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Keywords:

  • Asia;
  • hepatitis B;
  • hepatitis B virus;
  • interferon;
  • lamivudine;
  • vaccination

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HEPATITIS B IN THE ASIA–PACIFIC REGION
  5. PREVENTION OF HEPATITIS B VIRUS
  6. MANAGEMENT OF HEPATITIS B IN THE ASIA–PACIFIC REGION
  7. DISCUSSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

The Asia–Pacific Expert Committee on Hepatitis B Management recently reviewed the impact of hepatitis B in the region and assessed the differences and similarities observed in the practical management of the disease in individual Asia–Pacific countries. Hepatitis B is a major health concern in the Asia–Pacific region, and of all chronically infected carriers worldwide, approximately 75% are found in Asia. The disease poses a considerable burden on healthcare systems, and is likely to remain a cause of substantial morbidity and mortality for several decades. Disease prevention activities, including screening and vaccination programs, have been implemented successfully in some Asia–Pacific countries and similar measures are being established in other parts of the region. The management of hepatitis B in the Asia–Pacific varies throughout the region, with each country confronting different issues related to treatment options, disease monitoring and duration of therapy. The influence of cost, availability of diagnostic equipment, and patient awareness and compliance are of additional concern. Although guidelines such as those developed by the Asian Pacific Association for the Study of the Liver have been created to address problems encountered in the management of hepatitis B, many physicians in the region still find it difficult to make satisfactory management decisions because of the treatment choices available. This article examines the different approaches to hepatitis B management in a number of Asia–Pacific countries, and highlights the difficulties that can arise when adhering to treatment guidelines and disease prevention solutions that have proved to be successful in the region.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HEPATITIS B IN THE ASIA–PACIFIC REGION
  5. PREVENTION OF HEPATITIS B VIRUS
  6. MANAGEMENT OF HEPATITIS B IN THE ASIA–PACIFIC REGION
  7. DISCUSSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Hepatitis B virus (HBV) infection remains a major public health concern, and of the 350 million1 chronically infected carriers worldwide, approximately 75% are found in Asia.2 Patients with chronic hepatitis B (CHB) are at increased risk of developing cirrhosis and hepatocellular carcinoma (HCC),2 and the resultant morbidity and mortality from these complications are substantial. Furthermore, the costs associated with the treatment of hepatitis B and its complications are considerable,3 and are a significant economic burden to countries in the region.

Many countries in the Asia–Pacific region have implemented disease prevention programs, such as public awareness campaigns, health education, and active vaccination of newborn babies, as a means of controlling hepatitis B infection. Data from various Asia–Pacific countries have shown that the introduction of mass vaccination programs has been successful in reducing the prevalence of hepatitis B infection.2 Although antiviral treatments are widely available, very few patients in the region actually receive treatment because of various social and economic obstacles. In addition, understanding the evolving indications of the numerous new drugs for the treatment of hepatitis B, in development or emerging onto the market, may also result in clinical disease management problems.

This article reviews the management of hepatitis B infection in the Asia–Pacific region, and examines practical problems encountered by different countries. Japan has not been included in this review, because of this country's low prevalence rate of hepatitis B,2 and a high rate of hepatitis C-related mortality,4 a situation which is quite different to that observed in other countries in the region.

HEPATITIS B IN THE ASIA–PACIFIC REGION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HEPATITIS B IN THE ASIA–PACIFIC REGION
  5. PREVENTION OF HEPATITIS B VIRUS
  6. MANAGEMENT OF HEPATITIS B IN THE ASIA–PACIFIC REGION
  7. DISCUSSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Basic epidemiology

The prevalence of HBV infection in different countries in the Asia–Pacific region is shown in Table 1.5–18 Many of the Asia–Pacific countries that had been previously classified as areas of high endemicity for HBV have now shifted to being classified as regions of intermediate endemicity because of highly effective vaccination programs.19 China has the highest prevalence of HBV, with over one-third of the world's total estimated HBV carriers.19,20 Areas with intermediate endemicity include India, Pakistan, Korea, the Philippines, Taiwan and Thailand, and those with the lowest endemicity include Australia and Singapore.19 Epidemiological studies of HBV infection have also shown that there are wide variations in the prevalence rates within countries according to socioeconomic levels, geography and ethnic grouping.21,22

Table 1.  Epidemiology of hepatitis B infection in the Asia–Pacific region
CountryPrevalence of chronic HBV infection (%)Estimated number of hepatitis B carriers (million)Age group with highest number of carriersPrevalence of HBeAg- negative disease in the HBsAg-positive population (%)
  1. HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.

