CLINICAL UPDATES

Chronic hepatitis B has affected approximately 350 million people worldwide.1 In the United States, the Centers for Disease Control and Prevention (CDC) report a prevalence of 1.25 million. The incidence of acute hepatitis B has been in decline since the 1980s, as a corollary to preventive efforts against human immunodeficiency virus (HIV) infection in homosexual men and illicit injection drug use, in addition to perinatal screening and vaccination against hepatitis B virus (HBV).2–4 However, because of the increasing influx of immigrants from hepatitis B-endemic areas such as Asian Pacific regions and Eastern Europe, chronic hepatitis B is probably more prevalent than estimated in the United States, particularly on the East and West coasts and in metropolitan cities.5,6

To the advantage of clinicians who are confronted with the diagnosis and management of hepatitis B, our understanding of the virology of HBV has improved, and we now have an increasing appreciation for the complex clinical course of the disease. In addition, the availability of newer antiviral agents approved by the US Food and Drug Administration (FDA) provides clinicians with an increasing number of therapeutic options.

The hepatitis B virus and natural history

Hepatitis B virus is a partially double-stranded DNA virus that produces several proteins from four overlapping genes: the S (surface), C (core), P (polymerase), and X genes. The S gene produces three surface antigens, among which is HBsAg, used to diagnose HBV infection. The presence of HBsAg in the serum indicates ongoing infection and renders the carrier infectious.

The C gene produces hepatitis B early antigen (HBeAg) and hepatitis B core antigen (HBcAg). Presence of HBeAg in serum indicates a highly replicative virus, leading to a higher level of viral DNA in the serum and rendering the carrier highly infectious.

The P gene produces several enzyme proteins mainly involved in viral replication. During the HBV life cycle in the hepatocyte, HBV DNA goes through a pre-genomic RNA phase, which requires reverse transcriptase produced by the P gene to reverse-transcribe the RNA back to negative-strand DNA as part of the reproductive process. This process provides the unique opportunity for therapeutic intervention. The X gene produces hepatitis B X antigen (HBxAg), which probably plays an important role in carcinogenesis.

A clear dichotomy exists in the natural history of chronic hepatitis B between high-endemic regions (such as Asia and Africa), where hepatitis B infection almost always occurs perinatally through vertical transmission, and low-endemic regions (such as Western Europe and the United States), where the virus is usually acquired in early adulthood, when people begin to engage in behaviors that foster the spread of blood-borne agents.1,7 This difference in the age at infection translates into a huge difference in the rate of chronicity. Persons infected perinatally have about a 90% chance of becoming chronically infected, whereas those who are infected as young adults have less than a 5% chance of chronicity.

This distinction may be rooted in the difference in the level of maturity of the host's immune system. Infected newborns tend to tolerate the virus and produce no vigorous immune response, a situation that invariably leads to chronic infection. In adults, the immune response is robust, causing more symptomatic acute infection and resulting in less chronic infection. Furthermore, this tendency toward chronicity associated with early-life infection also translates to an eventual development of cirrhosis of the liver and hepatocellular carcinoma (HCC). The lifetime risk of dying of complications of chronic hepatitis B approaches 40% in high-endemic regions.7,8

The natural history of chronic hepatitis B infection in perinatally infected patients has four phases: immune tolerant, immune active (chronic hepatitis), nonreplicative (inactive carrier), and resolved (table 1).8 Infection with HBV involves a dynamic process between the host and the virus. Various diagnostic markers are used in classifying patients as being in one of these four phases (table 2).9

The immune tolerant phase is characterized by circulating HBsAg, HBeAg, and high serum levels of HBV DNA. This phase generally occurs with perinatal transmission and may last for decades. Patients are usually asymptomatic, showing normal or only slightly increased alanine aminotransferase (ALT) levels and minimal histologic evidence of inflammation of the liver. Such signs imply that the host has initiated little or no immune response against the infected hepatocyte.

During the course of chronic HBV infection, the immune system loses its tolerance for the virus and may enter the immune active phase, associated with a decrease in HBV DNA concentrations, elevated ALT levels, and increased histologic activity, reflective of immune-mediated lysis of the infected hepatocytes. This phase may last months or years.

The third phase, the low-replicative to nonreplicative phase (inactive carrier), occurs after seroconversion from HBeAg positive to negative and development of anti-HBeAg antibody (anti-HBe). This phase is usually preceded by a significant reduction in serum HBV DNA to low or undetectable levels; ALT levels are normal, and there is resolution of liver necroinflammation. In many patients, serum HBV DNA levels are detectable, however, by polymerase chain reaction assay.

The inactive carrier phase may last a lifetime. A certain percentage of patients in the inactive carrier phase may undergo spontaneous or immunosuppression-induced reactivation of HBV replication, signaled by a return to high levels of HBV DNA, with or without HBeAg seroreversion, and a rise in ALT levels. A mutation in the precore or precore promoter region of the HBV genome may cause a reduction in or abolition of HBeAg production, but the virus continues to be actively replicative and hepatic inflammation continues. It is now recognized that patients who have this mutation have the worst prognosis with regard to liver disease.10,11 Cirrhosis and HCC usually develop.

