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L. M. Frenkel*, S. K. Burchett, G. M. Aldrovandi, V. Carey, R. Oyomopito, M. Mahalanibis, D. Decker, and A. Kovacs for the Pediatric AIDS Clinical Trials Group 366 Team.
NIH, Bethesda, MD.
Background:HIV-1 reverse transcriptase (RT) has poor fidelity in its transcription of RNA into cDNA, with a mean misincorporation of one out every 1000 bases. A mutation in HIV-1 pol encoding RT, M184V/I, selected for by lamivudine therapy, confers a high level of resistance to the drug. In vitro studies have demonstrated that the M184V/I mutations increase the fidelity of RT. Hence, viral populations with these mutations would theoretically be slower to accumulate additional mutations. It has been hypothesized that the M184V/I mutations would slow the evolution of HIV-1 resistance to combinations of antiretroviral drugs.
Methods:Children with and without the M184V/I mutations at baseline who participated in PACTG 366 were evaluated for their virologic response to a new study regimen of a combination of four antiretrovirals. The study regimens were dictated by whether the child had received protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTI) and included at least two agents that the subject had not received previously. If possible a new class of drugs was prescribed (NNRTI and/or PI). Logistic regression was utilized to compare the probability of an undetectable plasma HIV-1 RNA (<400 copies/ml) at study weeks 12 and 24 in children with or without the M184V/I at baseline with calculation of the odds ratio (OR) and P values. Analysis was similarly done for the subgroups, with subjects stratified by their past experience with NNRTI and/or PI.
Results:A baseline pol sequence with M184V/I was associated with a greater chance of having undetectable plasma RNA at study weeks 12 and 24. At study week 12 the number of subjects with undetectable HIV-1 RNA/ the total number of subjects with vs. without M184V/I = 34/70 (49%) vs. 15/51 (29%), respectively, OR = 2.27 and P = 0.04, and at week 24 the OR = 3.46 and P < 0.01 for 115 subjects. The association of the mutation with undetectable plasma HIV-1 RNA was most pronounced amongst children who had previously received one or more PI but who were naïve to NNRTI. At study week 12 the number of subjects with HIV-1 RNA undetectable/ the total number of NNRTI-naïve subjects with vs. without M184V/I = 8/22 (36%) vs. 1/18 (6%); respectively, OR = 9.7 and P = 0.04, and at study week 24 OR = 5.23 and P=0.06 amongst the NNRT= naïve subgroup.
Conclusions:The M184V/I mutations may have a clinically beneficial effect in the suppression of viral replication in children during salvage therapy.
© 8th Conference on Retroviruses and Opportunistic Infections