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KINETIC ANALYSIS OF VIRAL REBOUND AND DRUG-RESISTANT VIRAL VARIANT DYNAMICS IN PATIENTS TREATED WITH ITMN-191 (RG7227) MONOTHERAPY SUGGESTS A HIGH BARRIER TO VIRAL ESCAPE
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Reported by Jules Levin
AASLD Oct 31-Nov 3 2009, Boston, MA
C. Sarrazin1, S. R. Lim2, X. Qin2, S. Susser1, C. Lange1, E. Herrmann1, L. Hooi2, S. Stevens2, J. Hong2, C. Moy2, A. Arfsten2, W. Z. Bradford2, S. Zeuzem1, K. Kossen2, I. Najera3, and S. Seiwert2
1J.W. Goethe Universität, Frankfurt, Germany; 2InterMune, Inc., Brisbane, CA, USA; 3Roche Palo Alto LLC, Palo Alto, CA, USA
ABSTRACT
Background: The NS3/4A protease inhibitor ITMN-191 has demonstrated significant antiviral activity against HCV genotype 1 in chronically infected patients. Fourteen day monotherapy with ITMN-191 resulted in viral load (VL) reductions of approximately 4-log10 IU/mL. When used for similar durations in combination with peginterferon alfa-2a and ribavirin, or with the NS5B inhibitor R7128, VL at end of treatment (EOT) was below the limit of quantification in the majority of patients. The current study examined the time course of viral rebound and the appearance of drug-resistant viral variants in the subset of patients that experienced virologic rebound during ITMN-191 monotherapy.
Methods: Virologic response patterns were defined by EOT and nadir VL. NS3 protease domain from rebound patients was sequenced pre-dose on days 1 (baseline), 3, 7, and 14 (EOT). Clonal analysis (n=80) provided a 75% probability of identifying substitutions present at a 2.5% frequency.
Results: Among 40 patients receiving ITMN-191 monotherapy, 14 patients experienced virologic rebound. Population sequence analysis of NS3 isolated from rebound patients indicated that all carried R155K substitution at EOT; only 3 rebound patients showed drug resistant viral variants at Day 3 (n=1) or Day 7 (n=3). Deeper clonal analysis in patients apparently lacking substitutions by population analysis indicated some carried variants at a low level (<7%) at Day 3 or Day 7. The incidence of rebound in subtype 1b (n=4) was considerably lower than in subtype 1a (n=10). Median time from start of therapy to VL increase of 0.5 log10 IU/mL above nadir was similar in subtypes 1a and 1b: 8 Days, 2 hrs vs. 7 Days, 4 hrs, respectively. Except one patient, clonal sequencing did not provide evidence for single nucleotide substitutions as intermediates of the doubly substituted codon required for R155K in subtype 1b.
Conclusions: In ITMN-191 monotherapy, R155K is the dominant drug-resistant viral variant for HCV subtypes 1a and 1b. The lower incidence of escape in subtype 1b compared to 1a may reflect the requirement for two nucleotide substitutions to obtain R155K in subtype 1b relative to the single change required in 1a. The similarly late emergence of R155K as the dominant sequence in most rebound patients, without evidence for intermediate transitions, suggests that this substitution is either selected from a small pre-existing population or that potential intermediates are transient. The seemingly high barrier to resistance evidenced here may relate to the lack of viral escape when ITMN-191 is used in combination with pegylated interferon and ribivirin or in combination with the NS5B inhibitor R7128.
1 These patients were inadvertently mis-dosed for their cohort. Two patients received 100 mg q12h for the entire dosing period. One patient received 100 mg q12h from Day 1 through the
first dose of Day 5 and 200 mg q12h from the second dose of Day 5 to Day 14.
Con-1 Replicon Wild-Type EC50 0.11 ± 0.06
2 EOT (Day 14 n=13 plus last available timepoint Day 7 n=1)
3 Variants that confer resistance to a protease inhibitor in clinic
4 Susser S, Welsch C, Wang Y, Zettler M, Domingues FS, Karey U, Hughes E, Ralston R, Tong X, Herrmann E, Zeuzem S, and Sarrazin C. Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology 2009; 50(10):1-10.
5 Calculation for viral fitness is based on infrequent observations of D168 variants
6 Sarrazin C, Kieffer TL, Bartels D, Hanzelka B, Muh U, Welker M, Wincheringer D, Zhou Y, Chu H-M, Lin C, Weegink C, Reesink H, Zeuzem S, and Kwong AD.
Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 2007; 132:1767-1777.
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