Journal of Hepatology
Volume 51, Issue 2 , Pages 403-410, August 2009

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

  • Yun-Fan Liaw

      Affiliations

    • Corresponding Author InformationTel.: +886 3 3281200x8120; fax: +886 3 3282824.

Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 199 Tung Hwa North Road, Taipei, Taiwan

published online 17 April 2009.

Associate Editor: M. Colombo

Article Outline

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: Chronic hepatitis B, Cost of drugs, Gross national income, Interferon-α, Nucleos(t)ide analogs

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

 

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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 [1], [2]. 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.

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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 [3]. Conceivably, the infrastructure of the healthcare system is not satisfactory in many lower-income countries [4], [5]. 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. [6]. 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 [7], [8], [9], [10], [11].

Table 1. Estimated annual cost of drugs and treatment in some Asian countries with different GNI/C.
CountryCHB/compensated cirrhosisaDecompensated cirrhosisbHCCb2007 GNI/Ce
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
USAc2482–8694c18,480c11,459c7533c46,040
EuropedNN8935d9048d36,020

∗Data of cost in US dollars.

CH-B, chronic hepatitis B; GNI/C, gross national income per capita [3]; HCC, hepatocellular carcinoma; N, data not available; NA, nucleos(t)ide analogs; peg IFN, pegylated interferon α2a.

aAbstracted from Ref. [66].

bData from Refs. [59], [61], [62], [64], [65].

cData from Refs. [60], [67].

dData expressed as median value of France, Italy, Spain and UK. Ref. [63].

eDerived from Ref. [3].

Although universal HBV vaccination in newborns has been implemented in Asian countries since 1984 [12], 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% [13]. 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% [14], not much less than the prevalence in studies conducted before 1984 [12].

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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 [15]. During the immune tolerant phase, the patients are hepatitis B e antigen (HBeAg) seropositive with high viral loads (>2×106–7IU/ml or >107–8copies/ml), normal serum aminotransferase (ALT) and near normal liver histology [1], [15]. 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 [16]. Following HBeAg seroconversion, the patients enter a remission or inactive phase with low serum HBV–DNA (<2000IU/ml) and normal ALT [17], [18]. 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 [19], [20], [21], [22]. 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 [23].

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”) [17], [18]. Similar to HBeAg-positive hepatitis, most patients with HBeAg-negative hepatitis are asymptomatic even if they develop an acute hepatitis flare [16]. 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% [17], [18], [24], being higher in males, genotypes C or D infected patients and those HBeAg seroconverted after age 40 [17], [25], [26], and significantly much lower (0.9%/year) in patients <30 years of age [24].

Patients in the immune tolerant phase or inactive phase have minimal or no disease progression as long as serum ALT remains normal [27], [28]. 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 [17]. 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 [17], [18], [29], [30]. 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 [22]. HCC develops at an annual incidence of 3–6% in patients with cirrhosis and far less frequently in non-cirrhotic patients [22], [31]. 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 [32]. 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 >2000IU/ml [33], [34], [35].

These findings suggest that HBV replication, with subsequent immune-mediated liver injuries, is the primary driving force for liver disease progression [36]. 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.

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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 [4]. 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 [12]. 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 [37]. Given the overall prevalence of 17.3% in Taiwan [14], 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 [38]. 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 [39]. 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.

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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 [4]. As shown in Table 2, Asian patients were the majority in almost all pivotal trials of anti-HBV agents [40], [41], [42], [43], [44], [45], [46], [47], [48], [49]. Many important further studies and the longest experience in the use of these agents have also been gained in Asian patients [50], [51], [52], [53], [54]. Studies from Asia have shown that IFN-based therapy may reduce fibrosis progression, decrease cirrhosis and HCC development [29], and NA therapy may rescue decompensation, reduce fibrosis progression, reverse cirrhosis and prevent further disease progression, including HCC [53], [54], [55], [56]. 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 [57], which has been updated periodically to its fourth version in 2008 [58].

Table 2. Asian patients in pivotal trials of anti-HBV agents.
Trial[Reference]PatientProportion of patients from Asia (%)
HBeAg serostatusNumber
LAM/placebo[40]HBeAg-positive285/73100/100
ADV/placebo[42]HBeAg-positive171/16760/60
[41]HBeAg-negative123/6129/33
ETV/LAM[45]HBeAg-positive354/35558/57
[46]HBeAg-negative325/31338/41
[47]LAM-refractory141/14525/25
TBV/LAM[48]HBeAg-positive458/46383/83
[48]HBeAg-negative222/22465/64
TDF/ADV[49]HBeAg-positive176/9036/36
[49]HBeAg-negative250/12525/24
Peg/Peg+LAM/LAM[44]HBeAg-positive271/271/27287/87/85
[43]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 [59], [60], [61], [62], [63], [64], [65]. 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 [59], [60], [61], [62], [63], [64], [65], [66]. Although the cost of drugs in Asia seems much lower than that in the USA [67], 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 [4]. In central Asia, Turkey is the only country where all drugs are available and fully reimbursed by the state [8]. Bangladesh, India, Indonesia, Malaysia and Philippines had no reimbursement scheme by the end of 2007 [66]. 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 [66]. Conceivably, this practice increases the chance of lamivudine resistance which may negate therapeutic effect and create new problems [68]. 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 [5], [69]. Lack of awareness among government officials results in lack of screening programs and inadequate reimbursement [4], [5], [7], [66]. 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 [58]. In addition, lack of specialists and state-of-art laboratory assays are also problems in some countries [5]. 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.

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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 [57], [58]. 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 [70], journal supplements [71] 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 [72]. Reduction of vaccine price and international technical or financial support have greatly extended the HBV vaccination program to many lower-income countries [72], [73]. 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 [66]. 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 [66]. 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 [74], [75], 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 [58], [68].

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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.

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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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☆ The author declared that he has no financial and personal relationships that could inappropriately influence (bias) his work, though he has been involved in clinical trials or served as a global advisory board member of Roche, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Gilead Sciences.

PII: S0168-8278(09)00242-6

doi:10.1016/j.jhep.2009.04.003

Journal of Hepatology
Volume 51, Issue 2 , Pages 403-410, August 2009

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