The Natural History of Chronic Hepatitis B Virus Infection

The Natural History of Chronic Hepatitis B Virus Infection Brian J. McMahon, M.D. 1 ABSTRACT Three stages of chronic hepatitis B virus (HBV) infection are recognized: the immune tolerant phase, the chronic hepatitis B phase, and the inactive hepatitis B carrier phase. Active liver disease is most often found in persons with elevated aminotransferase levels and HBV DNA levels >10 5 copies/ml. Possible risk factors for developing liver disease include older age, male gender, presence of hepatitis B e antigen (HBeAg), HBV genotype, mutations in the precore and core promoter regions of the viral genome, and coinfection with hepatitis D (delta) virus. All persons chronically infected with HBV should be followed every 6 to 12 months with aminotransferase levels. Those with elevated levels should be tested for HBeAg and its antibody (anti-hbe) as well as HBV DNA levels to determine if they are in need of further evaluation with a liver biopsy and are candidates for antiviral therapy. Future research will help clarify the outcome of chronic HBV infection. KEYWORDS: Hepatitis B virus, natural history, hepatocellular carcinoma Between 350 million and 400 million people worldwide are chronically infected with HBV. 1 Although most persons will not develop any illness related to this chronic infection, some will develop chronic liver disease, which can lead to cirrhosis or hepatocellular carcinoma (HCC), or both. The purpose of this article is to review what is known about the natural history of HBV infection and to discuss the identified risk factors that may contribute to the development of cirrhosis and HCC. In addition, the article discusses the gaps in our knowledge of chronic HBV infection and speculates on alternative factors that could play a role in disease progression. stages of chronic HBV infection were identified at the National Institutes of Health Workshop on Management of Chronic Hepatitis B 2000: the immune tolerant phase, the chronic hepatitis B phase, and the inactive hepatitis B (or asymptomatic) carrier phase (Table 1). 2 Immune Tolerant Phase The immune tolerant phase most commonly occurs after perinatal transmission and is characterized by the presence of HBeAg, high levels of serum HBV DNA but normal alanine aminotransferase (ALT) levels, and minimal or no inflammation on liver biopsy. STAGES OF HBV INFECTION Chronic HBV infection is most commonly defined as being present when a person tests positive for hepatitis B surface antigen (HBsAg) for at least 6 months. 2 Three Chronic Hepatitis B Phase The chronic hepatitis B phase is seen after horizontal transmission of HBV during early childhood or HBV Viral Kinetics and Clinical Management: Key Issues and Current Perspectives; Editor in Chief, Paul D. Berk, M.D.; Guest Editors, Emmet B. Keeffe, M.D., and Jules L. Dienstag, M.D. Seminars in Liver Disease, volume 24, supplement 1, 2004. Address for correspondence and reprint requests: Brian J. McMahon, M.D., 4055 Tudor Centre Drive, Anchorage, AK 99508-5902. E-mail: bdm9@cdc.gov. 1 Director, Viral Hepatitis Program, Alaska Native Medical Center, Anchorage, Alaska. Copyright # 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 0272-8087,p;2004,24,s1,017,021,ftx,en;sld00260x. 17

18 SEMINARS IN LIVER DISEASE/VOLUME 24, SUPPLEMENT 1 2004 Table 1 Definitions of Stages of Chronic HBV Infection (National Institutes of Health) Stage HBeAg/Anti-HBe Status ALT HBV DNA (copies/ml) Liver Histology Immune tolerant HBeAg Normal >100,000* Normal or minimal inflammation Chronic hepatitis B HBeAg or anti-hbe Elevated >100,000* Chronic inflammation Inactive hepatitis B Anti-HBe Normal <100,000* Normal or minimal inflammation *equivalent to >20,000 IU/mL From Lok et al. 2 adulthood. It usually occurs later in life in persons who acquired HBV infection from maternal transmission and have initially been through the immune tolerant phase. Elevated aminotransferase levels, high levels of HBV DNA, and active liver disease on biopsy characterize this phase. Persons with chronic hepatitis B may have HBeAg or anti-hbe in their sera. In persons who are HBeAg positive, spontaneous seroconversion from HBeAg to anti-hbe commonly occurs, often accompanied by a flare in aminotransferase levels. After the HBeAg to anti-hbe seroconversion, most persons have normal aminotransferase levels and lower levels of HBV DNA, usually <10 3 copies (or genome equivalents)/ml. This conversion from the HBeAg-positive chronic hepatitis B phase to the inactive hepatitis B carrier phase occurs in up to 50% of children and adults by 5 years and in up to 70% by 10 years. 3 5 Inactive Hepatitis B Carrier Phase Three outcomes have been observed once a patient enters the inactive carrier phase of HBV infection. Most carriers (as many as 70 to 80%) remain in the inactive carrier phase indefinitely. An additional 10 to 20% may have one or more reversions back to the HBeAg-positive state, usually accompanied by elevations in ALT levels, during which liver inflammation reactivates. 5 An undetermined proportion of others develop chronic anti-hbe positive hepatitis, which is characterized by elevated aminotransferase levels, HBV DNA levels >10 5 copies/ml or >20,000 IU/mL, and active liver disease. These persons with chronic anti- HBe positive hepatitis can exhibit a waxing and waning course of disease that can lead to cirrhosis. 