The Truvada warsBMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g3811 (Published 24 June 2014) Cite this as: BMJ 2014;348:g3811
- Julia Belluz, Knight Science Journalism fellow, Massachusetts Institute of Technology, Cambridge MA 02142, USA
Every night before going to bed, Patrick Buzzell steps into his kitchen and swallows a small blue pill that eases his worries about HIV. For more than a year, the 36 year old real estate agent, based in Boston, has been using a combination antiretroviral (brand name Truvada) for pre-exposure prophylaxis, or PrEP. The tenofovir/emtricitabine tablet was first approved by the US Food and Drug Administration to treat HIV positive patients in 2004, and licensed in 2012 for use among sexually active, seronegative patients—like Buzzell.
“My husband is HIV positive,” he told The BMJ. “PrEP moved HIV further on to the back burner so we are able to go about our lives every day. We talk more about the telephone bill now than his status or how it affects me.”
Not everyone has embraced PrEP. Michael Weinstein, president of the AIDS Healthcare Foundation, has called the pill a “party drug” and those who lived through the early days of the AIDS pandemic have raised concerns that PrEP undermines traditional advocacy messages about condom use.1 In fact, the notion of a pill for HIV prevention has triggered what AIDS activist Peter Staley calls “gay on gay shaming.”
“There’s a real stigma against this drug,” he said in an interview. “Any young gay man that considers using Truvada is viewed as somebody who must be putting himself at great sexual risk for HIV and therefore he gets stigmatized and called ‘Truvada whore.’”
Beyond controversy in the gay community, health officials are at odds with each other about the drug’s role in the prevention arsenal. In the UK, where HIV medication is free and the rate of treatment among positive patients is high, PrEP is being considered mainly for men who have sex with men—still the group most severely affected by HIV—but not serodiscordant couples. (The positive partner in this context is probably on treatment with an undetectable viral load and little chance of transmitting the virus.) In the US, where treatment coverage is lower, the target of new public health guidelines for PrEP is patients at risk in any demographic, including women and HIV negative partners in serodiscordant couples, signalling a shift in prevention messaging.2
Whether this is “HIV’s sexual revolution,” as some are calling it, remains to be seen. In the two years since PrEP hit the US market, concerns about adherence, cost, antimicrobial resistance, and risk compensation have public health leaders around the world wondering if this efficacious drug—not yet approved in Europe—can also be an effective public health tool in the fight against AIDS.
Efficacy and safety
For now, there seems to be little controversy over the efficacy and safety of emtricitabine and tenofovir disoproxil fumarate combination therapy (FTC/TDF). A three year clinical trial of the antiretroviral for PrEP was published in the New England Journal of Medicine in 2010.3 The Pre-Exposure Prophylaxis Initiative, or iPrEx, was a multi-country, randomized, double blind, placebo controlled study involving seronegative men who have sex with men. The PrEP arm saw an average of 44% additional protection from HIV. Among those who took the medication as prescribed, the risk of acquiring HIV was cut by more than 90%. Other more recent studies have found that PrEP is similarly effective for heterosexual men and women,4 as well as injection drug users.5 A 2012 Cochrane Collaboration systematic review synthesized the literature for PrEP and concluded that it reduces a patient’s risk of becoming infected with HIV in a range of high risk populations.6
What’s more, studies so far have demonstrated that FTC/TDF for PrEP carries few risks. The most common side effect is nausea, though this typically resolves within several weeks. More serious potential harms include renal problems and reductions in bone mineral density, though the former seems to dissipate after patients go off the medicine and the latter tends to be very mild.
Sheena McCormack, a clinical epidemiologist with the Medical Research Council Clinical Trials Unit at University College London, summed it up this way: “We’re impressed by the safety profile of Truvada, and not particularly concerned about using it in HIV negative populations at this stage.” Even though long term health effects of PrEP are unknown, she’s reassured by the decade’s worth of harms data from the drug for treatment in HIV positive people.
Adherence and risk compensation
Still, just because the drug may work well in individuals doesn’t mean there’s a straightforward public health case. One of the main concerns about PrEP is that any potential benefit or harm depends on how patients use it in real life, explained Jane Anderson, a practicing HIV clinician and the Public Health England lead on HIV, and sexual and reproductive health. “We know that there is clear proof of concept that using antiretroviral medication in a preventative way can be efficacious,” said Anderson. “Making it effective is a very different concept: if you don’t swallow the pill regularly, you won’t get the results.”
For example, in the iPrEx study, participants with ≥50% adherence had a 50% reduction in HIV acquisition, while those with ≥90% adherence saw a 73% reduction. Whether patients take the pill as prescribed may be determined by things like access and cost. If PrEP users can’t get regular access to reasonably priced treatment, noted Anderson, they may be less likely to use it regularly.
That’s not to mention fears that those using PrEP may engage in risky sexual behaviors and spread sexually transmitted infections (STI) more easily since they’ll have a heightened sense of protection and they won’t necessarily be wearing condoms. To know whether these concerns are unfounded, health officials want more information. An international continuation study of iPrEx, called iPrEx OLE, will provide additional data about PrEP safety and people’s behaviors while on the drug over a longer term. Further studies—such as the ADAPT study funded by the National Institutes of Health7—will also examine the feasibility of non-daily regimens of PrEP.
