4.0 Natural history of hepatitis B virus infection



  • Birth in highly endemic regions such as sub-Saharan Africa and East Asia is a risk factor for developing chronic hepatitis B (CHB) infection (1). The primary mode of transmission in such cases is vertical (i.e. mother to child).
  • The risk of developing CHB is highest in those who acquire hepatitis B virus (HBV) infection perinatally and lowest in those who acquire the infection in adulthood.
  • The natural history of HBV infection depends on complex interactions between host, virus and environment.
  • There are four phases of CHB, and the host immune response in each phase determines the outcome of infection and the severity of liver injury.
  • Liver damage is caused by the host immune response rather than the HBV itself.
  • Complications of CHB include cirrhosis with hepatocellular failure and hepatocellular carcinoma. All complications can be minimised with effective antiviral therapy.

Hepatitis B virus (HBV) is transmitted through infected blood or bodily fluids (semen and vaginal fluids). The virus enters the bloodstream either through a break in the skin or through mucous membranes (eyes, nose and mouth). The modes of transmission are summarised in Table 4.1

Table 4.1 Modes of transmission of hepatitis B virus
Vertically – from mother to child during childbirth This is the most common way the virus spreads in high-prevalence countries.
Breastfeeding does not appear to increase the risk of HBV transmission to the infant, and it should not be discouraged if vaccination and HBIG are administered at birth.
Most guidelines do not recommend caesarean section as an intervention to reduce vertical transmission (2).
Horizontally From a person with hepatitis B to other household contacts who are unvaccinated (e.g. through sharing toothbrushes, razors, nail files or other personal items that may lead to exchange  of body fluids).
Infection acquired in early childhood after delivery is well recognised and has been attributed to parent-to-child contact (3-5), sibling contact (5, 6) and medical procedures such as intramuscular injections (6).
Sexually Through unprotected vaginal, anal or oral sex with a person who has hepatitis B.
Percutaneously Through the sharing or re-use of injecting equipment, tattooing, body piercing, acupuncture, cupping and some other cultural practices.
Medically acquired There are still countries where blood transfusions, organ transplants and other medical interventions pose an extreme risk because donors are not screened for HBV. In most countries where screening is in place, the risk of infection is low.
Medical procedures – including dentistry, surgery, dialysis and alternative health-care procedures – pose a risk if appropriate infection control procedures are not adhered to.
Needlestick injury or splashing of infected blood or body fluids are a particular concern for health-care workers and emergency services providers.
HBIG, hepatitis B immune globulin; HBV, hepatitis B virus

Acute HBV infection, as with other acute viral hepatitis infections, is asymptomatic in most individuals. Symptoms are more likely to occur in adults acquiring the infection, and will usually be mild, comprising arthralgia and nausea with or without right upper quadrant abdominal pain preceding any overt jaundice. HBV infection can be associated with a range of extrahepatic manifestations, more common in chronic hepatitis B (CHB). Those who acquire HBV perinatally or in infancy are likely to progress from acute to chronic infection. The acute illness can be described as having four stages.

  1. Incubation: The incubation period of acute HBV infection can last up to 12 weeks.
  2. Symptomatic hepatitis: Acute hepatitis develops after the incubation period, and is characterised by elevated alanine transaminase (ALT) levels lasting 4–12 weeks. Symptoms and signs include anorexia, dark urine, jaundice and right upper quadrant abdominal discomfort. Acute symptoms are common in adults but not in infants and children.
  3. Recovery: A recovery period follows with normalisation of the levels of ALT.
  4. Viral clearance and immunity:

Hepatitis B surface antigen (HBsAg) clearance in the serum follows after a few months, coinciding with the development of hepatitis B surface antibodies (anti-HBs). Hepatitis B core antibodies (anti-HBc) appear much earlier than anti-HBs and, in those who clear the infection, hepatitis B e antigen (HBeAg) appears and is cleared before the appearance of anti-HBs (Figure 4.1).

