HIV-1 reverse transcriptase (RT) genotype and susceptibility to RT inhibitors during abacavir monotherapy and combination therapy

Objective: To examine changes in HIV-1 susceptibility (genotype and phenoty pe) during an initial abacavir monotherapy phase followed by the addition o f zidovudine and lamivudine. Design: Sixty HIV-1 infected, antiretroviral therapy-naive subjects were ra ndomized to receive 100, 300 or 600 mg abacavir twice daily. Subjects compl eting 24 weeks of randomized therapy or meeting a protocol defined switch c riterion could switch to open label abacavir/zidovudine/lamivudine. Methods: Plasma HIV-1 reverse transcriptase was genotyped at baseline, week 12, and at the last time point on ABC monotherapy. Drug susceptibility was analysed at baseline and on subsequent samples with sufficient HIV-1 RNA l evels using the recombinant virus assay. Virological responses (week 24) we re correlated to week 24 genotypes. Results: Mutant viruses were not detected before week 12 with the exception of one subject. At the latest time point on abacavir monotherapy (range, w eeks 6-48), 21 out of 43 subjects harboured virus with resistance conferrin g mutations including single, double and triple combinations of K65R, L74V, Y115F and M184V. The most common mutational pattern was L74V + M184V (11/2 1 cases). Twenty of the 21 subjects with isolates containing abacavir-assoc iated mutations reached week 48, and upon addition of lamivudine/zidovudiin e, 16 out of 20 (80%) had week 48 plasma HIV-1-RNA below 400 copies/ml. At week 48, 16 out of 46 genotypes were obtained; one of these was wild-type; 15 contained M184V either alone, in combination with K65R and/or L74V and/o r Y115F or with thymidine analogue-associated mutations. Week 48 viral load levels for these 15 subjects was low (median 3.43 log(10) copies/ml or -1. 99 log(10) copies reduction from baseline). Genotype correlated well with p henotypic resistance to ABC; four samples with three abacavir-associated mu tations had high level abacavir resistance (> 8-fold) and six samples with two or three mutations showed intermediate (4-8-fold) resistance. All sampl es with single mutations retained full ABC susceptibility. Conclusions: Resistance conferring mutations to abacavir were relatively sl ow to develop during the monotherapy phase, and did not preclude durable ef ficacy of abacavir/lamivudine/zidovudine up to 48 weeks. (C) 2000 Lippincot t Williams & Wilkins.