Background: The emergence of resistance to different drugs during combination antiretroviral (ARV) therapy may occur at substantially different rates. In this study, we analyzed the temporal emergence of NRTI and PI mutations in a blinded, comparative Phase III study of lopinavir/ritonavir (LPV/r) and nelfinavir (NFV) in combination with stavudine (d4T) and lamivudine (3TC) in 653 ARV-naive subjects.

Methods: Plasma samples were analyzed from all subjects with VL > 400 on therapy between wk 24 and final available study visit. Time to persistent emergence of thymidine-associated mutations (TAMs, defined as M41L, D67N, K70R, L210W, T215F/Y, and K219Q/E/N in RT), 3TC resistance (M184V/I/T in RT), and PI resistance (for NFV, D30N or L90M in protease or M46I/L with confirmed reduced susceptibility; for LPV, any primary or active site protease mutation) was assessed using Kaplan-Meier analysis.

Results: Baseline and post-rebound genotypes were available for 96/327 NFV- and 51/326 LPV/r-treated subjects. Through 2 yrs of therapy, Kaplan-Meier analysis of all enrolled subjects produced the following relative resistance rates: 3TC resistance in NFV-treated subjects (29%) > * NFV resistance in NFV-treated subjects (20%) > * 3TC resistance in LPV/r-treated subjects (7%) » TAMs in NFV-treated subjects (5%) > * TAMs or LPV resistance in LPV/r-treated subjects (0%, *p £ 0.001 for indicated pairwise comparisons, log-rank test). NFV and 3TC resistance was evident at the first available genotype in 26/46 (57%) and 75/79 (95%) of NFV-treated subjects who ultimately developed resistance, respectively. NFV resistance and TAMs were always accompanied by 3TC resistance, and NFV resistance emerged prior to the appearance of TAMs in 4/8 subjects who demonstrated resistance to all 3 drugs in the regimen.

Conclusions: Despite identical NRTIs in the two arms of this randomized comparative study, the incidence of resistance to each component of the regimen (PI, 3TC and d4T) was significantly lower in LPV/r-treated subjects than in NFV-treated subjects. Among subjects demonstrating resistant virus, PI resistance and 3TC resistance were commonly observed at the first available genotype. These results have implications for subsequent therapeutic options for patients instituting initial ARV therapy.