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Prepare for PrEP

, by Liz Highleyman

On July 16, 2012, the U.S. Food and Drug Administration (FDA) approved the Truvada combination pill for pre-exposure prophylaxis (PrEP) to prevent sexual transmission of HIV.

Several recent studies have provided strong evidence that Truvada—which contains the nucleoside/nucleotide reverse transcriptase inhibitors tenofovir (sold separately as Viread) and emtricitabine (Emtriva)is highly protective against HIV infection if taken regularly.

But while the medical science may be conclusive, a host of related issues—from drug side effects and resistance, to questions about adherence and safer sex, to concerns about cost and access—remain hotly debated. Is PrEP a marginally effective intervention that is too risky to deploy widely, or the most important breakthrough in HIV medicine since the advent of combination antiretroviral therapy?

What is PrEP?

Thirty years into the epidemic, the spread of HIV remains relentless. The Centers for Disease Control and Prevention (CDC) estimates that about 50,000 people are newly infected with HIV each year in the U.S.a number that has barely budged over the past decadewhile UNAIDS estimates that there were 2.7 million new infections worldwide in 2010.

Efforts to promote behavior change, such as condom use or fewer sex partners, have been unable to further stem the epidemic after a large decline during the first decade. Despite more than 20 years of research, an effective HIV vaccine remains out of reach. The bright spot in this bleak picture is the success of biomedical prevention approaches, including antiretroviral treatment as prevention, adult male circumcision, microbicides, and pre-exposure prophylaxis, better known as PrEP.

PrEP refers to HIV-negative people taking one or more antiretroviral drugs to prevent the virus from taking hold in the body after exposure. Monkey studies dating back to the mid-1990s provided proof-of-concept that antiretroviral agentsoral, injected, or in vaginal or rectal gelscould prevent infection with an HIV-like simian virus. Giving infants antiretroviral drugs to prevent mother-to-child transmission during breast-feeding is a practical application of PrEP that is well established worldwide.

Tenofovir, widely used as a component of combination antiretroviral therapy (ART), has been most extensively studied for PrEP, with or without emtricitabine. Several features make tenofovir attractive for this purpose, including its ease of use, relatively long half-life, and low toxicity compared with many other antiretrovirals.

Where Is PrEP Now?

Gilead Sciences of Foster City, California, requested priority review of a supplemental New Drug Application for Truvada PrEP in December 2011, not long after the results of the iPrEx study were published (described below).

In January 2011, the CDC issued interim PrEP guidance (published in the January 28, 2012, Morbidity and Mortality Weekly Report) recognizing that some HIV-negative people and their providers were interested in using tenofovir/emtricitabine for prevention right away. Truvada is widely available for HIV treatment, and physicians may prescribe approved drugs “off label” for other indications based on their professional judgment.

As FDA deliberations neared, debate within the HIV community heightened. In advance of the agency’s Antiviral Drugs Advisory Committee hearing in May, more than a dozen HIV/AIDS and health advocacy groupsincluding AVAC, the National Minority AIDS Council, Project Inform, and the San Francisco AIDS Foundationsubmitted public comments supporting approval of Truvada for PrEP.

Opposition was led by the AIDS Healthcare Foundation, arguing that Truvada PrEP was not sufficiently effective at preventing infection, caused dangerous side effects, and would lead people to stop using condoms.

On May 10, at the conclusion of an all-day hearing that featured public testimony both for and against approval, the committee voted 19 to 3 to recommend approving Truvada PrEP for men who have sex with men, 19 to 2 in favor of approval for HIV negative partners in serodiscordant couples, and 12 to 8 for approval for other groups at risk of acquiring HIV through sex.

“We don’t know how PrEP will work in the real world, but at this point the benefits of people taking a pill to prevent HIV transmission outweigh any risk in clinical trials to date,” said Matt Sharp, who served as a community representative on the committee. [Editor’s note: Matt Sharp writes BETA’s “Ask a Guinea Pig” Column; check it out here.]

The FDA is not required to follow committee recommendations, but it usually does. The agency was initially expected to issue its decision by June 15, based on the priority review timeline specified in the Prescription Drug User Fee Act. But given the concerns around PrEP and the new ground being broken in biomedical prevention, the review period was extended until September 14 to allow more time for Gilead to develop a Risk Evaluation and Mitigation Strategy, or REMS.

Taking many by surprise, the FDA approved Truvada PrEP on July 16, at a time when HIV was in the news in advance of the 19th International AIDS Conference in Washington, DC.

“Finally, after 30 years, HIV negative individuals have a new way to protect themselves from becoming infected,” said Project Inform executive director Dana Van Gorder. “While PrEP isn’t a tool that will be appropriate for broad use, we are thrilled to have a new option that could offer substantial benefit to those at highest risk for HIV, including gay and bisexual men and transgender women who struggle with consistent condom use, and heterosexual women living in areas with high HIV rates whose partners refuse to use condoms.”

What Does the Research Say?

Approval of Truvada for PrEP was informed by data from five Phase IIb or III randomized controlled trials looking at different populations.

These trials had two aspects in common that have bearing on real-world use. First, participants were directed to take tenofovir-based PrEP every day to maintain adequate levels in the body. It was not to be used sporadically before sex or as a “morning-after pill.”

