2 Clinical need and practice
2.1 Chronic hepatitis C is a disease of the liver caused by the hepatitis C virus. Generally the virus is transmitted parenterally, but the natural history of the disease is not completely understood. The virus is primarily acquired through percutaneous exposure to contaminated blood. Since the viral inactivation programme was implemented in the mid-1980s and blood donor screening started in 1991, the transmission of HCV in the UK, via transfusion of blood, blood products or organ transplantation, has all but ceased. However, injecting drug use, cosmetic and other practices involving percutaneous exposure remain common routes of transmission. HCV prevalence is correlated with markers of sexual activity, but HCV incidence in monogamous heterosexual partners of infected people is extremely low. There is a transmission rate of about 6% from mother to child if the mother is an HCV carrier. Concomitant HIV infection increases the risk of transmission.
2.2 People infected with HCV are often asymptomatic, but about 20% will develop overt hepatitis. Many people who are chronically infected will experience non-specific symptoms including malaise, weakness and anorexia. About 80% of those exposed go on to develop chronic hepatitis. The rate of progression of the disease is slow but variable, usually taking about 20–50 years from the time of infection. About 30% of those who are infected develop cirrhosis within 20–30 years, and a small percentage of these people are at a high risk of developing hepatocellular carcinoma. A third may never progress to cirrhosis or will not progress for at least 50 years. Some people with end-stage liver disease or hepatocellular carcinoma may need liver transplantation.
2.3 The effectiveness of treatment is related to the genotype of the virus. Six major genetic types of HCV have been found. Genotype 1 is the most common in the UK, accounting for about 40–50% of cases. Genotypes 2 and 3 contribute another 40–50%; and genotypes 4, 5 and 6 constitute the remainder, about 5%.
2.4 Recent estimates suggest that approximately 200,000 to 500,000 people are infected with HCV in England and Wales. (In 2005, the Department of Health estimated that only 47,000 people with HCV infection had been diagnosed and only 7000 had been treated.) There is also great variation in prevalence between subgroups of the population: 0.04% in blood donors, 0.4% in people attending antenatal clinics in inner London, 1% in people attending genitourinary clinics and up to 50% in intravenous drug users attending drug abuse clinics.
2.5 Because it is not possible in the short term to directly measure the effectiveness of treatment in reducing progression to cirrhosis and hepatocellular carcinoma, three surrogate markers have been used in trials:
virological loss of HCV-RNA (by quantitative polymerase chain reaction)
levels of alanine aminotransferase (an enzyme that indicates the presence of liver inflammation).
2.6 The previous NICE guidance (TA 75) applies only to people with moderate or severe chronic hepatitis C, which is defined as histological evidence of significant scarring (fibrosis) and/or significant necrotic inflammation of the liver. For the majority of people with moderate or severe hepatitis C, the standard treatment is combination therapy with ribavirin and either peginterferon alfa-2a or peginterferon alfa-2b. Monotherapy with peginterferon alfa is used only for people unable to tolerate ribavirin.
2.7 In trials for people with moderate or severe hepatitis C, about 75–85% of people with HCV genotype 2 or 3 had a sustained virological response 6 months after finishing a course of treatment with peginterferon alfa and ribavirin. For people with genotype 1, the rate of sustained virological response was about 40–50%, while for the three less common genotypes (4, 5 and 6) the rate appears to be between those for genotype 1 and genotypes 2 or 3.
2.8 For people with moderate or severe disease and with genotype 2 or 3, the maximum rate of sustained virological response is attained after 24 weeks of treatment. Further treatment does not increase the rate, so treatment beyond 24 weeks is not advised. For people with the other genotypes, it may take longer than 24 weeks to gain a sustained virological response, so the standard treatment length is 48 weeks. However, if no virological response has occurred by 12 weeks of treatment, a sustained response is unlikely to occur. Hence, it is recommended that people who do not attain a sufficient virological response by 12 weeks should not receive a further 36 weeks of treatment. People infected with genotypes 2 or 3 do not need a test of virological response at 12 weeks, because almost all respond by that time.
2.9 Peginterferons are formed by attaching strands of polyethylene glycol (PEG) to the interferon molecules. This slows the rate of absorption and excretion of interferon, reducing the fluctuations in serum concentrations that occur with unmodified interferon. The pegylation process increases the half-life of the interferon molecule in the body: in the case of peginterferon alfa-2a from about 4 hours to between 50 and 130 hours, and for peginterferon alfa-2b from about 4 hours to about 40 hours. Accordingly, people treated with peginterferon alfa need injections only once a week, compared with three times a week for people treated with non-pegylated interferon, referred to in this guidance as 'interferon'. In addition, clinical trials suggest that response rates to interferon among people with moderate or severe disease are significantly lower than response rates to peginterferon therapy.
2.10 Standard haematological tests and blood chemistry (that is, full blood count and differential platelet count, liver function tests, uric acid, serum bilirubin and serum creatinine) are necessary for all patients being considered for combination therapy. The HCV genotype with which the person is infected should be determined for all candidates for combination therapy. Liver biopsy has played a role in helping to determine disease staging, but it is no longer considered necessary for people with HCV of genotypes 2 and 3, or if biopsy poses an increased risk. Patients should be seen weekly for the first 4 weeks of treatment and then monthly for 6 months to check for haemolysis and changes in thyroid activity.
2.11 Both pegylated interferon and interferon give rise to flu-like symptoms in many people. Ribavirin leads, in a proportion of cases, to anaemia, pruritus, rash, insomnia and dyspnoea. For full details of side effects and contraindications, see the summary of product characteristics for each drug.
2.12 The standard measurement of the effectiveness of treatment, in people with chronic hepatitis C, is the virological response rate sustained for 6 months (known as the sustained virological response rate). This is defined as the proportion of people in whom the virus is undetectable in blood samples 6 months after treatment has been completed.
2.13 A direct measure of viral activity is viral load, which is the number of copies of the virus in a given quantity of blood. Although a high viral load is likely to mean that the liver deteriorates more quickly than it does under the influence of a low viral load, the relationship is not a simple one, and some people live with high viral loads for many years without progressing from mild disease to moderate disease.
2.14 A person is classified as having mild, moderate or severe chronic hepatitis C based on the extent of liver damage. If there is a sufficient need to know the extent of liver disease, this may be determined histologically by liver biopsy. The main indicator of liver damage is the degree of fibrosis, although the degree of necroinflammation also contributes to the diagnosis.
2.15 At a time before the treatment of mild chronic hepatitis C was routinely considered, it was the practice to perform a liver biopsy before prescribing interferon alfa or peginterferon alfa to determine whether a person with chronic hepatitis C had reached a moderate or severe stage of the disease. Initiating treatment at an earlier stage means this is no longer necessary.