Background:  Data on the use of lopinavir (LPV)/ritonavir (RTV) in advanced non-B subtype-infected patients are limited. We measured virologic response, drug levels, and genotypic and phenotypic resistance to LPV/RTV in C patients and compared them to B patients.

Methods:  All samples from infected patients receiving LPV/RTV with HIV RNA > 1000 were included. Population sequencing (TRUGENE^TM, Bayer) and phenotypic tests (PHENOSCRIPT^®, VIRalliance) were performed. Mutational patterns were determined, specific LPV/RTV algorithm scores were calculated, and longitudinal evolution of mutations identified by comparison with sequencing results from previous assays, were performed. Evolution of mutations in C- and in B-infected patients were compared with each other.

Results:  We genotyped 49 non-B and 35 B samples from patients failing LPV/RTV. We phenotyped 31 C and 15 B samples carrying selected PI-resistance-conferring mutations. Mean log HIV RNA was 5.14 and 5.24 copies/mL for C and B, respectively and mean CD4 cells count was 277 and 242 cell/µL. Mean PI-treatment duration was 19 and 21 months (range 2 to 68 and 1 to 99) for C and B patients, respectively. Mean number of previous PI was 2 (range 0 to 4); LPV/RTV was the first PI administrated for 12 patients (6 in each group). Patients were receiving ≥ 2 nucleoside reverse transcriptase inhibitor (NRTI). All mutations included in the LPV/RTV algorithm were found, with the following prevalence: L10I/V/F (40% and 41%), K20R (47% and 21%; p = 0.07), L24I (2% and 12%; p = 0.07), M46I (29% and 21%), F53L (2% and 9%), I54V (31% and 29%), L63P (51% and 68%; p = 0.004), A71V (18% and 26%), V82A (36% and 21%), I84V (9% and 18%), L90M (22% and 18%), for C and B patients, respectively. Mutations L24I and F53L were rare and last to appear. The mean LPN/RTV algorithm score was 3.24 (range 0 to 9; median 2) and did not reach statistical significance with that calculated for B patients (4.15; range 0 to 9; median 4). Subtypes B and C samples, which were selected for similar combinations of mutation, showed comparable phenotypic resistance cut-offs of 10 (partial resistance) and 30 (resistance).

Conclusions:  Following relatively long period of PI treatment all LPV-associated mutations characteristic of treatment failing subtype B patients are present with similar prevalence in subtype C. Multiple mutations were commonly present, as reflected by the LPV/RTV score, consistent with patterns seen in B. The emergence rate of these mutations, as in positions 20, 24, and 63, may differ between subtypes as a result of baseline polymorphism.

Keywords: subtype C; genotypic and phenotypic drug resistance; Lopinavir/Ritonavir