Hepatitis B Complications and Therapy

One of the most feared complications of Hepatitis B is the development of liver cell cancer.

The risk of developing primary hepatocellular carcinoma in asymptomatic carriers does vary according to the population studied.

Palmer Beasley studied 22,000 Hepatitis B surface antigen carriers in Taiwan and reported the risk of liver cell canc er at 500 per 100,000 per year.

This compared to a risk of only 5 per 100,000 per year in Hepatitis B surface antigen negative patients. Thus the relative risk was an astounding 94 in patients who were chronic carriers. It is estimated that the annual risk of developing liver cell cancer is 5% in cirrhotic patients.

It is noted overall that 75% of patients with Hepatitis B and liver cell cancer have cirrhosis. Healthy carriers then are also at risk.

Other risk factors may be duration of infection with Hepatitis B or coinfection with either Hepatitis D or Hepatitis C.

Progression of liver cell cancer overall may be slow with tumour doubling times approximately 6 months, which may help in formulating screening programs.

Therapy with Interferon

The goals of antiviral therapy in chronic Hepatitis B infection include sustained loss of viral replication, improvement in liver histology, and diminished infectivity.

These goals have been achieved, however whether the infection is actually eradicated permanently with complete resolution of liver disease remains to be determined.

There are no available data on whether antiviral therapy actually decreases the frequency of liver cell cancer or increases overall survival.

The current recommended treatment for Hepatitis B infection is with interferon.

Interferons are naturally occurring proteins which are produced in response to viral infection.

It has been shown in patients who have chronic viral hepatitis that interferon production is decreased compared to non-infected persons.

Thus this is the rationale behind treating patients with pharmacological doses of interferon. Interferon therapy is not easy to take and there are numerous side effects including malaise, chills, fever, headache, myalgia, anorexia, and fatigue in most patients during the first few weeks of treatment.

Patients can also have bone marrow suppression with thrombocytopen ia and neutropenia, although these side effects are reversible.

Numerous studies have been performed looking at the response in Hepatitis B to interferon therapy. Perrillo in 1990 showed that approximately 40% of patients treated with 5 million units of interferon daily for four months, responded by decreasing viral replication characterised by a loss of Hepatitis B DNA and e antigen.

Of this group only 10% actually lost Hepatitis B surface antigen. These findings are characteristic of most studies.

A recent long term follow up from the National Institutes of Health in the United States reported by Korenman et al in 1991 did show that patients who respond to interferon with a loss of viral replication if followed over time, are more likely to lose the infection.

In this group of patients at five years follow up there was a 65% loss of Hepatitis B DNA as detected by PCR and these patients became surface antigen negative.

This suggests that the response to interferon in Hepatitis B is a long term durable response with an increasing number of patients losing the infection overall. However this is only a small number of patients and further data will be required to confirm this.

The current Section 100 criteria from the Australian Government for subsidised interferon therapy for chronic Hepatitis B requires that the patient be HBe antigen positive with chronic active hepatitis for six months and that liver biopsy shows chronic active hepatitis.

The serum ALT level should be greater than 120 units per litre or greater than twice the upper limit of the laboratory reference range.

This will include patients who are more likely to respond as it has been shown that low serum ALT levels are a marker of non-response.

Exclusion critieria are patients with decompensated cirrhosis, ie patients with Childs B or C disease as these patients may have serious side effects if treated with interferon therapy. Also excluded are patients who have concomittant liver disease with Hepatitis C or delta hepatitis.

Clearly further study of interferon therapy in chronic Hepatitis B infection is needed in a number of groups

• including patients who are interferon non-responders,
• children,
• patients who are post liver transplantation,
• patients who are coinfected with HIV or Hepatitis C,
• patients with decompensated cirrhosis
• and those patients who have extra hepatic disease such as glomerulonephritis or polyarteritis nodosa.

There have been some studies of interferon therapy of chronic Hepatitis B in children. Children are in a state of immune tolerance as I mentioned earlier. However even though they are asymptomatic there has been evidence of progressive liver disease and the development of hepatocellular carcinoma in 1% of such infected children prior to the a ge of 15 years. Limited data are available but it appears that the response to interferon therapy is similar to adults.

There remain however questions as to the appropriate dose, the role of steroid priming, the importance of racial and ethnic differences and the underlying rate of spontaneous e antigen seroconversion which may vary from popu lation to population.

Clearly universal infant immunisation will be the way that this disease is controlled rather than trying to treat patients after they have become infected.

Co-infection

With regards to patients who have HIV and Hepatitis B coinfection, it is known that there is high prevalence of Hepatitis B infection in gay men and injecting drug users.

HIV coinfected patients have increased levels of Hepatitis B DNA and e antigen showing and evidence of enhanced replication and infectivity due to their underlying immunosuppres sion.

It does appear that coinfected patients respond poorly to interferon therapy for Hepatitis B. There is however no evidence so far that Hepatitis B accelerates HIV immunosuppression.

In patients who are coinfected with HIV and Hepatitis C, there is really very little data available.

It appears that injecting drug users and recipients of blood products are more likely to be coinfected than gay men which reflects the inefficient sexual transmission of the Hepatitis C virus.

There is an increased likelihood of vertical transmis sion of Hepatitis C if the mother is infected with HIV.

The natural history of coinfection is unclear.

There are infrequent reports of rapidly progressive liver disease in as many as 9% in one study although again the data are scant. It does appear in the few studies that have been done, that interferon response in HIV and HCV coinfected patients is similar to those patients who are infected with Hepatitis C alone.