Several difficulties remain in formulating treatments for hepatitis B. There are areas of disagreement on management of the disease, for example regarding the level above which HBV DNA concentrations are indicative of active disease or the threshold for initiating treatment. Thus, patients with mild disease may not require immediate treatment but careful monitoring.
Substantial health care resources are frequently required to manage patients with hepatitis B. Most clinicians consider that therapy should be considered only if there is evidence of moderate to severe activity or fibrosis. NICE guidance on the indications for treatment should be followed.
Indications and considerations
- Treatment is indicated for chronic progressive disease, although there is a role for rapidly acting nucleoside analogues in fulminant acute hepatitis B or subacute hepatic necrosis.
- Many clinicians would consider a liver biopsy helpful to ascertain the degree of necroinflammation and fibrosis. However, the limitations of biopsy (including sampling error, subjectivity and reproducibility) will mean risks and discomfort to the patient as well as costs. Assessment of fibrosis is necessary to measure how far the disease has progressed, although progression of disease in hepatitis B may not be linear and may be influenced by periods of activity.
- The European Association for the Study of the Liver (EASL) guidelines suggest that patients should be considered for treatment when HBV DNA levels are above 2000 IU/ml (i.e. approximately 10,000 copies/ml) and/or the serum ALT levels are above the upper limit of normal (ULN) for the laboratory, and liver biopsy (or non-invasive markers when validated in HBV-infected patients) shows moderate to severe active necroinflammation and/or fibrosis using a standardised scoring system (for example at least grade A2 or stage F2 by METAVIR scoring).
- Patients with mild chronic hepatitis B: patients with slightly elevated ALT (less than two times ULN) and mild histological lesions (less than A2F2 with METAVIR scoring) may not require immediate therapy. Follow-up is mandatory.
- Immunotolerant patients: most patients under 30 years of age with persistently normal ALT levels and a high HBV DNA level (usually above 107 IU/ml), without any suspicion of liver disease and without a family history of HCC or cirrhosis, do not require immediate liver biopsy or therapy. Follow-up is mandatory.
- Patients with severe, advanced hepatitis B and cirrhosis should receive rapid treatment.
It may also be necessary to monitor patients carefully to ascertain the change in the pattern of disease evidenced by the elevation of ALT. HBeAg-positive patients with greater disease activity are more likely to seroconvert on antiviral treatment – whether interferon or a nucleoside.
The major goals of therapy for hepatitis B are to prevent progression of the disease to cirrhosis and end stage liver disease.
The immediate objectives depend upon the stage of the disease and the level to which the disease has progressed.
Patients may request treatment to reduce viral replication and their own potential infectivity. If decompensated disease is already present, it is important to reduce viral load and stabilise the disease. Patients with decompensated hepatitis B cirrhosis may need liver transplantation and early treatment with appropriate antiviral therapy. Nucleoside analogues such as lamivudine, have been used in decompensated cirrhosis.
Other more potent nucleosides including tenofovir or entecavir are preferable. Interferon is contraindicated in decompensated cirrhosis.
Although it may be possible to reduce the cumulative incidence of decompensated cirrhosis by treating patients with cirrhosis, it is not clear whether suppression of HBV replication will reduce the incidence of HCC. Moreover, suppression of HBV replication in patients with advanced liver disease may not improve synthetic function in time. Exacerbations can occur as viral load is reduced.