Australia0.150.15620–50 years7407
China9.78120–130725–45 years740–457
Hong Kong8.890.707≥20 years7607
India3.34103410Varies: 1.3–12.7% in children <15 years, and 3.3–8.6% in adults111812
Korea2.832.25–2.27730–50 years7477
Malaysia5.2421.65730–40 years74513
New ZealandMaori 6%, Pacific Islanders 8%, Asians 7%70.06730–50 years7557
Pakistan51461420–30 years7Not known
The Philippines5–162Not known21–30 years (hospital data), 40–49 years (community data)7257
Singapore4150.1516Highest in pediatric group, subsequent peak in 40–49 years154015
Taiwan15–20173720–50 years74018
Thailand3–673720–40 years730–387
Vietnam10–2077–14720–50 years7407

Hepatitis e antigen-negative disease

Hepatitis e antigen (HBeAg)-negative disease is particularly common in Mediterranean countries and in Asia.23 The prevalence of HBeAg-negative disease throughout the region, which ranges from 18% in India to 60% in Hong Kong, is summarized in Table 1. Patients with HBeAg-negative disease are characterized as hepatitis B surface antigen (HBsAg)-positive, HBeAg-negative and/or HBV e-antibody (anti-HBe)-positive, with raised alanine aminotransferase (ALT) levels, and have been found to have persistent or intermittent high HBV replicative activity.24

Serotypes and genotypes

Four major serotypes (adw, ayw, adr, and ayr)25,26 and seven genotypes (A–G)26 of HBV have been identified. These have distinct geographic distributions, with genotype B prevalent in Taiwan, China and Vietnam, and genotype C prevalent in East Asia, China, Taiwan, Thailand, Korea, New Zealand, and Vietnam.26 Genotypes A and D are prevalent in industrialized countries and India.26 Genotype and serotype data for the region are summarized in Table 2. Pathogenic and therapeutic differences may exist between HBV genotypes,26 although further investigations need to be conducted to determine if the various genotypes can affect the clinical outcome of chronic HBV infection.

Table 2.  Prevalence of hepatitis genotypes and serotypes in the Asia–Pacific region
CountryGenotype and serotype data including the most frequent genotype/serotype seen
  1. HBV, hepatitis B virus; HCC, hepatocellular carcinoma.

AustraliaGenotype A 7%, B 29%, C 39%, D 24%, E 1%7
ChinaGenotype A 1.37%, B 17.27%, C 81.36%27
Hong KongGenotype B 20–25%, C 75–80%7
IndiaMost frequent genotypes are A and D28
KoreaGenotype C > 99%; adr most common serotype7
MalaysiaMost frequent genotypes are B and C29
New ZealandGenotype B 10%, C 50%, D 40%7
PakistanNo data currently available
The PhilippinesMost frequent genotypes are A, B and C7
SingaporeNo data currently available
TaiwanStudy in Taipei: 122 chronic HBV patients; serotype adw 70% and adr 30%. In adr HBV, genotype C 100%; in adw HBV, genotype B 81%, C 12%, F 6% and A 1%30
ThailandGenotype C 66%, B 28%7
VietnamAsymptomatic carriers (B 72%, C 20%, A 4%), and in cirrhosis, HCC (B 44%, C 50%, A 4%)7

Burden of hepatitis B in the Asia–Pacific region

Chronic hepatitis B imposes a considerable burden on the healthcare system, the patient and society. Hepatitis B is the leading cause of chronic hepatitis, cirrhosis and HCC in the Asia–Pacific region2(Table 3).31–39 As hepatitis B progresses from acute infection to chronic disease to cirrhosis and to liver cancer, there is increasing use of healthcare resources and costs associated with the sequelae of the disease.3 In the Asia–Pacific region these costs are significant. For example, in South Korea the estimated total annual cost of HBV infection in 1997 was 1078.3 billion Won or US$959.7 million.3 This figure takes into account the direct and indirect costs of HBV vaccination programs, and treatment of acute and chronic hepatitis, cirrhosis, and liver cancer. The direct costs of the HBV disease (prevention and disease treatment, amounting to 782.2 billion Won or US$696.2 million) are equivalent to 3.2% of the national healthcare expenditure for 1997.3 A major portion of indirect costs was associated with reduced work-related productivity caused by patients taking time off to receive treatment or hospitalization, high numbers of people leaving or losing their jobs, and premature death. Many patients with HBV-related diseases were men of working age; this resulted in a considerable impact on families when the individual was the sole income earner for the family.3 The high costs associated with CHB highlight the importance of disease prevention and treatment. Successful prevention of HBV infection, and the prevention or delay of disease progression, would offer considerable socioeconomic savings in the future.

Table 3.  Associated morbidity and mortality for hepatitis B and associated liver complications in Asia–Pacific countries
CountryAge-standardized HCC incidence rateAssociated morbidity and mortality for hepatitis B and associated liver complications
  • Includes HCC and cholangiocarcinoma. HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma.

