Treatment of Viral Hepatitis

There are many causes of hepatitis, or inflammation of the liver including alcohol, drugs, autoimmune diseases, metabolic diseases and viruses.

• Knowledge about viral hepatitis has increased dramatically over the last 40 years. Viral hepatitis is a major public health problem with significant morbidity and mortality.
• The World Health Organisation has estimated that hepatitis B has infected about a third of the world's population. They estimate that there are 1-2 million deaths per year attributable to this infection alone making it the 9th leading worldwide cause of death.¹
• 170 million people worldwide are currently infected with hepatitis C virus.²
• Effective new agents for the treatment of chronic viral hepatitis have been developed in recent years, but accurate assessment of patients can be complex.
• It is recommended that treatment is initiated by specialists.³
• Most low income countries cannot afford antiviral drugs. They have had little impact on the worldwide burden of disease.² Vaccination and preventive measures offer most hope of reducing the disease burden.

Viral hepatitis can be acute or chronic. Chronic infection includes carrier states as well as chronic hepatitis. There are several different types, not all of which have a chronic form of the infection.

• The main aim of antiviral treatment in chronic hepatitis is the inhibition of viral replication and ultimately eradication of the virus (reflected in, in for example HBV, by loss of HBeAg and HBV DNA).
• To reduce symptoms.
• To prevent progression of disease from chronic hepatitis to cirrhosis and hepatocellular carcinoma.

Interferon alfa

• This is used to treat chronic hepatitis B and C (as well as some lymphomas and tumours)
• It is used ideally with ribavirin (a nucleoside analogue)
• It has been used since the late 1990s.
• Side effects (including nausea, loss of appetite, flu-like symptoms, lethargy etc) are dose-related.
• Although side effects are quite common they limit use in only 5-10% of patients.
• Other more unusual side effects reported include depression, ocular effects and myelosuppression.
• Cardiovascular, hepatic and renal toxicity can occur and function should be monitored.
• Use in HBV is limited by low response rate (less than 50%). It is also less effective in HCV hepatitis than some of the alternatives (e.g. peginterferon alfa).
• Usage in chronic hepatitis C is subject to NICE guidance.⁴
• It is an immunomodulating drug and contraindicated with concomitant immunosuppressant treatment and also in decompensated liver disease (except with great caution and at low dose).

Peginterferon alfa

• "Pegylated" derivatives of interferon alfa were introduced in about 2000 (polyethylene glycol-conjugated).
• This breakthrough caused the interferon to persist longer in the blood (by reducing rate of clearance) and allowed it to be given subcutaneously once per week.
• Better results are seen with genotypes 2 and 3 in HCV.⁵

Lamivudine

• Indicated in chronic hepatitis B.
• This is a synthetic nucleoside analogue which inhibits virus replication (by inhibiting a reverse transcriptase enzyme).
• It is easy to take and has a low incidence of side effects.
• It is effective in patients where interferon has proved ineffective (i.e. where HBV DNA levels likely to be high).
• It can be used in decompensated hepatitis B cirrhosis and those with recurrent HBV infection after liver transplantation.
• However 24% of patients develop drug resistance in the first year of therapy increasing to 69% after 5 years (this has been explained by gene mutation).⁵
• In patients with HIV and HBV it is important to combine it with antiretroviral therapy to prevent lamivudine resistant HIV developing.

Adefovir dipivoxil

• Is licensed for chronic hepatitis B.
• It is another synthetic nucleoside analogue in use since 2002.
• It inhibits viral replication and is given orally as a once daily dosage.
• Resistance is very low but it is about three times the cost of lamivudine.

Ribavirin

• This is used in combination (with peginterferon alfa and interferon alfa) for chronic hepatitis C and is subject to NICE guidance.⁴
• Response rates to the interferon are greatly increased in combination with ribavirin.
• It inhibits a wide range of DNA and RNA viruses (and is even used unlicensed in Lassa fever).
• Adverse effects limit use of combination treatments in 15% of patients. Ribavirin can produce haemolytic anaemia and rashes.
• Ribavirin (and interferon) induced retinopathy can also occur.
• In HCV 24 weeks treatment for genotypes 2 and 3 is recommended and 48 weeks for genotype 1.

Entecavir

• A nucleoside analogue which received FDA approval in March 2005 is being used for lamivudine-resistant chronic hepatitis B.⁵

Acute hepatitis

Treatment is supportive. Antiviral drugs are not used but there are reports to suggest benefit of antiviral regimens in acute hepatitis B and C (although acute hepatitis C will be identified very rarely). In acute hepatitis C interferon alfa produced a sustained virologic response in 95% of patients.⁶ A recent small pilot study showed a biochemical response to lamivudine in acute hepatitis B.⁷

Chronic hepatitis B

Patients for antiviral therapy should have evidence of active HBV infection (defined by HBV DNA level and antibody status) and usually have abnormal liver function tests. Liver biopsy helps to define severity, but is not mandatory before starting antiviral drugs.

• Treatment with interferon alfa is appropriate for some patients (short history of HBV infection, ALT >100U/l, low HBV DNA level) but not for others (lifelong HBV infection, low ALT, high HBV DNA levels, end-stage renal disease, immunosuppression- including HIV infection and after organ transplantation). Adverse effects are common, including flu-like symptoms, neuropsychiatric symptoms, haematological disorders and a variety of others.
• Treatment with lamivudine produces good results in positive and negative HBeAg chronic hepatitis patients. Patients may need indefinite treatment to maintain viral suppression. It is easy to take and relatively free of side effects. It can be used in immunosuppressed patients (HIV and after organ transplantation, notably).
• Adefovir dipivoxil (and entecavir when licensed) can be used in lamivudine resistance.

Chronic hepatitis C

Treatment has improved in recent years with the advent of peginterferon alfa and the combination of this with ribavirin. NICE⁴ subsequently recommended in 2004 that this combination should be used in those over 18 years old:

• Not treated before with interferon
• Not treated with peginterferon alfa before
• Treated with peginterferon alfa before but relapsed, or treated with peginterferon alfa alone (rather than in combination with ribavirin).

Best results are achieved with:

• Genotype 2 or 3 status
• Lower baseline HCV RNA levels
• Good compliance
• Absence of cirrhosis.⁵

It should be noted that:

• Peginterferon alfa alone should be used if ribavirin is contraindicated or not tolerated.
• Ribavirin alone is ineffective.⁵

Unfortunately the combination treatment is not suitable for all patients, including:

• 15% of patients who suffer adverse effects causing discontinuation
• Some patients with pre-existing haematological disorders
• Some patients with underlying psychiatric disorders.

Special populations

• Patients with chronic renal failure can only be given reduced does of peginterferon alfa and ribavirin cannot be used.
• Patients with both HIV and HCV infection (In America about 1/3 of all HIV infected patients and 10% of HCV infection) must be identified and treated aggressively as this combination untreated causes high rates of cirrhosis and liver failure. Appropriate screening should be carried out in HIV patients.
• Co-infection with HBV and HDV is difficult to treat, with lamivudine and interferon less effective.