Treatment of chronic viral hepatitis
Professor J Hoofnagle,
Bethesda, Maryland, USA, presented his second quadrennial review on the treatment
of chronic viral hepatitis, having previously done so at the WCOG meeting in
Sydney, Australia. Professor Hoofnagle's eminence in the field of hepatitis
diseases was acknowledged in his introduction, which noted his many significant
publications in this area of medicine.
Although hepatitis B, C, and Delta, are clinically similar, they are, in fact, very different diseases, and respond differently to treatment. Due to limitations of time, Prof Hoofnagle restricted his discussion to hepatitis B and C, saying Delta hepatitis was too complex an issue to be covered as well.
Around five per cent of the world's population have hepatitis B, but there is wide geographical variation of prevalence, with 5-10 per cent in Asia and sub-Saharan Africa, but only 1 million people are infected in the USA. Although there are excellent vaccines for this disease, therapy is problematic. Typically, IFN is used at 5 MU per day, or 10 MU TIW, as treatment, for 4-6 months. Clearance of HBeAg is 30-40 per cent in typical patients with such regimens. However, therapy is expensive and poorly tolerated.
The end points used to measure treatment efficacy are loss of HBeAg and HBV DNA, normalisation of ALT, and improved histology. IFN causes a one (1) log fall in HBV DNA during the first three months of treatment, and then it suddenly disappears. There is also a flare of hepatic disease, due to increased enzyme activity, with eventual clearance of HBeAg, fall in enzyme activity, and development of anti-HBeAg. HbeAg is still present in one-third of patients at therapy end, but eventually disappears, as does HBsAg (surface antigen).
A long term follow-up (3-10 years) study of 103 patients has shown that loss of HBeAg is sustained, with only two of 31 responders redeveloping it, and these had serious underlying disease. Also, 86 per cent of the responders ultimately lost HBsAg. However, therapy does not cure hepatitis B. The strongest evidence for this comes from liver transplantation studies, where livers from people free of surface antigen have incurred hepatitis B subsequently in 78 per cent of the recipients. In addition, hepatitis B may become re-activated in AIDS patients, and those receiving cancer chemotherapy.
Several types of patient do not qualify for hepatitis B therapy, including children, people with HIV/AIDS, and those with end stage liver disease. However, there are a number of new treatments evolving, based on second generation nucleoside analogue drugs. These are lamivudine, famciclovir, lobucavir, adefovir dipivoxil, and clevudine.
A recently published study of 25 and 100 mg lamivudine daily in 300 Chinese patients has shown good results, with 98 and 93 per cent HBV DNA disappearance during therapy. Treatment lasted for one year, and resistance developed in 14 per cent of patients. Also, relapse occurred once therapy ended. These results underline problems relating to the length of time needed to ensure effective treatment, since it is unknown how long lamivudine treatment may be used successfully. However, new and promising therapies are forthcoming, which may include combinations of antivirals, and possibly immune modulators such as cytokinins.
Turning to hepatitis C, Prof Hoofnagle said this affects approximately 1-2 per cent of US citizens, which is the same rate in the PRC. Unlike hepatitis B, there is no vaccine for hepatitis C, but he went on to explain that therapy may well offer a cure. Recommended treatment for hepatitis C is 3 MU TIW of IFN for 12 months. A sustained response with clearance of HCV RNA and normalisation of ALT levels, is achieved in only 15-20 per cent of patients, and 40-50 per cent of patients do not respond to therapy.
Although virological, biochemical, and histological endpoints are used in assessing treatment, Prof Hoofnagle maintained that sustained virological response was the best measurement of efficacy. The reliability of this endpoint was illustrated by a small study of 10 patients who had been followed up for 10 to 12 years. Five of these had had a sustained virological response to treatment, and all of these are still free of HCV RNA and have normal ALT levels now. Also their liver biopsies show that cirrhosis has disappeared, suggesting that hepatitis C can be cured. However, therapy is expensive.
NIH recommendations for patients to be treated for hepatitis C include adults of 18-60 years, with elevated ALT levels, and HCV RNA in their serum. However, the situation is less clear cut for children, old people, patients with cirrhosis, and those with only mild disease. In fact, IFN treatment in those with hepatitis C and normal levels of ALT may be harmful. Treatment is contraindicated in children, transplant recipients, patients with renal failure, and those with HIV, as well as drug and alcohol abusers, in the USA.
The highest response to IFN treatment of hepatitis C is found in Asians, and the lowest in African Americans. Women respond better than men do, and shorter duration of disease also predicts favourable treatment outcome. However, virological factors of HCV genotype and viral load are the strongest predictors for treatment outcome. Every one log (ten-fold) drop in viral load equates to a doubling of response rate. There are six HCV genotypes, of which genotype 1 is most difficult to treat, whereas genotypes 2 and 3 are much more responsive.
Prof Hoofnagle reviewed possible methods to improve treatment response rates in hepatitis C. He did not recommend higher does of IFN, and was not convinced whether there are any differences between the various forms of IFN available. He did mention the newest form of IFN, which is covalently linked to a molecule of polyethyleneglycol (PEG). This form has a longer duration of action, better pharmacokinetics, fewer side effects, and is injected once weekly. He considered induction therapies to be an improvement only during the treatment time. Combination therapy with IFN plus ribavirin, a nucleoside analogue, was most promising.
In a trial conducted by McCutcheson involving 1700 therapy na´ve patients in four treatment arms, the combination of ribavirin plus IFN was shown to significantly improve response rates, reaching up to 50 per cent, in terms of patients becoming HCV RNA negative. It also decreased the number of patients who suffered relapse at treatment end. Genotypes 2 and 3 responded well to combination therapy, and although there was only a 17 per cent response rate amongst patients with HCV genotype 1, this was a vast improvement on the two per cent measured with IFN monotherapy.
Side effects are an issue for both IFN and ribavirin. The psychological effects of IFN are well known, and ribavirin produces dose dependent haemolysis, which can be dangerous in coronary artery and cerebrovascular disease. Ribavirin is also teratogenic and is contraindicated in renal failure. Despite all these problems, this combination treatment with IFN and ribavirin probably represent the best future treatment.
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