It is estimated that up to 400 million people worldwide are chronically infected with the hepatitis B virus (HBV), and treatment options to control active viral replication and disease progression continue to expand.^1–6 Although the prevalence of HBV infection in the US is lower than in many other countries, an estimated 1.25 million people are infected. However, this estimate of the number of individuals with chronic hepatitis B (CHB) in the US is likely to be an underestimate. The size of the Asian-American population has increased significantly over the last decade and is now approximately 10.5 million people, and recent surveys of Asian-, Korean-, and Vietnamese-Americans found that 10–23% were positive for hepatitis B surface antigen (HBsAg). For those infected with HBV early in life, the lifetime risk of developing cirrhosis and/or hepatocellular carcinoma (HCC) ranges from 15 to 25%, and the risk of these complications has been directly related to the level of serum HBV DNA.^7,8

Treatment
The natural history of HBV infection can be divided into four phases: immune tolerance; immune clearance (hepatitis e antigen (HBeAg)-positive CHB); inactive HBsAg carrier; and reactivation (HBeAg-negative CHB).¹ CHB is diagnosed in patients with high serum HBV DNA levels, elevated alanine aminotransferase (ALT) levels, and necroinflammation on liver biopsy (an optimal test best used selectively when diagnostic categorization and candidacy for therapy are uncertain). The revised normal ALT levels should be used when considering criteria for treatment: upper limits of normal for men are 30 IU/ml, and for women 19 IU/ml.² Treatment is recommended only for patients in the immune clearance and reactivation phases with CHB as defined above: elevated HBV DNA and ALT levels, or significant disease on biopsy.

The primary goal of therapy for CHB is long-term suppression of serum HBV DNA, which is likely to reduce progression to cirrhosis and HCC. In patients with advanced hepatic fibrosis, long-term lamivudine therapy has been shown to decrease the likelihood of decompensation and the incidence of new HCC.⁹ The therapies approved by the US Food and Drug Administration (FDA) for CHB include interferon alfa-2b (1991), lamivudine (1998), adefovir (2002), entecavir (2005), peginterferon alfa-2a (2005), and telbivudine (2006). The currently preferred treatment options are adefovir, entecavir, peginterferon alfa-2a, and, potentially, telbivudine. Standard interferon alfa-2b has been replaced by peginterferon alfa-2a in routine practice, and lamivudine is not a preferred first-line drug due to high rates of resistance.²

A treatment algorithm for CHB previously developed and published by a panel of US hepatologists was revised based on new developments in the understanding of CHB, the availability of more sensitive molecular diagnostic testing, the addition of new treatments, and better understanding of the advantages and disadvantages of approved therapies.² This updated algorithm was based on available evidence using a systematic review of the scientific literature, in addition to consensus expert opinion. This revised algorithm supplements evidence-based recommendations available from published society guidelines from the US, Europe, and Asia.^3–6

When to Start Therapy
The primary aim of antiviral therapy is durable suppression of serum HBV DNA to the lowest level possible.^2–6 The threshold level of HBV DNA for determination of candidacy for therapy is ≥20,000 IU/ml for patients with HBeAg-positive CHB (see Table 1).²

A lower serum HBV DNA threshold of ≥2,000 IU/ml is recommended for patients with HBeAg-negative CHB (see Table 2) and those with compensated cirrhosis (see Table 3), while an even lower level of ≥200 IU/ml is recommended for those with decompensated cirrhosis (see Table 3).²

Interferon alfa-2b, lamivudine, adefovir dipivoxil, entecavir, peginterferon alfa-2a, and telbivudine are all FDA-approved as initial therapy for CHB, and have a number of advantages and disadvantages, which are outlined in Table 4.

Matters for consideration in the selection of therapy include efficacy, safety, incidence of resistance, method of administration, and cost. Genotyping may be useful to help decide whether treatment with peginterferon alfa-2a is warranted, because it has been shown to be most effective in patients with genotype A. The preferred options for the treatment of CHB include adefovir, entecavir, peginterferon alfa-2a, and, potentially, telbivudine (providing serum HBV DNA is undetectable after 24 weeks of therapy, which predicts the absence or very low rate of resistance at year one and year two of therapy).

Interferon alfa-2b has been replaced in practice by peginterferon alfa-2a, and lamivudine is not an optimal choice because of high rates of resistance (65–70% after four to five years of therapy).2 Recent trends are to treat patients with compensated or decompensated cirrhosis associated with any elevation of HBV DNA levels. There are also increasing trends to use combination nucleoside/nucleotide agents in cirrhotic patients, as well as patients with HBV and HIV co-infection, and patients after liver transplantation performed for HBV infection.