In the resolved phase of chronic hepatitis B, patients become positive for anti-HBs and negative for HBsAg. ALT levels are normal. HBV DNA is undetectable, and histologic examination of the liver shows minimal or no disease activity, although various stages of fibrosis may be present, depending on the extent of disease activity before the disease resolved. HCC can still develop in patients in this phase who have cirrhosis.11

Initial patient evaluation

All persons in high-risk groups for hepatitis B (table 3) should be screened for serum HBsAg.12 It is important for the clinician to discuss the potential impact of the possible results with the patient before starting the screening process. In the United States, all pregnant women routinely undergo prenatal screening for HBsAg.

Chronic infection with HBV is diagnosed when tests for HBsAg in serum are positive for more than 6 months. Once a patient is found to test positive for HBsAg, further workup is needed. The initial evaluation should include a thorough history and physical examination; special emphasis should be placed on risk factors for coinfection, alcohol use, and family history of HBV infection and HCC. Other tests that should be done include testing for HBeAg and anti-HBe, as well as HBV DNA quantification by nucleic acid testing. Testing for hepatitis B core antibody (anti-HBc) of the immunoglobulin M (IgM) subtype should be done if acute infection or reactivation of chronic inactive hepatitis B is suspected. The interpretation of these tests is given in table 4.13 HCV-Ab and HIV-Ab should be tested in patients at risk. In addition, a liver biopsy is recommended as part of the initial evaluation of patients whose stage of liver disease is uncertain.

Patient monitoring

Monitoring is essential in assessing progression of liver disease and the need for treatment. Monitoring is also necessary in following response to treatment and conducting HCC surveillance. In the absence of supportive evidence-based data regarding patient monitoring, the following guidelines represent a consensus of most experts.12,13

HBeAg-positive chronic HBV infection

Patients who test positive for HBeAg and who have HBV DNA levels greater than 105 copies/mL and normal ALT values are considered to be in the immune tolerant phase. No treatment is necessary, although monitoring is essential. ALT levels should be evaluated every 3 to 6 months. If the ALT value is less than two times the upper limit of normal, it should be rechecked every 1 to 3 months. If it is more than two times the upper limit of normal for 3 to 6 months, liver biopsy and treatment should be considered.

HCC surveillance should be considered in high-risk patients, that is, men older than 45 years of age, patients with cirrhosis, and patients with a family history of HCC. The tests used for HCC surveillance should include alpha-fetoprotein level and ultrasound or computed tomographic scanning of the liver. No well-conducted, randomized, controlled study has been done to establish the efficacy of HCC surveillance. However, common practice is to test alpha-fetoprotein level every 6 months and perform imaging studies of the liver every year. The reliability of ultrasound studies is operator-dependent, and thus the clinician should take into account the capabilities of the local sonographer when deciding which imaging studies to use.

Inactive HBsAg carrier state

For patients who are inactive HBsAg carriers, monitoring ALT levels every 6 to 12 months is adequate. If the ALT value rises above normal but less than twice the upper limit of normal, serum HBV DNA level should be checked and other causes of liver disease ruled out. If the ALT value is more than two times the upper limit of normal for 3 to 6 months and HBV DNA levels are greater than 105 copies/mL, liver biopsy and treatment should be considered. Appropriate subpopulations within this category should be considered for HCC surveillance.

Patient counseling

Patients with chronic HBV infection should be counseled about lifestyle modifications and prevention of transmission. No specific dietary measures have been shown to have any effect on the progression of chronic HBV disease, although patients with cirrhosis of the liver should avoid raw shellfish because of the increased incidence of morbidity and mortality from Vibrio vulnificus infection. Heavy use of alcohol (>40 g/day) has been associated with accelerated deterioration of liver disease and the development of cirrhosis. In addition, a recent report has shown increased risk of HCC in male patients who consume alcohol.14 Carriers of HBV infection should be counseled concerning the risk of transmission to others. They should understand the precautions that are necessary to prevent sexual transmission, perinatal transmission, and inadvertent transmission by environmental contamination from a blood spill. Sexual and household contacts of carriers should be tested for HBV infection (including HBsAg and anti-HBs testing). If these test results are negative, these persons should receive hepatitis B vaccination.

Newborns of HBV-infected mothers should receive treatment with hepatitis B immunoglobulin and hepatitis B vaccine at delivery and should subsequently complete the recommended vaccination series. Persons who remain at risk for HBV infection, such as infants of HBsAg-positive mothers, healthcare workers, and dialysis patients, should be tested for response to vaccination. Infants of carrier mothers should be tested at 3 to 9 months after vaccination, and healthcare workers should be tested at 1 to 6 months. Dialysis patients should be tested annually.

All persons with chronic HBV infection who are not immune to hepatitis A should receive two doses of hepatitis A vaccine: an initial injection, followed by a booster injection in 6 to 18 months. Prevaccination screenings for antibody to hepatitis A (total or IgG) should be considered for patients from hepatitis A endemic areas such as Asia, Africa, and South America.

