CHAPTER 22 Hepatitis B: Global Epidemiology, Diagnosis, and Prevention

Gregory L. Armstrong, Susan T. Goldstein *,

Hepatitis B: Clinical Pearls in Refugees and Immigrants

• Many immigrants come from countries with intermediate or high hepatitis B virus (HBV) prevalence.

• Perinatal and early childhood infection accounts for most cases of chronic hepatitis B among immigrants. In addition, lack of access to vaccination, unsafe medical procedures, and percutaneous exposures during traditional cultural practices also contribute to the high prevalence of HBV infection.

• Screening for hepatitis B surface antigen (HBsAg) should be done irrespective of length of time residing in the United States.

• Persons with chronic HBV infection are at substantial lifetime risk for cirrhosis and hepatocellular carcinoma.

• Chronically infected immigrants should be counseled on the means of reducing further liver damage and on ways to prevent transmission of the virus to others.

• Referral of the chronically infected immigrant to a specialist in the management of hepatitis B is appropriate.

• Hepatocellular carcinoma is a vaccine-preventable cancer.

Virology

Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA virus of the Hepadnaviridae family. The virus replicates in the liver, where viral DNA often incorporates into the host genome, an important factor in HBV’s capacity to induce liver cancer. In the blood, the complete 42 nm HBV particle, known as the ‘Dane particle,’ includes an inner capsid made from hepatitis B core antigen (HBcAg) and containing hepatitis E antigen (HBeAg), a marker of infectivity. The core is enclosed within a lipid envelope containing the hepatitis B surface antigen (HBsAg). In patients with acute or chronic hepatitis B, envelope is produced in great excess and self-assembles into small spherical or tubular structures. These 22 nm particles do not contain core protein or DNA and are typically present in much higher numbers than Dane particles.

In the blood of infected individuals, HBV is present in extremely high concentrations, often in viral loads exceeding 10⁷ per milliliter. On environmental surfaces, HBV is highly stable, remaining infectious for at least 1 week.¹ Nonetheless, the virus is susceptible to commonly used disinfectants.²

HBV has been sub-classified by two separate classification systems: serotype and genotype. Nine serotypes of HBV have been described on the basis of serologic heterogeneity of HBsAg (adrq+, adrq−, ayr, ayw1, ayw2, ayw3, ayw4, adw2, adw4).³ At least eight genotypes of HBV have been described, designated A through H, on the basis of an 8% difference in nucleotide sequence. HBV serotypes and genotypes vary geographically.^4,⁵

Global Epidemiology

Burden of disease from hepatitis B

Worldwide, hepatitis B virus infection is one of the leading causes of infectious disease-related morbidity and mortality. An estimated two billion people – one-third of the world’s population – have serologic evidence of past or present HBV infection and 350 million people are chronically infected. Each year, an estimated 621 000 people die from HBV-related liver disease (Table 22.1).⁶ The majority (95%) of these deaths result from the chronic sequelae of infection, cirrhosis, and hepatocellular carcinoma (HCC). Although most of these deaths occur in adulthood, 21% result from HBV infection acquired in the perinatal period and another 48% from infection acquired in early childhood. Infection acquired after 5 years of age accounts for only 31% of deaths.

Table 22.1 Annual number of hepatitis B-related deaths, by World Health Organization region ⁶

Region	Number of deaths	Proportion of deaths from chronic infection
Africa	69 000	90%
Americas	12 000	92%
Eastern Mediterranean	21 000	90%
Europe	51 000	94%
Southeast Asia	143 000	92%
Western Pacific	325 000	95%
Global	621 000	94%

The world can be divided into areas of high, intermediate, and low HBV endemicity based on the prevalence of chronic HBV infection (i.e. the prevalence of HBsAg-positive individuals) in the general population (Fig. 22.1). Approximately 45% of the world’s population lives in countries of high endemicity where > 60% of the population has ever been infected with HBV and > 8% is chronically infected. Most of these countries are in Africa and Asia. In countries of intermediate endemicity, which include 43% of the world’s population, 20–60% of the population has evidence of prior infection and 2–7% is HBsAg-positive. Only 12% of the population lives in countries of low endemicity where the lifetime risk of infection is < 20% and the prevalence of chronic infection is < 2%.

Fig. 22.1 Prevalence of hepatitis B virus infection.

