Intermittent Prophylaxis with Oral Truvada Protects Macaques from Rectal SHIV Infection

Division of HIV/AIDS Prevention, National Center for HIV, Hepatitis, STD, and Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, USA.
Science translational medicine (Impact Factor: 15.84). 01/2010; 2(14):14ra4. DOI: 10.1126/scitranslmed.3000391
Source: PubMed

ABSTRACT HIV continues to spread globally, mainly through sexual contact. Despite advances in treatment and care, preventing transmission with vaccines or microbicides has proven difficult. A promising strategy to avoid transmission is prophylactic treatment with antiretroviral drugs before exposure to HIV. Clinical trials evaluating the efficacy of daily treatment with the reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) or Truvada (TDF plus emtricitabine) are under way. We hypothesized that intermittent prophylactic treatment with long-acting antiviral drugs would be as effective as daily dosing in blocking the earliest stages of viral replication and preventing mucosal transmission. We tested this hypothesis by intermittently giving prophylactic Truvada to macaque monkeys and then exposing them rectally to simian-human immunodeficiency virus (SHIV) once a week for 14 weeks. A simple regimen with an oral dose of Truvada given 1, 3, or 7 days before exposure followed by a second dose 2 hours after exposure was as protective as daily drug administration, possibly because of the long intracellular persistence of the drugs. In addition, a two-dose regimen initiated 2 hours before or after virus exposure was effective, and full protection was obtained by doubling the Truvada concentration in both doses. We saw no protection if the first dose was delayed until 24 hours after exposure, underscoring the importance of blocking initial replication in the mucosa. Our results show that intermittent prophylactic treatment with an antiviral drug can be highly effective in preventing SHIV infection, with a wide window of protection. They strengthen the possibility of developing feasible, cost-effective strategies to prevent HIV transmission in humans.

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Available from: Ae S Youngpairoj, Sep 26, 2015
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    • "As more acceptable PrEP regimens are being developed to improve adherence, there has been great interest in intermittent PrEP. Indeed, in animal models, oral intermittent PrEP, given at the time of virus inoculation, whether by vaginal or rectal challenge, provided an efficacy similar to that provided by use of daily PrEP [29]. This strategy of coitus-dependent PrEP is currently being assessed in two PrEP trials in MSM, under the assumption that the convenience of the regimen could increase PrEP adherence and therefore PrEP efficacy [30,31]. "
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    ABSTRACT: Following US Food and Drugs Administration approval in July 2012 of daily oral tenofovir and emtricitabine for pre-exposure prophylaxis (PrEP) to prevent HIV infection in high-risk individuals in the USA, there has been much controversy about the implementation of this PrEP regimen in other countries throughout the world, and in Europe in particular. In this review, we focus on the challenges and opportunities of a daily oral PrEP regimen to curb the rising incidence of HIV infection in high-risk groups, and particularly in men who have sex with men. A number of issues would need to be addressed before PrEP could be implemented, including assessing the real effectiveness and cost-effectiveness of daily PrEP, the sustainability of daily adherence, the risk of selecting resistance, the long-term safety, and the risk of change in sexual behavior that might offset the benefit of PrEP. Alternatives to a daily oral PrEP regimen are being explored.
    BMC Medicine 08/2013; 11(1):186. DOI:10.1186/1741-7015-11-186 · 7.25 Impact Factor
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    • "SHIV162P3 is a chimeric virus that contains the tat, rev, and env coding regions of HIV-1SF162 in a SIVmac239 background (National Institutes of Health AIDS Research and Reference Reagent Program [26]). All animals became infected during repeated weekly non-traumatic exposures to a low dose (10 TCID50) of SHIV162P3 as previously described [7,8]. Macaques AG80 and AG46 received daily PrEP with human-equivalent doses of FTC (20 mg/kg) and became infected after 5 and 10 rectal exposures, respectively. "
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    ABSTRACT: Pre-exposure prophylaxis (PrEP) with daily Truvada [a combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF)] is a novel HIV prevention strategy recently found to prevent HIV transmission among men who have sex with men and heterosexual couples. Acute infection in adherent persons who fail PrEP will inevitably occur under concurrent antiretroviral therapy, thus raising questions regarding the potential impact of PrEP on early viral dynamics. We investigated viral evolution dynamics in a macaque model of PrEP consisting of repeated rectal exposures to SHIV162P3 in the presence of PrEP. Four macaques were infected during daily or intermittent PrEP with FTC or FTC/TDF, and five were untreated controls. SHIV env sequence evolution was monitored by single genome amplification with phylogenetic and sequence analysis. Mean nucleotide divergence from transmitted founder viruses calculated 17 weeks (range = 12-20) post peak viremia was significantly lower in PrEP failures than in control animals (7.2 × 10-3 compared to 1.6 × 10-2 nucleotide substitutions per site per year, respectively, p < 0.0001). Mean virus diversity was also lower in PrEP failures after 17 weeks (0.13% vs. 0.53% in controls, p < 0.0001). Our results in a macaque model of acute HIV infection suggest that infection during PrEP limits early virus evolution likely because of a direct antiviral effect of PrEP and/or reduced target cell availability. Reduced virus diversification during early infection might enhance immune control by slowing the selection of escape mutants.
    Retrovirology 05/2012; 9:40. DOI:10.1186/1742-4690-9-40 · 4.19 Impact Factor
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    • "Tsai [8] later demonstrated the improved efficacy of PMPA (tenofovir) over zidovudine in protecting adult macaques against intravenous SIV challenge. More recent studies have demonstrated the efficacy of tenofovir or Truvada® in preventing infections when animals are challenged rectally with SIV [9]. "
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    ABSTRACT: Pre-exposure prophylaxis (PrEP) for HIV prevention is a promising experimental approach currently being tested globally. A number of PrEP trials are evaluating the safety and effectiveness of PrEP in men who have sex with men (MSM) and other populations at risk for HIV, and results will be available from this first generation of efficacy trials over the next few years. Here we review the rationale for orally-administered antiretrovirals for prevention, and outline issues the first generation trials will address as well as questions that may be addressed in future studies. We also describe the rationale for combination prevention approaches that may combine PrEP with other prevention modalities as part of a larger prevention package.
    AIDS and Behavior 02/2011; 15 Suppl 1(Suppl 1):S72-9. DOI:10.1007/s10461-011-9894-1 · 3.49 Impact Factor
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