Australia3.97 (male) and 0.99 (female) per 100 000 population51200 people die each year as a result of the sequelae of HBV infection6
China14.8 per 100 000 population7Liver cancer is the second most common cancer in China.7 Approximately half a million Chinese die from hepatitis B-induced HCC and endstage cirrhosis each year31
Hong Kong30 per 100 000 population7Liver cancer is the second most common cancer in Hong Kong, with 85.3–91.6% of HCC cases occurring in hepatitis B carriers7
India2.77 (male) and 1.28 (female) per 1000 population32HBV infection, often involving mutant forms of HBV, is the predominant factor for the development of HCC33
Korea27.7 (male) and 7.7 (female) per 100 000 population7Based on 1989–1994 data from the Korea Cancer Center, of 1370 patients with HCC, 68.8–76.0% of patients per year were positive for HBsAg34
Malaysia54.5 (Malay), 301.4 (Chinese), 28.5 (Indian) per 100 000 hospital admissions35HCC is one of the 10 most common cancers in Malaysian men. Nearly all patients presenting with HCC die within 4 months of diagnosis36
New Zealand10 (Maori and Pacific Islanders), 9 (Asian), and 3 (Caucasians) per 100 000 per year770% of liver-related mortality is because of HBV; 78% of HCC are as a result of HBV; and 35% of transplants are because of HBV (Auckland Hepatoma Clinic [305 patients over 5 years] and New Zealand Liver Transplant Unit)7
Pakistan8 per 100 000 per year3767% of HCC cases as a result of HBV37
The Philippines16.8 per 100 000 population, 25.6 (male), 9 (female)7HCC is the most common gastrointestinal cancer, and 86% of patients are positive for HBsAg. More than half (59%) of patients with cirrhosis are positive for HBsAg2
Singapore19.4 (male) and 5.6 (female) per 100 000 per year38HCC is the fourth most common cancer in men.38 Age-specific mortality rates for hepatitis B are 8.3 per 100 000 (25–34 years) and 7.8 per 100 000 (15–24 years)15
Taiwan30.9 (male) and 9.1 (female) per 100 000 per year711 000 die each year of liver cirrhosis and liver cancer related to HBV7
Thailand40.5 (male) and 16.3 (female) per 100 000 population930% of patients with cirrhosis, and 50-50-75% of patients with HCC are positive for HBsAg2,7
Vietnam37 per 100 000 in South Vietnam, lower incidence in the North7Based on data from the University Hospital in Ho Chi Minh City, the annual rate of cirrhosis is 5%7

PREVENTION OF HEPATITIS B VIRUS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HEPATITIS B IN THE ASIA–PACIFIC REGION
  5. PREVENTION OF HEPATITIS B VIRUS
  6. MANAGEMENT OF HEPATITIS B IN THE ASIA–PACIFIC REGION
  7. DISCUSSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Vaccination

The majority of countries in the Asia–Pacific region already implement universal hepatitis B vaccination of newborns, although it is not mandatory in India.7 The three-dose vaccination schedule is usually incorporated into a country's existing vaccination schedule, so that additional visits to the health center are not required. The vaccination schedules and infant vaccination coverage rates of each country are shown in Table 4. Additional immunization programs are implemented in some Asia–Pacific countries to target adolescents who were born before the introduction of neonatal vaccination, or those in high-risk groups, such as healthcare workers and injecting drug users (see Table 4). Catch-up immunization is not usually recommended in countries with a high CHB endemicity (a prevalence of HBsAg ≥ 8%), as most chronic infections are acquired among children <5 years of age; therefore routine infant vaccination is most beneficial for the rapid reduction of HBV transmission.40,41 In countries with lower endemicity, a higher proportion of chronic infections may be acquired among older children, adolescents and adults. This is the result of many individuals escaping exposure to hepatitis B in early childhood and not acquiring natural immunity. Consequently, catch-up immunization of children and adolescents born before the implementation of universal vaccination is recommended and has been employed in some countries in the region, such as Australia, China, Singapore, New Zealand and Taiwan (Table 4).

Table 4.  Hepatitis B vaccination programs throughout the Asia–Pacific region
Country (date first vaccination implemented)Neo-natal vaccination scheduleInfant coverage (%)Catch-up vaccinations, and at-risk groups
Australia (1996)0, 2, 4, 6 or 12 months94 (2001)40Adolescents High-risk groups
China (1992)0, 1 and 6 months70 (2001)8Pre-school children Adolescents Healthcare workers
Hong Kong (1988)0, 1 and 6 months1007Primary-school children who have an incomplete course of vaccinations. Adolescents Health-care workers
India3–6, 4–7, 9–12 months. Not mandatory, available for those who can afford itNo dataNot mandatory
Korea0, 1 and 6 months89 (2001)40Recommended for health-care workers
Malaysia (1989)0, 1 and 6 months94 (2001)40No government funded catch-up programs At-risk health-care workers vaccinated
New Zealand (1987)0, 1 and 3 months90 (2001)40Children entering high school. Since 2000 an adult catch-up program targeting high-risk groups (Maori, Pacific Islanders and Asians) At-risk groups
Pakistan (2002)0, 1 and 6 months (not compulsory)No dataHealth-care workers in some institutions
The Philippines0, 2 and 7 months80 (2001)40Adolescents in some regions Health-care workers and medical students
Singapore (1987)0, 1 and 6 months91 (2001)40Pre-school to secondary school children Adolescents Health-care workers Medical students
Taiwan (1984)0, 1 and 6 months9826Pre-school First graders All children <15 years of age
Thailand (1992)0, 1 and 6 months95 (2000)40High-risk groups Health-care workers
Vietnam (1997/8)0, 1 and 6 months, approximately 70% of provinces have implemented vaccine into the expanded immunization program97 (2001)40Health-care workers

