Emergence of zidovudine and multidrug-resistance mutations in the HIV-1 reverse transcriptase gene in therapy-naive patients receiving stavudine plus didanosine combination therapy. STADI Group.
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 (-2.22 log10 copies/ml) than in patients who developed resistance mutations (-1.14 log10 copies/ml).


CONCLUSIONS
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.
Pellegrin
I
I
Department of Virology, Bordeaux University Hospital, France.
Izopet
J
J
Reynes
J
J
Denayrolles
M
M
Montes
B
B
Pellegrin
J L
JL
Massip
P
P
Puel
J
J
Fleury
H
H
Segondy
M
M
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D016049:Didanosine / Q000008:administration & dosage*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D006801:Humans; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage*; D018119:Stavudine / Q000008:administration & dosage*; D019562:Viral Load; D015215:Zidovudine / Q000008:administration & dosage*
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D018119:Stavudine; D054303:HIV Reverse Transcriptase; D016049:Didanosine