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Antiviral therapy of chronic hepatitis B: Opportunities and challenges in Asia

Open AccessPublished:April 17, 2009DOI:https://doi.org/10.1016/j.jhep.2009.04.003
      Asia comprises more than 40 countries encompassing a wide geographic area with a very large population. Many of these countries have low-income economies together with high endemicity of chronic hepatitis B virus (HBV) infection, which is usually acquired perinatally or during early childhood. The well elucidated natural history of chronic HBV infection, together with the extensive research and the longest experience in the use of therapeutic agents in Asia have provided a great opportunity for Asian patients to benefit from recent advancements. However, treatment of chronic HBV infection is a complex task that requires individualized assessment, thus representing a great challenge for general physicians. The inherent problems of the drugs currently available, together with a lack of awareness of the disease among patients, government, and healthcare practitioners are obstacles to proper management of HBV. The most critical challenge and obstacle is the high cost of medical care and antiviral drugs. Lack of adequate reimbursement for treatment and diagnostic testing makes adherence to treatment guidelines impossible. Hence lamivudine is still widely used in Asia. To address these challenges, the ongoing awareness campaigns, active screening programs, educational activities are needed but must be enhanced. Cost-cutting measures and international support are essential to improve the difficult situation in this part of the world.

      Keywords

      Abbreviations:

      ALT (alanine aminotransferase), HBV (hepatitis B virus), HBeAg (hepatitis B e antigen), HCC (hepatocellular carcinoma), GNI (gross national income), NA (nucleos(t)ide analog), IFN (interferon)

      1. Introduction

      Chronic infection with hepatitis B virus (HBV) is a global public health problem because of its worldwide distribution and potential adverse sequelae. An estimated 350 million people around the world are chronically infected with HBV. About 75% of them reside in the Asia-Pacific region, where chronic HBV infection is usually acquired perinatally or in early childhood [
      • Liaw Y.F.
      • Chu C.M.
      Hepatitis B virus infection.
      ,
      • Lavanchy D.
      Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures.
      ]. Those chronically infected individuals are at increased risk of developing hepatic decompensation, cirrhosis and hepatocellular carcinoma (HCC), and 15–25% will eventually die of HBV-related liver disease. Obviously, timely management of chronic HBV infection is of paramount importance. During the past decades, substantial improvement in the understanding of HBV virology, host immune response and natural course, combined with the recent availability of highly sensitive HBV DNA assays and the advent of effective antiviral drugs with different mechanisms of action, have led to better therapeutic strategies for chronic HBV infection. Given their high endemicity of HBV infection, Asian countries have the greatest opportunity to benefit from such advancements. However, Asian countries differ greatly from each other. There are challenges ahead.

      2. Geography, economics and epidemiology of chronic HBV infection in Asia

      Asia consists of more than 40 countries stretching from Japan westwards to Turkey, with a very large population. Unfortunately, the majority of countries in Asia have low-income economies (Table 1) and are at high endemicity of HBV infection (Fig. 1). The 2007 gross national income (GNI) per capita varied greatly from country to country in Asia, being >30,000 USD in Japan, Australia and Singapore, 15,000–30,000 USD in New Zealand, South Korea and Taiwan, but <905 USD (low-income) or 906–3595 USD (lower–middle-income) in many countries [

      The World Bank. GNI 2007 Atlas Method. World development indicators database 2008 September. Available from: http://www.worldbank.org/.

      ]. Conceivably, the infrastructure of the healthcare system is not satisfactory in many lower-income countries [
      • Mohamed R.
      • Desmond P.
      • Suh D.J.
      • Amarapurkar D.
      • Gane E.
      • Guangbi Y.
      • et al.
      Practical difficulties in the management of hepatitis B in the Asia-Pacific region.
      ,
      • Lesmana L.A.
      • Leung N.W.Y.
      • Mahachai V.
      • Phiet P.H.
      • Suh D.J.
      • Yao G.B.
      • et al.
      Hepatitis B: overview of the burden of disease in the Asia-Pacific region.
      ]. The prevalence of chronic HBV infection also varies among Asian countries. High-prevalence (⩾8%) countries include China, Korea, Philippines, Taiwan, Thailand, Vietnam, and South Pacific island nations. Intermediate-prevalence (2–7%) regions include central Asia, Indian continent, Indonesia, Malaysia and Singapore. Australia and New Zealand are low-prevalence (<2%) countries but immigrants from high-prevalence Asian countries in recent years have increased the burden there. [
      • Weinbaum C.M.
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      • Wasley A.
      • et al.
      Centers for Disease Control and Prevention (CDC). Recommendations for identification and public health management of persons with chronic hepatitis B virus infection.
      ]. HBV genotype distribution also varies. Of the eight genotypes (A–H) that have been identified, genotypes B and C are the major genotypes in most East and Southeast Asian countries. Genotype B is most prevalent in Taiwan, genotype C is most prevalent in Korea, Japan and China, and genotype D is most prevalent in India, central Asia, and Mongolia [
      • Ryan J.
      • Tran T.T.
      Epidemiology and natural history of hepatitis B in Vietnam.
      ,
      • Yurdaydin C.
      • Bozdayi A.M.
      • Idilman R.
      • Bozkaya H.
      HBV prevalence, natural history, and treatment in Eastern Europe, Turkey, and Turkish-Speaking Countries in Central Asia.
      ,
      • Pan C.
      • Jia J.
      • Chu C.J.
      • Hou J.
      • Hu K.Q.
      Epidemiology, presentation, and treatment of chronic HBV infection in Mainland China, in Taiwan, and in Chinese Americans in the United States.
      ,
      • Han K.H.
      • Park J.Y.
      • Min A.D.
      HBV prevalence, natural history, and treatment in Korea and the United States.
      ,
      • Kao J.H.
      Role of viral factors in the natural course and therapy of chronic hepatitis B.
      ].
      Table 1Estimated annual cost of drugs and treatment in some Asian countries with different GNI/C.
      CountryCHB/compensated cirrhosis
      Abstracted from Ref. [66].
      Decompensated cirrhosis
      Data from Refs. [59,61,62,64,65].
      HCC
      Data from Refs. [59,61,62,64,65].
      2007 GNI/C
      Derived from Ref. [3].
      NAsPeg IFN
      Australia1618–677514,6277111705235,960
      Bangladesh183–36514,400NN470
      China704–19357968170247402360
      India76–1707NNN950
      Indonesia1935–239811,040NN1650
      Japan2097–4220NNN37,670
      Malaysia1044–208410,992NN6540
      Philippines2058–255513,713NN1620
      Singapore1570–273813,4408794703632,470
      South Korea1314–328596001419304419,690
      Taiwan1095–266557601173306617,930
      Thailand913–277416,464NN3400
      USA
      Data from Refs. [60,67].
      2482–8694
      Data from Refs. [60,67].
      18,480
      Data from Refs. [60,67].
      11,459
      Data from Refs. [60,67].
      7533
      Data from Refs. [60,67].
      46,040
      Europe
      Data expressed as median value of France, Italy, Spain and UK. Ref. [63].
      NN8935
      Data expressed as median value of France, Italy, Spain and UK. Ref. [63].
      9048
      Data expressed as median value of France, Italy, Spain and UK. Ref. [63].
      36,020
      ∗Data of cost in US dollars.
      CH-B, chronic hepatitis B; GNI/C, gross national income per capita

