HEPATITIS

What is hepatitis?

Viral hepatitis is an infection of the liver. Three hepatitis viruses cause most cases of the disease in the UK. Hepatitis A (HAV) is generally an acute disease that is only occasionally fatal, but hepatitis B (HBV) and hepatitis C (HCV), both transmitted through blood and body fluids, can lead to chronic infections that are a serious health problem. Adults infected by HBV mostly develop an acute infection and subsequently recover, but about 10 per cent develop chronic infection, which can progress to cirrhosis or to a form of liver cancer. Three main classes of HCV are mainly seen in the UK and these differ in their resistance to treatment. Vaccines are available for the prevention of hepatitis A and B, but not for hepatitis C.

Who does hepatitis affect?

The UK is regarded as a low incidence country for all three types of viral hepatitis and many cases are due to the movement of people between Britain and high-risk countries. The number of acute HAV infections reported in England and Wales fell below 1,000 in 2004 and has been declining since the early 1990s. The number of people chronically infected with HBV or HCV is not accurately known, but is estimated at under 1 per cent of the population in each case. However, only a small percentage of cases of HBV and HCV infection are thought to be diagnosed (17 per cent in the case of HCV) and these include some high-risk groups such as intravenous drug users, in whom rate of infection have been found to be significantly higher. Unlike many other countries, the UK does not have a policy of routine infant vaccination against HBV, preferring a selective approach.

Present treatments and shortcomings

The main therapy for chronic hepatitis B infection is a course of injections with interferon alpha (Viraferon, Schering-Plough) or a long-acting form of interferon alpha (Pegasys, Roche), or oral therapy with an antiviral compound such as lamivudine (Zeffix, GSK) or adefovir dipivoxil (Hepsera, Gilead). Prolonged treatment (e.g. 48 weeks) is needed in both cases for the greatest chance of viral suppression, but there is a risk that resistant viral mutations may emerge with prolonged therapy, and with lamivudine only about a quarter of patients become virus-free within one year. Relapse may occur when treatment is stopped.

The main therapy for chronic hepatitis C infection is a course of weekly injections for 24/48 weeks (depending on the type of HCV) with interferon alpha (ViraferonPeg, Schering-Plough or Pegasys, Roche) given together with the antiviral ribavirin (Rebetol, Schering-Plough; Copegus, Roche).

Interferons often provoke flu-like side effects that may limit their use, and may induce adverse psychiatric events, including depression. Severe adverse psychiatric events (depression, psychoses, hallucinations, aggressive or violent behaviour) have also been recorded with ribavirin. Lamivudine is given at a lower dose for HBV treatment than in HIV infection and is generally well tolerated.

What's in the development pipeline?

Several new antivirals are under development for the treatment of chronic HBV infections. Of these, entecavir (Baraclude, Bristol-Myers Squibb) is perhaps the nearest to becoming available in the UK. This compound has been found to give a higher rate of HBV suppression than lamivudine in patients being treated for the first time and to be effective in about 30 per cent of those who had become resistant to lamivudine. Another compound that has also shown greater efficacy than lamivudine in comparative trial is telbivudine (Novartis). Other antivirals still in clinical trials include tenofovir (Gilead) at Phase 3, valtorcitabine (Novartis), alamifovir (Eli Lilly), pradefovir (Valeant and Schering-Plough) and ANA380 (Anadys), all at Phase 2, and clevudine (Pharmasset) at Phase 1.

Two vaccines for the treatment of established HBV infections are under investigation: Oxxon Therapeutics' Hi-8 PrimeBoost HBV vaccine has shown evidence of efficacy in Phase 2 trial, while PowderMed's pdpSC18 vaccine is starting Phase 1 studies. Meanwhile, development of preventive vaccines has continued, with the introductionof the vaccine Fendrix (GSK) for those with kidney problems and trials of another new vaccine HEPLISAV (Dynavax Technologies, Phase 3).

New antivirals are also being developed for chronic HCV infections. Taribavirin (Viramidine, Valeant), which is expected to be less likely to cause anaemia than ribavirin, has reached Phase 3 trials in the United States. Novartis is developing valopicitabine (NMC283), which has shown promise in Phase 2 trial of greater efficacy in combination with a form of interferon in the re-treatment of treatment-resistant HCV than ribavirin. Roche has a polymerase inhibitor (R1626) which has now started Phase 2 trials. Also at Phase 2 are two protease inhibitors - SCH 503034 (Schering-Plough) and VX-950 (Vertex), and compounds with other ways of working, such as Pfizer's PF 3491390, Wyeth and Viropharm's HCV-796, the iminosugar UT-231B (United Therapeutics), Migenix's celgosivir, CPG 10101 (Actilon), a T-cell activator from Coley Pharmaceuticals, and a therapeutic vaccine IC41 from Intercell.

The longer-term future

Prospects for improved treatments for chronic Hepatitis C infections look bright, with several promising compounds in the Phase 1 and preclinical pipelines. Gilead and Achillion are investigating GS 9132, an HCV protease inhibitor, and Novelos Therapeutics has NOV-205 in Phase 1 study. Perhaps most excitingly, Novartis Vaccines has two Phase 1 clinical projects ongoing for the development of a vaccine that would protect against HCV. If this were successful, it would be the first preventive vaccine to become available for HCV and could be of great value in preventing further spread of this serious infection.

FOR FURTHER INFORMATION CONTACT:

The British Liver Trust
2 Southampton Road
Ringwood, BH24 1HY
Phone: 0870 770 8028 (Helpline)
Website: www.britishlivertrust.org.uk