Abstract
BackgroundTopically delivered tenofovir (TFV) from intravaginal rings, tablets, or gels is being evaluated for HIV prevention. We previously demonstrated that TFV delivered vaginally by gel protected macaques from vaginal infection with SHIV. Here we investigated efficacy of the TFV gel against vaginal transmission of a TFV-resistant SHIV containing the K65R mutation (SHIV162P3K65R) and its relationship to drug levels in vaginal tissues.ResultsSHIV162P3K65R shows approximately a 5-fold reduction in susceptibility to TFV compared to wild-type SHIV. Efficacy was evaluated in pig-tailed macaques exposed vaginally twice-weekly (up to 10 weeks) to SHIV162P3K65R 30 min after receiving placebo (n = 6) or 1% TFV (n = 6) gel. Four of the six controls were infected after a median of 5 exposures. In contrast, five of six macaques that received TFV gel remained uninfected after 20 vaginal SHIV162P3K65R exposures, resulting in an estimated efficacy of 75%. The mean intracellular TFV-diphosphate (TFV-DP) concentrations in vaginal lymphocytes 4 h after a single gel dose were found to be high (1,631 fmol/106 cells, range 492–3,847) and within the in vitro IC75 range (1,206 fmol/106 cells) for SHIV162P3K65R.ConclusionBoth the modest resistance conferred by K65R and the high TFV-DP exposure in vaginal lymphocytes, likely explain the observed protection. The findings in this model do not predict complete loss of protection by topical TFV against vaginal exposure to HIV-1K65R viruses and provide a tissue drug target for high efficacy. These data will facilitate the development of TFV delivery platforms that have high activity on both wild-type and TFV-resistant viruses.
Highlights
Delivered tenofovir (TFV) from intravaginal rings, tablets, or gels is being evaluated for human immunodeficiency virus (HIV) pre‐ vention
Efficacy of TFV gel against SHIV162P3K65R Vaginal 1% TFV gel provided complete protection against wild-type SHIV162P3 when applied 30 min before virus challenge [9]
Due to small group numbers and low transmissibility of SHIV162P3K65R (67% infection rate), the protective effect in animals treated with TFV gel and risk of infection between the two groups was not statistically significantly (p = 0.24, Fisher’s exact test)
Summary
Delivered tenofovir (TFV) from intravaginal rings, tablets, or gels is being evaluated for HIV pre‐ vention. While sub-analysis of this study demonstrated an ~55% protective effect amongst women identified as highly adherent, it is unclear if these data will support regulatory approval of this TFV-releasing product [4]. Implications of these results may include advancing the clinical development of other TFV-releasing topical products such as vaginal tablets or intravaginal rings that share the high biological efficacy of TFV gels but may be more desirable by women [5,6,7]. Efficacy studies in macaques exposed vaginally to wild-type SHIV demonstrated high protection by both 1% TFV gel and TDF intravaginal rings [7,8,9]
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