Antiretroviral Therapy as Pre-Exposure Prophylaxis: A Continuous Vaccine?

Researchers long-ago established that antiretroviral drugs reduce the risk of mother-to-child transmission of HIV, as well as the risk of post-exposure occupational transmission. Today, they are exploring the prevention of HIV infection in a new way, driven by this question: Can the antiretroviral drugs now used to treat HIV infection also be used to reduce the risk of HIV infection in HIV-negative but high-risk individuals? Given that an HIV vaccine is still unavailable and that millions of new infections continue to occur annually worldwide, this is an important public health question that needs to be answered.

The antiretroviral drugs that are currently being tested as prophylactic agents against HIV infection in humans and in other animals are tenofovir and emtricitabine. Tenofovir, a nucleotide analogue, was approved for therapeutic use by the United States Food and Drug Administration in 2001.¹ Emtricitabine, a nucleoside analogue, was approved in 2003.² Both drugs are taken once daily, with or without food, and are sold in a combined form as Truvada® in the United States.³

Data derived from recent animal studies involving rhesus macaques^4-6 and humanized BLT mice⁷ support the merits of using antiretroviral drugs as pre-exposure prophylaxis (PrEP) against HIV infection. Because the animals that were treated with tenofovir alone or with a combination of tenofovir and emtricitabine were protected at least partly -- if not completely -- against oral, rectal, or vaginal challenges of virulent SIV (rhesus macaques) or HIV-1 (humanized BLT mice), researchers believe that PrEP might slow the spread of HIV in high-risk human communities.

Results from a phase II clinical trial conducted by Family Health International in Ghana, Cameroon, and Nigeria among 936 HIV-negative women who were at high risk of HIV infection have bolstered this belief.⁸ As in the animal studies, the objective of this trial was to investigate the safety and effectiveness of tenofovir as a prophylactic treatment against HIV infection. Although the follow-up of many of the participants was thwarted by the premature closure of the study sites in Cameroon and Nigeria, and the investigators were therefore unable to evaluate the effectiveness of PrEP against HIV infection, none of the participants experienced any adverse effects from the prophylactic treatment.

Encouraged by these preliminary results, the Centers for Disease Control and Prevention (CDC) has undertaken separate randomized, double-blinded, and placebo-controlled trials of tenofovir -- with or without emtricitabine -- in three different countries among three different high-risk populations.^9,10 In Botswana, tenofovir/emtricitabine is being tested as PrEP among 1,200 HIV-negative heterosexual young adults (18-29 years of age) in that nation's two largest cities, Gaborone and Francistown. In Thailand, tenofovir alone is being tested as PrEP among 2,000 HIV-negative intravenous drug users at 17 drug treatment clinics in Bangkok. And in the United States, tenofovir alone is being tested as PrEP among 400 HIV-negative men who have sex with men (MSM) in San Francisco, Atlanta, and Boston. In addition, the National Institutes of Health plans to evaluate a once-daily dose of tenofovir/ emtricitabine among MSM in Peru and in Ecuador.¹¹

All of these clinical trials are expected to take between two and four years to complete. In addition to seeking greater evidence of the safety and efficacy of tenofovir and emtricitabine as prophylactic agents, investigators are anxious to determine whether treatment with a once-daily preventative drug alters HIV-related risk behaviors or induces individuals to abandon proven HIV-prevention strategies. This aspect of the clinical trials is crucial, because the data from the animal models suggest that oral PrEP will not provide 100% protection against HIV infection.⁵ Its proper use, however, has the potential to markedly reduce infections in certain at-risk groups. For health-care workers, a population that is also at high risk of exposure to HIV, this is especially significant. According to one estimate, the HIV-transmission rate among obstetricians-gynecologists may be reduced by as much as 81% with post-exposure prophylaxis.¹² PrEP, therefore, has the potential to be an effective prevention method for this at-risk group, along with other universal precautions, such as protective clothing, masks, and gloves.

Although PrEP will not be a panacea and may not provide the same protection as a vaccine against HIV infection, it may effect a small but important reduction in the number of new HIV cases among highly at-risk groups. If so, its use as an HIV preventative will expand in the years ahead.

References

1. United States Department of Health and Human Services. Tenofovir. Accessible at: www.aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx? MenuItem=Drugs&int_id=272&Search=Off&ClassID=&TypeID=.
2. United States Department of Health and Human Services. Emtricitabine. Accessible at: www.aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx? MenuItem=Drugs&int_id=208&Search=Off&ClassID=&TypeID=.
3. United States Department of Health and Human Services. Emtricitabine/Tenofovir disoproxil fumarate. Accessible at: www.aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?MenuItem=Drugs& int_id=406&Search=Off&ClassID=&TypeID=.
4. Van Rompay KKA, Kearney BP, Sexton JJ, et al. J Acquir Immune Defic Syndr. 2006;43 :6-14.
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7. Denton PW, Estes JD, Sun Z, et al. PLoS Med. 2008;5(1):e16. doi: 10.1371/journal.pmed.0050016.
8. Peterson L, Taylor D, Roddy R, et al. PLoS Clin Trials. 2007;2(5):e27. doi: 10.1371/journal/pctr.0020027.
9. Centers for Disease Control and Prevention. CDC Trials of Pre-exposure Prophylaxis for HIV Prevention: Clinical Trials in Botswana, Thailand, and the United States. Accessible at: http://www.cdc.gov/hiv/resources/factsheets/prep.htm.
10. Centers for Disease Control and Prevention. CDC's Clinical Studies of Pre-Exposure Prophylaxis for HIV Prevention. Accessible at: www.cdc.gov/hiv/resources/qa/prep.htm.
11. National Institutes of Health. Anti-HIV Medications for the Prevention of HIV Infection in Latin American Men Who Have Sex with Men. Accessible at: http://clinicaltrials.gov/ct2/show/NCT00350324?term=NCT00350324&rank=1.
12. Levison J. Obstet Gynecol. 2008;111:183-186.