The Promise of Pre-Exposure Prophylaxis

The advent of antiretroviral cocktails in the 1990s gave HIV-positive individuals a new lease on life. The newest drugs to treat HIV infection are much cheaper, safer and easier to use than earlier generations. And that has prompted researchers to test an idea that would have been unthinkable just a decade ago; using the same drugs that doctors use to treat infection to instead prevent infection. That means giving HIV-negative adults antiretroviral medicines before they are ever exposed to HIV, an idea known as pre-exposure prophylaxis (PrEP). Scientists have already begun clinical trials to test whether the strategy can safely reduce a person's risk of contracting HIV. And the first results may be available as soon as this year.

Despite past disappointments in the field of HIV prevention, many experts are optimistic that PrEP will work. But even if the strategy proves to be effective in reducing the risk of transmission, significant hurdles remain. A once-daily antiretroviral will not be cheap, and it will not be for everyone.

Stopping Infection Before It Starts

The idea of taking a drug to prevent disease is not novel in medicine. "The concept has been out there for a long time," says Lynn Paxton, an epidemiologist at the U.S. Centers for Disease Control and Prevention (CDC). Physicians regularly prescribe anti-malaria pills for travelers headed to regions where malaria is endemic. The rationale is straightforward: having anti-malarial drugs in the body at the time of exposure can prevent a few stray parasites from becoming a full-blown infection.

Researchers think the same principle might apply to HIV. Antiretrovirals cannot eliminate HIV once an individual is infected, but, if taken early enough, they may be able to stop the virus before it takes hold. "When we are treating HIV infection," says Robert Grant, a virologist at the University of California in San Francisco, "the amount of virus is enormous. There's HIV in the blood, in the lymph nodes, in the associated lymphoid tissue." But at the time of transmission, often only a few virus particles are present, so the virus may be easier to block.

The two drugs being tested, tenofovir disoproxil fumarate (tenofovir) and its sister drug Truvada -- a combination of tenofovir and emtricitabine -- stop the virus from manufacturing a protein called reverse transcriptase. Without reverse transcriptase, HIV cannot turn its viral RNA into DNA, which means that it cannot replicate. "It is possible that these drugs would block the first round of viral replication," Grant says. But even if they don't, he says, they may be powerful enough stop subsequent replication, thereby staving off systemic infection.

Laying the Groundwork

Researchers began talking about using antiretrovirals as an HIV prevention tool in the 1990s. In fact, a team of scientists at the University of Washington published a study as early as 1995 showing that tenofovir could prevent HIV infection in macaque monkeys when injected either two days before exposure, four hours after exposure, or a day after exposure.1 However, at the time, tenofovir was still experimental, and the approved drugs were expensive and often toxic.

However, doctors did begin prescribing antiretroviral therapy for people who had reason to believe they'd already been exposed to HIV. The strategy, known as post-exposure prophylaxis, was aimed at health care workers who stuck themselves with infected needles. In those cases, the benefit seemed to outweigh the risk. A case-control study in the mid-1990s suggested that health workers who took AZT soon after a needle stick reduced their chances of contracting HIV by 80%.2

Still, post-exposure prophylaxis never caught on as a widespread prevention strategy. One reason is that people who contract HIV outside of the workplace often have a hard time determining when they've been exposed. With pre-exposure prophylaxis, no decision is necessary; the drugs are already on board when exposure occurs.

Although post-exposure prophylaxis has never been tested in rigorous randomized controlled trials, the data suggest that it works. And if post-exposure prophylaxis works, chances are pre-exposure prophylaxis will work too.

Additional indications that PrEP will be effective in curbing HIV transmission come from research on prevention of mother-to-child transmission. "There are trials in which only the baby has been given antiretrovirals after birth and it prevents infection," Mellors says. Although it is not sexual transmission, he says, "it gives strength to the argument that this can be successful."

Furthermore, PrEP seems to provide at least partial protection against an HIV-like virus in non-human primates. Researchers at the CDC have tested the strategy in macaque monkeys, giving the animals antiretrovirals once a day and then simulating sexual exposure. They report partial protection with tenofovir, and even better protection with Truvada.3,4 And the latest study, presented by CDC virologist J. Gerardo García-Lerma at the Conference on Retroviruses and Opportunistic Infections in Montreal in February 2009, suggests that even intermittent antiretroviral drugs taken orally can protect against rectally transmitted infection in macaques.

