• antiviral treatment;
  • elimination;
  • eradication;
  • hepatitis B vaccine;
  • hepatitis B virus;
  • interferon treatment;
  • transmission routes


  1. Top of page
  2. Abstract
  3. Introduction
  4. Natural history of chronic HBV infection
  5. Strategies for elimination or eradication of hepatitis B
  6. Future perspectives
  7. References

Hepatitis B virus (HBV) causes important human health problems. It has infected one-third of the world's population and approximately 360 million people are chronic carriers. Worldwide, 0.5–1.2 million deaths are attributed to HBV infection annually. Therefore, global control of HBV infection is important. HBV infection can be intervened by interrupting routes of transmission, treating the chronically infected, and preventing the susceptibles with immunoprophylaxis. All these measures are effective. Nevertheless, although pegylated interferons or nucleos(t)ide analogs are effective for the treatment of chronic hepatitis B, chronic carriage of HBV is not easy to eliminate, as revealed by the frequent persistence of hepatitis B surface antigen, despite satisfactory responses to these treatments. On the other hand, hepatitis B vaccination has been shown to preclude HBV infection effectively. This is particularly true for pre-exposure prophylaxis. Worthy of note is the universal vaccination of newborn infants. This is the most effective means of preventing HBV infection, especially for those born to HBV carrier mothers. To eliminate and eradicate hepatitis B, first, HBV in the chronically infected should be eradicated or strongly and efficiently suppressed, so that the infection does not spread rampantly. Second, all the transmission routes should be interrupted. Lastly, but most effectively, is to immunize all susceptibles. The difficulties and possible solutions of each approach are discussed. In conclusion, the existing means to prevent and treat HBV infection render our goal toward eliminating and eradicating hepatitis B possible, although it will take much time and effort to achieve this objective.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Natural history of chronic HBV infection
  5. Strategies for elimination or eradication of hepatitis B
  6. Future perspectives
  7. References

Hepatitis B virus (HBV) is one of the most important human pathogens. It causes significant diseases spanning from fulminant hepatitis to end-stage liver disease. Furthermore, chronic HBV infection is closely associated with hepatocellular carcinoma (HCC); this is especially true in the developing countries.1,2 Worldwide, approximately 360 million people are chronically infected and approximately 1 million deaths are attributed to HBV infection each year,3 making HBV infection the 10th leading cause of death. In the meantime, HCC ranks the fifth among the most frequent cancers in humans.2 Of note is the observation that in areas where chronic HBV infection is endemic, most chronic liver disease and cases of HCC are caused by HBV. These facts underline the importance of HBV infection, and indicate the necessity for its control.

In the management of an infectious agent, five levels can be achieved according to the Dahlem Conference:4 (i) control; (ii) elimination of disease; (iii) elimination of infection; (iv) eradication; and finally (v) extinction (Table 1). Eradication/extinction is the ultimate goal in communicable disease control and sustainability. However, it is not easy to achieve, and needs tremendous efforts from all over the world. Nevertheless, after HBV was identified in the mid-1960s, in the last 40 years, the virus and its infection have been thoroughly characterized. Subsequent advances in prevention and treatment have shed light on the elimination and eradication of hepatitis B.5

Table 1.  Definitions relating to the spectrum from disease control to extinction4
  1. After Hinman A.4

ControlReduction of disease incidence, prevalence, morbidity or mortality to a locally acceptable level as a result of deliberate efforts.
Continued intervention measures are required to maintain the reduction.
Elimination of diseaseReduction to zero of the incidence of a specified disease in a defined geographic area as a result of deliberate efforts.
Continued intervention measures are required.
Elimination of infectionReduction to zero of the incidence of infection caused by a specific agent in a defined geographic area as a result of deliberate efforts.
Continued measures to prevent reestablishment of transmission are required.
EradicationPermanent reduction to zero of the worldwide incidence of infection caused by a specific agent as a result of deliberate efforts.
Intervention measures are no longer needed.
ExtinctionThe specific agent no longer exists in nature or in the laboratory.

