The HIV prevention toolbox just got a headline-grabbing addition. On July 16, the FDA approved Truvada as a pill that certain HIV-negative people can take to prevent them from getting HIV through sex. When taken as pre-exposure prophylaxis, or PrEP, Truvada, which is manufactured by Gilead Sciences, is supposed to be used daily along with safer-sex practices such as condoms and regular HIV testing. How does Truvada as PrEP work? Who is a good candidate for it, and what are the risks? For answers, AIDSmeds spoke with three specialists: Jared Baeten, MD, PhD, an associate professor of global health and medicine at the University of Washington at Seattle and co-leader of the Partners PrEP study; Gal Mayer, MD, the medical director of the Callen-Lorde Community Health Center in New York City, whose primary focus is gay men; and Albert Liu, MD, MPH, the director of prevention interventions at the San Francisco Department of Public Health and also the medical director of the iPrEX study (more details on these studies later). Together, we break down the basic science and real-world application of Truvada as PrEP.

How does Truvada as PrEP work?
To better understand this, it’s helpful to know how HIV meds work in someone who is positive. A person living with HIV takes at least three or four HIV drugs—called combination antiretroviral therapy—that work together to keep the virus from replicating. The meds don’t seek out the virus and attack it directly; rather, they each halt different steps of the complicated process in which the virus uses immune cells to make new copies of itself. A similar thing happens in PrEP. “Truvada is a combination pill of two HIV medications (tenofovir and emtricitabine) commonly used for HIV treatment,” explains Albert Liu. “When taken as PrEP, Truvada can block HIV replication from occurring and prevent HIV from establishing infection in the body.”

Why can’t a person only take Truvada before or after sex, as opposed to every day?
“It takes a while for Truvada to build up to levels in the body that can protect people from HIV infection,” Liu explains. “We don’t yet know exactly how long this takes, but it likely takes at least a few days.” Additional studies are exploring this topic and testing alternative dosing schedules, such as four and two times a week. “In the meantime,” Liu stresses, “it is recommended that people take PrEP once a day, as this was how it was tested in previous PrEP studies.” Jared Baeten adds that “it’s also important to have some amount of medication use after exposure.”

And Gal Mayer points out another prevention tactic for people to be aware of: PEP, or post-exposure prophylaxis, which is when a person not on PrEP is possibly exposed to HIV (if a condom breaks, for example) and takes HIV meds to reduce the likelihood of infection. PEP should be started no later than 72 hours after possible exposure, and it’s usually taken for a month; three meds are generally used for PEP instead of the two for PrEP.

What happens if you miss a dose of Truvada as PrEP?
This is a question researchers are still exploring. They aren’t exactly sure how many doses could be missed, or how often, without undercutting protection against HIV. It seems clear that better adherence equals better protection. “Missing one dose of PrEP in someone taking it consistently probably would have no impact,” Baeten says. He makes an analogy with HIV treatment: “We prescribe it for every day, but we know that not everyone uses it every day. Everyone misses a dose once in a while—that’s human nature. But most people who take it on a regular basis still get really strong HIV treatment benefits. So PrEP probably is similar in that way.”

Liu also acknowledges it can be difficult to take PrEP every day. “If you miss a dose,” he says, “you should just try to get back on track with taking a pill a day. If you miss doses frequently, it can be helpful to talk with your clinician who can discuss strategies to help with pill taking. Also, life changes happen, and some people change their mind about taking PrEP. In these cases, your clinician can help work through decisions about whether to continue taking PrEP.”

What do we know about side effects of Truvada as PrEP?
“Rates of side effects were low in PrEP studies of Truvada,” Liu says. “Some people may experience some side effects when they first start taking PrEP. These symptoms are usually mild and often go away or get better after the first month. Most of the time, people who do have side effects experience [gastro intestinal] changes, such as stomach cramps or nausea. There are things people can do to reduce these symptoms, such as taking the medication with food or at night before going to bed. It’s important to talk with your clinician if you’re having side effects, as there are other strategies to help reduce these symptoms.”

“The biggest concerns for long-term use are the effects this medication can have on the kidneys and bone density,” says Mayer, who adds that those problems are uncommon and that most people can take Truvada safely for years. Nonetheless, he monitors his patients for those two issues.

