The Promise of PrEP: Using Antiretrovirals to Prevent HIV Infection
Jeffrey Laurence, M.D., and Rowena Johnston, Ph.D.
February 9, 2010—The holy grail of HIV prevention is a vaccine, but given our current knowledge and technology, along with several failures in human trials, that may be a long way off. Scientists searching for alternative ways to prevent HIV are investigating pre-exposure prophylaxis (PrEP), which involves the administration of antiretroviral therapy to HIV-negative individuals to decrease the risk of infection should exposure to the virus occur. A similar strategy has already been proven to be highly effective at blocking mother-to-child HIV transmission by administering antiretroviral drugs to both the pregnant woman and her newborn infant.
amfAR fellow Dr. Paul Denton and his mentor Dr. Victor Garcia-Martinez, a former amfAR grantee. (Photo: John Krisko)
amfAR fellow Dr. Paul Denton, writing in the January issue of the online journal PloSOne, sought to extend this concept to rectal and intravenous transmission of HIV. Working at the University of Texas Southwestern Medical Center in Dallas in collaboration with colleagues at the National Cancer Institute, Dr. Denton builds on work he reported two years ago. Previously, his lab had devised a “humanized” mouse, born with a deficient immune system and implanted with cells from fetal human bone marrow (B), liver (L), and thymus gland (T) to mimic a human immune system. Such “BLT mice” express HIV receptors and co-receptors typical of humans. And, unlike genetically normal mice, they are highly susceptible to HIV infection.
Dr. Denton and colleagues had already demonstrated that certain antiretroviral drugs could block vaginal HIV infection in humanized mice. In their recent study, they sought to test the potential of PrEP to protect BLT mice from rectal or intravenous HIV exposure. Dr. Denton used two common anti-HIV drugs, emtricitabine (FTC) and tenofovir (TDF), injecting them into the abdomens of the animals daily for three days. (This is a very common way to administer drugs to mice.) Three hours after the third dose, HIV was introduced rectally, or intravenously via a tail vein. The anti-HIV drugs were continued for an additional four days. At various times thereafter, blood and tissue samples were examined for evidence of HIV infection.
In terms of rectal exposure, all 19 BLT mice that received only a placebo became infected, while none of the nine mice that were given FTC/TDF showed evidence of HIV. In the intravenous challenges, all six placebo-treated mice became infected, but only one of eight animals given PrEP succumbed.
Along with work published earlier by others, this very encouraging research is proof-of-principle that PrEP might prevent HIV infection by all routes—vaginal, rectal, and intravenous. Like a vaccine or microbicide, its use could be controlled by the susceptible partner. And its impact could be enormous. Already, approximately 500,000 HIV-positive pregnant women a year receive anti-HIV drugs to prevent mother-to-child transmission; if PrEP were validated in humans, its use could be even more widespread.
Clinical testing will be important. Whether PrEP succeeds in providing sufficient protection will most likely depend on achieving critical anti-HIV drug levels. In addition, the optimal drug combination and regimen is yet to be determined. Drug-based prevention research pioneered by Denton and colleagues using a small animal model should yield many insights into this promising strategy.
Dr. Laurence is amfAR’s senior scientific consultant and Dr. Johnston is vice president and director of research.
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