Hepatitis B: Latest Treatment Guidelines

ABSTRACT: Patients with chronic hepatitis B who are candidates for treatment include those in the immune clearance phase (positive for hepatitis B e antigen [HBeAg], elevated alanine aminotransferase level, moderate to severe inflammation on liver biopsy, and evidence of viremia) and those in the reactivation phase (negative for HBeAg, documented viremia, active liver disease, or moderate to severe inflammation on liver biopsy). Monitor infected patients in whom liver enzyme levels are normal or slightly elevated or in whom biopsy shows minimal or mild inflammation. The long-term goals of treatment are sustained viral suppression, biochemical remission of liver disease, and prevention of decompensated cirrhosis and hepatocellular carcinoma. FDA-approved treatment options include interferon alfa, lamivudine, and adefovir. Virologic and biologic responses at the end of treatment appear fairly comparable for the 3 therapies; a sustained response is slightly more likely in interferon responders. Interferon therapy is associated with significant side effects and at times is contraindicated in patients with cirrhosis. Key words: hepatitis B, therapy ____________________________________________________________________________________________________________________

An estimated 1.25 million Americans have chronic hepatitis B virus (HBV) infection.1  Worldwide, almost 2 billion persons have serologic evidence of exposure to HBV and 400 million are HBV carriers.2  In 15% to 40% of those with chronic infection, cirrhosis, decompensated liver disease, and hepatocellular carcinoma develop3 ; about 5000 Americans die each year of complications of hepatitis B.4 Therapy for HBV infection continues to evolve. However, despite recent improvements, it still involves prolonged treatment, high costs, and significant side effects. Moreover, it does not lead to permanent eradication in the vast majority of treated patients. In this article, we present the latest information on the most effective therapies, discuss how to identify those patients for whom treatment is appropriate, and provide guidance on minimizing adverse effects.

This review focuses on the treatment of patients with compensated liver disease; those with decompensated HBV infection should be treated by a hepatologist. NATURAL COURSE OF CHRONIC HBV INFECTION HBV infection is easily transmitted via unprotected sexual intercourse and use of illicit injection drugs. In those parts of the world in which the disease is endemic, such as Asia and the Pacific islands, it is transmitted vertically from mother to newborn and horizontally among toddlers. Infection at birth or in early childhood is also likely in US immigrant communities whose roots are in a country with widespread infection. In fact, the CDC recommends routine screening for HBV infection in all pregnant women. The administration of hepatitis B immunoglobulin and monovalent hepatitis B vaccine is recommended within 12 hours of birth in all infants born to infected mothers.5 Chronic infection develops in approximately 90% of persons infected at birth and in about 30% of those infected before age 6 years.1  Most persons who are infected later in life clear the infection completely; chronic HBV infection develops in only about 6% of these patients.1 The natural course of chronic HBV infection is divided into 4 phases: • Immune tolerance. • Immune clearance. • Inactive carrier. • Reactivation. The immune tolerant phase occurs secondary to perinatal (ie, vertical) transmission or horizontal transmission in toddlers; it rarely occurs in patients who are infected as adolescents or adults.