There is talk about drug resistance with PrEP. What does this means, and why is it a concern?
HIV is a tricky virus. It replicates constantly and mutates often. When there is only some HIV medication present, but not enough to halt the replication process—for example, if a person doesn’t take HIV meds daily or doesn’t take enough of them—then the virus can shape-shift to resist them. “In this way,” Mayer notes, “that which does not kill HIV literally makes it stronger.”

Remember that Truvada is made of two HIV meds and that people with HIV usually take a cocktail of three or four meds to control the virus. Well, if a person unknowingly has HIV and starts taking PrEP, it would be like taking an inadequate cocktail treatment and the virus would be able to mutate and become resistant to one of both of the drugs in Truvada. “So it’s important to be sure you’re negative before you start PrEP,” Baeten stresses. “The only people who developed HIV resistance in the PrEP studies so far have been people who were already infected when they started PrEP. They were in the window period”—the weeks between infection and the point at which antibodies become detectable using available tests—“and the researchers didn’t know they had HIV because the tests were negative for HIV.” [See editor’s note below.]

Baeten reiterates the lessons from PrEP studies thus far. If people who don’t have HIV start PrEP and adhere to treatment, then PrEP should protect them from HIV. Those who did get HIV were the ones who received placebo in the study or, in many cases, were not taking their Truvada as recommended.

But what about condoms? Won’t guys on PrEP forget about safe sex and start barebacking—and won’t that increase their HIV risk, especially if they’re missing daily PrEP doses?
In the PrEP trials, participants actually reduced their risk-taking actions, but they also received free condoms and lube as well as counseling and screenings for sexually transmitted infections—and they didn’t know whether they were taking an effective medicine or a placebo. Additional studies are now needed, Liu says, to look for changes in risky behavior when PrEP is implemented in the real world.

But some critics are also saying that men who can’t use condoms regularly will not succeed in taking PrEP daily. “I think that will turn out to be wrong,” Mayer says. “Adherence to medication that has almost no side effects can be achieved by incorporating [Truvada] into life’s other rituals. Brush your teeth every morning? Leave your PrEP by your toothbrush and you’ll be less likely to skip doses.

“In contrast,” he says, “using a condom is a complex social interaction. For those who haven’t found a way to incorporate it seamlessly into their sex lives, it may involve two people interrupting a pleasurable experience to remind themselves of an unpleasant reality. You may also have to convince a partner to use it or let you use it, stay hard while putting it on, and then find a way to resume the sex where you left off.

“Despite all that, every day thousands of people use condoms successfully to prevent HIV infection. Because it’s so effective, has no side effects and is so cheap, a condom is still the best way to prevent HIV infection. But I reject the idea that people who can’t use condoms consistently will categorically be unable to adhere to taking PrEP daily. I would even say that those who struggle with condoms and feel bad or anxious about failing to use them correctly, may have tremendous motivation to use PrEP correctly.”

Mayer continues: “Someone who is using condoms consistently and has good safer-sex practices does not need PrEP with Truvada. However, let’s consider the person—call him Joe—who is struggling with condom use, which is true for many men in the gay community. Joe doesn’t want to become infected with HIV but only succeeds at using condoms 50 percent of the time, whether because of drug use, depression, peer pressure or whatever. Currently, Joe is risking HIV infection the other 50 percent of the time. Joe is probably very anxious about acquiring HIV [and is] an excellent candidate for PrEP. Once on daily PrEP, [provided that he uses it daily as prescribed,] he is going to be over 90 percent protected against HIV even when he doesn’t use condoms. So even if his condom use drops to 20 percent because he feels protected by PrEP, there is still a far lower HIV infection risk for him, and in turn, for all Joe’s partners, than without PrEP. But the key is consistent use, which is why it’s important to discuss adherence with Joe and to follow him closely.

“Importantly,” Mayer says, “we should also explore the reasons Joe is having trouble with condoms. If it’s depression, we should also treat Joe’s depression. If it’s drug or alcohol use, we should provide Joe with substance use treatment. We should be aiming to help Joe with the problems he’s having using condoms and working toward the day when Joe won’t need PrEP anymore.

“But I also know that many gay men are having unprotected sex as a personal choice, and not because they’re depressed or have a drug problem. Those men are generally trying to avoid HIV by other strategies: having unprotected sex only with partners who claim to be negative (serosorting), having unprotected sex only when they’re the top (seropositioning), having unprotected sex only with partners they trust, and so on. All those strategies have been proven time and again to be far from fail-proof, and that’s why we see so many gay men becoming infected with HIV. For those men, PrEP could be enormously helpful.

