Mutations in hepatitis C virus genotype 1b and the sensitivity of interferon-ribavirin therapy after liver transplantation

Background & Aims

The results of post-transplant antiviral therapy for recurrent hepatitis C virus (HCV) are poor, and significant pre-transplant predictors for sustained viral response (SVR) have not yet been identified.

Methods

Pegylated interferon/ribavirin therapy was performed for more than 48 weeks in 50 patients who underwent liver transplantation (LT) for HCV genotype 1-related liver disease. Of these, 22 patients achieved SVR. The predictive potential of the viral mutations, including amino acids (aa) 70 and 91 in the Core region, interferon sensitivity-determining region (ISDR, aa 2209–2248) and interferon/ribavirin resistance-determining region (IRRDR, aa 2334–2379) in NS5A, was evaluated.

Results

In 16 patients, the sequences in the pre- and post-transplant samples were the same, except for aa 70 in the Core of 1 patient. The SVR achievement percentage was significantly lower in the Non-double wild (DW) at aa 70 and 91, the ISDR < 2 and IRRDR < 6 groups than in the DW (30% vs. 65%, p = 0.015), the ISDR ⩾ 2 (35% vs. 69%, p = 0.035) and IRRDR ⩾ 6 (25% vs. 78%, p <0.001) groups, respectively. Predictive scoring with these three items provides a newly established and significant predictor for SVR after LT (p = 0.015).

Conclusion

DW, ISDR ⩾ 2 and IRRDR ⩾ 6 were found to be significant predictors for SVR after LT. In addition, it is possible that the establishment of a new scoring system consisting of these three factors may be a useful marker to predict interferon sensitivity for recurrent HCV after LT.

Introduction

Hepatitis C virus (HCV) infection is estimated to chronically infect more than 170 million people worldwide, and its consequences, cirrhosis and hepatocellular carcinoma (HCC), are life-threatening. The development of sustained viral response (SVR) due to combined pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy can prevent the progression of HCV-related disease [1]. However, the probability of SVR depends on the viral genotype or the pre-treatment viral RNA titre, and the treatment results of genotype 1b have been unsatisfactory [2]. The current therapy for decompensated cirrhosis and unresectable advanced HCC is LT. HCV-related liver diseases are the leading indication for LT not only in Western countries but also in Japan [3], [4]. However, several reports have shown the postoperative prognosis of liver transplantation for HCV-related disease to be worse than that for other diseases because of the recurrence of HCC and HCV re-infection [5].

A pre-transplant evaluation is essential to obtain better post-transplant outcome. The Milan criteria have been successfully used to evaluate the necessity of LT for patients with HCC, and have contributed to predicting the post-transplant outcome [6], [7]. However, the predictive factors of the progression of fibrosis and graft loss due to re-infected HCV have not been fully elucidated [8]. Re-infection of HCV occurs in most recipients, especially in the severe and life-threatening recurrent pattern now known as fibrosing cholestatic hepatitis (FCH), which results in graft loss. Currently, post-transplant antiviral therapy has become essential for LT recipients with HCV [9]. However, IFN therapy sometimes has severe side effects, and its high medical cost cannot be ignored [10], [11]. It is possible that the persistence of IFN therapy sometimes leads to the poor clinical course of the patients. Therefore, the identification of prognostic factors for post-transplant IFN therapy is essential.

The Core protein and non-structural protein 5A (NS5A) are known to be important multifunctional proteins that are critical not only for viral replication but also for the pathogenesis of HCV-related liver disease. The impact of viral mutations on these proteins, including amino acids 70 and 91 in the Core protein [12], the interferon sensitivity-determining region (ISDR) [13], and IFN/RBV resistance-determining region (IRRDR) [14], on the sensitivity of IFN therapy in patients with chronic hepatitis C has been shown. It is possible that the simultaneous evaluation of these three regions could lead to more accurate prediction of SVR compared to each region on its own.

In this study, we suggest the significant impact of the combined analysis of the Core and non-structural protein 5A (NS5A) regions for predicting the sensitivity of IFN/RBV combined therapy for recurrent HCV infection after LT.