Basic Answers to Complicated Questions for the Course of Chronic Hepatitis C Treatment

Necati Örmeci; Hakan Erdem


Expert Rev Gastroenterol Hepatol. 2012;6(3):371-382. 

In This Article

Abstract and Introduction


Hepatitis C virus infection is a long-lasting disease, which causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma, thus leading to liver-related death. Currently, the optimal treatment for chronic hepatitis C infection is the combination of pegylated interferon and ribavirin. The aim of this review is to assess the long-term clinical outcomes of interferons alone or in combination with ribavirin in the management of chronic hepatitis C.


Hepatitis C virus (HCV), discovered in 1989, is an enveloped virus, with a 9600 bases in length, single-stranded RNA genome contained in a capsid, itself enveloped by a lipid bilayer in which two different glycoproteins are combined. The genome encodes a polyprotein of approximately 3000 amino acid residues that is processed post-translationally by host and viral proteases into ten structural and nonstructural proteins. The nonstructural proteins encode several enzymes required for protein processing and replication. The HCV RNA genome serves as a template for viral replication and as a viral messenger RNA for viral production. There are six genotypes. Genotypes 1 and 4 are associated with a lower rate of therapeutic response.[1]

Overall, 2–3% of the human population, reaching approximately up to 170 million people around the world, is infected with HCV.[2] HCV infection is the leading cause of chronic hepatitis (55–85% per year), liver cirrhosis (2–5% per year) and hepatocellular carcinoma (HCC; 1–3% per year) in the world.[3] After the acquisition of HCV, 15–35% of patients resolve spontaneously, the serum is cleared from HCV-RNA and antibodies for HCV are detected. Accordingly, the remainder of the patients (65–85%) appear to experience a chronic course.[3–5] The natural history of the disease is largely modulated by cofactors – for example, progression to cirrhosis is high in HIV/HCV coinfection, or concomitant, even moderate, alcohol consumption combined with hepatitis C infection. This unfavorable natural course can be substantially improved when cofactors are removed – that is, by constant effective antiretroviral therapy or abstinence from alcohol consumption.[6–8] The approximate time intervals between infection and the occurrence of chronic hepatitis, liver cirrhosis or hepatocellular carcinoma (HCC) are approximately 6 months to 10, 20 and 30 years, respectively. Among the patients with chronic hepatitis C (CHC), progression of fibrosis is either minimal or absent in 15–33% of cases during the following 1–2 decades, and those cases do not usually experience liver cirrhosis. However, 75% of the patients with CHC may progress and develop cirrhosis. Among those patients with liver cirrhosis, three-quarters of the patients remain stable, whereas the remaining cases may develop liver decompensation, leading to life-threatening complications such as ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy, liver cancer and death within 5 years. Moreover, the most common indication for liver transplantation is HCV-induced cirrhosis in the USA, Japan, Europe and Australia.[4]

Since its discovery in 1989, treatment of HCV has evolved from conventional interferon (IFN) monotherapy to the currently recommended combination of pegylated IFN (PEG-IFN)-α and ribavirin (RBV).[9–12] IFN has been shown to have immune-modulating, antiviral, antifibrotic and antiproliferative effects in CHC. RBV is a guanosine nucleoside analog that has been shown to have antiviral activity by various means. The drug blocks viral replication via RNA polymerase, enhances the host-adaptive antiviral immune response and increases the mutational frequency by the mutagens, thus leading to lethal mutagenesis.[13] In fact, higher RBV serum concentrations are known to correlate with improved treatment outcomes.[14,15] However, it is still not clear how RBV works synergistically with IFN to improve sustained virological response (SVR) rates.[16]

SVR is defined as the loss of HCV-RNA with a sensitive PCR method for a minimum of 6 months after the end of treatment in CHC.[17] The liver is the main site of HCV replication, although the process can take place in extrahepatic locations, such as in peripheral blood mononuclear cells and monocyte-derived dendritic cells. It may be assumed that reactivation from those reservoirs may occur easily on some occasions, particularly in patients with immune suppression and advanced fibrosis or those infected with genotype 1 HCV.[18–20]

A number of studies reported that the SVR rate of IFN-α monotherapy varies between 5 and 15% of patients.[4,21] By contrast, RBV has been demonstrated to be unable to maintain the SVR alone. However, adding RBV to IFN significantly improved treatment outcomes so that SVR rates increased up to 54–56%,[22–24] and this approach has been accepted as the mainstay of CHC management. This combination has been well tolerated even in thalassemia major patients, except for an increase in blood transfusion requirements because of RBV side effects.[25]

Approximately 70–75% of patients who are infected with HCV in the USA are infected with genotype 1, which is associated with a lower rate of response. Currently, standard treatment with PEG-IFN and RBV results in less than 50% SVR rates in these patients. Recently, several molecular targets, such as NS3 protease and NS4A protein, which cleave the viral gene products and are necessary for the life cycle of the virus, have been identified. The combinations of NS3 protease and NS4A protein inhibitors, together with PEG-IFN and RBV, improved SVR in naive patients, and also in relapsers and nonresponders.[1]

The combination of telaprevir, a protease inhibitor specific to the HCV NS 3/4A serine protease, together with PEG-IFN and RBV for 24 weeks in naive patients who had genotype 1 HCV infection, resulted in 75% SVR in a Phase II trial.[26] Similarly, the combination of telaprevir and PEG-IFN plus RBV for 12 weeks in previously treated patients led to an-SVR of 88%.[27]

The combination of bocepravir, another potent HCV protease inhibitor, and PEG-IFN plus RBV for 24 or 44 weeks in naive non-black patients with HCV genotype 1 achieved a 67 or 68% SVR in Phase II studies. However, the same combination at 24 or 44 weeks had a 42 or 53% SVR in HCV-naive black patients.[28] Similarly, the combination of bocepravir and PEG-IFN plus RBV for 44 weeks in previously treated patients with HCV genotype 1 had an 88% SVR if the patients had undetectable HCV-RNA after the first 8 weeks of treatment.[29]

In terms of health-related quality of life, eradication of HCV with PEG-IFN plus RBV results in better quality of life and decreased fatigue, even in normal alanine aminotransferase (ALT) patients.[30] Treatment of patients with PEG-IFN-α2a was associated with less disabling fatigue and less impairment in patient functioning compared with IFN-α2a in patients with CHC as well.[31–33] In the literature, there are numerous reports using different methodologies and patient populations in the treatment and course of CHC. This multifaceted accumulation of the data in the literature habitually prevents meta-analysis of the current knowledge. Thus, the aim of this review is to project the long-term outcomes of IFN or PEG-IFN and their combinations with RBV in terms of durability of SVR, regression of liver fibrosis and cirrhosis, mortality and morbidity, and improving survival and quality of life. These tricky issues are summarized by basic answers to complicated questions for CHC in this paper.


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