Natural history of chronic HBV infection

  1. Top of page
  2. Abstract
  3. Introduction
  4. Natural history of chronic HBV infection
  5. Strategies for elimination or eradication of hepatitis B
  6. Future perspectives
  7. References

In the past decades, the epidemiology, virology, immunology and clinical course of HBV infection have made the natural history clearer than ever. A thorough understanding of the natural history can provide us with necessary information in forming strategies to prevent and manage HBV infection. For this reason, the natural history of HBV infection is briefly depicted here.

Hepatitis B virus usually causes acute and inapparent infections. However, in immunocompromised persons, HBV infection often becomes chronic. Chronicity of HBV infection is related to the age when the subject contracts the infection. The younger the age, the higher the chronicity rate. This is particularly true in childhood. The hepatitis B surface antigen (HBsAg) carriage rate after infection can be as high as 90% in newborns, 25% in preschool children, and less than 3% in adolescents and young adults6–8 (reviewed in 8).

Hepatitis B virus infection in infancy occurs most frequently from family members. In Asia, perinatal transmission from HBV-carrier mothers to their newborn infants is common, especially when the mother is positive for hepatitis B e antigen (HBeAg)6,7 or has a high hepatitis B viral load.9 Most infants born to these highly infectious carrier mothers also become carriers in early life (65–100%). The infection occurs perinatally, and thus can be prevented by appropriate immunoprophylaxis soon after birth (reviewed in 5). Nevertheless, in a small proportion of HBsAg carrier mothers' newborns (∼1.2%), HBsAg is already present in substantial levels at birth, indicating the likelihood of intrauterine HBV infection.10 Transplacental leakage of the maternal HBV is the most likely route for in utero infection. Threatened abortion and/or threatened preterm labor have been shown to be significant risk factors.11 All those who are infected in utero become HBsAg carriers, but the natural history of this kind of HBV-infected persons remains unclear.

Once the infection becomes chronic, HBsAg carriage is refractory; the average annual incidence of loss of serum HBsAg is 0.6% in children.12 Although the low rate of serum HBsAg clearance persists in adulthood, cumulated clearance rate can reach 40% after 25 years of follow up.13 Whether this “seroclearance” of HBsAg means that serum HBsAg decreases to the detection limit of the assay or is a real clearance of HBV from the host remains to be seen.

The clinical course of chronic HBV infection is not monotonous; it actually evolves from a replicative phase to a non-replicative phase. Replication of HBV is a prerequisite for hepatic injury. The natural course of chronic HBV infection can be divided into the following phases (Fig. 1).1,8,14,15


Figure 1. Natural history of chronic hepatitis B virus infection.1 AC, Active cirrhosis; CAH, Chronic active hepatitis; CPH, Chronic persistent hepatitis; HBeAg, hepatitis B e-antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; IC, Inactive cirrhosis; LH, Lobular hepatitis; NSRH, Nonspecific reactive hepatitis.

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Virus tolerance phase

In this phase, the host's immune system is tolerant to the virus, and the attempts to eliminate the virus are weak or absent. The virus replicates very actively as can be seen from the extremely high serum HBV DNA levels and the presence of HBeAg as well as the abundant levels of HBsAg in the serum and hepatitis B core antigen (HBcAg) in the hepatocytes. The virus tolerance phase is especially evident in subjects who contract HBV infection through perinatal mother-to-infant transmission.1,8,14 In this phase, hepatic injury is minimal, because of the lack of host immune responses against the virus.

Virus clearance phase

The disease activity begins to appear or increase after 2–3 decades of virus tolerance. The reason why the previously tolerant host begins to exert efforts to get rid of the virus is unclear. Perhaps due to prolonged carriage of HBV, viral replication starts to wane and the state of immune tolerance is no longer maintained. Non-cytolytic intracellular inactivation of HBV by certain inflammatory cytokines released by activated lymphomononuclear cells may have an important role in clearing the virus.16 HBcAg/HBeAg-specific cellular immune responses result in lysis of the infected liver cells17,18 (reviewed in 18). The liver then begins to have active disease as revealed by the presence of lobular hepatitis. The previously symptomless HBV carrier may then start to have symptoms of acute hepatitis. However, many remain asymptomatic despite active hepatitis. After a variable period of time, usually decades, the host eventually gets rid of active viral replication and only residual HBV genome is found integrated into the host chromosomes.

