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Treatment for Hepatitis B: When to Start, What to Use, and When to Stop

Hepatitis B Virus

At the 13th International Symposium on Viral Hepatitis and Liver Disease held in Washington March 20-24, 2009, invited experts presented their views on a variety of important issues related to the treatment and management of hepatitis B and C.

Dr. Anna Lok of the University of Michigan at Ann Arbor summarized her opinions on key aspects of therapy for chronic hepatitis B. Following is a summary of her remarks.

Therapy for Hepatitis B

Substantial advances have been made in the treatment of hepatitis B. However, current treatments suppress but [do] not eradicate hepatitis B virus (HBV). Therefore, most patients will require long durations if not life-long treatment to maintain virus suppression and to derive continued clinical benefit.

When to start treatment?

With better understanding of the fluctuating nature of chronic HBV infection, and improved treatment options, the question is no longer whom to treat but when should treatment be initiated. When deciding whether to start or to defer treatment, one needs to have information on the HBV replication status, and activity and stage of liver disease at the time of assessment and the predicted risk of cirrhosis and hepatocellular carcinoma (HCC) for that particular patient.

Thus, treatment should be initiated in patients who have active or advanced liver disease at presentation or who are predicted to have a high risk of cirrhosis or HCC in the foreseeable future. On the other hand, treatment can be deferred in patients who have quiescent, early stage liver disease, and who are predicted to have a low risk of cirrhosis and HCC. The latter patients should continue to be monitored and treatment initiated when the indications arise.

Traditionally, treatment recommendation is based on evidence of liver disease, i.e. elevated aminotransferase (ALT), histological evidence of inflammation or fibrosis, or clinical evidence of cirrhosis. Recently, it has been suggested that treatment should be based on virus level. Several cohort studies indicate that persistently high virus level (lasting several decades) is associated with increased risk of cirrhosis and HCC.

These data indicate that the threshold HBV DNA and ALT levels for initiating treatment should be lower in older patients who may have been infected for a longer duration. Thus, decisions regarding hepatitis B treatment should consider clinical features, ALT, serum HBV DNA, and when available liver histology.

The decisions are further modified by patients' age, hepatitis B "e" antigen (HBeAg) status, plans to start a family in women of reproductive age, occupational requirements, and patient preference.

Because current HBV treatments suppress but do not eradicate the virus, most patients require long durations and often life-long treatment with associated risks of drug resistance, adverse events, and costs. Therefore, the decision to initiate treatment should also take into account the anticipated duration of treatment and the likelihood of achieving sustained virus suppression after a finite course of treatment.

Which treatment?

There are 7 [FDA-] approved therapies for hepatitis B: 2 formulations of interferon (standard [Roferon A and Intron A] and pegylated [Pegasys and PegIntron]) and 5 oral nucleoside/nucleotide analogues: lamivudine [Epivir-HBV], adefovir [Hepsera], entecavir [Baraclude], telbivudine [Tyzeka], and tenofovir [Viread].

The initial decision regarding which drug to use involves a choice between interferon vs. nucleoside/nucleotide. Interferon has the advantage that it is administered for a finite duration and is not associated with specific drug-resistant mutations, but it has to be administered parenterally [by injection], is associated with many side effects, and is contraindicated in patients with decompensated liver disease.

Nucleoside/nucleotide analogues have the advantage that they are administered orally and have very little side effects, but they have to be administered for many years which may lead to selection of drug-resistant mutations. Among the nucleoside/nucleotide analogues, entecavir, telbivudine, and tenofovir have more potent antiviral activity; and entecavir and tenofovir have higher genetic barrier to resistance.

Selection of the initial therapy is critical as resistance to the first drug may diminish the response to other drugs due to cross-resistance.

When to stop treatment?

In general, treatment should continue until a patient achieves therapeutic endpoint. Discontinuation of treatment may be followed by virologic relapse, hepatitis flare, and hepatic decompensation. Therefore, all patients must be closely monitored after treatment is withdrawn.

Interferon is usually given for a finite duration regardless of response because immunological effects of interferon may persist after treatment is discontinued. With pegylated interferon, the recommended duration is 12 months for both HBeAg positive and HBeAg negative patients. Whether a shorter course of pegylated interferon will suffice in HBeAg positive patients with favorable HBV genotype and if a longer course will result in a higher rate of sustained virus suppression in HBeAg negative patients is being studied.

The endpoint for oral nucleoside/nucleotide analogue therapies is unclear. For HBeAg positive patients, the general recommendation is to continue treatment until 6-12 months after HBeAg to HBe antibody (anti-HBe) seroconversion. Some experts have argued that HBeAg seroconversion is not an appropriate endpoint because virus replication persists. However, many studies have shown that 50%-70% of patients will remain in remission (low or undetectable serum HBV DNA and normal ALT) for many years if the above recommendation is followed.

For HBeAg negative patients, treatment can be stopped in patients who lose HBsAg, but that happens in roughly 5% of patients after 5 years of treatment. For patients with underlying cirrhosis, treatment is usually administered indefinitely.



AS Lok. Therapy of Hepatitis B. Invited Speaker Abstracts. 13th International Symposium on Viral Hepatitis and Liver Disease (ISVHLD). Washington, DC. March 20-24, 2009. Abstract SP-18.

Other Citations

1. JH Hoofnagle, E Doo, TJ Liang, and others. Management of hepatitis B: summary of a clinical research workshop. Hepatology 45: 1056-1075. 2007.

2. AS Lok and BJ McMahon. Chronic hepatitis B. Hepatology 45: 507-539. 2007.

3. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B. Journal of Hepatology 50(2): 227-242. February 2009.

4. JL Dienstag. Hepatitis B virus infection. New England Journal of Medicine 359: 1486-1500. 2008.


























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FDA-approved Therapies for Chronic HBV Infection
Baraclude  (entecavir)
  (lamivudine; 3TC)
  (adefovir dipivoxil)
Intron A  (interferon alfa-2b)
Pegasys  (peginterferon alfa-2a)
Viread  (tenofovir)
Tyzeka   (telbivudine)

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