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PEARLS (ACTG A5175): a multinational study of didanosine-EC, emtricitabine and atazanavir vs. co-formulated zidovudine/lamivudine and efavirenz for initial treatment of HIV-1 infection
Presented by Thomas Campbell, United States.
T. Campbell1, L. Smeaton2, V. De Grutolla2, J. Hakim3, N. Kumarasamy4, T. Flanigan5, K. Klingman6, A. Martinez6, S. Berendes7, S. Cardoso8, C. Firnhaber9, M. Hosseinipour10, A. Joglekar11, R. Mngqibisa12, C. Rivière13, J. Sanchez14, B. Santos15, K. Supparatpinyo16, A. Nair17, A. Walawander17, L. Hosey18, L. Moran18, R. Barnett19, E. Swann6, E. Loeschel20, P. Piliero21, G. Pakes22, J. Rooney23, W. Snowden20, G. Thal24, J. Uy24, A. Andrade25, J. Currier26, J. Eron27, S. Eshleman28, S. Fiscus27, R. Gulick29, D. Haas30, S. Hammer31, R. Mitsuyasu26, R. Schooley32, PEARLS study team of the ACTG
1University of Colorado Denver, Denver, United States, 2Harvard School of Public Health, Boston, United States, 3University of Zimbabwe College of Health Sciences, Harare, Zimbabwe, 4YRG Centre for AIDS Research & Education, Chennai, India, 5Brown Medical School, Providence, United States, 6National Institutes of Health, HIV Research Branch, Bethesda, United States, 7University of Malawi College of Medicine, Blantyre, Malawi, 8Instituto de Pesquisa Clinica Evandro Chagas, Rio de Janeiro, Brazil, 9University of Witwatersrand, Johannesburg, South Africa, 10Kamuza Central Hospital, Lilongwe, Malawi, 11National AIDS Research Institute, Pune, India, 12University of KwaZulu Natal Medical School, Durban, South Africa, 13Les Centres GHESKIO, Port-au-Prince, Haiti, 14IMPACTA PERU Clinical Trials Unit, Lima, Peru, 15Hospital Nossa Senhora da, Conceicao/GHC, Porto Alegre, Brazil, 16Chiang Mai University, Chiang Mai, Thailand, 17Frontier Science & Technology Research Foundation, Buffalo, United States, 18Social & Scientific Systems, Inc., Silver Spring, United States, 19National Institutes of Health, Office of Science Policy, Bethesda, United States, 20GlaxoSmithKline, Greenford, United Kingdom, 21Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, United States, 22GlaxoSmithKline, Research Triangle Park, United States, 23Gilead Sciences, Foster City, United States, 24Bristol-Myers Squibb, Princeton, United States, 25Johns Hopkins University, Baltimore, United States, 26University of California, Los Angeles, Los Angeles, United States, 27University of North Carolina, Chapel Hill, United States, 28Johns Hopkins Medical Institution, Baltimore, United States, 29Weill Medical College of Cornell University, New York, United States, 30Vanderbilt University College of Medicine, Nashville, United States, 31Columbia University Medical Center, New York, United States, 32University of California, San Diego, San Diego, United States
Background: An antiretroviral (ARV) regimen of didanosine-EC (ddI), emtricitabine (FTC) and unboosted atazanavir (ATV) potentially has advantages over commonly used regimens. ddI+FTC+ATV is an alternative initial regimen in US Department of Health and Human Services guidelines; efficacy of this combination is unknown.
Methods: Phase IV, randomized, open-label, multinational clinical trial in HIV-1-infected, ARV-naïve participants ³ 18 years with CD4+ lymphocytes (CD4) < 300 mm-3. Participants were randomized to Arms A: co-formulated zidovudine/lamivudine (ZDV/3TC) BID + efavirenz (EFV) QD, B: ddI QD + FTC QD +ATV QD, or C: co-formulated tenofovir/emtricitabine QD + EFV QD. Primary efficacy endpoint (PE) was time from randomization to: 1) two consecutive plasma HIV-1 RNAs (VL) ³1000 c/mL week 16 onward (VF); 2) HIV-1 disease progression (AIDS); or 3) death due to any cause. Enrollment was completed August, 2007. Data/Safety Monitoring Board planned interim review on 6-May-2008 recommended disclosure of Arm B versus A comparison. We report 99.8% confidence intervals (CI), which were used for stopping guidelines.
Results: 1,045 participants (547 men and 498 women) from 8 developing countries and the USA received Arm A and B regimens; 72 weeks median follow-up. Probability of PE in Arm B was 16.2% at 48, and 23.9% at 96 weeks. The relative hazard of PE (HR) for Arm B versus A was 1.67 (CI 1.02, 2.75); this HR did not change over time (P=0.33). For PE components: VF (HR 1.77; CI 1.04, 3.03), AIDS (HR 3.0; CI 0.61, 14.9), and death (HR 0.99; CI 0.23, 4.26). Safety data were generally as expected. Gender, age, CD4 cell count, tuberculosis and AIDS history, geographical location and early adherence were independently associated with failure risk in Arm B. Follow-up in Arms A and C is unchanged and ongoing.
Conclusions: ddI+FTC+ATV had inferior outcome compared to ZDV/3TC+EFV; study participants currently taking this regimen are switching to alternate ARVs.
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