Second, trial participants received an extensive package of prevention support, including education and counseling, regular HIV and sexually transmitted infection (STI) testing, and free condoms, which they were urged to use in addition to their study medication. They were informed that they might receive a placebo instead of active drug and told that it was not yet known whether PrEP was effective at preventing HIV infection.

Gay Men

The Phase III iPrEx trial, sponsored by the National Institutes of Health (NIH), enrolled 2,499 men who have sex with men and a small proportion of transgender women in six countries (Brazil, Ecuador, Peru, South Africa, Thailand, and Boston and San Francisco in the U.S.) between July 2007 and December 2009.

Participants were generally young, with an average age of about 27 years; about three-quarters were Hispanic/Latino. They tested HIV negative at study entry but were considered at high risk for infection. They reported an average of 18 sexual partners in the three months prior to enrollment and about 60% said they had unprotected receptive anal sex.

Participants were randomly assigned to receive either Truvada (300 mg tenofovir plus 200 mg emtricitabine) or placebo once-daily.

The study’s primary analysis, published in the November 23, 2010, advance online edition of the New England Journal of Medicine, showed that over a median follow-up period of 1.2 years, PrEP reduced the risk of HIV acquisition by 44% overall. There were 36 new infections among people taking Truvada vs. 64 in the placebo group, for incidence rates of 5.1 and 2.8 per 100 persons, respectively.

Effectiveness was strongly influenced by adherence. Participants who took their assigned pills at least 90% of the time, as indicated by self-reports and pill counts, saw a risk reduction of 73%.

Dr. Robert Grant (photo: Liz Highleyman)

“This study provides the first proof that oral PrEP works in people, and the first proof of any biomedical intervention to prevent infection in gay and bisexual men,” said iPrEx study chair Robert Grant from UCSF’s Gladstone Institute of Virology and Immunology.

Grant presented further data at the 2011 Conference on Retroviruses and Opportunistic Infections (CROI) and at the 2011 International AIDS Society (IAS) meeting in Rome.

After three years of follow-up, the number of new infections rose to 48 among people taking Truvada and 84 among those taking placebo, an overall risk reduction of 42% in a modified intent-to-treat analysis. Again, the protective effect depended on adherence, reaching 92% for participants with detectable tenofovir in their blood.

There were no significant differences in protection by age, race/ethnicity, circumcision status, education level, or alcohol use. However, participants at greatest riskthe nearly 1,500 who reported receptive anal sexsaw a larger risk reduction.

Results were less impressive for the 366 participants who self-identified as male-to-female transgender or reported using female sex hormones (almost none of whom had undergone genital surgery). In this subgroup there were 11 new HIV infections in both the Truvada and placebo arms, indicating no significant risk reduction.

Truvada was generally well tolerated with no serious adverse events. Among participants who became infected, there was no evidence of resistance to tenofovir or emtricitabine. (Side effects and resistance are discussed in more detail in “Problems with PrEP,” below.)

The iPrEx results were greeted with widespread acclaim, with some advocates comparing the study’s importance to that of combination antiretroviral treatment in 1996. President Barack Obama lauded the findings, and Science magazine named it one of the top ten achievements of 2010.

But skeptics countered that that Truvada PrEP’s effectiveness was not very impressive; the 42% overall risk reduction was the number that matteredand would most likely predict real-world outcomeswhile the higher figures came from post hoc data dredging.

Joseph Sonnabend, a pioneering AIDS doctor in the early years of the epidemic, declared on his Aidsperspective blog that the iPrEx trial was a “failure.” He calculated that the absolute risk reduction was about 2% (falling from 5 to 3 cases per 100 persons)far less impressive-sounding than the 42% relative risk reductionand that 45 people would need to use tenofovir/emtricitabine PrEP to prevent a single new infection.

Heterosexual Men and Women

Two large trials conducted in AfricaPartners PrEP and TDF2showed that tenofovir-based PrEP also reduces the risk of HIV acquisition among heterosexual men and women, with the protective effect again rising for people who took the drugs as directed.

Results from both studies were released in July 2011, after a Data Safety and Monitoring Board recommended that the placebo arm of Partners PrEP should be halted due to the clear efficacy of the PrEP regimen.

PrEP researchers at AIDS 2011 (photo: Liz Highleyman)

Jared Baeten from the University of Washington reported the initial findings at the Rome IAS meeting, speaking behind a hastily hand-written name tag. Further results were presented at CROI 2012 and the study was published in the July 11, 2012, advance edition of the New England Journal of Medicine.

Partners PrEP, funded by the Bill and Melinda Gates Foundation, enrolled 4,758 mostly heterosexual serodiscordant couples at nine sites in Kenya and Uganda. The mean age of participants was 33 years. The couples, mostly married, had been together for seven years on average; about one-quarter reported unprotected sex and one-third said they had sex outside the primary relationship. In 62% of the couples the man was HIV positive and the woman negative.

HIV-negative partners had high enough CD4 T-cells counts (median of about 500 cells/mm3) that they were not eligible for antiretroviral treatment according to national guidelines at study entry, but about 20% started ART during follow-up. They were randomly allocated into three arms, receiving tenofovir/emtricitabine, tenofovir alone, or placebo once-daily.

