Tailor-Made Therapy for Viral Hepatitis: Recent Advances

Combination therapy of pegylated interferonwith ribavirin (PEG-IFN/RBV) is a standard of care for chronic hepatitis C (CHC). The majority of CHC patients are infected with HCV genotype I. The recent discovery revealed by a genome-wide association study technology provides the important role of interleukin-28B (IL28B) and inosine triphosphatase (ITPA) in HCV infection. In addition, response to PEG-IFN/RBV therapy is correlated with insulin resistance, hepatic steatosis, and hepatic fibrosis in CHC patients. Double-filtration plasmapheresis together with IFN therapy has proved to be effective in the reduction of viral load during the early stage of treatment. In CHC patients, not only IL28B status, but also the treatment period of PEG-IFN/RBV is important. Even when new polymerase/protease inhibitors are introduced in the treatment of CHC, tailor-made treatment for CHC using IL28B, inosine triphosphatase testing or double-filtration plasmapheresis treatment prolonged treatment strategy is highly recommended. The relative etiologic role of prior hepatitis B virus infection in the development of non-B non-C hepatocellular carcinoma is also known in hepatitis B-endemic areas. Copyright © 2011 S. Karger AG, Basel Published online: December 2, 2011 Masatoshi Kudo Department of Gastroenterology and Hepatology Kinki University School of Medicine Ohno-Higashi, Osaka-Sayama 589-8511 (Japan) Tel. +81 72 366 0221, E-Mail m-kudo @ med.kindai.ac.jp © 2011 S. Karger AG, Basel 0012–2823/11/0845–0001$38.00/0 Accessible online at: www.karger.com/dig Kudo Digestion 2011;84(suppl 1):1–4 2 Double-Filtration Plasmapheresis The use of double-filtration plasmapheresis (DFPP), approved in Japan in April 2008 for the retreatment of chronic CHC patients with genotype 1b and high viral loads, together with IFN administration has produced a substantial reduction in the viral load during the early stages of treatment and has effected a high sustained virological response (SVR) [8, 9] , suggesting that this treatment is a new modality for difficult-to-treat CHC patients. Recent reports have revealed factors associated with response to pegylated interferon with ribavirin (PEGIFN/RBV) therapy such as single nucleotide polymorphisms (SNPs), as host genetic factors, located in interleukin-28B (IL28B; rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917, rs7248668, and rs12979860) on chromosome 19 [10–13] ; amino acid (aa) substitutions in nonstructural protein 5a, especially those in the IFN/RBV resistance-determining region [14] and the IFN sensitivity-determining region (ISDR) [15] , and the core regions of HCV [16] , as viral genetic polymorphisms. Kim et al. [17] reported that early viral dynamics with DFPP + IFN/RBV then PEG-IFN/RBV therapy is superior to the previous PEG-IFN/RBV combination therapy. There was a significant difference in viral reduction at 24 and 48 h, and 1, 2, 4, 8 and 12 weeks between nonviral response (NVR) and relapse patients. The rate of rapid viral response (RVR) and complete early viral response (cEVR) showed a significant difference between NVR and relapse patients: among the 20 patients, RVR was obtained in 75% (6/8) of relapse patients but in 0% (0/12) of NVR patients, and cEVR in 88% (7/8) of relapse patients but in only 8% (1/12) of NVR patients. On the basis of the above results, DFPP + IFN/RBV then PEGIFN/RBV therapy is indicated more for relapse than for NVR patients. We could conclude that relapse patients would be better candidates than NVR patients [17] . IL28B and Inosine Triphosphatase The recent discovery revealed by a genome-wide association study (GWAS) technology provides the unexpected role of IL28B and inosine triphosphatase (ITPA) in HCV infection. The former SNPs around the IL28B gene could improve the diagnostics on the prediction of spontaneous clearance and the response to anti-HCV treatment, suggesting that these findings could be strong evidence to enhance the development of a novel therapeutic strategy and the basic study of IFNs. Interestingly, the discovered IL28B SNPs revealed the enigma that the viral clearance rate was dependent on ethnic type. The latter functional SNP in ITPA locus was the most significant SNP associated with RBV-induced anemia as well as IFNinduced thrombocytopenia. Note that severe Hb decline, which is mainly found in ITPA -CC patients, was inversely correlated with platelet reduction, contributing to an association between severe anemia and relative reactive increase in platelet count. The efficacy of triple therapy of telaprevir/PEG-IFN/ RBV was high in the patients with genotype TT (rs8099917), who achieved SVR (84%), irrespective of substitution of core aa70. In the patients having genotype non-TT, those of Arg70 gained high SVR rate (50%), and SVR rate (12%) was the worst in patients who possessed both genotype non-TT and Gln70 (His70), suggesting genetic variation near the IL28B gene and aa substitution of the core region as predictors of SVR to a triple therapy in Japanese patients infected with HCV genotype 1b [18] . Genetic variants leading to ITPA deficiency, a condition not thought to be clinically important, protect against hemolytic anemia in CHC patients receiving RBV [19] . Results obtained in one GWAS study need to be evaluated in the context of different geographical and racial populations and independent cohorts. Tanaka confirmed that ITPA SNP (rs1127354) was a useful predictor of RBVinduced anemia in Japanese patients [20] . Excluding those with genotype 1b and high viral load, patients with ITPA minor variant A achieved significantly higher SVR rates than those with the major variant (CC; 96 vs. 70%, respectively, p = 0.0066) [20] . Because the typical PEGIFN/RBV treatment period is shorter (24 weeks) in genotype 1 low viral load and genotype 2 patients than in genotype 1 high viral load (48 weeks) patients, early dose reduction in RBV may be more critical for the final outcome. The recent discovery revealed by GWAS technology provides the unexpected role of IL28B and ITPA in HCV infection. These data may provide a valuable pharmacogenetic diagnostic tool for tailoring PEG-IFN/RBV dosing to minimize drug-induced adverse events and for further optimization of clinical anti-HCV chemotherapeutics. Total PEG-IFN Dose, Core 70 Substitution and ISDR