On the horizon

An influx of antiviral drugs in the next few years should help to combat hepatitis B

Hepatitis can be caused by many factors, including alcoholism, drug-related toxicity and autoimmune disease, but the majority of presenting hepatitis is viral.

The hepatitis B virus (HBV) is a small DNA virus of the hepadnaviridae family, which consists of an outer surface coat and an inner shell, containing the viral DNA and DNA polymerase.

Once the viral particle has infected a host liver cell, the viral DNA and DNA polymerase are released into the hepatocyte's nucleus, whereupon the cell's own replication machinery is employed to propagate the viral lifeline.

The route of HBV infection differs geographically. In Asia, for example, the virus is transmitted predominantly via the parenteral route (vertical mother-to-child infection), while in Westernised developed countries infection mainly occurs horizontally (via transmission of infected bodily fluids, such as unprotected sex, sharing infected needles and, in the past, blood transfusions).

The natural course of HBV infection differs according to whether the virus is acquired vertically or horizontally. This article will look at the treatment of horizontally transmitted disease.

Infection patterns
When a person is initially infected with hepatitis B, an acute inflammatory response is evoked; in 69 per cent of patients this is asymptomatic, while 31 per cent experience flu-like symptoms, including nausea and vomiting, fever, muscle and joint pain, tenderness in the right upper abdominal quadrant and jaundice.

No antiviral therapy is required for this acute phase, as it will resolve on its own in 90 per cent of patients. However, 5 to 10 per cent of immunocompetent adult patients infected with the virus will be unable to recover and so develop chronic HBV infections (defined as positivity for the surface antigen for at least six months).

This figure rises significantly to 50 per cent in children and can be up to 90 per cent in infants that are exposed to the virus. These patients will continue to have chronic hepatitis and experience liver damage including cirrhosis, which may lead to end-stage liver failure and an increased risk of hepatocellular carcinoma if the viral infection is left untreated.

Patients who experience few or no symptoms during the acute infection phase are more likely to develop chronic hepatitis B.

The virus is highly infectious, much more so than the human immunodeficiency virus (HIV), but it is easily prevented by vaccination. However, 12 million people in the US alone are infected with HBV, and more than one million of these have chronic infections.

What's on the market?
Traditional pharmacological therapies for chronic hepatitis B infections that are currently approved by the US Food and Drug Administration (FDA) include Interferon-a, lamivudine (Epivir) and adefovir dipivoxil (Hersera).

When used alone, these agents have similar efficacy. Only 30 to 40 per cent of patients respond to these treatments and those receiving antiviral medicines such as these experience myriad unfavourable adverse events.

More recently approved antivirals used in the treatment of chronic hepatitis B include Peginterferon-a-2a and Baraclude (entecavir).

Unmet need
Clearly, the viral HBV market represents an unmet need, which threatens millions of patients' quality of life and is also a substantial economic burden on society.Several antiviral agents are currently in late-phase development for the treatment of HBV infections:

Pharmasset's clevudine is a DNA polymerase inhibitor currently in phase III development in South Korea.

A study presented at the 55^th Annual Meeting and Postgraduate Course of the American Association for the Study of Liver Diseases (AASLD, 2004) indicated that further treatment with clevudine is effective in patients suffering from chronic unresponsive hepatitis B.

In this multicentre, randomised, double-blind study, conducted in 31 patients, treatment was associated with a median decrease in viral load from baseline of 3.13 and 3.07 log₁₀ copies/ml after 12 and 24 weeks of further treatment, respectively.

A viral load of <400 copies/ml was achieved in 35 per cent of patients after 12 weeks, and in 65 per cent of patients after 24 weeks.

The results of this study also showed that clevudine is well tolerated. There were no serious or severe treatment-related adverse events, and none of the patients discontinued treatment as a result of adverse events.

Clevudine is also being investigated as a potential therapy for Epstein-Barr virus infections.

Telbivudine
Another drug approaching the market is telbivudine, a DNA polymerase inhibitor being developed by Idenix Pharmaceuticals for the treatment of HBV infections.

In a prospective study, telbivudine was found to be more virologically active than lamivudine in patients with chronic hepatitis B.

Viral loads decreased by 5.2 and 3.9 log₁₀ copies/ml from baseline, respec-tively, and were undetectable in 71 per cent and 32 per cent of patients (p < 0.05). ALT normalisation occurred in 81 per cent and 47 per cent of patients, respectively (p < 0.05).

Telbivudine + lamivudine combination therapy was more active than lamivudine alone, but no more active than telbivudine alone. The primary endpoint was achieved in the GLOBE study, which compared the efficacy of telbivudine and lamivudine in patients with chronic hepatitis B.

This endpoint was defined as viral suppression in combination with either ALT normalisation or loss of detectable hepatitis B e-antigen. Subject to positive data from this trial, Novartis and Idenix expect to file US, EU and international marketing applications for telbivudine in the fourth quarter of 2005 and the first quarter of 2006, respectively.

Elvucitabine
Elvucitabine is an orally bioavailable nucleoside reverse transcriptase inhibitor that has shown activity against both the hepatitis B virus and HIV.

Originally developed at Yale University, elvucitabine has demonstrated anti-HBV activity 10- to 30-fold greater than lamivudine in both in vivo and in vitro studies.

The drug is in phase II development with Achillion, which is seeking a corporate partner to assist in the compound's clinical and commercial development for hepatitis B as a primary indication and for HIV as a secondary indication.

In a multicentre, double-blind study conducted in 40 patients in the US and Canada, elvucitabine produced statistically significant decreases in the hepatitis B viral load. During the 14-day dosing period, a rapid, multi-log decrease in HBV DNA levels was observed.

In another randomised, double-blind, placebo-controlled trial, elvucitabine demonstrated potent anti-HBV activity over 12 weeks in treatment-naive patients.

A mean decrease in HBV DNA level of 3.15 log₁₀ was seen after 12 weeks of therapy with all three doses of elvucitabine.

Clearly, the market for pharmaceutical agents aimed at the treatment of chronic HBV infections is advancing rapidly.

While only a small cross-section of drugs currently in development are presented here, the next several years will see the approvals and launches of several anti-virals that will add to the armamentarium of therapies for this disabling and costly condition.