Treatment of Hepatitis B

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From [Clinical Cornerstone 3(6):24-36, 2001 ?2001 Excerpta Medica, Inc.] Published in today's Medscape Mag. Treatment of Hepatitis B Vivek Raj, MD, MRCP (UK), Assistant Professor, Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas -------------------------------------------------------------------------------- Abstract Hepatitis B virus (HBV) is a major world health problem and a common cause of cirrhosis and hepatocellular carcinoma. The natural history of HBV varies with many factors, including age of acquisition. Persistent elevation of alanine aminotransferase (ALT) levels and presence of hepatitis B surface antigen for >6 months after infection suggest chronic HBV. Presence of hepatitis B e antigen (HBeAg) and HBV DNA in serum indicate active disease. Treatment is indicated for chronic active HBV. The aim of treatment is to suppress viral replication and eliminate the virus. Endpoints of treatment are normalization of ALT levels and elimination of HBeAg and HBV DNA from the blood. Available treatments are interferon alfa and lamivudine. Interferon is effective in 25% to 40% of patients, but has serious side effects. Lamivudine is effective in a similar percentage of patients and has fewer side effects; however, it is associated with the emergence of viral mutations and drug-resistant strains. [Clinical Cornerstone 3(6):24-36, 2001 ?2001 Excerpta Medica, Inc.] -------------------------------------------------------------------------------- Introduction Chronic hepatitis B virus (HBV) affects >5% of the world's population -- it is the primary cause of cirrhosis and hepatocellular carcinoma and the ninth leading cause of death worldwide. In the United States, ~1 million persons are chronically infected with HBV. The HBV carrier rate in the United States, Western Europe, and Australia is 0.1% to 0.2%, but is as high as 10% to 20% in China, Southeast Asia, and sub-Saharan Africa. An effective vaccine has been available since 1982, but its use has been primarily restricted to high-risk groups. Since 1991 the vaccine has been given to all newborns in the United States. Because treatment of chronic active HBV can prevent cirrhosis and liver cancer, effective therapy and universal immunization are highly desirable goals. To treat HBV, it is important to understand the epidemiology, natural history, and serologic markers of the disease. Natural History The clinical presentation of acute HBV ranges from subclinical hepatitis (70%) to icteric hepatitis (30%) with rare cases of fulminant hepatitis (0.1% to 0.5%). Elevation of liver enzyme levels, primarily alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with levels typically up to 1000 to 2000 IU/L (ALT > AST), is a hallmark of acute HBV. Elevation of bilirubin levels occurs after an increase in liver enzymes. In acute HBV the best indicators of prognosis are parameters of hemostasis (prothrombin time). In patients who recover, ALT levels normalize within 1 to 4 months. Persistent elevation (>6 months) of serum ALT levels usually indicates progression to chronic HBV. The outcome of acute HBV depends on age of acquisition, immune status of the host, and rate of replication of the virus. In the perinatal period or childhood, infection is usually associated with mild or no symptoms but a high risk of chronicity. In adults, infection is usually symptomatic with a low risk of chronicity. With perinatal infection, the initial phase is characterized by high levels of HBV replication, hepatitis B e antigen (HBeAg) in serum, and high levels of HBV DNA, but no evidence of active liver disease. The patient is asymptomatic, has normal ALT levels, and minimal changes on liver biopsy. Minimal liver disease, despite high levels of HBV replication, may be caused by immune tolerance in infants and children. These patients usually experience an immune-clearance phase during the second and third decade when spontaneous HBeAg seroconversion to antibody to HBeAg (anti-HBe) increases to an annual rate of 10% to 20%. Chronic HBV ranges from the asymptomatic carrier, to chronic active HBV, to cirrhosis and hepatocellular carcinoma. The rate of progression from acute to chronic HBV is ~90% for perinatal infection, 20% to 50% for infection acquired between the ages of 1 to 5 years, and <5% for adult-acquired infection. Of these adults, some develop chronic active HBV while others are asymptomatic carriers. In healthy hepatitis B surface antigen (HBsAg) carriers, prognosis is very good with a low rate of progression to cirrhosis. However, in HBV patients from endemic areas and in patients with chronic HBV, the risk of progression over 5 years from chronic hepatitis to cirrhosis is 12% to 20%, from cirrhosis to decompensation 20% to 23%, and from compensated cirrhosis to hepatocellular carcinoma 6% to 15%. Serologic Diagnosis Serologic tests used to diagnose HBV infection are shown in the Table. http://gastroenterology.medscape.com/ExcerptaMed/ClinCornerstne/2001/v03.n06/clc0306.04.raj/tab-clc0306.04.raj.html#Table HBsAg and Anti-HBs HBsAg is the serologic hallmark of HBV infection. HBsAg appears 1 to 10 weeks after acute infection and before the onset of symptoms or elevation of ALT levels. In patients who recover, HBsAg becomes negative 4 to 6 months later. Persistence of HBsAg beyond 6 months suggests progression to chronic HBV. Antibody to HBsAg (anti-HBs) appears as HBsAg disappears, and in most cases anti-HBs persists and confers lifelong immunity. In 25% of cases the titers of anti-HBs are not sufficient to neutralize circulating virions, and HBsAg and anti-HBs coexist. Individuals with this combination are considered carriers. HBcAg and Anti-HBc Hepatitis B core antigen (HBcAg) is an intracellular antigen in infected hepatocytes and is not detectable in serum. Antibody to HBcAg (anti-HBc) appears early in the infection and is then detected throughout the course of infection. In the acute phase, it is primarily an immunoglobulin (Ig) M antibody. In patients who recover, the anti-HBc changes to IgG and remains detectable with anti-HBs. It is also detectable in patients with chronic active HBV with HBsAg. IgM anti-HBc may be detectable during HBV exacerbations. HBeAg and Anti-HBe HBeAg is a marker of active HBV replication and infectivity. HBeAg is usually associated with high titers of HBV DNA in the serum, active liver disease, and high rates of infectivity; however, patients with perinatal HBV infection can be HBeAg positive but have minimal liver inflammation and normal ALT levels. Seroconversion from HBeAg to anti-HBe is associated with recovery and the disappearance of serum HBV DNA. Although rare, some patients have a viral mutation in the precore region that prevents expression of HBeAg; these patients have active liver disease and HBV DNA in the serum but are HBeAg negative. Serum HBV DNA The presence of serum HBV DNA is sensitive and specific for viral replication. Hybridization or signal amplification (branched DNA) assays detect 105 to 106 viral equivalents/mL, while the more sensitive polymerase chain reaction (PCR)-based assays detect 102 to 103 viral equivalents/mL. Recovery from acute HBV and HBeAg seroconversion in chronic HBV is associated with the disappearance of HBV DNA by non-PCR-based assays. PCR-based assays may remain positive for many years, which suggests the persistence of small numbers of virions that are contained by the host immune system. The main use of HBV DNA assays is to assess chronic active HBV patients for treatment a

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