C h ro n i c H e p a t i t i s B Vi r u s Infection Brian J. McMahon,
MD, MACP
KEYWORDS Chronic hepatitis B Natural history Management KEY POINTS The Centers for Disease Control and Prevention (CDC) recommend that people born in Asia, Africa, or other regions endemic for hepatitis B virus (HBV) should be tested for hepatitis B surface antigen and antibody to hepatitis B surface antigen (anti-HBs), as 2% to 10% will have chronic HBV. All people with chronic HBV infection should be followed regularly (every 6 months), as HBV infection can have a complicated course progressing through several phases that can be further complicated by regression back to earlier phases. Candidates for antiviral therapy include patients with moderate-to-severe liver disease as determined by elevated alanine aminotransferase and/or liver biopsy and elevated HBV DNA levels above 2000 IU/mL as per evidenced-based practice guidelines. Antiviral medications of choice are pegylated interferon, entecavir, or tenofovir in treatment-naı¨ve patients and pegylated interferon or tenofovir in lamivudine-experienced patients. All persons undergoing cancer chemotherapy or immunosuppressive therapy should be screened for hepatitis B and given HBV antiviral prophylaxis if chronically infected.
INTRODUCTION
Chronic hepatitis B virus (HBV) is one of the most common chronic infections in the world. An estimated 2 billion people have been infected, and up to 400,000 people worldwide are believed to have chronic HBV.1 This article discusses the epidemiology, natural history, and clinical management of HBV, but also highlights some special circumstances that are associated with chronic HBV infection. EPIDEMIOLOGY OF HBV AND SCREENING FOR PATIENTS WITH CHRONIC HBV INFECTION Prevalence of HBV Worldwide and Whom to Screen for HBV in Developed Countries
In most countries of the world, the prevalence of people with chronic HBV, defined as hepatitis B surface antigen (HBsAg)-positive for at least 6 months, is over 2%. The Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, 4315 Diplomacy Drive, Anchorage, AK 99508, USA E-mail address: [email protected] Med Clin N Am 98 (2014) 39–54 http://dx.doi.org/10.1016/j.mcna.2013.08.004 medical.theclinics.com 0025-7125/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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prevalence is 8% or more in much of Africa and Asia (Fig. 1).2 In western countries, including the United States and western Europe, the Centers for Disease Control and Prevention (CDC) recommend testing everyone born in Asian-Pacific regions (except Japan), Africa, eastern and southern Europe, Central America except Mexico, and selected indigenous populations in developed countries. In addition, certain other high-risk groups in which the prevalence of HBsAg is above 2% (a level shown to be cost-effective by the CDC), such as household and sexual partners of persons with chronic HBV, men who have sex with men, human immunodeficiency virus (HIV)infected patients, and institutionalized patients, should be tested.3 Other high-risk groups should be screened for vaccination, such as people with multiple sexual partners, and intravenous drug uses, understanding that they have a lower risk of chronic HBV. The Hepatitis B Foundation sponsored a panel of experts in primary care and hepatology who developed a very useful algorithm for screening and management of HBV (Fig. 2, Table 1).4 Risk of Developing Chronic HBV After Acute Infection
Table 2 shows the risk of developing chronic HBV after acute HBV infection. Risk is highest in infants whose mothers are HBsAg positive5 as well as in children infected under 5 years of age through horizontal transmission by open bug bites, cuts, scratches, or impetigo sores.6 HBV is infectious outside the body on environmental surfaces for at least 7 days and likely much longer, making this the most infectious viral agent in these circumstances.7 Natural History of Chronic HBV
Patients with chronic HBV infection can have a complicated course progressing through several phases that can be further complicated by regression back to earlier
Fig. 1. Global prevalence of chronic hepatitis B infection. (Courtesy of Centers for Disease Control and Prevention, Atlanta, GA.)
