EMERGENCE AND CLINICAL RELEVANCE OF MUTATIONS ASSOCIATED WITH ZIDOVUDINE RESISTANCE IN ASYMPTOMATIC HIV-1-INFECTED PATIENTS

The dynamics leading to the emergence of a zidovudine-resistant mutation at codon 215 of the reverse transcriptase coding region was investigated in a cohort of HIV-infected individuals who received early zidovudine therapy. Clinical implications and the role of the resistance mutation at codon 41 were also assessed. Thirty-eight initially asymptomatic HIV-infected patients with a CD4+ cell count above 400 cells/mm(3) were followed for a mean period of 121 weeks (20 received zidovudine and 18 matching placebo). Specific mutations in the HIV-1 reverse transcriptase coding region conferring resistance to zidovudine were detected using a selective polymerase chain reaction. During the followup period a mutation at codon 215 was detected in eight (40 %) of the individuals in the zidovudine group, and in two of these eight subjects, a mutation at codon 41 was found. During the study, disease progression occurred in seven of the eight (88 %) patients with a mutation at codon 215, compared with 7 of 18 (39 %) patients assigned to the placebo group and 3 of the 12 (25 %) patients receiving zidovudine treatment who did not develop a 215-mutant strain (p < 0.05). At entry, none of the patients harbored MT-2 tropic virus. Therefore, the emergence of a zidovudine-resistant mutation at codon 215 is associated with subsequent disease progression in asymptomatic HIV-infected patients who receive zidovudine monotherapy. This association suggests that the mutation at codon 215 is involved in a loss of therapeutic efficacy and, therefore, patients should be monitored during treatment with zidovudine.