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Multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 strains isolated from patients from different European countries

Schmit, Jean-Claude1,2,8; Van Laethem, Kristel1; Ruiz, Lidia3; Hermans, Philippe4; Sprecher, Suzanne4; Sönnerborg, Anders5; Leal, Manuel6; Harrer, Thomas7; Clotet, Bonaventura3; Arendt, Vic2; Lissen, Eduardo6; Witvrouw, Myriam1; Desmyter, Jan1; Clercq, Erik De1; Vandamme, Anne-Mieke1

Clinical: Original papers

Objective: To study the prevalence of multiple dideoxynucleoside (ddN)-resistant (MddNR) HIV-1 in European patients under treatment with multiple ddN analogues, and to characterize MddNR strains genotypically and phenotypically.

Design and methods: Blood samples from patients after ≥ 6 months of treatment with multiple ddN were screened for the MddNR mutation Q 151M. After confirmation of MddNR in 15 patients from five European countries, genotypic resistance was evaluated by DNA sequencing of the reverse transcriptase (RT) gene. Phenotypic resistance was measured by the recombinant virus assay. Results were compared with the clinical evolution of the patients.

Results: The prevalence of MddNR strains in European patients treated with multiple ddN analogues was 3.5%. Viruses typically contained amino acid substitutions V75F, F77L, F116Y and Q151M in the RT gene. A new mutation, S68G, was frequently associated with MddNR. Phenotypically, viruses displayed high-level resistance to zidovudine (ZDV), didanosine (ddl), zalcitabine (ddC), stavudine (d4T) and partial resistance to lamivudine (3TC) once multiple mutations were present. Under in-vivo treatment pressure, some MddNR strains additionally developed resistance to protease inhibitors or non-nucleoside RT inhibitors (NNRTI). Clinically, most patients had advanced HIV disease with low CD4 cell counts, high viral loads and a rapid progression, but two patients harbouring MddNR virus responded well to dual protease inhibitor associations.

Conclusions: MddNR resistant HIV-1 can be found in European patients. MddNR is characterized by a specific set of drug resistance mutations, cross-resistance to most ddN analogues and a fast clinical progression. MddNR can be associated with protease inhibitor or NNRTI resistance.

1Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium

2Laboratoire de Rétrovirologie, CRP-Santé, Luxembourg

3Retrovirology Laboratory IRSI-Caixa, Barcelona, Spain

4Centre Hospitalier Universitaire St Pierre and Institut Pasteur, Brussels, Belgium

5Division of Clinical Virology, Karolinska Institute, Stockholm, Sweden

6Viral Hepatitis and AIDS Study Group, Sevilla, Spain

7Department of Internal Medicine III, University of Erlangen-Nürnberg, Germany.

8Requests for reprints to: Jean-Claude Schmit, MD, PhD, Laboratoire de Rétrovirologie, Centre de Recherche Public-Santé, 4 rue Barblé, L-1210 Luxembourg.

Sponsorship: Supported by the Biomedical Research Programme of the European Union (EU Biomed 2 grant BMH4-CT-95–1634), the Belgian Geconcerteerde Onderzoeksacties (project GOA 95/5), the Belgian Nationaal Fonds voor Wetenschappelijk Onderzoek (NFWO) grant G.3304.96 and the Programa Nacional de Salud, Plan Nacional l+D, grant SAF 97-0219 (Spain). J.C. Schmit acknowledges a grant from the EU Biomed 1 Programme (grant BMH1-CT-94-5599) and from the Centre de Recherche Public-Santé, Luxembourg (grant 96/09). The Rega Institute for Medical Research, Leuven, Belgium, the Laboratoire de Rétrovirologie, Luxembourg-City, Luxembourg and the Retrovirology Laboratory IRSI-Caixa, Barcelona, Spain are members of the European Network for the Virological evaluation of international trials for new Anti-HIV therapies (ENVA).

Date of receipt: 29 April 1998; revised: 22 July 1998; accepted: 28 July 1998.

© 1998 Lippincott Williams & Wilkins, Inc.