Analysis of virological response to ABT-378/ritaonavir therapy in protease inhibitor-experienced patients with respect to baseline viral phenotype and genotype.
Originally Published on February 1, 2000
D Kempf, H Mo, S Brun, A Molla, , B Bernstein, K Hertogs, B Larder, K Orth, C Fields, M King Y Xu, A Japour, E Sun and the M97-765 Study Team
ABSTRACT: Background: ABT-378 is a potent protease inhibitor (PI) that, when co-dosed with small amounts of ritonavir, maintains plasma levels 25- to 100-fold above its EC50 for wild-type HIV. ABT-378/ritonavir plus stavudine/lamuvidine therapy produces a decline in HIV RNA to <400 copies/ml in 93-95% of antiretroviral-naïve patients at 24 weeks. Study M97-765 is an ongoing clinical trial of ABT-378/ritonavir in patients who have failed PI triple therapy with viral loads (VL) of 103-105 copies/mL.
Objective: To analyze the response to ABT-378/ritonavir therapy in PI-experienced patients with respect to baseline genotype and phenotype. Methods: Baseline phenotype was measured by the Virco Antivirogram method and compared to the phenotype of HXB2. Baseline genotype was determined by population sequencing. Data was obtained from 57/70 subjects at study baseline.
Results: The EC50 of ABT-378 against baseline viruses ranged from 0.005 to 0.18 mM (0.7- to 26-fold relative to wild-type, mean 2/8-fold). Quantifiable (>fourfold) change in EC50 to Pis was as follows: nelfinavir, 57%; indinavir, 44%; ritonavir, 42%; ABT-378, 19%; and saquinavir, 10%. Declining or undetectable VL was observed in all treated patients during the first 2 week period, during which the only treatment change was replacement of the previous PI with ABT-378/ritonavir. Neither initial decline from baseline or VL at week 24 correlated with baseline genotype of baseline susceptibility to ABT-378. VL increase from nadir to >1000 copies/mL, without reported treatment interruption during the increase, was observed in 4/13 (31%) patients whose baseline virus demonstrated >four-fold change in EC50 to =2 drugs in their regimen, in contrast with 4/44 (9%) of patients whose baseline virus was susceptible (<four-fold change in EC50) to at least three drugs.
Conclusions: Because of high and sustained plasma levels, ABT-378/ritonavir regimens suppress VL in many PI-experienced patients for =24 weeks despite significant resistance to PIs and RTIs. However, virological response in this population is lower than in naïve patients. The use of accompanying agents expected to have activity, in addition to ABT-378/ritonavir, is likely to be necessary for a durable antiretroviral response.
