Genotypic and phenotypic cross-resistance patterns to lopinavir and amprenavir in protease inhibitor-experienced patients with HIV viremia

Genotypic correlates of reduced phenotypic susceptibility to amprenavir (APV) and lopinavir (LPV) were examined in 271 HIV isolates from 207 protease inhibitor (PI)-experienced subjects. All samples were from LPV-naive subjects; two were from APV-experienced subjects. Using a fold resistance (FR) of <2.5, 179 (66%) were APV susceptible. Using FRs of <2.5 and <10, 107 (39%) and 194 (72%), respectively, were LPV susceptible. The I84V mutation was the strongest APV resistance marker in PI-experienced subjects in both univariate and multivariate analyses, with an increased relative incidence (RI) of 6.9 with >2.5 FR. Mutations L10I (RI, 1.7), M46I (RI, 2.3), and L90M (RI, 1.9, but 65% linked with the I84V) were associated with decreased APV susceptibility in the univariate analysis (p<0.001). Mutations L10I, G48V, I54T, I54V, and V82A were significantly associated with decreased LPV susceptibility (p < 0.001 for each) and had increased RIs of 2.2, 4.4, 13, 4.6, and 3.2, respectively. Decreased susceptibility to LPV (FR, greater than or equal to10) was significantly associated with prior exposure to the following PIs: ritonavir (RTV) (p< 0.001), saquinavir (SQV) (p< 0.001), nelfinavir (NFV) (p = 0.008), and indinavir (IDV) (p = 0.028). Decreased APV susceptibility (FR, greater than or equal to2.5) was significantly associated with prior exposure to RTV (p = 0.009), NFV (p = 0.003), and IDV (p = 0.021) but not with prior SQV (p = 0.103). These results suggest that APV and LPV have different cross-resistance mutation patterns that may help determine choice of PI therapy after therapy failure.