Transmission of hepatitis B virus

Hepatitis B virus is transmitted from person to person through exposure to infected blood or body fluids, including semen and vaginal fluid. Modes of transmission include percutaneous and permucosal exposures to infectious body fluids, sexual contact with an infected person, and perinatal transmission from an infected mother to her infant. Rare instances of transmission of HBV through saliva have been reported.⁷

Perinatal transmission of HBV occurs from blood exposure during labor and delivery. In utero transmission is relatively rare, accounting for < 3% of perinatal infections in most studies.⁸^–¹² The risk of transmission from an infected mother to her infant depends on the HBeAg status of the mother, being 70–90% for infants born to HBsAg-positive/HBeAg-positive mothers and 5–20% for infants born to HBsAg-positive/HBeAg-negative mothers.¹³^–¹⁸ Although HBV is found in low concentrations in breast milk, transmission of HBV has not been documented through breast-feeding.¹⁹

Horizontal transmission, also known as intrafamilial or household transmission, refers to percutaneous transmission of HBV within the household, from infected family members – most often mothers and older siblings – to young children.²⁰^–²⁸ Horizontal transmission is most important in countries of high HBV endemicity, but its occurrence in the United States has also been well documented.²⁹^–³² Horizontal transmission of HBV to adult members of households has also been reported, including in families of children adopted from overseas.³²^–³⁴

Sexual transmission of HBV is most common among persons at increased risk for other sexually transmitted infections, including those with many sexual partners or a history of other sexually transmitted infections. Sexual intercourse with a known infected person puts one at risk and engaging in certain sexual practices, such as anal intercourse, may facilitate transmission of HBV.³⁵ Men who have sex with men are at particularly high risk for HBV infection, with up to 60% having serologic markers of past or current infection.^35,³⁶

Percutaneous and permucosal transmission of HBV can result from transfusion of unscreened blood, injection drug use, occupational exposure (e.g. needle stick injuries) and nosocomial exposures (e.g. unsafe injection and other unsafe medical practices). In the United States, blood transfusion has not been an important mode of transmission since the institution of routine screening for markers of HBV in the early 1970s. However, blood transfusion remains an important source of infection in many less developed countries.

In recent years, unsafe injection and other unsafe medical practices have become increasingly recognized as major routes of HBV transmission, particularly in developing and transitional countries.³⁷ Unsafe injections, which account for an estimated 32% of new HBV infections annually,³⁸ are a consequence of both the reuse of injection equipment without proper sterilization and the overuse of injections where oral therapy would be indicated. The burden of disease from other unsafe medical practices is not known. Nosocomial transmission of HBV is not limited to less developed countries. In the United States and other developed countries, transmission of HBV in healthcare settings – both inpatient and outpatient – continues to occur.³⁹^–⁴² Traditional healing practices that involve breaches in the skin barrier, such as piercing and scarification, have also been documented to transmit HBV. These practices may continue once immigrants and refugees have migrated to a host country.³⁰

In healthcare settings, most transmission of HBV occurs from patient to patient, although transmission from patient to provider and provider to patient also occurs. Before widespread vaccination of healthcare workers, the prevalence of HBV infection in this group was three- to fivefold higher than that of the general US population.⁴³ Currently, an estimated 75% of healthcare workers in the United States are vaccinated.⁴⁴

Illicit injection drug use is another common mode of transmission among adults worldwide and accounts for a substantial fraction of HBV infections in developing and transitional countries, including, or especially in, the countries of the former Soviet Union.⁴⁵^–⁴⁷ Drug users often share injection equipment, including needles and syringes as well as other paraphernalia such as cotton and cookers. This sharing, together with the stability of HBV outside the body, provides an easy route for the transmission of the virus. In the United States, approximately 64% of injection drug users have been infected with HBV.⁴⁸

Global patterns of HBV transmission

In highly endemic countries, the patterns of HBV transmission are very different from those seen in developed, low endemicity countries (Table 22.2). In particular, perinatal and early childhood transmission play key roles, both because they are common and because infections acquired early in life frequently lead to chronic infection (see below). Because most (>60–70%) residents of highly endemic countries are exposed to HBV during childhood, transmission during adulthood is relatively less important.

Table 22.2 Differences in the epidemiology of hepatitis B virus infection by endemicity

Endemicity	Most common age at infection	Most common modes of transmission
High	Infancy Early childhood	Perinatal Horizontal Unsafe injections and other medical practices Unscreened blood
Intermediate	All age groups	Perinatal Horizontal Unsafe injections and other medical practices Sexual Injection drug use
Low	Adolescents Adults	Sexual Injection drug use

In developed countries with a low endemicity of HBV infection, hepatitis B is known predominantly as a disease of adulthood. Nonetheless, perinatal and childhood infections in these settings, although commonly clinically silent, do occur and may account for 50% or more of all chronic infections.

