The Influence of the M184V Mutation in HIV-1 Reverse Transcriptase on the Virological Outcome of Highly Active Antiretroviral Therapy Regimens with Or without Didanosine

Abstract

Background: In vitro phenotypic resistance studies suggest that the presence of the M184V mutation leads to a reduction in HIV-1 susceptibility to didanosine (ddI). The relevance of this to clinical outcomes remains unclear. In this study, we compared the virological response of ddI- and non-ddI-containing regimens in the presence or absence of the M184V mutation. Methods: Data from an observational cohort study of all HIV-1 patients who had phenotypic resistance testing following the emergence of virological failure to an existing highly active antiretroviral therapy (HAART) regimen were analysed. A total of 586 patients entered the study and were followed-up over 48 weeks; 281 (48%) were switched to ddI-containing HAART, of whom 105 had the M184V mutation at baseline. Virological efficacy of combination therapy was studied by reference to average area under the curve of viral load (VL) response and the proportion of patients attaining an undetectable VL (<400 copies/ml). Baseline characteristics and univariate analysis of changes in VL were compared using the Wilcoxon rank sum test. Multivariate analyses were performed using the Van Elteren test. Additional variables included the number of baseline nucleoside reverse transcriptase inhibitor mutations and the number of active antiretroviral drugs given to each group as compared by ‘real phenotype’ resistance test results. Results: Amongst patients on ddI-containing HAART, median fold changes in phenotypic susceptibility to ddI were greater in patients with the M184V mutation (fold changes of 2.2 vs 1.2, P<0.001). Nonetheless, the median change in VL and percentage of patients attaining an undetectable VL were similar in those taking ddI, irrespective of whether the M184V mutation was present at baseline. In the group of patients with the M184V mutation at baseline, the virological outcome was significantly better in those treated with ddI-containing HAART than in those on HAART without ddI ( P<0.05). Conclusions: While the M184V did increase the fold resistance of HIV to ddI, these changes appeared to be lower than the clinically relevant threshold for phenotypic resistance for this drug.