Objectives: To investigate genotypic drug resistance in HIV-1 subtype A/E infection associated with failure of double/triple-nucleoside reverse transcriptase (RT) inhibitor therapy.
Methods: Patients from HIV-NAT 002 [stavudine (d4T)/didanosine (ddI) dose reduction study] and HIV-NAT 003 (zidovudine (ZDV)/lamivudine (3TC) versus ZDV/3TC/ddI) whose HIV-1 RNA was > 1000 copies/ml at week 48 and/or week 96 were tested for genotypic resistance. In both studies, after 48 weeks, patients were switched to the other dual or triple-nucleoside RT inhibitor (NRTI) either according to randomization or to the occurrence of virological failure.
Results: Resistance mutations found in the d4T/ddI, ZDV/3TC, and ZDV/3TC/ddI groups: none at baseline; at week 48, nucleoside analogue mutations (NAM), 2/17 (12%), 2/10 (20%), and 1/8; Q151M complex, 3/17 (18%), 0%, and 0%; M184V, 0%, 10/10 (P < 0.001), 3/8; V75T, 3/17 (18%), 0%, and 0%; L74V, 3/7 (18%), 0%, and 0%, respectively. At week 96, among the switchers, i.e., group A d4T/ddI to ZDV/3TC, group B ZDV/3TC to d4T/ddI, and group C ZDV/3TC/ddI to d4T/3TC/abacavir: NAM, 12/21 (57%), 4/7 and 1/3; Q151M, 4/21 (19%), 0% and 1/3, respectively. Interestingly, four or more NAM were observed in a higher proportion in group A (4/17 versus none in the others).
Conclusions: Multi-NRTI resistance (NAM and Q151M) and M184V (only in 3TC failure) are commonly found in HIV-1 subtype A/E infection associated with NRTI failure. Suboptimal d4T/ddI therapy led to a high incidence of V75T and L74V mutations. Switching from d4T/ddI to ZDV/3TC may be associated with a higher incidence of four or more NAM. Thus, suboptimal and dual NRTI therapy is not recommended for global application.