Hepatitis B

What are the diagnostic criteria for chronic hepatitis B? How is its DNA measured? What are the newer therapeutic options and who should receive them? When is liver biopsy warranted? These and other questions are addressed.

By Mark W. Russo, MD, MPH

What is hepatitis B?

Hepatitis B is a DNA virus that may lead to acute or chronic hepatitis. An estimated 1.25 million people in the United States have chronic hepatitis B infection, making it less common than chronic hepatitis C, which affects an estimated 2.9 million Americans. Hepatitis B is transmitted through blood and body fluids. Therefore, individuals at risk for hepatitis B include injection drug users, persons born in hyperendemic areas, men who have sex with men, dialysis patients, HIV-infected individuals, and family members, household members, and sexual contacts of hepatitis B-infected persons. In the United States, sexual contact is the most common mode of transmission, while in Asia perinatal transmission is more common.

The risk of developing chronic hepatitis after infection with the hepatitis B virus depends on the patient's age at the time of infection. Transmission from mother to infant at childbirth is as high as 90%. Perinatal transmission can be dramatically reduced by the administration of hepatitis B immunoglobulin at childbirth and the hepatitis B vaccine. Adults have a much lower rate of progression to chronic infection; only 6% develop chronic hepatitis after infection.
 

How does acute hepatitis B present?

Fewer than 30% of individuals with acute hepatitis B will develop symptoms. When symptoms are present, they are often nonspecific—fatigue, loss of appetite, and arthralgias, for example. A minority of patients will develop jaundice, bilirubinuria, and right-sided abdominal pain.
 

What diagnostic tests are usually ordered for hepatitis B?

Initial testing for hepatitis B should include hepatitis B surface antigen and hepatitis B core antibody, which is frequently reported as total core antibody and subsequently fractionated into its IgM and IgG components. The presence of hepatitis B core IgM indicates acute infection or, in some cases, reactivation; the presence of hepatitis B core IgG indicates prior infection.

Aminotransferases are typically elevated and may reach levels greater than 1,000 U/L. They rise most sharply 8 to 12 weeks after infection, then decline. The level itself does not necessarily indicate compromise in hepatic synthetic function. However, an elevation in the INR or prothrombin time does indicate such compromise.

Hyperbilirubinemia indicates more severe liver injury. (It may take months for serum bilirubin to normalize in patients who developed marked jaundice.) Hepatic encephalopathy and the presence of coagulopathy are signs of acute liver failure and carry a poor prognosis without liver transplantation. Patients should be referred to a transplant center if hyperbilirubinemia, hepatic encephalopathy, or coagulopathy develops.
 

What is the standard treatment regimen for hepatitis B?

Since most adult patients will clear the hepatitis B virus spontaneously after acute infection, therapy is rarely indicated. Babies born to infected mothers should be treated as noted earlier. Because prophylaxis is effective in preventing maternal transmission, screening of pregnant women for the hepatitis B virus is recommended.
 

What risks does chronic hepatitis B pose?

Individuals with chronic hepatitis B are at risk for developing cirrhosis and hepatocellular carcinoma (HCC). Chronic hepatitis B infection is one of the few conditions associated with HCC in the absence of cirrhosis, although the risk of cancer is much higher in patients with cirrhosis. Individuals with viral replication have higher rates of HCC. Alpha-fetoprotein and abdominal ultrasound are used to screen patients for HCC.
 

What are the diagnostic criteria for chronic hepatitis B?

The presence of hepatitis B surface antigen in the serum for more than six months defines chronic infection. Patients with chronic infection may have normal aminotransferases, especially those who acquired the virus through perinatal transmission. Patients with risk factors should be screened for hepatitis B even if they have normal aminotransferases.

One of the more important distinctions to make in patients with hepatitis B is to determine if replication is present or if patients are inactive carriers. The presence of hepatitis B DNA (more than 105 copies/ml) and hepatitis B e antigen indicate viral replication. Antiviral therapy is indicated for patients with evidence of viral replication. One of the goals of therapy is to develop hepatitis B e antibody to the e antigen, which may prevent hepatitis B viral replication.
 

What type of assay is used to measure hepatitis B DNA?

