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    HIV Prophylaxis for Heterosexuals: Conflicting Trial Results

    July 11 2012

     Information from Industry

    Medscape News — HIV prophylaxis with tenofovir disoproxil fumarate (TDF) alone or in combination with emtricitabine (FTC), together with counseling and other preventive measures, appears to effectively combat HIV transmission in heterosexuals according to the findings of 3 randomized controlled trials. The findings of 1 of the trials, however, highlighted potential problems with patient compliance.

    The FEM-PReP Study Group, TDF2 Study Group, and Partners PReP Study Team presented their findings in separate articles published online July 11 in the New England Journal of Medicine.

    The FEM-PReP trial compared the efficacy of TDF-FTC and placebo and recruited 2120 HIV-negative women in Kenya, South Africa, and Tanzania. Similarly, the TDF2 trial compared the efficacy of TDF-FTC and placebo but recruited 1219 men and women from the Botswana cities of Francistown and Gaborone.

    The Partners PReP trial compared the efficacy of TDF alone, TDF-FTC, and placebo and recruited 4758 HIV-serodiscordant couples from Kenya and Uganda. All 3 trials had equal randomization into the placebo and treatment groups.

    Efficacy

    In the TDF2 trial, after the exclusion of 3 participants (2 in the placebo group and 1 in the TDF-FTC group) who were infected at the time of enrollment, 9 participants in the TDF-FTC group and 24 participants in the placebo group became infected with HIV during the study period, resulting in a protective efficacy of TDF-FTC compared with placebo of 62.2% (95% confidence interval [CI], 21.5% - 83.4%; P = .03) in an intent-to-treat analysis.

    In the Partners PReP study, 17, 13, and 52 participants in the TDF, TDF-FTC, and placebo groups, respectively, became infected with HIV, which resulted in efficacies of TDF and TDF-FTC compared with placebo of 67% (95% CI, 44% - 81%; P < .001) and 75% (95% CI, 55% - 87%; P < .001), respectively. No significant difference was observed in the efficacies of TDF and TDF-FTC (P = .23).

    Conversely, 33 and 35 participants in the TDF-FTC and placebo groups, respectively, in the FEM-PReP study became infected with HIV during the study period, resulting in a hazard radio for the TDF-FTC group of 0.94 (95% CI, 0.59 - 1.52; P = .81). At 12 months, the cumulative probabilities of infection for the placebo and TDF-FTC groups were 0.46 and 0.49, respectively.

    Although patient adherence exceeded 80% in the Partners PReP (overall adherence in all groups: 92.1%) and TDF2 trials (TDF-FTC group, 84.1%; placebo group, 83.7%; P = .79), less than 40% of HIV-uninfected women in the TDF-FTC group of the MEM-PReP trial had evidence of recent medication usage in either the beginning (27/78; 35%) or end (35/95; 37%) of the infection window, according to plasma tenofovir levels.

    Safety Profile

    In the MEM-PReP trial, there were 36 and 24 serious adverse events in the TDF-FTC and placebo groups, respectively, including 1 death in the TDF-FTC group resulting from diarrhea and severe dehydration and 1 death in the placebo group resulting from unknown causes. Only nausea (P = .04), vomiting (P < .001), and alanine aminotransferase elevation (P = .03) occurred more commonly in the treatment group.

    The incidence of most adverse events was similar among the TDF, TDF-FTC, and placebo groups in the Partners PReP trial, although neutropenia was more common in the TDF-FTC group than in the TDF and placebo groups. TDF and TDF-FTC treatment were associated with modestly higher rates of gastrointestinal adverse effects, particularly during the first month of treatment.

    In the TDF2 trial, dizziness (P = .03), nausea (P < .001), and vomiting (P = .008) were significantly more common in the TDF-FTC group than in the placebo group, whereas the incidence of urethral discharge (P = .03) and leucorrhea (P = .01) were more common in the placebo group. Importantly, significant reductions in bone mineral density were observed in the forearm, hip, and lumbar spine among participants in the TDF-FTC group compared with the placebo group.

    Implications

    In a related commentary, Myron S. Cohen, MD, from the University of North Carolina in Chapel Hill, North Carolina, and Lindsey R. Baden, MD, from Brigham and Women's Hospital in Boston, Massachusetts, indicate that these studies highlight the need for additional research on HIV prophylaxis.

    "The striking differences in these findings highlight the importance of conducting additional studies to allow a proper understanding of the potential efficacy of and adverse events associated with preexposure prophylaxis and to identify other factors that might influence efficacy," Dr. Cohen and Dr. Baden write. "The differing results also emphasize the central role of the data safety and monitoring boards...charged with overseeing study conduct and results in real time, reviewing the progress of a trial, and ensuring the safety of the study participants."

    In addition, Dr. Cohen and Dr. Baden note that HIV prophylaxis must be a component of a comprehensive prevention program. "Preexposure prophylaxis is emerging as part of an integrated HIV prevention strategy," they write. "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."

    Researchers participating in the FEM-PReP trial received or have applied for support from or served as a consultant with the Impact Research and Development Organization, United States Agency for International Development, FHI 360, the Bill and Melinda Gates Foundation, Siemens Diagnostics, the London School of Hygiene and Tropical Medicine, Gilead Sciences, and the Setshaba Research Centre. Researchers participating in the TDF2 trial received or have applied for support from or served as a consultant with the Bill and Melinda Gates Foundation, PhRMA Foundation, the US Centers for Disease Control and Prevention Foundation, Merck, the National Institute of Allergy and Infectious Diseases, Abbott, Roche, the National Institutes of Health, Seattle Children's Research Hospital Institute, the International AIDS Vaccine Initiative, the National Institute of Mental Health, University of Washington, International Association of Physicians in AIDS Care, Gene Security Network, Harvard Center for AIDS Research, the Agency for Healthcare Research and Quality, the National Institute of Child Health and Human Development, the US Centers for Disease Control and Prevention, Gilead Sciences, Prosetta Bioconformatics, Taso Uganda, Bill and Melinda Gates Foundation, CLS Board, Elevation Board, Unitaid PRC, Wave 80, Children’s Investment Fund Foundation, the European and Developing Countries Clinical Trials Partnership, Elizabeth Glaser Pediatric AIDS Foundation, and Up To Date. Researchers participating in the Partners-PReP trial received or have applied for support from or served as a consultant with Roche Diagnostics, US Centers for Disease Control and Prevention, the National Institutes of Health, and Gilead Sciences. Dr. Cohen received or has applied for support from or served as a consultant or board member for University of Maryland HMI, Golden Corral Corporation, National Institutes of Health, GlaxoSmithKline, McGraw-Hill, Up To Date, and the Bill and Melinda Gates Foundation. Dr. Baden has disclosed no relevant financial relationships.

    N Engl J Med. Published online July 11, 2012

    Joe Barber Jr., PhD