This phase typically lasts for 10 to 30 years and is associated with elevated levels of serum HBV DNA but normal liver enzyme levels. The immune clearance phase occurs in the second to fourth decade of infections acquired at birth or in early childhood; it is usually the first phase of the disease in patients infected after childhood. The immune clearance phase is characterized by high levels of serum HBV DNA, fluctuating liver enzyme levels, and the presence of hepatitis B e antigen (HBeAg). The elevations in liver enzyme levels represent multiple episodes of necroinflammation. Serum levels of HBV DNA ultimately decrease, but patients are at increased risk for cirrhosis and hepatocellular carcinoma. Aside from fatigue, there are no physical symptoms in this phase of the disease. The inactive carrier phase is characterized by low levels of HBV DNA, normal liver enzyme levels (even though histologic evidence of cirrhosis may be present), the disappearance of HBeAg, and the presence of hepatitis B e antibody (anti-HBe). The inactive carrier phase can be interrupted by the reactivation of HBV replication. When this occurs, a patient is said to be in the reactivation phase. In this phase, levels of HBV DNA are high, liver enzyme levels are elevated, HBeAg is absent, and anti-HBe is present. Although many studies use serum HBeAg positivity as a surrogate marker of active HBV infection, it is not uncommon for patients to be HBeAg-seronegative yet have active viremia, as indicated by elevated levels of serum HBV DNA. This is the expected clinical picture in the reactivation phase. HBeAg seronegativity and active viremia are also seen in earlier phases of the illness in patients infected with HBV that contains mutations in the precore, or basal core promoter region. These “precore mutations” prevent the production of HBeAg. WHEN TO WATCH, WHEN TO TREAT Patients in the immune tolerant or inactive carrier phase. Patients in whom liver enzyme levels are normal or slightly elevated and in whom biopsy shows minimal or mild inflammation are not, at present, candidates for treatment. Instead, monitor patients in the immune tolerant phase every 3 to 6 months and those in the inactive carrier phase every 6 to 12 months. Exacerbations develop in up to 40% of patients in the immune tolerant phase, and reactivation occurs in approximately 30% of those in the inactive carrier phase; consider treatment if such a change in status occurs. Patients in the immune clearance phase. If spontaneous seroconversion has not occurred after 3 to 6 months of observation, treatment is recommended for HBeAg-positive patients whose alanine aminotransferase (ALT) level is more than twice the normal level, who have moderate to severe inflammation on liver biopsy, and whose level of HBV DNA is higher than 105  copies/mL. Patients in the reactivation phase. Treatment is recommended for patients who are HBeAg-negative, in whom viral replication has been documented (serum HBV DNA higher than 105  copies/mL), and who have active liver disease (ALT level more than twice the normal level) or moderate to severe inflammation on liver biopsy. Patients who require immunosuppressive therapy. Consider prophylactic treatment for any patient who tests positive for hepatitis B surface antigen (characteristic of all phases of HBV infection) and who requires immunosuppressive therapy. Reactivation rates of between 20% and 50% have been reported in this population; reactivation is especially common in patients being treated with corticosteroids. Currently, prophylaxis with lamivudine is indicated to reduce HBV reactivation, severity of associated hepatitis, and mortality. For patients undergoing chemotherapy, current recommendations are to administer antiviral therapy for the duration of active chemotherapy and for 6 months after completion. For patients who require lifelong immunosuppression, the benefit of antiviral therapy is less clear. Patients with refractory disease. If a patient with chronic HBV infection has failed one therapy, consider enrolling him or her in a clinical trial to determine the efficacy of an alternative antiviral agent. TREATMENT Because the current armamentarium in most cases is able only to achieve control and not cure, therapy is aimed at preventing or delaying disease progression. The long-term goals of treatment are: • Sustained viral suppression (undetectable HBV viremia or reduction in serum HBV DNA to less than 105  copies/mL, loss of HBeAg, and development of anti-HBe in patients who are HBeAg-positive). • Biochemical remission of liver disease (normalization of ALT levels). • Prevention of decompensated cirrhosis and hepatocellular carcinoma. FDA-approved treatment options include monotherapy of finite duration with interferon alfa or antiviral therapy with nucleoside/nucleotide analogs (lamivudine and/or adefovir) for an undefined duration. Because there are no studies that involve all 3 agents, comparison of the efficacy of the currently approved therapies is difficult. However, in patients with chronic hepatitis who are HBeAgpositive, as well as in those who are HBeAg-negative, the virologic and biochemical response at the end of treatment with a 16- to 20-week course of standard interferon appears to be comparable to that seen with a 1-year course of lamivudine or adefovir (Tables 1 and 2). Sustained response following treatment is uncommon in all groups of treated patients; however, rates are slightly higher among interferon responders. Interferon alfa. This agent has antiviral, antiproliferative, and immunomodulatory effects. The dose in adults is 5 million units daily subcutaneously or 10 million units 3 times per week. The recommended duration of treatment is 4 months for patients who are HBeAg-positive and 12 months for those who are HBeAgnegative. Pegylated interferon has a longer half-life than standard interferon, and a phase 2 trial suggests that it may be more efficacious. However, further studies are needed to determine the optimal dosage and duration of therapy.6 A 1993 meta-analysis of 25 randomized controlled trials showed that, in patients who were HBeAgpositive, standard interferon for 4 months was associated with HBeAg seroconversion in 33% and serum HBV DNA “clearance” in 37%.7  However, the HBV DNA assays used in clinical trials of the late 1980s and early 1990s were considerably less sensitive than today’s commercially available assays, which have lower detection limits. Current assays undoubtedly would have found significant HBV viremia in many patients whose serum HBV DNA levels were reported as “undetectable” in those early studies. Clinical trials in patients who were HBeAg-negative showed that 6 to 12 months of interferon resulted in undetectable levels of serum HBV DNA and normalization of ALT levels in 40% to 90% of patients.8,9  Durability of HBeAg clearance is 80% to 90% in patients who are HBeAg-positive.10  However, the rate of long-term viral suppression that is achieved in patients who are HBeAgnegative is much lower. In the 2 previously cited trials,8,9  a sustained response was seen in only 20% to 25% of those treated with interferon for 12 to 24 months. Of those treated with lamivudine or adefovir for 1 year, a sustained response was seen in only 10%.11,12  In another study, only 10% to 25% showed a sustained response after 12 to 24 months of therapy.9 More recently, a 48-week course of pegylated interferon was associated with undetectable levels of HBV DNA in 19% of treated patients 6 months after therapy.13 Patients with HBeAg-positive chronic hepatitis who are most likely to show a favorable response to interferon therapy include: • Those whose pretreatment ALT levels are more than twice the normal levels. • Those whose pretreatment levels of serum HBV DNA are low. • Those with a high pretreatment histologic activity index.  • Women. • Those who acquired HBV infection as adults. • Those who have no coinfection with hepatitis C virus or HIV. • Those who exhibit evidence of acute flare during treatment. Interferon therapy is associated with significant side effects. These include flu-like symptoms, hair loss, fatigue, depression, emotional lability, suicidality, and—of greatest concern—the unmasking or worsening of autoimmune disorders and bone marrow suppression. In addition, for patients with cirrhosis, there is increased risk of severe sepsis, worsening liver failure, unpredictable ALT flares, and possibly life-threatening hepatic decompensation.