ABSTRACT: Purpose: Protocol 075 is an ongoing 48 week, open-label, multicenter study comparing the safety, tolerability and virological activity of an indinavir-containing combination regimen in protease inhibitor (PI)-naïve patients and in patients who experienced virological failure on nelfinavir. We examined the mutational patterns in the protease gene at study baseline and their relationships with subsequent virological response to the indinavir-containing combination regimen.
Methods: All patients in the nelfinavir failure arm were naïve to other PIs, received 16 or more weeks of nelfinavir in combination with currently licensed nucleoside analogue RT inhibitors and had experienced „10-fold increase in vRNA following an initial „10-fold decrease on that regimen. All patients remained on nelfinavir until day 1 of the study, when they received indinavir (1000 mg every 8 h)/efavirenz (600 mg once daily at bedtime/adefovir dipivoxil (120 mg once daily until week 8; 60 mg once daily thereafter)/L-carnitine (500 mg once daily).
Results: At study entry, viruses from patients in the nelfinavir failure arm carried protease substitutions D30N (17/29), L90M (11/29) or neither (1/29). D30N and L90M were mutually exclusive and were not observed in the PI-naïve patients (n=14). Patients carrying D30N often expressed N88D and A71(T/V) substitutions. In contrast, L90M was often seen combined with L10(I/V), K20(T/I/V/M), M46(I/L), D60E, A71(V/T), G73S and T74(S/A/P). None of these additional substitutions was seen frequently in the PI-naïve patients. Within the nelfinavir failure arm, virological failure of the salvage regimen (plasma vRNA >400 copies/ml by week 24) occurred significantly more frequently among patients with L90M than among those with D30N.
Conclusions: These data show that in this cohort, nelfinavir resistance had evolved along two mutually exclusive generic pathways characterized by the presence of either D30N or L90M substitutions. Each occurred at a similar frequency and each was accompanied by additional substitutions. These genetic patterns were associated with differing virological responses to the indinavir-containing salvage regimen by week 24.