Final results after up to three years of follow-up revealed 13 new HIV infections in the tenofovir/emtricitabine group, 17 in the tenofovir monotherapy group, and 52 in the placebo group; corresponding incidence rates were 0.50, 0.65, and 1.99 per 100 person-years. Risk of infection decreased by 75% with combination PrEP and 67% with tenofovir alone compared with placebo; the difference in protection between tenofovir/emtricitabine and tenofovir monotherapy was not statistically significant.

Combination PrEP appeared somewhat less effective for women than for men (66% vs. 84%, respectively), while the reverse was true for tenofovir monotherapy (71% vs. 63%). But the gender differences did not reach statistical significance, and both regimens were significantly better than placebo for both sexes.

Here, too, PrEP was generally well tolerated, with similar rates of serious adverse events in the PrEP and placebo arms. Gastrointestinal symptoms were more common in the two arms that took tenofovir, but were generally mild-to-moderate and tended to resolve after the first month.

“This study demonstrates that antiretrovirals are a highly potent and fundamental cornerstone for HIV prevention and should become an integral part of global efforts for HIV prevention,” said Partners PrEP principal investigator Connie Celum, also from the University of Washington.

The TDF2 trial, sponsored by the CDC, looked at rates of new infection among 1,219 heterosexual men (55%) and women (45%) in Botswana. Participants were randomly assigned to receive either tenofovir/emtricitabine or placebo once-daily.

Michael Thigpen from the CDC presented findings at the Rome IAS meeting and this study was also published in the July 11, 2012, advance New England Journal of Medicine.

Nine new HIV infections occurred in the PrEP arm and 24 in the placebo arm, for an overall risk reduction of 62% in a modified intent-to-treat analysis. But looking only at people infected within 30 days after their last medication visitwhile the drugs were presumed to be still activethe protective effect reached 78%.

PrEP conferred only 49% protection for women overall, but this rose to 76% within 30 days of the last medication visit.

Again, gastrointestinal side effects were more common among tenofovir recipients, but the frequency of serious adverse events was similar in both arms.

Women at High Risk

While iPrEx, Partners PrEP, and TDF2 demonstrated that tenofovir-based PrEP had a protective effect, two studies looking at women in Africa produced less promising findings.

The FEM-PrEP trial, sponsored by Family Health International, was halted ahead of schedule in April 2011 after an interim analysis found that it was unlikely to show a reduction in risk of infection. Results were also published in the July 11, 2012, advance New England Journal of Medicine.

This study enrolled 2,120 HIV negative women in Kenya, South Africa, and Tanzania, who were randomly assigned to receive either tenofovir/emtricitabine or placebo once-daily.

Participants were generally young, with more than half being under 25 years. They were considered to be at high risk for infection, engaging in an average of about four acts of vaginal sex per week, and 13% reported transactional sex.

By the time of the interim analysis, 28 new HIV infections were reported in each group, showing no difference in risk reduction between PrEP and placebo recipients.

Dr. Lut Van Damme (photo: Liz Highleyman)

Follow-up data presented at CROI 2012 by Lut Van Damme from FHI 360 revealed 33 infections in the PrEP group and 35 in the placebo group, for incidence rates of 4.7 vs. 5.0 per year, respectively—a non-significant risk reduction of just 6%.

The VOICE trial (MTN 003), sponsored by the Microbicide Trials Network, compared three HIV prevention interventions: oral tenofovir/emtricitabine, oral tenofovir alone, and a vaginal gel containing tenofovir.

The study enrolled approximately 5,029 women in Uganda, South Africa, and Zimbabwe who were randomly assigned to use one of the tenofovir products or an oral or gel placebo once-daily.

The tenofovir monotherapy and gel arms were discontinued ahead of schedule in September 2011, again after interim data indicated that it was unlikely to show a significant protective effect; the oral tenofovir/emtricitabine vs. oral placebo comparison is ongoing.

The interim VOICE data failed to confirm findings from another recent microbicide study, CAPRISA 004, published in the July 19, 2010, issue of Science and announced with much fanfare at the 18th International AIDS Conference in Vienna.

This Phase IIb trial of 889 high-risk women in South Africa showed that a 1% tenofovir gel microbicide inserted into the vagina before and after sex reduced the risk of HIV acquisition by 39% compared with an inert placebo gel, with the protective effect rising to 54% among women who achieved the best adherence.

Problems with PrEP

While tenofovir-based PrEP appears highly effective—at least when used as intended by well-selected, high-risk populations in a clinical trial setting—advocates and public health officials have raised concerns about how it will fare in the real world. Key concerns include suboptimal adherence, side effects, drug resistance, increased risk behavior, and cost and access issues.

  • Poor adherence or incorrect use
  • Short-term side effects
  • Long-term toxicities
  • Emergence of drug resistance
  • Behavioral disinhibition (increased risk-taking)
  • Inappropriate distribution
  • Inequitable access
  • Unsustainable cost

Adherence and Real-World Effectiveness

With any medical intervention, outcomes in clinical trialswhich usually enroll highly motivated participants and provide frequent monitoring and support around adherence and side effects managementare often better than those seen under normal, real-world conditions.

