Chronic hepatitis C constitutes a major global health concern as it is a leading cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. The goal of therapy is to prevent these complications through viral eradication.
The hepatitis C virus (HCV) was first identified in 1989 and HCV infection has become a major health problem worldwide. Approximately 0.8% of the Scottish population is thought to be chronically infected with HCV (around 37,500 individuals). The prevalence of infection varies between population groups ranging from 50% in injecting drug users (IDU) to less than 0.04% among new blood donors.
Up to 80% of patients infected with HCV become chronically infected and most of these patients will show evidence of chronic hepatitis.
Hepatitis C is usually slowly progressive over a period of many years. Five to fifteen per cent of patients with chronic hepatitis may progress to liver cirrhosis over 20 years. Four to nine per cent of patients with cirrhosis will develop liver failure; and two to five per cent of patients with cirrhosis will develop primary hepatocellular carcinoma.
In the UK the two major routes of transmission of HCV have been sharing of drug injecting equipment by IDU and transfusion of infected blood or blood products. Virus inactivation treatment of blood products began in 1987 and since 1991, blood donations have been screened for hepatitis C, eliminating blood products as a source of HCV infection. Until recently, HCV infection can be effectively treated with combination drug therapy (peginterferon alfa, ribavirin and the new directly-acting antivirals) with Sustained Viral Response (SVR) rates in 50-80% of patients.
HCV is characterised by genotypes and subgroups with prevalence varying depending on the geographical location. Genotype 1 subgroup a and genotype 3 are the most common in Scotland. HCV genotype 1 and particularly subgroup b, does not respond to therapy as well as genotypes 2 and 3.
Genotype 1b occurs in a small percentage of patients in Scotland, subtype 1b is difficult to eradicate using current medications; this type is most prevalent in Europe, Turkey, and Japan
Genotypes 2 occurs in less than 10% of patients; these subtypes are most responsive to medication
Genotypes 3 occur in around 50% of patients in GGC; these subtypes are most prevalent in India, Pakistan, Thailand, Australia, and Scotland (IVDU population)
Genotype 4 occurs in less than 5% of patients; it is most prevalent in the Middle East and Africa
Within a region, a specific genotype may also be associated with a specific mode of transmission, such as genotype 3 among persons in Scotland who abuse intravenous drugs.
Treatment of chronic HCV infection has 2 goals. The first is to achieve sustained eradication of HCV (i.e. sustained virologic response [SVR]), which is defined as the persistent absence of HCV RNA in serum 3 months or more after completing antiviral treatment. The second goal is to prevent progression to cirrhosis, hepatocellular carcinoma (HCC), and decompensate liver disease requiring liver transplantation.
Antiviral therapy for chronic hepatitis C should be determined on a case-by-case basis. However, treatment is generally recommended for patients with elevated serum ALT levels who meet the following criteria;
Age greater than 18 years
Positive HCV antibody and serum HCV RNA test results
Compensated liver disease (e.g. no hepatic encephalopathy or ascites)
Acceptable hematologic and biochemical indices (hemoglobin at least 13 g/dL for men and 12 g/dL for women; neutrophil count >1500/mm3, serum creatinine < 1.5 mg/dL)
Willingness to be treated and to adhere to treatment requirements
No contraindications for treatment
Until now, some patients with normal liver enzyme levels and minimal liver fibrosis on ultrasound have elected to defer treatment until more effective and less toxic medications become available, whereas patients with more advanced liver injury prefer to initiate treatment sooner. Patients should be advised that the treatment of HCV infection in those with normal liver enzyme levels remains controversial.
The treatment of hepatitis C has evolved over the years. Initial studies used interferon (IFN) monotherapy. Current treatments are combination therapy consisting of ribavirin and IFN to which polyethylene glycol (PEG) molecules have been added to increase the half life, i.e. peginterferon (PEG-IFN). Protease inhibitors emerged as a third feature of combination therapy for patients with genotype 1 infection (G1). The first protease inhibitor indicated for use in HCV infection, boceprevir (Victrelis®), was approved by the EU approval July 2011 followed soon afterwards by telaprevir (Incivo®).
The creation of the new standard 'triple therapy' with the DAA (Directly Acting Antiretroviral) medications has led to significant improvements in the response rates for patients with G1 HCV, with SVR rates as high as 63–75% and reduction in duration of therapy by half for many patients based on response-guided therapy.
Whilst the appropriate use of protease inhibitors with peginterferon-ribavirin provided significant increases in cure rates of G1 chronic HCV infection, therapeutic options for HCV were still far from optimal. Many new side effects were encountered; drug interactions took on new importance and issues with resistance and intolerance persist, there is also an increased rate of adverse effects with the use of triple therapy.