Chronic Hepatitis B Virus Infection
HBV Screening Algorithm for At-Risk Patients
At-Risk Groups include:
(See notes 1 & 2)
HBsAg and anti-HBs tests
HBsAg (-)
HBsAg (+)
(See note 3)
Collect baseline data: •ALT •HBeAg, anti-HBe •HBV DNA level
anti-HBs (+)
anti-HBs (-)
If reported anti-HBc (+) see note 3
— and — Go to evaluation and monitoring algorithm
Immune to HBV Vaccinate No follow-up needed
Persons born in HBV endemic regions of the world: Asia, Africa, Pacific Islands, Middle East, Eastern Europe, Mexico, Central America, and the Caribbean (see note 2 for full list) Injection drug users Men who have sex with men Persons with conditions that may require immune-modifying therapy Persons with elevated ALT/AST of unknown etiology Blood or tissue donors Pregnant women Infants born to HBV-infected mothers Hemodialysis patients Household and sexual contacts of HBV-infected individuals HIV-positive individuals
* New norms establish elevated ALT as 19 IU/L for women and 30 IU/L for men
HBV Evaluation and Monitoring Algorithm
HBV DNA >20,000 IU/mL ALT normal
Immune tolerant
HBeAg (+)
Retest HBeAg, HBV DNA and ALT every 6 months (See note 5)
HBV DNA >20,000 IU/mL ALT elevated* HBeAg (+)
Immune active
(See note 4)
HBV DNA >2,000 IU/mL ALT elevated*
(See note 6)
HBeAg (-) anti-HBe (+) HBV DNA 6 mo to countries with high or intermediate prevalence of HBV)
Behavioral
Intravenous drug users More than 1 sex partner in previous 6 mo Recently acquired sexually transmitted disease (STD), including all clients in STD clinics Men who have sex with men
Occupational
Health professionals Public safety workers with exposure to blood
Medical
Hemodialysis Patients receiving clotting factor concentrates
Data from Weinbaum CM, Mast EE, Ward JW. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. Hepatology 2009;49(5):S35–44.
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Table 2 Age-specific risk of developing chronic HBV infection after exposure Age at Exposure
Risk of Chronic HBV
Birth
90%
Infancy to 2 y
50%
Infancy to 5 y
25%–30%
Above 5 y
5%–7%
phases.8 At National Institutes of Health (NIH) workshop, 4 phases of chronic HBV were identified: the immune-tolerant, immune-active, inactive, and HBsAgclearance phases.9 Table 3 details the 4 phases of chronic HBV. In the immune-tolerant phase, patients are positive for hepatitis B “e” antigen (HBeAg), and their immune systems do not recognize this virus as a foreign invader, which results in high viral loads and no elevation of alanine aminotransferase (ALT) levels or liver inflammation. This phase is primarily seen in patients infected at birth from HBeAg-positive mothers who are usually infected with HBV genotype C, found in eastern and southeast Asian and the Pacific Islands regions as well as northwest Alaska,10 or certain subtypes of genotype B recombined with genotype C in east Asia. As people in the immune-tolerant phase age, their immune systems begin to recognize this virus and mount a response, resulting in elevation of ALT followed by reduction in the levels of HBV DNA (the immune-active phase) and eventual loss of HBeAg and development of antibody to HBeAg (anti-HBe). People exposed after birth, primarily with genotypes A, B1 and B6, D, E, and F, who develop chronic infection, often skip the immune-tolerant phase and go right into the immune-active phase. These genotypes are most commonly found in Africa, the Middle East, Europe, the Indian subcontinent and southwestern Alaska. Between 65% and 75% of these patients over time will mount a strong immune response and suppress HBV DNA to low levels (below 1000 IU/ml) and have normalization of their ALT levels that is often permanent, the inactive HBV phase. Their risk of developing cirrhosis due to HBV is very low, if indeed at all, and liver fibrosis can slowly reverse and even disappear over time. Some of these patients will eventually lose HBsAg at a rate of 0.5% to 2.0% per year11–13 and, while they are still at risk for liver cancer, that risk will decrease several fold. Unfortunately, a minority of patients who lose HBeAg can revert back to HBeAg, usually accompanied by an asymptomatic flare of hepatitis, and up to 20% of those who develop anti-HBe can have chronic hepatitis despite HBeAg seroconversion or reactivate their hepatitis when seeming to be in the inactive phase.14 Thus, patients with chronic HBV need to be followed carefully for life. The 2 most dreaded complications of chronic HBV are hepatocellular carcinoma (HCC) and end-stage cirrhosis. Prospective population-based studies have shown that 20% to 40% of men and 15% of women with chronic HBV who are infected early in life develop HCC.15,16 Although the data are not as good for end-stage liver disease or decompensated cirrhosis, it has been estimated that 10% to 15% of patients will die of this complication. Risk factors for developing HCC include male gender, coinfection with HIV, hepatitis C virus (HCV) or hepatitis delta virus (HDV), HBV genotype, HBV DNA of greater than 20,000 IU/mL, and mutation in the basal core promoter region (BCP) of the virus.10,17 A mutation in the precore (PC) region of the virus was previously thought to be a risk factor, but the only large population-based study that looked at this found the PC mutation was associated with a lower risk of HCC. This was also seen in a population-based nested case–control study from Alaska.18,19
Table 3 Four phases of chronic HBV infection Risk of HCCa for Patients >40 y
Phase
HBeAg
ALT Level
HBV DNA Level
Liver Histology
Immune-Tolerant
Positive
Normal
>20,000 IU/mL
Normal
No
111
ImmuneActive
Positive or Negative
Elevated
>2000 IU/mL
Mild-to-severe inflammation/fibrosis
Yes
111
Inactive
Negative
Normal
MD, MACP
KEYWORDS Chronic hepatitis B Natural history Management KEY POINTS The Centers for Disease Control and Prevention (CDC) recommend that people born in Asia, Africa, or other regions endemic for hepatitis B virus (HBV) should be tested for hepatitis B surface antigen and antibody to hepatitis B surface antigen (anti-HBs), as 2% to 10% will have chronic HBV. All people with chronic HBV infection should be followed regularly (every 6 months), as HBV infection can have a complicated course progressing through several phases that can be further complicated by regression back to earlier phases. Candidates for antiviral therapy include patients with moderate-to-severe liver disease as determined by elevated alanine aminotransferase and/or liver biopsy and elevated HBV DNA levels above 2000 IU/mL as per evidenced-based practice guidelines. Antiviral medications of choice are pegylated interferon, entecavir, or tenofovir in treatment-naı¨ve patients and pegylated interferon or tenofovir in lamivudine-experienced patients. All persons undergoing cancer chemotherapy or immunosuppressive therapy should be screened for hepatitis B and given HBV antiviral prophylaxis if chronically infected.
