’s risk of HIV infection. Hope is now being placed in the topical use of antiretroviral agents, such as tenofovir gel[33
], as the next class of candidate microbicides and on new formulations to improve adherence, such as vaginal rings. Most recently, results from the CAPRISA 004 trial, showed that tenofovir gel had a protective effect of 39% against HIV [33
]. The protective efficacy of tenofovir gel has demonstrated that microbicides can prevent HIV infection and could potentially alter the course of the HIV epidemic[33
]. While efforts to bring tenofovir gel into widespread public health use are underway, there are limitations to using prescription-only medications, including their potential for drug resistance, and potential adverse effects on concomitant viral infections such as hepatitis B. For these reasons, the microbicide field should not abandon the search for a safe, single-use with sex, over-the-counter microbicide, as had been hoped for when we undertook this study of PRO2000 Gel and BufferGel.