The Human Element

Although researchers have good scientific reasons to believe that PrEP will work, they still need data from carefully controlled human studies. To date, they have completed only one human PrEP trial. The Family Health International study, which began in 2003, set out to test the safety and efficacy of pre-exposure prophylaxis among 1200 HIV-negative women in West Africa.

But the study was fraught with setbacks. The Nigerian arm closed prematurely after local investigators failed to comply with complex protocol requirements. And the study in Cameroon was halted early at the request of government officials. Ultimately, the investigators enrolled fewer participants than they had originally planned -- just 936. And because incidence of HIV among these women was lower than expected, they weren't able to look at efficacy. However, the study did show that the drug appears to be well tolerated.5

Today at least five trials are underway, and two more are planned. Researchers hope to enroll 18,000 participants in the next several years. But they will not be looking just at high-risk women. One study tests the efficacy of PrEP among more than 2,000 injection drug users. And studies will examine the effect of PrEP among gay men. Some trials will also test the efficacy of antiretroviral-laced microbicides. Mellors says that the efficacy of the drug may vary depending on the route of transmission. According to Paxton, at the CDC, the first results should be available no later than 2010.

The Fine Print

Even if the trials do show that PrEP offers protection, other questions must be answered before implementation. One major concern is drug resistance. PrEP may prove to be highly efficacious, but no one believes it will provide 100% protection. And that means that at least some individuals will become infected while taking the medications. If these HIV-infected individuals continue to take their drugs, the virus can become resistant. That could jeopardize the infected individual's future treatment, and it could also lead to a larger, community-wide pool of resistance.

The two antiretrovirals being tested in the trials were chosen in part because they are least likely to spawn resistance. Still, researchers will be monitoring the trial participants closely, giving them monthly HIV tests to ensure that any participants who do become HIV-positive are taken off the medications. However, such rigorous measures may not be possible if PrEP becomes part of the prevention toolbox. Consequently, one of the goals of the trials will be to determine whether resistance is an issue.

Another concern is cost. In the world's poorest countries, the manufacturer of tenofovir and Truvada has agreed to sell the drugs at cost, which would cut the price to $200 or $300 a year. Yet even a few hundred dollars is more than many in the developing world could afford, so the burden will undoubtedly fall on international donors. In the developed world, the drugs can cost thousands of dollars each year. A group of researchers from Yale and Harvard concluded in March that PrEP could significantly reduce transmission of HIV among men who have sex with men in the U.S., but they added that, unless drug prices fall, the benefits would likely not justify the cost.

Yet even with these limitations, the strategy could still be a boon to HIV prevention because despite intensive research efforts, the HIV prevention toolbox is still only half full. "Any new tool we have to reduce the spread of this virus," Cates says, "is a reason for breaking out the champagne."

Cassandra Willyard is a freelance science writer in Brooklyn, NY.


  1. Tsai C. et al. "Prevention of SIV Infection in Macaques by (R)-9(2-Phosphonylmethoxypropyl)adenine." Science 270.5239 (1995).

  2. Centers for Disease Control. "Case-Control Study of HIV Seroconversion in Health-Care Workers After Percutaneous Exposure to HIV Infected Blood. France, United Kingdom, and United States. January 1988 - August 1994." Morbidity and Mortality Weekly Report, 40.50 (1995).

  3. Subarrao S. et al. "Chemophylaxis with Tenofovie Disoproxil Fumarate Provided Partial Protection Against Infection with Simian Human Immunodeficiency Virus in Macaques Given Multiple Virus Challenges." The Journal of Infection Diseases 194 (2006).

  4. Garcia-Lerma J. G. et al. "Prevention of Rectal SHIV Transmission in Macques by Daily or Intermittent Prophylaxis with Emtricitabine and Tenofovir. PLoS Medicine 5.2(2008).

  5. Peterson L. et al. "Tenofovir disoproxil fumarate for Prevention of HIV Infection in Women: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Trial. PLoS Clinical Trials 2.5 (2007).

Want to read more articles in the June 2009 issue of GMHC Treatment Issues_? Click here._