Penetration of Tenofovir and Emtricitabine in Mucosal Tissues: Implications for Prevention of HIV-1 Transmission

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Science Translational Medicine  07 Dec 2011:
Vol. 3, Issue 112, pp. 112re4
DOI: 10.1126/scitranslmed.3003174

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HAARTening News for HIV Prevention

Antiretroviral drug therapy (ART) has been used successfully for treating HIV-1. However, HIV transmission, principally through sexual intercourse, is still a major problem, with 7000 new infections reported daily worldwide. ART is now being investigated as a way not only to treat individuals with HIV but also to prevent the transmission of HIV infection. This strategy, called PrEP, or PrEP, requires that the concentrations of the antiretroviral drugs under investigation are at high enough concentrations in the target mucosal tissues, predominantly genital and colorectal, to prevent HIV infection. Such knowledge will be essential for designing new HIV prevention trials and also for interpreting the data from several prevention trials that have yielded conflicting results. In a new study, Patterson et al. set out to obtain this information for two antiretroviral drugs that have shown promise for HIV prevention: tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC).

The researchers gave 12 healthy men and women a single oral dose of the fixed-dose combination pill TDF/FTC (Truvada) and then took samples of blood plasma, genital secretions, and vaginal, cervical, and rectal tissue biopsies over the next 14 days. The pro-drug forms TFV and FTC were measured in blood plasma and genital secretions, whereas the active intracellular phosphorylated metabolites of these drugs (TFV-DP and FTC-TP) were measured in vaginal, cervical, and rectal tissues. After a single oral dose, TFV and FTC were detected in blood plasma for the 14-day duration of the study. Encouragingly, the concentration of FTC was 27-fold greater in genital secretions than in blood plasma. However, the concentration of TFV was only 2.5-fold greater in genital secretions than in blood plasma. Both TFV and its active phosphorylated form TFV-DP were detected in rectal tissue for 14 days after dosing, and the cumulative exposure of rectal tissue to TFV-DP was 100-fold greater than that in vaginal and cervical tissues. In contrast, the cumulative exposure of vaginal and cervical tissues to FTC was only 10- to 15-fold greater than that for rectal tissue. Despite high concentrations of the pro-drug FTC in vaginal and cervical tissues, its active form FTC-TP was detected for ≤2 days in these tissues. This study demonstrates that the penetration of different human mucosal tissues and their exposure to the pro-drugs TFV and FTC and their active metabolites TFV-DP and FTC-TP is wide ranging and dependent on the tissue type. These findings reinforce the fact that the success of PrEP will depend on selecting the correct ART that achieves a critical concentration and duration of exposure in vulnerable mucosal tissues. Continuing pharmacological investigations will be crucial for ensuring the success of PrEP and ultimately for preventing HIV transmission.


  • * Present address: GlaxoSmithKline, Research Triangle Park, NC 27709, USA.

  • Present address: United Therapeutics, Research Triangle Park, NC 27709, USA.

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