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Truvada Protects Macaques From Rectal Exposure to FTC-Resistant Virus
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International HIV and Hepatitis Drug Resistance Workshop, June 8-12, 2010, Dubrovnik, Croatia
Mark Mascolini
Intermittent oral prophylaxis with tenofovir/emtricitabine (Truvada) protected all 5 macaques exposed to emtricitabine (FTC)-resistant SHIV (a simian immunodeficiency virus with an HIV coat) in a Centers for Disease Control (CDC) trial [1]. Although the findings may not be directly applicable to humans, they suggest that this two-in-one drug could work in ongoing pre-exposure prophylaxis (PrEP) studies in humans, perhaps even against emtricitabine-resistant virus circulating in the community, and perhaps even without daily dosing. But because the monkeys got a Truvada dose shortly after SHIV exposure, the trial involves both PrEP and PEP (postexposure prophylaxis).
Earlier work by the Gerardo Garcia-Lerma and CDC colleagues showed that intermittent Truvada protected macaques from rectal exposure of nonmutant (wild-type) SHIV [2]. In the new study, the CDC team used site-directed mutagenesis to create a SHIV carrying the M184V mutation and thus resistant to emtricitabine.
They gave 5 macaques a human-equivalent dose of Truvada for 14 weeks, 3 days before and 2 hours after 14 exposures to emtricitabine-resistant SHIV at a dose of 40 TCID(50). Efficacy of Truvada against SHIV162p3-M184V was investigated using a rectal transmission model consisting of 14 weekly vurus challenges. Five macaques received 2 weekly human-equivalent doses of Truvada by oral gavage. Five untreated animals exposed to the same virus were use as controls. The investigators monitored infection by serology and RT-PCR. Macaques received Truvada through a tube to make sure they swallowed the drugs. Five macaques exposed to emtricitabine-resistant SHIV for 14 weeks did not get Truvada (controls).
Lab tests showed that the mutant SHIV was more than 100-fold resistant to emtricitabine but 5 times more susceptible to tenofovir than nonmutant SHIV. Replication capacity ("fitness") of the mutant SHIV was 30-fold lower than replication capacity of nonmutant SHIV.
All 5 Truvada-treated macaques were protected from all 14 rectal exposures of the mutant SHIV. In contrast, all 5 untreated animals became infected with mutant SHIV after a median of 3 exposures (range 2 to 11 exposures) (P = 0.0008).
Peak viral load in the untreated animals averaged 6.1 log copies/mL (range 5.2 to 7.3), which is significantly lower than peak viral loads seen in earlier studies of 22 macaques rectally exposed to nonmutant SHIV. That blunted viral load, perhaps a results of the lower replication capacity of the mutant SHIV, may explain why Truvada may protect against emtricitabine-resistant SHIV. Garcia-Lerma speculated that the hypersusceptibility of resistant SHIV to tenofovir could also be a contributing factor. Finally, he proposed that emtricitabine may retain some antiviral activity against M184V viruses.
Attendees observed that the CDC team made two nucleotide changes to get the M184V mutation (ATG to GTT), whereas one change can create M184V in humans. Garcia-Lerma and colleagues used the double-nucleoside change to keep the mutation from reverting to wild-type. But as a result, the mutation studied in these macaques does not precisely reflect the mutation typically seen in human.
References
1. Cong M, Youngpairoj AS, Zheng Q, et al. Complete protection against rectal transmission of an emtricitabine (FTC)-resistant SHIV162p3M184V mutant by intermittent prophylaxis with Truvada. International HIV and Hepatitis Drug Resistance Workshop. June 8-12, 2010. Dubrovnik, Croatia. Abstract 31.
2. García-Lerma JG, Cong ME, Mitchell J, et al. Intermittent prophylaxis with oral truvada protects macaques from rectal SHIV infection. Sci Transl Med. 2010;2(14):14ra4. http://www.ncbi.nlm.nih.gov/pubmed/20371467
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