      The World Bank. GNI 2007 Atlas Method. World development indicators database 2008 September. Available from: http://www.worldbank.org/.

      ; HCC, hepatocellular carcinoma; N, data not available; NA, nucleos(t)ide analogs; peg IFN, pegylated interferon α2a.
      a Abstracted from Ref.
      • Dan Y.Y.
      • Aung M.O.
      • Lim S.G.
      The economics of treating chronic hepatitis B in Asia.
      .
      b Data from Refs.
      • Li S.C.
      • Ong S.C.
      • Lim S.G.
      • Yeoh K.G.
      • Kwong K.S.
      • Lee V.
      • et al.
      A cost comparison of management of chronic hepatitis B and its associated complications in Hong Kong and Singapore.
      ,
      • Hsieh C.R.
      • Kuo C.W.
      Cost of chronic hepatitis B virus infection in Taiwan.
      ,
      • Yang B.M.
      • Kim C.H.
      • Kim J.Y.
      Cost of chronic hepatitis B infection in South Korea.
      ,
      • Zhiqiang G.
      • Zhaohui D.
      • Qinhuan W.
      • Dexian C.
      • Yunyun F.
      • Hingtao Liu
      • et al.
      Cost of chronic hepatitis B infection in China.
      ,
      • Butler J.R.G.
      • Pianko S.
      • Korda R.J.
      • Nguyen S.
      • Gow P.J.
      • Roverts S.K.
      • et al.
      The direct cost of managing patients with chronic hepatitis B infection in Australia.
      .
      c Data from Refs.
      • Lee T.A.
      • Veenstra D.L.
      • Iloeje U.H.
      • Sullivan S.D.
      Cost of chronic hepatitis B infection in the United States.
      ,
      • Hoofnagle J.H.
      • Doo E.
      • Liang T.J.
      • Fleischer R.
      • Lok A.S.
      Management of hepatitis B: summary of a clinical research workshop.
      .
      d Data expressed as median value of France, Italy, Spain and UK. Ref.
      • Brown R.E.
      • De Cock E.
      • Colin X.
      • Antoñanzas F.
      • Iloeje U.H.
      Hepatitis B management costs in France, Italy, Spain, and the United Kingdom.
      .
      e Derived from Ref.

      The World Bank. GNI 2007 Atlas Method. World development indicators database 2008 September. Available from: http://www.worldbank.org/.

      .
      Figure thumbnail gr1
      Fig. 1Geographic distribution of chronic hepatitis B virus infection and its dominant genotype(s) in Asia. Adapted from CDC traveler’s health, yellow book, Atlanta GA 2008 [http:/wwwn.cdc.gov/travel/yellowbookch4-HepB.aspx] with modification. When two genotypes are common in a region, the genotype with larger character is the most dominant one.
      Although universal HBV vaccination in newborns has been implemented in Asian countries since 1984 [
      • Chen D.S.
      • Hsu N.H.
      • Sung J.L.
      • Hsu T.C.
      • Hsu S.T.
      • Kuo Y.T.
      • et al.
      A mass vaccination program in Taiwan against hepatitis B virus infection in infants of hepatitis B surface antigen-carrier mothers.
      ], there are still large numbers of chronically infected individuals with HBV in Asia. Taiwan is perhaps the best example in that the HBsAg prevalence in children aged <15 decreased from 9.8% in 1984 to 0.7% in 1999 and 0.5% in 2004, 20 years after implementation of universal HBV vaccination with a coverage of 97% [
      • Ni Y.H.
      • Huang L.M.
      • Chang M.H.
      • Yen C.J.
      • Lu C.Y.
      • You S.L.
      • et al.
      Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies.
      ]. However, a survey in 157,720 adults aged ⩾18 in Taiwan between 1996 and 2005 showed that the overall prevalence of HBsAg was 17.3% [
      • Chen C.H.
      • Yang P.M.
      • Huang G.T.
      • Lee H.S.
      • Sung J.L.
      • Sheu J.C.
      Estimation of seroprevalence of hepatitis B virus and hepatitis C virus in Taiwan from a large-scale survey of free hepatitis screening participants.
      ], not much less than the prevalence in studies conducted before 1984 [
      • Chen D.S.
      • Hsu N.H.
      • Sung J.L.
      • Hsu T.C.
      • Hsu S.T.
      • Kuo Y.T.
      • et al.
      A mass vaccination program in Taiwan against hepatitis B virus infection in infants of hepatitis B surface antigen-carrier mothers.
      ].

