Natural History of Chronic Hepatitis B – Clinical Implications

Introduction

Worldwide, between 350 and 400 million persons are estimated to be chronically infected with hepatitis B virus (HBV) and 15% to 40% of those persons are at risk of developing cirrhosis and/or hepatocellular carcinoma (HCC) without intervention.[1] High and intermediate rates of HBV prevalence, defined as > 8% and 2% to 8%, respectively, of hepatitis B surface antigen (HBsAg), the marker for active infection, are found in all of the continents of Asia, the South Pacific and Africa, much of Eastern Europe, the Amazon region of South America, several Mediterranean countries, the Caribbean, and indigenous populations of the Arctic, New Zealand, and Australia.[2] Persons who are born in one of these regions and who immigrate to the United States or Western Europe should be screened for HBV markers. Recently, a double-blind, placebo-controlled trial involving 651 persons from Taiwan who had cirrhosis showed that lamivudine, a nucleoside analog that inhibits the reverse transcriptase activity of HBV, significantly reduced the rate of death from liver disease and HCC.[3] The medications currently approved by the US Food and Drug Administration (FDA) for the treatment of hepatitis B include interferon alfa-2b, pegylated interferon alfa-2a, and the oral nucleoside/nucleotide analogs lamivudine, adefovir, entecavir, and telbivudine. Two other medications, tenofovir and emtricitabine, already approved for the treatment of HIV infection, also demonstrate activity against HBV.[4] This article explores the natural history of HBV, with a focus on how to best select those individuals who might be candidates for treatment.

Phases of HBV Infection

Three phases of chronic hepatitis B infection have been identified: the immune-tolerant phase, the immune-active phase, and the inactive hepatitis B phase (“inactive carrier”) (Table 1).[5] The immune-tolerant phase is seen almost exclusively in children infected at birth by mothers who are positive for hepatitis B e antigen (HBeAg) and who have high levels of HBV DNA in their sera. HBV is nonpathogenic in the immune-tolerant person and these individuals are positive for HBeAg, have high levels of HBV DNA (well above 20,000 IU/mL [> 100,000 copies/mL]), normal liver aminotransferase levels, and no or minimal pathology on liver biopsy. Although the immune-tolerant phase can last well into adulthood, most individuals go into the immune-active phase during childhood. During this phase, the immune system recognizes HBV as foreign and tries to eradicate the virus, but the cytotoxic response is weak. This phase is characterized by elevated or fluctuating levels of alanine aminotransferase (ALT), HBV DNA levels > 2000 IU/mL (usually > 20,000 IU/mL), and active liver inflammation. After some years in the immune-tolerant phase, most persons eventually develop HBeAg-positive chronic hepatitis (immune active phase), with elevated ALT levels and active liver inflammation that can be accompanied by liver fibrosis. At some point, most individuals with HBeAg-positive chronic hepatitis B will lose HBeAg and seroconvert spontaneously to antibody to HBeAg (anti-HBe).[6]

Table 1.

Phases of Chronic Hepatitis B Infection[5]

Phase	HBeAg/anti-HBe status	HBV DNA	ALT Level	Liver Biopsy	Treatment Candidate
Immune Tolerant	HBeAg+	> 20,000 IU/ml	Normal	Normal or minimal activity	No
Immune Active	HBeAg+ or anti-HBe+	> 2000 IU/mL	Elevated	Active inflammation	Yes
Inactive Hepatitis B	HBeAg negative/anti-HBe+	< 2000 IU/mL	Normal	Normal or minimal activity	No

HBeAg = hepatitis B e antigen; HBV = hepatitis B virus; ALT = alanine aminotransferase

Three scenarios can occur after spontaneous seroconversion from HBeAg to anti-HBe:

1. Most individuals go into the inactive hepatitis B phase (“inactive carrier”), characterized by normalization of serum ALT, lowering of HBV DNA below 2000 IU/mL, and improvement in liver inflammation and fibrosis.