In both virus tolerance phase and virus clearance phase, HBV replicates actively in the hepatocytes. HBV replication is unique in that in the replication cycle, the viral RNA is reversely transcribed to DNA. This is the target of current antiviral therapy. HBV forms a covalently closed circular DNA (cccDNA) which resides in the nucleus of infected hepatocytes and serves as the transcriptional template for HBV RNA production. HBV cccDNA is not affected directly by the currently available anti-HBV nucleos(t)ide analogs, and therefore is an important cause of HBV recurrence after current anti-HBV treatment.

Inactive residual HBV integrated phase

In this phase, the carrier is now HBeAg-negative and anti-HBe-positive. The virus replication is minimal, the hepatocytes are spared from attacks by the host immune cells. Serum HBV DNA decreases to low levels and the liver disease becomes quiescent at this stage. The prognosis is generally good.19 However, the underlying pathological changes in the liver at the onset of this stage is crucial in determining the clinical outcome for the HBsAg carrier. In the absence of hepatic inflammation, the disease processes will cease and hepatic fibrosis may regress. However, if cirrhosis is already well-established, the likelihood of remitting to normal hepatic architecture is low.8

Reactivation from inactive residual HBV integrated phase

Although after entering the residual HBV integrated phase the activity of liver disease becomes quiescent, a certain proportion of HBeAg-negative, anti-HBe-positive HBsAg carriers will have chronic hepatitis again. Thus, HBV replication reactivates and serum HBV DNA increases again, frequently accompanied by active hepatic injury. The course is refractory and clinical sequelae will follow. Although a single nucleotide mutation at position 1896 in the precore region from G to A (which creates a stop codon and abolishes the production of HBeAg) was identified,20 whether this is associated with the reactivation is uncertain, because the same mutation has also been identified in healthy anti-HBe-positive HBsAg carriers.21 In addition, hepatitis B core promoter mutants with point mutations A1762T and G1764A have also been claimed to affect the formation of HBeAg, because these mutations may abort the transcription of pre-C mRNA but not that of pregenomic RNA.22 These mutations have been found to correlate with lower serum HBV DNA levels and lower expression of HBcAg in the liver.23 In a case–control study, the mutation was shown to increase the risk of HCC in HBsAg carriers.24 The results were confirmed recently in a community-based cohort study.25 With long-term follow up, these mutations were found to increase the risk of HCC (hazard ratio = 1.76, 95% CI = 1.19–2.61). Intriguingly, the precore G1896A mutation was associated with a decreased risk of HCC in this study.25

Strategies for elimination or eradication of hepatitis B

  1. Top of page
  2. Abstract
  3. Introduction
  4. Natural history of chronic HBV infection
  5. Strategies for elimination or eradication of hepatitis B
  6. Future perspectives
  7. References

A thorough understanding of the natural history of HBV infection can indicate the directions and the possible means to control the infection. Figure 2 illustrates the three essential components of HBV infection: (i) an infection source; (ii) a susceptible host; and (iii) an established route of transmission. In the past, preventing susceptible individuals from HBV infection was thought to be the only way to control HBV infection.26 Nevertheless, recent advances in the specific treatment of HBV infection have enabled us to suppress this refractory chronic viral infection in humans for the first time.


Figure 2. The three components of hepatitis B virus infection and the relation to elimination/eradication of the infection. HBeAg, hepatitis B e-antigen; HBV, hepatitis B virus.

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Decrease or eliminate the infection source by the treatment of chronic hepatitis B

Chronic hepatitis B can be treated by α-interferon (IFN-α; regular or pegylated) or nucleos(t)ide analogs.27

In properly chosen patients with chronic hepatitis B, 30–40% will have a sustained virological response 6–12 months after IFN-α treatment. More importantly, 30–71% of the initial virological responders will clear serum HBsAg on follow up.28 The wide range of HBsAg clearance may be due to different durations of follow up, different treatment regimens, different distributions of HBV genotypes and different ethnic background of the patients. Seronegativity of HBsAg has very important implications. It signifies a better prognosis in the patient and a much lower infectivity of the previous HBsAg carrier. The intrahepatic HBV cccDNA has been shown to correlate with serum HBsAg levels and declines after antiviral therapy.29 Whether those who have cleared serum HBsAg still have intrahepatic HBV cccDNA needs to be studied.

