Anti-HIV effect of saquinavir combined with ritonavir is limited by previous long-term therapy with protease inhibitors

Combination therapy of saquinavir (SQV) and ritonavir (RTV) seems to have a strong antiretroviral effect pharmacokinetically, The purpose of this stud y was to examine the effectiveness of combined therapy using SQV and RTV in patients previously treated with protease inhibitors (PIs) and to identify the factors compromising the response to such combination therapy. Ninetee n HIV-infected Japanese patients participated in this trial between June 19 97 and July 1998, and were monitored until November 1998, Patients were tre ated with SQV (400 mg twice daily) and RTV (300 or 400 mg twice daily). Amo ng the 17 patients who continued such therapy for longer than 3 months, 6 w ere responders. Among nonresponders, the duration of PI therapy was longer and a higher frequency of preexisting PI resistance viral mutations was det ected than in responders. No significant differences were found in previous use of reverse transcriptase inhibitor therapy, CD4(+) and CD8(+) T cell c ounts, viral load at baseline, and plasma concentrations of SQV and RTV bet ween responders and nonresponders, Our results suggest that the response to SQV combined with RTV therapy is complicated by previous long-term treatme nt with PIs, probably owing to multiple PI resistance mutations. Even in pa tients with a PI-sensitive HIV genotype, however, resistance mutations can develop during therapy and abrogate the effect of high plasma SQV concentra tions.