Chronic hepatitis B virus (HBV) infection is a major global health problem whose greatest impact is in the Asia-Pacific region. Much progress has been made in the understanding and management of this disease in the past decade. The introduction of universal vaccination in the late 80s to early 90s has significantly changed the prevalence of HBV infection in children and young adults. With the availability of sensitive HBV DNA assays and studies based on long-term longitudinal databases, the natural history of chronic HBV infection has become much better understood. The advances in antiviral therapy have also greatly improved the prognosis of this dreadful condition. Nonetheless, many challenges still remain. This review article summarizes the recent progress in the epidemiology, understanding of the natural history and the challenges of management of chronic hepatitis B in the Asia-Pacific region.
Chronic hepatitis B virus (HBV) infection is a major health problem in the Asia-Pacific region. In the past decade, much progress has been made in the understanding and management of this disease. The introduction of universal vaccination has significantly reduced the incidence of perinatal infection in most Asia-Pacific countries. As the majority of the adult population have not been immunized at birth, we are still facing a large population of young HBV-infected patients in the coming two decades. The study of long-term longitudinal databases has provided deeper insight into the clinical significance of HBV DNA suppression, hepatitis B e antigen (HBeAg) seroconversion and hepatitis B surface antigen (HBsAg) seroclearance in chronic hepatitis B. With a better understanding on the natural history of HBV infection, one can now stratify the risk of chronic hepatitis B patients for adverse clinical outcomes and use this to individualize management. The introduction of non-invasive assessment of liver fibrosis can potentially reduce the necessity of liver biopsy. There have also been great advances in the development of antiviral therapy in the past decade. However, the high cost of HBV antiviral drugs poses major challenges to health authorities in many Asia-Pacific countries. Properly performed cost-effective analysis and understanding on the best timing of stopping antiviral drugs will be important to facilitate the most appropriate allocation of resources.
Epidimology of chronic hepatitis B
Importance of HBV infection
It is estimated that at least 2 billion people or one third of the world population have been exposed to HBV infection. Approximately 400 million people worldwide or about 6% of the world population are chronically infected with HBV.1,2 Globally, 57% of cirrhosis is caused by either HBV (30%) or hepatitis C virus (HCV) (27%), and 78% of hepatocellular carcinoma (HCC) is caused by HBV (53%) or HCV (25%) infection.3 Each year, an estimated 500 000 people die of HBV-related cirrhosis and HCC. In China, the Nationwide Disease Surveillance and Monitoring System has reported HCC-related mortality to be 15 per 100 000 in 1991 and 21 per 100 000 in 2000; HCC mortality was higher in the rural population than that in the urban population, and higher in men than women.
Chronic HBV infection in the Asia-Pacific region
The prevalence of HBV infection is highly endemic throughout the world, with much higher prevalence in Asia and the Pacific Islands, sub-Saharan Africa, the Amazon Basin, and Eastern Europe.4 About three quarters of chronic HBV carriers live in the Asia-Pacific region and 15% to 25% of them will eventually die of HBV-related liver disease.5 Although less than one third of the global population inhabits the Western Pacific region, defined by World Health Organization as 37 countries including China, Japan, South Korea, Philippines and Vietnam, it accounts for nearly 50% of all chronic HBV infection worldwide.6 The seroprevalence of HBsAg is generally lower in women than in men. Before the introduction of the HBV vaccine, the male-to-female ratio was 1.4:1 in mainland China, 1.3:1 in Thailand and 1.1:1 in Hong Kong.7
Among Asian countries, the prevalence of chronic HBV infection also varies greatly. High-prevalence (≥8%) regions include mainland China, Taiwan, Korea, Philippines, Thailand, Vietnam, and South Pacific island nations. In China, nationwide survey in 1992 showed that the prevalence of hepatitis B surface antigen (HBsAg) was 9.75%, while the HBV infection rate in the general population was nearly 60%.8 Intermediate-prevalence (2%–7%) regions include central Asia, the Indian subcontinent, Indonesia, Malaysia and Singapore. Australia and New Zealand belong to the low-prevalence (< 2%) countries, but the prevalence has increased in recent years due to immigrants from high-prevalence countries.9
Impact of HBV vaccination
