Chronic hepatitis B

This guideline has been approved by the American Association for the Study of Liver Diseases and represents the position of the Association. These guidelines have been written to assist physicians and other health care providers in the recognition, diagnosis, and management of patients chronically infected with the hepatitis B virus (HBV). These recommendations provide a data-supported approach to patients with hepatitis B. They are based on the following: (1) formal review and analysis of published literature on the topic — Medline search up to February 2006 and meeting abstracts in 2003-2005; (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the AGA Policy Statement on Guidelines2; and (4) the experience of the authors in hepatitis B. In addition, the proceedings of the 2000 and 2006 National Institutes of Health conferences on the “Management of Hepatitis B”, the EASL 2002 International Consensus Conference on Hepatitis B and the Asian-Pacific Consensus Statement on the Management of Chronic Hepatitis B: a 2005 Update, were considered in the development of these guidelines.3-6 The recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible. Specific recommendations are based on relevant published information. In an attempt to characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a category to be assigned and reported with each recommendation (Table 1). These guidelines may be updated periodically as new information becomes available. HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HBeAg, hepatitis B e antigen; cccDNA, covalently closed circular DNA; anti-HBe, antibody to hepatitis B e antigen; ALT, alanine aminotransferase; anti-HBs, antibody to hepatitis B surface antigen; PCR, polymerase chain reaction; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HDV, hepatitis D virus; HBIG, hepatitis B immunoglobulin; AFP, alpha fetoprotein; US, ultrasonography; IFN-α, interferon-alfa; pegIFN-α, pegylated interferon-alfa. An estimated 350 million persons worldwide are chronically infected with HBV.7 In the United States, there are an estimated 1.25 million hepatitis B carriers, defined as persons positive for hepatitis B surface antigen (HBsAg) for more than 6 months.8, 9 Carriers of HBV are at increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC).10 Although most carriers will not develop hepatic complications from chronic hepatitis B, 15% to 40% will develop serious sequelae during their lifetime.11 The following guidelines are an update to previous AASLD guidelines and reflect new knowledge and the licensure of new antiviral agents against HBV. Recommendations in these guidelines pertain to the (1) evaluation of patients with chronic HBV infection, (2) prevention of HBV infection, (3) management of chronically infected persons, and (4) treatment of chronic hepatitis B. Management of hepatitis B in patients waiting for liver transplantation and prevention of recurrent hepatitis B post-liver transplant have been covered in a recent review article and will not be discussed in these guidelines.12 The global prevalence of HBsAg varies greatly and countries can be defined as having a high, intermediate and low prevalence of HBV infection based on a prevalence of HBsAg carriers of ≥8%, 2%-7%, and <2% respectively.7, 9, 13, 14 In developed countries, the prevalence is higher among those who immigrated from high or intermediate prevalence countries and in those with high risk behaviors.7, 9 HBV is transmitted by perinatal, percutaneous, and sexual exposure, as well as by close person-to-person contact presumably by open cuts and sores, especially among children in hyperendemic areas.9 HBV can survive outside the body for prolonged periods.15, 16 The risk of developing chronic HBV infection after acute exposure ranges from 90% in newborns of HBeAg-positive mothers to 25% to 30% in infants and children under 5 and to less than 5% in adults.16-20 In addition, immunosuppressed persons are more likely to develop chronic HBV infection after acute infection.22, 23 In countries such as the United States where most of the infants, children, and adolescents have been vaccinated against HBV, the risk of transmitting HBV in daycare centers or schools is extremely low and HBsAg-positive children should not be isolated or prevented from participating in activities including sports. Table 2 displays the population and high risk groups that should be screened for HBV infection and immunized if seronegative. The tests used to screen persons for HBV should include HBsAg and hepatitis B surface antibody (anti-HBs). Alternatively, hepatitis B core antibody (anti-HBc) can be utilized as long as those who test positive are further tested for both HBsAg and anti-HBs to differentiate infection from immunity. Some persons may test positive for anti-HBc but not HBsAg or anti-HBs. The finding of isolated anti-HBc can occur for a variety