Adherence, in particular, was a major factor in the recent PrEP trials. In iPrEx, as noted, the overall protective effect was 42%, compared with 73% among people who reported good adherence and 92% among people with measurable blood tenofovir levels.

While iPrEx participants reported around 90% adherence, drug level measurements told a different story. A subgroup analysis found that half had no measurable tenofovir in their blood, indicating that they did not seem to be taking PrEP as directed; only about 18% had levels consistent with daily use. Looking just at people who became infected while taking tenofovir/emtricitabine, only 9% had detectable drugs in their blood or cells, compared with 51% of those who remained uninfected.

“No one in iPrEx acquired HIV infection with a drug level that would have been expected with daily dosing,” according to investigator Grant.

In Partners PrEP, participants achieved better than 90% adherence according to self-reports and monthly pill counts. But as Deborah Donnell from Fred Hutchinson Cancer Research Center reported at CROI 2012, a subgroup comparison showed that only one-third of infected individuals had measurable tenofovir in their blood, compared with about 80% of uninfected individuals. Risk of infection decreased by 90% with tenofovir/emtricitabine and by 86% with tenofovir alone for people with detectable blood levels.

In FEM-PrEP, adherence reached 95% according to self-reports and 88% based on pill counts. But a case-control analysis revealed that only 15% of infected women and 24% of uninfected participants had consistently detectable tenofovir blood levels, which could explain why the study was unable to show a protective effect.

While there are individual variations in how the body metabolizes drugs, most experts attribute the observed drug level differences in these studies to variable adherence. Many factors are known to influence adherence to medical treatment—including demographic, socioeconomic, and situational characteristics—but which ones came into play in the PrEP trials is not fully understood.

Some have suggested, for example, that study participants in low-income countries may have passed along their pills to relatives or friends with HIV who did not have access to treatment. With regard to the good overall adherence in Partners PrEP, Baeten proposed that within stable relationships HIV-positive partners may encourage negative partners to use PrEP consistently.

In short, it is no surprise that tenofovir-based PrEP did not offer adequate protection against HIV infection if people did not take it regularly.

Some PrEP critics contend that people who are healthy are less likely to take drugs regularly because they do not feel sick (although we know that millions of women take daily oral contraceptives consistently enough to avoid pregnancy).

PrEP proponents predict that people may be more likely to maintain good adherence now that Truvada PrEP is approved, as they will know they are getting the active drug and have solid evidence that it works. Only PrEP demonstration projects will show which conjectures are correct.

Side Effects

Tenofovir and emtricitabine are among the mostly widely used medications for HIV treatment and are generally considered safe and well tolerated; according to Gilead, tenofovir has seen more than 1.8 million patient-years of use.

While there are no notable side effects linked to emtricitabine, studies have shown that tenofovir can cause kidney problems and bone loss in susceptible individuals, and its effects beyond ten years are not yet known.

While these risks are considered acceptable for an effective drug that suppresses viral replication and helps maintain the health of HIV-positive people, the risk-benefit calculation is different for healthy, HIV-negative individuals.

Looking at short-term side effects, the large PrEP trials saw higher frequencies of gastrointestinal symptoms such as nausea, vomiting, and diarrhea in tenofovir-using arms compared with placebo arms, but these were mostly mild-to-moderate and tended to diminish over time.

Fatigue, dizziness, unintentional weight loss, and neutropenia (a blood disorder) were associated with tenofovir/emtricitabine in some trials but not others.

In all trials, however, rates of serious adverse events were similar in tenofovir (with or without emtricitabine) and placebo arms. In particular, these studies have not revealed evidence of major kidney or bone problems, though there have been some signals that warrant caution.

In iPrEx, only a small proportion of participants experienced increases in serum creatininea potential marker of kidney impairmentand the difference between tenofovir and placebo recipients was not statistically significant (2% vs. 1%, respectively).

In Partners PrEP, about 1% of participants in all three arms experienced mild serum creatinine elevations and less than 1% had grade 2/3 elevations. Likewise, less than 1% of women in FEM-PrEP had grade 2 or higher creatinine abnormalities, with no significant differences between the two arms.

Because clinical kidney problems related to tenofovir are uncommon, PrEP trials to date may have been too small or follow-up too short to see such effects; outcomes in tenofovir treatment trials can provide additional relevant data.

In one recent study of 10,841 U.S. veterans taking tenofovir as part of ART, Rebecca Scherzer from San Francisco Veterans Affairs Medical Center and colleagues found that each additional year of tenofovir use was associated with a 34% increase in the likelihood of protein in the urine, an 11% increase in the risk of rapid kidney decline, and a 33% increase in chronic kidney disease.

But while the relative risk increases appear large, the absolute risks remains small; annual incidence of chronic kidney disease, for example, rose from about 1% for non-users to about 2% for tenofovir users.

Turning to bone problems, less than 2% of tenofovir/emtricitabine recipients in iPrEx, Partners PrEP, TDF2, and FEM-PrEP sustained fracturesnot significantly more than placebo recipients.

But in an iPrEx substudy by Kathleen Mulligan from the University of California at San Francisco and colleagues, presented at CROI 2011, participants in the tenofovir/emtricitabine arm experienced a small but statistically significant decrease in bone mineral density according to DEXA scans of the hip and spine at 24 weeks, while those in the placebo arm remained stable.