2. Some patients who undergo seroconversion to anti-HBe maintain elevated ALT and HBV DNA levels. These patients remain in the immune-active phase.[7]

3. Most persons go into the inactive hepatitis B phase. Although the majority will remain in the immune-active phase (probably for life) and thus be at a lower risk of developing cirrhosis or HCC, others will either revert back to the HBeAg-positive state, usually accompanied by a flare of hepatitis, or repeated flares of HBeAg-negative anti-HBe positive chronic hepatitis and thus revert back to the immune-active phase.[6,8,9] Thus, in the immune-active phase of chronic hepatitis B, infected persons can be either HBeAg-positive or HBeAg-negative/anti-HBe antibody positive. Persons in the immune-active phase of HBV infection are those at highest risk of developing cirrhosis and/or HCC and may need antiviral treatment. Because the course of chronic HBV infection varies widely, with patients going from active liver inflammation to inactive disease and some reverting back to active liver inflammation again, patients with hepatitis B must be followed on a regular basis every 6 to 12 months, with measurement of liver aminotransferase levels.[4]

Risk Factors for Progressive Disease

Several factors will increase the likelihood of developing liver damage and HCC in chronic HBV infection. Viral factors include HBV genotype; persistently elevated HBV DNA levels; and specific mutations in the HBV genome, including mutations in the precore (PC) and core promoter regions of the virus. Eight genotypes of HBV (A-H) have been identified that differ in complete genomic sequence by ≥ 8% from each other. In addition, many subgenotypes, which differ by 4% to 8% are now also recognized.[10] Genotype A is found in sub-Saharan Africa (A1) and northern Europe and the United States (A2). Genotype A1 is associated with HCC in young males, often without cirrhosis, whereas genotype A2 is associated with cirrhosis and HCC in older persons.[10] Genotypes B and C are found in the Far East, Southeast Asia, and the Pacific.[10] Genotype B comprises 2 subgroups, one where part of genotype C is recombined into the core region of genotype B (B2–5) and one without recombination (B1 and B6).[7,11] Genotype C is believed to be linked to a more aggressive disease course, associated with high rates of HCC and cirrhosis.[12,13] With regard to their association with more severe liver disease, genotype C is thought to take a more aggressive disease course than genotypes B2–5, which in turn are thought to take a more severe disease course than genotypes B1/B6. Genotype D is found in the Mediterranean countries, eastern Europe, the Middle East, and the Indian subcontinent and has been associated with chronic anti-HBe-positive hepatitis B.[7] Comparison studies have suggested that genotype D is associated with a more adverse outcome than genotype A2.[14] Genotype E is found in Central Africa, but little is known about the outcome of those infected with this genotype.[10] Genotypes F and H are found in indigenous populations in the Americas; genotype F has been associated with HCC in children and young adult Alaska natives, often without cirrhosis.[15] Although HBV genotype testing is commercially available, this testing is not yet recommended in routine evaluation; more information regarding HBV genotypes and subgenotypes is necessary before a role for these tests in the evaluation of infected patients can be advocated in clinical practice.

Certain viral mutations, including the PC and basal core promoter (BCP) mutations have been associated with an increased risk of developing cirrhosis and HCC.[16] The PC mutation is a single substitution at base pair 1896, resulting in a G to A mutation. This mutation results in the creation of a stop codon that prevents the formation of HBeAg (at the translation level) and downregulates HBV DNA – however, HBV DNA replication can still occur at a sufficiently high rate so as to result in liver inflammation and ongoing fibrosis.[6] This mutation is more frequently found in individuals with anti-HBe-positive chronic hepatitis B, but can also be found in inactive anti-HBe-positive carriers. The BCP mutation is a double mutation in the core region of HBV that reduces the production of HBeAg by downregulating the transcription of precore mRNAs; this mutation is associated with HCC in individuals infected with genotypes A, B, C, and D, but not genotype F.[15,16] Tests for both of these mutations are commercially available but because these mutations can occur in patients without serious liver disease, their interpretation requires a detailed analysis of the individual clinical situation.

Co-infection with hepatitis C virus increases the risk for cirrhosis, and especially for HCC.[17] Co-infection with the hepatitis D or “delta” virus also increases the risk for cirrhosis.[18] HBV and HIV coinfection is associated with more severe liver inflammation.[4] Other risk factors for HCC in HBV-infected individuals are male sex, older age, and family history of HCC (Table 2). Persons with hepatitis B who have these risk factors should be screened semiannually with liver ultrasound and perhaps measurement of serum alpha-fetoprotein in an attempt to detect HCC at a treatable stage.[4] All persons found to be HBsAg-positive should be tested for hepatitis C, HIV, and hepatitis D virus infection.[4]

Table 2.