      3. Natural course of chronic HBV infection in Asia

      The natural history of chronic HBV infection acquired perinatally or in early childhood has been well elucidated during the past decades. Asian patients with chronic HBV infection typically have a long immune tolerant phase whereas this phase is not apparent or very short in patients in Western countries or those who acquired HBV infection during adulthood [
      • Chu C.M.
      • Liaw Y.F.
      Natural history differences in perinatally versus adult-acquired disease.
      ]. During the immune tolerant phase, the patients are hepatitis B e antigen (HBeAg) seropositive with high viral loads (>2 × 106–7 IU/ml or >107–8 copies/ml), normal serum aminotransferase (ALT) and near normal liver histology [
      • Liaw Y.F.
      • Chu C.M.
      Hepatitis B virus infection.
      ,
      • Chu C.M.
      • Liaw Y.F.
      Natural history differences in perinatally versus adult-acquired disease.
      ]. Patients who enter the immune clearance phase usually have intermittent or continuing hepatitis activity or episodic acute hepatitis flares, sometimes complicated with hepatic decompensation. These events may lead to disease progression but may also result in declining serum HBV–DNA level and eventually lead to spontaneous HBeAg seroconversion to its antibody (anti-HBe) at a rate of 2–15% per year [
      • Liaw Y.F.
      Hepatitis flares and hepatitis B e antigen seroconversion: implication in anti-hepatitis B virus therapy.
      ]. Following HBeAg seroconversion, the patients enter a remission or inactive phase with low serum HBV–DNA (<2000 IU/ml) and normal ALT [
      • Hsu Y.S.
      • Chien R.N.
      • Yeh C.T.
      • Sheen I.S.
      • Chiou H.Y.
      • Chu C.M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ,
      • Chu C.M.
      • Hung S.J.
      • Lin J.
      • Tai D.I.
      • Liaw Y.F.
      Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels.
      ]. Spontaneous HBsAg seroclearance may occur several years after HBeAg seroconversion at an annual rate of 0.5–2%, depending on age, HBV genotype and underlying disease state [
      • Liaw Y.F.
      • Sheen I.S.
      • Chen T.J.
      • Chu C.M.
      • Pao C.C.
      Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study.
      ,
      • Yuen M.F.
      • Wong D.K.
      • Sablon E.
      • Tse E.
      • Ng I.O.
      • Yuan H.J.
      • et al.
      HBsAg seroclearance in chronic hepatitis B in the Chinese: virological, histological, and clinical aspects.
      ,
      • Chu C.M.
      • Liaw Y.F.
      HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up.
      ,
      • Chen Y.C.
      • Chu C.M.
      • Yeh C.T.
      • Liaw Y.F.
      Natural course following the onset of cirrhosis in patients with chronic hepatitis B: a long-term follow-up study.
      ]. HBsAg seroclearance usually confers excellent prognosis but HCC may still occur at a very low rate and usually in those individuals in whom cirrhosis or superinfection with other virus(es) had already developed before HBsAg seroclearance [
      • Chen Y.C.
      • Sheen I.S.
      • Chu C.M.
      • Liaw Y.F.
      Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection.
      ].
      Active hepatitis may relapse due to reactivation of HBV with either HBeAg seroreversion (HBeAg-positive chronic hepatitis) or with precore or basal core prompter mutations that abolish or down-regulate the production of HBeAg (“HBeAg negative chronic hepatitis”) [
      • Hsu Y.S.
      • Chien R.N.
      • Yeh C.T.
      • Sheen I.S.
      • Chiou H.Y.
      • Chu C.M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ,
      • Chu C.M.
      • Hung S.J.
      • Lin J.
      • Tai D.I.
      • Liaw Y.F.
      Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels.
      ]. Similar to HBeAg-positive hepatitis, most patients with HBeAg-negative hepatitis are asymptomatic even if they develop an acute hepatitis flare [
      • Liaw Y.F.
      Hepatitis flares and hepatitis B e antigen seroconversion: implication in anti-hepatitis B virus therapy.
      ]. Therefore, most of them are detected either during a screening program or follow-up. The estimated annual incidence of hepatitis relapse following HBeAg seroconversion was 1.5–3.3% [
      • Hsu Y.S.
      • Chien R.N.
      • Yeh C.T.
      • Sheen I.S.
      • Chiou H.Y.
      • Chu C.M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ,
      • Chu C.M.
      • Hung S.J.
      • Lin J.
      • Tai D.I.
      • Liaw Y.F.
      Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels.
      ,
      • Chu C.M.
      • Liaw Y.F.
      Spontaneous relapse of hepatitis in inactive HBsAg carrier.
      ], being higher in males, genotypes C or D infected patients and those HBeAg seroconverted after age 40 [
      • Hsu Y.S.
      • Chien R.N.
      • Yeh C.T.
      • Sheen I.S.
      • Chiou H.Y.
      • Chu C.M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ,
      • Chu C.M.
      • Liaw Y.F.
      Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline.
      ,
      • Papatheodoridis G.V.
      • Chrysanthos N.
      • Hadziyannis E.
      • Cholongitas E.
      • Manesis E.K.
      Longitudinal changes in serum HBV DNA levels and predictors of progression during the natural course of HBeAg-negative chronic hepatitis B virus infection.
      ], and significantly much lower (0.9%/year) in patients <30 years of age [
      • Chu C.M.
      • Liaw Y.F.
      Spontaneous relapse of hepatitis in inactive HBsAg carrier.
      ].
      Patients in the immune tolerant phase or inactive phase have minimal or no disease progression as long as serum ALT remains normal [
      • Hui C.K.
      • Leung N.
      • Yuen S.T.
      • Zhang H.Y.
      • Leung K.W.
      • Lu L.
      • et al.
      Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase.
      ,

      Tai DI, Lin SM, Sheen IS, Chu CM, Lin DT, Liaw YF. Long-term outcome of hepatitis B e antigen-negative hepatitis B surface antigen carriers in relation to changes of alanine aminotransferase levels over time. Hepatology 2009. doi:10.1002/hep.22878.