INTRODUCTION
Chronic hepatitis B virus (HBV) is one of the most common chronic infections in the world. An estimated 2 billion people have been infected, and up to 400,000 people worldwide are believed to have chronic HBV.1 This article discusses the epidemiology, natural history, and clinical management of HBV, but also highlights some special circumstances that are associated with chronic HBV infection. EPIDEMIOLOGY OF HBV AND SCREENING FOR PATIENTS WITH CHRONIC HBV INFECTION Prevalence of HBV Worldwide and Whom to Screen for HBV in Developed Countries
In most countries of the world, the prevalence of people with chronic HBV, defined as hepatitis B surface antigen (HBsAg)-positive for at least 6 months, is over 2%. The Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, 4315 Diplomacy Drive, Anchorage, AK 99508, USA E-mail address: [email protected] Med Clin N Am 98 (2014) 39–54 http://dx.doi.org/10.1016/j.mcna.2013.08.004 medical.theclinics.com 0025-7125/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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McMahon
prevalence is 8% or more in much of Africa and Asia (Fig. 1).2 In western countries, including the United States and western Europe, the Centers for Disease Control and Prevention (CDC) recommend testing everyone born in Asian-Pacific regions (except Japan), Africa, eastern and southern Europe, Central America except Mexico, and selected indigenous populations in developed countries. In addition, certain other high-risk groups in which the prevalence of HBsAg is above 2% (a level shown to be cost-effective by the CDC), such as household and sexual partners of persons with chronic HBV, men who have sex with men, human immunodeficiency virus (HIV)infected patients, and institutionalized patients, should be tested.3 Other high-risk groups should be screened for vaccination, such as people with multiple sexual partners, and intravenous drug uses, understanding that they have a lower risk of chronic HBV. The Hepatitis B Foundation sponsored a panel of experts in primary care and hepatology who developed a very useful algorithm for screening and management of HBV (Fig. 2, Table 1).4 Risk of Developing Chronic HBV After Acute Infection
Table 2 shows the risk of developing chronic HBV after acute HBV infection. Risk is highest in infants whose mothers are HBsAg positive5 as well as in children infected under 5 years of age through horizontal transmission by open bug bites, cuts, scratches, or impetigo sores.6 HBV is infectious outside the body on environmental surfaces for at least 7 days and likely much longer, making this the most infectious viral agent in these circumstances.7 Natural History of Chronic HBV
Patients with chronic HBV infection can have a complicated course progressing through several phases that can be further complicated by regression back to earlier
Fig. 1. Global prevalence of chronic hepatitis B infection. (Courtesy of Centers for Disease Control and Prevention, Atlanta, GA.)
