It begins with a study published in 1994 that showed that retrovir (AZT) given to HIV-positive pregnant women before and during birth—and to the infants immediately after delivery—reduced the risk of HIV transmission to the child by 67%. Next came guidelines, issued by the Centers for Disease Control (CDC) in 1998, recommending post-exposure prophylaxis (PEP) for health care workers who were accidentally exposed to HIV, followed by PEP recommendations for sexual and injection-drug exposure, issued in 2005. Then, in 2006, the world got a glimpse of some intriguing data gleaned from studying HIV-negative monkeys who remained uninfected even after being “rectally challenged” with the HIV virus. They had been given a combination of Gilead Science’s tenofovir (Viread) and emtrictabine (Emtriva).
These studies raised a logical question: Could an HIV drug (or drugs) already on the market be used by people before being potentially exposed to the virus to reduce risk of HIV infections? Are we, in essence, sitting on a valuable addition to the prevention arsenal? The idea is known as PrEP—pre-exposure prophylaxis—and at first glance it seems to present one of the most promising fronts in prevention research. The implications are many. If ARVs like Viread and Emtriva proved effective in preventing (or reducing the risk of) HIV transmission in negative people, serodiscordant couples, gay or straight, could add another layer of reliable protection or quite possibly forgo the condoms in favor of pills. And heterosexual couples could conceive the old fashioned way, without risking passing on the virus to the HIV-negative partner—let alone the baby.
“There’s no reason to believe it won’t work,” says Mark Harrington, executive director of Treatment Action Group in New York City. “People are going to have unsafe sex no matter what, so we are trying to get as many prevention interventions as we can. We desperately need any tool we can get.”
Harrington and many other treatment activists believe that we live in an age of exhaustion: Health workers complain of “condom fatigue,” ambivalence and a drop in AIDS literacy in the ARV era. Despite funding lavished on vaccines and microbicides, new prevention techniques have been very slow in coming. Because PrEP would make use of existing, FDA-approved drugs, it would seem to offer the most immediate hope for a new approach to stemming new infections, which remain at 40,000 a year in the United States and are continually skyrocketing abroad.
Despite PrEP’s promise and the potential for its use in the near future, every attempt made by researchers from the United States to Ghana, Cambodia, Thailand and Peru to answer the question of whether PrEP can be made a reality has encountered setbacks and disappointments. The biggest barrier? Overcoming the inevitable ethical dilemmas involved in human PrEP trials, in which the placebo group must risk exposure to HIV to prove efficacy.
“The dirty secret they don’t say is that they need seroconversion for the [PrEP] trial to work,” says Karyn Kaplan, an activist at the Thai Treatment Action Group, who has objected to a PrEP trial sponsored by the CDC now being conducted among Thai injection-drug users. And though four trials are under way both here and abroad, it is still not known whether PrEP will succeed in preventing or reducing the rate of HIV transmission. And, even if PrEP works, it’s not clear that people could afford it (it is yet to be determined how long someone would have to take a course of very expensive meds, meds that would not likely be covered, in the case of PrEP, by health insurance) or would use it properly. Finally, there is a real theoretical danger associated with PrEP: “disinhibition,” and as a result, more infections.
Here in the United States, the ethical concerns surrounding PrEP are not limited to drug trials. Some worry that the idea of PrEP offering risk reduction (especially before its efficacy has been established) could make people less inhibited, and therefore lead to more infections. “If risky behavior increases in a population because of or associated with [PrEP], then does the individual benefit outweigh the larger cost?” asks Steve Gibson, executive director of Magnet, a San Francisco gay men’s health center.
A handful of major news stories in the U.S. press have suggested that gay men are using ARVs for prevention as part of a set of hot new party drugs. “[ARVs are] being sold in packets along with Viagra and Ecstasy in gay dance clubs—and even prescribed by physicians,” wrote Daniel Costello in the Los Angeles Times in December 2005. Unnamed “health officials” said use is growing quickly, Costello wrote: “They worry that the practice could spread into other high-risk segments of the population, such as sex workers and IV-drug users, and then into the general public.” The stories cited a CDC survey conducted in 2004 at gay-pride events in four cities that reported about a quarter of people had heard about PrEP, and that 5 percent had even tried it. Upon closer inspection, however, many of the respondents may have confused PrEP with PEP—post-exposure prophylaxis, the aforementioned practice of prescribing a course of ARVs—in this case, a combination of drug classes—after unsafe or accidental contact with HIV. The stories quoted only one doctor who said he’d prescribed PrEP for patients whose sexual habits he thought put them at risk.