of reasons. (1) Anti-HBc may be an indicator of chronic HBV infection; in these persons, HBsAg had decreased to undetectable levels but HBV DNA often remains detectable, more so in the liver than in serum. This situation is not uncommon among persons from areas with high prevalence of HBV infection and in those with human immunodeficiency virus (HIV) or hepatitis C virus (HCV) infection.24 (2) Anti-HBc may be a marker of immunity after recovery from a prior infection. In these persons, anti-HBs had decreased to undetectable levels but anamnestic response can be observed after one dose of HBV vaccine.25 (3) Anti-HBc may be a false positive test result particularly in persons from low prevalence areas with no risk factors for HBV infection. These individuals respond to hepatitis B vaccination similar to persons without any HBV seromarkers.9, 25, 26 (4) Anti-HBc may be the only marker of HBV infection during the window phase of acute hepatitis B; these persons should test positive for anti-HBc IgM. Recommendations for Persons Who Should Be Tested for HBV Infection: 1. The following groups should be tested for HBV infection: persons born in hyperendemic areas (Table2), men who have sex with men, persons who have ever used injecting drugs, dialysis patients, HIV-infected individuals, pregnant women, and family members, household members, and sexual contacts of HBV-infected persons. Testing for HBsAg and anti-HBs should be performed, and seronegative persons should be vaccinated. (I) Patients with chronic HBV infection should be counseled regarding lifestyle modifications and prevention of transmission and the importance of life long monitoring. No specific dietary measures have been shown to have any effect on the progression of chronic hepatitis B. However, heavy use of alcohol (>20 g/d in women and >30 g/d in men) may be a risk factor for the development of cirrhosis.27, 28 Carriers of HBV should be counseled regarding transmission to others (see Table 3). Household members and steady sexual partners are at increased risk of HBV infection and therefore should be vaccinated if they test negative for HBV serologic markers.9 For casual sex partners or steady partners who have not been tested or have not completed the full immunization series, barrier protection methods should be employed. HBsAg-positive women who are pregnant should be counseled to make sure they inform their providers so hepatitis B immune globulin (HBIG) and hepatitis B vaccine can be administered to their newborn immediately after delivery.9 HBIG and concurrent hepatitis B vaccine have been shown to be 95% efficacious in the prevention of perinatal transmission of HBV, the efficacy is lower for maternal carriers with very high serum HBV DNA levels (>8 log10 IU/ml).9, 29 Transmission of HBV from infected health care workers to patients has also been shown to occur in rare instances.30, 31 For HBV carriers who are health care workers, the Centers for Disease Control and Prevention recommends that those who are HBeAg-positive should not perform exposure prone procedures without prior counseling and advice from an expert review panel regarding under what circumstances, if any, they should be allowed to perform these procedures.32 These circumstances would include notifying prospective patients of their HBV status prior to procedures. While the CDC does not use serum HBV DNA levels as criteria for restriction of clinical procedures, several European countries use a threshold level varying from 200 to 20,000 IU/ml to determine if HBsAg-positive health care workers are allowed to perform exposure prone procedures.33, 34 The risk of infection after blood transfusion and transplantation of non-hepatic solid organs (kidneys, lungs, heart) from persons with isolated anti-HBc is low: 0% to 13%.35 The risk of infection after transplantation of liver from HBsAg-negative, anti-HBc-positive donors has been reported to be as high as 75% and is related to the HBV immune status of the recipients.36, 37 If anti-HBc-positive donor organs are used for HBV seronegative recipients, antiviral therapy should be administered to prevent de novo HBV infection. While the optimal duration of prophylactic therapy has not been determined, a limited duration such as 6-12 months may be sufficient for transplantation of non-hepatic solid organs. For transplantation of livers, life-long antiviral therapy is recommended, but whether HBIG is necessary is unclear.38 Recommendations for vaccination are outlined in a recent CDC and Advisory Committee on Immunization Practices (ACIP) guideline.9, 9a Follow-up testing is recommended for those who remain at risk of infection such as health care workers, infants of HBsAg-positive mothers and sexual partners of persons with chronic HBV infection. Furthermore, annual testing of hemodialysis patients is recommended since immunity wanes rapidly in these individuals who are at a high