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Complete protection against repeated vaginal SHIV exposures in macaques by a combination emtricitabine and tenofovir topical gel
Presented by Walid Heneine, United States.
U.M. Parikh1, S. Sharma1, M.-E. Cong1, H. Jia1, A. Martin1, C.-P. Pau1, D. Hanson1, J. Smith1, J.G. Garcia-Lerma1, F.J. Novembre2, R.A. Otten1, T. Folks1, W. Heneine1
1Centers for Disease Control and Prevention, Division of HIV/AIDS Prevention, Atlanta, United States, 2Emory University, Yerkes Primate Center, Atlanta, United States
Background: An effective vaginal gel would provide women with a prevention option to protect themselves from aquisition of HIV. Discouraging results from human trials with surfactant gels have fueled interest in evaluating new-generation gels containing HIV-specific drugs such as the reverse transcriptase inhibitor tenofovir (TFV). Here, we used a repeat-exposure macaque model simulating human transmission to evaluate whether vaginal application of an emtricitabine (FTC)/TFV combination gel can prevent SHIV transmission.
Methods: Fourteen naïve female pigtail macaques were assigned to 3 arms: no gel (n=2), 2% hydroxyethyl cellulose (HEC) placebo gel (n=6), or combination gel (5% FTC and 1% TFV in 2% HEC; n=6). Three milliliters of gel product was applied to the vaginal vault 30 min prior to virus challenge. All animals were subjected to twice weekly vaginal exposures of low-dose SHIV-SF162p3 (10 TCID-50; ~11.6x10e6 RNA copies) for up to 20 challenges. Infection was monitored by serology and PCR amplification of SHIV gag sequences from plasma. To measure systemic drug absorption after each gel application, plasma TFV and FTC levels were determined by liquid chromatography-mass spectrometry (LC-MS).
Results: Seven of 8 control macaques (5/6 placebo; 2/2 no gel) became infected after a median of 3.5 challenges (range = 2-11). In contrast, all 6 macaques receiving FTC/TFV gel remained protected from SHIV infection after 20 challenges (p<0.005; Fisher’s exact test). Low levels of both FTC (median=67 ng/ml) and TFV (median=22 ng/ml) were consistently detected in the plasma of all macaques 30 min after vaginal application.
Conclusions: FTC/TFV gel conferred complete protection against repeated vaginal exposures in pig-tailed macaques. The detectability of low levels of both FTC and TFV in plasma 30 minutes after application suggests rapid drug absorption with relatively higher levels of drug remaining in vaginal tissue. These findings support further evaluation of FTC/TFV gel in human clinical trials.
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