CONTEXT: Three-drug antiretroviral regimens are standard of care for initial treatment of human immunodeficiency virus 1 (HIV-1) infection, but a 4-drug regimen could improve antiretroviral activity and be more effective than a 3-drug regimen. OBJECTIVE: To compare the safety/efficacy of 3-drug vs 4-drug regimens for initial treatment of HIV-1 infection. DESIGN: The AIDS Clinical Trials Group (ACTG) A5095 study, a randomized, double-blind, placebo-controlled study with enrollment and follow-up conducted from March 22, 2001, to March 1, 2005, and enrolling treatment-naive, HIV-1-infected patients with HIV-1 RNA levels of 400 copies/mL or greater from US clinical trials units of the ACTG. INTERVENTIONS:Zidovudine/lamivudine plus efavirenz (3-drug regimen) vs zidovudine/lamivudine/abacavir plus efavirenz (4-drug regimen). MAIN OUTCOME MEASURES: Time to virologic failure (defined as time to first of 2 successive HIV-1 RNA levels > or =200 copies/mL at or after week 16), CD4 cell count changes, and grade 3 or 4 adverse events. HIV-1 RNA data were intent-to-treat, regardless of treatment changes. RESULTS:Seven hundred sixty-five patients with a baseline mean HIV-1 RNA level of 4.86 log10 (72,444) copies/mL and CD4 cell count of 240 cells/mm3 were randomized. After a median 3-year follow-up, 99 (26%) of 382 and 94 (25%) of 383 patients receiving the 3-drug and 4-drug regimens, respectively, reached protocol-defined virologic failure; time to virologic failure was not significantly different (hazard ratio, 0.95; 97.5% confidence interval, 0.69-1.33; P = .73). In planned subgroup analyses, increased risk for virologic failure was seen in non-Hispanic black patients (adjusted hazard ratio, 1.66; 95% confidence interval, 1.18-2.34; P = .003). At 3 years, the HIV-1 RNA level was less than 200 copies/mL in 152 (90%) of 169 and 143 (92%) of 156 patients receiving the 3-drug and 4-drug regimens, respectively (P = .59), and less than 50 copies/mL in 144 (85%) of 169 and 137 (88%) of 156 patients (P = .39). CD4 cell count increases and grade 3 or 4 adverse events were not significantly different. CONCLUSIONS: In treatment-naive patients, there were no significant differences between the 3-drug and 4-drug antiretroviral regimens; overall, at least approximately 80% of patients had HIV-1 RNA levels less than 50 copies/mL through 3 years. These results support current guidelines recommending 2 nucleosides plus efavirenz for initial treatment of HIV-1 infection; adding abacavir as a fourth drug provided no additional benefit. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov Identifier: NCT00013520.
RCT Entities:
CONTEXT: Three-drug antiretroviral regimens are standard of care for initial treatment of human immunodeficiency virus 1 (HIV-1) infection, but a 4-drug regimen could improve antiretroviral activity and be more effective than a 3-drug regimen. OBJECTIVE: To compare the safety/efficacy of 3-drug vs 4-drug regimens for initial treatment of HIV-1 infection. DESIGN: The AIDS Clinical Trials Group (ACTG) A5095 study, a randomized, double-blind, placebo-controlled study with enrollment and follow-up conducted from March 22, 2001, to March 1, 2005, and enrolling treatment-naive, HIV-1-infectedpatients with HIV-1 RNA levels of 400 copies/mL or greater from US clinical trials units of the ACTG. INTERVENTIONS:Zidovudine/lamivudine plus efavirenz (3-drug regimen) vs zidovudine/lamivudine/abacavir plus efavirenz (4-drug regimen). MAIN OUTCOME MEASURES: Time to virologic failure (defined as time to first of 2 successive HIV-1 RNA levels > or =200 copies/mL at or after week 16), CD4 cell count changes, and grade 3 or 4 adverse events. HIV-1 RNA data were intent-to-treat, regardless of treatment changes. RESULTS: Seven hundred sixty-five patients with a baseline mean HIV-1 RNA level of 4.86 log10 (72,444) copies/mL and CD4 cell count of 240 cells/mm3 were randomized. After a median 3-year follow-up, 99 (26%) of 382 and 94 (25%) of 383 patients receiving the 3-drug and 4-drug regimens, respectively, reached protocol-defined virologic failure; time to virologic failure was not significantly different (hazard ratio, 0.95; 97.5% confidence interval, 0.69-1.33; P = .73). In planned subgroup analyses, increased risk for virologic failure was seen in non-Hispanic black patients (adjusted hazard ratio, 1.66; 95% confidence interval, 1.18-2.34; P = .003). At 3 years, the HIV-1 RNA level was less than 200 copies/mL in 152 (90%) of 169 and 143 (92%) of 156 patients receiving the 3-drug and 4-drug regimens, respectively (P = .59), and less than 50 copies/mL in 144 (85%) of 169 and 137 (88%) of 156 patients (P = .39). CD4 cell count increases and grade 3 or 4 adverse events were not significantly different. CONCLUSIONS: In treatment-naive patients, there were no significant differences between the 3-drug and 4-drug antiretroviral regimens; overall, at least approximately 80% of patients had HIV-1 RNA levels less than 50 copies/mL through 3 years. These results support current guidelines recommending 2 nucleosides plus efavirenz for initial treatment of HIV-1 infection; adding abacavir as a fourth drug provided no additional benefit. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov Identifier: NCT00013520.
Authors: Mary F Kearney; Ann Wiegand; Wei Shao; John M Coffin; John W Mellors; Michael Lederman; Rajesh T Gandhi; Brandon F Keele; Jonathan Z Li Journal: J Virol Date: 2015-11-18 Impact factor: 5.103
Authors: Chanelle J Howe; Stephen R Cole; Sonia Napravnik; Jay S Kaufman; Adaora A Adimora; Beth Elston; Joseph J Eron; Michael J Mugavero Journal: AIDS Res Hum Retroviruses Date: 2014-01-20 Impact factor: 2.205
Authors: Marlene Smurzynski; Ann C Collier; Susan L Koletar; Ronald J Bosch; Kunling Wu; Barbara Bastow; Constance A Benson Journal: HIV Clin Trials Date: 2008 Jul-Aug
Authors: Chanelle J Howe; Sonia Napravnik; Stephen R Cole; Jay S Kaufman; Adaora A Adimora; Beth Elston; Joseph J Eron; Michael J Mugavero Journal: Am J Epidemiol Date: 2014-05-08 Impact factor: 4.897
Authors: Heather J Ribaudo; Kimberly Y Smith; Gregory K Robbins; Charles Flexner; Richard Haubrich; Yun Chen; Margaret A Fischl; Bruce R Schackman; Sharon A Riddler; Roy M Gulick Journal: Clin Infect Dis Date: 2013-09-17 Impact factor: 9.079