Serologic testing for hepatitis B can be overwhelming because of the number of diagnostic tests available. It is important, however, to consider the type of assay used to measure hepatitis B DNA. Before the widespread availability of polymerase chain reaction (PCR) assays, the methods used to measure hepatitis B DNA included branched DNA, hybrid capture, and liquid hybridization, all of which are much less sensitive than PCR assays. Today, PCR assays are widely available, and most labs will measure hepatitis B DNA with such an assay. The diagnostic tests for hepatitis B and their significance are reviewed in the box below.

What is hepatitis D?

Hepatitis D is an RNA virus that can only exist in the presence of hepatitis B, because it requires hepatitis B enzymes to replicate. Hepatitis D is uncommon in the United States; it is more common in Mediterranean countries. Individuals with hepatitis B who are infected with hepatitis D tend to have more severe disease and lower rates of response to therapy.
 

When are the terms "precore mutant" and "YMDD mutant" applied to hepatitis B patients?

Precore mutant is applied when hepatitis B DNA is present in individuals who are hepatitis B e antigen negative and e antibody positive. In these patients there is a stop codon before the core region of the viral DNA, and consequently the virus does not translate e antigen. The term YMDD mutant is applied to patients taking lamivudine who initially become hepatitis B DNA negative and subsequently manifest hepatitis DNA in their serum while on therapy. The YMDD mutation can be thought of as lamivudine-resistant virus. These and other common scenarios encountered in hepatitis B testing are summarized in the table below.

Are there genotypes of hepatitis B?

There are six well described genotypes of hepatitis B (A, B, C, D, E, and F). The use of hepatitis B genotyping is confined to research settings, although it may eventually have a role in risk stratification for cirrhosis, HCC, and response to therapy.
 

What is the goal of therapy for chronic hepatitis B?

The goal of treatment for chronic hepatitis B is to reduce or eliminate the patient's risk of developing cirrhosis and HCC. Because a clinical trial using these outcomes as endpoints would require following thousands of patients for decades, intermediate markers are used instead as endpoints. These markers are seroconversion from hepatitis B e antigen to e antibody, suppression of hepatitis B DNA, and histologic improvement on liver biopsy.

Chronic hepatitis B infection was initially managed with interferon. Patients who were hepatitis B surface antigen positive and e antigen positive were treated with interferon alpha 5 million units subcutaneously daily (or 10 million units three times a week) for 16 weeks. The goal of therapy was seroconversion from hepatitis B e antigen to e antibody. This was achieved in 33% of interferon-treated patients, compared to 12% of controls. Clearance of hepatitis B surface antigen is not a goal of therapy; also, a low rate of spontaneous seroconversion occurs among untreated control patients. Prednisone priming is not recommended for primary treatment of chronic hepatitis B.

The alpha interferons are associated with numerous side effects, including constitutional symptoms, leukopenia, and depression, which led to the development of alternative agents. If interferon is prescribed to cirrhotic patients with hepatitis B, it should be by clinicians who are experienced in treating patients with advanced liver disease, because these patients are at risk for developing decompensated liver disease.
 

How is hepatitis B currently treated?

Lamivudine is an oral agent that was originally designed to treat HIV-infected patients and was subsequently found to have anti-hepatitis B properties. It is usually reserved for patients with more than 100,000 copies of hepatitis B DNA on a PCR-based assay. Incorporation of the lamivudine metabolite into growing DNA chains results in inhibition of hepatitis B DNA synthesis.

In a 52-week trial of lamivudine (100 mg daily) versus placebo, 17% of patients in the lamivudine group underwent hepatitis B e antigen seroconversion to e antibody, compared with 6% in the placebo group. Also, 52% of treated patients had histologic improvement on liver biopsy, compared with 23% of patients in the placebo group (see graph). Hepatitis B DNA levels, measured by liquid hybridization, sharply declined during the first two weeks of lamivudine therapy.

Treatment was well tolerated, with an incidence of adverse events similar to that in the placebo group. At the end of the treatment period, 32% of the treated patients had YMDD mutants. These patients also had lower hepatitis B DNA levels and lower rates of histologic response compared to subjects with the wild-type virus.

Lamivudine therapy can be prescribed safely for patients with cirrhosis and, in certain circumstances, for patients with decompensated cirrhosis.
 

Is combination therapy sometimes used to treat hepatitis B?

