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The identification of hepatitis C virus (HCV) in 19891 illuminated many dark corners in the natural history of the infection formerly known as non-A, non-B hepatitis. Chronic infection with HCV, we now know, affects more than 170 million people worldwide, and up to 90% of these will progress to chronic liver disease.2 Prevalence rates of infection range from 0.5-2% in the developed world, through 6.5% in parts of equatorial Africa, to as high as 20% in Egypt. The virus is transmitted by blood-to-blood contact and most infections in the Western world were acquired either through intravenous drug abuse or, before the advent of anti-HCV screening in 1992, through transfusion of blood or blood products. A high proportion of individuals with HCV infection in the USA3 and the UK were infected 20-25 years ago by sharing of drug injection equipment, so we face a substantial rise in the prevalence of end-stage liver disease. In the UK, between 200 000 and 400 000 individuals are believed to harbour the infection, most of whom have yet to be diagnosed. In developing countries the principal vehicle of transmission is inadequately sterilized medical equipment,4,5 and the high prevalence in Egypt may be attributable to lack of hygiene in schistosomiasis prevention programmes after the Second World War.6 Sexual transmission contributes few cases,7 and vertical transmission is likewise uncommon (< 6% of children becoming HCV-positive) unless the mother has high viraemia or is coinfected with HIV.8 The virus has not been shown to be transmitted by breast feeding.
Within 30 years after HCV infection nearly one-third of patients have developed cirrhosis. Independent factors associated with rapid progression to fibrosis include age at infection greater than 40 years, daily alcohol consumption 50 g or more and male sex.9 Other possible factors are immunodeficiency (for example due to HIV) and coinfection with hepatitis B virus.
Infection with the hepatitis C virus results in extrahepatic as well as hepatic diseases. In a minority of patients the first sign is an acute syndrome resembling other forms of acute hepatitis. The mean incubation period is 7 weeks and symptoms last 2-12 weeks. Patients with chronic HCV are often symptom-free, but fatigue, muscle aches, anorexia, and right upper quadrant pain do occur. Disorders linked to the infection include autoimmune hepatitis, Sjögren's syndrome, lichen planus, thyroiditis, membranous glomerulonephritis, polyarteritis nodosa, and essential mixed cryoglobulinaemia.10,11 Hepatocellular carcinoma is commonly associated with chronic HCV infection—probably as a consequence of cirrhosis or chronic necroinflammation rather than a direct carcinogenic effect.12
Individuals with suspected HCV infection should be tested for virus antibody by enzyme-linked immunosorbent assay (ELISA).13 If antibody is detected or the patient is thought to be at risk despite negative or indeterminate serological tests, viraemia should be sought by polymerase chain reaction (PCR). A liver biopsy provides the best measure of the extent of disease—routine liver tests correlate poorly with both necroinflammatory and fibrosis scores—and is also useful for excluding other diagnoses such as alcohol-induced liver disease. All patients with chronic HCV should be considered for treatment. The goal of treatment is to achieve a sustained virological response (PCR-negativity 6 months after the end of treatment).14 In the first interferon trials, subcutaneous interferon alpha three times a week achieved sustained virological responses in 12-16% of patients. Addition of ribavirin then raised response rates to 35-45%,15,16 and the results have since been further improved (50-60%) by use of pegylated interferons.17 Variables that favour a sustained response to therapy include low pretreatment HCV RNA levels, HCV genotype 2 or 3, female sex, younger age, less hepatic fibrosis on liver biopsy and lower body weight.18 Patients with chronic HCV infection should be warned that alcohol abuse speeds progression to cirrhosis and hepatocellular carcinoma.10
Pegylation is the process by which an inert molecule of polyethylene glycol (PEG) is covalently attached to a protein, conferring a higher molecular weight and an increase in serum half-life. Two forms of pegylated interferon have been developed—peginterferon alpha-2a (Pegasys, in which the interferon is bound to 40 kDa PEG) and peginterferon alpha-2b (Pegintron, in which it is bound to 12 kDa PEG). These pegylated interferons, though both administered subcutaneously once a week, have different pharmacokinetic and pharmacodynamic properties. PEG alpha-2a has the longer half-life and the smaller volume of distribution, is excreted mainly by the liver, and is given in a standard dose (180 μg); PEG alpha-2b is excreted mainly by the kidney and the dose is determined by body weight.