“Do I think a person on PrEP will use condoms less frequently? The studies don’t show that they do, but real life might be very different, and I think some will inevitably use condoms less. But I also think that using PrEP correctly will still be more protective, even with less condom use. Only time will tell.”

Who would be a good candidate for PrEP?
In short, Beaten says, “a patient with ongoing potential HIV risk would be a person to talk to about PrEP.” More specifically, he points to the different at-risk populations who were studied in the clinical trials: men who have sex with men (MSM, like the hypothetical Joe mentioned above), trans women, and HIV-negative heterosexuals whose partner is positive but not taking medication yet.

“It is the medical provider’s job to match the intervention to the person correctly and to evaluate that intervention over time,” Mayer adds.

Mayer, who primarily works with gay men, lists a few qualities his ideal PrEP patients would possess: They’d understand the key to successful prevention is adherence; they’d undergo frequent monitoring with their medical provider to ensure the meds weren’t harmful; and “importantly, [they’d] also have insurance that covers this use of Truvada. With a monthly cost of over $1,000, it would be impossible for most people to take PrEP without appropriate insurance coverage.”

Who is contracting HIV in the United States nowadays?
Perhaps another way to frame the “who’s a good PrEP candidate” is to look at who is contracting HIV in the United States today. According to the Centers for Disease Control and Prevention (the CDC), about 1.2 million people are living with HIV in the United States, with nearly 50,000 people becoming positive each year (and one in five don’t know they’re living with the virus). Here are specific breakdowns of the main population groups who contracted HIV in 2009, the latest data available:

  • White MSM — 11,400 infections
  • Black MSM — 10,800
  • Latino MSM — 6,000
  • Black Heterosexual Women — 5,400
  • Black Heterosexual Men — 2,400
  • Latina Heterosexual Women — 1,700
  • White Heterosexual Women — 1,700
  • Black Male Injection Drug Users — 1,200
  • Black Female Injection Drug Users — 940

When you consider that African Americans represent only 14 percent of the U.S. population but account for 44 percent of new infections—and similarly, that Latinos represent 16 percent of the population but comprise 20 percent of new infections—you can see that the epidemic is hitting minority populations (and poor people) particularly hard.

But MSM share the brunt. (“MSM,” or “men who have sex with men,” is a term researchers use; it refers to behaviors that transmit HIV and does not delve into self-identities and labels such as “gay” or “bisexual.”) MSM account for 2 percent of the U.S. population and yet make up 61 percent of new infections—and more and more of those diagnoses are happening to young MSM and to MSM of color. Why is HIV becoming more and more a gay epidemic again? Mayer thinks the answer is condom fatigue. Gay men “don’t want to become infected with HIV,” he says, “but those of us with the most condom fatigue are losing the battle. Because it’s an effective prevention that isn’t a condom, PrEP can play a major role in preventing new infections in the gay community.”

How long should a person be on PrEP?
PrEP is appropriate for periods of time when people have greater risk for contracting HIV, Baeten explains. Those periods may be short or long or recurrent, depending on the individual. He likens it to the way women use oral contraceptives at different times in their lives depending on their risk of pregnancy at those times. “That discussion—when to use, and when not to use—is a discussion patients should be having with health care providers,” he says. “The general goal is that PrEP is not lifelong. When you have HIV, treatment is lifelong. But PrEP is not.”

Mayer refers again to his hypothetical patient, Joe: “Ideally, I would like to use PrEP as a stopgap measure to protect Joe while we work toward addressing the obstacles that stand between him and regular condom use. For example, there are plenty of patients out there who will use condoms more consistently if they sober up. PrEP might be a wonderful way to keep them safe as they get treatment, but they may not need it after they get sober.”

What have we learned from PrEP studies?
Seven major studies have been done, or are currently being done, involving PrEP: one with MSM and trans women, two with straight couples, three with women-only and one that’s underway with injection drug users. They’ve been making headlines for a few years now, often with confusing and seemingly contradictory findings. The big picture? “Taken together, these data suggest that PrEP can be effective for both men and women at risk for HIV infection,” Liu says. “People who take PrEP consistently are able to achieve higher levels of protection. Medication adherence (taking the pill regularly) appears to be an important factor.” Further studies are needed, and several are ongoing. For now, here’s a general summary of the results we do have:

