Hepatitis B and Hepatitis D Viruses

Transmission

The principal modes of HBV transmission are (1) percutaneous, (2) sexual, and (3) perinatal. HBV is present in high titers in blood and exudates (e.g., skin lesions) of acutely and chronically infected people. Moderate viral titers are found in semen, vaginal secretions, and saliva. Other body fluids that do not contain blood or serous fluid, such as feces or urine, are not generally a source of HBV transmission. Although HBV is found in human milk, breastfeeding has not been shown to increase HBV transmission. ^, Transmission between household contacts, especially in developing countries, can occur through contact with skin lesions (e.g., eczema or impetigo), sharing of potentially blood-contaminated objects (e.g., toothbrushes or razor blades), or, in rare instances, in association with human bites. All people who are HBsAg positive are potentially infectious and can transmit the virus to others.

HBV is stable in the environment for at least 7 days and can be found in high titers on environmental surfaces, even in the absence of visible blood. Inoculation can occur from contact with environmental surfaces or equipment contaminated with HBV. The virus is inactivated by household bleach solution.

Percutaneous and permucosal transmission of HBV results from transfusion of unscreened blood, injection-drug use, occupational exposure (e.g., needlestick injuries), and other nosocomial exposures (e.g., unsafe injections, breach in aseptic technique). Acquisition of HBV infection from transfused blood is rare in the US because all donor blood is screened for HBV markers. However, blood transfusion remains an important source of infection in many developing countries. Globally, unsafe injection practices are thought to account for 32% of new HBV infections annually ; the burden of disease from other unsafe medical practices is unknown. Nosocomial transmission is not limited to developing countries; in the US and other developed countries, nosocomial transmission is associated with improper infection control and continues to occur despite longstanding infection control recommendations and guidelines. Since the mid-2000s, nosocomial hepatitis B outbreaks have involved reuse of fingerstick devices (meant for individual use) for multiple persons during assisted blood glucose monitoring, and reuse of single-use vials or devices for multiple patients.

Horizontal transmission (or intrafamilial or household transmission) refers to percutaneous transmission from infected family members within the household (most often mothers and older siblings to young children). Although this mode of transmission is most important in countries of high hepatitis B endemicity, its occurrence in the US also has been well documented.

Sexual transmission of HBV results from sexual contact (heterosexual or homosexual) with an infected person. Increased risk has been associated with ≥1 sexual partners in a 6-month period; history of another sexually transmitted infection; and sexual practices that facilitate HBV transmission, such as anal intercourse. Among young men who have sex with men (MSM), the prevalence of past or chronic HBV infection was reported to be 21% in 2000. ^,

Perinatal HBV transmission occurs during delivery and is highly efficient. In utero transmission is relatively rare, accounting for <3% of vertical infections. Risk for perinatal transmission is related to the HBeAg status of the mother; presence of HBeAg indicates increased viral load and infectivity. The risk for perinatal transmission is 70%–90% for infants born to mothers who are both HBsAg positive and HBeAg positive, and 5%–20%, for infants born to mothers who are HBsAg positive but HBeAg negative. When HBV is acquired during pregnancy, third-trimester infections carry the highest risk for mother-to-child transmission. ^,

Risk Factors, Prevalence, and Incidence of Infection in the US

Risk factors for acute HBV infection in the US include injection-drug use and high-risk sexual behaviors (e.g., multiple sex partners and MSM).

Data from the National Health and Nutrition Examination Survey estimated that, in 2016, 862,000 (95% CI, 668,000–1,056,000) non-institutionalized people in the US were HBsAg-positive, or 0.28% (95% CI, 0.22%–0.35%) of the population. Asians had the highest prevalence of HBsAg (3.37%, 95% CI, 2.62%–4.32%). ^,

Since the mid-1990s, the incidence of acute HBV infection in the US has declined significantly. National surveillance data indicate that the incidence decreased from 11.5 per 100,000 population in 1985 to 1.0 per 100,000 in 2018 ( https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm#overview ) ( Fig. 213.1 ). Incidence is estimated to be about 6 times the reported number of cases after adjustment for underreporting and asymptomatic infections. In 2018, an estimated 21,600 (12,300 to 52,800) people were newly infected ( https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm#overview ).

The effect of hepatitis B vaccination is reflected in the dramatic decline in incident cases among the cohort of children for whom recommendations for routine infant and adolescent catch-up vaccination applied. From 2000 through 2012, the incidence of acute HBV infection declined >95% (from 0.6 per 100,000 to 0.02 per 100,000) among children <20 years old ( https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm#overview ).