      ]. The incidence of cirrhosis is almost zero (1 of 184) during the first 18 years of follow-up in those with sustained remission after HBeAg seroconversion [
      • Hsu Y.S.
      • Chien R.N.
      • Yeh C.T.
      • Sheen I.S.
      • Chiou H.Y.
      • Chu C.M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ]. In contrast, patients with hepatitis during the immune clearance phase (HBeAg-positive hepatitis) or reactivation phase (HBeAg-negative hepatitis) may lead to cirrhosis development at an incidence of 2–4% per year, being higher in males, patients with longer HBeAg-positive or active hepatitis phase, and those with severe or more extensive liver injuries [
      • Hsu Y.S.
      • Chien R.N.
      • Yeh C.T.
      • Sheen I.S.
      • Chiou H.Y.
      • Chu C.M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ,
      • Chu C.M.
      • Hung S.J.
      • Lin J.
      • Tai D.I.
      • Liaw Y.F.
      Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels.
      ,
      • Liaw Y.F.
      • Tai D.I.
      • Chu C.M.
      • Chen T.J.
      The development of cirrhosis in patients with chronic type B hepatitis: a prospective study.
      ,
      • Lin S.M.
      • Yu M.L.
      • Lee C.M.
      • Chien R.N.
      • Sheen I.S.
      • Chu C.M.
      • et al.
      Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma.
      ]. At the onset of cirrhosis about 50% of the patients are still seropositive for HBeAg and/or HBV–DNA thus further disease progression to hepatic decompensation, HCC or mortality may follow [
      • Chen Y.C.
      • Chu C.M.
      • Yeh C.T.
      • Liaw Y.F.
      Natural course following the onset of cirrhosis in patients with chronic hepatitis B: a long-term follow-up study.
      ]. HCC develops at an annual incidence of 3–6% in patients with cirrhosis and far less frequently in non-cirrhotic patients [
      • Chen Y.C.
      • Chu C.M.
      • Yeh C.T.
      • Liaw Y.F.
      Natural course following the onset of cirrhosis in patients with chronic hepatitis B: a long-term follow-up study.
      ,
      • Chu C.M.
      • Liaw Y.F.
      Hepatitis B virus-related cirrhosis: natural history and treatment.
      ]. It was calculated that Asian patients with chronic HBV infection have a lower proportion of HBeAg-negative hepatitis, lower incidence of cirrhosis but higher incidence of HCC than their European counterparts [
      • Fattovich G.
      • Bortolotti F.
      • Donato F.
      Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.
      ]. Large, community-based studies have confirmed that age, sex, HBeAg serostatus and ALT levels are factors for the development of liver cirrhosis and HCC. These studies further indicate that serum HBV–DNA level is associated with cirrhosis and HCC development at a dose-dependent manner starting from serum HBV–DNA level >2000 IU/ml [
      • Yang H.I.
      • Lu S.N.
      • Liaw Y.F.
      • You S.L.
      • Sun C.A.
      • Wang L.Y.
      • et al.
      Hepatitis B e antigen and the risk of hepatocellular carcinoma.
      ,
      • Iloeje U.H.
      • Yang H.I.
      • Su J.
      • Jen C.L.
      • You S.L.
      • Chen C.J.
      Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (the REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load.
      ,
      • Chen C.J.
      • Yang H.I.
      • Su J.
      • Jen C.L.
      • You S.L.
      • Lu S.N.
      • et al.
      Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.
      ].
      These findings suggest that HBV replication, with subsequent immune-mediated liver injuries, is the primary driving force for liver disease progression [
      • Liaw Y.F.
      Hepatitis B virus replication and liver disease progression: the impact of antiviral therapy.
      ]. Obviously, both cirrhotic and non-cirrhotic patients with HBV replication and active hepatitis require effective therapeutic intervention. In contrast, no drug therapy is required in patients during the immune tolerant phase or the inactive residual phase.

      4. Awareness campaigns and active screening program

      Most patients with chronic hepatitis B or compensated cirrhosis have few or no symptoms. Thus persons with chronic HBV infection largely remain undiagnosed. Detection of these asymptomatic carriers requires active screening programs, which have been carried out sporadically in Asian countries [
      • Mohamed R.
      • Desmond P.
      • Suh D.J.
      • Amarapurkar D.
      • Gane E.
      • Guangbi Y.
      • et al.
      Practical difficulties in the management of hepatitis B in the Asia-Pacific region.
      ]. However, a survey showed that the diagnostic rate of HBV was only 25% in USA, ∼18% in Europe and even lower (4%) in Asia except Japan (13%) [Decision Resources 2006]. Since the early 1980s, both the importance and the high prevalence of chronic HBV infection have been emphasized repeatedly through the mass media and other measures of public education [
      • Chen D.S.
      • Hsu N.H.
      • Sung J.L.
      • Hsu T.C.
      • Hsu S.T.
      • Kuo Y.T.
      • et al.
      A mass vaccination program in Taiwan against hepatitis B virus infection in infants of hepatitis B surface antigen-carrier mothers.
      ]. Screening at blood donation or upon entry to school, military service and new employment has become routine practice in Taiwan. Even so, a survey in 1025 adults aged >30 in Taiwan showed that only 52% knew about chronic HBV infection, 54% did not know about any effective therapeutic medicine for hepatitis B and only 8% reported that they were chronically infected with HBV [

      IMS Health Taiwan. Taiwan hepatitis B disease awareness and attitude in general population 2005. [File of Bristol-Myers Squibb].

