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5th International Congress on Drug Therapy
in HIV Infection S Brun, DJ Kempf, B
Bernstein, A Hsu, A Molla, H Mo, C Deetz, K Real, C Renz, |
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SHARE THIS ABSTRACT WITH A COLLEAGUE ABT-378/r is a new protease inhibitor (PI) that has a high inhibitory quotient (IQ, Ctrough/EC50 ratio) for wild-type HIV and displays antiviral activity both in both ARV-naïve and in experienced patients with PI-resistant HIV. The selection of resistance to ABT-378/r in vivo in ARV-naïve patients has not been documented. In vitro, 11 protease mutations have been associated with reduced susceptibility to ABT-378 in viral isolates selected by other PIs. In order to investigate the genetic barrier to in vivo resistance to ABT-378/r, we examined the genotype (population sequencing) and phenotype (Antivirogram™ or PhenoSense™) of baseline and rebound viral isolates from PI-experienced adult and pediatric patients who initiated combination therapy with ABT-378/r, an NNRTI and NRTIs, and subsequently experienced either a lack of complete response or viral rebound. Genotypic susceptibility to ABT-378 was evaluated using the ABT-378 mutation score (number of protease mutations selected from L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and L90M). Four adult and 5 pediatric patients had baseline ABT-378 mutation scores of 0-2. Upon rebound, isolates from each patient were NNRTI-resistant but remained phenotypically susceptible to ABT-378 and displayed no evidence of genetic selection by ABT-378. The lack of ABT-378/r resistance emergence in PI-experienced patients with low mutation score is consistent with the absence of detectable resistance in ARV-naïve patients treated with ABT-378/r. A PK/PD model simulating several adherence scenarios demonstrated that selective NNRTI resistance development is likely due to a combination of the large increase in EC50 of the first NNRTI-mutant and the long half-life of the NNRTI, which can produce prolonged periods under selective pressure following missed doses. In contrast, rebound isolates from 5 experienced patients who initiated therapy with baseline ABT-378 mutation scores of 4-5 demonstrated the concomitant development of resistance to both the NNRTI of the regimen and to ABT-378/r (as evidenced by the evolution of 1-3 additional protease mutations and further decrease in ABT-378 susceptibility). These results suggest that the genetic barrier to resistance to ABT-378/r is high, and that a genetic platform of 4-5 mutations may be required for facile evolution to occur under selective pressure by ABT-378/r. Isolates that developed resistance to ABT-378/r retained susceptibility or displayed modestly reduced susceptibility to amprenavir. In addition, all post-rebound isolates that were tested against tipranavir were fully sensitive, suggesting that amprenavir and tipranavir, which have resistance patterns dissimilar to ABT-378, may be useful with ritonavir pharmacokinetic enhancement for salvage therapy when ABT-378 resistance is present
Abstract: Examination
of the Genetic Barrier to In Vivo Resistance to ABT-378/Ritonavir
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