Translational Research of Hepatitis C Virus
From discovery to eradication
Ming-Lung Yu
Distinguished Professor
Department of Internal Medicine, Kaohsiung Medical University Hospital; School of
Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Hepatitis C virus (HCV) has been identified as the major etiology responsible for
transmission-related non-A, non-B hepatitis by using cDNA immunoscreening
approach in 1989. HCV is a positive-sense, single-stranded 9600 kb RNA virus. A
single HCV polyprotein of 3011 aminoacids is translated, and then cleaved by cellular
and viral proteases into three structural proteins (core, E1, and E2) and seven
non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). The
prevalence rate for anti-HCV antibodies worldwide is estimated to have increased
from 2.3% (122 M) to 2·8% (185 M) between 1990 and 2005. Six major HCV
genotypes are identified worldwide, which has been related to disease progression
and treatment outcome. HCV infection frequently causes chronic liver disease (75%)
leading to cirrhosis and HCC and has become the main indication for liver
transplantation in Western countries. Chronic HCV infections have been associated
with several extrahepatic manifestations, including diabetes, mixed cryoglobulinemia,
renal involvement and cardiovascular events.
The goal of HCV treatment is to eradicate the virus from host, by achieving a
sustained virological response (SVR, HCV RNA undetectable 24-w after antiviral
therapy). IFN-based therapy has been the mainstay of treatment for chronic hepatitis
C (CHC). Currently, the “standard-of-care”, 48 weeks and 24 weeks of pegylated IFN
(Peg-IFN) plus ribavirin (RBV) could attain SVR rates of 50% (Western countries) and
75% (Eastern countries) for HCV genotype 1 (HCV-1) and 85%-90% for HCV-2
patients, respectively. The ethnicity-specific difference of SVR rate in HCV-1 between
West and East is because of genetic difference of Interleukin-28B polymorphisms.
Introduction of response-guided therapy by viral kinetics during treatment could
shorten treatment duration without compromising treatment efficacy. More recently,
IFN-free regimens, with combination of several new oral directly acting antiviral
agents (DAA), have been approved for both IFN-eligible and IFN-ineligible patients,
with an overall SVR rates of around 98% across the viral genotypes.
Long-term beneficial effects of antiviral therapy were observed in terms of
reducing the progression of cirrhosis, hindering HCC development, and prolonging
survival among both patients who achieved a sustained virological response (SVR).
SO far, no prophylactic vaccine exists due to high genomic mutation of HCV and
lack of broadened neutralizing antibodies, but several are in development and in
early-stage clinical trials