With FDA approval in 2005 of peginterferon alfa-2a (Pegasys) and entecavir (Baraclude), there are now three oral nucleoside/tide analog and two injectible interferon drugs--standard interferon alfa-2b (Intron A) and Pegasys available for the treatment of chronic hepatitis B. This represents an impressive 40% percent increase in the number of approved drug treatment options for HBV infection.

Peginterferon alfa-2a and entecavir both lay claim to providing significant advantages over existing therapies in the anti-HBV arsenal: entecavir is touted as the “most powerful antiviral to date” and as possessing a “lower resistance rate than lamivudine (Epivir-HBV) or adefovir (Hepsera),” while Pegasys is said to offer “increased efficacy and convenience” over Intron A and “superior effectiveness over lamivudine.”

Although there is no denying that having more treatment options for chronic hepatitis B represents a step forward, some clinicians view the expanded array of therapeutic choices as further complicating the challenging process of choosing the “right” drug and knowing the “best time” to use it. While there are existing consensus guidelines for which drugs to use there are insufficient data to identify in whom and when to use them.

Some HBV treatment and management thought leaders recommend using peginterferon first, in particular in those patients who have not yet developed cirrhosis. They point to the risk of resistance from the oral drugs and the necessity, as in HIV infection, for life-long use of these antivirals, a definite disadvantage for younger patients.

Yet, although the effectiveness of interferon may be durable, may require only a six-month or less course of treatment, and could produce a “cure,” the drug works successfully in less than 50% of patients, produces sometimes serious adverse effects and is costly.

The oral antivirals, on the other hand, work to some extent is just about every patient, in most cases are better tolerated and more convenient to administer than peginterferon, but are prone to the development of resistance, especially lamivudine. Among the three available antivirals—lamivudine, adefovir and entecavir—lamivudine has the least favorable resistance profile, with up to 70% of patients taking the drug becoming resistant with 36-48 months. Still, lamivudine produces almost no adverse side effects and is less expensive than adefovir and entecavir (or peginterferon). Drug cost looms as a large issue, especially in developing countries.

Both adefovir and entecavir are active against wild-type HBV as well as effective against lamivudine-resistant virus, characteristics that highly recommend these drugs for use by the vast pool of lamivudine-experienced patients.

Unlike adefovir, entecavir carries no risk of renal toxicity. The recommended dose of adefovir is 10 mg daily. Nephrotoxicity has been seen in none of the patients with compensated liver disease who received adefovir 10 mg for one year. However, nephrotoxicity has been reported in 2.5% of patients with compensated liver disease who received 2 years of adefovir 10 mg, and in 12% of transplant recipients and 28% of patients with decompensated cirrhosis who received one year of adefovir 10 mg (Lok and McMahon. Hepatology 39(3). March 2004). The primary advantages of adefovir are a very low rate of adefovir resistance during initial therapy and the drug’s activity against lamivudine-resistant HBV.

Anti-HBV Drugs in Development

Many are expecting that the best anti-HBV drugs are still in the pipeline. The oral antivirals telbivudine and clevudine perhaps hold the greatest promise, based on the available data. Both these drugs are currently in Phase III clinical trials in the US. The results of pivotal trials of telbivudine and clevudine (both nucleoside analogues) are highly anticipated, and a third drug, tenofovir, already FDA-approved for treatment of HIV disease, has just entered Phase III trials for use against HBV infection. Early data suggest that tenofovir, another nucleotide analogue from Gilead Sciences, holds even greater promise as an anti-HBV drug than adefovir.

Finally, there is a good possibility that the most effective regimen for the treatment of chronic hepatitis B will emerge from combination therapy with two or more of the FDA-approved and /or pipeline compounds discussed here. If the history of drug development for HIV infection is any indication, such a notion is not just a possibility but rather a good bet.

The downside to this potentially bright scenario is that there have been as yet few combination studies conducted in this field, and the necessary clinical trials for FDA-approval of dual or triple therapy for chronic hepatitis C cannot be completed for another five to ten years. Let us hope that in the meantime that the current crop of monotherapies in development will succeed in safely suppressing HBV in the short-term until more potent and tolerable combination regimens can be tested and approved.

Following is a chart of 24 hepatitis B virus therapies and vaccines that are either FDA-approved or in the developmental pipeline.

Click here to view chart.

08/29/05