Liver International
Special Issue: Proceedings of the 5th Paris Hepatitis Conference. International Conference of the Management of Patients with Viral Hepatitis: Special Edition Hepatitis C
Volume 32, Issue Supplement s1, pages 141–145, February 2012
Abstract
Genotype 3 is a common type of HCV infection, and standard therapy using pegylated interferon (PEG-IFN) and ribavirin (RBV) is quite effective in these patients. While a short course of 16 weeks may result in comparable end of therapy responses, relapse rates are often high. A 24-week course is therefore preferable, and is expected to result in sustained virological response (SVR) rates of more than 70%. The 24-week course is especially recommended in the presence of steatosis (often associated with Genotype 3 infection), fibrosis stage two or more, high BMI and high viral load. In patients who do not achieve a rapid viral response (RVR) with combination therapy, an extended course up to 48 weeks should be considered. While not as definite as for genotype 1 patients, the presence of the CC variant of IL28b could help in the initial prognosis and the need for additional treatment, if an RVR is not achieved. The role of directly acting antiviral agents (DAA) has not been fully evaluated in treatment naïve, non-responders and relapsers in genotype 3 patients. Initial results with the cyclophilin inhibitor Debio-025 are quite encouraging. There is an urgent need for large clinical trials using DAA and host modulators in patients with G3 infection.
According to WHO, around 130–170 million people are chronically infected with the hepatitis C virus (HCV) worldwide, reflecting the magnitude of this global health burden [1]. The estimated prevalence is around 2%. Epidemiological surveys have also shown a geographical variation in the prevalence and distribution of hepatitis C genotypes worldwide. Although HCV genotype 1 predominates in the Western countries, genotype 3 accounts for 35–80% of chronic HCV infections in regions such as the Indian subcontinent [2], Southeast Asia and Australia [3].
The standard of care (SOC) therapy for patients with chronic HCV infection has been the combination of peginterferon (PEG-IFN) and ribavirin (RBV). These drugs are administered for either 48 weeks (HCV genotypes 1, 4, 5 and 6) or 24 weeks (HCV genotypes 2 and 3), inducing sustained virological response (SVR) rates of 40–50% in those with genotype 1, and of 80% or more in those with genotypes 2 and 3 infections [4]. However, the rates of SVR in patients infected with genotype 3 are lower than those with genotype 2 [5]. Second, compared with other genotypes, genotype 3 is associated with a higher incidence of hepatic steatosis and the rapid progression of liver fibrosis [6]. We have previously shown that the median rate of the progression of fibrosis per year is 0.25 (0.0–1.5) fibrosis units in patients with genotype 3 in India and higher in patients who acquire infection after 30 years of age. The median time for progression to cirrhosis was 16 years [7]. According to a recent meta-analysis, the odds ratio for the association of genotype 3 infection and accelerated progression of liver fibrosis was 1.52 in single biopsy studies suggesting faster fibrosis progression compared with other genotypes [8].
In a retrospective study of 353 patients, Nkontchou et al. [9] showed that hepatitis C genotype 3 was associated with a higher incidence of hepatocellular carcinoma (HCC) in patients with ongoing cirrhosis. The risk factors for an increased risk of HCC were male gender, older age, higher body mass index, low platelet count and genotype 3. Probably because of the rapid progression to fibrosis, genotype 3 could predispose to HCC along with other defined risk factors. The HCV genotype 3 core protein causes steatosis [10, 11, 12] that can lead to oxidative stress and reactive oxygen species predisposing to carcinogenesis [13, 14]. Thus, better treatment must be found for this dreadful yet curable infection.
