1st International Workshop on HIV Drug Resistance & Treatment Strategies


25-28 June 1997, St. Petersburg, Florida, USA


REDUCED SENSITIVITY OF CLINICAL ISOLATES OF HIV TO SAQUINAVIR IS ASSOCIATED ONLY WITH 48V OR 90M

Antiviral Therapy 1997;2 (Suppl 5):26 (abstract no. 40)

J Sheldon, C Craig, E Race, L Whittaker, J Rose, A Moffatt, L Rawlings, IB Duncan and N Cammack
Roche Discovery, Welwyn, UK

Approximately 4000 full sequences of the HIV proteinase gene have been derived from PBMC and plasma from patients prior to and during treatment with saquinavir. Analysis of these data combined with associated phenotypic data confirm that two mutations in the proteinase gene (48V and 90M) are key to the development of reduced sensitivity to saquinavir. These key resistance mutations and their absence in samples from untreated patients distinguish saquinavir from other proteinase inhibitors. For the 90M mutation, the advantage gained by the virus in terms of decreased drug sensitivity is modest, usually less than 10-fold. In addition, >40% of clinical isolates with 90M show less than a fourfold reduction in sensitivity to saquinavir. Despite the relatively greater decrease in drug sensitivity associated with 48V, its incidence in the clinic is lower than 90M, suggesting that this mutation significantly debilitates the virus; this view is supported by in vitro data.

Correlation between the saquinavir- resistance mutations (48V and 90M) and the accompanying compensatory changes was examined. During monotherapy with the current hard-gelatin formulation of saquinavir (1800mg/day), significant correlation (P<0.05, Chi-squared) was observed between 90M and specific residues at the polymorphic sites 10(I), 71(T/V) and, to a lesser extent, 63(P/Q/T). However, no significant correlation was found with these residues at higher doses of saquinavir or following combination therapy. Furthermore, isolates containing 90M plus 10I and/or 71T,V were no less sensitive to saquinavir than isolates containing 90M with consensus residues 10L and 71A, demonstrating their compensatory role. The presence of variation at these positions in pretreatment sequences does not predict the selection of 90M post-treatment. Correlative analysis will also be presented for the 48V mutation.

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1997-06-25
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