Similarly, a TDF2 substudy found that tenofovir/emtricitabine recipients experienced a greater decline in bone mineral density of the hip, spine, and forearm compared with placebo recipients.

It is not known whether the overall 1% decrease in bone density seen in iPrEx is clinically significant; more worrisome is the fact that twice as many tenofovir/emtricitabine recipients as placebo recipients experienced spinal bone loss of 5% or greater (14% vs. 6%, respectively).

It is also not yet known whether bone problems will progress with longer PrEP use, though some prior studies suggest that tenofovir-related bone loss tends to occur during the first year or so on treatment and then stabilizes.

As described below, newly revised Truvada prescribing information advises that kidney function should be checked before starting PrEP and regularly monitored while taking the regimen. Routine bone density monitoring is not included in the new prescribing information.

While the likelihood of serious toxicities related to tenofovir appears low, even a small increase in risk could have considerable impact if a large number of people start using PrEP, and side effects can contribute to poor adherence.

Trials to date have included relatively few men of African descent, who have a higher risk of kidney disease than white men, or older individuals, who are more susceptible to both kidney and bone problems. Longer follow-up from studies such as the ongoing iPrEx Open-Label Extension is needed to assess outcomes of prolonged Truvada PrEP.

Drug Resistance

Drug resistance has often been cited as a potential problem with PrEP, reflecting a two-fold concern. First, for people who are unaware that they are already infected with HIV, taking only two NRTIs without a potent third drug typically does not maintain viral suppression for long. When HIV is allowed to replicate in the presence of a drug, resistance can rapidly emerge.

Second, some fear that drug resistance could become more widespread on a community level, so that more people are infected with virus that is already resistant, thereby limiting initial or future treatment options.

Studies to date have found that drug resistance does not appear to be a major concern among people who become infected while using PrEP. In iPrEx, Partners PrEP, and TDF2, no mutations conferring resistance to either tenofovir or emtricitabine were detected among participants who were newly infected during the studies.

But people who are already infected with HIV when they start PrEP do not fare as well.

In iPrEx, three people who were mistakenly identified as uninfected at the start of the trial had emtricitabine-resistant HIV, though none became resistant to tenofovir. Of the eight Partners PrEP participants with undetected HIV who accidentally received active drugs, one developed tenofovir resistance (K65R mutation) and one developed emtricitabine resistance (M184V mutation). A TDF2 participant with unrecognized acute infection developed three resistance mutations (K65R, M184V, and A62V).

In the clinical trials this usually happened when participants with acute infection were tested for HIV but did not yet have enough antibodies to show up on a standard screening test. In the real world, resistance could occur if people already infected with HIV use PrEP informally without medical oversight.

HIV RNA tests, which directly measure viral genetic material, and other more sensitive assays can reduce this risk. People with symptoms of acute viral syndrome (e.g., fever, headache, nausea, diarrhea, body aches) should delay starting PrEP, according to the revised prescribing information.

There has been little discussion about whether two-drug PrEP can protect against infection with highly resistant HIV. This is unlikely to be a major concern on a public health level, as there are relatively few people with multidrug-resistant virus due to previous suboptimal treatment, and most are now on antiretroviral therapy and have low or undetectable viral load. On an individual level, further research is needed to determine whether PrEP is effective against resistant virus.

Behavioral Disinhibition

“Behavioral disinhibition” or “risk compensation” is the tendency to take fewer safety precautionssuch as using condomswhen people believe a pill will provide adequate protection.

“I believe [Truvada PrEP] will result in less condom use and more infections,” said Michael Weinstein of the AIDS Healthcare Foundation. “They wouldn’t be taking heavy-duty chemotherapy if they intended to practice safe sex.”

The National Association of People with AIDS (NAPWA) came to the opposite conclusion, however, predicting that the number of gay men using PrEP as their only and first-ever HIV protection measure will be greater than the number discontinuing condom use because PrEP is available.

Increased sexual risk behavior was not a problem in PrEP clinical trials, in which participants received a comprehensive prevention package including risk-reduction counseling and condoms. In fact, they generally said they engaged in less risky behavior.

Men in both the active drug and placebo arms of iPrEx reported more condom use, less unprotected receptive anal intercourse, and fewer sex partners, falling from 18 on average at study entry to six. In Partners PrEP, the proportion of participants reporting sex without a condom fell from 27% at study entry to 13% at 12 months and 9% at 24 months. In TDF2, self-reported frequency of unprotected sex remained stable during the study, while the number of sex partners decreased. And in FEM-PrEP there were “modest but significant” reductions in number of sex partners, acts of vaginal intercourse, and sex without a condom.

While some PrEP critics think the risk of side effects and drug resistance is a high price to pay to avoid using condoms, three decades into the epidemic it is clear that exhortations to practice safer sex are not enough to halt the spread of HIV.

PrEP advocates have positioned it as an alternative for people who cannot or will not use condoms. Some men find it difficult to achieve or maintain an erection while wearing a condom, or feel that condoms reduce pleasure or intimacy. Some people neglect condoms when they use alcohol or drugs, or simply in the heat of the moment. And some women and men lack the social and economic power to demand that their partners use condoms or remain monogamous.