Across the Asia–Pacific region, there are continuing ongoing efforts to make sure that the total population is covered by universal vaccination programs. In China, the vaccination program has been remodeled to ensure the inclusion of people living in rural areas. The improved program also allows the vaccination of a significant proportion of people, particularly in Shanghai, who are not permanent residents and were therefore not previously vaccinated. In Taiwan, heterosexual contact is the dominant cause of hepatitis B transmission for susceptible adults. As a result, vaccination has been recommended for those approaching a sexually active age and screening is recommended for those entering into marriage.

Studies from China, Thailand, Malaysia, Hong Kong, Korea and Singapore have all shown the effectiveness of routine infant hepatitis B vaccination.19,31,42–45 These studies have reported marked decreases in the HBV carrier rate and HBsAg seropositivity among children and adolescents born since the introduction of the infant vaccination program in their country, compared with children and adolescents born prior to its implementation. In Taiwan, other reported benefits of mass hepatitis B vaccination have been demonstrated throughout the country, such as a decrease in the incidence of HCC in children following the introduction of infant vaccination, along with a significant decline in the mortality associated with fulminant hepatitis in infants.26,46 In Singapore, the incidence of acute hepatitis B has declined from 10.4 per 100 000 in 1985 to 4.8 per 100 000 in 1996; and the age-standardized incidence rate of primary liver cancer among men has also dropped from 27.8 per 100 000 per year (1978–1982) to 19.0 per 100 000 per year (1988–1992).47

These data show that infant vaccination programs have had a positive impact on reducing the prevalence of HBV and associated complications, highlighting the importance of continued disease prevention through vaccination. Current evidence indicates that a booster vaccination is probably not needed for at least 15 years, although continued hepatitis B surveillance will address this issue further.48 Although the prevalence of HBV infection among children has been reduced by infant vaccination programs, the virus is still circulating within the adult population. The disease is now mainly observed in adults and adolescents born before the initiation of immunization programs. Therefore, although vaccination will be effective in controlling hepatitis B over time, the burden of hepatitis B is likely to remain high for a considerable time.

Screening programs and awareness campaigns

Screening programs for CHB and HCC have been implemented in several countries in the region. In New Zealand, for example, the Government has funded a screening program targeting all Maori, Pacific Islander and Asian New Zealanders over the age of 15 years who were born before the neonatal vaccination program was implemented.7 The rationale for this screening program is to enable the earlier detection of CHB (allowing treatment with antivirals) and HCC (allowing curative resection/transplantation). Many countries also offer routine antenatal screening to detect the presence of HBsAg and/or HBeAg, as the risk of chronic carriage of HBV is highest for newborns whose mothers are positive for HBeAg.1,2,25 If mothers test positive for HBsAg and/or HBeAg, hepatitis B immunoglobulin (HBIg) is administered in combination with hepatitis B vaccine to infants at birth. Prevention of infection in this group is a key element in any nation's strategy to reduce the incidence, and lead to the eventual elimination, of hepatitis B infection in the population, as persistently infected infants are a reservoir of infection throughout their lives. In other countries, such as Malaysia, Vietnam, Pakistan and India, however, screening of pregnant women is only available in a small number of hospitals. Screening in China also includes children and adolescents before admission to kindergarten, elementary, middle school and university, and most hospitalized patients. In Singapore, there is also screening of persons applying for residential visas. Routine testing for hepatitis B occurs every 2 years in Korea with national insurance, and HBsAg testing is also carried out on the commencement of employment or army service. Thailand has stopped the screening of pregnant women for HBsAg and HBeAg since the HBV vaccination program was adopted for all newborn babies.