In Asian regions with high HBV endemicity, most HBV infection occurs within the first five years of life.10 In China, the prevalence of HBsAg in un-vaccinated children at the age of one already reached that of the general population, implying that chronic HBV infection starts in early life in most patients.8 Therefore, vaccination against HBV infection in early life, especially during infancy, is of paramount importance for prevention of chronic HBV infection in adults. By the end of 2006, 168 countries had implemented an universal HBV immunization program for newborns, infants and/or adolescents.2
HBV vaccination has already changed the epidemiology of chronic hepatitis B in Asia. There were high rates of chronic HBV infection (7.8%–13%) in Cambodian blood donors before the introduction of HBV vaccination (World Health Organization 2002, unpublished data).11,12 The seroprevalence among Cambodian immigrants (15–92 years of age) in Australia was 8% before the era of vaccination.13 A more recent study in Cambodia to evaluate the impact of hepatitis B vaccination programs showed HBsAg seroprevalence of 3.5% among five-year-old children.14 In Malaysia, the HBsAg seroprevalence in 7–12-year-old children decreased from 1.6% in 1997 to 0.3% in 2003 after the implementation of a universal infant vaccination program in 1990.15 Recent data in Hawaii show a reduction of 97% in the prevalence of HBsAg since the start of infant hepatitis B vaccination program in 1991. The incidence of acute HBV infections in children and adults was reduced from 4.5/100 000 in 1990 to zero in the period between 2002 and 2004 in Hawaii.16 In Taiwan, where universal vaccination of newborn was started in 1983–1985, the HBsAg prevalence in children younger than 15 years of age decreased from 9.8% in 1984 to 0.7% in 1999, and further to 0.5% in 2004.17
Mainland China is perhaps an excellent example where a lengthy process is required before the universal infant immunization program can be implemented. The Ministry of Health in China has recommended a 3-dose active HBV immunization to all infants since 1992, but families had to pay for such vaccination. In 2002, the Chinese government fully integrated HBV vaccine into the routine immunization program (Expanded Programme on Immunization, EPI), in which free HBV vaccine was provided to all infants, but the families still had to pay for the service of the vaccination procedure. In 2005, the central government issued the “Regulation on Vaccine Circulation and Immunization Management”, which finally waived all vaccination-associated charges. Eventually, infants born after June 2005 were offered completely free HBV vaccination. With the efforts of the government and free vaccination implemented, HBV vaccine coverage rate in children increased gradually from about 30% in 1992 to 90% in 2005.18 Because of the uneven economic development across different regions, immunization coverage still remained relatively low in rural areas and in the western part of China. However, by the end of 2005, the coverage of HBV vaccination was believed to be 90%, 80%, and 70% in urban, rural and remote areas, respectively. In 2006, a national survey of HBV seroepidemiology already showed a decrease in general prevalence of HBsAg from 9.75% in 1992 to 7.18% in 2006, and a decrease in the prevalence of HBsAg in children ≤ 5 years old from 9.67% in 1992 to 0.96% in 2006.19
Natural history of chronic hepatitis B
Phases of HBV infection in Asian patients
Perinatally acquired chronic hepatitis B is traditionally classified into three phases.20 The immune tolerance phase marks the initial two to three decades when hepatitis B e antigen (HBeAg) is positive, HBV DNA is very high, alanine aminotransferase (ALT) is normal, and histologic injury is minimal. It is followed by the immune clearance phase when host immune clearance leads to a reduction in HBV DNA and elevation of ALT. Patients who have prolonged, unsuccessful immune clearance will have progressive liver fibrosis, which eventually develops into liver cirrhosis. Successful immune clearance will lead to the third, low replicative phase, which is characterized by HBeAg seroconversion with positive anti-HBe antibodies, suppression of HBV DNA and normalization of ALT. Patients in the low replicative phase are believed to have good prognosis. There is increasing evidence that a fourth phase, the immune escape phase, is also common in Asian patients in association with evolution of HBeAg negative mutant forms of HBV.21 These patients have elevated HBV DNA with intermittent elevated ALT levels. Similar to the reports in Europe, HBeAg-negative patients with persistent viremia and biochemical activity have a higher risk of cirrhotic complications and HCC.22
Importance of HBeAg seroconversion