“It is easy, but somewhat naive, to say that people should just try harder to use condoms,” said Van Gorder. “We must give people at risk for HIV the ability to choose for themselves which proven prevention methods are most likely to meet their needs in the effort to remain HIV negative.”

Van Gorder emphasized that interventions similar to PrEP are common in the public health realm. Doctors routinely prescribe statins to reduce the risk of heart attacks, for example, rather than simply badgering patients to stop smoking and get more exercise.

Cost and Access

PrEP also raises issues of cost and availability at a time when the healthcare landscape in the U.S. is undergoing major shifts. How can using HIV drugs for prevention be justified when so many people who need treatment worldwide can’t get them? Who will have access to PrEP and who is going to pay for it?

Medication shortages are unlikely to be a major roadblock to rolling out PrEP, however, as Gilead (and other pharmaceutical companies down the road) will produce enough drugs to meet the demand of paying customers.

Drs. Salim and Quarraisha Abdool-Karim (photo: Liz Highleyman)

“Although it is a legitimate concern that eligible HIV positive patients should be prioritized for ART for their own health and to save their lives, it is spurious to trade off treatment and prevention as if these drugs are being taken away from sick and dying patients to be given to healthy people,” CAPRISA investigators Salim and Quarraisha Abdool-Karim wrote in a June 2, 2012, editorial in The Lancet.

Funding is a more pressing concern. Some treatment advocates fear losing resources to prevention, while those already in the prevention field worry that biomedical interventions such as PrEP could supplant traditional behavioral approaches. While clinicians have been able prescribe Truvada for PrEP “off label,” FDA approval has implications for insurance coverage and public health programs.

Once-daily Truvada currently costs about $13,000 per year. Private insurers and public programs such as Medicaid consider it cost-effective for HIV treatment, but the calculation may be different for prevention.

PrEP proponents assert that preventing a person from becoming infected with HIV is far less expensive than the cost of lifetime combination antiretroviral treatment and management of HIV-associated medical complications. Furthermore, the price of Truvada is within the range of other prevention interventions such as statins or blood pressure medication. PrEP will be more cost-effective if it is targeted to individuals and groups at greatest risk of infection.

By law, no money from AIDS Drug Assistance Programs (ADAPs) or the Ryan White Care Act may be spent on healthcare for HIV-negative people, according to David Evans of Project Inform. Advocates are calling for new money for PrEP rather than tapping into existing treatment or prevention funds, but budgets are tight at city, state, and federal levels.

Gilead indicated prior to approval that it would provide Truvada for PrEP free to people without health insurance or other coverage, but did not offer further details in its announcement of the FDA decision. The company did say it will provide vouchers for free HIV testing and condoms, an opt-in service for regular reminders about HIV testing, and subsidized resistance testing for people newly infected while taking Truvada for PrEP.

Unanswered Questions

Many questions remain unanswered about PrEP, and further research is needed before it can be declared a mainstay of biomedical prevention.

Other Populations

A key issue is whether PrEP will work for populations other than those studied to date. So far tenofovir-based PrEP has only been shown to prevent sexual transmission of HIV. It is not yet clear whether it will work for direct entry of the virus into the bloodstream, as can occur when sharing needles to inject drugs. The CDC’s Bangkok Tenofovir Study (CDC4370), looking at daily oral tenofovir PrEP for injection drug users, is currently underway in Thailand.

People in serodiscordant heterosexual couples who want to have unprotected sex in order to conceive a child represent another group that potentially could benefit from PrEP. Pregnant and breastfeeding women have been excluded from PrEP trials to date. While tenofovir appears safe for pregnant women with HIV who use it for treatment, as well as for babies exposed to the drug in the womb or via breastfeeding, further study is needed.

Effectiveness for Women

There remains some debate about whether tenofovir-based PrEP works as well for women as it does for men. Concern that women might not benefit equally arose after FEM-PrEP and VOICE produced disappointing findings after the good results from iPrEx.

Some research suggests that gender differences in PrEP efficacy may be related to variations in drug concentrations in vaginal and rectal tissue.

A small study by Kristine Patterson from the University of North Carolina at Chapel Hill and colleagues, published in the December 7, 2011, issue of Science Translational Medicine, found that after a single oral dose of Truvada, the active metabolite of tenofovir reached 100-fold higher concentrations in rectal compared with vaginal/cervical tissue. Conversely, concentrations of emtricitabinethe weaker of the two drugswere 10- to 15-fold higher in vaginal/cervical vs. rectal tissue.

Partners PrEP and TDF2 showed that tenofovir/emtricitabine can prevent infection among women with good adherence. Lower tenofovir concentrations in the vagina may mean that suboptimal adherence is more detrimental for women than for men, suggesting that women might do better with higher oral doses or the gel formulation tested in CAPRISA 004, which produced vaginal drug levels 100 times higher than oral dosing.

Some experts, however, think apparent differences in effectiveness between women and men in PrEP trials to date are more attributable to socioeconomic and other non-biological factors. Some women may have had more difficulty taking study drugs as directed and may have been more hesitant to report missed doses, leading to greater discrepancy between reported and actual adherence.

