1st International Workshop on HIV Drug Resistance & Treatment Strategies 25-28 June 1997, St. Petersburg, Florida, USA

GENOTYPIC AND PHENOTYPIC ANALYSIS OF THE PROTEASE GENE IN HIV-1-INFECTED PATIENTS THAT FAILED LONG-TERM SAQUINAVIR THERAPY AND SWITCHED TO OTHER PROTEASE INHIBITORS

Antiviral Therapy 1997;2 (Suppl 5):11 (abstract no. 17)

Mark A Winters, Jonathan M Schapiro, Jody Lawrence and Thomas C Merigan
Stanford University School of Medicine, Stanford, California, USA

Recent reports show that the protease gene mutations most associated with saquinavir therapy are G48V and L90M, and that these mutations demonstrate little cross-resistance to other protease inhibitors. We examined the genotypes of patients who failed long-term (1 to 2 years) saquinavir therapy and found that while most patients (58%) possessed either G48V or L90M mutations, 35% of patients also had mutations that have been associated with resistance to other protease inhibitors (M36I, M46I, V82A, I84V). Results with subsequent therapy with indinavir or nelfinavir suggested several pathways of genotypic resistance. The G48V mutation occurred at a higher frequency in patients receiving higher saquinavir doses as monotherapy. All patients (6/6) who initially developed G48V acquired the V82A mutation during saquinavir treatment [monotherapy or in combination with a reverse transcriptase (RT) inhibitor], or after switching to either nelfinavir or indinavir. Patients who initially developed L90M on saquinavir therapy either had no further genotypic changes (5/9), or acquired M36I or M46I following nelfinavir or indinavir (3/9). Only one of the nine patients that had the L90M mutation when switched to nelfinavir showed evidence of the D30N mutation after nelfinavir failure. Patients without L90M or G48V following saquinavir treatment acquired L90M (4/7) or D30N (1/7) on nelfinavir, or had no significant genotypic changes following 6 months of indinavir plus two RT inhibitors (4/4). In vitro susceptibility testing showed that isolates from some saquinavir-treated patients already had reduced susceptibility to nelfinavir and/or indinavir prior to treatment with these protease inhibitors. Furthermore, viruses with reduced susceptibility to more than one protease inhibitor developed after treatment with the second protease inhibitor. These results suggest that mutations induced by initial long-term saquinavir therapy may provide a genotypic foundation for the development of resistance to other protease inhibitors. However, further studies need to examine the development of these mutational pathways in patients that have more effective suppression of viral replication with combinations of saquinavir plus RT inhibitors.

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1997-06-25
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