Combination therapy, which has improved treatment efficacy in HIV-infected patients, is under investigation for hepatitis B. The disadvantages are the additional cost and the potential for drug interactions. Studies evaluating interferon plus lamivudine have not demonstrated improved efficacy, as measured by hepatitis B e antigen seroconversion and histology. However, possible flaws in the timing of liver biopsy, the administration of interferon, and sample size have led to renewed interest in combination therapy.
 

Are there any new hepatitis B drugs on the market?

Adefovir dipivoxil was recently approved by the FDA for treatment of chronic hepatitis B. Like interferon, this agent was initially designed for HIV patients, but at high doses it was found to be nephrotoxic. When it is used at lower doses, however, for hepatitis B, nephrotoxicity is rarely a problem. Adefovir dipivoxil is an analogue of adenosine monophosphate; its active intracellular metabolite, adefovir diphosphate, inhibits hepatitis B DNA polymerase.

In a trial randomizing subjects to adefovir dipivoxil (10 mg or 30 mg daily) or placebo for 48 weeks, histologic improvement was seen in 59% and 25% of subjects, respectively. Hepatitis B e antigen seroconversion, however, was seen in only 12% of the treated patients. The sharpest decline in hepatitis B DNA levels, measured by PCR, was seen during the first four weeks of therapy, but levels continued to decline through week 24.

Adefovir dipivoxil-associated viral resistance was not seen. Therapy was well tolerated at the 10-mg dose, but nephrotoxicity may develop with the 30-mg dose. Adefovir dipivoxil has also been shown to be beneficial in patients with the precore mutant.
 

Are there other agents available for treating hepatitis B?

Famciclovir suppresses hepatitis B virus replication, but it is less potent than lamivudine and must be administered three times a day. Because of its low efficacy and potential for cross-resistance with lamivudine, therapy with famciclovir is not recommended.

Thymosin stimulates T-cell responses and may have antiviral properties. Data on the efficacy of thymosin in treating chronic hepatitis B are conflicting, however, and therapy is not routinely recommended.
 

Which patients with hepatitis B should be treated?

Patients who should be considered for therapy are those with evidence of replication (hepatitis B e antigen positive, hepatitis B DNA positive, or both), elevated alanine transaminase (ALT), or inflammation on liver biopsy. Patients with elevated ALT levels (more than twice the upper limit of normal) respond better to therapy than those with normal ALT values. Patients with inflammation on liver biopsy also have better response rates. Those without replication, undetectable replication, or low-level replication (less than 105 copies/ml hepatitis B DNA levels) are not good candidates for therapy. Patients who are candidates for therapy but have low response rates are those with normal ALT levels but marked inflammation on liver biopsy.

Well-compensated cirrhosis can be treated with interferon or lamivudine, but cirrhotic patients need to be carefully monitored for signs of decompensation. Patients with decompensated liver disease, as evidenced by ascites, encephalopathy, or varices, should not be treated with interferon. They may be considered for lamivudine and should be referred to a liver transplant center.
 

Which patients should have a liver biopsy?

Patients often ask if the extent of liver injury caused by the hepatitis B virus can be determined by blood tests or abdominal imaging. Although great advances have been made in assessment of the liver with magnetic resonance imaging, and blood tests for fibrosis are under development, these have not yet replaced liver biopsy as the gold standard for liver histology. A frequent misconception is the belief that normal liver tests rule out significant hepatic fibrosis. Patients with normal ALT levels may have severe necroinflammation and advanced hepatic fibrosis.

Patients with active replication are potential candidates for liver biopsy. Those who are clearly cirrhotic (with thrombocytopenia, splenomegaly, or ascites, for example) do not necessarily require a liver biopsy.

Is there a vaccine for hepatitis B?

The vaccine for hepatitis B is a recombinant protein of the surface antigen. The goal is for patients to develop surface antibody. All infants born in the United States should be given the hepatitis B vaccine intramuscularly after birth. Second and third doses should be given at one and six months. Adolescents who have not been vaccinated and any individual with risk factors should be offered the hepatitis B vaccine, which would also be administered in three doses.

If surface antibody does not develop after the first series of vaccinations, then a second series can be administered. A preparation combining the hepatitis A and B vaccines is also available.

back to top

Printable version of this article

E-mail this article