      ]. Given the overall prevalence of 17.3% in Taiwan [
      • Chen C.H.
      • Yang P.M.
      • Huang G.T.
      • Lee H.S.
      • Sung J.L.
      • Sheu J.C.
      Estimation of seroprevalence of hepatitis B virus and hepatitis C virus in Taiwan from a large-scale survey of free hepatitis screening participants.
      ], it can be calculated that only 46% of the individuals with chronic HBV infection in Taiwan were aware that they were infected. In the highly developed USA, a survey in 3163 Asian American adults showed that only 35% of the chronically infected persons were aware that they were infected [
      • Lin S.Y.
      • Chang E.T.
      • So S.K.
      Why we should routinely screen Asian American adults for hepatitis B: a cross-sectional study of Asians in California.
      ]. Another survey in 6130 Korean-Americans showed an overall prevalence of 6.1% and, more importantly, detailed evaluation in 139 incidentally identified HBV carriers showed cirrhosis in 11%, chronic hepatitis in 42% and only 47% were inactive carriers [
      • Hann H.W.
      • Hann R.S.
      • Maddrey W.C.
      Hepatitis B virus infection in 6,130 unvaccinated Korean-Americans surveyed between 1988 and 1990.
      ]. These findings highlight the importance of active screening programs to identify unrecognized victims of chronic HBV infection for appropriate monitoring and timely interventions. So far, the awareness among the general population and HBsAg carriers is far from satisfactory.

      5. Antiviral therapy for chronic HBV infection: challenges in Asia

      Currently, conventional interferon α (IFN), pegylated interferon-α2a (Peg IFN), and four nucleoside or nucleotide analogs (NA) (lamivudine, adefovir, entecavir and telbivudine) have been approved widely in Asia, tenofovir in a few Asian countries, Clevudine in Korea only and thymosin α1 in countries including China, India, Korea, Malaysia, Singapore, Thailand and Vietnam [
      • Mohamed R.
      • Desmond P.
      • Suh D.J.
      • Amarapurkar D.
      • Gane E.
      • Guangbi Y.
      • et al.
      Practical difficulties in the management of hepatitis B in the Asia-Pacific region.
      ]. As shown in Table 2, Asian patients were the majority in almost all pivotal trials of anti-HBV agents [
      • Lai C.L.
      • Chien R.N.
      • Leung N.W.
      • Chang T.T.
      • Guan R.
      • Tai D.I.
      • et al.
      A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group.
      ,
      • Hadziyannis S.J.
      • Tassopoulos N.C.
      • Heathcote E.J.
      • Chang T.T.
      • Kitis G.
      • Rizzetto M.
      • et al.
      Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B.
      ,
      • Marcellin P.
      • Chang T.T.
      • Lim S.G.
      • Tong M.J.
      • Sievert W.
      • Shiffman M.L.
      • et al.
      Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.
      ,
      • Marcellin P.
      • Lau G.K.K.
      • Bonino F.
      • Farci P.
      • Hadziyannis S.
      • Jin R.
      • et al.
      Peginterferon alfa-2a alone, lamivudine alone and the two in combination in patients with HBeAg negative chronic hepatitis B.
      ,
      • Lau G.K.
      • Piratvisuth T.
      • Luo K.X.
      • Marcellin P.
      • Thongsawat S.
      • Cooksley G.
      • et al.
      Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.
      ,
      • Chang T.T.
      • Gish R.G.
      • de Man R.
      • Gadano A.
      • Sollano J.
      • Chao Y.C.
      • et al.
      A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.
      ,
      • Lai C.L.
      • Shouval D.
      • Lok A.S.
      • Chang T.T.
      • Cheinquer H.
      • Goodman Z.
      • et al.
      Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.
      ,
      • Sherman M.
      • Yurdaydin C.
      • Sollano J.
      • Silva M.
      • Liaw Y.F.
      • Cianciara J.
      • et al.
      Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B.
      ,
      • Lai C.L.
      • Gane E.
      • Liaw Y.F.
      • Hsu C.W.
      • Thongsawat S.
      • Wang Y.
      • et al.
      Telbivudine versus lamivudine in patients with chronic hepatitis B.
      ,
      • Marcellin P.
      • Heathcote E.J.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
      ]. Many important further studies and the longest experience in the use of these agents have also been gained in Asian patients [
      • Chien R.N.
      • Liaw Y.F.
      • Atkins M.
      for Asian Hepatitis Lamivudine Trial Group
      Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B.
      ,
      • Liaw Y.F.
      • Chien R.N.
      • Yeh C.T.
      • Tsai S.L.
      • Chu C.M.
      Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy.
      ,
      • Song B.C.
      • Suh D.J.
      • Lee H.C.
      • Chung Y.H.
      • Lee Y.S.
      Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea.
      ,
      • Chien R.N.
      • Lin C.H.
      • Liaw Y.F.
      The effect of lamivudine therapy in hepatic decompensation during acute exacerbation of chronic hepatitis B.
      ,
      • Liaw Y.F.
      • Sung J.J.Y.
      • Chow W.C.
      • Farrell G.
      • Lee C.Z.
      • Yuen H.
      • et al.
      Lamivudine for patients with chronic hepatitis B and advanced liver disease.
      ]. Studies from Asia have shown that IFN-based therapy may reduce fibrosis progression, decrease cirrhosis and HCC development [
      • Liaw Y.F.
      • Tai D.I.
      • Chu C.M.
      • Chen T.J.
      The development of cirrhosis in patients with chronic type B hepatitis: a prospective study.
      ], and NA therapy may rescue decompensation, reduce fibrosis progression, reverse cirrhosis and prevent further disease progression, including HCC [
      • Chien R.N.
      • Lin C.H.
      • Liaw Y.F.
      The effect of lamivudine therapy in hepatic decompensation during acute exacerbation of chronic hepatitis B.
      ,
      • Liaw Y.F.
      • Sung J.J.Y.
      • Chow W.C.
      • Farrell G.
      • Lee C.Z.
      • Yuen H.
      • et al.
      Lamivudine for patients with chronic hepatitis B and advanced liver disease.
      ,
      • Leung N.W.
      • Lai C.L.
      • Chang T.T.
      • Guan R.
      • Lee C.M.
      • Ng K.Y.
      • et al.
      Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy.
      ,
      • Liaw Y.F.
      • Chang T.T.
      • Wu S.S.
      • Schiff E.R.
      • Han K.H.
      • Lai C.L.
      • et al.
      Long-term entecavir therapy results in reversal of fibrosis/cirrhosis and continued histologic improvement in patients with HBeAg(+) and (−) chronic hepatitis B: results from studies ETV-022, -027 and -901.
      ]. This array of therapeutic drugs with their short-term/long-term efficacy has indeed provided a great opportunity for Asian patients to benefit from these advancements. Based on these and earlier studies on the natural history of chronic HBV infection, experts from the region were able to issue a consensus statement on the management of chronic hepatitis B as early as year 2000 [

      Consensus statements on the prevention and management of hepatitis B and hepatitis C in the Asia-Pacific region. Core Working Party for Asia-Pacific Consensus on Hepatitis B and C. J Gastroenterol Hepatol 2000;15:825–41.