Epidemiology in the United States

Before the introduction of hepatitis B vaccination, there were approximately 300 000 new HBV infections annually in the United States, including 24 000 among infants and children.⁴⁹ Beginning in the 1980s, the United States adopted a series of measures designed primarily to prevent chronic HBV infection and its long-term complications, cirrhosis and liver cancer. Since 1990, the incidence of hepatitis B has decreased by 90% among children and 63% among adults.⁵⁰

The success of the US hepatitis B immunization program has highlighted the importance of hepatitis B prevention among immigrants. In a 2001–2002 study of US cases among children born after 1990, 8 of 19 cases were among children born outside of the United States. Many of these children were international adoptees.⁵¹

The decline in incidence of HBV infection in the United States has led to an increase in the proportion of new chronic HBV infections attributable to immigration. From 2000 to 2004, over 900 000 persons immigrated to the United States each year. Taking into account their countries of origin, an estimated 42 000 were chronically infected with hepatitis B (CDC, unpublished data). During the same time period, there were approximately 75 000 new infections annually in the United States, of which 5000 were chronic (CDC, unpublished data and ref. 49). Thus, almost 90% of new cases of chronic hepatitis B in the United States are now attributable to immigration.

Epidemiologic features of immigrants and refugees in the United States

Most immigrants, refugees, and international adoptees come from countries of high and intermediate HBV endemicity where the prevalence of HBV infection is substantially higher than in the United States (see Fig. 22.1). Surveys among these migrant populations have generally shown HBsAg prevalence rates similar to those of their region of origin (Table 22.3).^30,⁵²^–⁶⁸ However, among their US-born children, even before the widespread use of hepatitis B vaccine, HBsAg prevalence was substantially lower.^69,⁷⁰

Table 22.3 Prevalence of HBV infection among immigrants and refugees in North America

The prevalence of chronic HBV infection varies by region and country of origin, with the highest prevalence among persons coming from East Asia, Southeast Asia and the Pacific (12–18% in most studies; see Table 22.3). The prevalence of anti-HBc among adults in these populations ranges 63–93%. The prevalences of HBsAg and anti-HBc among children and adolescents shown in Table 22.3, which are generally lower than among adults, do not reflect the impact of hepatitis B immunization, as few of the countries had implemented immunization before 2000.

In a population-based study in a community in Minnesota with a large immigrant population, the prevalence of chronic HBV infection was 2.1% among Asians, 1.9% among Africans, and 0.02% among Caucasians. The overwhelming majority (99%) of Asians were immigrants, mainly from Vietnam, Cambodia, China, and Laos; 91% of Africans were immigrants from Somalia.⁷¹

Chronic HBV infection is one of the most important causes of hepatocellular carcinoma (HCC). Globally, HCC accounts for an estimated 6% of all cancer deaths, with the highest incidence in countries of high HBV endemicity, especially in Asia and sub-Saharan Africa.⁷² In the United States, HCC mortality is highest among persons of Asian race/ethnicity, followed by Blacks and Hispanics.⁷³ It is lowest among whites. Although whites have the lowest age-adjusted incidence rates, they account for the largest proportion of the US population and thus they account for largest number of HCC cases.

In a study of cases of newly diagnosed liver cancer conducted in California, Hawaii, and Washington using data from a national cancer registry, the Surveillance, Epidemiology and End Results (SEER) program, the incidence of HCC was substantially higher among Asians (from China, Japan, Philippines) compared to whites. HCC incidence was also higher among foreign-born Asians compared to Asians born in the United States.⁷⁴

Clinical Manifestations

The manifestations of acute HBV infection range from asymptomatic infection to acute hepatitis to fulminant, life-threatening liver failure. If the virus is not cleared during this acute phase, a chronic, lifelong infection ensues.

The clinical presentation and long-term outcome of acute HBV infection are dependent on the immune response elicited by the infection. This immune reaction is responsible both for clearance of the virus and, because HBV is not cytopathic by itself, for the clinical presentation of acute hepatitis. In general, a more vigorous immune response will lead to more severe hepatitis and a lower likelihood of chronic HBV infection.

The characteristic age dependency of clinical outcomes from acute HBV infection ^75,⁷⁶ is probably at least partly due to age-dependent differences in the robustness of this immune response. In general, the younger the person at the time of infection, the less likely the person is to have symptoms of acute hepatitis and the more likely he or she is to develop chronic infection. Children infected at birth through perinatal transmission rarely develop signs of acute hepatitis but almost always (>90%) proceed to chronic infection. Children aged 1–5 years occasionally develop signs of acute hepatitis but have a lower risk (25–50%) of developing chronic infection. Adults more commonly develop acute hepatitis and are even less likely (less than 5–10%) to progress to chronic infection.