risk of continued exposure to HBV. Carriers should be counseled regarding prevention of transmission of HBV (Table3). (III) Sexual and household contacts of carriers who are negative for HBV seromarkers should receive hepatitis B vaccination. (III) Newborns of HBV-infected mothers should receive HBIG and hepatitis B vaccine at delivery and complete the recommended vaccination series. (I) Persons who remain at risk for HBV infection such as infants of HBsAg-positive mothers, health care workers, dialysis patients, and sexual partners of carriers should be tested for response to vaccination. (III) Postvaccination testing should be performed at 9 to 15 months of age in infants of carrier mothers and 1-2 months after the last dose in other persons. (III) Follow-up testing of vaccine responders is recommended annually for chronic hemodialysis patients. (III) Abstinence or only limited use of alcohol is recommended in hepatitis B carriers. (III) Persons who are positive only for anti-HBc and who are from a low endemic area with no risk factors for HBV should be given the full series of hepatitis B vaccine. (II-2) Eight genotypes of HBV have been identified labeled A through H.39, 40 The prevalence of HBV genotypes varies depending on the geographical location. All known HBV genotypes have been found in the United States, with the prevalence of genotypes A, B, C, D and E-G being 35%, 22%, 31%, 10%, and 2%, respectively.41 Recent data suggest that HBV genotypes may play an important role in the progression of HBV-related liver disease as well as response to interferon therapy.39 Studies from Asia found that HBV genotype B is associated with HBeAg seroconversion at an earlier age, more sustained remission after HBeAg seroconversion, less active hepatic necroinflammation, a slower rate of progression to cirrhosis, and a lower rate of HCC development compared to genotype C.41-46 The relation between other HBV genotypes and liver disease progression is unclear. Several studies of standard interferon-alpha (IFN-α) and one study of pegylated IFN-alpha (pegIFN-α) therapy showed that genotypes A and B were associated with higher rates of HBeAg seroconversion compared to genotypes C and D.47-50 Another study of pegIFN-α reported that genotype A but not genotype B was associated with a higher rate of HBeAg seroconversion.52 Studies of nucleos(t)ide analogue (NA) therapies have not shown any relation between HBV genotypes and response. Thus, additional data on the relation between HBV genotypes and treatment response are needed before testing for HBV genotypes in clinical practice is recommended. The consensus definition and diagnostic criteria for clinical terms relating to HBV infection adopted at the National Institutes of Health (NIH) conferences on Management of Hepatitis B in 2000 and 2006 are summarized in Table 4.3, 4 During the initial phase of chronic HBV infection, serum HBV DNA levels are high and HBeAg is present. The majority of carriers eventually loses HBeAg and develop antibody to HBeAg (anti-HBe).13, 52-55 Among individuals with perinatally acquired HBV infection, a large percent of HBeAg-positive patients have high serum HBV DNA but normal ALT levels.57, 58 These patients are considered to be in the “immune tolerant” phase. Many of these patients develop HBeAg-positive chronic hepatitis B with elevated ALT levels in later life.56, 59, 60 In sub-Saharan Africa, Alaska, and Mediterranean countries, transmission of HBV usually occurs from person to person during childhood.20, 60-62 In these populations most children who are HBeAg positive have elevated ALT levels and seroconversion to anti-HBe is common near or shortly after the onset of puberty. In developed countries, HBV infection is usually acquired during adulthood through sexual transmission and injecting drug use.8, 9, 64 Very little longitudinal data are available, but liver disease is generally present in persons with high HBV DNA levels. Among carriers with elevated ALT levels, the rate of clearance of HBeAg averages between 8% and 12% per year52-55, 65 but is much lower in carriers who are in the immune tolerant phase (mostly Asian children and young adults with normal ALT levels)57, 58 and in immunocompromised subjects.23, 66 HBeAg clearance may follow an exacerbation of hepatitis, manifested by an elevation of ALT levels.54, 56 Older age, higher ALT, and HBV genotype B (vs. C) are associated with higher rates of spontaneous HBeAg clearance. After spontaneous HBeAg seroconversion, 67% to 80% of carriers have low or undetectable HBV DNA and normal ALT levels with minimal or no necroinflammation on liver biopsy — the “inactive carrier state.”13, 52-55, 62, 65, 67 Approximately 4% to 20% of inactive carriers have one or more reversions back to HBeAg. Among those who remain anti-HBe positive, 10% to 30% continue to have elevated ALT and high HBV DNA levels after HBeAg seroconversion, and