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/mm3 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 follow-up 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.
Calderón
E J
EJ
Department of Internal Medicine, Virgen del Rocio University Hospital, Seville, Spain.
Torres
Y
Y
Medrano
F J
FJ
Luque
F
F
Larder
B
B
Rey
C
C
Sánchez-Quijano
A
A
Lissen
E
E
Leal
M
M
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D001483:Base Sequence; D018791:CD4 Lymphocyte Count; D003062:Codon; D015331:Cohort Studies; D018450:Disease Progression; D004311:Double-Blind Method; D004352:Drug Resistance, Microbial / Q000235:genetics; D005260:Female; D054303:HIV Reverse Transcriptase; D006679:HIV Seropositivity / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D015215:Zidovudine / Q000627:therapeutic use*
D000998:Antiviral Agents; D003062:Codon; D015215:Zidovudine; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase