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. 2015 Aug 8:12:69.
doi: 10.1186/s12977-015-0195-z.

Efficacy of topical tenofovir against transmission of a tenofovir-resistant SHIV in macaques

Charles W Dobard  1 , Sunita Sharma  2 , Mian-Er Cong  3 , Rolieria West  4 , Natalia Makarova  5 , Angela Holder  6 , Chou-Pong Pau  7 , Debra L Hanson  8 , Francis J Novembre  9 , Jose Gerardo Garcia-Lerma  10 , Walid Heneine  11
Affiliations

Efficacy of topical tenofovir against transmission of a tenofovir-resistant SHIV in macaques

Charles W Dobard et al. Retrovirology. .

Abstract

Background: Topically 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.

Results: SHIV162P3K65R 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/10(6) cells, range 492-3,847) and within the in vitro IC75 range (1,206 fmol/10(6) cells) for SHIV162P3K65R.

Conclusion: Both 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.

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Figures

Fig. 1
Fig. 1
Efficacy of TFV gel against SHIV162P3K65R. a Survival curves representing the cumulative percentage of uninfected macaques as a function of the number of challenges. After 20 SHIV162P3K65R exposures, challenges were stopped and animals were monitored for ten additional weeks for infection in the follow-up period. b Breakthrough infections show no evidence of blunted viremia. Individual virus load kinetics of controls (black lines) and breakthrough infection (red line) under continued twice-weekly gel dosing. Time zero indicates the time of first SHIV RNA detection in plasma. Time zero indicates the time of first SHIV RNA detection in plasma. The dashed line denotes the limit of quantification of the virus load assay (50 copies/ml).
Fig. 2
Fig. 2
Systemic drug exposure following vaginal TFV gel dosing. a Cumulative plasma TFV levels in macaques following twice-weekly dosing over the 10 week challenge period. b Longitudinal assessment of individual plasma TFV levels in macaques at time of each SHIV challenge (30 min post gel dosing). TFV concentrations (LLOD = 3 ng/ml) are shown in black and red for uninfected and infected macaques, respectively. Shaded gray bar indicates estimated time of infection.
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