Masashi Mizokami

Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C

The recommended treatment for patients with chronic hepatitis C, pegylated interferon-α (PEG-IFN-α) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in all patients. We report a genome-wide association study (GWAS) to null virological response (NVR) in the treatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We found two SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P = 1.93 × 10−13, and rs8099917, 3.11 × 10−15). We replicated these associations in an independent cohort (combined P values, 2.84 × 10−27 (OR = 17.7; 95% CI = 10.0–31.3) and 2.68 × 10−32 (OR = 27.1; 95% CI = 14.6–50.3), respectively). Compared to NVR, these SNPs were also associated with SVR (rs12980275, P = 3.99 × 10−24, and rs8099917, P = 1.11 × 10−27). In further fine mapping of the region, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668) located in the IL28B region showed the most significant associations (P = 5.52 × 10−28–2.68 × 10−32; OR = 22.3–27.1). Real-time quantitative PCR assays in peripheral blood mononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P = 0.015).

Hepatitis B Virus Genotype and Mutations Related to Clinical Outcome

Hepatitis B virus (HBV) infection is a high risk factor on severe liver diseases. HBV is currently divided into ten genotypes based on the genetic sequence of HBV, which has regional characteristics on clinical outcomes. Recently, cross-border incursion of HBV genotypes occurs worldwide. The nationwide epidemiological study in Japan showed that the number of acute hepatitis B patients was about 8000–8400 people per year. Interestingly, the European–US genotype HBV/A2 has made up an increasing proportion of acute HB cases over 50% in Japan. And 29% of acute HB patients infected with HBV/A became negative for HBsAg within 6–12 months, which were considered “prolonged,” rather than chronic hepatitis B. The acute infection of HBV/A2 is more likely to become chronic compared to HBV/B or C in Japanese population. The invasion of HBV genotypes into other region or country could provide new insights on clinical outcomes of HBV genotypes. The observation of long-term prognosis is needed to collect the clinical evidences on the infection of new genotype into a population.

Treatment Effects and Resistance-Associated Variants of Sofosbuvir Regimen for Japanese Patients with Chronic Hepatitis C Virus Genotypes 1 and 2

More than 40,000 people have already been treated in Japan since September 2014 when the first interferon-free all-oral therapy with daclatasvir (DCV), an NS5A inhibitor, and asunaprevir (ASV), an NS3/4A protease inhibitor (PI), was approved for treatment of chronic hepatitis C virus genotype 1. On the other hand, regimens containing the nucleic acid-type NS5B polymerase inhibitor sofosbuvir in combination with a PI, NS5A inhibitor, and/or ribavirin are now becoming standard throughout the world and achieving greater than 95 % sustained virological response (SVR) rates against multiple HCV genotypes. On March 23, 2015, sofosbuvir was approved for treatment of genotype 2 in Japan, priced at 61,700 yen per pill. Furthermore, Harvoni, a combination drug containing sofosbuvir co-formulated with the NS5A inhibitor ledipasvir, was approved in Japan on July 3, 2015, for treatment of genotype 1 with pricing set at 81,171 yen per pill. While the 6,800,000 yen price tag of 12 weeks of Harvoni is higher than that of DCV/ASV therapy, the therapy is more effective, and the one pill per day dosing and 12-week duration provides simpler and shorter therapy. Similarly, sofosbuvir is approved for and effective against both genotypes 1 and 2. This review discusses the mechanism and characteristics of sofosbuvir and summarizes results of phase III clinical trials for genotypes 1 and 2 and reports on the effects of antiviral resistance.

Hepatitis C Virus Genotypes and Their Evolution

The hepatitis C virus (HCV) genome is highly heterogeneous. Its genetic variability (genotypes and subtypes) is related to its biological and clinical properties. In 2005, a consensus was reached regarding a unified nomenclature system for HCV genotypes and subtypes. Since then, many complete genome sequences have been reported, resulting in the identification of new genotypes and subtypes. To determine the current status of HCV genotypes, complete genome sequences and their annotations were retrieved from public databases. These viral sequences were arranged according to genotype/subtype and geographical distribution and analyzed phylogenetically to determine the relationships between classification and geography. In addition, the relationships between the HCV genome and the genomes of various related viruses were analyzed phylogenetically to determine the HCV origin. These analyses showed that the viruses evolved along with their hosts and that, worldwide, HCV should be classified into seven major genotypes with their serial subtypes.

Host Genetics and Responses to Antiviral Therapy in Chronic Hepatitis C

Genome-wide association studies (GWAS) have revealed recently that certain interleukin-28B (IL28B) polymorphisms are strongly associated with responses to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy in patients chronically infected with hepatitis C virus (HCV) genotype 1. Subsequent reports revealed that these IL28B polymorphisms also affect treatment efficacy in chronic infection with other HCV genotypes. Therapy of chronic hepatitis C (CHC) recently has entered a new era with the availability of direct-acting antiviral agents (DAAs). These include non-structural 3/4A protease inhibitors which have shown promise in combination with PEG-IFN/RBV in several clinical trials, as well as in clinical practice. IFN-free therapy is expected to be useful especially for IFN-resistant patients and may become the standard of care in the future. Several clinical trials have revealed an association between IL28B genotype and treatment efficacy in triple therapy and in some interferon-free regimens. Recently, it was shown that a polymorphism of IFN-lambda 4 (IFNL4) is in high linkage disequilibrium with that of near IL28B and more strongly associated with spontaneous or treatment-induced HCV clearance than the IL28B polymorphisms, especially in individuals of African ancestry. This finding provides new insights into the genetic regulation of HCV clearance and its clinical management. IL28B genotyping will be useful for personalized treatment of CHC in the forthcoming era of DAAs.