Acute hepatitis B presents after an incubation period of 6 weeks to 6 months, generally lasts 1–2 weeks, and is followed by a prolonged convalescent period that may last for weeks or months. Symptoms during the acute phase are clinically indistinguish able from those of other acute viral hepatitides and include fever, jaundice, dark urine, fatigue, and abdominal pain. Malaise and anorexia commonly precede jaundice by a few days. Fulminant hepatitis B occurs in less than 1% of cases and is frequently fatal if liver transplantation is not possible.

Chronic HBV infection is defined as the continued presence of HBsAg 6 months after acute illness or HBsAg in the absence of any clinical or serologic evidence of acute hepatitis B. Risk factors for progression to chronic infection, in addition to infection at a young age, include immunosuppression, and chronic, underlying illness.⁷⁷ Chronic hepatitis B is generally asymptomatic, although circulating immune complexes occasionally result in extrahepatic manifestations such as membranous or membranoproliferative glomerulonephritis or polyarteritis nodosa.

Natural History of Chronic Hepatitis B

The greatest burden of disease attributable to hepatitis B is from the long-term complications of chronic infection, cirrhosis and HCC, which typically occur years to decades after the initial infection. The persistent, low-level hepatitis that occurs in persons with chronic hepatitis B results in a slowly progressive fibrosis of the liver.⁷⁸ The rate of progression of this fibrosis varies largely from individual to individual and is greater in those with additional risk factors for fibrosis such as alcohol use or coinfection with hepatitis C virus or hepatitis D virus. The end stage of fibrosis is hepatic cirrhosis. Cirrhosis is initially asymptomatic in many patients or may be associated with mild, non-specific symptoms such as fatigue. However, each year about 5% of persons with HBV-related cirrhosis will develop decompensated cirrhosis, with classic manifestations of cirrhosis such as ascites, esophageal varices, and encephalopathy.⁷⁹ Decompensated cirrhosis carries a poor prognosis, with high 5-year mortality rates.

HCC is particularly characteristic of chronic hepatitis B and is believed to be due to the regenerative hyperplasia associated with chronic fibrosis as well as insertional mutagenesis. Because of the latter, hepatitis B-associated HCC may occur in the absence of cirrhosis, which is distinctly different from hepatitis C-associated HCC, which generally occurs only after the development of cirrhosis.

HCC is the fourth leading cause of cancer deaths worldwide, and in countries where hepatitis B is highly endemic, liver cancer is generally the most common cause of cancer death or the second most common cause after lung cancer.⁸⁰ In a classic study of chronically HBV-infected Taiwanese civil servants, most of whom had probably been infected in infancy or childhood, the incidence of HCC ranged from 2 per 1000 per year among men in their 30s to almost 10 per 1000 among men in their 60s.⁸¹ Using the estimates from this study, 20% of men with chronic hepatitis B could expect to develop liver cancer before the age of 70 years. The incidence of liver cancer among women with chronic hepatitis B is approximately half that among men.⁸² In addition to male sex, other risk factors for HCC among persons with chronic hepatitis B include alcohol use, cigarette smoking, and the presence of HBeAg, which is associated with a sixfold increase in risk.⁸³

Serologic Diagnosis

Acute infection

After infection, the first detectable serologic markers are HBsAg and antibody of the IgM subclass to hepatitis B core antigen (IgM anti-HBc). Both appear within 1–2 months after infection and are present at symptom onset (Fig. 22.2; Table 22.4). IgM anti-HBc is diagnostic of acute HBV infection. There are no commercially available tests for HBcAg; thus, this marker is not included in diagnostic algorithms. HBeAg is also detectable in acute infection and its presence is associated with viral replication and high viral load.

Fig. 22.2 Serologic pattern of acute hepatitis B virus infection with resolution.

Table 22.4 Interpretation of serologic markers for HBV infection

Resolution of acute infection

During resolution of infection (see Fig. 22.2), IgM anti-HBc is replaced by antibody of the IgG subclass (IgG anti-HBc). Around the same time, there is clearance of HBsAg followed by the appearance of antibody to HBsAg (anti-HBs), a protective, neutralizing antibody whose presence indicates recovery from acute infection and immunity from reinfection. There may be a brief ‘window period’ between the clearance of HBsAg and the appearance of anti-HBs during which neither HBsAg nor anti-HBs is detectable. IgM anti-HBc may be the only serologic marker present during this time. During resolution, there is also loss of HBeAg and the appearance of anti-HBe. In persons with resolved HBV infection, IgG anti-HBc usually remains detectable throughout life but anti-HBs may become undetectable after many years.

