Drug Information Center

• Drug Information Group
• Department of Pharmacy Practice
• About Us
• People
• Potential Partnerships
• The RxPress
• Residency Program
• Frequently Asked Questions
• Contact Us
• Feedback

What are the current treatment recommendations for Hepatitis B?

Hepatitis B is an acute or chronic infection that attacks the liver and is caused by the highly infectious hepatitis B virus (HBV). The virus is often transmitted perinatally, through sexual contact, or through contact with blood and other bodily fluids. ¹ The overall incidence of infection by HBV reported to the Centers for Disease Control and Prevention (CDC) in 2007 was 1.5 per 100,000 people. ² Since the infection often remains asymptomatic, this incidence is likely underestimated about tenfold. The age of acute infection by HBV often predicts its conversion to chronic infection; 90% of infants and 25% to 50% of children ages 1 through 5 develop chronic infection. Alternatively, only about 5% to 10% of infected adults progress to chronic infection.^1,2

The incorporation of the HBV vaccine into routine childhood vaccinations, as recommended by the World Health Organization (WHO) in 1992, has drastically decreased the rate of chronic infection to less than 1%, most notably in areas where 8% to 15% of children had previously become chronically infected.¹ Despite these prevention efforts, chronic HBV infection still persists.² The CDC estimates that there are between 800,000 and 1.4 million people in the United States who are living with chronic HBV infection. The global impact of chronic infection from HBV is even more alarming with an estimated 350 million people affected and 620,000 annual deaths due to HBV-related liver diseases, which include hepatocellular carcinoma, cirrhosis, and liver failure.^1,2 To curtail the risk of liver-associated morbidity and mortality and improve viral suppression, the American Association for the Study of Liver Diseases (AASLD) has published guidelines for the diagnosis and treatment of chronic hepatitis B infection based upon the most recent literature.^3,4

The chronic hepatitis B guidelines were last published by the AASLD in 2007.⁴ Symptomatic patients were recommended to receive treatment with any of the 6 approved antiviral agents at that time, including interferons (IFNs), both pegylated interferon alfa (pegIFN-α) and interferon alfa (IFN-α), as well as the nucleoside analogues (NAs): adefovir, entecavir, telbivudine, and lamivudine. PegIFN-α, adefovir, and entecavir were the preferred agents based on data from randomized controlled trials. Due to high rates of resistance reported with long-term treatment, lamivudine and telbivudine were only preferred when a short course of treatment was anticipated.

Tenofovir, a nucleotide reverse transcriptase inhibitor, was first approved for the treatment of human immunodeficiency virus (HIV).^{3, 5} In 2008, tenofovir’s labeling was expanded to include the treatment of chronic hepatitis B. An update to the 2007 AASLD chronic hepatitis B guidelines was released in September 2009, which reflects the incorporation of this newly approved agent.³ Tenofovir disoproxil fumarate is an oral prodrug that undergoes hydrolysis to the active metabolite, tenofovir.⁵ The current update to the hepatitis B guidelines now recommends the replacement of adefovir with tenofovir as a preferred agent.³ PegIFN-α and entecavir also remain preferred agents for the treatment of HBeAg-positive symptomatic patients. Table 1 summarizes the recommendations from the 2009 updated AASLD guidelines for treatment of hepatitis B in adults; only patients who should be treated are listed in the table.

The replacement of adefovir with tenofovir as a preferred agent is based upon tenofovir’s potent viral suppression and limited antiviral resistance.⁶ In a recent study conducted by Marcellin and colleagues, viral suppression at 48 weeks in HBeAg-negative patients receiving tenofovir was 93% compared to 63% for adefovir (P<0.001). Similarly, HBeAg-positive patients attained viral suppression of 76% by 48 weeks on tenofovir versus 13% on adefovir (P<0.001). Viral suppression was defined as HBV DNA levels less than 400 copies/mL and histologic improvement. HBeAg-positive patients treated with tenofovir also had higher rates of normalized biochemical markers of liver function (68% vs. 54%, P=0.03) and higher rates of seroconversion (3% vs. 0%, P=0.02) than their comparators in the adefovir treatment group.