The presence of viral mutations and immune escape has cast doubt on the importance of HBeAg seroconversion. Previous reports suggested that approximately one-third of patients would develop HBeAg reversion or disease reactivation within 6 months after HBeAg seroconversion.23,24 HBV DNA usually falls to below 20 000 IU/mL after HBeAg seroconversion, but no clear HBV DNA level can predict viral reactivation.25,26 With long-term follow-up studies, we now learn that the long-term prognosis is better if the age of HBeAg seroconversion is younger. In a long-term follow-up of 64 untreated Caucasian pediatric chronic hepatitis B patients who cleared HBeAg without liver cirrhosis, 59 (92%) of them had stable disease.27 Among 408 Taiwanese patients who had no evidence of cirrhosis at the time of HBeAg seroconversion, the 15-year cumulative incidences of HBeAg-negative hepatitis, cirrhosis and HCC among patients who seroconverted at age younger than 30 versus those seroconverted after age 40 were 31.2% vs 66.7% (P < 0.001), 3.7% vs 42.9% (P < 0.001) and 2.1% vs 7.7% (P = 0.29), respectively.28
The age of HBeAg seroconversion is influenced by the HBV genotype. Patients infected with HBV genotype A, B, D and F tend to undergo HBeAg seronconversion at a much earlier age than those infected with genotype C HBV.29 Furthermore, patients infected with genotype C HBV also tend to have more frequent hepatitis B reactivation after HBeAg seroconversion than those infected with genotype B HBV.30 All these findings have provided supportive evidence on the higher rate of HBeAg-negative active hepatitis,31 worse liver histology32,33 and higher risk of HCC34,35 among patients infected with genotype C HBV.
Importance of HBV DNA Level
In the last decade, HBV DNA could only be measured by the relatively insensitive non-polymerase chain reaction (PCR) based assays with a lower limit of detection at approximately 20 000 IU/mL.36 The lack of sensitivity of the HBV DNA assays precluded accurate assessment of the viral load among HBeAg-negative patients who tend to have lower viremia than their HBeAg-positive counterparts.37 The development of real-time PCR based assays has brought the sensitivity of HBV DNA measurement down to lower than 20 IU/mL (or 100 copies/mL). In several recent histologic series, HBV DNA lower than 2000 IU/mL were associated with mild histologic necroinflammation and fibrosis among HBeAg-negative patients.38–40 One of the most important studies in the recent decade is The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer in HBV (the REVEAL-HBV) study from Taiwan, in which over 3500 chronic hepatitis B patients, predominantly at the age of 40 or above with negative HBeAg and normal ALT levels, were followed up for over 10 years. An HBV DNA over 2000 IU/mL at the initial visit could predict an increased risk of HCC and liver cirrhosis on subsequent follow-up, and the risks were particularly high if the HBV DNA level was persistently high till the last follow-up visit.41,42 This finding was confirmed by two large longitudinal cohorts in Hong Kong followed up for more than eight years.43 The annual incidence of HCC and liver-related death among inactive carriers (HBV DNA < 2000 IU/mL, normal ALT and absence of liver cirrhosis) was approximately 0.06% and 0.04% in the REVEAL-HBV study, respectively.44 Therefore, most regional guidelines have recommended observation for HBeAg-negative patients if their HBV DNA is below 2000 IU/mL.45–47
Importance of HBsAg clearance
Clearance of HBsAg has long been taken as the hallmark of ultimate viral clearance. In a Taiwanese cohort including 1965 HBeAg-negative adult patients, the chance of spontaneous HBsAg clearance tend to increase with age with an annual rate of 0.77% among patients younger than 30 years old to 1.83% among patients older than 50 years old.48 In studies in Taiwan, Hong Kong and Alaska, low level HBV DNA can be detected in the serum in approximately 5% to 18% of patients with spontaneous HBsAg clearance.49–51 On the other hand, all patients who cleared HBsAg with liver biopsy available still had detectable intrahepatic HBV DNA.51,52 Overall, the prognosis of patients with HBsAg clearance is excellent among patients without liver cirrhosis. However, cirrhotic complications and HCC can still develop after HBsAg clearance, particularly among patients who clear the HBsAg at an older age with pre-existing liver cirrhosis.49,51,52 Therefore, in Asian countries, occult HBV infection (HBeAg negative but anti-HBC positive and HBV DNA present in liver) should be carefully investigated as a possible etiology of liver cirrhosis and HCC, particularly when antiviral prophylaxis for liver transplantation is considered.53
Management of chronic hepatitis B patients
Patient selection for treatment
The improvement in the knowledge of natural history and the advances in antiviral therapies have great impact on the selection of patient for treatment. As cirrhotic patients have the highest risk of HCC and other liver-related complications, there has been little controversy to commence antiviral therapy as far as viral replication can be documented. In the 2003 European and Asian-Pacific consensus statements, ALT > 2 times the upper limit of laboratory normal was taken as the indicator of significant hepatitis among non-cirrhotic patients who may warrant antiviral therapy.54,55 Recent data have increasingly recognized that patients with normal or mildly elevated serum ALT are not guaranteed to be free from liver damage and liver-related mortality.56 In fact patients who have persistent active HBV viremia can have progressive liver damage despite normal or mildly elevated ALT levels, regardless of the HBeAg status.40,57–59 As a result, in the recent updated regional guidelines, liver biopsy is recommended among patients with normal or mild elevated (< 2 time upper limit of normal) ALT levels if they are older than 40 years old with elevated HBV DNA levels.45–47 Antiviral therapy should be commenced if significant hepatic necroinflammation and/or fibrosis are detected on liver biopsy regardless of the ALT levels. These recommendations have emphasized the importance of accurate histologic assessment and broadened the scope of patients who need to be treated with antiviral therapy.