6,7 Many of these individuals contain the HBV precore variant in their sera. 8 The most common precore variant is a G to A mutation at base pair 1896 that creates a premature stop codon abolishing the production of HBeAg. HBV DNA can still be produced in high quantities, although levels are not as high as those seen in HBeAg-positive persons. The precore variant appears in the sera of most persons around the time of HBeAg seroconversion. However, the precore variant is believed to be the dominant form of HBV in persons who have anti-hbe positive hepatitis. A few carriers of chronic HBV infection eventually lose HBsAg at a rate of approximately 0.5% per year. 5 Regardless of what course HBV infection takes in a patient, all affected persons, even those who remain in the inactive carrier state, are at risk of developing HCC. 9 Because carriers in the inactive phase could have a flare of liver disease at anytime during their lifetimes (and thus could benefit from antiviral therapy) or could develop HCC, all persons chronically infected with HBV should be followed routinely with aminotransferase levels (ALT and aspartate aminotransferase [AST]) every 6 to 12 months. Surveillance for HCC with at least a-fetoprotein monitoring should be considered. 1 IMPACT OF HEPATITIS B VACCINATION Hepatitis B vaccination programs have had a dramatic impact on the outcome of liver disease in population groups in which HBV infection is endemic. In Alaska, the proportion of HBV carriers who were HBeAg positive in the population decreased from 35 to 3% by 15 years after the introduction of hepatitis B vaccine in newborns and the completion of a mass vaccination catch up program. 5 This effort halted transmission, yielding a cohort of children under age 10 who were free of chronic HBV infection. As a result, no new HBeAg-positive carriers entered into the population, and HBeAg naturally cleared from a large proportion of existing HBeAg-positive carriers. 10 Thus, in populations undergoing large-scale vaccination programs, the proportion of persons harboring chronic HBV infection with HBeAg will likely decrease, and anti-hbe positive chronic hepatitis may become the predominant form of liver disease. In Taiwan, the introduction of routine immunization of newborns has not only dramatically decreased the prevalence of HBsAg in children but also reduced the incidence of HCC in this age group. 11 HBV GENOTYPES Eight genotypes of HBV have recently been identified. Table 2 lists these genotypes and the geographic areas where they have been found. In the United States, genotypes A, B, C, and D were found to be the most common, with genotypes A and D predominant among white and black patients and genotypes B and C predominant among Asian patients. 12 At present, it is not known whether disease progression and HCC are associated with certain genotypes. In China and Japan, some

NATURAL HISTORY OF HBV/MCMAHON 19 Table 2 Genotype Genotypes of HBV Geographic Distribution 1. A Northern Europe, Africa, United States 2. B and C Asia 3. D Southern Europe, Middle East 4. E Africa 5. F and H Central and South America 6. G Africa 7. A, B, C, and D United States* *From Chu et al. 12 studies have found more severe liver disease to be associated with genotype C and than with genotype B, 13 whereas other studies have found no such association. 14 Some evidence suggests that HBeAg seroconversion occurs at a younger age among persons infected with genotype B than among those with genotype C. 13 15 Genotype D has been associated with anti-hbe positive chronic hepatitis B infection in the Mediterranean area. 16 In a nationwide survey conducted in the United States, the precore variant of HBV was found in >70% of persons with genotype D and in almost 50% of those with genotype C, but it was rare in association with genotype A. 17 In that study, persons with the precore variant and core promoter mutations had higher HBV DNA levels in sera than did persons who did not harbor these mutations. ANTI-HBE CHRONIC HEPATITIS B Chronic hepatitis of the HBeAg-negative, anti-hbe positive type is now recognized as an important form of chronic hepatitis B. In the Mediterranean area, this form of chronic hepatitis B is associated with HBV genotype D. Several patterns of anti-hbe associated liver disease have been observed in patients from this area. 17 In some patients, the disease is manifested by persistently elevated ALT levels. Other individuals have low degrees of ALT elevation but experience periodic exacerbations with increased ALT levels (without HBeAg reversion) during which ALT levels may rise to more than two to four times above the baseline level. Still other persons may have long periods of normal ALT levels with short periods of exacerbation of hepatitis during which ALT levels rises to more than two to four times above the upper limit of normal, then fall back within the normal range. Progressive liver damage may result over many years from any of these patterns and may lead to cirrhosis and even liver failure. Patients may be asymptomatic during the course of these patterns. Cumulative experience with anti-hbe positive chronic hepatitis B reinforces the practice guidelines recommended by the American Association for the Study of Liver Diseases for chronic hepatitis B, advocating careful follow-up of Table 3 Guidelines for Follow-Up of Persons With Chronic HBV Infection Phase Immune tolerant Chronic hepatitis B Inactive hepatitis B Follow-Up ALT/AST every 6 12 months HBeAg/anti-HBe every 1 2 years ALT/AST every 6 months Full liver panel and CBC every 1 2 years Consider AFP and US every 6 12 months if high risk for develop of HCC ALT/AST every 6 12 months Consider AFP every 6 months If ALT or AST > normal limit, obtain HBV DNA, HBeAg, anti-hcv; BMI, alcohol, medication history; clinical evaluation BMI, body mass index; CBC, complete blood count; US, ultrasound (liver). all persons with chronic HBV infection, including those who are anti-hbe positive and have normal ALT levels (inactive hepatitis B carriers). 