iPreX: This study looked at Truvada as PrEP among men who have sex with men and trans women. “The overall protection was around 42 percent,” explains Mayer, “meaning that among all the participants receiving PrEP there were 42 percent fewer HIV infections than in the participants receiving placebo. However, not everyone receiving PrEP was taking it correctly. Hair and blood tests for Truvada could tell the researchers who was taking it. And it turned out that most of the infections in the group receiving Truvada were, in fact, in participants with negative hair and blood samples—in other words, participants who were not taking the medication correctly. When [researchers] compared the number of new HIV infections in the group who were not only receiving PrEP, but also taking it correctly, the efficacy rose to 92 percent This is a fantastic result, when you compare it to condoms being 90 to 95 percent effective at stopping HIV transmission.”

Partners PrEP and TDF2: These were among heterosexual couples in which one partner was positive for HIV and the other was negative for the virus. “In both studies, HIV protection was strong in men and women [who took the pills consistently],” Baeten says. TDF2 involved Truvada. In Partners PrEP, some participants received Truvada, some got only Viread (tenofovir, which is one component of Truvada), and some placebo. The best results—73 percent fewer infections—were among the Truvada arm.

CAPRISA 004: This was a vaginal microbicide study of a topical tenofovir gel. Depending on how you crunch the data and during what time period, it offered between 50 and 35 percent reduction. But it’s a gel, and therefore difficult to compare with oral Truvada as PrEP.

Fem-PrEP: This involved Truvada pills as PrEP for women. It was stopped because it was not offering protection. However, only a minority of participants took the meds as directed, so no firm conclusions could be drawn.

VOICE: This study, among women, has many components. The tenofovir gel study was stopped because of a lack of efficacy. (It seems that tenofovir by itself doesn’t work as well as Truvada, which is tenofovir plus emtricitabine.) The Truvada pill component of the study is still going on. Many women across the globe are not in relationships in which they can force their partners to wear condoms—or to be monogamous. A prophylaxis in the form of a pill or gel would arm these women with valuable protection.

Were there any caveats or strings attached to the FDA approval?
“As part of PrEP, HIV-uninfected individuals who are at high risk will need to take Truvada daily to lower their chances of becoming infected with HIV should they be exposed to the virus,” the FDA said. “Truvada for PrEP is meant to be used as part of a comprehensive HIV prevention plan that includes risk reduction counseling, consistent and correct condom use, regular HIV testing, and screening for and treatment of other sexually transmitted infections. Truvada is not a substitute for safer-sex practices.”

As part of its approval requirement, Gilead will provide a medication guide along with training and education for health care providers. Specifically, it will address the issues of drug resistance along with the potential dangers for people living with hepatitis B (tenofovir and emtricitabine also work against hep B, and for this population, the meds can cause serious liver problems if not taken as directed). In addition, Gilead will study women who become pregnant while taking Truvada for PrEP. And the company will provide vouchers for free condoms and testing for HIV and hep B. For more info, see the AIDSmeds article “FDA Approves Truvada as PrEP.”  

What are the next steps, now that Truvada as PrEP has been approved?
“The immediate next steps,” Baeten says, “are understanding who will take it, who is interested, who starts it, who continues to take it, who takes it with high adherence. Because each of those steps will determine how big of an impact PrEP will have in preventing HIV.”

Liu underscores an obvious point: “It’s important to remember that PrEP should be taken under the care of a clinician.”

If you think you’re a candidate for Truvada as PrEP, talk to your health care provider or local AIDS service organization for more info (you can locate one near you on the POZ Health Services Directory). Also keep your eyes on AIDSmeds for information regarding PrEP demonstration projects—programs to study PrEP in different geographic areas and communities, which may potentially offer Truvada free of charge.  

“Matching PrEP to the right patient and appropriate monitoring will be, in my opinion, key to making PrEP a success in the real world,” says Mayer, adding that it’s also important for everyone taking PrEP to be screened for HIV and hepatitis B before starting. PrEP also requires that health care providers monitor blood work, urine samples and HIV and STI tests every three to six months. “That might be a challenging model for primary care providers to adopt,” Mayer acknowledges, “but I think being cautious at this preliminary stage is appropriate. We really want to keep an eye on our patients to make sure we’re not causing more harm than benefit as PrEP rolls out.”

Editor’s note: Following the publication of this article, data from the Fem-PrEP clinical trial indicated a few cases of resistance to the emtricitavine among some women who became infected with HIV while prescribed Truvada in the study.