Contributing factors to the rate at which antiviral resistant mutants are selected include HBV DNA levels prior to treatment, viral suppression rate, treatment duration, and prior NA exposure.³ Virologic breakthrough is the first display of antiviral resistance. A large percentage of virologic breakthroughs can be attributed to non-compliance, and medication adherence should be assessed prior to genetic testing for resistant mutations. When virologic breakthrough occurs, HBV DNA is initially low, but then increases to the point of exceeding HBV DNA levels prior to treatment as resistant mutants replicate. Because initial virologic breakthrough can be detected for years before biochemical breakthrough manifests, early detection of resistant mutants by HBV DNA can potentially reduce complications such as hepatitis flares and hepatic decompensation. Early detection may prevent cross-resistance with other NAs.

Because antiviral resistance is so rampant among NAs, it is important to take precautions against the development of antiviral resistance.³ This may be accomplished by limiting NA treatment to older patients with more extensive disease who have a high probability of achieving a lasting virologic response to the treatment. Treatment should be initiated with the most potent NA that has the least associated genotypic resistance. In addition, the drug(s) to which a patient has developed resistance dictate whether the resistant drug(s) should be continued in the presence of a new agent or discontinued altogether. The guidelines serve as a resource for more specific recommendations. The current guidelines do not offer recommendations for combination therapy at this time; however, it is thought that combination therapy may have the potential to decrease antiviral resistance despite its inability to produce enhanced antiviral activity in terms of viral suppression.⁷

The recent update to the guidelines also addresses patients with coinfections, specifically with the hepatitis C virus (HCV) and HIV.³ Several studies have compared HCV treatment with IFN-α or pegIFN-α and ribavirin in the setting of coinfection, as well as HCV infection alone. To date, these studies have found no difference between virologic suppression of HCV between the 2 groups, but report conflicting data on virologic rebound of HBV DNA in some cases. Because limited data exist for the treatment of both HBV and HCV in combination, specific treatment recommendations have not been made at this time.

Due to the dual indications for HIV and HBV treatment of lamivudine, emtricitabine, and tenofovir, there are considerably more data upon which the AASLD are able to base treatment recommendations for coinfection with HIV and HBV.³ For those coinfected patients in whom HAART is not planned, an agent should be selected to target HBV alone.^3,8 Options include pegIFN-α or adefovir; however adefovir therapy has the potential for the development of HIV resitance. Despite the inability of telbivudine to target HIV, it should not be used in these patients for its potential to select for a specific mutation.³ Patients who require treatment of both viruses should receive a drug that retains its activity against both. Preferred agents to target both viruses include the combinations of tenofovir with lamivudine or emtricitabine.^{3, 8} The addition to tenofovir to a lamivudine-resistant regimen is generally preferred in this specific group of patients. Lastly, in patients currently taking an effective HAART that does not include an HBV-active agent, pegIFN-α or adefovir are preferred treatment options. PegIFN-α may be considered first line for those on HAART with CD4 counts >500 cells/μL that require HBV treatment; these patients have a higher likelihood to respond than those with lower CD4 counts. Another potential benefit of pegIFN-α in these patients is the finite duration of therapy. In treating patients who are coinfected, it is important to reevaluate the drug regimen continuously for both HIV and HBV coverage as HAART will likely be modified throughout the course of HIV treatment.³These recommendations for patients coinfected with HIV are summarized in table 2.

Summary

The AASLD updated the practice guidelines for HBV in September 2009. One major change is the place in therapy for tenofovir. Tenofovir is now recommended as one of the preferred agents in place of adefovir due to concerns with adefovir resistance. Clinicians are referred to the full document (see reference 3 below) for more specific information.

References

By Lisa Klodnicki, PharmD candidate