Telbivudine: New Oral Therapy for Chronic Hepatitis B

The once-daily oral agent telbivudine (Tyzeka; Novartis) has now been added to the treatment armamentarium available for the estima-ted 1.25 million American adults with chronic hepatitis B virus (HBV) infection.

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Two additional drugs had been approved for this indication last year: pegylated interferon alfa-2a (Pegasys) and entecavir (Baraclude). “With the approval of telbivudine and the prior approval of lamivudine [Epivir-HBV] and adefovir [Hepsera], we now have 5 drugs approved for use” (Table), Adrian M. Di Bisceglie, MD, FACP, tells .

Dr Di Bisceglie, acting chairman of internal medicine and chief of hepatology at the Saint Louis University School of Medicine in Missouri, says that these new drugs are needed because, “as we treat hepatitis B, we’re looking forward to prolonged or indefinite courses of therapy. In order to do that, the more drugs we have, the better able we are going to be to treat our patients.”

A standard interferon alfa-2b (Intron A) is also indicated for HBV infection, but “its use has really declined, and at this point, we would go straight to pegylated interferon alfa rather than to standard interferon alfa,” explains Dr Di Bisceglie.

The Case for Telbivudine

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The FDA’s approval of telbivudine in November 2006 was based on first-year data from the GLOBE trial (see , December 2006), the largest study to include both hepatitis B e-antigen (HBeAg)-positive and HBeAg-negative patients. This randomized trial, which included 1367 patients (aged ≥16 years), showed that telbivudine therapy resulted in significantly faster and better viral suppression after 1 year of therapy compared with lamivudine.

One advantage of telbivudine is that it is in pregnancy category B, while all other available treatments are in pregnancy category C. But its greatest benefit may be its rapidity of action. In the GLOBE trial, 60% of HBeAg-positive patients treated with telbivudine had cleared serum HBV DNA after 1 year of treatment compared with only 40% of those treated with lamivudine. For HBeAg-negative patients, the respective figures were 88% and 71%. Dr Di Bisceglie added that unpublished results from an international study show that telbivudine also acts much more rapidly than adefovir.

Other than hypersensitivity to telbivudine, there are no contraindications to its use.

The package insert for telbivudine does warn that severe acute exacerbations of hepatitis B have been reported when treatment stops, and that myopathy has occurred within weeks to months after starting therapy.

Which Drug to Use?

Treatment is indicated for all patients with chronic HBV infection who have high levels of circulating virus and evidence of liver injury, according to the current guidelines of the American Association for the Study of Liver Disease (www.aasld.org/eweb/docs/update_chronichep_B.pdf). Although the exact definition of “high level of virus” is still being debated, Dr Di Bisceglie asserts that “everyone would agree that treatment is required for patients with serum HBV DNA levels greater than 105 copies/mL associated with an alanine aminotransferase level more than 2 times normal or evidence of moderate-to-severe hepatitis on a biopsy.”

The decision about which drug to use is not so clear-cut, Dr Di Bisceglie says. “None of our practice guidelines really deal effectively with what should be the first-line treatment,” he says, attributing this to the dearth of head-to-head comparison trials of newer agents.

Pegylated interferon still has a small role as a potential treatment for HBeAg-positive patients infected with hepatitis B genotype A, but, he says, “I wouldn’t even consider it in anybody else. The potential advantage of pegylated interferon is that the treatment period is limited. After 1 year, it either works or it doesn’t.”

For other patients, nucleoside or nucleotide analogs should be considered, although “at this stage lamivudine probably doesn’t have much of a role as a first-line treatment, and adefovir is losing favor, as it appears to be not very potent and it is slow to act,” he says. This leaves entecavir and telbivudine as acceptable first-line choices, Dr Di Bisceglie advises.

Treatment Considerations

Resistance: The type of resistance that has emerged with telbivudine is the same as that seen with lamivudine.

Treatment duration: All available treatment options were studied for 1 or 2 years before being approved by the FDA. But Dr Di Bisceglie says, “It’s looking like we’re committing the patients potentially to long-term or even indefinite therapy. That sort of clinical practice is somewhat ahead of the research we have about the safety and effectiveness of long-term therapy.” The only exception would be HBeAg-positive patients who seroconvert. “If that occurs, we normally give them an extra 6 months of consolidation therapy, and then we think we can stop.”

Compliance: While compliance is an issue with any long-term treatment, Dr Di Bisceglie says that as with hypertension and other chronic conditions, the keys are patient education and communication, follow-up, and providing drugs with few side effects.

Cost is another problem. “These medicines are not cheap,” he says. But the oral agents telbivudine and lamivudine have the advantage over other options at this point. One year of therapy can cost from $2500 for telbivudine or lamivudine to $18,500 with pegylated interferon. However, “The main complications of hepatitis B are liver cancer or cirrhosis requiring liver transplantation, both of which are very expensive outcomes that we would hope to prevent,” Dr Di Bisceglie notes.

“A lot of people who may need treatment may not have the costs of their medicines covered,” he concedes. This argues for being selective when determining which patients should be treated.

“There are people who really need treatment, and everybody agrees on those. And then there are people who absolutely don’t need treatment—the inactive carrier of hepatitis B.” In the gray area are patients who may have low levels of active liver disease or who have “in-between” levels of virus. “Since we don’t really know yet the benefits of treating those kinds of individuals, you might argue, ‘Maybe they should be observed, rather than treated immediately because of the issues of compliance and cost.’”

Some physicians also do not comply with recommended follow-up, which calls for monitoring all patients with chronic HBV at least twice annually. “To just see someone with hepatitis B and say, ‘You don’t need treatment,’ and then dismiss him is potentially very dangerous,” he warns.

Primary care physicians play a pivotal role in finding the people who have HBV infection, he emphasizes, noting that only a small fraction of Americans with chronic HBV infection have been identified. “This is because most patients are asymptomatic until they have very advanced liver disease.”

All immigrants from endemic countries should be screened, he stresses. “If we start with that, we’ll catch a lot of them….And we can vaccinate their sexual partners…and their children to prevent the ongoing spread of hepatitis B in this country.”