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Nucleoside analogue mutations and Q151M in HIV-1 subtype A/E infection treated with nucleoside reverse transcriptase inhibitors

Sirivichayakul, Suneea,b; Ruxrungtham, Kiata,b; Ungsedhapand, Chaiwatb; Techasathit, Wichaic; Ubolyam, Sasiwimolb; Chuenyam, Theshineeb; Emery, Seand; Cooper, Davidb,4; Lange, Joepb,e; Phanuphak, Praphana,b

Basic Science

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.

From the aDepartment of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, the bHIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration, The Thai Red Cross AIDS Research Centre, cSiriraj Hospital, Mahidol University; Bangkok, Thailand, the dNational Centre in HIV Epidemiology and Clinical Research (NCHECR), Sydney, Australia, and the eNational AIDS Therapy Evaluation Centre (NATEC), Amsterdam, the Netherlands.

Correspondence to K. Ruxrungtham, HIV-NAT, the Thai Red Cross AIDS Research Centre, 104 Rajadamri Road, Bangkok 10330, Thailand.

Received: 3 October 2002; revised: 27 February 2002; accepted: 11 March 2003.

© 2003 Lippincott Williams & Wilkins, Inc.