It was an all too familiar story to those who study HIV. Kimberly Page, an epidemiologist at the University of California, San Francisco (UCSF), had just returned from Cambodia, where she had been conducting research on how to protect people from getting infected with the AIDS-causing virus.
She felt she had made the best use of her time there, by targeting women in the commercial sex trade who are at especially high risk of contracting HIV. “She told me that it was devastating,” says Dr. Robert Grant, a professor medicine at UCSF and an investigator at the Gladstone Institute of Virology and Immunology. “She said, ‘We provide them with condoms, we counsel them, provide HIV testing, and we help them think through some social solutions to avoid getting exposed.'” But women were still becoming infected with HIV at extremely high rates. “She didn’t know what to do,” Grant says.
There wasn’t much she could do. It was 2001, and while treatments for HIV had advanced by leaps — with the introduction of powerful antiretroviral (ARV) drugs that could reduce the body’s levels of the virus to almost zero — the prevention effort had stalled.
Yes, there were condoms, but using them wasn’t high on most people’s lists; for prostitutes and other oppressed women, using them wasn’t an option. Safe-sex counseling was proving only marginally effective, certainly not doing enough to dissuade anyone bent on having unprotected sex with multiple partners. Trials of one of the most promising new ways to prevent infection — a microbicide gel designed to kill the virus in vaginal cells — had just failed miserably. As for a vaccine against HIV, it seemed like a fantasy. Prevention efforts had hit a scientific, social and cultural wall.
Then, in 2001, the U.S. Food and Drug Administration approved a new anti-HIV drug called tenofovir. In theory, it was similar to the ARVs that had come before it, but tenofovir had some advantages over the older drugs, namely that it was a once daily pill and had relatively few side effects. That would make it an ideal vehicle for testing a new and controversial idea — using antiretrovirals not just to treat HIV, but to actually prevent it, by giving it prophylactically to healthy, uninfected people like the girls in Cambodia.
“A lot of people said this was stupid,” says Dr. Raphael Landovitz, assistant professor of medicine at the University of California, Los Angeles, Center for Clinical AIDS Research and Education. “They said it was stupid because you were giving…drugs for a prolonged period of time to someone who was HIV uninfected. You would be putting people at risk of toxicity to prevent something for which we already have a prevention strategy that works — condoms.” (Except, of course, condoms weren’t working that well at all.)
Not to be dissuaded, Grant found himself championing the “treatment as prevention” idea, and even pushed to test it rigorously in a clinical trial. In 2007, he launched the first such study of its kind, not in Cambodian girls — that country’s government refused — but in 2499 HIV-free, high-risk gay and transgendered men in Central and South America, South Africa, Thailand and the U.S. Half of the men randomly received a combination of tenofovir and emtricitabine, and half a placebo. Then, it became a waiting game. Only by comparing the rates of HIV between the two groups after a year and a half or so would it be possible to know whether anti-HIV drugs really had the potential to prevent as well as treat infection.
The evolution of every epidemic reaches a turning point, a critical shift in thinking and resources that marks, generally, the beginning of the end of the disease. When the urgent and pressing tide of new patients starts ever so slightly to wane, and when the threat of death grows ever so slightly more distant, that is the time to start thinking longer term, about how to manage the disease within a population. Now, 30 years after the human immunodeficiency virus was first identified, we may finally be coming close to that point with AIDS.
According to the Joint United Nations Program on HIV-AIDS (UNAIDS), the number of people living with HIV has reached record levels, owing in large part to better drug treatments and better ways of getting the drugs to people who need them most. HIV has gone from death sentence to a disease one lives with.
The fact remains, however, that you can’t treat every infected person, and that each infected person remains a potential reservoir of infection of other people, which is what keeps an epidemic like AIDS alive. The disease got its foothold among gay men, intravenous drugs users and commercial sex workers, but it is now being perpetuated by the much larger population of heterosexuals, who make up most of those living with HIV today.
To truly turn the tide of the epidemic, it would require a vaccine that prevents infection close to 100% of the time. Short of that, says Grant, other efforts to prevent HIV infection need to become the priority — and potentially the key to managing the disease for the foreseeable future. Using treatment as prevention in healthy people may be an important way to do that.
In 2001, when Page told him about the high rates of HIV in Cambodia, Grant had been mulling over the results of two recently published studies. The trials, one in San Francisco and the other in Rio de Janiero, had hinted that giving people ARVs immediately after exposure to HIV — within 72 hours — could lower their risk of getting infected. The problem, the researchers of those studies found, was that even when participants were explicitly told that taking the drugs after exposure could protect them from infection, a majority of people didn’t take them.
The enrollees were told about encouraging results from other studies involving health care workers who were accidentally exposed to HIV via needle sticks or by being splashed with body fluids from HIV positive patients; those who took ARVs immediately lowered their risk of developing AIDS. It was enough for the Centers for Disease Control and Prevention to recommend ARVs for all health care workers who were accidentally exposed to HIV, but it wasn’t enough to get the participants in the San Francisco and Rio studies to take the medications.
“That study brought home to me the fact that people have a hard time starting treatment after exposure,” says Grant. “You have to admit failure, admit that you failed to protect yourself in some way, and now you need to be rescued by some sort of pills. So for those reasons, we started thinking about pre-exposure prophylaxis as a possibility.”
Pre-exposure prophylaxis (PrEP) is a fancy name for giving treatment before a person even has a chance to be exposed and infected. As a way of fighting infectious disease, it isn’t entirely radical: Malaria treatment is built on the same concept, and people routinely take antimalarial drugs before traveling to endemic regions in order to prevent infection.
