GENOTYPIC CHANGES IN HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ASSOCIATED WITH LOSS OF SUPPRESSION OF PLASMA VIRAL-RNA LEVELS IN SUBJECTS TREATEDWITH RITONAVIR (NORVIR) MONOTHERAPY

Ten subjects received 600 to 1,200 mg of the human immunodeficiency vi rus type 1 (HIV-1) protease inhibitor ritonavir per day, Following 2 w eeks of therapy, plasma HIV RNA levels decreased by a mean of 1.57 (ra nge, 0.89 to 1.96) log units, With continued therapy, HIV RNA levels b egan to rise in eight subjects. The initial rise in plasma RNA levels was temporally associated with the development and quantitative increa se in the V82 resistance mutation. Doubling times of the V82A mutant v irus were estimated to be 2.4 to 4.8 days. An L63P/A mutation was comm only present at baseline even in subjects with a durable virologic res ponse. The concomitant acquisition of an L63P/A mutation with the V82A /F mutation at the time when plasma RNA levels rebounded suggests a ro le for the L63P/A mutation in improving the fitness of the V82A/F muta tion. Subsequent additional genotypic changes at codons 54 and 84 were often associated with further increases in plasma RNA levels. Ongoing viral replication in the presence of drugs resulted in the appearance of additional genotypic changes, including the L90M saquinavir resist ance mutation, and decreased phenotypic susceptibility. The relative f itness of the protease V82A ritonavir resistance mutation and reverse transcriptase T215Y/F zidovudine resistance mutation following drug wi thdrawal were estimated to be 96 to 98% that of the wild type. Durabil ity of the virologic response was associated with plasma RNA levels at the nadir. A virologic response beyond 60 days was not observed unles s plasma HIV RNA levels were suppressed below 2,000 copies/ml, consist ent with estimates from V82A doubling times for selection of a single resistance mutation to dominate the replicating population.