roughly 10% to 20% of inactive carriers may have reactivation of HBV replication and exacerbations of hepatitis after years of quiescence.56, 60, 65, 67, 68 Therefore, serial testing is necessary to determine if an HBsAg-positive, HBeAg-negative carrier is truly in the “inactive carrier state” and life long follow-up is required to confirm that the inactive state is maintained. Clearance of HBeAg, whether spontaneous or after antiviral therapy, reduces the risk of hepatic decompensation and improves survival.68-76 Moderate or high levels of persistent HBV replication or reactivation of HBV replication following a period of quiescence after HBeAg seroconversion leads to HBeAg-negative chronic hepatitis B, which is characterized by HBV DNA levels >2,000 IU/ml and continued necroinflammation in the liver.78 Most patients with HBeAg-negative chronic hepatitis B harbor HBV variants in the precore or core promoter region.78-84 Patients with HBeAg-negative chronic hepatitis B tend to have lower serum HBV DNA levels than those with HBeAg-positive chronic hepatitis B (2,000-20 million vs. 200,000-2 billion IU/ml) and are more likely to run a fluctuating course. These patients are also older and have more advanced liver disease since HBeAg-negative chronic hepatitis B represents a later stage in the course of chronic HBV infection.78, 83, 86 Approximately 0.5% of HBsAg carriers will clear HBsAg yearly; most will develop anti-HBs.65, 87 However, low levels of HBV DNA remain detectable in the serum in up to half of these persons. The prognosis is improved in carriers who cleared HBsAg but HCC has been reported years after clearance of HBsAg, particularly in those who were older or had progressed to cirrhosis before HBsAg clearance.65, 86-90 Host and viral risk factors associated with increased rates of cirrhosis include older age (longer duration of infection), HBV genotype C, high levels of HBV DNA, habitual alcohol consumption, and concurrent infection with hepatitis C virus (HCV), hepatitis D virus (HDV) or human immunodeficiency virus (HIV).92, 93 Environmental factors that are associated with an increase risk of cirrhosis or HCC include heavy alcohol consumption, carcinogens such as aflatoxin, and, more recently smoking. Host and viral risk factors for HCC include male gender, family history of HCC, older age, history of reversions from anti-HBe to HBeAg, presence of cirrhosis, HBV genotype C, core promoter mutation, and coinfection with HCV.65, 69, 92, 93 Although cirrhosis is a strong risk factor for HCC, 30% to 50% of HCC associated with HBV occur in the absence of cirrhosis.11 Recently, several prospective follow-up studies of large cohorts of carriers from Asia found that the presence of HBeAg and high levels of HBV DNA were independent risk factors for the subsequent development of cirrhosis and HCC.47, 93-96 Given that most of the carriers in these studies likely acquired HBV infection perinatally and their mean age at enrollment was around 40 years, these data indicate that high levels of HBV replication persisting for more than 4 decades are associated with an increased risk of HCC. However, due to the fluctuating nature of chronic HBV infection, the accuracy of one high HBV DNA level at a single time point in predicting the prognosis of individual carriers may be limited and the risk of HCC in a younger carrier who is HBeAg-positive with one high HBV DNA level may be substantially lower. Coexistent HCV infection has been estimated to be present in 10% to 15% of patients with chronic hepatitis B and is more common among injecting drug users.98 Acute coinfection with HBV and HCV may shorten the duration of HBs antigenemia and lower the peak serum aminotransferase concentrations compared with acute HBV infection alone.99, 100 However, acute coinfection of HCV and HBV, or acute HCV on preexisting chronic HBV have also been reported to increase the risk of severe hepatitis and fulminant hepatic failure.101 Patients with dual HBV and HCV infection have a higher rate of cirrhosis and HCC development compared to patients infected by either virus alone.102, 103 HDV is a satellite virus, which is dependent on HBV for the production of envelope proteins.104 HBV/HDV coinfection most commonly occurs in the Mediterranean area and parts of South America. The availability of HBV vaccines and public health education on the prevention of transmission of HBV infection has led to a significant decline in the prevalence of HDV infection in the past decade.105 HDV infection can occur in two forms. The first form is caused by the coinfection of HBV and HDV; this usually results in a more severe acute hepatitis with a higher mortality rate than is seen with acute hepatitis B alone,104, 106 but rarely results in chronic infection. A second form is a result of a superinfection of HDV in a HBV carrier and can manifest as a severe “acute” hepatitis in previously asymptomatic