Figure 4.1 Acute hepatitis B virus infection with clearance

anti-HBc, antibody to core antigen; anti-HBe, antibody to e antigen; anti-HBs, antibody to surface antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IgM, immunoglobulin M

Adapted from: Centers for Disease Control and Prevention. Recommendations for Identification and Public Health Management of Persons with Chronic Hepatitis B Virus Infection. MMWR 2008;57(No. RR-8):1-10.

The transition from acute to chronic infection (Figure 4.2) signifies a failure of the immune response to eradicate the virus. Progression from acute to CHB infection is influenced by the age at which the subject acquires the virus. The overall risk of chronic infection is highest in those who acquire the virus perinatally (80–90%) (8). This is related to the inability of the immune system to recognise the virus and the high level of viral replication; it results in immunological tolerance. In adults, a cell-mediated response to foreign HBV proteins results in acute hepatitis, which may be asymptomatic; the response leads to clearance of the infection in all but 1–5% of patients (9).

In those who acquire the infection in childhood, the risk of chronic hepatitis is 30% (10) (Table 4.2).

Figure 4.2 Progression to chronic hepatitis B virus infection

anti-HBc, antibody to core antigen; anti-HBe, antibody to e antigen; anti-HBs, antibody to surface antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IgM, immunoglobulin M

Adapted from: Centers for Disease Control and Prevention. Recommendations for Identification and Public Health Management of Persons with Chronic Hepatitis B Virus Infection. MMWR 2008;57(No. RR-8):1-10.


Table 4.2 Risk of progression, by age at infection (11)
Risk of development of chronic infection (%) 80–90 30 <5
Risk of advanced liver disease (% exposed to HBV) 20-30 5-10 1-2
Risk of advanced liver disease (% of those with chronic liver disease) 20-30 20-30 20-30
Length of immune tolerance phase Prolonged Variable Short
HBV, hepatitis B virus

The American Association for the Study of Liver Diseases (AASLD) practice guidelines define CHB as a chronic necroinflammatory disease of the liver caused by persistent infection with HBV. CHB is defined serologically as HBsAg positivity for more than 6 months (12).

The terminology used to describe the different phases in the natural history of CHB infection varies considerably, and has been the subject of much debate and confusion. In particular, the immune control phase has been incorrectly referred to as the ‘healthy carrier’ state, the ‘inactive carrier’ state or the ‘non-replicative’ state of CHB. There is no such thing as a ‘healthy carrier’ – the term fails to reflect the fluctuating nature of CHB virus infection over time. The terms used in Table 4.3 to describe the phases of CHB reflect the importance of the immune system in controlling this infection.

Table 4.3 Terminology of chronic hepatitis B
Preferred termNumericalAlso known as
Immune tolerance Phase I Immunotolerant phase
Replicative state
Immune clearance Phase II Immune competence phase
Immunoactive phase
Immune control Phase III Non-replicative state
Immune escape Phase IV HBeAg-negative CHB
Precore mutant disease
Reactivation phase
CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen

The four phases outlined in Table 4.3 are dependent on the complex interaction between host immune responses and viral and environmental factors. These factors determine the outcome of infection and the severity of liver injury at any particular point in time in the natural history of HBV infection, as shown in Figure 4.3.

Figure 4.3 The four phases and relevance to treatment decisions
Natural History of Chronic HBV: The 4 Phases and Relevance to Treatment Decisions

ALT, alanine aminotransferase; anti-HBe, antibody to e antigen; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LFT, liver function test

4.4.1 Immune tolerance phase

The immune tolerance phase is characterised by hepatitis B e antigen (HBeAg) positivity, high HBV DNA levels (>20,000 IU/mL, and commonly over 1 million IU/mL), normal ALT levels and minimal level liver injury. During this phase, which may persist for decades, liver inflammation or fibrosis is either absent or minimal. This phase is associated with a low risk of progression to advanced liver disease, and it is thought to occur most commonly in those who acquire the infection vertically from HBeAg-positive mothers (13).