Intermittent PrEP

Many people would no doubt prefer to use PrEP intermittently rather than every day, and this would reduce cumulative toxicity and lower the cost. Tenofovir’s long half-life suggests this may be feasible. In Patterson’s study, tenofovir and emtricitabine could be detected in blood plasma 14 days after a single oral dose of Truvada. Tenofovir was still present in rectal tissue at day 14.

At CROI 2012 Peter Anderson from the University of Colorado at Denver presented findings from a case-control study of intracellular tenofovir concentrations in a subgroup of iPrEx participants and people in the earlier STRAND study, which established effective levels of tenofovir in plasma and hair. They estimated that taking tenofovir twice weekly would reduce the risk of HIV infection by 76% and four times weekly would lower it by 97%—almost matching the 99% protection expected with daily dosing.

An ongoing Phase III study in France and Canada known as ANRS IPERGAY is testing intermittent tenofovir/emtricitabine PrEP taken at the time of sex. The pilot phase includes 300 men who have sex with men, with plans to expand to 1,900 if early results are promising.

The Phase II ADAPT trial (HPTN 067), now enrolling in South Africa and Thailand, will evaluate intermittent tenofovir/emtricitabine PrEP for high-risk gay men and heterosexual women. Participants will be randomly assigned to receive daily PrEP, event-driven PrEP taken before and after sex, or time-driven PrEP taken every two weeks plus after sex.

Other Drugs

Finally, other antiretroviral regimens may offer pre-exposure protection equaling or exceeding that of tenofovir/emtricitabine. Will three drugs work better than two? Or might one be enough under certain circumstances?

Animal studies and early-stage clinical trials suggest that various agents may work well for PrEP, reaching adequate levels in vaginal or rectal tissue and lasting long enough to allow acceptable dosing schedules.

Integrase inhibitors such as raltegravir (Isentress) may be particularly attractive given their favorable side effect profiles. One study using a humanized mouse model found that both oral raltegravir and the CCR5 inhibitor maraviroc (Selzentry) provided full protection against vaginal infection.

Maraviroc PrEP will be evaluated in the Phase II NEXT-PREP trial (HPTN 069). This study, also now enrolling, will compare the safety and tolerability of four PrEP regimensmaraviroc alone, maraviroc plus emtricitabine, maraviroc plus tenofovir, and tenofovir plus emtricitabinefor high-risk men who have sex with men in the U.S.

Long-acting injectable PrEP could provide an attractive option that minimizes the role of adherence. As described at CROI 2012, Akil Jackson and colleagues found that an injectable form of the NNRTI rilpivirine (TMC278) achieved high concentrations in vaginal and rectal tissue, with vaginal levels sustained for 28 days.

What’s Next for PrEP?

The FDA’s recent approval of Truvada for PrEP was based on medical evidence regarding safety and efficacy. The agency is not mandated to consider issues such as cost, access, whether people will take their drugs as directed, or social consequences such as increased sexual risk behavior. But many stakeholders are thinking about these issues.

The new Truvada for PrEP indication comes with a number of precautions and procedures to maximize safety and effectiveness. Prescribing information has been updated to include PrEP considerations, and the Risk Evaluation and Mitigation Strategy features a medication guide for prospective PrEP users and an education program for providers.

The updated product information states, “Truvada is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk.” This includes individuals who have sex partners known to be HIV positive, as well as those who “engage in sexual activity within a high-prevalence area or social network.”

To address the risk of drug resistance among people who are already infected, prospective PrEP recipients must have a negative HIV test before starting Truvada and should be retested every three months.

The product label now includes a black box warning stating, “Truvada used for a PrEP indication must only be prescribed to individuals confirmed to be HIV negative immediately prior to initial use and periodically during use. . . . Do not initiate Truvada for a PrEP indication if signs or symptoms of acute HIV infection are present unless negative infection status is confirmed.”

People who wish to use PrEP should also be tested for other STIs and hepatitis B virus (HBV); tenofovir and emtricitabine are active against HBV as well as HIV, which adds complexity to decisions about starting and stopping the drugs.

Because of the need for initial evaluation and ongoing monitoring, Truvada for HIV prevention should not be used without medical supervision. Until further research shows otherwise, Truvada for PrEP must be taken every daynot just before or after having sex.

As a condition of approval, Gilead is required to collect virus samples for resistance testing from people who become infected, and must keep records of outcomes among women who become pregnant while taking Truvada for PrEP.

Since the iPrEx data were first published in late 2010, advocacy groups have stressed the need for demonstration projects to help answer some of the outstanding questions about PrEP under real-world conditions.

The National Institute of Allergy and Infectious Diseases, working with local health departments, will roll out the first two demonstration projects in San Francisco and Miami in late August. The programs will enroll confirmed HIV-negative men who have sex with men and transgender women who have substantial, ongoing risk for HIV infection. Participants will receive a comprehensive prevention package that includes risk reduction and adherence counseling, condoms, and regular HIV and STI testing.

Stephanie Cohen, medical director at San Francisco City Clinic, said that the goals of the demonstration project include determining the level of community interest in PrEP, evaluating how well people adhere to a daily prevention regimen in a real-world setting, collecting additional safety data, and assessing whether and how sexual practices change when people know they are taking a pill that can lower their risk of infection.

