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HIV PrEP Can Be Highly Effective, but Only if Used Consistently

Pre-exposure prophylaxis (PrEP) with tenofovir or Truvada can dramatically lower the risk of HIV sexual transmission for heterosexual men and women -- as has previously been shown for gay men -- but good adherence is crucial to its success, according to a trio of studies published in the July 11, 2012, advance online edition of the New England Journal of Medicine.

PrEP refers to HIV negative people taking one or more antiretroviral drugs to prevent the virus from taking hold in the body after exposure. The drugs most extensively studied for this purpose are Gilead Science's tenofovir (Viread) and the tenofovir/emtricitabine combination pill Truvada.

In May of this year the Antiviral Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) recommended approval of Truvada PrEP for men who have sex with men, HIV negative partners in serodiscordant couples, and other individuals at risk for acquiring HIV through sex. A decision had been expected by June 15, but was postponed until September 14to allow more time for development of a Risk Evaluation and Management Strategy.

The recommendation was based on results from a set of large randomized controlled trials. Findings from iPrEx -- which looked at gay/bisexual men and transgender women in 6 countries -- were published in the New England Journal of Medicineon November 23, 2010, with follow-up data presented at this year's Conference on Retroviruses and Opportunistic Infections (CROI). This study found that daily tenofovir/emtricitabinereduced the risk of HIV acquisition by 44% overall, rising to 92% for participants with measurable drug levels in their blood.

The 3 studies published this week looked at PrEP for heterosexual men and women in Africa.

Partners PrEP

In the first study, Jared Baeten and Connie Cellum from the University of Washington and fellow investigators with the Partners PrEP teamenrolled 4758 serodiscordant couples in Kenya and Uganda. In 62% of the couples the man was HIV positive and the woman negative. HIV negative partners had high enough CD4 T-cells counts that they were not eligible for treatment according to national guidelines at study entry, but 21% started combination antiretroviral therapy (ART) during follow-up.

HIV negative partners were randomly assigned to take tenofovir/emtricitabine, tenofovir alone, or placebo, all once-daily. Couples also received regular prevention counseling, HIV and sexually transmitted infection testing, and free condoms, which they were encouraged to use along with their study medication.

Participants were followed monthly for up to 36 months. Preliminary results were released in July 2011 and presented at the International AIDS Society meeting in Rome, again with final data presented at CROI 2012.

Results

• A total of 82 new HIV infections occurred among previously negative partners during the study: 13 in the tenofovir/emtricitabine group, 17 in the tenofovir monotherapy group, and 52 in the placebo group.
• Incidence rates were 0.50, 0.65, and 1.99 per 100 person-years, respectively.
• HIV infection risk decreased by 75% in the combination PrEP group and by 67% in the tenofovir monotherapy group, relative to placebo recipients; the difference in protection between the 2 active drug arms was not statistically significant.
• Both PrEP regimens significantly reduced HIV incidence among both men and women; men saw a somewhat larger reduction in the combination arm (84% vs 66%, respectively), while women fared a bit better in the tenofovir monotherapy arm (71% vs 63%).
• Adherence was very good in this study, estimated at 92% based on self-reports and pill counts.
• Among 29 participants who became infected in the 2 active PrEP arms, 31% had a detectable tenofovir in their blood, compared with 82% of a random subgroup of people who remained HIV negative.
• Participants with detectable tenofovir blood levels saw an estimated risk reduction of 90% with tenofovir/emtricitabine and 86% with tenofovir alone.
• Rates of serious adverse events were similar across all study groups.
• People receiving tenofovir alone or in combination were more likely to experience gastrointestinal side effects and fatigue, mainly during the first month.
• Abnormal serum creatinine and phosphorus levels -- indicators of kidney dysfunction, a known possible side effect of tenofovir -- were also similar in the active PrEP and placebo arms.
• Among 8 people taking active PrEP were later found to actually have been HIV-infected at study entry, 2 developed drug resistance mutations.
• 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.

"Oral [tenofovir] and [tenofovir/emtricitabine] both protect against HIV-1 infection in heterosexual men and women," the Partners PrEP team concluded.

"Additional studies are needed of proximal renal tubular function, bone mineral density, and other aspects of long-term safety of [tenofovir]-based pre-exposure prophylaxis, as well as safety in pregnant, breast-feeding, or adolescent women, among whom HIV-1 rates are high," they continued in their discussion.