      ], which has been updated periodically to its fourth version in 2008 [
      • Liaw Y.F.
      • Leung N.
      • Kao J.H.
      • Piratvisuth T.
      • Gane E.
      • Han K.H.
      • et al.
      Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update.
      ].
      Table 2Asian patients in pivotal trials of anti-HBV agents.
      Trial[Reference]PatientProportion of patients from Asia (%)
      HBeAg serostatusNumber
      LAM/placebo
      • Lai C.L.
      • Chien R.N.
      • Leung N.W.
      • Chang T.T.
      • Guan R.
      • Tai D.I.
      • et al.
      A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group.
      HBeAg-positive285/73100/100
      ADV/placebo
      • Marcellin P.
      • Chang T.T.
      • Lim S.G.
      • Tong M.J.
      • Sievert W.
      • Shiffman M.L.
      • et al.
      Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.
      HBeAg-positive171/16760/60
      • Hadziyannis S.J.
      • Tassopoulos N.C.
      • Heathcote E.J.
      • Chang T.T.
      • Kitis G.
      • Rizzetto M.
      • et al.
      Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B.
      HBeAg-negative123/6129/33
      ETV/LAM
      • Chang T.T.
      • Gish R.G.
      • de Man R.
      • Gadano A.
      • Sollano J.
      • Chao Y.C.
      • et al.
      A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.
      HBeAg-positive354/35558/57
      • Lai C.L.
      • Shouval D.
      • Lok A.S.
      • Chang T.T.
      • Cheinquer H.
      • Goodman Z.
      • et al.
      Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.
      HBeAg-negative325/31338/41
      • Sherman M.
      • Yurdaydin C.
      • Sollano J.
      • Silva M.
      • Liaw Y.F.
      • Cianciara J.
      • et al.
      Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B.
      LAM-refractory141/14525/25
      TBV/LAM
      • Lai C.L.
      • Gane E.
      • Liaw Y.F.
      • Hsu C.W.
      • Thongsawat S.
      • Wang Y.
      • et al.
      Telbivudine versus lamivudine in patients with chronic hepatitis B.
      HBeAg-positive458/46383/83
      • Lai C.L.
      • Gane E.
      • Liaw Y.F.
      • Hsu C.W.
      • Thongsawat S.
      • Wang Y.
      • et al.
      Telbivudine versus lamivudine in patients with chronic hepatitis B.
      HBeAg-negative222/22465/64
      TDF/ADV
      • Marcellin P.
      • Heathcote E.J.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
      HBeAg-positive176/9036/36
      • Marcellin P.
      • Heathcote E.J.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
      HBeAg-negative250/12525/24
      Peg/Peg + LAM/LAM
      • Lau G.K.
      • Piratvisuth T.
      • Luo K.X.
      • Marcellin P.
      • Thongsawat S.
      • Cooksley G.
      • et al.
      Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.
      HBeAg-positive271/271/27287/87/85
      • Marcellin P.
      • Lau G.K.K.
      • Bonino F.
      • Farci P.
      • Hadziyannis S.
      • Jin R.
      • et al.
      Peginterferon alfa-2a alone, lamivudine alone and the two in combination in patients with HBeAg negative chronic hepatitis B.
      HBeAg-negative177/179/18160/62/61
      HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; ADV, adefovir; ETV, entecavir; LAM, lamivudine; Peg-IFN, pegylated interferon α2a; TBV, telbivudine; TDF, tenofovir.
      However, currently available anti-HBV agents are far from satisfactory and treatment strategies are still evolving. Problems in drug therapy per se include low therapy-induced HBeAg seroconversion rate, frequent unpleasant side effects that require close monitoring during IFN-based therapy, HBV suppression not durable after short-term NA therapy, and drug resistance increases upon prolonged NA therapy. These inherent problems have made treatment of chronic HBV infection a complex task that requires individualized assessment and decision, therefore representing a great challenge to general physicians. A more important and most critical challenge is the high cost of medical care and antiviral drugs. Cost analyses have shown that progression of liver disease is associated with increasing healthcare costs, and suggest that measures to prevent progression from chronic hepatitis B to cirrhosis and its complications would be financially beneficial [
      • Li S.C.
      • Ong S.C.
      • Lim S.G.
      • Yeoh K.G.
      • Kwong K.S.
      • Lee V.
      • et al.
      A cost comparison of management of chronic hepatitis B and its associated complications in Hong Kong and Singapore.
      ,
      • Lee T.A.
      • Veenstra D.L.
      • Iloeje U.H.
      • Sullivan S.D.
      Cost of chronic hepatitis B infection in the United States.
      ,
      • Hsieh C.R.
      • Kuo C.W.
      Cost of chronic hepatitis B virus infection in Taiwan.
      ,
      • Yang B.M.
      • Kim C.H.
      • Kim J.Y.
      Cost of chronic hepatitis B infection in South Korea.
      ,
      • Brown R.E.
      • De Cock E.
      • Colin X.
      • Antoñanzas F.
      • Iloeje U.H.
      Hepatitis B management costs in France, Italy, Spain, and the United Kingdom.
      ,
      • Zhiqiang G.
      • Zhaohui D.
      • Qinhuan W.
      • Dexian C.
      • Yunyun F.
      • Hingtao Liu
      • et al.
      Cost of chronic hepatitis B infection in China.
      ,
      • Butler J.R.G.
      • Pianko S.
      • Korda R.J.
      • Nguyen S.
      • Gow P.J.
      • Roverts S.K.
      • et al.
      The direct cost of managing patients with chronic hepatitis B infection in Australia.
      ]. The major cost of chronic hepatitis B and compensated cirrhosis is that of drug therapy while that of decompensated cirrhosis and HCC is that incurred with hospitalization [
      • Li S.C.
      • Ong S.C.
      • Lim S.G.
      • Yeoh K.G.
      • Kwong K.S.
      • Lee V.
      • et al.
      A cost comparison of management of chronic hepatitis B and its associated complications in Hong Kong and Singapore.
      ,
      • Lee T.A.
      • Veenstra D.L.
      • Iloeje U.H.
      • Sullivan S.D.
      Cost of chronic hepatitis B infection in the United States.