Other measures that have been used in the Asia–Pacific region in an attempt to control hepatitis B infection include screening of voluntary blood donors for HBsAg carriers (all countries), and public awareness campaigns (China, India, Malaysia, Thailand, Hong Kong, Singapore, Pakistan and Vietnam). In Malaysia, for example, there is a ‘Hepatitis B Awareness Day’ in various states throughout the country. These campaigns increase public awareness of hepatitis B, educate about various aspects of the disease, including prevention and treatment, and increase hepatitis B vaccination coverage. In Taiwan, a mass hepatitis education program was initiated for both physicians and the public via the mass media. The program highlighted the risk of superinfection with other hepatitis viruses, prevalent among prostitutes and their contacts. As a result, there was a dramatic decrease in the incidence of hepatitis D. In Singapore and Thailand, public education programs on the importance of hepatitis B vaccination are provided for primary healthcare physicians and the public by way of lectures, workshops, health literature and the media. A ‘Liver Day’ is held in Korea every October and public education is provided via television and lectures in different regions across the country. Similarly, in Pakistan, the Medical Association holds annual hepatitis awareness campaigns to educate both practitioners and the general public.

MANAGEMENT OF HEPATITIS B IN THE ASIA–PACIFIC REGION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HEPATITIS B IN THE ASIA–PACIFIC REGION
  5. PREVENTION OF HEPATITIS B VIRUS
  6. MANAGEMENT OF HEPATITIS B IN THE ASIA–PACIFIC REGION
  7. DISCUSSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Choice of treatment

Traditional Chinese medicines and other herbal medicines have been used for many years to treat CHB. Although there are some reported therapeutic benefits of these agents, no randomized trials have been conducted that can confirm their efficacy.49 Many patients, particularly in Korea, Pakistan, India, Vietnam, Singapore and China, believe these treatments are beneficial and, as a result, may take traditional/herbal medicines alone or in combination with licensed medicines. The drugs currently licensed in the Asia–Pacific region for the treatment of CHB are α-interferon (IFN-α), lamivudine and thymosin-α 1. Adefovir dipivoxil, which is already licensed for the treatment of CHB in Europe and the USA, is becoming available in some Asia–Pacific countries through compassionate access programs. The treatments used in different countries in the region are shown in Table 5. New therapies are currently being investigated in clinical trials, including entecavir,49–51 ganciclovir,51 emtricitabine, clevudine, BL-thymidine (L-dT),49,51 therapeutic vaccines, interleukin-12,49 and pegylated IFN. The emergence of these new agents will provide more choice of treatment for hepatitis B, but there is still controversy as to the precise indications for the individual drugs.

Table 5.  Treatments for hepatitis B available in the Asia–Pacific region
CountryTreatments availableTreatment costs reimbursed
  1. IFN, interferon.

AustraliaIFN-α and lamivudineYes
ChinaIFN-α, lamivudine, thymosin α-1 and herbal medicinesNo
Hong KongIFN-α, lamivudine and herbal medicinesNo
IndiaIFN-α, lamivudine, thymosin α-1 and herbal medicinesNo
KoreaIFN-α, lamivudine and thymosin α-1,Yes, 1 year of lamivudine
MalaysiaIFN-α, lamivudine and thymosin α-1Yes, in government hospitals
New ZealandIFN-α and lamivudineYes, up to 3 years of lamivudine
PakistanIFN-α, lamivudine and herbal medicinesNo
The PhilippinesIFN-α and lamivudineNo
SingaporeIFN-α, lamivudine, thymosin α-1, famciclovir, and ganciclovirNo
TaiwanIFN-α and lamivudineNo
ThailandIFN-α, lamivudine and thymosin α-1No
VietnamIFN-α, lamivudine, thymosin α-1 and herbal medicinesNo

Available evidence indicates that patients with normal ALT levels respond poorly to treatment with lamivudine or IFN-α, so no drug treatment is recommended under the Asian Pacific Association for the Study of the Liver (APASL) guidelines for these patients.49 However, patients with replicative activity (HBeAg and/or HBV-DNA positive) and raised ALT levels are candidates for treatment according to certain parameters set out in these guidelines.49,50 Lamivudine appears to be better tolerated than IFN-α, and is the drug of choice for patients with decompensated cirrhosis and recurrent HBV infection after liver transplantation.51 Lamivudine monotherapy has been associated with the emergence of drug-resistant HBV polymerase (YMDD) variants. However, there are several studies that have demonstrated that long-term treatment with lamivudine, even after the appearance of  YMDD variants, is still beneficial.50 Both adefovir dipivoxil and entecavir appear to be effective in patients with YMDD variants.49,52 In the future, a combination of one or more of these agents with lamivudine may be effective in decreasing the rate of lamivudine resistance.