The California HIV/AIDS Research Program of the University of California is also planning PrEP demonstration projects in several California cities, including Los Angeles, Oakland, and San Diego, focusing on young gay and bisexual men of color, the group with the highest HIV incidence rate.

Prevention Justice

While antiretroviral treatment as prevention taken by HIV-positive people has the potential to dramatically curtail the epidemic, PrEP has some unique advantages. Studies have shown that a majority of HIV sexual transmission involves people who are unaware they are infected, so they are not on treatment and may have high viral load.

Furthermore, PrEP offers HIV-negative people a way to protect themselves, without requiring a partner’s acquiescence or even knowledge.

PrEP holds significant promise, but it will be important to ensure that it is made available to the people who need it most, regardless of ability to pay. Some fear Truvada for PrEP could become a sort of “boutique” drug available only to gay men with money or good health insurance, even though the people at highest risk for infection are disproportionately poor and have less access to care.

“Implementation of PrEP must not contribute to HIV-related health care disparities,” said HIV Medicine Association chair Judith Aberg. “This is a particular concern because the low-income and minority populations most heavily affected by HIV infection are less likely to be engaged in health care and are more likely to be uninsured or rely on Medicaid coverage.”

“We’re really ushering in new era of HIV prevention,” added James Loduca of the San Francisco AIDS Foundation. “If we’re successful in the rollout of PrEP, the mandate for all of us is to develop innovative programs that can successfully deliver Truvada for PrEP and the wrap-around medical services it requires to hard-to-reach communities that traditionally are not in care.”

In conclusion, PrEP may not deserve all the hype it’s gotten—either positive or negative—but it represents an important new addition to a multifaceted prevention approach.

“Daily oral PrEP is not a silver bullet or a stand-alone prevention solution,” said AVAC executive director Mitchell Warren. “However, there will be men and women around the world for whom daily oral PrEP using [tenofovir/emtricitabine] can be a life-saving prevention tool. Choice matters. For the millions of men and women who remain at risk for HIV worldwide, each new HIV prevention option offers additional hope that we will achieve the end of the epidemic.”

PrEP Resources

  • Truvada Medication Guide: revised version including considerations for PrEP.
  • PrEP Watch: breaking news, PrEP status updates, testimony from the FDA advisory committee hearing, and statements from advocacy organizations.
  • My PrEP Experience: real stories from people who have chosen to use PrEP to protect themselves against HIV.
  • FDA Briefing Materials: materials from the May 10, 2012, Antiviral Drugs Advisory Committee meeting, including an overview of clinical trials of tenofovir-based PrEP.

Liz Highleyman (liz@hivandhepatitis.com) is a freelance medical writer and editor-in-chief of HIVandHepatitis.com.

Selected Sources

Abdool Karim, Q. and others. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 329(5996):11681174. September 3, 2010.

Anderson, A. and others. Intracellular Tenofovir-DP concentrations associated with PrEP efficacy in MSM from iPrEx. 19th Conference on Retroviruses and Opportunistic Infections. Seattle. March 58, 2012. Abstract 31LB.

Baeten, J. and others (Partners PrEP Study Team). Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. New England Journal of Medicine. July 11, 2012 (epub ahead of print).

Cohen, M. and Baden, L. Preexposure prophylaxis for HIVWhere do we go from here? New England Journal of Medicine. July 11, 2012 (epub ahead of print).

Donnell, D. and others. Tenofovir disoproxil fumarate drug levels indicate PrEP use is strongly correlated with HIV-1 protective effects: Kenya and Uganda. 19th Conference on Retroviruses and Opportunistic Infections. Seattle. March 58, 2012. Abstract 30.

Grant, R. and others. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. New England Journal of Medicine 363(27):2587–99. December 30, 2010 (published online November 23, 2010).

Grant, R. and others. Pre-exposure chemoprophylaxis for prevention of HIV among trans-women and MSM: iPrEx Study. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27–March 2, 2011. Abstract 92.

Jackson, A. and others. Rilpavirine-LA Formulation: pharmacokinetics in plasma, genital tract in HIV- females and rectum in males. 19th Conference on Retroviruses and Opportunistic Infections. Seattle. March 58, 2012. Abstract 35.

Mulligan, K. and others. Effects of FTC/TDF on bone mineral density in seronegative men from 4 continents: DEXA results of the global iPrEx study. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27–March 2, 2011. Abstract 94LB.

Patterson, K. and others. Penetration of tenofovir and emtricitabine in mucosal tissues: implications for prevention of HIV-1 transmission. Science Translational Medicine 3(12):112re4. December 7, 2011.

Scherzer, R. and others. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS 26(7):867–75. April 24, 2012.

Smith, D. and others. Interim guidance: preexposure prophylaxis for the prevention of HIV infection in men who have sex with men. Morbidity and Mortality Weekly Report 60(03):6568. January 28, 2011. 

Thigpen, M. and others (TDF2 Study Group). Antiretroviral preexposure prophylaxis for heterosexual hiv transmission in Botswana. New England Journal of Medicine. July 11, 2012 (epub ahead of print).

Van Damme, L. and others (FEM-PrEP Study Group). Preexposure prophylaxis for HIV infection among African women. New England Journal of Medicine. July 11, 2012 (epub ahead of print).


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