Abstract and Introduction
Abstract
Background Over the past several years, hepatitis C therapy has been pegylated interferon and ribavirin based. Although protease inhibitor-based therapy has enhanced response rates in genotype 1, the recent advances in therapy have demonstrated a challenge in genotype 3, a highly prevalent infection globally.
Aim To provide a comprehensive summary of the literature evaluating the unique characteristics and evolving therapies in genotype 3.
Methods A structured search in PubMed, the Cochrane Library and EMBASE was performed using defined key words, including only full text papers and abstracts in English.
Results HCV genotype 3 is more prevalent in Asia and among intra-venous drug users. Furthermore, it interferes with lipid and glucose metabolism, and the natural history involves a more rapid progression of liver disease and a higher incidence of hepatocellular carcinoma (HCC). New therapies with protease inhibitors have focused on genotype 1 largely and have demonstrated enhanced responses, but have limited activity against genotype 3. Thus far, in clinical trials, NS5B and NS5A inhibitors have performed more poorly in genotype 3, while a cyclophilin inhibitor, alisporivir, has shown promise.
Conclusions As treatments for HCV have evolved, genotype 3 has become the most difficult to treat. Furthermore, genotype 3 has special characteristics, such as insulin resistance and alterations in lipid metabolism, which may partly explain the lower treatment responses. A great deal of emphasis on advancing therapy is needed in this population that appears to have a more rapid progression of liver disease and a higher incidence of HCC.
Introduction
Hepatitis C virus (HCV) infection is a global health problem that affects 170 million people worldwide, and approximately 55% (95 million) of the infected population is in South East Asia and Western Pacific countries. Chronic hepatitis C is associated with significant morbidity and mortality, which result mainly from the progression towards cirrhosis and hepatocellular carcinoma (HCC). Factors associated with rapid progression include: (i) host factors (i.e. older age at infection, male gender, Afro-American race, alanine aminotransferase level, liver fibrosis, genetic factors, metabolic factors); (ii) viral factors (i.e. genotype, viral load, viral kinetics); (iii) co-infections (i.e. hepatitis B virus or human immunodeficiency virus); (iv) exposure to toxic agents (i.e. alcohol, tobacco or cannabis). Fibrosis progression in hepatitis C genotype 3 seems to be more rapid than in genotype 1 and is probably related to a higher degree of steatosis.
Hepatitis C virus does not integrate into the human genome. Thus, a sustained virological response (SVR), a feature strongly linked to reduced likelihood of progressive liver disease and mortality, is key to achieving cure. Traditionally, genotypes 2 and 3 have been placed in the same group when making a decision on the dose of ribavirin or treatment duration. More recently, genotype 2, unlike genotype 3, has been found to be sensitive to various direct-acting anti-virals (DAAs), thus resulting in differences in SVR rates. Therefore, genotype 2 and genotype 3 should not be grouped together for analyses of SVR rate or for therapeutic strategies. Given the recent approval of the DAAs for genotype 1 and with new imminent therapies, it is important that we recognise that genotype 3 is now the more difficult genotype to treat. With the unique features and challenges in treatment in mind, we reviewed the literature and provide a perspective on chronic hepatitis C genotype 3.