4.4.2 Immune clearance phase

The immune clearance phase is also called the ‘immune competent’ or ‘active’ phase. The liver injury in HBV is determined by the immune response to the virus. The host’s immune system recognises the HBV as foreign, and mounts a cytotoxic response to infected hepatocytes. This phase is characterised by fluctuating HBV DNA and ALT levels. Recurrent bouts of active inflammation and, eventually, fibrosis can occur in the liver following these repeated immune-mediated attacks. An important outcome of this phase is the seroconversion of HBeAg to HBe antibody (anti-HBe), which is associated with a lower level of viraemia. The observed rate of clearance of HBeAg in those with or without elevated ALT levels averages 8%–12% per year (14). However, a number of people will still develop active liver disease after HBeAg seroconversion, generally owing to immune escape; that is, emergence of HBV mutant variants, particularly the core or precore mutation that renders the virus unable to encode for HBeAg (15) (see Chapter 2).

4.4.3 Immune control phase

Patients in the immune control phase have previously been described as ‘inactive carriers’ of the infection. Liver inflammation is minimal, HBV DNA is undetectable or at a low level (<2,000 IU/mL), and liver function tests (LFTs) are usually normal (minor fluctuations of ALT may occur in relation to intercurrent infections, medication reactions and, possibly, early attempts to clear the virus). These patients are at low risk of developing advanced liver disease and its related complications (16). In a study assessing the long-term outcomes for HBsAg-positive individuals who had normal LFTs and normal or minimal changes on liver biopsy, liver histology and ALT remained unchanged over a 12-year follow-up period.

About 10–20% of patients who are anti-HBe positive may develop subsequent reactivation of HBV, with immune escape, after many years (17). This is associated with flares of hepatitis with HBV reactivation and ALT elevation (3). In addition, some patients may enter the control phase with already moderate to severe fibrosis. Therefore, all patients should be followed up indefinitely with 6-monthly ALT and annual measurement of HBV DNA, to monitor whether they remain in the immune control phase.

In addition, there is now emerging evidence that, in patients with an HBV DNA level of less than 2,000 IU/mL who were thought to have a comparable risk of hepatocellular carcinoma (HCC), an HBsAg level greater than 1,000 IU/mL is an independent risk factor for HCC development (18). However, it is currently not routine practice to measure HBsAg titres, and the role of measuring this antigen in clinical practice is an area for further studies.

4.4.4 Immune escape phase

The immune escape phase of CHB is characterised by negative HBeAg, positive anti-HBe and detectable viral load (HBV DNA >2,000 IU/mL). It is often termed ‘precore mutant HBV’, because a mutation in the precore region of the DNA results in a lack of HBeAg production.

HBeAg-negative CHB is more common in Asian and Mediterranean countries. It occurs due to the selection of a mutant HBV that does not produce HBeAg but is still able to replicate. This immune selection process is likely to occur late
in the natural history of CHB.

Patients who are HBeAg negative tend to be older and have more advanced liver disease. The natural course of patients with HBeAg-negative disease is characterised by fluctuations in clinical status, and in biochemical and viral load parameters, caused by recurrent hepatic flares. About 70% of those with eAg-negative CHB have a fluctuating course characterised by periods of apparent inactivity (19). Although patients with HBeAg-negative disease tend to have lower HBV viral load than those with HBeAg-positive infection (<20,000 IU/mL vs >20,000 IU/mL), they display more hepatic inflammation on liver biopsy (20). Consequently, the annual incidence of cirrhosis is significantly higher (8–10%) in HBeAg-negative CHB patients than in those with HBeAg-positive CHB (2–5%) (21).

Low levels of HBV DNA remain in hepatocytes after recovery from acute hepatitis B. Patients who have been exposed to HBV are at risk of reactivation of hepatitis B in the context of immunosuppression (22). Reactivation of HBV can occur in those who are HBsAg positive, and even in those who are both HBsAg negative and anti-HBc positive, if there is potent immunosuppression. Reactivation may be characterised by positive anti-HBc immunoglobulin M (IgM), but at lower titres than acute infection. Current AASLD guidelines suggest that patients who are at high risk of HBV infection should undergo testing for HBsAg and anti-HBc before chemotherapy or immunosuppressive therapy. Reactivation has been reported in 20–50% of those who are HBsAg positive and who undergo immunosuppressive treatment; the reactivation may result in hepatic decompensation and death (23). Thus, it is important for people with HBV infection undergoing immunosuppressive therapy to be carefully monitored, and managed appropriately with prophylaxis as indicated (see Chapter 11). 

