Emergence of zidovudine and multidrug-resistance mutations in the HIV-1 reverse transcriptase gene in therapy-naive patients receiving stavudine plusdidanosine combination therapy

Objective: Assessment of genotypic changes in the reverse transcriptase gen e of HIV-1 occurring in antiretroviral naive patients treated by stavudine plus didanosine combination therapy. Methods: Sequence analysis (codons 1-230) was-performed after amplification of the reverse transcriptase gene from plasma samples collected at baselin e and at the end of treatment from 39 previously treatment-naive patients t reated for 24-48 weeks. Results: At baseline, mutations associated with zidovudine resistance were detected in plasma from two patients: Asp67Asn/Lys219Gln and Leu210Trp. Amo ng the 39 subjects, 18 (46%) developed mutations: one developed the Val75Th r/Ala mutation, four (10%) developed a Gln151Met multidrug-resistance mutat ion (MDR), associated in one of them with the Phe77Leu and the Phe116Tyr MD R mutations and 14 (36%) developed one or more zidovudine-specific mutation s (Met41Leu, Asp67Asn, Lys70Arg, Leu210Trp, Thr215Tyr/Phe). The development of a Met41Leu zidovudine-specific mutation was associated with the develop ment of a Gln151Met mutation in one patient. Other reverse transcriptase mu tations known to confer resistance to nucleoside analogues were not detecte d. At inclusion, there was no statistical difference in HIV-1 load between patients who developed resistance mutations and those who did not. RNA HIV- 1 load decrease was higher (P = 0.05) in patients who maintained a wild-typ e reverse transcriptase genotype (-2.22 log(10) copies/ml) than in patients who developed resistance mutations (-1.14 log(10) copies/ml). Conclusion: Stavudine/didanosine combination therapy is associated with eme rgence of zidovudine-related resistance or MDR mutations in naive patients. These findings should be considered when optimizing salvage therapy for pa tients who have received a treatment including stavudine/didanosine combina tion. (C) 1999 Lippincott Williams & Wilkins.