Spontaneous viral clearance in a patient with chronic hepatitis C who relapsed after telaprevir-based treatment
J. de Bruijne1; T. L. Kieffer2; J. Sullivan2; M. Botfield2; B. Shames2; J. Schinkel3; R. Molenkamp3; C. J. Weegink1; H. W. Reesink1
1. Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands.
2. Vertex Pharmaceuticals, Cambridge, MA, United States.
3. Department of Medical Microbiology, Section of Clinical Virology, Academic Medical Center, Amsterdam, Netherlands.
Background: In three recent Phase 2 studies (PROVE1, PROVE2, PROVE3), telaprevir (TVR) in combination with peginterferon alfa-2a (Peg-IFN) and ribavirin (RBV), significantly increased the sustained viral response rate in treatment-naïve and treatment-experienced patients infected with HCV genotype 1.
Methods: An HCV genotype 1b Caucasian patient, a non-responder to prior Peg-IFN/RBV therapy, participated in the PROVE3 study and was randomized to receive TVR (750 mg q8h) with Peg-IFN (180 µg per week) and RBV (1200 mg per day) for 24 weeks followed by Peg-IFN/RBV for 24 weeks. HCV RNA measurements (LLOQ 25 IU/mL) were performed at all time points during treatment and follow-up. All time points with HCV RNA >1000 IU/mL were sequenced and analyzed for known resistant variants by clonal sequencing.
Results: HCV RNA became undetectable after 4 weeks of treatment and remained undetectable until week 40. At week 40, Peg-IFN/RBV treatment was discontinued due to grade 3 laboratory side effects (gamma-glutamyltransferase 650 U/L, direct bilirubin 24 µmol/L, platelets 37 GI/L). This patient experienced a viral relapse 4 weeks after the end of dosing and HCV RNA levels continued to increase through week 14 of follow-up. Sequence analysis revealed the presence of the V36A variant (132/132 clones). The post-treatment viral population experienced a significant reduction in genomic diversity relative to baseline, with only 10% of the baseline NS3-4A variability maintained after the treatment-induced genetic bottleneck. Additionally, whereas 34% and 14% of the residues of the HVR1 and HVR2 regions of E2 were polymorphic at baseline, the post-treatment population had no observable variation by population sequencing. Subsequently, 12 weeks later (26 weeks post-end of treatment), HCV RNA could no longer be detected and remained negative thereafter for 3 additional time points up to 54 weeks later (80 weeks post-end of treatment). Thus, it appears as though this patient experienced a spontaneous viral clearance. SNP analysis demonstrated a heterozygote C/T genotype at position rs12979860. Serum alanine transaminases increased at time of relapse and normalized when HCV RNA became undetectable. The Grade 3 laboratory values returned to baseline levels within a few weeks after therapy cessation. One potential hypothesis for this spontaneous clearance is that the significant genetic bottleneck resulted in an HCV population more sensitive to an induced host immune response.
Conclusion: This is the first report of a spontaneous clearance of an HCV infection in patients with a relapse or non-response after experimental antiviral therapy.
(AASLD 2010 Annual Meeting #1051) |
