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Two Doses of Tenofovir/FTC Protect Monkeys From Rectal Simian HIV
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2nd International Workshop on HIV Transmission
August 26-28, 2007
Washington, DC
Mark Mascolini
Two doses of tenofovir plus emtricitabine (TFV/FTC) protected macaques from rectal infection with a simian HIV (SHIV) as effectively as daily TFV/FTC did in an earlier study. If the same holds true in humans, intermittent timed dosing could prove just as promising as daily pre-exposure prophylaxis (PrEP), a strategy being tested in three trials.
But dose timing could be critical. Monkeys in this study got injected 2 hours before and 24 hours after a weekly rectal SHIV exposure for 14 weeks. Oral dosing didn't work quite as well.
Earlier work by Gerardo Garcia-Lerma and Centers for Disease Control (CDC) colleagues found that a daily dose of 20 mg of FTC per kg of body weight plus 22 mg of TFV per kg consistently protected 6 of 6 macaques from rectal exposures of SHIV. The CDC group picked these doses to approximate drug levels attained in humans taking standard-dose FTC and tenofovir disoproxil fumarate (TDF).
Because both FTC and TFV have long half-lives, the CDC team set out to see if the double-dose injected regimen or a single injected dose 2 hours before exposure would keep rectally applied SHIV from infecting the animals. They compared 6 macaques in the two-dose group and 6 in the one-dose group with 21 monkeys exposed to SHIV without drug protection, 12 in earlier studies and 9 during the current trial.
All 6 macaques who got a dose of TFV/FTC before and after each weekly SHIV exposure withstood the virus for 14 weeks. SHIV infected 2 of the 6 macaques who got a single TFV/FTC shot 2 hours before exposure, after the eighth and thirteenth exposures. Both infections were significantly delayed when compared with monkeys who got no drugs (P = 0.0004). Single-dose TFV/FTC improved the chance of protection 8.7 times compared with no drugs (P = 0.005).
SHIV infected 20 of 21 untreated monkeys after a median of 2.5 rectal exposures. Sixteen of these 21 (76%) became infected during the first four exposures, and 4 got infected between exposures eight and 12 (median 10.5). Only 1 untreated animal remained uninfected after 14 exposures.
To test the protective prowess of orally administered drugs in monkeys, Garcia-Lerma gave 6 animals a double dose of Truvada (coformulated TDF/FTC) 2 hours before and 24 hours after 14 rectal SHIV exposures. He gave the drugs by intragastric tube to make sure each animal received the full dose. Five of six macaques remained free of infection after 14 challenges, a result translating into a 14.1 times better chance of protection than SHIV exposure with no drugs (P = 0.01).
Of the 3 animals who became infected while taking the drugs, one had low drug levels. That finding suggests that if an animal got the drugs much earlier--or later--than they did in this study, the drugs would not have stopped SHIV from establishing infection. Garcia-Lerma noted that he picked dosing times to offer the best drugs levels and thus the best protection against infection. If Truvada prophylaxis works as well in humans as TFV/FTC worked in these monkeys, dose timing could be critical despite the long half-lives of these drugs.
"Short but potent intermittent PrEP regimens are promising strategies for sexual HIV prevention," Garcia-Lerma concluded. He rated single-dose PrEP "highly effective" but clearly not fully protective, probably because the extended activity of the second dose contributes to protection.
Three PrEP efficacy studies with these drugs are under way, one involving Thai injecting drug users taking TDF, a second assessing TDF/FTC in heterosexuals in Botswana, and a third testing the same two drugs in men who have sex with men in Peru and Ecuador.
Reference
1. Garcia-Lerma J, Otten R, Masciotra S, et al. Intermittent antiretroviral
prophylaxis with tenofovir and emtricitabine protects macaques against repeated rectal SHIV exposures. 2nd International Workshop on HIV Transmission. August 26-28, 2007.
Washington, DC. Abstract 21.
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