In the UK context, Anderson and her colleague, Noel Gill of the HIV/STI surveillance department at Public Health England, are eagerly awaiting results from the PROUD demonstration trial.8 To date, the pilot study involves 13 clinics and 539 men in England who have had unprotected anal intercourse within the last 90 days and intend to do so again. Participants are randomized to either immediate PrEP or delayed PrEP after one year, and then monitored every three months to check in about their sexual behaviors and adherence.
Gill hopes the PROUD trial will give UK health officials answers about how and where PrEP might fit into the public health agenda. “We need more interventions in addition to behavioral interventions and treatment as prevention for men who have sex with men,” he said. Despite high rates of HIV diagnosis, and good linkage to care and treatment—there is no convincing evidence of a diminution of HIV incidence and prevalence of undiagnosed infection in this population. “It means enough uninfected people are putting themselves at risk and enough infectious people are not diagnosed. And that’s enough to keep infection going along.”
In other words, the optimism for treatment as prevention is not being realized among men who have sex with men. Gill speculated that hypernetworking applications such as Grindr may be to blame, or perhaps most of the transmission is being driven by acute infections in the undiagnosed. And this is where he thinks PrEP comes in. “The question for me is: can we sustain a high coverage of PrEP in the most networked group of men who have sex with men for a number of years.” He added: “Can it be used to stem the uncontrolled incidence of HIV in this community?”
After the data will come the tricky question of who pays for PrEP in the UK, said McCormack. “Would it be NHS England, local authorities or—most likely—a bit of both? How can it be justified when commissioners of healthcare are struggling to find the money to pay for a second cataract operation? Asking them to pay for Truvada to provide a back up for occasions when gay men don’t use condoms for sex is quite a hard sell when the current situation is that gay men buy most of the condoms they need themselves.”
The US experience
In the US, the cost of FTC/TDF for patients ranges from free to thousands per year depending on insurance coverage and income. As of March last year, there were at least 1774 people in America on Truvada PrEP according to data from the drug manufacturer Gilead Sciences.9 Women—and notably not gay men—accounted for nearly half of the prescriptions in the sample. While some observers have wondered whether this modest number means PrEP uptake failed, Dawn Smith—a biomedical interventions implementation officer at the US Centers for Disease Control (CDC)—noted that it can take decades before a new drug or therapy becomes the standard of care.
“It seems like PrEP is at that tipping point,” she said, adding that more patients and doctors are hearing about and asking for the medication. “We’re now turning to a lot of the implementation questions. We have learned a lot from clinical trials. Now we’re interested in how to deliver it effectively and what kinds of support are necessary from the CDC, from professional clinical associations, so that we help this become part of the HIV prevention practice of clinicians or help them identify appropriate people to give PrEP to.”
According to the Gilead data, most PrEP patients got the prescription from their family doctors, which did not surprise Smith. Because PrEP is for uninfected people, she said general practitioners and not specialists are probably going to be the primary prescribers. From the CDC perspective, good candidates for PrEP include patients who are not consistent condom users, and who either don’t know the HIV status of their partners or know their partners have HIV infection. “This can include men who have sex with men, heterosexual men and women, injection drug users, or HIV discordant couples.” She also suggested doctors look for other indirect evidence that a patient might be a suitable candidate. “If someone has been treated for two to three STIs in the last couple of years, or they have come to you asking for post-exposure prophylaxis, those are people you might want to think about having a discussion about PrEP with.”
The new CDC guidelines for PrEP recommend regular monitoring of HIV infection status, side effects, and sexual or injection risk behaviors, as well as counseling about adherence and condom use. Screening for acute HIV infection is another must since it’s these patients who hold the potential for developing drug resistant infection, Smith added. “All clinical trials have shown that among people who were uninfected—when they started taking the medication using standard measures of drug resistance—there was no drug resistance detected in any of those people who seroconverted.” However, in patients with acute HIV infection, who start on PrEP, the virus then has the potential to become resistant.
The extent to which drug resistance is a concern is unknown—like the answers to many other questions about PrEP in the public health context. “That’s one of the things we’ll learn as the first few demonstration projects begin telling us,” said Smith. Until then, the models suggest that it can be cost effective and have a significant impact—under a couple of conditions. “If it’s targeted to people who are truly at risk of HIV infection, and if they are taking the drug regularly, and if you have good coverage,” she said. “If you give it very well but only to 1% of the at-risk population you wouldn’t expect to have impact.”
In the US, like the UK, men who have sex with men are still those most affected by HIV and the number of infections has not budged in a decade. Making an effective intervention in this community will also mean overcoming stigma around PrEP. “We are not suggesting people stop using condoms,” said Smith. “We are suggesting that for people who are already not using condoms, we have another option to help protect them from HIV infection. It’s part of being practical and realistic.”
For his part, the AIDS activist Peter Staley said he will continue speaking out in support of PrEP. “The science suggests that it is an incredibly useful tool to help prevent HIV. And therefore we should all be pro-PrEP. It’s not for everyone. It’s not a panacea. Nobody’s calling it that. But it should be something that we offer as an option to everyone who wants to stay HIV negative.”
Cite this as: BMJ 2014;348:g3811
Competing interests: I have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare.
Provenance and peer review: Commissioned; not externally peer reviewed.