Development and significance of the HIV-1 reverse transcriptase M184V mutation during combination therapy with lamivudine, zidovudine, and protease inhibitors

To analyze the emergence and role of the lamivudine (3TC)-selected HIV-1 re verse transcriptase (RT) M184V mutation under triple therapy, we performed a retrospective study of 40 nucleoside RT inhibitor-pretreated and 16 drug- naive patients who were switched to combined treatment with zidovudine (ZDV ) plus 3TC plus a protease inhibitor (PI). Plasma viral load and pol genoty pe were analyzed at baseline and after 24 and 48 weeks of combination thera py. Emergence of the M184V RT mutation at week 48 was detected in 3 of 16 ( 18.7%) initially drug-naive subjects as opposed to 21 of 40 (52.5%) ZDV-pre treated patients. Multivariate logistic analysis detected HIV-1 RNA load at week 24 as the best predictor of subsequent selection of the M184V mutant (p = .0121). Among ZDV-resistant study subjects at week 24 (n = 17), those with mutant RT M184V codon bad a more favorable HIV-1 RNA slope than those with wild-type RT 184M codon (p = .0551). This trend was observed, although in a less evident manner, even in pretreated ZDV-sensitive patients. These findings suggest that development of the 3TC-resistance M184V mutation und er triple therapy with 3TC, ZDV, and a PI may have unexpected beneficial ef fects in vivo in addition to those associated with resensitization of ZDV-r esistant virus to ZDV.