      ,
      • Hsieh C.R.
      • Kuo C.W.
      Cost of chronic hepatitis B virus infection in Taiwan.
      ,
      • Yang B.M.
      • Kim C.H.
      • Kim J.Y.
      Cost of chronic hepatitis B infection in South Korea.
      ,
      • Brown R.E.
      • De Cock E.
      • Colin X.
      • Antoñanzas F.
      • Iloeje U.H.
      Hepatitis B management costs in France, Italy, Spain, and the United Kingdom.
      ,
      • Zhiqiang G.
      • Zhaohui D.
      • Qinhuan W.
      • Dexian C.
      • Yunyun F.
      • Hingtao Liu
      • et al.
      Cost of chronic hepatitis B infection in China.
      ,
      • Butler J.R.G.
      • Pianko S.
      • Korda R.J.
      • Nguyen S.
      • Gow P.J.
      • Roverts S.K.
      • et al.
      The direct cost of managing patients with chronic hepatitis B infection in Australia.
      ,
      • Dan Y.Y.
      • Aung M.O.
      • Lim S.G.
      The economics of treating chronic hepatitis B in Asia.
      ]. Although the cost of drugs in Asia seems much lower than that in the USA [
      • Hoofnagle J.H.
      • Doo E.
      • Liang T.J.
      • Fleischer R.
      • Lok A.S.
      Management of hepatitis B: summary of a clinical research workshop.
      ], the costs are actually much higher when compared with the GNI per capita of each respective country (Table 1). Lack of full or adequate reimbursement for treatment and diagnostic testing is so common in Asia that adequate drug therapy is restricted only to those who can afford it [
      • Mohamed R.
      • Desmond P.
      • Suh D.J.
      • Amarapurkar D.
      • Gane E.
      • Guangbi Y.
      • et al.
      Practical difficulties in the management of hepatitis B in the Asia-Pacific region.
      ]. In central Asia, Turkey is the only country where all drugs are available and fully reimbursed by the state [
      • Yurdaydin C.
      • Bozdayi A.M.
      • Idilman R.
      • Bozkaya H.
      HBV prevalence, natural history, and treatment in Eastern Europe, Turkey, and Turkish-Speaking Countries in Central Asia.
      ]. Bangladesh, India, Indonesia, Malaysia and Philippines had no reimbursement scheme by the end of 2007 [
      • Dan Y.Y.
      • Aung M.O.
      • Lim S.G.
      The economics of treating chronic hepatitis B in Asia.
      ]. Even in countries with higher GNI per capita such as Korea, Singapore and Taiwan, there are limitations in the reimbursement of anti-HBV therapy, either in the selection of agent or the duration of dosing. Therefore, lamivudine is still widely used in Asia, especially in countries where generic lamivudine is available [
      • Dan Y.Y.
      • Aung M.O.
      • Lim S.G.
      The economics of treating chronic hepatitis B in Asia.
      ]. Conceivably, this practice increases the chance of lamivudine resistance which may negate therapeutic effect and create new problems [
      • Chien R.N.
      • Liaw Y.F.
      Nucleos(t)ide analogues for hepatitis B virus: strategies for long-term success.
      ]. The aforementioned limitations have made adherence to treatment guidelines impossible.
      Besides lack of reimbursement for treatment and diagnostic tests, lack of disease awareness among patients, government and healthcare practitioners are also obstacles to the proper management of HBV disease. Lack of disease awareness or understanding of the disease and fear of stigmatization in society among patients are associated with poor patient adherence to therapy or inappropriate health-seeking behavior or both [
      • Lesmana L.A.
      • Leung N.W.Y.
      • Mahachai V.
      • Phiet P.H.
      • Suh D.J.
      • Yao G.B.
      • et al.
      Hepatitis B: overview of the burden of disease in the Asia-Pacific region.
      ,
      • Tan N.C.
      • Cheah S.L.
      What barriers do primary care physicians face in the management of patients with chronic hepatitis B infection in primary care?.
      ]. Lack of awareness among government officials results in lack of screening programs and inadequate reimbursement [
      • Mohamed R.
      • Desmond P.
      • Suh D.J.
      • Amarapurkar D.
      • Gane E.
      • Guangbi Y.
      • et al.
      Practical difficulties in the management of hepatitis B in the Asia-Pacific region.
      ,
      • Lesmana L.A.
      • Leung N.W.Y.
      • Mahachai V.
      • Phiet P.H.
      • Suh D.J.
      • Yao G.B.
      • et al.
      Hepatitis B: overview of the burden of disease in the Asia-Pacific region.
      ,
      • Ryan J.
      • Tran T.T.
      Epidemiology and natural history of hepatitis B in Vietnam.
      ,
      • Dan Y.Y.
      • Aung M.O.
      • Lim S.G.
      The economics of treating chronic hepatitis B in Asia.
      ]. Lack of adequate education and awareness among heath-care providers is obviously an even more serious problem because adequate explanation, counseling and individualized assessment are essential for successful anti-HBV therapy [
      • Liaw Y.F.
      • Leung N.
      • Kao J.H.
      • Piratvisuth T.
      • Gane E.
      • Han K.H.
      • et al.
      Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update.
      ]. In addition, lack of specialists and state-of-art laboratory assays are also problems in some countries [
      • Lesmana L.A.
      • Leung N.W.Y.
      • Mahachai V.
      • Phiet P.H.
      • Suh D.J.
      • Yao G.B.
      • et al.
      Hepatitis B: overview of the burden of disease in the Asia-Pacific region.
      ]. Even if the government and society are well aware of the problems, costs of screening, monitoring and therapy may be well beyond their threshold of willingness-to-pay. These factors not only are responsible for the low diagnostic rate of HBV in Asia, but also for the low treatment rate among diagnosed patients (4%, versus 20% in USA, 17–28% in Europe and 8% in Japan) [Decision Resources 2006]. These contrasting figures reflect the difference in the level of development or income of the countries and also clearly indicate that lack of economic resources is the main obstacle to proper management of HBV in Asia.