HBV carriers or as an exacerbation of underlying chronic hepatitis B. Unlike coinfection, HDV superinfection in HBV carriers almost always results in chronic infection with both viruses. A higher proportion of persons with chronic HBV/HDV coinfection develop cirrhosis, hepatic decompensation, and HCC compared to those with chronic HBV infection alone.107, 108 Studies have found that between 6% and 13% of persons infected with HIV are also coinfected with HBV. Coinfection with HIV is more common in persons from regions where both viruses are endemic, such as sub-Saharan Africa.9 Individuals with HBV and HIV coinfection tend to have higher levels of HBV DNA, lower rates of spontaneous HBeAg seroconversion, more severe liver disease, and increased rates of liver related mortality.108-111 In addition, severe flares of hepatitis can occur in HIV co-infected patients with low CD4 counts who experience immune reconstitution after initiation of highly active antiretroviral therapy (HAART).110 Elevated liver enzymes in patients with HBV/HIV coinfection can be caused by other factors besides HBV including HAART and certain opportunistic infections such as cytomegalovirus and Mycobacterium Avium. Patients with HIV infection can have high levels of HBV DNA and hepatic necroinflammation with anti-HBc but not HBsAg, so called “occult HBV”.110 Therefore it is prudent to test all HIV infected persons for both HBsAg and anti-HBc and if either is positive, to test for HBV DNA. Persons who are negative for all HBV seromarkers should receive hepatitis B vaccine. If feasible, hepatitis B vaccine should be given when CD4 cell counts are >200/ul as response to vaccine is poor below this level. Persons with CD4 counts below 200 should receive HAART first and HBV vaccine when CD4 counts rise above 200/uL.110,111 The initial evaluation of patients with chronic HBV infection should include a thorough history and physical examination, with special emphasis on risk factors for coinfection, alcohol use, and family history of HBV infection and liver cancer. Laboratory tests should include assessment of liver disease, markers of HBV replication, and tests for coinfection with HCV, HDV, or HIV in those at risk (Table 5). Vaccination for hepatitis A should be administered to persons with chronic hepatitis B as per Centers for Disease Control recommendations.113 Most HBV DNA assays used in clinical practice are based on polymerase chain reaction (PCR) amplification with lower limits of detection of 50-200 IU/ml (250-1,000 copies/ml),114 and a limited dynamic range, up to 4-5 log10 IU/ml. Recently, HBV DNA assays that utilize real-time PCR technology with improved sensitivity (5-10 IU/ml) and wider dynamic range (up to 8-9 log10 IU/ml) have become available.115 Quantification of serum HBV DNA is a crucial component in the evaluation of patients with chronic HBV infection and in the assessment of the efficacy of antiviral treatment. A major dilemma in the interpretation of serum HBV DNA levels is the determination of cutoff values used to define treatment indications and response. Because HBV DNA persists even in persons who have serological recovery from acute HBV infection,116 low levels of HBV DNA may not be associated with progressive liver disease and viral clearance is an unrealistic treatment endpoint. An arbitrary value of 20,000 IU/ml (>105 copies/ml) was chosen as a diagnostic criterion for chronic hepatitis B at the 2000 NIH conference.3 However, chronic hepatitis, cirrhosis and HCC have been found in patients with lower HBV DNA levels. Also, some patients with chronic hepatitis B have widely fluctuating HBV DNA levels that may vary from undetectable to >2,000,000 IU/ml.117 Thus, serial monitoring of HBV DNA levels is more important than any single arbitrary cutoff value in prognostication and in determining the need for treatment. It is now recognized that lower HBV DNA levels (3-5 log10 IU/ml) may be associated with progressive liver disease and may warrant treatment, particularly in those who are HBeAg-negative or have already developed cirrhosis. The purpose of a liver biopsy is to assess the degree of liver damage and to rule out other causes of liver disease. However, it must be recognized that liver histology can improve significantly in patients who have sustained response to antiviral therapy or spontaneous HBeAg seroconversion. Liver histology also can worsen rapidly in patients who have recurrent exacerbations or reactivations of hepatitis. Liver biopsy is most useful in persons who do not meet clear cut guidelines for treatment listed below. Recent studies suggest that the upper limits of normal for ALT and AST should be decreased to 30 U/l for men and 19 U/l for women.118 HBV infected patients with ALT values close to the upper limit of normal may have abnormal histology and can be at increased risk of mortality from liver disease especially those above age 