Assessment of liver fibrosis
Liver biopsy has been the gold standard of liver fibrosis assessment. The invasiveness of the procedure and the potential sampling error have posed some limitation to this procedure. In liver biopsy examination, only 1/50 000 of the organ is analyzed. An adequate liver biopsy sample size is important for accurate assessment of liver fibrosis and decisions regarding anti-viral treatment.60 A biopsy length of 15 mm and 25 mm may only have 65% and 75% accuracy, respectively, to determine the true stage of histologic fibrosis.61 Numerous methods for non-invasive assessment of liver fibrosis have been investigated in the past decade. A few serum indices have been derived from cohorts of chronic hepatitis B patients in whom liver biopsy was also performed, but validation by other investigators is awaited before they can be recommended for clinical use.62–64 These serum indices are composed of markers of fibrogenesis and/or fibrolysis but do not measure the severity of liver fibrosis directly.
Transient elastography (Fibroscan, Echosens, Paris) is a rapid, non-invasive and reproducible method which uses shear wave technology to measure liver stiffness. A higher liver stiffness reflects more severe liver fibrosis. The use of transient elastography has been extensively validated by numerous investigators in chronic hepatitis B.65 It is most accurate to exclude or confirm the presence of advanced fibrosis (METAVIR stage F3-4). In general, the performance of transient elastography is superior to most serum indices with respect to its concordance with histologic staging.66,67 However, when serum ALT is elevated, transient elastography tends to over-estimate the severity of liver fibrosis and should be interpreted with caution.68–70 There is increasing interest to use non-invasive markers of liver fibrosis, including serum indices and transient elastrography, and to avoid liver biopsy in the selection of patients for antiviral therapy.46
Choice of antiviral therapy
Conventional interferon-alfa was the only available antiviral therapy for chronic hepatitis B between 1985 and 1996. Since the registration of lamivudine in 1997 and onwards, there has been an explosion in the development of antiviral treatments for chronic hepatitis B. Currently, interferon-alfa, peginterferon alfa-2a, lamivudine, adefovir dipivoxil, entecavir and telbivudine have been registered globally. Peginterferon alfa-2b is registered in some Asia-Pacific countries, including mainland China. Tenofovir has been registered in Australia as well as Europe and North America and registration in Asia-Pacific regions is ongoing. Clevudine is registered only in Korea and the Philippines, but not in other countries due to the risk of myopathy. In the American and European recommendations, entecavir and tenofovir are the preferred oral antiviral agents due to their potent antiviral effect and very low risk of drug resistance.46,47 However, in the Asia-Pacific consensus statement, no clear recommendation has been made on the choice of antiviral agents.45 The major reason is the vast difference in the economic situation and medical reimbursement arrangements between different Asia-Pacific countries. In fact, the estimated annual cost of antiviral drugs, if accepted across the affected population, might exceed the gross national income per capita in countries such as India, Indonesia, the Philippines and Papua New Guinea.5 In economic deprived countries, lamivudine may be the only reimbursable antiviral agent due to its low cost.71 In Taiwan, Indonesia and Korea, antiviral drugs are only reimbursed for a limited duration of time.71 In Hong Kong, although entecavir can be reimbursed indefinitely, the indication for reimbursement is very restricted and most patients need to pay for their antiviral treatment.72 Detailed cost-effective analysis is therefore warranted to guide usage policies for HBV antiviral drugs in the Asia-Pacific region. One possibility is the roadmap-approach, in which an inexpensive antiviral drug is started as the first-line treatment and the drug regime is modified according to the on-treatment HBV DNA response.73,74 However, the emergence of lamivudine- or Adefovir-resistant mutant forms of HBV, which rapidly develop entecavir (but not tenofovir) resistance would be a concern with this approach.