"Successful prevention of HIV-1 infection on a population scale will need to incorporate multiple, evidence-based biomedical and behavioral strategies to achieve maximum benefits," they wrote. "Potential implementation of pre-exposure prophylaxis as a public health measure will require clinical monitoring, methods for encouraging adherence, and ensured access to antiretroviral therapy for HIV-1-infected persons."

TDF2

As described in the second report, Michael Thigpen from the Centers for Disease Control and Prevention (CDC) and colleagues with the TDF2 study team evaluated new infection rates among1219 HIV negative heterosexual men (54%) and women (46%) in Botswana. Participants were randomly assigned to receive either tenofovir/emtricitabineor placebo; there was no tenofovir monotherapy arm.

Participants were followed for a median of about 1 year. Again, they received a comprehensive package of prevention services and adherence support. As with Partners PrEP, the TDF2 findings were first announced in July 2011 and presented at the Rome IAS meeting. Because of low retention and logistical problems, the researchers ended the study early and followed already enrolled participants through an orderly closure.

Results

• 9 people in the tenofovir/emtricitabine group and 24 in the placebo group were newly infected, for incidence rates of 1.2 and 3.1 infections per 100 person-years, respectively.
• In a modified intent-to-treat analysis (excluding people with unrecognized HIV infection at study entry), Truvada reduced the risk of HIV acquisition by 62%.
• In an as-treated analysis that looked only at outcomes up to 30 days after the last reported medication dose -- a period in which the drugs presumably would still be active -- the protective effect reached 78%.
• Adherence rates were 84% based on pill counts and 94% base on self-reports.
• In a subgroup analysis, 2 of 4 infected participants (50%) did not have detectable blood levels of tenofovir and emtricitabine, compared with about 20% of people who remained uninfected.
• Participants taking tenofovir/emtricitabine had higher rates than placebo recipients of nausea (19% vs 7%), vomiting (11% vs 7%), and dizziness (15% vs 11%).
• Rates of serious adverse events, however, were similar.
• Tenofovir/emtricitabine recipients experienced a significantly greater decline in bone mineral density than the placebo group, another known side effect of tenofovir.·
• 1 participant who had unrecognized acute HIV infection at study entry developed drug resistance mutations.
• Self-reported frequency of unprotected sex remained stable over the course of the study and the reported number of sexual partners decreased.

"Daily [tenofovir/emtricitabine] prophylaxis prevented HIV infection in sexually active heterosexual adults," the researchers concluded. "The long-term safety of daily [tenofovir/emtricitabine] prophylaxis, including the effect on bone mineral density, remains unknown."

"In our study, risky sexual behavior did not increase among the participants receiving study medication; however, taking a medication with known efficacy might lead to increased sexual disinhibition," they noted in their discussion. "Additional data from open-label and pilot implementation studies are needed to better understand the ways in which adherence to and acceptability of medication and potential increases in risky sexual behavior while taking medication alter the effectiveness of pre-exposure prophylaxis."

"Our findings that participants who did not undergo seroconversion were more likely than those who did to have detectable plasma levels of drug and to have higher drug levels when detected highlight the critical importance of adherence," they wrote, suggesting that this could help explain the large protective effect in iPrEx and Partners PrEP compared with minimal or no risk reduction in 2 studies of African women, VOICE and FEM-PrEP.

FEM-PrEP

In the third report, Lut Van Damme from FHI 360 and colleagues described findings from FEM-PrEP, a randomized trial in which 2120 HIV negative women in Kenya, South Africa, and Tanzania were randomly assigned to receive either tenofovir/emtricitabine or placebo once-daily.

The study was stopped ahead of schedule in April 2011 due to lack of efficacy in an interim analysis. Van Damme presented follow-up data at CROI 2012.

Results

• 33 women in the tenofovir/emtricitabine group and 35 in the placebo group were infected, for incidence rates of 4.7 and 5.0 per 100 person-years, respectively -- not a significant difference.
• Adherence was poor in this study, with fewer than 40% of HIV negative women in the tenofovir/emtricitabine group having blood drug levels consistent with recent pill use, despite 95% self-reported adherence and 85% based on pill counts.
• Nausea, vomiting, and elevated ALT levels (a sign of potential liver toxicity) were significantly more common in the tenofovir/emtricitabine arm.
• In addition, more women in the tenofovir/emtricitabine arm discontinued drugs due to liver or kidney abnormalities compared with the placebo arm (5% vs 3.0%, respectively).
• During follow-up there were modest but significant reductions in the numbers of sexual partners, acts of vaginal intercourse, and sex without a condom.

