**2. Reviews on the epidemiology, Quality of Life, and management of Chronic Hepatitis B (CHB)**

This chapter first reviews the epidemiology of hepatitis B virus (HBV) and recommended management for CHB to identify the health problems and service needs of these patients. The findings from studies on health-related quality of life (HRQOL) and CHB is highlighted to identify any knowledge gaps. Finally, available HRQOL measures are reviewed to determine which one is the most suitable for applications for the evaluation of Chinese CHB patients in Hong Kong.

#### **2.1 Epidemiology and management for Chronic Hepatitis B (CHB)**

#### **2.1.1 Epidemiology and natural history of CHB**

Hepatitis B is one of the most common infectious diseases and a leading cause of death in the world (Lai, Ratziu, Yuen, & Roynard, 2003; Lavanchy, 2004, 2005; Maynard, 1990; Wright, 2006). Approximately 2 billion are infected and more than 400 million people of those are chronically infected with hepatitis B virus (HBV) (Fattovich, Bortolotti, & Donato, 2008; Lai et al., 2003). Chronically infected individuals defined as those who have diagnosed with hepatitis B surface antigen (HBsAg) for more than six months (A S Lok & McMahon, 2009; Maddrey, 2000). It was estimated that 75% of chronic hepatitis B (CHB) carriers were found in Asia and the Western Pacific regions (Gust, 1996; Maddrey, 2000; Maynard, 1990; Merican et al., 2000). HBV results in 500,000 to 1.2 million deaths per year caused by cirrhosis, liver failure or hepatocellular carcinoma (HCC) (Lavanchy, 2004, 2005). The incidence of HCC is increasing and is the fifth most common cancer worldwide killing 300,000-500,000 people per year (Lavanchy, 2004). Worldwide, approximately 30% of cirrhosis was attributable to HBV and over half (53%) of HCC was due to HBV (Perz, Armstrong, Farrington, Hutin, & Bell, 2006). HBV infection accounted for more than 50% of HCC (65%) and cirrhosis (57%) in Western Pacific regions (Perz et al., 2006).

Reviews on the Epidemiology, Quality of Life, and Management of Chronic Hepatitis B (CHB) 375

Wright, 2006). During this phase, patients are hepatitis B e-antigen (HBeAg) positive and have high levels of serum HBV DNA (ranges between 107-1011 copies/mL) (Lai et al., 2003; McMahon, 2008; Merican et al., 2000; Wright, 2006). However, liver inflammatory disease is minimal or absent, with normal or minimally elevated alanine aminotransferase (ALT) level and minimal histological activity in the liver (Lai et al., 2003; McMahon, 2008; Merican et al., 2000; Wright, 2006). It usually occurs in children and young adults and may last for 10-30 years in Asian patients who acquired HBV infection during the perinatal period (Lai et al., 2003; Merican et al., 2000; Yuen, 2007). Patients in this phase are highly contagious and can

The second phase is immune clearance and it usually occurs when patients are aged between 15-35 years old (Lai et al., 2003; McMahon, 2008; Merican et al., 2000). It is characterized by HBeAg positive, lower level of viral replication (presented by low serum HBV DNA level), evaluated or fluctuating levels of ALT, moderate or severe liver necroinflammation and more rapid progression of fibrosis compared to the previous phase (Lai et al., 2003; McMahon, 2008; Merican et al., 2000). This phase may last for several weeks to several years (Merican et al., 2000). Liver damage has been established and the progression of the disease to a more advanced stage of illness such as cirrhosis depends on

In the third phase, patients undergo HBeAg seroconversion, with loss of HBeAg and appearance of an antibody to HBeAg, namely anti-HBe (European Association For the study of the liver, 2008; Keeffe et al., 2008; Lai et al., 2003; McMahon, 2008; Merican et al., 2000; Wright, 2006; Yuen, 2007). This phase is usually characterized by very low or undetectable serum HBV DNA levels (usually 103-105 copies/mL), persistent normal ALT level and inactive liver histology with minimal fibrosis (European Association For the study of the

Some patients may progress to the immune phase (phase 4), with clearance of HBsAg and appearance of an antibody to HBsAg (anti-HBs) (Merican et al., 2000). It indicates the development of full immunity to HBV (Merican et al., 2000). Serum HBV DNA tends to become undetectable and risk of re-infection or reactivation is low (Merican et al., 2000). However, this phase is rare in Asian patients, but it may occur in Caucasians at the rate of 1-

