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. 2009 Oct;83(20):10358-65.
doi: 10.1128/JVI.01073-09. Epub 2009 Aug 5.

Complete protection from repeated vaginal simian-human immunodeficiency virus exposures in macaques by a topical gel containing tenofovir alone or with emtricitabine

Urvi M Parikh  1 , Charles Dobard, Sunita Sharma, Mian-er Cong, Hongwei Jia, Amy Martin, Chou-Pong Pau, Debra L Hanson, Patricia Guenthner, James Smith, Ellen Kersh, J Gerardo Garcia-Lerma, Francis J Novembre, Ron Otten, Thomas Folks, Walid Heneine
Affiliations

Complete protection from repeated vaginal simian-human immunodeficiency virus exposures in macaques by a topical gel containing tenofovir alone or with emtricitabine

Urvi M Parikh et al. J Virol. 2009 Oct.

Abstract

New-generation gels that deliver potent antiretroviral drugs against human immunodeficiency virus type 1 have renewed hopes for topical prophylaxis as a prevention strategy. Previous preclinical research with monkey models suggested that high concentrations and drug combinations are needed for high efficacy. We evaluated two long-acting reverse transcriptase inhibitors, tenofovir (TFV) and emtricitabine (FTC), by using a twice-weekly repeat challenge macaque model and showed that a preexposure vaginal application of gel with 1% TFV alone or in combination with 5% FTC fully protected macaques from a total of 20 exposures to simian-human immunodeficiency virus SF162p3. FTC and TFV were detected in plasma 30 min after vaginal application, suggesting rapid absorption. FTC was detected more frequently than TFV and showed higher levels, reflecting the fivefold-higher concentration of this drug than of TFV. Two of 12 repeatedly exposed but protected macaques showed limited T-cell priming, which did not induce resistance to infection when macaques were rechallenged. Thus, single drugs with durable antiviral activity can provide highly effective topical prophylaxis and overcome the need for noncoital use or for drug combinations which are more complex and costly to formulate and approve.

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Figures

FIG. 1.
FIG. 1.
Study design. Three milliliters of gel was applied intravaginally to each macaque. After 30 min, blood was collected intravenously and the animal was vaginally challenged with 10 TCID50 of SHIVSF162P3. Each macaque received 20 twice-weekly challenges and was followed for 10 weeks after the last challenge.
FIG. 2.
FIG. 2.
Gel with TFV-FTC combination or TFV alone fully protects macaques against vaginal SHIVSF162P3 infection. The Kaplan-Meier curves show data on the number (#) of twice-weekly challenges with 10 TCID50 of SHIVSF162P3 and the number of uninfected macaques. (A) TFV-FTC gel. The differences in infection between the TFV-FTC gel arm and the placebo gel arm were statistically significant (P = 0.004; log rank test). (B) TFV gel. The differences in infection between the TFV group and the placebo gel group were statistically significant (P = 0.001; log rank test).
FIG. 3.
FIG. 3.
Acute viral loads in naïve and exposed macaques. Mixed-effects-model-based estimates of virus loads at times postinfection in macaques receiving placebo who were virus exposure naïve or had remained uninfected after 20 virus challenges in the TFV-FTC gel arm and were reenrolled in the placebo arm (exposed). Bars denote the standard errors of the means.
FIG. 4.
FIG. 4.
SHIV-specific IFN-γ-secreting T-cell responses in protected and infected macaques. IFN-γ-secreting T-cell frequencies in PBMC from infected control animals were compared to those for animals protected by TFV-FTC or TFV gel. Results were measured by an ELISPOT assay and are expressed as SFU/1 million PBMC. The animal identifiers shown on the x axis are color coded as follows: black, naïve macaques; red, macaques previously protected by TFV-FTC gel and reenrolled in the placebo control group or the TFV group. The difference in reactivity between infected and protected macaques was statistically significant (P = 0.002; Wilcoxon rank sum test).
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