That doctor, Marcus Conant, of San Francisco, told POZ he had prescribed the drug to about six people, each of whom requested it after reading about it. None, he said, ever asked for a refill. “If you have someone who says that they’re having unsafe sex and they’re not willing to use a condom, what would you do?” he asks. “It was an issue that I think the press made a bigger deal of than it was.”
In a subsequent CDC survey conducted in 2005 that defined PrEP more clearly, 19 percent of respondents said they knew about the concept but only one-third of 1 percent had tried it. A recent survey from the San Francisco Department of Public Health that sought out men at clinics and sex parties showed that 18 percent had heard of the idea, though only one person said he had actually tried it. Given his description of the treatment, he may well have gotten the ARVs only after his potential exposure to HIV, not before. Again, a case of PrEP being confused with PEP.
“We were glad to see that PrEP use did not appear to be widespread,” said Albert Liu, MD, director of HIV prevention intervention studies at the SFDPH. “Given that PrEP currently hasn’t been established as a prevention strategy, and the safety of this approach hasn’t been proven, we don’t recommend that people use this until it’s been evaluated in studies.”
A more recent spot-check by POZ shows that, from a bathhouse in Rhode Island to HIV clinics in Boston and New York, all the way to crystal meth treatment centers in the Bay Area, health care workers have not received a single firsthand report of PrEP use from their patients. (One doctor reported hearing about taking “MTV”: meth, tenofovir and Viagra.)
“We’re not having guys walk in and say ‘I got hooked up with some tenofovir over the weekend,’” says Gibson. The CDC is close to enrolling a total of 400 men in San Francisco, Boston and Atlanta to study whether tenofovir is safe for daily use by negative men and, perhaps more important, whether taking the drug brings on a false sense of security that leads to risky behavior.
The danger is real, according to Michael Siever, who runs the Stonewall Project, a San Francisco harm-reduction program, and tweaker.org, a crystal meth information site. “More and more, the discussions are around what do we do about the fact that the condom code has evaporated. Consistent use of condoms is unusual these days as opposed to the norm, regardless of PrEP.”
“My own opinion is that the fear about behavioral disinhibition is probably not borne out by the facts. But we need to quantify it,” says Melanie Thompson, MD, principal investigator at the AIDS Research Consortium of Atlanta, who is running the Georgia branch of the study.
Existing research on whether disinhibition occurs when people perceive themselves to be safer is mixed, but a tougher issue may be how effective PrEP turns out to be—assuming it works at all. If the practice can reduce infections from risky contact by 50 percent, would it still be worth promoting? By 30 percent? How effective would PrEP have to be to get a red-carpet rollout into the community?
“If it only works moderately well this may be too expensive to see it widely used,” says Mitchell Warren of AIDS Vaccine Advocacy Coalition (AVAC). “We need to know how many infections we might be able to avert in order to make that decision.”
It’s certain that the earliest data we’ll have to answer these questions will come from drug trials overseas. (The U.S. studies won’t test efficacy.) The CDC and NIH are currently running trials in Thailand, Botswana, Peru and Ecuador, enrolling a total of 5,000 subjects. After protests, cancellations and inconclusive results from a first round of trials conducted in Ghana, Cambodia, Cameroon and Nigeria, this critical second round of trials is expected to produce results in 2008 and 2009.
Historically, PrEP trials have provoked conflict wherever they have set up shop, which, to date, has only been in developing nations. That may be understandable, given the stereotype of U.S.-based researchers in white lab coats dropping into the developing world and—rather than helping people out of poverty—conducting a test that may result in HIV transmission. Those opposed to the PrEP trials contend that studies like these are inherently unethical—particularly where there is an inescapable power imbalance between the researchers and their subjects, and where access to ARVs, much less basic medical care, may be scant.
On the other side of the argument are utilitarians who point out that these tests are essential for prevention options to progress and that they would take years to conduct in low-prevalence countries like the United States. “To do a trial is really a balancing act, going to an area where there is enough of the disease so that you can enroll as few people as possible and get an answer,” says Thompson.
Mitchell Warren, executive director of the AVAC, the closest thing that exists to a PrEP coordinating body, argues that the classic approach in which researchers are responsible for preventing research-related injury does not quite apply here. “HIV infection is not research-related in that it’s not a side effect of being in the trial. It’s a product of behavior. Trials do a good job of risk reduction.” Adds Julie Davids, executive director of the Community HIV/AIDS Mobilization Project: “It’s not the trial that exposes people to HIV. It’s a world that hasn’t taken HIV seriously enough to develop prevention. It’s not the trial that causes harm.”
