3rd International Workshop on HIV Drug Resistance 2-5 August 1994, Kauai, Hawaii, USA

GENOTYPIC CHARACTERISATION OF HIV-1 FROM PATIENTS AFTER PROLONGED TREATMENT WITH PROTEINASE INHIBITOR SAQUINAVIRr

Int Wkshop HIV Drug Res 1994 Aug 2-5;3:16 (abstract no. 15)

H. Jacobsen¹, F. Brun-Vezinet², I. Duncan³, M. Hänggi¹, M. Ott¹. S. Vella⁴, J. Weber⁵ and J. Mous^1
1F.Hoffmann-La Roche Ltd, Basel, Switzerland, ²Laboratoire de Virologie, Hôpital Bichat-Claude Bernard, Paris, France, ³Roche Products Ltd, Welwyn Garden City, UK, ⁴Istituto Superiore di Sanita, Laboratory of Virology, Rome; Italy, ⁵St.Mary‘s Hospital, London, UK

OBJECTIVE: As reported previously, HIV-1 resistance to Saquinavir (Ro 31-8959) can occur in vitro after extended, dose-escalating selection. The objective of this study was to investigate whether HIV-1 virus with reduced sensitivity to this drug can be found in patients treated with Saquinavir.

METHODS: Plasma samples from patients treated with 600 mg Saquinavir tid alone or in combination with Zidovudine were cocultured with stimulated donor PBMC for drug susceptibility testing according to standard procedures. Genotypic analysis of HIV proteinase genes was performed on parallel samples using PCR amplification followed by DNA sequencing of subcloned genes.

RESULTS: Sequences were obtained from currently ca.30 patients after up to 1 yr of treatment with proteinase inhibitor. Ca.10 sequences were obtained per patient and timepoint and their peptide sequence was evaluated for exchanges indicative of resistance to Saquinavir. The more frequently observed mutation was L90M whereas the G48V genotype was less common. Combined mutations at both positions occurred rarely. Additional exchanges were noted at e.g. pos.36 (M36I) and 71 (A71 V/T).

CONCLUSION: Mutations which have been previously shown to lead to reduced sensitivity to proteinase inhibitor Saquinavir in vitro could also be detected in vivo after prolonged treatment with high doses of inhibitor.

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1994-08-02
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