Chronic hepatitis B can also be treated with oral nucleos(t)ide analogs. They are effective and very well-tolerated. Early generation drugs had the disadvantage of drug resistance that causes biochemical breakthroughs, and the sustained responses after cessation of the therapy were lower than IFN-α. However, the recently developed drugs have generally overcome these disadvantages. All the benefits of a single year of IFN therapy have been regarded to be achievable with newer, low-resistance oral agents continued for a longer period.30 Nevertheless, compared with IFN therapy, it has generally been found that HBeAg seroconversion and HBsAg clearance are less remarkable after treatment with nucleos(t)ide analogs. Prolonged follow up in those who receive long-term potent nucleoside analogs, such as entecavir or tenofovir, should be done to see if there is a substantial and comparable proportion of patients who clear HBsAg and the intrahepatic HBV cccDNA.

At present, these treatments are not indicated for all HBV carriers. Only those with disease activities need to be treated. Nevertheless, there may be exceptions. Because high maternal viral load of HBV is the most critical factor in perinatal HBV transmission,9 even after on-schedule immunoprophylaxis, there remains a substantial proportion of newborns who still contract HBV infection from their mothers and become HBV carriers themselves.31 By analogy with the situation in HIV infection,32 lowering the maternal viral load by antiviral therapy may reduce the perinatal HBV infection. Indeed, there are two studies33,34 that explored this possibility. In one small study, eight highly viremic HBV carrier mothers received lamivudine in the last month of pregnancy (from week 34 on), one of eight (12.5%) hepatitis B immunized newborns became chronically infected. In the historical controls, seven of 25 (28%) had chronic HBV infection.33 Another study recruited 150 HBsAg-positive expecting mothers, 89 received lamivudine from week 32 of gestation to week 4 postpartum, 61 received placebo. Infants in the group of treated mothers had a lower HBsAg seropositivity (10/56 vs 23/59 or 18% vs 39%, P = 0.014).34 Unfortunately, the high rate of lost to follow up or consent withdrawal weakened the conclusions of this important study. Hence, whether giving antivirals to near-term HBV carrier mothers will decrease the perinatal mother-to-infant HBV infection needs to be addressed further with randomized control trials.

In dealing with this issue, the cost and safety in both the mothers and newborns should also be considered. Pregnancy category of the currently available drugs for the treatment of chronic hepatitis B is shown in Table 2. In most instances, the reservation is because of insufficient data in humans to guarantee absence of embryonal adverse effects including teratogenicity. In this regard, the experience in HIV infection is extremely helpful.35

Table 2.  Drugs for the treatment of chronic hepatitis B categorized by fetal risks in pregnancy
Pregnancy category*Drugs
  • *

    US Food and Drug Administration Pharmaceutical Pregnancy Category.


Because humans are the only reservoir of HBV, if HBV can be eradicated, or strongly and effectively suppressed in the human HBsAg carriers, it will prevent spreading HBV to others, and thus will be an important step toward the elimination and eradication of hepatitis B.

Interrupt all routes of transmission

The transmission routes of HBV can be classified into horizontal and perinatal (“vertical”) modes (Fig. 2). HBV is highly infectious, because a very tiny amount of body fluids from an HBV carrier can contain a large number of viruses, and infect a susceptible person through mucocutaneous disruptions. Intimate contacts with a virus carrier such as household activities and sharing toys among children can cause the infection. Sexual transmissions are also well-documented. Use of condoms may help to prevent such transmissions. Ear or other body piercings, acupuncture, tattoo or any procedures that disrupt mucocutaneous barriers are all potentially dangerous. All the instruments that are used in these procedures should be adequately sterilized. Unsafe injections by using unsterilized or inadequately sterilized needles and syringes also result in the spread of HBV.36 This is most serious in illicit injection drug users. Whether a needle/syringe exchange program will reduce the risk of HBV infection among the injection drug users remains to be seen.37,38 Insect bites have also been suspected to spread HBV, but the evidence does not seem strong.

