Session Title: Category 5g. VIRAL HEPATITIS: g. HEPATITIS C - CLINICAL (THERAPY)
Presentation Date: Apr 15, 2010
SEQUENCE HETEROGENEITY OF NS5A OF HCV GENOTYPES 2A AND 2B AFFECTS RVR AND SVR TO PEG-IFN/RBV COMBINATION THERAPY
H. Hotta1*, A. El-Shamy1, S.R. Kim2, S. Imoto2, C. Aoki3, Y. Ide1, I. Shoji1
1Division of Microbiology, Kobe University Graduate School of Medicine, 2Division of Gastroenterology, Kobe Asahi Hospital, Kobe, 3The Intitute of Medical Science, The University of Tokyo, Tokyo, Japan. *email@example.com
Background and aims: Pegylated-interferon(PEG-IFN)/ribavirin(RBV) combination therapy has been used to treat chronic hepatitis C. Treatment outcome is thought to be affected by both host and viral factors. Recently, IL28B was identified as the major host factor that determines the treatment outcome. As for the viral factor(s), we and other research groups have reported that heterogeneity of NS5A and the core protein of HCV genotype 1b (HCV-1b) are correlated with the treatment outcome. In this study, we aimed to examine whether the sequence heterogeneity of NS5A, especially in IFN/RBV resistance-determining region (IRRDR) and IFN sensitivity-determining region (ISDR), is correlated with the treatment outcome when used against HCV-2a and -2b infections.
Methods: Patients chronically infected with HCV-2a or -2b were treated with PEG-IFN/RBV for 24 weeks, followed by observation for another 24 weeks. HCV RNA was obtained from sera of the patients and amplified by RT-PCR. The nucleotide sequences of the amplified fragments were determined and the amino acid sequence of NS5A deduced. Titers of HCV RNA and HCV core antigen were monitored by using commercially available kits.
Results: HCV-2a isolates with IRRDR having two or more mutations (IRRDR≥2) were significantly associated with sustained virological response (SVR) to PEG-IFN/RBV therapy for 24 weeks, followed by 24-week observation (17/18 for IRRDR≥2 vs. 2/5 for IRRDR≤1; p=0.02). Also, HCV-2a isolates with ISDR/+C (part of ISDR plus a carboxy-flanking region) having one or more mutations (ISDR/+C≥1) were significantly associated with SVR (14/14 for ISDR/+C≥1 vs. 5/9 for ISDR/+C=0; p=0.01). Rapid virological response (RVR) at 4 weeks of therapy was associated with IRRDR≥3 (p=0.005). On the other hand, HCV-2b isolates with an N-terminal half of IRRDR having two or more mutations (IRRDR/N≥2) were significantly associated with RVR (10/10 for IRRDR/N≥2 vs. 5/11 for IRRDR/N≤1; p=0.01).
Conclusions: HCV-2a isolates with IRRDR≥2 and those with ISDR/+C≥1 were significantly associated with SVR. Also, HCV-2a isolates with IRRDR≥3 and HCV-2b isolates with IRRDR/N≥2 were significantly associated with RVR. These results emphasize that a viral factor, e.g., NS5A sequence heterogeneity, indeed plays an important role in determining the sensitivity of HCV to PEG-IFN/RBV therapy.