Chronic Hepatitis B Virus Infection
HBV Screening Algorithm for At-Risk Patients
At-Risk Groups include:
(See notes 1 & 2)
HBsAg and anti-HBs tests
HBsAg (-)
HBsAg (+)
(See note 3)
Collect baseline data: •ALT •HBeAg, anti-HBe •HBV DNA level
anti-HBs (+)
anti-HBs (-)
If reported anti-HBc (+) see note 3
— and — Go to evaluation and monitoring algorithm
Immune to HBV Vaccinate No follow-up needed
Persons born in HBV endemic regions of the world: Asia, Africa, Pacific Islands, Middle East, Eastern Europe, Mexico, Central America, and the Caribbean (see note 2 for full list) Injection drug users Men who have sex with men Persons with conditions that may require immune-modifying therapy Persons with elevated ALT/AST of unknown etiology Blood or tissue donors Pregnant women Infants born to HBV-infected mothers Hemodialysis patients Household and sexual contacts of HBV-infected individuals HIV-positive individuals
* New norms establish elevated ALT as 19 IU/L for women and 30 IU/L for men
HBV Evaluation and Monitoring Algorithm
HBV DNA >20,000 IU/mL ALT normal
Immune tolerant
HBeAg (+)
Retest HBeAg, HBV DNA and ALT every 6 months (See note 5)
HBV DNA >20,000 IU/mL ALT elevated* HBeAg (+)
Immune active
(See note 4)
HBV DNA >2,000 IU/mL ALT elevated*
(See note 6)
HBeAg (-) anti-HBe (+) HBV DNA 6 mo to countries with high or intermediate prevalence of HBV)
Behavioral
Intravenous drug users More than 1 sex partner in previous 6 mo Recently acquired sexually transmitted disease (STD), including all clients in STD clinics Men who have sex with men
Occupational
Health professionals Public safety workers with exposure to blood
Medical
Hemodialysis Patients receiving clotting factor concentrates
Data from Weinbaum CM, Mast EE, Ward JW. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. Hepatology 2009;49(5):S35–44.
41
42
McMahon
Table 2 Age-specific risk of developing chronic HBV infection after exposure Age at Exposure
Risk of Chronic HBV
Birth
90%
Infancy to 2 y
50%
Infancy to 5 y
25%–30%
Above 5 y
5%–7%
phases.8 At National Institutes of Health (NIH) workshop, 4 phases of chronic HBV were identified: the immune-tolerant, immune-active, inactive, and HBsAgclearance phases.9 Table 3 details the 4 phases of chronic HBV. In the immune-tolerant phase, patients are positive for hepatitis B “e” antigen (HBeAg), and their immune systems do not recognize this virus as a foreign invader, which results in high viral loads and no elevation of alanine aminotransferase (ALT) levels or liver inflammation. This phase is primarily seen in patients infected at birth from HBeAg-positive mothers who are usually infected with HBV genotype C, found in eastern and southeast Asian and the Pacific Islands regions as well as northwest Alaska,10 or certain subtypes of genotype B recombined with genotype C in east Asia. As people in the immune-tolerant phase age, their immune systems begin to recognize this virus and mount a response, resulting in elevation of ALT followed by reduction in the levels of HBV DNA (the immune-active phase) and eventual loss of HBeAg and development of antibody to HBeAg (anti-HBe). People exposed after birth, primarily with genotypes A, B1 and B6, D, E, and F, who develop chronic infection, often skip the immune-tolerant phase and go right into the immune-active phase. These genotypes are most commonly found in Africa, the Middle East, Europe, the Indian subcontinent and southwestern Alaska. Between 65% and 75% of these patients over time will mount a strong immune response and suppress HBV DNA to low levels (below 1000 IU/ml) and have normalization of their ALT levels that is often permanent, the inactive HBV phase. Their risk of developing cirrhosis due to HBV is very low, if indeed at all, and liver fibrosis can slowly reverse and even disappear over time. Some of these patients will eventually lose HBsAg at a rate of 0.5% to 2.0% per year11–13 and, while they are still at risk for liver cancer, that risk will decrease several fold. Unfortunately, a minority of patients who lose HBeAg can revert back to HBeAg, usually accompanied by an asymptomatic flare of hepatitis, and up to 20% of those who develop anti-HBe can have chronic hepatitis despite HBeAg seroconversion or reactivate their hepatitis when seeming to be in the inactive phase.14 Thus, patients with chronic HBV need to be followed carefully for life. The 2 most dreaded complications of chronic HBV are hepatocellular carcinoma (HCC) and end-stage cirrhosis. Prospective population-based studies have shown that 20% to 40% of men and 15% of women with chronic HBV who are infected early in life develop HCC.15,16 Although the data are not as good for end-stage liver disease or decompensated cirrhosis, it has been estimated that 10% to 15% of patients will die of this complication. Risk factors for developing HCC include male gender, coinfection with HIV, hepatitis C virus (HCV) or hepatitis delta virus (HDV), HBV genotype, HBV DNA of greater than 20,000 IU/mL, and mutation in the basal core promoter region (BCP) of the virus.10,17 A mutation in the precore (PC) region of the virus was previously thought to be a risk factor, but the only large population-based study that looked at this found the PC mutation was associated with a lower risk of HCC. This was also seen in a population-based nested case–control study from Alaska.18,19
Table 3 Four phases of chronic HBV infection Risk of HCCa for Patients >40 y
Phase
HBeAg
ALT Level
HBV DNA Level
Liver Histology
Immune-Tolerant
Positive
Normal
>20,000 IU/mL
Normal
No
111
ImmuneActive
Positive or Negative
Elevated
>2000 IU/mL
Mild-to-severe inflammation/fibrosis
Yes
111
Inactive
Negative
Normal