40. Thus, decisions on liver biopsy should take into consideration age, the new suggested upper limits of normal for ALT, HBeAg status, HBV DNA levels, and other clinical features suggestive of chronic liver disease or portal hypertension. Initial evaluation of persons newly diagnosed with chronic HBV infection should include history, physical examination and laboratory testing as outlined in Table5. (III) All persons with chronic hepatitis B not immune to hepatitis A should receive 2 doses of hepatitis A vaccine 6 to 18 months apart. (II-3) These patients should be monitored at 3 to 6 month intervals (Table 5, Fig. 1). More frequent monitoring should be performed when ALT levels become elevated.54, 56, 60, 119 Patients who remain HBeAg positive with HBV DNA levels greater than 20,000 IU/ml after a 3 to 6 month period of elevated ALT levels greater than two times the upper limit of normal should be considered for liver biopsy and antiviral treatment (Fig. 1). Liver biopsy and treatment should also be considered in patients with persistent borderline normal or slightly elevated ALT levels particularly if the patient is above the age of 40. Liver biopsy is usually not necessary in young patients (below 30) who are HBeAg-positive and have persistently normal ALT. Algorithm for follow-up of HBV carriers who are HBeAg-positive (A) or HBeAg-negative (B). ALT, alanine aminotransferase; ULN, upper limit of normal; Rx, treat; HCC, hepatocellular carcinoma. These patients should be monitored with ALT determination every 3 months during the first year to verify that they are truly in the “inactive carrier state” and then every 6-12 months.86, 117 If the ALT level is subsequently found to be elevated, more frequent monitoring is needed. In addition, an evaluation into the cause of ALT elevation, including HBV DNA tests, should be initiated if it persists or recurs (Table 5, Fig. 1). HBeAg-positive and HBeAg-negative patients who meet criteria for chronic hepatitis B (Table4) should be evaluated for treatment. (I) HBeAg-positive patients: HBeAg-positive patients with persistently normal ALT should be tested for ALT at 3-6 month intervals. ALT along with HBV DNA should be tested more often when ALT levels become elevated. HBeAg status should be checked every 6-12 months. (III) Patients who remain HBeAg positive with HBV DNA levels >20,000 IU/ml after a 3-6 month period of elevated ALT levels between 1-2 × ULN, or who remain HBeAg positive with HBV DNA levels >20,000 IU/ml and are >40 years old, should be considered for liver biopsy, and treatment should be considered if biopsy shows moderate/severe inflammation or significant fibrosis. (III) Patients who remain HBeAg positive with HBV DNA levels >20,000 IU/ml after a 3-6 month period of elevated ALT levels >2 × ULN should be considered for treatment. (III). HBeAg-negative patients: HBeAg-negative patients with normal ALT and HBV DNA <2,000 IU/ml should be tested for ALT every 3 months during the first year to verify that they are truly in the “inactive carrier state” and then every 6-12 months. (III) Tests for HBV DNA and more frequent monitoring should be performed if ALT or AST increases above the normal limit. (III) A recent AASLD practice guideline on HCC has been published.120 Of the two tests prospectively evaluated as screening tools for HCC, alpha-fetoprotein (AFP) and ultrasound (US), the sensitivity, specificity, and diagnostic accuracy of US are higher than those of AFP. The AASLD Practice Guideline for HCC recommended surveillance of carriers at high risk of HCC with US every 6-12 months and AFP alone when US is not available or cost is an issue.120 Because the interpretation of US findings is operator dependent, clinicians may choose to employ both US and AFP for HCC surveillance. HBV carriers at high risk for HCC such as Asian men over 40 years and Asian women over 50 years of age, persons with cirrhosis, persons with a family history of HCC, Africans over 20 years of age, and any carrier over 40 years with persistent or intermittent ALT elevation and/or high HBV DNA level >2,000 IU/ml should be screened with US examination every 6-12 months. (II-2) For HBV carriers at high risk for HCC who are living in areas where US is not readily available, periodic screening with AFP should be considered. (II-2) The aims of treatment of chronic hepatitis B are to achieve sustained suppression of HBV replication and remission of liver disease. The ultimate goal is to prevent cirrhosis, hepatic failure and HCC. Parameters used to assess treatment response include normalization of serum ALT, decrease in serum HBV DNA level, loss of HBeAg with or without detection of anti-HBe, and improvement in liver histology. At the 2000 and 2006 NIH conferences on Management of Hepatitis B, it was proposed that responses to antiviral therapy of chronic hepatitis B be categorized as biochemical (BR), virologic (VR), or histo