Treatment

Pharmacotherapy for chronic hepatitis B has been evolving rapidly over the last few years. At present, five FDA-approved drugs are available for the treatment of this disease: interferon alfa-2b, lamivudine, adefovir dipivoxil, entecavir, and pegylated interferon alfa-2a. Treatment guidelines and position papers describing the selection of patients for treatment, agents used, and duration of treatment have been developed by various national and international liver study societies and expert panels.15–17 These documents differ in the criteria they specify for patient management in the various clinical settings. For instance, the opinions of the expert panel differ from the criteria of the more stringent, evidence-based guidelines in that the expert panel recommends a lower viral load threshold for initiation of therapy in patients with HBeAg-negative compensated disease as well as in cirrhosis (tables 5 and 6).17,18

Although various treatments can be used for the different clinical presentations of chronic hepatitis B (tables 7 and 8),15–17 the treatment guidelines agree that interferon is contraindicated in patients with decompensated cirrhosis. (It is important to note that these treatment guidelines have not yet been updated to reflect the recent licensing of entecavir and pegylated interferon alfa-2a.) Because these guidelines conflict in other respects, clinicians are well advised, when in doubt, to refer patients to specialists who are familiar with current, state-of-the-art treatments for chronic hep-atitis B.

Summary

Chronic hepatitis B is a complex disease for which there are an increasing number of approved treatment options. Clinicians who strive to keep up to date on the diagnosis and treatment of hepatitis B will be in the best position to meet the challenge of managing patients with this serious infection.

Dr Tsai is on the advisory board for Bristol-Meyers-Squibb and Idenix; is on the speakers' bureau for Bristol-Meyers-Squibb, Roche, Schering-Plough, and Gilead; and has received research support from Bristol-Meyers-Squibb, Roche, Schering-Plough, Gilead, and Idenix. Dr Tsai is professor of medicine, division of gastroenterology, John A. Burns School of Medicine, Honolulu, Hawaii.

References

1. World Health Organization. Hepatitis B fact sheet. Available at: http://www.who.int/mediacentre/factsheets/fs204/en/ Accessed June 30, 2006
2. Centers for Disease Control and Prevention. Chapter 15. Hepatitis B. In: Epidemiology and prevention of vaccine-preventable disease. 9th ed. Available at: http://www.cdc.gov/nip/publications/pink/hepb. Accessed June 30, 2006
3. Incidence of acute hepatitis B-United States, 1990-2002 MMWR 2004; 52( 51&52): 1252-4
4. Centers for Disease Control and Prevention, National Center for Infectious Diseases. Viral hepatitis surveillance. Disease burden from hepatitis A, B, and C in the United States. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/resource/PDFs/disease2004.pdf. Accessed June 30, 2006
5. Barnes JS, Bennett CE. The Asian population 2000: Census 2000 Brief. US Dept of Commerce, Economics and Statistics Administration, US Census Bureau. Available at: http://www.census.gov/prod/2002pubs/c2kbr01-16.pdf. Accessed June 30, 2006
6. GuaneR, SiuP, LamK, et al. Prevalence of HBV and risk of HBV acquisition in hepatitis B screening programs in large metropolitan cities in the United States. (abstr 1269) Hepatology 2004; 40( 4 suppl l): 716A
7. FattovichG . Natural history and prognosis of hepatitis B Semin Liver Dis 2003; 23( 1): 47-58
8. McMahonBJ . The natural history of chronic hepatitis B virus infection Semin Liver Dis 2004; 24( suppl 1): 17-21
9. FunkML, RosenbergDM, LokAS . World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promoter variants J Viral Hepat 2002; 9( 1): 52-61
10. HadziyannisSJ, VassilopoulosD . Hepatitis B e antigen-negative chronic hepatitis B Hepatology 2001; 34( 4, Pt 1): 617-24
11. HsuYS, ChienRN, YehCT, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B Hepatology 2002; 35( 6): 1522-7
12. LokAS, McMahonBJ; Practice Guidelines Committee, American Association for the Study of Liver Diseases . Chronic hepatitis B Hepatology 2001; 34( 6): 1225-41
13. ConjeevaramHS, LokAS . Management of chronic hepatitis B J Hepatol 2003; 38( suppl1): S90-103
14. YangHI, LuSN, LiawYF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma N Engl J Med 2002; 347( 3): 168-74
15. de FranchisR, HadengueA, LauG, et al; EASL Jury . EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002, Geneva Switzerland. Consensus statement (long version) J Hepatol 2003; 39( suppl 1): S3-25
16. LiawY-F, LeungN, GuanR, et al; Asian-Pacific consensus update working party on chronic hepatitis B . Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update Liver Int 2005: 25( 3): 472-89
17. KeeffeEB, DieterichDT, HanSH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States Clin Gastroenterol Hepatol 2004; 2( 2): 87-106
18. LokAS, McMahonBJ . Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD). Chronic hepatitis B: update of recommendations Hepatology 2004; 39( 3): 857-61