1 These persons should be followed carefully with periodic evaluation of aminotransferase levels every 6 to 12 months (Table 3). 1 ESTABLISHED RISK FACTORS FOR HCC Several factors have been identified with an increased risk of HCC. They include male gender, age >45 years, having a first-degree relative with HCC, the presence of cirrhosis, HBeAg-positive status in adults, and reversion from anti-hbe to HBeAg status. 5,18 Studies examining the influence of HBV genotype on the subsequent development of HCC have been inconclusive. Although the aforementioned risk factors account for most cases that progress to HCC, they do not account for all cases. In other words, persons with none of these risk factors can still develop HCC, including individuals in the inactive anti-hbe phase who have normal liver enzymes and persons with low or absent levels of serum HBV DNA. 19 In addition, carriers who clear HBsAg can still develop HCC. In this case, integration of HBV DNA into the human liver genome can cause replication errors in regenerating liver cells. Such errors could conceivably result in the stimulation of a promoter gene or ablation of a stop codon, allowing for the uncontrolled growth of hepatocytes. 5 OTHER HCC RISK FACTORS Many other factors have been implicated in the progression of liver disease and the development of HCC.

20 SEMINARS IN LIVER DISEASE/VOLUME 24, SUPPLEMENT 1 2004 Coinfection with either hepatitis C virus (HCV) or hepatitis D (delta) virus (HDV) has been shown to increase the risk of cirrhosis. 1,19 Persons coinfected with both HBV and HCV also have an increased risk of developing HCC, as compared with those infected with either virus alone. 5 Although coinfection with HDV has not been shown to increase the risk of HCC, one study demonstrated that HCC appears at a younger age in coinfected persons than it does in those infected solely with HBV. Chronic alcohol use also appears to increase the risk of cirrhosis. Aflatoxin in the diet greatly increases the risk of HCC in HBVinfected persons. More data are needed on the role of ethnicity, HBV genotype, and specific HBV mutations of the HBV genome (such as viral mutations in the precore, core promoter, and X region) in the development of HCC. Mutation in the X region, for example, is believed to code for transactivation protein. 5 Finally, the role of host immune factors needs to be studied, not only in relationship to the development of liver disease but also in connection with the clearance of HBeAg and HBsAg. CONCLUSION Much has been learned about the natural history of chronic HBV infection, including specific factors that increase the risk of HCC. However, our knowledge of the risk factors leading to the development of progressive liver inflammation, fibrosis, and cirrhosis remains limited. Further prospective studies are needed, conducted among population-based cohorts of HBsAg carriers encompassing all of the HBV genotypes, men and women, all age groups, and diverse ethnic groups. Aminotransferase levels and HBV DNA levels should be assessed in these cohorts, and subsets of persons should be tested for HBV mutations, including (but not limited to) precore and core promoter mutations, to determine associations of demographic, clinical, and viral factors in the development of chronic liver disease. Associations elucidated from these studies may improve patient management through such measures as enhanced clinical surveillance of subsets of identified at-risk carriers and earlier intervention with antiviral therapy and other preventive measures to decrease the risk of complications in chronic HBV infection. In the meantime, it is reasonable for clinicians who care for persons with chronic HBV infection to follow all HBsAg carriers at regular intervals to determine whether liver disease is occurring and to prepare to treat patients manifesting progressive liver inflammation with antiviral medications. DISCLOSURE OF COMMERCIAL FINANCIAL SUPPORT Dr. McMahon has received research support from GlaxoSmithKline Biologicals, Rixensart, Belgium. ABBREVIATIONS ALT alanine aminotransferrase AST aspartame aminotransferase HBV hepatitis B virus HBeAg hepatitis B e antigen HBsAg hepatitis B surface antigen HCC hepatocellular carcinoma HCV hepatitis C virus HDV hepatitis D (delta) virus REFERENCES 1. Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. AASLD Practice Guideline. Hepatology 2004;39:857 861 2. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000. Summary of a workshop. Gastroenterology 2001;120:1828 1853 3. Lee PI, Chang MH, Lee CY, et al. Changes in serum hepatitis B DNA and aminotransferase levels during the course of chronic hepatitis B virus infection in children. Hepatology 1990;12:657 660 4. Bortolotti F, Cadrobbi P, Crivellaro C, et al. Long-term outcome of chronic type B hepatitis in patients who acquire hepatitis B infection in childhood. 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