Over the last several years, tremendous advances have been made in understanding the pathogenesis and natural history of chronic hepatitis B virus (HBV) infection and in the development of new agents for its treatment. Clinicians have numerous resources available to assist with making treatment decisions for their patients with chronic HBV, including treatment guidelines published by government and professional advisory groups.^1-5 Lok and McMahon have recently updated their landmark guidelines, commissioned by the American Association for the Study of Liver Diseases (AASLD), which first appeared in 2001 and were updated in 2004.^1,2,6 These guidelines, along with the others, provide an invaluable framework for the management of chronic HBV.

This brief report will summarize and reinforce several key concepts from the updated AASLD treatment guidelines.⁶ Clinicians, however, should familiarize themselves with the published document's complete contents to gain the most benefit from these guidelines.

Screening for HBV

Individuals from high-risk populations—such as those living in hyperendemic areas (eg, Southeast Asia, Africa, and Eastern Europe), persons who have ever used injection drugs, men who have sex with men, dialysis patients, and persons with HIV infection—should be screened for chronic HBV with hepatitis B surface antigen (HBsAg) and antibody (anti-HBs) testing.⁶ Seronegative persons should receive the HBV vaccination series. HBsAg carriers who are not immune to hepatitis A should receive the hepatitis A vaccine. An influx of immigrants from endemic regions has contributed to an increase in the prevalence of chronic hepatitis B in the United States.

Screening for Hepatocellular Carcinoma

HBV carriers at high risk for hepatocellular carcinoma (HCC) include Asian men over age 40, women over age 50, patients with a family history of HCC, patients with cirrhosis, Africans over age 20, and any carrier over the age of 40 with persistent or intermittent elevation of alanine aminotransferase (ALT) and/or HBV DNA levels >2000 IU/mL.⁶ These high-risk individuals should be screened for HCC every 6 to 12 months with hepatic ultrasound examinations.

Selecting Candidates for Antiviral Therapy

Carriers of HBsAg should be tested to determine serum ALT activity, replicative status (HBeAg and anti-HBe), and serum levels of HBV DNA.⁶ With this information, treatment candidates can be selected (Table 1).⁶ HBeAg-positive and HBeAg-negative patients with active liver disease, as evidenced by abnormal ALT and elevated HBV DNA levels, are generally considered candidates for antiviral therapy. It is important to note that disease activity in chronic hepatitis B is only loosely linked to levels of HBV DNA. In HBeAg-positive disease, 20,000 IU/mL is considered significant and the threshold for treatment, while in HBeAg-negative chronic hepatitis B, that threshold is lowered 10-fold to 2000 IU/mL.

Patients who are inactive HBsAg carriers or patients with persistently normal serum ALT activity are generally not considered candidates for antiviral therapy.⁶ Since ALT and HBV DNA levels may fluctuate considerably and disease activity can evolve over time, these patients should be monitored. For HBeAg positive patients, ALT levels should be monitored at regular 3- to 6-month intervals. For HBeAg-negative patients, ALT levels should be monitored every 3 months for the first year and, if persistently normal, then every 6 to 12 months thereafter.

Liver Biopsy

The value of liver biopsy at baseline has been an evolving and controversial issue. Lok and McMahon confirm that liver biopsy is of the greatest benefit for patients whose candidacy for treatment is equivocal.⁶ For example, new suggested upper limits of normal for ALT have been decreased to 30 U/L for men and 19 U/L for women. Patients with ALT levels near the upper limit of normal may have abnormal liver histology, which would increase the risk of mortality. The risk is greatest for patients over the age of 40 or with a family history of HCC. The decision to biopsy or not, therefore, should consider factors such as patient age, ALT levels, e antigen status, HBV DNA levels, and family history.

Selection of First-line Therapeutic Agent

Six drugs—interferon alfa-2b, peginterferon alfa-2a, lamivudine, adefovir, entecavir, and telbivudine—are approved by the Food and Drug Administration (FDA) for the treatment of chronic hepatitis B. Several other commercially available agents, including peginterferon alfa-2b, tenofovir, emtricitabine, and tenofovir in combination with emtricitabine, are also active against HBV, but are not approved by the FDA for this indication.

Choosing a specific treatment for an individual patient may be challenging and is influenced by factors such as patient age, HBV genotype, e antigen status, the presence of cirrhosis, compensation status, and patient preference, among others. An agent's potential for drug resistance should also be considered when selecting a treatment. Thus, standardized recommendations for every clinical situation are not possible and clinicians must utilize all available information when making treatment decisions. A comparison of approved antiviral agents included in the AASLD guidelines is shown in Table 2.

Antiviral Resistance

Resistance during prolonged nucleos(t)ide analog therapy is the major treatment-limiting consequence of these potent agents. The prevalence of resistant mutations over time varies with the oral agent. Lamivudine therapy has the highest rate of resistant mutations over time in nucleos(t)ide-naive patients.⁶ In contrast, entecavir has the lowest, with recent data suggesting that the development of resistant mutations is rare during 3 years of therapy.^6,7 Patients with pre-existing lamivudine-resistant mutations are more likely to develop evidence of entecavir resistance. A thorough knowledge of resistance profiles will enable clinicians to choose appropriate first-line agents, substitute or add additional agents without cross-resistance, and monitor for the consequences of resistance (Table 3).⁶

Response to Antiviral Therapy

Response to treatment may be measured by normalization of serum ALT activity, loss of serum HBV DNA, and seroconversion of HBeAg, when present. While treatment with peginterferon is of finite duration—48 weeks—regardless of response, the duration of therapy with oral nucleos(t)ide analogs is unpredictable and dependent upon achieving virologic or serologic endpoints, or upon the recognition of treatment failure. Patients with HBeAg-positive disease should continue nucleos(t)ide analog therapy through HBeAg seroconversion plus 6 months beyond appearance of anti-HBe. Patients with HBeAg-negative disease should continue nucleos(t)ide analog therapy until HBsAg clearance.

Special Populations

Recent case series and limited controlled studies suggest two populations for whom treatment with nucleos(t)ide analogs may be beneficial. Patients with fulminant hepatitis B and those with protracted, severe, acute hepatitis B (increasing protime/INR and prolonged jaundice > 4 weeks) should be considered for treatment with an oral agent, preferably lamivudine, telbivudine, or entecavir due to their rapid viral suppression.⁶

Similarly, serious and/or fatal reactivation of hepatitis B has been reported in chronic HBV carriers undergoing cytotoxic chemotherapy.⁶ Prophylactic nucleos(t)ide analogs are indicated in this population and should be started before cytoreduction chemotherapy and continued for at least 6 months afterward. Close monitoring for HBV reactivation is warranted for any patient that is withdrawn from nucleoside/nucleotide therapy.

References

1. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2001;34:1225-1241.
2. Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology. 2004;39:857-861.
3. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol. 2006;4:936-962.
4. de Franchis R, Hadengue A, Lau G, et al. EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002 Geneva, Switzerland. Consensus statement (long version). J Hepatol. 2003;39(suppl 1):S3-25.
5. Liaw YF, Leung N, Guan R, Lau GK, Merican I. Asian-Pacific consensus statement on the management of chronic hepatitis B: an update. J Gastroenterol Hepatol. 2003;18:239-245.
6. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507-539.
7. Colonno RJ, Rose RE, Pokornowski K, et al. Assessment at three years shows high barrier to resistance is maintained in entecavir-treated nucleoside naïve patients while resistance emergence increases over time in lamivudine refractory patients. Hepatology. 2006;44:532A.