Global Prevalence of Infection and Patterns of Transmission

Countries and regions can be divided into areas of low (HBsAg prevalence <2%), intermediate (HBsAg prevalence of 2%–7%), and high (HBsAg prevalence of ≥8%) hepatitis B endemicity based on the prevalence of chronic HBV infection in the general population. Most high-endemic countries are in Africa and Asia. Hepatitis B prevalence is highest in the WHO Western Pacific Region and the WHO African Region, where 6.2% and 6.1% of the adult population is infected, respectively. In the WHO Eastern Mediterranean Region, the WHO South-East Asia Region, and the WHO European Region, an estimated 3.3%, 2.0%, and 1.6% of the general population is infected, respectively. In the WHO Region of the Americas, 0.7% of the population is infected. Global differences of HBsAg positivity prevalence between males (3.9%) and females (3.5%) are small. ^,

Acute Infection

The usual incubation period for HBV infection is about 3 months but can range from 6 weeks to 6 months. Clinical manifestations vary from asymptomatic infection to fulminant hepatitis. The likelihood that symptoms will develop is age dependent. Perinatal HBV infections usually are subclinical, whereas symptomatic illness is noted in 5%–15% of children aged 1–5 years and in 33%–50% of older children, adolescents, and adults. ^,

Clinical signs and symptoms of acute HBV infection can include nausea, abdominal pain, vomiting, fever, jaundice, dark urine, changes in stool color, hepatomegaly, or splenomegaly. Malaise and anorexia might precede jaundice by 1–2 weeks. Fulminant hepatitis B is uncommon (<1%) but frequently leads to death or liver failure necessitating liver transplantation.

Chronic Infection

Chronic infection is associated with progressive liver disease, including cirrhosis, liver failure, and HCC. Chronic infection is defined as persistence of HBsAg in serum for >6 months after acute infection.

Most chronically infected people remain asymptomatic until development of cirrhosis or end-stage liver disease. Cirrhosis can lead to the development of liver failure manifest by coagulopathy, ascites, encephalopathy, and increased risk for HCC. Among people with chronic infection, the overall annual incidence of cirrhosis is 2%–3%. ^, At 5 years, the survival rate of people with compensated and uncompensated cirrhosis is 84% and 14%, respectively. Risk factors for HBV-related cirrhosis and HCC include earlier age at infection, advancing age, male sex, aflatoxin exposure, HBV genotypes A, C, or F, prolonged immune active phase of chronic infection, HBeAg positivity, prolonged elevation of HBV DNA, and co-infection with HDV. ^{, ,} Although severe HBV-related liver disease is uncommon in childhood, chronic infection during infancy and childhood can lead to development of cirrhosis and HCC as early as the first decade of life. Up to 25% of infants and older children with chronic infection eventually develop HBV-related cirrhosis or HCC. ^{, ,}

Extrahepatic Manifestations

Both acute and chronic HBV infection can be associated with extrahepatic clinical manifestations, including polyarteritis nodosa, membranous and membranoproliferative glomerulonephritis, polyradiculoneuritis, essential mixed cryoglobulinemia, porphyria cutanea tarda, polyneuritis, papular acrodermatitis, and thyroid dysfunction. In addition to HCC, HBV infection has been associated with risk of stomach cancer, colorectal cancer, oral cancer, pancreatic cancer, and lymphoma. Urticarial rashes, arthralgia, and arthritis commonly are associated with acute HBV infection; thrombocytopenia preceding jaundice also has been reported.

Natural History of Chronic Infection

There are four phases of chronic HBV infection: (1) immune tolerant, (2) immune active, (3) immune inactive, (4) and reactivation (or HBeAg-negative immune active). ^{, ,}

People in the immune tolerant phase are HBsAg positive and HBeAg positive and have high HBV DNA levels (>20,000 IU/mL), normal serum alanine aminotransferase (ALT) levels, and no to minimal hepatic inflammation or fibrosis. Most chronically infected children will remain in the immune tolerant phase until late childhood or adolescence.

The immune active phase is characterized by an active immune response resulting in inflammation (with or without fibrosis), hepatocyte damage, and a resultant rise in serum ALT levels. Persons in the immune active phase are HBsAg positive, have HBV DNA levels >2000 IU/mL, and can be either HBeAg positive or HBeAg negative/anti-HBe positive. People who remain in the immune active phase for prolonged periods are at high risk for developing cirrhosis and HCC.

Persons in the immune inactive phase are HBsAg positive, have HBV DNA <2000 IU/mL, are HBeAg negative and anti-HBe positive, and have improvement of hepatic inflammation and fibrosis. Risk for progression to HCC is lower among persons in the inactive phase than among persons in the active phase.

Persons in the reactivation phase (or HBeAg-negative immune active phase) are HBsAg positive, HBeAg negative, and anti-HBe positive with HBV DNA levels >2000 IU/mL. There is active liver inflammation (with or without fibrosis), and serum ALT levels can be elevated or normal. HBeAg-negative immune active disease often is caused by a mutant HBV, which can be more virulent than nonmutant forms. Persons with hepatitis B receiving treatment for hepatitis C also are at risk for moving into the reactivation phase ( https://www.hcvguidelines.org/evaluate/testing-and-linkage ).