      6. Facing the challenges in Asia

      Tangible measures had to be taken in these circumstances. Shortly after the introduction of lamivudine to Asia, the Asian-Pacific Association for the study of the Liver (APASL) acknowledged that lack of education and awareness among healthcare providers was a serious and widespread problem in many Asian countries. This led to the publication of guidelines on the management of chronic hepatitis B [

      Consensus statements on the prevention and management of hepatitis B and hepatitis C in the Asia-Pacific region. Core Working Party for Asia-Pacific Consensus on Hepatitis B and C. J Gastroenterol Hepatol 2000;15:825–41.

      ,
      • Liaw Y.F.
      • Leung N.
      • Kao J.H.
      • Piratvisuth T.
      • Gane E.
      • Han K.H.
      • et al.
      Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update.
      ]. In addition, supported by independent unrestricted educational grants from pharmaceutical companies, a group of experts from the Asian-Pacific region has established a committee for advancing clinical therapy of HBV and set up local chapters in many countries since 2005. Provision of pocket guide books [
      ], journal supplements [
      • Liaw Y.F.
      Advancing the clinical treatment of hepatitis B virus in the Asian-Pacific region.
      ] or internet programs, outreach education for primary care physicians, internists, gastroenterologists and even hepatologists are ongoing to improve the standard of care.
      For the most important and critical challenge, there is no easy way to overcome the economic disadvantage or financial difficulties. This difficult situation is similar to that of the HBV vaccination program in its early years in that lack of financial resources for infrastructure and cost of vaccine were major deterrents to countries [
      • Namgyal P.
      Impact of hepatitis B immunization, Europe and worldwide.
      ]. Reduction of vaccine price and international technical or financial support have greatly extended the HBV vaccination program to many lower-income countries [
      • Namgyal P.
      Impact of hepatitis B immunization, Europe and worldwide.
      ,
      • Zanetti A.R.
      • Van Damme P.
      • Shouval D.
      The global impact of vaccination against hepatitis B: a historical overview.
      ]. Similar support will be extremely helpful for screening, monitoring and antiviral therapy of chronic HBV infection in lower-income Asian countries. Before this becomes available, cost-cutting measures should be implemented. Lamivudine and adefovir are generics in a few Asian countries already [
      • Dan Y.Y.
      • Aung M.O.
      • Lim S.G.
      The economics of treating chronic hepatitis B in Asia.
      ]. The cost of these two drugs is conceivably more affordable in these countries. Further reduction of prices is needed, particularly regarding the drugs with higher genetic barriers to resistance. Cost-effective analyses in the specific context of each Asian country may help to guide towards the most cost-effective approach in each respective country [
      • Dan Y.Y.
      • Aung M.O.
      • Lim S.G.
      The economics of treating chronic hepatitis B in Asia.
      ]. Application of a road-map concept of approach, by starting with the cheapest agent and switching to other agent(s) if serum HBV–DNA is still detectable at 24 weeks of treatment [
      • Keeffe E.B.
      • Zeuzem S.
      • Koff R.S.
      • Dieterich D.T.
      • Esteban-Mur R.
      • Gane E.J.
      • et al.
      Report of an international workshop: roadmap for management of patients receiving oral therapy for chronic hepatitis B.
      ,
      • Liaw Y.F.
      On-treatment outcome prediction and adjustment during chronic hepatitis B therapy: now and future.
      ], may also reduce the cost. Perhaps the most important goal is to educate physicians well enough to ensure that there is a clear indication for starting therapy and avoid inappropriate expansion of indications or unnecessary drug therapy. It is also important to start therapy in the right patients at the right time so that the response endpoint can be achieved earlier hence, shortening the duration of therapy [
      • Liaw Y.F.
      • Leung N.
      • Kao J.H.
      • Piratvisuth T.
      • Gane E.
      • Han K.H.
      • et al.
      Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update.
      ,
      • Chien R.N.
      • Liaw Y.F.
      Nucleos(t)ide analogues for hepatitis B virus: strategies for long-term success.
      ].

      7. Summary and perspectives

      Chronic HBV infection is a serious problem in Asia. The majority of Asian countries are lower-income countries and at high or intermediate endemicity of HBV infection, which is usually acquired perinatally or in early childhood. They are at increased risk of adverse chronic sequalae, including HCC. Although new generations of anti-HBV drugs are available, the inherent problems of the current drugs, lack of awareness among patients, government, and healthcare practitioners and, more importantly, high cost and lack of reimbursement are obstacles to proper management of HBV disease. To address these problems, awareness campaigns, active screening programs, educational activities are ongoing but need to be enhanced. Careful selection of patients, on-treatment adjustment strategy and every measure to cut down the cost of treatment are all needed. Cost-effective analysis in the specific context of each country is also necessary to guide the most cost-effective approach in each of these countries. Financial or technical support from international agencies and reduction of price by companies producing anti-HBV drugs or HBV assays would be the most direct and effective measures to improve the situation.

      Acknowledgements

      The author has received long-term grant support provided by Chang Gung Medical Research Fund and the Prosperous Foundation, Taipei, Taiwan.
      The author thanks the excellent assistance of Ms. Su-Chiung Chu.

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