2 Clinical need and practice
2.1 Chronic hepatitis C (CHC) is a disease of the liver caused by the hepatitis C virus (HCV). Generally, the virus is transmitted by blood-to-blood contact. Before the introduction of screening in 1991 it was also spread through blood transfusions. Before the viral inactivation programme in the mid-1980s it was also spread through blood products. HCV can be acquired by people who inject drugs through the sharing of needles. There is a small risk of infection associated with tattooing, electrolysis, body piercing and acupuncture. Infection through sexual intercourse can also occur. There is a transmission rate of about 6% from mother to child if the mother is an HCV carrier. Concomitant HIV infection is thought to increase the risk of transmission.
2.2 People are often asymptomatic after exposure to the virus, but about 20% will develop acute hepatitis; some of them will experience malaise, weakness and anorexia. Up to 85% of those exposed do not clear the virus and go on to develop CHC. Progression of the disease occurs over 20–50 years. About 5–30% of people initially infected will develop cirrhosis within 20 years and a small percentage of these are at high risk of developing hepatocellular carcinoma. One-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 require liver transplantation.
2.3 Six major genetic types of HCV have been identified. Genotype 1 (G1) is the most common in the UK, and is found in about 40–50% of cases. Genotypes 2 and 3 (G2/3) contribute another 40–50%, and genotypes 4, 5 and 6 constitute the remainder of about 5%. Response to treatment varies between different genotypes. G1 is relatively more common among people infected through blood products, and G2/3 is relatively more common among people who inject themselves with illicit drugs.
2.4 Many individuals with HCV infection do not display symptoms. However, non-specific symptoms, such as fatigue, irritability, nausea, muscle ache, anorexia, abdominal discomfort and pain in the upper right quadrant, have been reported even in the absence of secondary pathology. If cirrhosis develops, people may have severe symptoms and complications.
2.5 Estimates of prevalence for hepatitis C in England and Wales vary considerably. The extant NICE guidance (see Section 8.1) puts the figure between 200,000 and 400,000, whereas the Assessment Report suggests between 50,000 and 500,000. There is also great variation in prevalence between certain subgroups of the population: 0.04% in blood donors, 0.4% in people attending antenatal clinics (in London), 1% in people attending genito-urinary clinics and up to 50% in injecting drug users.
2.6 About two-thirds of people with HCV infection are men, mainly because more men inject themselves with illicit drugs, but also because there are far more men than women with haemophilia.
2.7 Because it is not possible to measure directly the effectiveness of treatment in reducing progression to cirrhosis and hepatocellular carcinoma in the short term, three surrogate markers have been used in trials: hepatic histology; virological loss of HCV-RNA (measured by the polymerase chain reaction, PCR); and levels of alanine aminotransferase (ALT, an enzyme that indicates liver inflammation).
2.8 The primary aim of treatment for people with CHC is to clear HCV (defined as undetectable HCV-RNA in the serum) for at least 6 months after treatment cessation, in order to improve quality of life for patients and reduce the risk of cirrhosis and hepatocellular carcinoma.
2.9 The diagnosis of hepatitis C causes considerable anxiety to people. It is generally accepted, though without formal trial evidence, that all people diagnosed with the condition should receive adequate advice and information from a healthcare professional with knowledge and experience in the field.
2.10 The current standard treatment for moderate and severe chronic HCV infection is combination treatment with interferon alfa and ribavirin, except for people who cannot tolerate ribavirin, when interferon alfa monotherapy is used (Section 8.1 references the NICE guidance that is replaced by this guidance). The precise antiviral mode of action of interferon alfa is unknown. However, it appears to alter host-cell metabolism. It is available in the UK in two forms, interferon alfa-2a (Roferon A, Roche) and interferon alfa-2b (Viraferon, Schering-Plough).
2.11 Interferon alfa is eliminated from the body rapidly, having a plasma half-life of only about 4 hours. To maintain effectiveness against HCV, doses must be administered by injection on a minimum of 3 days a week.
2.12 The duration of monotherapy treatment is 48 weeks. For monotherapy, more than half of people who clear the virus after treatment relapse within 6 months of treatment cessation, but for those who remain clear after 6 months, about 90% remain so after 6 years. Thus, for this group, treatment may be called a cure. The dosage for interferon alfa treatment is usually 3 million units three times per week by subcutaneous injection. Injections are administered by clinical staff or by the patient after adequate training. People who respond usually do so within 12–16 weeks. Those who respond continue with this dose of interferon alfa for 48 weeks.
2.13 Many, but not all, people find interferon alfa therapy very hard to tolerate. After each injection, they may suffer influenza-like symptoms, and up to one-half of all people treated suffer from fatigue, headaches, pyrexia (fever), myalgia (aches and pains), insomnia and/or nausea. About one-quarter suffer hair loss, arthralgia (pain in the joints), rigors, irritability, pruritus (itching), depression, dermatitis and/or decreased appetite. There are significant problems of dropout and non-adherence with treatment as a result. Dropout rates of 7–14% have occurred. Figures on adherence are more difficult to quantify.
