Melissa Whitehouse, PharmD Candidate 2/6/2013

TITLE AND BACKGROUND Title

Antiretroviral prophylaxis for HIV prevention in heterosexual men and women

Authors M.D. with extensive research with HIV Journal impact factor ~53 Antiretroviral medications are a promising strategy for preventing the spread of HIV-1. Antiretroviral prophylaxis has been shown to be effective for infants of exposed to HIV-1 during birth or breastfeeding. Partial or full protection against mucosal simian HIV challenge in primates. GENERAL STUDY OVERVIEW Bill and Melinda Gates Foundation. Gilead Sciences donated the study medication but had no role in the data collection, analysis, or manuscript preparation. Samples sent to University of Washington to be evaluated. This PrEP study was a multisite, phase 3, randomized, double-blind, three group, placebocontrolled trial. To determine the efficacy of preexposure prophylaxis of HIV-1 transmission using once daily tenofovir or combination tenofovir and emtricitabine in heterosexual HIV-1 serodiscordant couples in Kenya and Uganda. METHODS 7856 HIV-1 serodiscordant couples screened at 9 different sites throughout Kenya and Uganda. 4758 couples were enrolled and randomized using fixed block randomization after meeting eligibility criteria. A total of 11 were assigned groups but later found to be ineligible and did not receive treatment. 14 were assigned groups and received treatment but were found to have had HIV-1 at time of enrollment. Removed from ITT groups. N= 4708 (modified ITT groups) 1572 in TDF group,1568 in TDF-FTC group,1568 in placebo group 36 months

Authors/ Journal Background Rationale behind this study?

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Trial Design Objectives

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Once daily tenofovir (TDF) 300 mg: 1589 Combination tenofovir and emtricitabine (TDF-FTC) 300/200 mg: 1579 Placebo: 1586 The primary endpoint was seropositivity in partners previously seronegative for HIV-1 in antiretroviral prophylaxis groups versus placebo. A sample size of 4700 was required to achieve the target number of seroconversions to provide 80% power to detect a difference of 60% between the antiretroviral groups and placebo with a 95% confidence interval and one-sided alpha level 0.025 Efficacy analyses were performed interim and on a modified intent-to-treat population. The primary efficacy analysis was performed using a Cox regression, stratified according to site to estimate the relative rates of time to first positive and then a Kaplan-Meier method to estimate the cumulative probability of HIV-1 infection. S+SeqTrial Software was used for the interim monitoring using the Lan-DeMets spending approach to adjust the OBrien-Fleming sequential-monitoring boundaries. The final analysis was completed using SAS software. Additional efficacy end points included percent change from randomization baseline to week 12 for each treatment group with the placebo treatment group, using a significance level of p = 0.05 RESULTS Characteristics reported on ITT group, not modified ITT group Same across ITT group Primary Endpoint: TDF reduced transmission of HIV-1 to seronegative partners by 67% (P<0.001) and TDF-FTC had a reduction of 75% (P<0.001). Number of HIV-1 seroconversions: 82 (17 in TDF group, 13 in the TDF-FTC group, and 50 in the placebo group) AUTHORS CONCLUSIONS Limitations of study not mentioned Suggest further research in patients who are pregnant, have renal failure, adolescent women, and breastfeeding women.

Statistical Analyses

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Oral TDF and TDF-FTC protect against HIV-1 infection in heterosexual men and women. (Not mentioned at end of article) GENERALIZABILITY/CRITIQUE/DISCUSSION All patients were receiving the standard for HIV-1 prevention and treatment. Doses were appropriate. 36 months was an acceptable length of study. The outcomes were measurable and quantifiable. MY CONCLUSIONS Preferred study design Modified ITT Protocol Placebo indistinguishable Similar patient demographics throughout the three study groups Monitored for compliance Most statistical details were only in the supplementary materials. Complex resistance data Final data analyzed using modified ITT group, patient demographics reported using original randomized groups(including patients later found to have been HIV-1 positive) Antiretroviral therapy pre-exposure prophylaxis using either TDF or TDF-FTC will help prevent HIV-1 transmission in heterosexual men and women.

Works Cited Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012;367:399-410. Baeten JM, Donnell D, Ndase P, et al. Supplementary Appendix to: Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012;367:S1-39. Baeten JM, Donnell D, Ndase P, et al. DisclosureForms: Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012;367