On the other hand, transfusion of blood or blood products is also an important route of transmission. Despite screening by sensitive serological assays, HBV transmission still occurs in a substantial proportion of susceptible recipients.39 Based on the results of a prospective study in Taiwan from 1987–1994, it was projected that approximately 200 cases of post-transfusion HBV infection could occur for every 1 million units of transfused blood in Taiwan where HBV infection is hyperendemic.39 Another study in 2001–2003 again confirmed the substantial rate of transmission of occult HBV by blood transfusion in Taiwan at a rate of 100/1 million units of transfused blood.40 And thus, a more sensitive assay such as the nucleic acid amplification test to detect occult HBV infection should be implemented to minimize the transmission through blood transfusion.41

As to perinatal transmission, the most effective means for prevention is immunization (vide infra). Nevertheless, whether modes of obstetric delivery are associated with HBV infection has been studied. A meta-analysis based on four randomized controlled clinical trials including a total of 789 HBsAg carrier mothers found perinatal HBV infection in infants delivered by elective cesarean section and vaginal delivery was 10.5% and 28.2%, respectively.42 However, other studies did not favor cesarean section in preventing maternal transmission of HBV.43,44 Elective cesarean section in HBsAg-carrier mothers is not recommended as long as the newborn infant receives appropriate hepatitis B immunoprophylaxis.45

Under immunoprophylaxis, breast-feeding also does not pose additional risk for HBV transmission from chronic HBV-carrier mothers.46

Immunize all susceptible persons

Because of the extreme effectiveness of hepatitis B vaccine in precluding HBV infection, universal vaccination against hepatitis B is regarded to be the key toward elimination and eradication of hepatitis B.5

Pre-exposure prophylaxis

Pre-exposure prophylaxis with hepatitis B vaccine has been most extensively studied in men who have sex with men and health-care workers. Randomized, double-blind, placebo-controlled clinical trials demonstrated a protective efficacy of 80–88% in male homosexuals as well as health-care workers (reviewed in 5). The efficacy in immunocompromised hosts, such as patients with end-stage renal disease, chronic liver disease, HIV infection or organ transplants, was inadequate. However, if these patients have been vaccinated against hepatitis B before, a booster before transplantation can yield good protection. This was documented by a recent study from Taiwan where a mass hepatitis B vaccination has been implemented since 1984.47 The study indicated that boosting the antibody to HBsAg (anti-HBs) in children who had received hepatitis B vaccination in infancy prevented HBV infection in most of the 60 children who received living donor liver transplantation. Those with anti-HBs levels of more than 1000 IU/L were all protected from HBV infection in this study.48

Post-exposure prophylaxis

In this setting, the most thoroughly population studied is infants born to HBeAg-positive HBsAg carrier mothers. Because HBeAg-positive mothers are highly infectious, the gap between exposure to maternal HBV and the newborn's own active production of anti-HBs induced by hepatitis B vaccine should be bridged as soon as possible with hepatitis B immune globulin (HBIG). The efficacy of protecting from chronic HBsAg carriage with passive-active immunoprophylaxis in these infants is more than 90%.5 In case HBIG is skipped, active immunization is still effective, but the effectiveness of protecting from chronic HBV infection decreases slightly to more than 83%.5

Because serum HBV DNA levels are more accurate than HBeAg in predicting maternal infectivity,9 to decide whether HBIG should be given to newborns of HBsAg carrier mothers, serum HBV DNA rather than HBeAg appears to be more logical. Nevertheless, further studies are needed to provide more evidence on this issue.49 In addition, HBV DNA assays are expensive, and cost consideration is also a practical concern. The other means to increase the effectiveness of immunization against perinatal mother-to-infant HBV infection is to give HBIG to newborns of all HBsAg carrier mothers, as is done in the USA.5 Again, the cost should be considered.

Mass vaccination against HBV infection

In implementing hepatitis B immunization, it was soon found that targeting populations at risk of hepatitis B was not easy.50 On the other hand, universal hepatitis B vaccination in newborns has been shown to be easier, practical and cost-effective, especially when hepatitis B vaccine was incorporated into the routine Expanded Program on Immunization.5 By the end of 2007, according to World Health Organization (WHO), global coverage of completing three doses of hepatitis B vaccine was estimated at 65%, and was 88% in the Americas. The African Region was 69% and the lowest was 30% in the South-East Asia Region (, accessed 7 September 2009).

