End-points in hepatitis B treatment

published online 08 March 2010.

Article Outline

• Why is reduction of fibrosis an important endpoint?

• References

• Copyright

High prevalence of viral hepatitis B infection is associated with chronic hepatitis and serious liver diseases. The health burden of chronic hepatitis B (CHB) is high in Asia-Pacific region [1], [2], [3] and, to a certain extent, significant in many Eastern European countries, Middle East, and certain part of Africa. Whether recent advances in chronic hepatitis B therapy can soon revert this is still controversial. However, gathering evidence showed that effective viral suppression is usually followed by normalization of serum alanine aminotransferase, resolution of histologic necroinflammation. Progression of fibrosis can be prevented by therapy, and the excitement is the demonstration of regression of fibrosis and reversion of cirrhosis, thereby improving the quality of life of the patients.

Why is reduction of fibrosis an important endpoint?

Many of the fatal complication of CHB are related to fibrosis. Advanced fibrosis will increase portal pressure which leads to accumulation of ascites and increase mortality from spontaneous peritonitis, formation of oesophageal and/ or gastric varices and increase mortality from bleeding, porto-systemic shunt and increase morbidity and mortality risk from hepatic encephalopathy. Increasing severity of fibrosis is also directly correlated with increase risk of hepatocellular carcinoma development.

Food and Drug Administration (FDA) of USA requires histologic improvement as one of the primary endpoints in phase 3 therapeutic clinical trials for CHB [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. Paired liver biopsies of evaluable size and quality performed at baseline and 1year after therapy are to be assessed by central pathologist blinded to the sequence of the paired biopsies. Knodell’s histologic activity index (HAI) on a scale of 0–22 is used. It consists of two components: (i) necroinflammation which includes periportal bridging necrosis (0–10), portal inflammation (0–4), intralobular degeneration and focal necrosis (0–4) and (ii) fibrosis (0–4). Ishak fibrosis score is also used in some study which ranged from 0 to 6. Histologic improvement in clinical trial is usually defined as reduction in necroinflammation score by 2 or more points. This is an important and achievable endpoint after 1year of therapy; and is associated with parallel improvement in fibrosis score by ranked assessment. Ranked assessment of fibrosis is used clinical trial of 1year seldom results in one or more point improvement in fibrosis score. In longer term studies over 1year, this has been demonstrated among patients with maintained suppression of the virus. Histologic improvement is essential if complications of chronic hepatitis B are to be prevented. Reduction of fibrosis prevents progressive deterioration in portal hypertension. This was clearly demonstrated in the 3years lamivudine therapy for CHB with advanced fibrosis or cirrhosis [6]. Significant reduction in disease progression and possibly reduced incidence of hepatocellular carcinoma was achieved, especially among patients with maintained viral suppression and without emerging drug resistant mutants. Many oral anti-viral agents have good first year results only to be negated by subsequent development of drug resistance and relapse of hepatitis [5], [6], [7], [8], [9].

In the clinical practice, we are faced with CHB patients of diverse age groups with different expectations, wide range of disease severity and urgency for therapy, and many other limitations such as finance and healthcare structure. The endpoint of therapy for an individual CHB patient is quite different from those discussed extensively in clinical trials. Rather than short term response assessment, we need long term sustainable and cost-effective response to therapy. Reduction of fibrosis is no doubt a crucial endpoint we should aim for to improve patient’s survival benefit and life quality.

References

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The Chinese University of Hong Kong, Alice Ho Miu Ling Nethersole Hospital, Hong Kong

PII: S1687-1979(09)00313-X

doi:10.1016/j.ajg.2009.12.006

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