Occult hepatitis B infection refers to the presence of the HBV DNA in the blood or liver, in the absence of HBsAg in the serum. With the emergence of highly sensitive HBV DNA polymerase chain reaction (PCR) assays, a population of patients has been identified with occult HBV infection. Its presence may be related to the persistence of HBV DNA within hepatocytes, in the form of covalently closed circular DNA (ccc DNA), which remains present even in people who are HBsAg negative (24). The reactivation of hepatitis B following immunosuppression has been described in patients with occult infection. Occult hepatitis B infection may contribute to the development of HCC, and there is evidence that it may also accelerate the progression of liver disease in the context of hepatitis C virus (HCV) co-infection (25).

Sequelae of HBV infection range from asymptomatic disease, to decompensated liver failure, to extrahepatic manifestations. Cirrhosis and HCC are major causes of morbidity and mortality. It is estimated that 600,000 patients worldwide die annually from HBV-related liver disease (26). The cumulative 5-year survival rate once decompensated cirrhosis ensues is 35% (27). The development of cirrhosis is influenced by several factors, most of which are virus and host related (Table 4.4).

Table 4.4 Factors influencing progression to cirrhosis and hepatocellular carcinoma

Risk factor

Active HBV DNA replication / viral load Chen CJ et al (2006) (28)
HBV genotype C Yang et al (2002) (29)
HBeAg-negative core promoter mutation  Yang et al (2002) (29)
Cirrhosis  Schiff et al (2006) (30)
Male sex  Bosch (1999) (31)
Asian/African/Aboriginal and Torres Strait Islander ethnicity 

Fattovich (2003) (32)

Parker (2014) (33)

Coexisting non-alcoholic fatty liver disease and diabetes  El-Serag (2001) (34)
Smoking, alcohol, obesity  Marrero (2005) (35)
Positive family history 1st degree relative  Loomba (2013) (36)
HBeAg, hepatitis B e antigen; HBV, hepatitis B virus

Studies provide strong evidence that the risk of HCC in HBV is linked to levels of serum HBV DNA. In HBV-related HCC, 30–40% of HCC cases develop in the absence of cirrhosis (37).

HBV has the ability to integrate its genome into the host’s hepatocyte DNA. Over many decades, especially during the immune tolerance phase, persistently high levels of HBV DNA lead to an accumulation of multiple sites of integration, thus increasing the risk of HCC even in the absence of active inflammation and fibrosis (38).

The importance of HBV viral replication to the natural history of the infection has been reported in the REVEAL HBV study (28, 39). The study showed that virusserum HBV DNA level was an independent risk factor for the development of cirrhosis and HCC after adjusting for other risk factors (e.g. male gender, alcohol use, cigarette smoking and older age).

There is ample data to suggest that patients who achieve long-term HBV DNA suppression through antiviral medications have reduced incidence of both HCC (40) and cirrhosis (41).

Newer, more potent agents such as entecavir and tenofovir have replaced lamivudine and adefovir as first-line antiviral medication for CHB (4) (see Chapter 7).

The outcome of HBV infection and progression to chronicity is determined particularly by age at acquisition. The natural history of CHB virus infection is characterised by four distinct phases that depend on complex interactions between host, virus and environment. In each phase, it is the host’s immune response that determines the outcome of infection and the severity of liver injury. Sequelae of HBV infection range from asymptomatic carrier status to decompensated liver failure and HCC (42). Effective antiviral therapy can alter the natural course of HBV infection and reduce long-term complications related to the disease.

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James Pang & Amany Zekry, Gastroenterology & Hepatology Unit, St George Hospital, Kogarah, NSW