Cost

Despite the wide availability of treatments for hepatitis B, the proportion of patients actually receiving treatment is frequently low. The main obstacle to treatment in the Asia–Pacific region is the cost of drug therapy. A standard course of IFN-α is generally three-fold that of a 12-month course of lamivudine.53 Reimbursement for treatment is only available in New Zealand, Australia and Korea. The New Zealand Pharmaceutical Management Agency (PHARMAC) funds 1 year of lamivudine therapy and, if the patient has had a positive response but has not achieved HBeAg seroconversion, the funding of treatment is extended for a further 2 years. IFN-α treatment is funded by PHARMAC for up to 1 year. In Korea, the government reimburses the first year of lamivudine treatment and all patients request treatment, regardless of the possibility of incurring financial debt. There are no reimbursements for hepatitis B treatment in other Asia–Pacific countries, except for government employees in China, Thailand, and Malaysia. The majority of patients in these countries have to fund their own treatment, and only a very small number of patients have private health insurance. In countries where there are no reimbursements, drug treatment is restricted to those who can afford it. In Vietnam, for example, only an estimated 10% of patients in rural communities can afford treatment for 1 year, compared with approximately 60% of patients in large cities.7 In addition, poorer patients may not be able to afford the initial diagnostic tests needed to confirm a diagnosis of hepatitis B.

The treatment duration for lamivudine in countries where therapy is not reimbursed is often determined by the patient's ability to pay for the drug. As a result, although a longer treatment duration (>1 year) has been shown to be more beneficial and to lead to increased,54 more durable55 seroconversion and improvements in liver histology,54,56 in practice the treatment period is often much shorter because of the cost. It is imperative that physicians explain to the patient that treatment may need to be long-term, and that there may be little clinical benefit in using a short duration of treatment (i.e. 6 months). In countries where treatment is reimbursed, such as Australia, the minimum treatment duration of lamivudine therapy is 12 months.

Management of HBeAg-negative disease

Treatment of HBeAg-negative disease varies considerably across the Asia–Pacific region. HBeAg-negative patients with active HBV replication or cirrhosis are treated with the aim of suppressing HBV-DNA, normalizing ALT and improving liver histology.49,50 The differences observed in treatment strategies from country to country are predominantly physician-driven as opposed to country-dependent. The recommended treatment criterion of elevated ALT, along with positive DNA,49 is the basis for lamivudine therapy in many countries, including Vietnam, Thailand, China, Hong Kong, the Philippines, and Singapore. In Australia, however, treatment with lamivudine is only initiated if there is additional moderate inflammatory activity or fibrosis on biopsy. HBeAg-negative patients are usually treated for a minimum of 1 year (Malaysia, China), although long-term therapy may be administered if the patient is cirrhotic or has stage 3 fibrosis. While the endpoint for treatment of HBeAg-negative patients is not universally agreed upon,50 most physicians across the region appear to stop therapy when patients exhibit persistently normal ALT and HBV-DNA levels below the detectable limit. In India, Singapore, Taiwan, Thailand and China, IFN-α therapy may also be given for the management of HBeAg-negative disease. Although IFN-α can result in good biochemical and virological responses at the end of treatment, high relapse rates are frequently seen.55 These, along with the occurrence of side-effects, have led to the avoidance of IFN-α therapy in other countries such as Vietnam.

Other treatment issues

Education

Another major barrier to treatment, other than the cost of treatment, is a lack of education and awareness about hepatitis B disease. There is low public awareness of the disease in many countries throughout the region, and patients in some countries, including China and India, believe that hepatitis B is untreatable. Furthermore, even if a patient is aware of being in poor health, there may be a reluctance to seek medical attention because of the social stigma associated with hepatitis B and the fear of discrimination, frequently encountered in China, or the denial of employment, which is evident in Korea and the Philippines. In some countries in the region, the use of traditional or herbal medicines is still preferred, and alternative medicines are often used before Western medicines are introduced. The natural progression of the disease is not always fully understood and, as a result, treatment may be withheld or traditional medications used. Lack of education can also play a part in the inappropriate administration of lamivudine. Many primary care physicians prescribe lamivudine to patients with normal ALT levels, resulting in poor treatment outcomes in HBeAg-positive subjects.

Primary care physicians can prescribe treatment for hepatitis B in several countries, such as India, Australia, Malaysia, Vietnam, Hong Kong, the Philippines, Pakistan, Taiwan and China. However, primary care physicians may show a reluctance to treat patients, because of incomplete knowledge about hepatitis B, resulting in the referral of numerous patients to specialists. In other countries, such as New Zealand, only gastroenterologists and hepatologists can prescribe treatments for HBV infection. In Singapore, only specialists are permitted to prescribe lamivudine, although primary care physicians can prescribe IFN-α and thymosin-α 1.

Liver biopsy

There are also problems relating to patient adherence to pretreatment evaluations, such as liver biopsy. Liver biopsy is recommended for viremic patients with raised ALT levels prior to the commencement of treatment.49 In some countries, such as Australia, it is compulsory for patients to have a liver biopsy prior to the start of treatment. In countries where patients are very reluctant to have a biopsy, such as in India, Taiwan, Vietnam, the Philippines, China, Pakistan and Malaysia, treatment may be initiated without biopsy. In many countries in the region, performing a liver biopsy is advised and patient compliance is encouraged by the provision of information about the risks and benefits associated with the procedure. In certain countries in the region (e.g. Singapore) liver biopsy is only available at tertiary centers. The cost and availability of liver biopsy may also affect the frequency of the procedure.

