NIH Issues Guidelines on Hepatitis B Management

Laurie Barclay, MD

January 08, 2009

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January 8, 2008 — The National Institutes of Health (NIH) have issued a consensus development conference statement on management of hepatitis B virus (HBV) infection and have published the new guidelines in the January 20 print issue of the Annals of Internal Medicine.

"Hepatitis B is a major cause of liver disease worldwide, ranking as a substantial cause of cirrhosis and hepatocellular carcinoma," write Michael F. Sorrell, MD, from University of Nebraska Medical Center in Omaha, and colleagues. "The development and use of a vaccine for...HBV has resulted in a substantial decline in the number of new cases of acute hepatitis B among children, adolescents, and adults in the United States. However, this success has not yet been duplicated worldwide, and both acute and chronic HBV infection continue to represent important global health problems."

This NIH statement was prepared by independent panels of health professionals and public representatives based on a systematic review of the literature contracted by the Agency for Healthcare Research and Quality as well as on presentations, conferences, and other communication with pertinent experts and among panel members.

Issues addressed by this statement included the current burden of HBV infection, the natural history of HBV, benefits and risks of currently available treatments of HBV infection, which persons with HBV infection should be treated, available measures to monitor treatment and evaluate outcomes, and the most pressing needs and opportunities for future research on HBV infection.

The major goals of anti-HBV therapy are to prevent disease progression, specifically development of cirrhosis and liver failure, and to prevent the development of hepatocellular carcinoma and reduce mortality rates.

In the United States, 7 drugs are currently approved for treatment of adults with chronic HBV infection: interferon-alpha; pegylated interferon-alpha; and the nucleoside or nucleotide analogues lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate. For children with HBV infection, only interferon-alpha and lamivudine have been approved.

These 7 drugs have been shown in short-term randomized controlled trials to improve intermediate disease markers such as HBV DNA level, loss or seroconversion of hepatitis B surface antigen (HBsAg), liver enzyme tests, and liver histologic features. However, evidence is limited regarding their effects on important long-term clinical outcomes such as overall mortality rate, liver-specific mortality rate, or development of hepatocellular carcinoma, because the outcomes often do not occur for many years after infection with HBV.

Interferon use has a defined, self-limited course (16 - 48 weeks) and is not associated with the development of antiviral resistance, whereas treatment with nucleoside or nucleotide analogues can be long term, are often indefinite in duration, and may promote emergence of resistance. All approved treatments decrease HBV DNA levels, but the amount of decrease is greater, and the time to decrease is shorter with nucleoside or nucleotide analogues vs interferon.

Interferon is given by subcutaneous injection and may cause systemic symptoms of headache, nausea, flu-like symptoms, depression, and some hematologic abnormalities. In contrast, nucleoside and nucleotide analogues are given orally and may be used safely in patients who have not responded to interferon therapy. If treatment with nucleoside and nucleotide analogues is stopped prematurely, however, there may be resurgence of HBV DNA levels or reactivation of hepatitis. Some nucleoside and nucleotide analogues may cause renal toxicity, myopathy, and/or mitochondrial toxicity.

Treatment with nucleoside and nucleotide analogues is indicated for patients with rapidly deteriorating liver function and for those with decompensated cirrhosis complicated by ascites, hepatic encephalopathy, or hemorrhage from portal hypertension. Because of the risk for hepatic failure, interferons are contraindicated in this group.

Patients with compensated cirrhosis should also be treated because they are at increased risk for clinically significant complications. Patients with HBV infection who receive immunosuppressive or cancer chemotherapy for other medical conditions are at high risk for exacerbation of hepatitis, and they should therefore be treated with antiviral therapy before starting immunosuppressive or cancer chemotherapy.

"The evidence available at this time does not permit concrete recommendations regarding selection of a particular therapeutic course," the statement authors write. "Health care providers should discuss the risks and benefits of treatment options with patients to arrive at the best possible decisions."

In persons with chronic HBV infection, persistently elevated HBV DNA and alanine aminotransferase (ALT) levels in the blood are the most important predictors of cirrhosis or hepatocellular carcinoma. In addition, other risk factors include HBV genotype C infection, male sex, older age, family history positive for hepatocellular carcinoma, and coinfection with hepatitis C virus or HIV.

Various monitoring strategies have been proposed, but there is no clear evidence allowing selection of a single best approach. The loss of HBsAg may be the best marker because it reflects immunity to HBV, lowered risk for development of cirrhosis and hepatocellular carcinoma, and better survival rates, but such seroconversion seldom occurs in response to treatment.

Elevated HBV DNA level appears to predict development of cirrhosis and hepatocellular carcinoma, and suppression of HBV DNA has been associated with improvement of ALT levels and improved histologic features. However, it is not as clear whether treatment-induced decreases in HBV DNA levels are associated with improved clinical outcomes.

"From the time of initial diagnosis, optimal management of HBV infection requires a lifetime of routine monitoring, even when patients are asymptomatic," the statement authors write. "We wish to emphasize that provider and patient education are key to ensuring ongoing adherence with routine disease and treatment response monitoring and with therapy."

The statement identifies the most important research needs as defining the natural history of the disease with representative prospective cohort studies; and determining the effects of available treatments on clinical health outcomes in large, randomized controlled trials of monotherapy and combined therapies, including placebo-controlled trials.

Routine screening for HBV infection is recommended for newly arrived immigrants to the United States from countries where the prevalence of HBV infection exceeds 2%. Although the screening test should not be used to prohibit immigration, it should provide public health data on the burden of disease in immigrant populations and improve provision of medical and public health services for infected patients and their families.

The accompanying review of available studies indicates that "evidence was insufficient to assess treatment effect on clinical outcomes or determine whether inconsistent improvements in selected intermediate measures are reliable surrogates. Future research is needed to provide evidence-based recommendations about optimal antiviral therapy in adults with chronic hepatitis B infection."

The statement authors and review authors have disclosed no relevant financial relationships.

Ann Intern Med. 2009;150:104-110, 111-124.

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