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.
BACKGROUND
In vitro phenotypic resistance studies suggest that the presence of the M184V mutation leads to a reduction in HIV-1 susceptibility to didanosine (ddl). The relevance of this to clinical outcomes remains unclear. In this study, we compared the virological response of ddl- and non-ddl-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 ddl-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 ddl-containing HAART, median fold changes in phenotypic susceptibility to ddl 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 ddl, 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 ddl-containing HAART than in those on HAART without ddl (P<0.05).


CONCLUSIONS
While the M184V did increase the fold resistance of HIV to ddl, these changes appeared to be lower than the clinically relevant threshold for phenotypic resistance for this drug.
Sproat
Michael
M
St Stephens Centre, Chelsea and Westminster Healthcare NHS Trust, London, UK.
Pozniak
Anton L
AL
Peeters
Monika
M
Winters
Bart
B
Hoetelmans
Richard
R
Graham
Neil M
NM
Gazzard
Brian G
BG
D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D015331:Cohort Studies; D016049:Didanosine / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D009154:Mutation; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D012194:RNA-Directed DNA Polymerase; D016049:Didanosine