Practical issues

Other obstacles to treatment in Asia–Pacific countries relate to practical issues, such as a lack of hepatologists and gastroenterologists, and the small number of medical clinics in rural areas, such as in New Zealand, India, Malaysia, Vietnam, Pakistan and Taiwan. Patients in these areas have limited access to diagnostic testing, screening or treatment. Some diagnostic tests, such as HBV-DNA or HBV genotype, are not readily available (in rural Australia, India, Vietnam, Thailand and Pakistan) and are only offered at large medical research centers. Often the patient population that requires treatment for CHB has not been identified, such as in the Philippines, and even in those countries with screening programs there is a low take-up rate in rural populations, such as in the Maori population in New  Zealand.

Treatment duration

Other issues include who should be treated and the treatment duration. For IFN-α, the recommended duration of treatment is 4–6 months.49,50 However, there are issues with regards to stopping treatment with lamivudine. Although available guidelines provide adequate instruction on the criteria required for treatment, many physicians face difficulty when assessing patients on a case-by-case basis, particularly if patients have decompensated disease, concurrent hepatitis C virus and hepatitis D virus infections, or are immunosuppressed. In New Zealand, those with bridging fibrosis or cirrhosis with significant viral replication receive treatment regardless of ALT levels. In many countries in the Asia–Pacific region, such as Thailand, Vietnam, China, Pakistan, Singapore and Malaysia, there are issues concerning the duration of treatment with lamivudine. Although there are guidelines regarding when to start treatment, there are no clear instructions on when to stop treatment in the absence of HBeAg seroconversion and in HBeAg-negative disease. The guidelines suggest that the decision to stop lamivudine therapy in these circumstances should be based on disease severity and virological response.49 However, there is an ongoing collation of data and management guidelines will become clearer in time. Many physicians, such as those in Malaysia, are unsure whether treatment should be continued if HBeAg seroconversion has not occurred after prolonged treatment of HBeAg-positive patients. In many countries in the Asia–Pacific region, long-term therapy is administered if ALT levels remain normal. The higher incidence of  YMDD variants that occurs with extended treatment with lamivudine51,52,57 creates a dilemma with regard to the duration of therapy. Although there is concern about the emergence of YMDD variants, numerous studies have demonstrated that most patients who continue on lamivudine therapy after the emergence of YMDD variants have lower serum HBV-DNA and ALT levels compared with their pretreatment levels, and that approximately 25% of patients go on to achieve HBeAg seroconversion.50

Monitoring

There are also issues regarding the monitoring of patients with hepatitis B and adherence to monitoring recommendations (e.g. in Pakistan). Patients with normal ALT, who are not recommended for hepatitis B treatment, should undergo surveillance for HCC every 3–6 months.49 For patients with elevated ALT who are receiving therapy, ALT, HBeAg and/or HBV-DNA should be monitored at least every 3 months. IFN-α-treated patients should also be routinely observed for adverse effects.49

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HEPATITIS B IN THE ASIA–PACIFIC REGION
  5. PREVENTION OF HEPATITIS B VIRUS
  6. MANAGEMENT OF HEPATITIS B IN THE ASIA–PACIFIC REGION
  7. DISCUSSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Hepatitis B infection is a major public health problem in the Asia–Pacific region, causing considerable morbidity and mortality, and is likely to remain so for several decades. Of all the cases of hepatitis B that are diagnosed annually worldwide, three-quarters are located in Asia. As a result of the introduction of HBV vaccination programs and other disease prevention activities, the prevalence of hepatitis B is declining in more developed Asia–Pacific countries. However, further effort should be made to eradicate hepatitis B in the region, and to reduce the current rate of HBV infection. There is a need to improve hepatitis B prevention strategies and to encourage the appropriate use of antiviral therapies throughout the Asia–Pacific region.

The management of hepatitis B varies throughout the region, with each country facing different issues regarding adherence to treatment guidelines. Many Asia–Pacific countries use the APASL guidelines that have been presented by Liaw et al.49 as a framework upon which to base their hepatitis B clinical management practices. The current guidelines were developed by the APASL, based on a consensus and recommendations reached following the presentation of data by hepatitis experts from the Asia–Pacific region at the APASL biennial meeting in Taipei, Taiwan on 27 September, 2002. The APASL guidelines aim to resolve problems faced in the management of the disease and to ensure that new developments in hepatitis B prevention and treatment are incorporated into existing management policies and practices within the region. Other guidelines followed include those developed by the American Association for the Study of Liver Diseases.

