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Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects.

Gallant JE, Rodriguez AE, Weinberg WG, Young B, Berger DS, Lim ML, Liao Q, Ross L, Johnson J, Shaefer MS,

Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. jgallant@jhmi.edu

BACKGROUND: Antiretroviral combinations that reduce the number of pills and dosing frequency have the potential to simplify therapy. We compared 2 regimens dosed as 2 pills once daily. METHODS: This was a randomized, open-label, multicenter study of tenofovir disoproxil fumarate versus efavirenz, both administered once daily with the abacavir/lamivudine fixed-dose combination in treatment-naive human immunodeficiency virus type 1 (HIV-1)-infected subjects. After reports of early nonresponse, an unplanned interim analysis was performed. Virologic nonresponse was defined as (1) a <2.0-log(10) copies/mL decrease in HIV-1 RNA level by week 8, (2) an HIV-1 RNA rebound of > or =1.0 log(10) copies/mL above the nadir, or (3) for subjects with 2 consecutive HIV-1 RNA measurements <50 copies/mL, a subsequent increase to >400 copies/mL on 2 consecutive occasions. RESULTS: We randomized 340 subjects. Median baseline HIV-1 RNA level and CD4+ cell count were 4.7 log(10) copies/mL and 251 cells/mm3, respectively; 194 subjects with HIV-1 RNA data from > or =8 weeks were included in the interim analysis. Virologic nonresponse occurred in 50 (49%) of 102 subjects in the tenofovir disoproxil fumarate arm, compared with 5 (5%) of 92 of subjects in the efavirenz arm (P<.001). Within 12 weeks, viral genotypes for nonresponders in the tenofovir disoproxil fumarate arm showed M184V or I/M/V mixtures in 40 (98%) of 41 subjects and K65R and M184V or mixtures in 22 (54%) of 41 subjects. The protocol was immediately amended to modify the tenofovir disoproxil fumarate arm. The efavirenz arm continued unchanged; after 48 weeks, 120 (71%) of 169 subjects achieved HIV-1 RNA levels <50 copies/mL. CONCLUSION: The tenofovir disoproxil fumarate/abacavir/lamivudine regimen resulted in an unexpected and unacceptably high rate of nonresponse and incidence of K65R and M184V/I. This 3-drug regimen should not be used.

Published 3 November 2005 in J Infect Dis, 192(11): 1921-30.
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