Chronic infection

In chronic infection, HBsAg persists for > 6 months and anti-HBs does not develop (Fig. 22.3; also see Table 22.4). As with acute infection with resolution, IgM anti-HBc disappears and is replaced by IgG anti-HBc. HBeAg, when present in chronic infection, indicates viral replication, high viral titers, increased infectivity, and higher probability of progression to HCC.⁸³ Conversely, the absence of HBeAg and presence of anti-HBe correlates with a lower viral load.

Fig. 22.3 Serologic pattern of acute hepatitis B virus infection with progression to chronic infection.

Perinatal infection

Because HBsAg does not cross the placenta, the presence of HBsAg in the serum of an infant is diagnostic of perinatal HBV infection. Both IgG anti-HBc and anti-HBs cross the placenta and thus neither is a useful diagnostic marker of infection in young infants. Passively acquired maternal anti-HBc antibody usually disappears within the first 1–2 years of an infant’s life.⁸⁴^–⁸⁷

The presence of HBsAg alone, with no other markers of infection, may be seen very early in infection, before the development of IgM anti-HBc, or immediately after hepatitis B vaccination (see Table 22.4). This transient presence of HBsAg within the first 3 weeks after vaccination has been documented in infants, adolescents, and adults.⁸⁸^–⁹⁰

Isolated anti-HBc:

Detection of anti-HBc without any other marker of infection, may occur in three situations: (1) false-positive result; (2) remote, past infection with the loss of detectable levels of anti-HBs; and (3) chronic infection in which HBsAg level is below level of detection of commercial assays. In this latter situation, person-to-person transmission of HBV rarely, if ever, occurs.⁹¹

Persistent or recurring IgM anti-HBc:

Certain persons with chronic HBV infection test intermittently or consistently positive for IgM anti-HBc. The appearance of IgM anti-HBc in these individuals may be associated with exacerbations of their underlying hepatitis.

Molecular Laboratory Methods

HBV DNA can be detected in the serum and tissues of persons with acute and chronic HBV infection through the use of a variety of hybridization and polymerase chain reaction (PCR) assays, some of which are commercially available. Detection of HBV DNA is not used for routine diagnostic purposes but may be useful for following the response to treatment. Subtyping and genotyping are useful only within the context of epidemiologic investigations.

Prevention of Hepatitis B

Hepatitis B vaccines

Hepatitis B vaccines are composed of HBsAg adsorbed to an adjuvant of aluminum hydroxide. HBsAg elicits production of anti-HBs, which confers protection from infection. Historically, two types of vaccine, one with plasma-derived HBsAg and the other with recombinant HBsAg, have been used. Recombinant vaccines are now almost exclusively used. Plasma-derived vaccines are manufactured from HBsAg purified from the plasma of persons with chronic HBV infection. Recombinant vaccines are produced through the insertion of the gene for HBsAg into yeast cells (Saccharomyces cerevisiae, or baker’s yeast) or, less commonly, mammalian cells (Chinese hamster ovary cells). Hepatitis B vaccines are formulated to contain 5–40 μg of HBsAg protein per dose of vaccine. In the United States, hepatitis B vaccines do not contain the preservative thimerosal, and are sold under the trade names Engerix-B® (GlaxoSmithKline Biologicals) and Recombivax® HB (Merck & Co., Inc.). Plasma-derived and recombinant vaccines are considered equivalent in their immunogenicity and effectiveness.

Vaccination schedule

Hepatitis B vaccines are typically given as a three-dose series and there are a variety of vaccination schedules. In the most common schedule in the United States, the second and third doses of vaccine are administered 1–2 months and 6–12 months after the first dose (i.e. 0, 1–2, 6–12 month schedule, Table 22.5).⁹² For routine infant immunization, the first dose of vaccine should be administered within the first 24 hours after birth and the third dose should be given after 6 months of age.⁹² Other schedules, including a two-dose series for adolescents 11–15 years old⁹³ and a four-dose series, are also approved for use in the United States.⁹²

Table 22.5 Hepatitis B vaccination schedule for children, adolescents, and adults

Age	Schedule
Children (1–10 years)*	0, 1, 6 months^†
	0, 2, 4 months^†
	0, 1, 2, 12 months^†^¶
Adolescents (11–19 years)*	0, 1, 6 months^†
	0, 1, 4 months^†
	0, 2, 4 months^†
	0, 12, 24 months^†
	0, 4–6 months^§
	0, 1, 2, 12 months^†^¶
Adults (≥20 years)*	0, 1, 6 months**^††
	0, 1, 4 months**
	0, 2, 4 months**
	0, 1, 2, 12 months^¶ **