Chronically infected persons do not necessarily pass through the phases of chronic infection in a linear fashion. Chronically infected persons may spend little to no time in the immune tolerant phase. Twenty percent of HBeAg-negative persons will revert back to HBeAg positivity ; 10%–30% of HBeAg-negative/anti-HBe-positive persons will remain in the immune active phase with elevated serum ALT and HBV DNA levels; and 10%–30% of HBeAg-negative/anti-HBe-positive persons will revert from the inactive phase to an anti-HBe-positive hepatitis with elevated serum ALT and HBV DNA levels. ^, As such, the current practice guidelines of the American Association for the Study of Liver Diseases (AASLD) recommend lifelong follow-up with repeated testing to monitor changes in the phase of chronic infection.

Influence of Age and Hepatitis B e Antigen

Age at time of acute infection is the primary determinant of progression to chronic infection. More than 90% of perinatally infected infants develop chronic infection. Between 25% and 50% of children infected between 1 and 5 years of age become chronically infected, whereas only 6%–10% of acutely infected older children and adults develop chronic infection. ^{, ,} Elderly adults have higher rates of developing chronic infection, ^, as do patients who have acute HBV infection while immunosuppressed or concurrently with an underlying chronic illness.

Perinatally infected children usually remain in the immune tolerant phase for extended periods, whereas chronic infection acquired during later childhood or adolescence usually is accompanied by more active liver disease and elevated serum ALT values. Children infected perinatally have lower annual rates of HBeAg loss than children infected later in childhood or in adolescence. Of Taiwanese children infected perinatally, HBeAg seroconversion occurred in <2% annually during the first 3 years of life and only in one-third by 10 years of age. ^, Children infected horizontally clear HBeAg more rapidly; in one study, 35% of older Asian children cleared HBeAg >5 years after infection, and 83% of European children cleared HBeAg during an average of 13 years of follow-up.

Presence of HBeAg indicates ongoing virus replication. HBeAg-positive patients usually have high serum levels of HBV DNA. Clearance of HBeAg and development of anti-HBe (HBeAg seroconversion) are accompanied by reductions in serum HBV DNA and ALT levels and might be preceded by a temporary exacerbation of liver disease. HBeAg seroconversion occurs at a rate of 5%–10% per year. Most patients who seroconvert have little to no progression of liver disease (immune inactive phase). In these patients, the risk for HCC is reduced but remains higher than in patients without chronic infection. Serologic reversion (reappearance of HBeAg) is common in the absence of anti-HBe. However, reversion to HBeAg positivity also can occur with loss of anti-HBe.

HBeAg positivity during pregnancy greatly increases the risk for perinatal transmission. In the absence of appropriate postexposure prophylaxis, nearly all neonates born to mothers who are both HBsAg and HBeAg positive become infected. Clearance of HBeAg and development of anti-HBe is associated with decreased risk for perinatal transmission; approximately 25% of infants born to HBsAg-positive and anti-HBe-positive mothers become infected, and 10%–15% develop chronic infection. ^, Among infected infants, approximately 90% develop chronic infection. In a setting where infants generally receive postexposure prophylaxis, the relative risk for transmission for maternal HBeAg-positive (versus HBeAg-negative) status was an incidence rate ratio of nearly 80.

Influence of Genotype

The clinical significance of HBV genotypes remains unclear. Existing studies suggest that genotype influences the time to HBeAg seroconversion and response to treatment. Among Alaska Natives, the median time to seroconversion is approximately 18 years among people with genotype C, 8 years among people with genotype F, and <6 years among people with genotypes A, B, and D. Reversion to HBeAg positivity is more common among Alaska Natives infected with genotypes C and F. Because genotype influences the rate of HBeAg seroconversion during childbearing years, genotype might play a role in the risk for perinatal transmission.

Resolved Acute Infection and the “Recovery Phase” of Chronic Infection

Resolved acute infection is defined as the clearance of HBsAg, loss of detectable HBV DNA, and normalization of serum ALT levels; development of anti-HBs might occur. Resolved acute infection is not a risk factor for subsequent chronic liver disease or HCC. However, viral clearance still might be incomplete; patients with a history of acute hepatitis B and apparent resolution (anti-HBs positivity and HBsAg negativity) can experience reactivation of hepatitis B if they become immunosuppressed, and HBV DNA has been detected in blood of patients 20 years after resolution of acute infection.

People with chronic infection who clear HBsAg enter what is often called the recovery phase. During childhood, the annual clearance rate of HBsAg is <1%. ^, People who clear HBsAg generally have a better prognosis, with improvements in hepatic inflammation and fibrosis over time. ^, However, HCC still can develop in HBsAg-negative people, and HBV DNA can be found in serum of a significant minority of HBsAg-negative people. ^, In persons who achieve sustained HBsAg seroclearance, routine ALT and HBV-DNA monitoring are not required unless immunocompromised or undergoing chemotherapy or immunosuppressive therapy. HCC surveillance should continue if the person has cirrhosis, a first-degree family member with HCC, or a long duration of infection (>40 years for males and >50 years for females who have been infected with HBV from a young age). ^,