The aim of treatment central to all Asia–Pacific countries is the suppression of HBV-DNA, the continued suppression of viral replication, and prevention of disease progression to cirrhosis. The issues of when to stop treatment and the duration of treatment are key concerns. Numerous studies have demonstrated that lamivudine is effective in the treatment of all types of hepatitis B disease when administered for a minimum of 12 months. Most countries in the region administer lamivudine for 1 year, with long-term therapy considered if HBeAg seroconversion is not achieved and if there is no change in ALT levels. The exact duration of optimum treatment with lamivudine is not known, particularly in the treatment of HBeAg-negative disease. The issue of clinical breakthrough being related to the emergence of YMDD variants that are resistant to lamivudine cannot be optimally managed at present. The imminent availability of adefovir dipivoxil should rectify this and allow more confident long-term use of oral antiviral therapy. Recommendations on treatment duration are provided in the APASL guidelines to help clinicians make satisfactory treatment decisions. These recommendations state that therapy should be stopped if the patient has achieved HBeAg seroconversion with HBV-DNA loss in two assessments at least 6 months apart. For those who have not seroconverted after 1 year of lamivudine therapy, the treatment decision should be determined by the disease severity and the clinical response. Treatment duration algorithms (Figs 1,2) complementary to the recommendations stated in the APASL practice guidelines have been developed by the Asia–Pacific Expert Committee on Hepatitis B Management to provide an overview of the clinical management approach for patients with mild-to-moderate HBeAg-positive or HBeAg-negative disease. For HBeAg-positive disease, the primary aim of treatment is HBeAg seroconversion (Fig. 1) and if this is achieved, treatment with lamivudine should be stopped after 6 months. In the absence of HBeAg seroconversion, however, lamivudine therapy can be administered for a duration of 24 months. Long-term lamivudine treatment of >24 months can be considered if there is no change in ALT levels. In those patients who do exhibit an ALT increase, there is the likelihood of emerging YMDD variants and the clinician has the choice of switching to adefovir dipivoxil therapy, continuing with lamivudine therapy or stopping treatment. For the treatment of HBeAg-negative disease (Fig. 2), lamivudine therapy can be continued indefinitely if there is no change in the ALT level. If an increase in ALT is seen (and there is the possibility of the emergence of YMDD variants) adefovir dipivoxil can be substituted, lamivudine therapy continued or treatment stopped.

image

Figure 1. Management algorithm for hepatitis B e antigen-positive [HBeAg(+)] patients. ALT, alanine aminotransferase.

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image

Figure 2. Management algorithm for hepatitis B e antigen-negative [HBeAg(–)] patients. ALT, alanine aminotransferase.

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Other issues, such as those pertaining to pretreatment testing, also arise. In many countries it is difficult to convince patients to have a liver biopsy; however, this is not always a hindrance to treatment and in the majority of cases, blood tests are adequate to decide whether or not treatment should be initiated. Although much progress has been made in the last decade, the results following treatment are not always satisfactory from either the patients’ or the doctors’ perspective as the percentage of sustained responses is relatively low. The availability of better treatment options is still awaited. The cost of treatment and monitoring is a major obstacle to hepatitis B management in the Asia–Pacific region and very few patients with chronic HBV infection are treated at present. Improvement in drug availability and the subsidization of treatment are required to increase patient access to therapy.

In order to successfully control hepatitis B in the Asia–Pacific region, measures have to be taken to ensure that there is better education of both the public and general practitioners. An improved understanding of the disease will help general practitioners identify those who are at risk of infection or in need of treatment, and promote a better relationship with the patient. Adequate screening programs will allow the disease prevalence to be monitored and highlight those who are at risk and require treatment or vaccination. Along with an increase in both education and screening, efforts have to be made to increase the overall awareness of hepatitis B infection, in particular the burden of the disease. At the national policy level, a hepatitis B vaccination program is needed to reduce the incidence of HBV infection in the future. The majority of Asia–Pacific countries have implemented hepatitis B immunization programs for neonates, but for adolescents born before the initiation of such programs there is still a high prevalence of disease. Hepatitis B vaccination needs to be implemented more rigorously throughout the Asia–Pacific region to prevent the continuing spread of the disease.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HEPATITIS B IN THE ASIA–PACIFIC REGION
  5. PREVENTION OF HEPATITIS B VIRUS
  6. MANAGEMENT OF HEPATITIS B IN THE ASIA–PACIFIC REGION
  7. DISCUSSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

This work was supported in part by GlaxoSmithKline (Asia).

This paper is based on the deliberations of the Asia–Pacific Expert Committee on Hepatitis B Management at meetings on the 17–18 March 2002, Singapore; 15–16 June 2002, Bangkok, Thailand; 25 September 2002, Taipei, Taiwan; 5–6 April 2003, Sydney, Australia; and 27 September 2003, Singapore.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HEPATITIS B IN THE ASIA–PACIFIC REGION
  5. PREVENTION OF HEPATITIS B VIRUS
  6. MANAGEMENT OF HEPATITIS B IN THE ASIA–PACIFIC REGION
  7. DISCUSSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES
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