Activists in Thailand, where the CDC is working on enrolling 2,000 HIV-negative injection-drug users in a PrEP trial, disagree. They claim medical ethics and research controls dictate that all subjects must be given the best current prevention practices. In an HIV drug study involving injection-drug users, that means offering access to clean needles, which reduces transmission rates and, studies show, does not increase drug use. But U.S. policy does not allow money to be spent on needle exchange. “Everyone and their mother has proven that providing clean injection equipment is the best tool we have for preventing HIV,” says Kaplan, of the Thai Treatment Action Group. She says attempts to improve the test protocol fell on deaf ears. “In retrospect, we should have tried to stop the trial altogether.”
Lynn Paxton, director of PrEP research at the CDC, counters that needles are cheap and available, and that the CDC can refer subjects to other non-U.S.-funded needle exchange programs. “The fact that we are not able to provide them with clean needles doesn’t actually prevent them from getting clean needles,” she says, adding that she personally disagrees with the U.S. policy.
Even when protocol is as good as possible, the results can be disappointing, as was the case in a 2006 trial in Ghana, the only PrEP study ever to make it to completion. There, Family Health International (FHI), with funding from the Gates Foundation, recruited more than 900 high-risk HIV-negative women, mostly sex workers. For more than a year, half took tenofovir daily; the other half took a placebo. The women returned once a month for HIV testing, a survey of behavior, and more pills. Before enrolling, the women signed consent forms after getting a long explanation (many are illiterate) from FHI about placebo trials. They also got a medical exam, treatment for other STDs, sex-ed counseling and condoms. For those infected during the course of the trial, FHI agreed to set up medical care and 15 years of ARV treatment. These procedures passed FHI’s stringent internal guidelines and Ghana’s ethics review boards.
Ironically, the surprisingly low number of infections during the study made it impossible to conclude that the drug worked. “[The low infection rate] was likely related to our intensive counseling and risk-reduction messages that we gave at every visit, as well as condom dispensation,” explains FHI investigator Leigh Peterson. This extraordinarily effective counseling led sex workers’ reported condom use to jump from about 50 percent to over 90 percent. “Consistent counseling and supplying condoms on any basis does decrease the risk,” says Peterson.
In the end, the sex ed the researchers were compelled to provide undermined the study’s ability to produce results on the efficacy of PrEP. FHI’s survey was supposed to include data from Cambodia, Cameroon and Nigeria, as well as Ghana. That information could have given solid evidence of efficacy, but each of those trials was shut down; protests and media attention led to their cancellation.
These dispiriting outcomes have led all parties to dot their Is and cross their Ts very carefully. “[The shutdown of the PrEP trials] set the research back two years,” says UCSF’s Robert Grant, MD, who is running the NIH trial in Peru and Ecuador. Nonetheless, PrEP proponents hope this is a new era.
It may be only after we look abroad, where the need for PrEP is arguably more pressing, that we can answer questions about how to use it here in the United States. Among the issues that remain: Will there be side effects for negative people who take these drugs for long stretches of time? Will people be willing to take a course of medication possibly for a week or more prior to potential exposure? What if they also had to take doses for days after potential exposure to make it effective? What about the psychological effects of being negative and popping ARVs? Who will be the target market? After all, if people believe in risk reduction, wouldn’t they employ a long proven technique like condoms to protect against STDs? If they wouldn’t use condoms, why would they subscribe to PrEP?
The question of whether there is a viable market for PrEP remains. If effective, it is difficult to imagine how the company would market such a drug. “At this point in time we do not have plans to actively market either Viread or Truvada for preprophylaxis,” says James Rooney, Gilead’s VP of Medical Affairs. He says Gilead, which has already supplied free meds to PrEP trials, would “make sure the drugs are available in whatever ways the public health authorities decide they should be utilized.”
“I think you need to be patient when you have a new idea,” says UCSF’s Grant. “We’re coming out of a period where the minute you said ‘PrEP’ it was a red flag for controversy,” adds Mitchell Warren of AVAC. “I think we are in a new period where when you say ‘PrEP’ you are getting some renewed enthusiasm to get an answer to the question. I don’t know if PrEP is going to work or not, but by God I want an answer and I want it fast.”