"Prophylaxis with tenofovir/emtricitabine did not significantly reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo," the researchers concluded. "Despite substantial counseling efforts, drug adherence appeared to be low." 

When the disappointing findings from FEM-PrEP and VOICE were initially reported, following the good results from iPrEX, some suggested the disparity might be attributable to differences in PrEP efficacy in men and women, perhaps related to tenofovir reaching lower levels in vaginal compared with rectal mucosa.

However, the FEM-PrEP researchers wrote, "in Partners PrEP there was a highly significant protective effect of both [tenofovir] and [tenofovir/emtricitabine] in the overall study population and among female participants...[t]hus, if there are biologic differences between drug responses in men and those in women or between HIV exposure with vaginal and rectal sex, it appears that these differences may be overcome with high rates of adherence."

"It is important to understand why so many women came for the monthly visits and underwent frequent blood testing but did not take their pills," they continued. "We hypothesize that the women's perception that they were at low risk for HIV infection may have contributed to the poor adherence...Understanding these issues and identifying characteristics predictive of high adherence will be important in developing strategies for adherence counseling for future studies and programs."

Where Do We Go from Here?

While scientific evidence that antiretroviral drugs -- when used consistently -- can greatly reduce the risk of HIV infection is now all but incontrovertible, several related concerns remain, including how to ensure good adherence, short-and long-term side effects, drug resistance -- especially among people who start PrEP when they are unknowingly already infected -- and issues of cost and access.

Taken together, these 3 studies show that adherence is the key determinant of PrEP effectiveness. In these trials participants received a comprehensive prevention package and support for adherence, and it remains to be seen how well PrEP will work in the "real world." But the studies do suggest that one widely expressed concern -- that using PrEP will lead people to have more unprotected sex -- may not be a major problem.

"Because [tenofovir] and [truvada] are readily available for clinical use, questions emerge as to how to consider these data in practice," Myron Cohen from the University of North Carolina at Chapel Hill and Lindsey Badenfrom Brigham and Women's Hospital in Boston wrote in an editorial accompanying these reports.

"Most anti-infective prophylactic agents are used as a bridge through an exposure window, much as antimicrobials are used at the time of surgery to prevent wound infection," they continued. "If pre-exposure prophylaxis is started, how and when will it be stopped? What messages should the health care worker provide to the patient? And how should preexposure prophylaxis be monitored for adherence and safety?"

They also noted that providing daily medication to healthy HIV negative people "demands an extraordinarily high degree of safety," and that the effects of long-term PrEP, such as the potential for kidney and bone toxicity, are not yet known.

"The prevention of HIV infection is a critical global public health priority," Cohen and Baden concluded. "Pre-exposure prophylaxis is emerging as part of an integrated HIV prevention strategy. The health care provider who recommends preexposure prophylaxis needs a management plan that recognizes the effects of this intervention on the patient's sexual behavior, safety, and well-being as well as the ramifications of the intervention for the health of the public."

7/13/12

References

JM Baeten, D Donnell, P Ndase, et al (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).

MC Thigpen, PM Kebaabetswe, LA Paxton, et al (TDF2 Study Group). Antiretroviral Preexposure Prophylaxis for Heterosexual HIV Transmission in Botswana. New England Journal of Medicine. July 11, 2012 (Epub ahead of print).

L Van Damme, A Corneli, K Ahmed, et al (FEM-PrEP Study Group). Preexposure Prophylaxis for HIV Infection among African Women.New England Journal of Medicine. July 11, 2012 (Epub ahead of print).

MS Cohen and LR Baden. Preexposure Prophylaxis for HIV -- Where Do We Go from Here? (Editorial). New England Journal of Medicine. July 11, 2012 (Epub ahead of print).

Other Sources

AVAC. Publication of PrEP Trial Data Provides Clear Evidence that PrEP Works for Men and Women. Press release. July 11, 2012.

FHI 360. Final Results Of FEM-PrEP HIV-Prevention Study Indicate Great Attention To Adherence Will Be Required In PrEP Programs. Press release. July 11, 2012.