2.14 In the late 1990s, combination treatment of interferon alfa and ribavirin commenced, following trials that showed that, although ribavirin alone showed no activity against HCV, the effect of the combination of ribavirin with interferon alfa was much enhanced compared with that of interferon alfa alone. Since the introduction of combination therapy, monotherapy is used only for people unable to tolerate ribavirin.
2.15 Ribavirin (Copegus, Roche; Rebetol, Schering-Plough) is a nucleoside analogue with a broad spectrum of antiviral activity against RNA viruses. It is licensed for use in combination with interferon alfa-2a or interferon alfa-2b for treatment of CHC in:
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adult patients with histologically proven, previously untreated CHC, without liver decompensation, who are positive for serum HCV-RNA and who have fibrosis or high inflammatory activity
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adult patients with CHC who have previously responded (with normalisation of ALT at the end of treatment) to interferon alfa but subsequently relapsed.
2.16 Ribavirin is administered orally, usually in divided doses (200 mg per capsule or tablet). The dosage varies according to the patient's weight. Regular monitoring of full blood count to detect haemolytic anaemia is needed in order to judge whether to reduce or cease ribavirin treatment.
2.17 Ribavirin is contraindicated in pregnancy and breastfeeding, in severe debilitating medical conditions (particularly of the heart, blood, kidneys and liver), in haemoglobinopathies and in the presence of autoimmune diseases or severe psychiatric conditions. It may also cause haemolytic anaemia, for which close monitoring is required and a reduction in dose or cessation of treatment may be necessary.
2.18 Adverse effects related to combination therapy are similar in type and frequency to those of interferon alfa monotherapy and include influenza-like symptoms (fatigue, headache and fever), decreases in haematological parameters (neutrophil, white blood cell and platelet counts), gastrointestinal complaints (anorexia and nausea), dermatological symptoms (alopecia) and psychiatric disturbances (depression and anxiety). The trials indicate that discontinuation of treatment is more frequent (10–20%) for combination therapy than for monotherapy. Studies of combination therapy show that haematological events were the most common reason for either study withdrawal or dose reduction.
2.19 Standard treatment with interferon alfa combination therapy is either for 24 weeks (for people with G2/3) or for 48 weeks (for people with G1).
2.20 Treatment with interferon alfa monotherapy or combination therapy is not licensed for people younger than 18 years of age.
2.21 The following factors affect the efficacy of treatment.
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Genotype of the virus. This is the most important determinant of efficacy of treatment.
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High viral load. The higher the viral load, the lower the proportion of people with HCV who have a sustained virological response (SVR), all other things being equal. High viral load is the second most important determinant of efficacy of treatment.
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Age. Younger people fare better than older people. This may be because older people tend to have been infected for longer, although there appears to be an independent factor beyond that.
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The period between infection and treatment. Longer delays appear to adversely affect the efficacy of treatment.
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Weight. People who weigh more than the average have a lower response rate to treatment than those who weigh less than the average, when the dosages of interferon alfa (and ribavirin for combination therapy) are fixed.
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Fibrosis and cirrhosis of the liver (which act as markers for the damage done by the virus). The greater the damage, the less likely it is that the body can rid itself of the virus.
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The pre-treatment ALT level. The higher the pre-treatment ALT level, the lower the probability of treatment success.
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Racial group. Studies in the USA have shown that black people had a poorer response to treatment than white people, but there is no evidence of the impact of ethnicity in a UK setting.
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Gender. Women respond somewhat better than men to fixed doses (though evidence suggests that this may be due to women's lower average weight, and hence to the effective dose per kilogram).
2.22 Because HCV and HIV share common routes of transmission, many people with HIV are also infected with HCV. In these people, hepatitis C is a leading cause of death. It appears that HIV is associated with an acceleration of liver disease caused by HCV. Treatment of co-infected people is complicated by the possibility of adverse drug interactions, particularly with ribavirin. Studies show that treatment of people co-infected with HIV and HCV with interferon alfa combination therapy results in worthwhile (if somewhat lower) clearance rates of HCV than in people with HCV but not HIV. This is likely to be attributable to higher discontinuation rates and problems of drug interactions.
2.23 A 4-week cycle of interferon alfa at 3 million units three times a week costs around £200. Ribavirin for the same period costs from about £350 to £500. (All prices exclude VAT, British National Formulary 45th edition.) Therefore, 24 weeks of combination therapy of interferon alfa plus ribavirin will cost around £4000 (excluding monitoring costs). The cost of treatment depends on which of interferon alfa-2a or interferon alfa-2b is used, and on weight, because the accompanying ribavirin dose is differentially weight-related.
2.24 The value of triple therapy (combination therapy of interferon alfa and ribavirin plus amantadine) has to be fully assessed.