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. 2012 Jan;86(2):718-25.
doi: 10.1128/JVI.05842-11. Epub 2011 Nov 9.

Durable protection from vaginal simian-human immunodeficiency virus infection in macaques by tenofovir gel and its relationship to drug levels in tissue

Charles Dobard  1 , Sunita Sharma, Amy Martin, Chou-Pong Pau, Angela Holder, Zsuzsanna Kuklenyik, Jonathan Lipscomb, Debra L Hanson, James Smith, Francis J Novembre, J Gerardo García-Lerma, Walid Heneine
Affiliations

Durable protection from vaginal simian-human immunodeficiency virus infection in macaques by tenofovir gel and its relationship to drug levels in tissue

Charles Dobard et al. J Virol. 2012 Jan.

Abstract

A vaginal gel containing 1% tenofovir (TFV) was found to be safe and effective in reducing HIV infection in women when used pericoitally. Because of the long intracellular half-life of TFV and high drug exposure in vaginal tissues, we hypothesized that a vaginal gel containing TFV may provide long-lasting protection. Here, we performed delayed-challenge experiments and showed that vaginal 1% TFV gel protected 4/6 macaques against vaginal simian-human immunodeficiency virus (SHIV) exposures occurring 3 days after gel application, demonstrating long-lasting protection. Despite continued gel dosing postinfection, neither breakthrough infection had evidence of drug resistance by ultrasensitive testing of SHIV in plasma and vaginal lavage. Analysis of the active intracellular tenofovir diphosphate (TFV-DP) in vaginal lymphocytes collected 4 h to 3 days after gel dosing persistently showed high TFV-DP levels (median, 1,810 fmol/10(6) cells) between 4 and 24 h that exceed the 95% inhibitory concentration (IC(95)), reflecting rapid accumulation and long persistence. In contrast to those in peripheral blood mononuclear cells (PBMCs) following oral dosing, TFV-DP levels in vaginal lymphocytes decreased approximately 7-fold by 3 days, exhibiting a much higher rate of decay. We observed a strong correlation between intracellular TFV-DP in vaginal lymphocytes, in vitro antiviral activity, and in vivo protection, suggesting that TFV-DP above the in vitro IC(95) in vaginal lymphocytes is a good predictor of high efficacy. Data from this model reveal an extended window of protection by TFV gel that supports coitus-independent use. The identification of protective TFV-DP concentrations in vaginal lymphocytes may facilitate the evaluation of improved delivery methods of topical TFV and inform clinical studies.

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Figures

Fig 1
Fig 1
TFV gel provides durable protection against vaginal SHIV162P3 infection. (A) Study design. Macaques received one weekly vaginal gel application (solid blue bars) and were exposed to SHIV162P3 at 30 min and again at 72 h after the gel dose (red arrows). (B) Survival curves representing the cumulative percentage of uninfected macaques as a function of the number of months in the study period (8 challenges per month). After 2.5 months (20 SHIV162p3 exposures), challenges were stopped and animals were monitored for 10 additional weeks for infection in the follow-up period. Controls include 1 real-time control and 9 historic controls (dotted black line).
Fig 2
Fig 2
Intracellular TFV-DP concentrations after vaginal gel or oral dosing. TFV-DP concentrations in mononuclear cells isolated from vaginal tissues collected 4, 24, 48, and 72 h after a single vaginal TFV gel dose (solid blue line) are shown. For oral dosing, six macaques each received a single human equivalent oral TDF dose (22 mg/kg) and, TFV-DP levels were measured in PBMCs from blood collected at 2, 5, 24, 48, 120, and 168 h (red line).
Fig 3
Fig 3
Correlation between extracellular TFV and intracellular TFV-DP. Intracellular TFV-DP levels measured in PBMCs incubated for 24 h in RPMI medium containing various concentrations of TFV are shown. Dotted lines indicate extracellular TFV concentrations in the range of the previously reported in vitro IC50 and IC95 (28, 31). Red arrows denote intracellular TFV-DP levels in vaginal lymphocytes at 4 h and 3 days after in vivo dosing with 1% TFV gel. †, TFV concentration in gel (32.8 mM).
Fig 4
Fig 4
Breakthrough infections show no evidence of blunted viremia or K65R emergence (A) Individual virus load kinetics in breakthrough infections under continued once-weekly gel dosing (n = 2, red and blue dotted lines) and median virus load kinetics of placebo-infected macaques (n = 9, black line). Time zero indicates the peak plasma virus load. (B) Undetectable K65R mutation in plasma or cervicovaginal (CVL) viral RNA in breakthrough infections. Red circles and black arrows indicate samples tested for plasma and CVL fluid, respectively. The broken line denotes the limit of detection of the virus load assay (50 copies/ml).
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