With HIV, studies in monkeys have shown that giving drugs before exposure is remarkably effective in protecting animals from simian HIV. And there is actually some precedent for pre-treating people as well. In Africa, giving the anti-HIV drug nevirapine to pregnant HIV-positive women is an important way to prevent transmission to the next generation. Anywhere from 15% to 45% of babies born to HIV-positive mothers will have HIV themselves, but among babies born to moms who are treated with nevirapine before, during and after delivery, transmission rates drop below 5%. “People say that if PEP [for postexposure prophylaxis] is the morning after pill, then PrEP would be like the birth control pill,” says Landovitz.
To test the validity of PrEP, Grant turned first to commercial sex workers in Cambodia for his first trial. What he didn’t count on was the perennial problem that plagues so many HIV-prevention studies. Cambodian health officials wanted assurances that if the participants became HIV positive, the researchers would provide proper care for them by providing anti-HIV medications. That was no problem, but the study then became embroiled in protests surrounding other HIV studies in neighboring Thailand, where AIDS advocates weren’t happy with the standard of care that trial participants received. Ultimately, Cambodian health officials became concerned enough that they withdrew their support for Grant’s study.
Grant then turned to the one country that, at the time, had had some success with HIV trials – Peru. Javier Lama, a professor of global health at the University of Washington and also a supporter of testing PrEP, became instrumental in enrolling gay men in Peru and Ecuador for the trial — even though the idea of studying men instead of women was radical at the time. “I was told that testing this idea in men was inappropriate,” says Grant. “Men should just change their behavior…to protect themselves, by using condoms. We disagreed, and felt that men, like women, were doing that what they could to stay safe, but it wasn’t always easy.”
As other prevention efforts started to look less and less promising, the idea of at least testing PrEP seemed a little less crazy. “People objected to it because they asked, Why treat uninfected people when we don’t even have the resources to treat all the infected people? But the thing that won the day was that it was really interesting to know if it in fact works,” says Dr. Anthony Fauci, director of the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID), which became a sponsor of Grant and Lama’s study. “It wasn’t only intellectual curiosity, but the realization that under certain circumstances, it would be a useful took in the tool kit for preventing HIV infection.”
The Bill and Melinda Gates Foundation joined NIAID and expanded the test sites to include Brazil, South Africa, Thailand and the U.S.
The first set of results were promising. Men taking a daily dose of the tenofovir combined with emtricitabine cut their risk of HIV infection by 44%, compared with men taking a placebo. What’s more, the more faithfully the men took the drugs, the better their chances of avoiding infection; those who reported taking the medication 90% of the time were 73% less likely to become infected, compared with those taking placebo.
These groundbreaking results, published in 2010, were followed up by similar successes in other trials. Just this year, two studies involving some 6,000 heterosexual men and women — including couples in which one partner was HIV-positive and the other was not — found that when healthy, uninfected people took ARVs prophylactically for up to three years, they cut their risk of HIV infection by 63% to 73%.
In an ironic turn, the same failed to hold true in a study of high-risk women. In a study of nearly 2000 commercial sex workers in Kenya, South Africa and Tanzania, PrEP did not appear to lower the risk of infection, so the trial’s sponsor, Family Health International, stopped the study early, after just two years. The researchers aren’t sure why PrEP didn’t appear to work in the women, suspect part of the problem may have to with the fact they weren’t taking their medication as faithfully as they should have.
Despite the disappointing results from the study in sex workers, AIDS experts say they have high hopes that PrEP will help turn the tide of a decades-long epidemic. “Clearly, behavioral modification of putting on a condom when you are ready for a sexual encounter is more difficult to negotiate than getting up in the morning, brushing your teeth and taking a pill,” says Fauci. “The combination of the psychological and practical with PrEP means we should ask the question, Does it work? And it does.”
But that doesn’t mean it will be easy to get PrEP to the populations that are hit by HIV the hardest. And some critics of the strategy say that rather than giving drugs to the uninfected, ARVs should be reserved for those who are already HIV-positive and need treatment. When that happens, treatment in essence becomes prevention, since treated individuals who get their viral loads down to undetectable levels are less able to transmit HIV to their sexual partners.
“The argument that drugs are in short supply, as if they were a scarce mineral and therefore should be used to only treat those who are infected, is an argument I never understood well,” says Stefano Bertozzi, director of HIV and Tuberculosis at the Bill and Melinda Gates Foundation. “Drugs are not at all in short supply. We can have as many as we want. What is in short supply is money. So the question is whether using ARVs as prevention compares favorably to other prevention modalities or not. What we need to do is make sure that we fund the prevention modalities that have the greatest value for the money in terms of how much prevention we get for the money invested.”
That could mean that PrEP, which is expensive, becomes feasible only for specific groups of particularly high-risk people, such as gay men or couples with one infected partner. For other men in nations with high rates of HIV, options like male circumcision may prove more economical and practical; studies have shown that circumcision can lower the risk of HIV infection by up to 60%, which, if current plans to circumcise 80% of males in 13 of the hardest hit HIV countries in Africa are met, could save up to $16.5 billion in HIV health care costs.
“I have a bigger vision for prevention,” says Page. “We’ve got circumcision, we have some microbicides that might show promise, and we’ve got PrEP. The next phase is going to be the implementation phase — how to deal with the structural, political and cultural factors that impede progress. We are at an interesting cross roads in the epidemic, and it’s exciting.”
Prevention is not about having the solution for containing an epidemic. It’s about providing several solutions, so that the ultimate goal — protecting people from getting infected — is met.