Because of the very high HBsAg carriage in the general population in Taiwan and the extremely heavy disease burden caused by HBV, a national hepatitis B control program was implemented in the early 1980s. Among all the measures of hepatitis B control, the most effective is a mass immunization program which was launched in 1984,47 one of the earliest in the world. The program has been extremely successful, and has generated very important information for further control of hepatitis B.5 The coverage rate of hepatitis B vaccine in newborns was more than 97% country-wide, and HBsAg carriage decreased drastically after implementation of the universal hepatitis B vaccination in infants.5 This pioneering experience was confirmed in many other parts of the world in being effective in decreasing chronic HBV infection of 64–100% as shown in Table 3. In some less endemic areas, such as Singapore or Alaska, the post-vaccination HBsAg carrier rate even reached zero, harbingering the elimination and eventual eradication of HBV in these populations (Table 3).5

Table 3.  Effectiveness of protecting from hepatitis B surface antigen (HBsAg) carriage after hepatitis B immunization5
CountryHBsAg (%)Efficacy (%)
China, rural14.61.490.4
China (Shanghai)110.6394.3
Egypt (Alexandria)
Indonesia (Lombok)6.21.461.1
Italy (Afragola)13.40.993.3
Japan (Iwate)0.90.0396.7
Saudi Arabia6.70.395.5
South Africa12.83.076.6
Taiwan (Taipei)100.793.0
USA (Alaska)160100

After universal hepatitis B vaccination in infants, diseases caused by acute HBV infection decreased remarkably, as has been documented clearly in Taiwan, Italy and Singapore.5 In line with the decrease of HBsAg carriage in the population, diseases associated with chronic HBV infection also decreased. Most excitingly, 10 years after the hepatitis B mass vaccination, a decrease of HCC was found in Taiwanese child vaccinees.51 Recently, the decrease of HCC was found to have extended to young adults 20 years after the mass vaccination.52 A similar trend in the decrease of HCC after hepatitis B vaccination has also been reported in Singapore, China, Saudi Arabia,5 and more recently in Khon Kaen, Thailand.53

Challenges that need to be solved to expand hepatitis B mass vaccination

Although the hepatitis B vaccine has been available since 1982, and at least 1 billion people have received the vaccine, there are still many people who are not immunized. According to WHO, in 2007, 35% of infants worldwide had not received a complete course of hepatitis B vaccine. The coverage rate was especially low in the South-east Asia Region. The causes of failing to offer mass hepatitis B vaccination in each country are complex. Briefly, the infrastructure of public health delivery system needs to be improved and education should be strengthened for the general public, medical personnel as well as influence general opinion and political leaders (reviewed in 5). Economic burdens of hepatitis B immunization are always a major obstacle. Constant endeavors from government and the WHO are absolutely needed, and continued efforts from non-government organizations are also essential. Those from the Global Alliance on Vaccines and Immunization (GAVI) are most remarkable. As of January 2009, 67 of 69 eligible developing countries were approved for the support for hepatitis B vaccine by GAVI (, accessed 10 September 2009). Millions of children have received hepatitis B vaccine with the help of GAVI since 2000. It has been estimated that 2.5 million deaths will be averted through the GAVI vaccination project against HBV infection.

Future perspectives

  1. Top of page
  2. Abstract
  3. Introduction
  4. Natural history of chronic HBV infection
  5. Strategies for elimination or eradication of hepatitis B
  6. Future perspectives
  7. References

Because HBV infects humans almost exclusively, and there are rare or no animal reservoirs, the combined efforts of effective treatment of HBV carriers, total interruption of transmission routes and universal hepatitis B vaccination make elimination of HBV infection possible, and eventually the efforts will very likely result in the eradication of HBV. To reach this goal, all the efforts need to be implemented and continued. A long-term commitment from each government, the WHO or non-government organizations is essential. Support should sustain and cover the existing backlog of HBV carriers in the population. To eradicate HBV is plausible, but every endeavor has to be pursued to make it become a reality. Even if the goal cannot be reached, all these efforts will result in a marked decrease of HBV infection, that will lead to the decrease of disease burdens caused by its infection.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Natural history of chronic HBV infection
  5. Strategies for elimination or eradication of hepatitis B
  6. Future perspectives
  7. References