The effect of virus genotype on response rates is striking. After 48 weeks' combined peginterferon/ribavirin therapy, patients with HCV genotype 1 show response rates of 40-45%, whereas after 24 weeks' therapy patients with genotypes 2 or 3 have response rates approaching 80%. For genotype 2 and 3, 24 weeks may suffice; moreover, trials with Pegasys indicate that these patients require a ribavirin dose of only 800 mg daily, compared with 1000-1200 mg for those with genotype 1.19-21 In patients with genotype 1, a quantitative PCR 12 weeks into treatment gives an indication of future response: a negative PCR or a > 2 log fall in HCV RNA signifies a good chance of achieving a sustained virological response.2
The side-effect profile of the pegylated interferons is similar to that of unmodified interferons, and includes flu-like illness, fever, fatigue, nausea, hair loss, depression, paranoia and severe anxiety.16,17 In patients with a history of alcohol or drug abuse, the neuropsychiatric effects can lead to a disastrous return to the habit. In those with depression, interferons should be used with special caution. Ribavirin similarly has unwanted effects. Because of its teratogenicity in animals, women of child-bearing age should be advised on the need for contraception.18 Renal failure is a contraindication. Ribavirin can cause a haemolytic anaemia (for which erythropoietin analogues may be effective) and is best avoided in patients with severe pulmonary or cardiovascular disease. Other side-effects are cough, rash, neutropenia, thrombocytopenia and thyroid dysfunction. When ribavirin is contraindicated in a patient with HCV, pegylated interferon can be given as monotherapy.18,22 So far, no direct comparison of the two pegylated interferons has been reported.
Before decisions on treatment, a liver biopsy is desirable but not always essential. A normal serum alanine aminotransferase, found in 30% of patients at diagnosis and during prolonged follow-up,23 might be thought a favourable sign, but about one-fifth of such patients have histological liver disease1 and a 2002 consensus conference suggested that this group should not be excluded from treatment.18 The decision to treat should take account of liver histology, patient age, motivation, HCV genotype, viral load and comorbidities. Where cirrhosis has already developed, side-effects tend to be more frequent and sustained response rates lower—33-41% for patients with compensated cirrhosis treated with thrice weekly interferon alpha together with ribavirin.18 In patients with decompensated cirrhosis or with recurrent hepatitis C after transplantation, treatment may not be beneficial and, if undertaken, should ideally be offered in the context of a clinical trial.18
In a patient whose first course of antiviral therapy has failed, the likelihood of future success will depend on the nature of previous treatment, the HCV genotype, the level of HCV RNA and the quantitative viral response previously observed. In patients who had not responded to interferon monotherapy, combined treatment with peginterferon and ribavirin yielded sustained remission rates of 34-40%.18
The UK National Institute for Clinical Excellence (NICE) recommends interferon alpha and ribavirin for moderate to severe hepatitis C (as judged from biopsy or clinical data) in patients aged 18 or more who have not previously received combination therapy. Treatment should last six months, with a further six months for patients with genotype 1 who have shown clearance of circulating viral RNA. Interferon monotherapy should be considered when ribavirin is contraindicated or not tolerated. In a 2004 update, NICE declares a peginterferon the standard for newly treated patients and recommends substitution in patients already on interferon alpha.
New approaches to the treatment of chronic hepatitis C include small-molecule inhibitors of HCV enzymes (protease, helicase and polymerase), immune modulators, ribavirin analogues, vaccines and antisense molecules. Several years will elapse before we know their safety and efficacy. For the immediate future, peginterferon-based regimens, with ribavirin, will be the mainstay. A question that deserves investigation, and prospective trials, is whether patients who prove unresponsive to standard courses of therapy will benefit from long-term treatment to reduce the likelihood of decompensated cirrhosis and hepatocellular carcinoma.