Present treatment for hepatitis C genotype 3
According to the recent AASLD guidelines [15], PEG-IFN ![[alpha]](https://lh3.googleusercontent.com/blogger_img_proxy/AEn0k_v5EHux2jk_tRqSeC4yj-uBCVg8Uxfbt6H_Htwyh4io0bRqB326fMM25l5LI3Ra9Qt-Qo6EAPxxkUJOmRqk0wZu1cu5Yk-c92iHGi_5qz1ydum8r7s-jxqiMN8HdNLfOH1LVM3Bmohb4E3N=s0-d)
Predictors of response
IL28b polymorphism
There is recent evidence suggesting that polymorphisms near the IL28b gene, which codes for interferon (IFN)-λ3, predict response to PEG-IFN-
Other predictors of response
In a recent retrospective study by Amanzada et al. [23], a subgroup of patients with genotype 3, who were under the age of 40, who had an ‘ultrarapid’ virological response within 2 weeks (HCV RNA undetectable at week 2 of treatment), low ƴ-GT/ALT ratios and an absence of steatosis on liver biopsy, were found to achieve an SVR with IFN-
| Age < 40 years |
| Female gender |
| White race |
| Body weight < 85 kgs |
| Absence of diabetes mellitus |
| Absence of steatosis on liver biopsy |
| Fibrosis on liver biopsy ≤ 2 |
| IL 28B polymorphisms |
| rs12979860 (CC allele) |
| rs8099917 (TT allele) |
| Viral load < 4 × 10^5 IU/ml |
| Consumption of coffee (> 3 cups per day) |
Future treatment options for patients with genotype 3
HCV is a 9.6-kb positive-sense, single-stranded RNA virus. It encodes a large single open reading frame corresponding to a poly-protein precursor of about 3000 amino acids, which is proteolytically processed by cellular signal peptidases and HCV-encoded proteases into at least 10 individual proteins, in the order of C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B. Newer antivirals, more commonly known as directly acting antivirals (DAA), have mainly focused on two viral proteins, the NS3-4A serine protease and the NS5B RNA-dependent RNA polymerase, both of which have enzymatic activities essential for viral replication [24]. The peptidomimetic inhibitors of the NS3/4A serine proteases, telaprevir (VX-950) and boceprevir (SCH-503034) have created a revolution in the treatment of genotype 1 and have recently been recommended in combination with the standard bitherapy PEG-IFN/RBV for the treatment of patients with chronic hepatitis C genotype 1 [4]. However, these drugs have not shown to be of great benefit in the treatment of patients with genotype 3.
An alternative strategy is to target host factors that are also required for viral replication. Cyclophilins are a family of cellular peptidyl-prolyl isomerases required for HCV replication [25]. In an in vitro study by Mathy et al., combinations of a host factor (cyclophilin) inhibitor, NIM811, were studied with the three main classes of virus specific inhibitors: BILN2061 (ciluprevir), first NS3-4A protease inhibitor, a non-nucleoside NS5B polymerase inhibitor thiophene-2-carboxylic acid, and NM107, the active moiety of NM283 (valopicitabine), the first nucleoside NS5B inhibitor. Based on mathematical modelling, the effect of these combinations was shown to be synergistic for NIM811 with a nucleoside or a non-nucleoside viral polymerase inhibitor and additive for NIM811 with a viral protease inhibitor. The key advantages of targeting host factors are long lasting antiviral response and a greater genetic barrier to the emergence of viral escape mutants. The use of the oral cyclophilin B inhibitor Debio-025 was first investigated in a randomized double blind, placebo controlled trial of 19 patients co-infected with HIV and HCV [26]. Of the 19 co-infected patients, those treated with Debio-025 1200 mg twice daily for 15 days (n = 16) experienced a significantly greater maximum reduction of log10 HCV RNA copies/ml (only in genotypes 1, 3 and 4) than placebo treated (n = 3) patients. The least squares mean of the maximum reduction of log10 HCV RNA copies/ml for the Debio-025 group was −3.63 compared with −0.73 in the placebo group. The greatest response was observed in patients with genotype 3 who achieved a least squares mean maximum reduction of log10 HCV RNA copies/ml of −4.46 log10. None of the patients developed a viral breakthrough in the treatment arm, and time to relapse varied after the end of treatment. This was the first study to show the antiviral effects of oral cyclophilin inhibitors in a clinical study; however, larger studies are needed before this regimen can be clinically recommended. Another group of host factors was studied by Lupberger et al. [27]. The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that regulates a number of key processes, including cell proliferation, survival and differentiation during development, tissue homeostasis and tumorigenesis.
Ephrin receptor A2 (EphA2) mediates cell positioning, cell morphology, polarity and motility. HCV entry is a multistep process involving viral envelope glycoproteins and host cell factors. Attachment of the virus to the target cell is mediated through binding of HCV envelope glycoproteins to glycosaminoglycans. HCV is internalized in a clathrin-dependent endocytic process requiring CD81, scavenger receptor type B class I (SR-BI), claudin-1 (CLDN1) and occludin (OCLN). Inhibition of EGFR or EphA2 activity reduced CD81-CLDN1 association, hence hampering the cell entry process of HCV. The in vitro results showed that EGFR or EphA2 inhibition was associated with decreased cell entry, fusion, cell-to-cell transmission and subsequently decreased viral spread. This was extrapolated in in vivo studies conducted using an erlotinib (EGFR inhibitor) chimeric urokinase plasminogen activator–severe combined immunodeficiency (uPA-SCID) mouse model. Its treatment decreased steady-state HCV RNA levels by more than 90%. However, viral load increased, once the treatment was discontinued. Treatment was well-tolerated and did not induce any marked changes in safety parameters such as serum concentrations of alanine transaminase, albumin or body weight. These fascinating results provide a glimmer of hope, although there is a long way to go before they can be recommended in patients with chronic hepatitis C. There are many drugs in the pipeline, some of which are being studied in phase III trials (Table 2).
Conflicts of interest
The authors declare no conflicts of interest.
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