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. 2014 Sep;69(9):2470-6.
doi: 10.1093/jac/dku162. Epub 2014 May 26.

Tenofovir diphosphate concentrations and prophylactic effect in a macaque model of rectal simian HIV transmission

Peter L Anderson  1 , David V Glidden  2 , Lane R Bushman  3 , Walid Heneine  4 , J Gerardo García-Lerma  4
Affiliations

Tenofovir diphosphate concentrations and prophylactic effect in a macaque model of rectal simian HIV transmission

Peter L Anderson et al. J Antimicrob Chemother. 2014 Sep.

Abstract

Objectives: This study evaluated the relationship between intracellular tenofovir diphosphate concentrations in peripheral blood mononuclear cells and prophylactic efficacy in a macaque model for HIV pre-exposure prophylaxis (PrEP).

Methods: Macaques were challenged with simian HIV (SHIV) via rectal inoculation once weekly for up to 14 weeks. A control group (n=34) received no drug, a second group (n=6) received oral tenofovir disoproxil fumarate/emtricitabine 3 days before each virus challenge and a third group (n=6) received the same dosing plus another dose 2 h after virus challenge. PBMCs were collected just before each weekly virus challenge. The relationship between tenofovir diphosphate in PBMCs and prophylactic efficacy was assessed with a Cox proportional hazards model.

Results: The percentages of animals infected in the control, one-dose and two-dose groups were 97, 83 and 17, respectively. The mean (SD) steady-state tenofovir diphosphate concentration (fmol/10(6) cells) was 15.8 (7.6) in the one-dose group and 30.7 (10.1) in the two-dose group. Each 5 fmol tenofovir diphosphate/10(6) cells was associated with a 40% (95% CI 17%-56%) reduction in risk of SHIV acquisition, P=0.002. The tenofovir diphosphate concentration associated with a 90% reduction in risk (EC90) was 22.6 fmol/10(6) cells (95% CI 13.8-60.8).

Conclusions: The prophylactic EC90 for tenofovir diphosphate identified in macaques exposed rectally compares well with the EC90 previously identified in men who have sex with men (MSM; 16 fmol/10(6) cells, 95% CI 3-28). These results highlight the relevance of this model to inform human PrEP studies of oral tenofovir disoproxil fumarate/emtricitabine for MSM.

Keywords: HIV pre-exposure prophylaxis; intracellular pharmacology; non-human primate model; nucleoside analogues; pharmacodynamics.

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Figures

Figure 1.
Figure 1.
Kaplan–Meier analysis of the proportion infected with SHIV in relation to number of inoculations (challenges) in the three groups of macaques.
Figure 2.
Figure 2.
Tenofovir diphosphate (TFV-DP) (a) and emtricitabine triphosphate (FTC-TP) (b) accumulation in viable PBMCs over time in groups given two doses per week (open circles) and one dose per week (open squares). Data points represent mean values and bars represent SDs, with the number of macaques contributing to the data shown below the graphs.
Figure 3.
Figure 3.
Relative risk of SHIV acquisition in relation to tenofovir diphosphate (TFV-DP) concentration (continuous line). Broken lines represent the 95% CI.
See this image and copyright information in PMC

References

    1. Romano J, Kashuba A, Becker S, et al. Pharmacokinetics and pharmacodynamics in HIV prevention; current status and future directions: a summary of the DAIDS and BMGF sponsored think tank on pharmacokinetics (PK)/pharmacodynamics (PD) in HIV prevention. AIDS Res Hum Retroviruses. 2013;29:1418–27. - PMC - PubMed
    1. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329:1168–74. - PMC - PubMed
    1. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367:399–410. - PMC - PubMed
    1. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587–99. - PMC - PubMed
    1. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367:423–34. - PubMed

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