Duration of antiviral therapy
Most pivotal clinical trials on antiviral drugs are based on their efficacy at 1–2 years.47 However, relapse of hepatitis is common (> 70% cases) after premature drug cessation. Some authorities recommend long-term extended treatment by antiviral drugs. In the Asia-Pacific consensus, it was recommended to stop the antiviral drug when HBeAg seroconversion has developed for more than 6 months among HBeAg-positive patients.45 However, HBeAg seroconversion induced by antiviral drugs is not as sustained as that induced by interferon therapy.75 In two small case series' in Hong Kong and Taiwan, 27% to 45% of HBeAg-positive patients had HBV DNA relapse after cessation of lamivudine despite maintenance lamivudine post-HBeAg seroconversion according to the regional recommendation.76,77 In a Korean study including 178 patients with lamivudine stopped after HBeAg seroconversion, patients aged less than 40 years and had lamivudine stopped more than 12 months after the onset of HBeAg seroconversion had a higher chance of sustained remission.78 For HBeAg-negative patients, the Asian-Pacific consensus recommended stopping antiviral treatment when HBV DNA remained undetectable for three separate occasions, 6 months apart. In a double-blinded, placebo-control trial of lamivudine in HBeAg-negative patients in Hong Kong and China, more than 50% of patients on lamivudine with virological response at end of treatment had viral relapse 6-months after cessation of lamivudine.79 In a Greek cohort of 33 patients who achieved undetectable HBV DNA with adefovir treatment for 4–5 years, 46% of them had HBV DNA relapse to > 2000 IU/mL after adefovir was stopped for 5 years.80 HBsAg seroclearance is a better endpoint to stop antiviral therapy, but the chance of HBsAg seroclearance is generally lower than 5% in 5 years.81,82 Therefore, patients should be carefully monitored after stopping antiviral drugs, even if the Asia-Pacific consensus is closely observed. Challenges remain in the future definition of criteria for treatment cessation and best treatment endpoints.83
With the universal vaccination programs for HBV across the Asia-Pacific, one can anticipate that the prevalence of HBV infection is going to decline in the foreseeable future. Although some trends are already evident it may take 1–2 decades before the incidence of HCC shows an obvious decline. As the majority of the adult population has not been immunized at birth, we are still facing a large population of HBV-infected adults. With a better understanding on the natural history of HBV infection, one can now stratify the disease risks of chronic hepatitis B so as to individualize patient management. The introduction of non-invasive assessment of liver fibrosis can potentially reduce the necessity of liver biopsy, which is not widely acceptable by patients in this region. Owing to the economic conditions of most countries, the high cost of antiviral drugs is now a major challenge to health authorities. In order to increase the coverage of antiviral therapy to those patients who need it most, a lower drug cost seems inevitable in many part of the Asia-Pacific. Drug cost is also a key limitation to the use of the newer, yet more expensive, antiviral agents that have greater antiviral efficiency, are also active against lamivudine resistant HBV, and carry lower risk of drug resistance. A better understanding on the best timing to stop antiviral drugs will also be important to reduce the overall drug expenditure and improve patient compliance.