The search for cost-effective treatment of chronic hepatitis B.

Treatment of chronic hepatitis B remains challenging due to medication-resistant viral mutations, unanswered questions for initiation and duration of treatment, and risk for chronic liver complications. More than 400 million people worldwide are chronically infected with hepatitis B virus (HBV).1 Of those, an estimated 1 million die annually of HBV-related liver diseases.1 In the past decade, HBV-related hospitalizations, cancers, and deaths have more than doubled in the United States.2 Cirrhosis develops in 15%-20% of actively infected HBV patients within 5 years.3,4 For those patients, the incidence of hepatocellular carcinoma (HCC) is increased, with 70%-90% of HCC cases occurring in cirrhotics.5 With the advent of telbivudine, the sixth medication approved for treatment of chronic hepatitis B by the U.S. Food and Drug Administration (FDA) in October 2006, treatment regimen complexity is predicted to increase due to HBV mutations leading to antiviral resistance.6 Combination therapies are being further explored, especially for treatment-experienced patients who face issues of resistance and adverse effects. Although vaccination to prevent hepatitis B became available in 1982, continued unawareness of modes of transmission and immigration from endemic areas are concerns for potential new exposures and development of costly chronic complications.2 Prevention is crucial to halt the increasing health care costs for hepatitis B, but current therapies have efficacy limitations for treatment-experienced patients. Further research to determine appropriate starting and ending treatment criteria is needed. Hepatitis B treatment could reach the complexity of treatment of human immunodeficiency virus (HIV) with multiple medications in multiple classes. However, an increased ability to detect mutations may permit selection of the medication most likely to be effective for individual patients. For example, knowledge of the tyrosine-methionine-aspartate-aspartate (YMDD) mutation resulting from lamivudine therapy led to investigation of addon therapy such as adefovir to decrease viral load and reduce resistance.7 Hepatitis B e antigen (HBeAg)-negative patients with lamivudine resistance who were treated for 3.5 years with adefovir plus lamivudine had less adefovir resistance (4.4%) than did patients treated with adefovir alone (33.3%).8 The approval of tenofovir for treatment of chronic hepatitis B is expected within the next year, and other nucleoside analogues such as clevudine and emtricitabine remain in phase 3 trials.9 New advancements offer additional hope for treatment options for nonresponsive or resistant hepatitis B. A key to controlling the virus may lie in combination drug therapy. To date, 8 genotypes for hepatitis B are known but are not routinely determined in patients outside of academic or clinical trial settings.10 Genotype determination may become standard in the near future and could increase the cost-effectiveness of treatment. One study demonstrated the positive predictive value for response in genotype A patients treated with interferon compared with genotypes B, C, and D.11 Another study showed that genotype B was more responsive than genotype C to interferon in HBeAg-positive patients.12 Knowledge of a patient’s genotype could also influence initial treatment decisions. Treating a patient with interferon injections for 16 to 32 weeks instead of prescribing lifelong oral medication could be cost saving, especially considering that immunomodulators such as peginterferon alfa-2a carry no risk for viral resistance. More data on the correct medication choice based on genotype are needed. FDA approval of entecavir in 2005 substantially increased the ability to manage chronic hepatitis B. Lamivudine is no longer recommended as a first-line choice in treatment-naïve patients.13 With a reportedly low incidence of adverse effects, entecavir therapy is well tolerated. Lamivudine’s reported resistance rate of 14% to 32% in the first year, increasing up to 20% each year thereafter, cannot compare with entecavir’s 0% reported resistance at 1 and 2 years for nucleoside-naïve patients.14-16 Although the long-term resistance profile of entecavir is still unknown, 4-year data in a cohort of 120 nucleoside-naïve patients showed that virologic rebound occurred in only 1 subject without evidence of genotypic or phenotypic resistance.17 As treatment benefits are obsolete once resistance develops and HBV DNA levels increase, maintenance of viral suppression is critical. Telbivudine, the most recently approved oral medication for treatment of chronic hepatitis B, has a lower reported resistance compared with lamivudine, 21.6% for HBeAg-positive and 8.6% for HBeAg-negative patients at 92 weeks of treatment.18 Because of the higher rate of resistance for telbivudine compared with entecavir, telbivudine may eventually play the greater role in combination therapy. Adefovir and tenofovir are treatment options for telbivudine resistance. The PROACTIV Study is under way to evaluate continued therapy with (1) adefovir alone versus (2) telbivudine plus adefovir versus (3) telbivudine plus tenofovir. Release of the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEALHBV) trial results in 2006 precipitated the revision of national guidelines for the treatment of HBV to focus on viral levels versus the previous focus on alanine aminotransferase (ALT) elevations.19 More emphasis is now placed on suppressing viral loads. Data showed an increased risk of cirrhosis with HBV-DNA levels ≥ 104 copies per mL. Although an increased risk of progression to cirrhosis was associated with HBeAg-positive status and serum ALT elevations, the strongest predictor of future cirrhosis risk was elevated viral levels, providing evidence The Search for Cost-Effective Treatment of Chronic Hepatitis B