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

Pellegrin, Isabelle; Izopet, Jacquesa; Reynes, Jacquesb; Denayrolles, Muriel; Montes, Brigitteb; Pellegrin, Jean-Luc; Massip, Patricea; Puel, Jacquelinea; Hervé Fleury and Michel Segondyb for the STADI Group

Clinical: Original Papers

Objective: Assessment of genotypic changes in the reverse transcriptase gene 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 baseline and at the end of treatment from 39 previously treatment-naive patients treated for 24-48 weeks.

Results: At baseline, mutations associated with zidovudine resistance were detected in plasma from two patients: Asp67Asn/Lys219Gln and Leu210Trp. Among the 39 subjects, 18 (46%) developed mutations: one developed the Val75Thr/Ala mutation, four (10%) developed a Gln151Met multidrug-resistance mutation (MDR), associated in one of them with the Phe77Leu and the Phe116Tyr MDR mutations and 14 (36%) developed one or more zidovudine-specific mutations (Met41Leu, Asp67Asn, Lys70Arg, Leu210Trp, Thr215Tyr/Phe). The development of a Met41Leu zidovudine-specific mutation was associated with the development of a Gln151Met mutation in one patient. Other reverse transcriptase mutations known to confer resistance to nucleoside analogues were not detected. 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-type reverse transcriptase genotype (-2.22log10 copies/ml) than in patients who developed resistance mutations (-1.14log10 copies/ml).

Conclusion: Stavudine/didanosine combination therapy is associated with emergence of zidovudine-related resistance or MDR mutations in naive patients. These findings should be considered when optimizing salvage therapy for patients who have received a treatment including stavudine/didanosine combination.

From the Departments of Virology and Infectious Diseases, Bordeaux University Hospital, Bordeaux, the aDepartments of Virology and Infectious Diseases, Toulouse University Hospital, Toulouse, and the bDepartments of Virology and Infectious Diseases, Montpellier University Hospital, Montpellier, France. *See Appendix.

Sponsorship: Supported by grants from Bristol-Myers Squibb (Paris-La Défense, France).

Correspondence to I. Pellegrin, Laboratoire de virologie, Hopital Pellegrin, place Amélie Raba Léon, 33076 Bordeaux Cedex, France.

Received: 9 March 1999; revised: 24 May 1999; accepted: 1 June 1999.

© 1999 Lippincott Williams & Wilkins, Inc.