Risk Factors for the Development of Hepatocellular Carcinoma (HCC) in Persons With Chronic Hepatitis B^*[4,19]

Family history of HCC

Age: Men over 40 years and women over 50 years

Presence of cirrhosis

^*Persons with these risk factors should be screened with liver ultrasound examination every 6 months; the use of alpha-fetoprotein determinations in addition to ultrasound may enhance early detection of HCC.

HCC = hepatocellular carcinoma

Who Should Be Treated?

How can our current knowledge of the epidemiology and natural history of hepatitis B help us detect, follow, and select those individuals who are suitable for treatment? First, before we can help persons with this chronic infection, we have to identify them, as most individuals with HBV infection are asymptomatic and unaware of their disease. The largest reservoir of chronic HBV infection in the United States is among foreign-born persons from the high and intermediate endemic areas of the world, as discussed previously, and these individuals should be tested for HBsAg and its antibody, anti-HBs (Table 3). Second, once an individual is found to be chronically infected and HBsAg positive for at least 6 months, the phase of HBV infection should be ascertained by performing liver function tests, as well as by serologic testing for HBeAg and anti-HBe and measurement of HBV DNA (Table 1). Finally, after an individual has been identified as having chronic HBV infection, a commitment must be made by the healthcare provider and the patient for lifetime follow-up, with liver function tests, HBV serology, and HBV DNA testing done at least yearly and preferably every 6 months regardless of the phase of infection, given that hepatitis B is unstable and can reactivate or inactivate at any time.[3]

Table 3.

Persons Who Should Be Screened for Hepatitis B Infection[4]

Persons born in countries with an HBsAg prevalence ≥ 2%	Asia
	Africa
	Mid-Pacific/South Pacific Islands
	Eastern Europe including Russia and certain Mediterranean Countries
	Amazon Basin of South America
	Parts of the Caribbean
	Indigenous populations of the Arctic, New Zealand and Australia
Other groups with HBsAg prevalence > 2%	Household and sexual contacts of HBsAg-positive persons
	Men who have sex with men
	HIV-infected persons
	Injecting drug users
	All persons with elevated liver function tests

HBsAg = hepatitis B surface antigen

Other persons with high risk for hepatitis B virus infection but with an HBsAg prevalence < 2% should be screened for HBV seromarkers and vaccinated if negative as per current Centers for Disease Control recommendations[2]

A comprehensive discussion regarding the treatment of HBV infection, including which medications to use and how to follow patients on antiviral therapy, is not within the purview of this article, and the reader is referred to the guidelines published by the American Association for the Study of Liver Diseases.[4] However, it is important for clinicians to recognize which patients are candidates for evaluation for treatment should be referred to specialists with experience in the management of hepatitis B. Patients who are candidates for evaluation for treatment are listed in Table 4. Table 5 lists those patient populations that can be followed on a 6- to 12-month basis by their primary care provider; these include: patients in the immune-tolerant phase of infection who are < 30 years of age as well as those in the inactive carrier phase.

Table 4.

Patients Who Should Be Evaluated for Treatment for Chronic Hepatitis B by a Healthcare Provider Experienced in the Management of HBV Infection[4]

Persons over 18 years with:	Elevated HBV DNA
	ALT elevation > 30 U/L men, > 19 U/L women
	HBV DNA > 2000 IU/mL
	Persons co-infected with HIV, HDV, or HCV
	Persons > 30 years of age in the immune-tolerant phase

HBV = hepatitis B virus; ALT = alanine aminotransferase; HDV = hepatitis D virus; HCV = hepatitis C virus

Table 5.

Patients With Chronic Hepatitis B Infection Who Can Be Followed Every 6 to 12 Months by Their Primary Care Provider[4]

Persons < 30 years of age in the immune tolerant phase	HBeAg-positive
	Persistently normal ALT
Persons in the inactive hepatitis B phase	HBeAg-negative and anti-HBe-positive
	Normal ALT
	HBV DNA < 2000 IU/mL

HBeAg = hepatitis B e antigen; ALT = alanine aminotransferase; HBV = hepatitis B virus

Conclusion

Chronic hepatitis B infection is a serious viral disease, that in the absence of careful monitoring, can lead to the development of HCC and cirrhosis in more than one third of patients.[19] However, the use of antiviral therapy and the institution of screening for HCC in those patients at highest risk for progression can dramatically reduce morbidity and mortality. Identification of infected persons by screening at-risk populations, especially foreign-born individuals from endemic areas; lifetime regular monitoring of the status of infection; and appropriate selection of patients for treatment, can result in significant improvement in the risk for complications.