Clinical cross-resistance between the HIV-1 protease inhibitors saquinavirand indinavir and correlations with genotypic mutations

Objectives: To determine the clinical efficacy of the HIV-1 protease inhibi tor indinavir (IDV) in saquinavir (SQV)-experienced patients and delineate the developing drug-resistance patterns. Design: Open-label prospective clinical trial. Setting: University hospital research center. Patients: Ten patients who had completed a SQV monotherapy study in which t hey had received SQV at a dose of 3600 or 7200 mg daily (two and fourfold t he standard dose). Interventions: At enrollment patients received IDV for 4 weeks as monothera py, after which zidovudine (ZDV) and lamivudine (3TC) were added to their d rug regimen. Patients then received combination therapy (IDV-ZDV-3TC) for a n additional 20 weeks to complete a total of 24 weeks of therapy. Main outcome measures: Plasma HIV RNA viral load and CD4+ T-cell counts wer e monitored. Sequencing of the HIV protease gene was performed to determine the development of resistance mutations. Plasma samples for sequencing wer e taken before initial SQV therapy, after SQV therapy before starting IDV, and after 24 weeks of IDV therapy. Results: The average duration of high-dose SQV before starting IDV was 58 /- 29.2 weeks. A 0.58 log(10) RNA copies/ml increase was noted during the 3 -week washout phase followed by a mean reduction in plasma HIV RNA viral lo ad of 1.2 log(10) RNA copies/ml after 4 weeks of IDV. After the addition of ZDV and 3TC at week 4, HIV RNA continued to fall reaching a mean reduction of 1.96 log(10) RNA copies/ml at week 24. Plasma HIV RNA was below 400 RNA copies/ml in six out of nine patients at week 24. CD4+ T-cell counts showe d a gradual rise from 328 x 10(6)/l to 453 x 10(6)/l by week 24. SQV therap y had resulted in multiple mutations in the protease gene. Six of the patie nts had developed five or more mutations: L90M in two, G48V in four (of whi ch three also contained L10l), and V82A in three. Patients in whom plasma H IV RNA was not durably suppressed by subsequent IDV combination therapy dev eloped multiple (up to four) additional mutations within 24 weeks, includin g codons 54, 82 and 93 amongst others. No clear correlation was found betwe en the mutations that had developed in individual patients after SQV and th e subsequent efficacy of IDV. Conclusion: Prolonged use of SQV at potent doses in the presence of elevate d viral load levels resulted in the development of multiple resistance muta tions. Individual resistance patterns varied greatly between patients, as d id their virological response to therapy. Resistance assays may be useful i n identifying which patients will benefit from salvage therapy with a secon d protease inhibitor. (C) 1999 Lippincott Williams & Wilkins.