Understanding the epidemiology and natural history of CHB infection helps us to prevent HBV infection and to use anti-viral treatment more effectively. There is little benefit to treat patients in phase 1 or phase 3 (Merican et al., 2000). Based on current clinical guidelines, the goal of treatment for CHB is to reduce the risk of disease progression in phase 2, aiming to

Most patients with hepatitis B have no symptoms until they have developed cirrhosis or HCC, both of which are very debilitating conditions that can markedly decrease HRQOL. Patients in the advanced stages of illness often have fatigue, pain, poor appetite, jaundice, ascites, variceal bleeding, and impaired cognitive function(L. M. Martin, Dan, & Younossi, 2006; L. M. Martin & Younossi, 2005), all of which may affect the patient's physical functioning, work, activities of daily living, social functioning and emotions. These domains should be included in the evaluation of the HRQOL of CHB patients. Anti-viral treatments for phase 2 CHB to prevent or delay disease progression not only reduce mortality but can

the duration of this stage (McMahon, 2008; Wright, 2006; Yuen, 2007).

liver, 2008; Keeffe et al., 2008; McMahon, 2008; Wright, 2006; Yuen, 2007).

2% annually which increase with time (Merican et al., 2000).

eliminate the viral replication of HBV (Merican et al., 2000).

preserve HRQOL through the prevention of morbidity.

transmit the disease easily (Yuen, 2007).

In Hong Kong, HCC is the fourth common cancer and the third leading cause of cancer deaths (H. A. Hong Kong Cancer Registry, 2008). In 2006, there were 1745 (1462) new cases (deaths) of liver cancer registered in Hong Kong, representing 7.3% (12.1%) of all cancers in total (H. A. Hong Kong Cancer Registry, 2008). There was a male predominance with a male-to-female ratio of 3:1 (Hong Kong Cancer Registry, 2006), and the age of onset is earlier in males (Department of Health HKSAR, 1998). The age-standardized incidence (mortality) rates for males and females were 29.3 (23.3) and 8.0 (6.7) per 100,000 population, respectively (Hong Kong Cancer Registry, 2006). HBV was significantly contributed to HCC, with 80% of HCC patients found to be hepatitis B carriers (Department of Health HKSAR, 1998). Therefore, HBV infection accounts for the majority of both cirrhosis and HCC worldwide (Perz et al., 2006).

The prevalence of HBV varies notably between and within countries (Custer et al., 2004; Gust, 1996; Lavanchy, 2004, 2005; Maddrey, 2000; Maynard, 1990). It could be categorized as high, intermediate and low HBV endemicity (Custer et al., 2004; Lavanchy, 2004; Maddrey, 2000). In areas of high endemicity, ≥8% are CHB carriers and account for a total of 45% of the global population (Lavanchy, 2004). They include South East Asia, China including Hong Kong, sub-Saharan Africa and the Amazon Basin (Custer et al., 2004; Lavanchy, 2004; Maddrey, 2000). In areas of intermediate endemicity, such as eastern and southern Europe, the Middle East, Japan and part of South America, 2-7% of the population are chronic carriers (Custer et al., 2004; Lavanchy, 2004; Maddrey, 2000). The endemicity of HBV is low in most developed countries, such as North America, Northern and Western Europe and Australia, where less than 2% of the population are chronic carriers (Custer et al., 2004; Maddrey, 2000).

Hepatitis B virus (HBV) is present in the blood, saliva, semen, vaginal secretions, menstrual blood, and to a lesser degree sweat, breast milk, tears and urine of infected individuals (Lavanchy, 2004; Wright, 2006). Since HBV is resistant to breakdown outside the body, it is easily transmitted through contact with infected body fluids (Lavanchy, 2004; Wright, 2006). Three modes of HBV transmission have been categorized as: perinatal (from an infected mother to her child), horizontal transmission through mucosal contact with infected blood or bodily fluid secretions and parenteral or percutaneous transmission (such as injection drug use and needlestick injury) (C. J. Chen, Wang, & Yu, 2000; Gust, 1996; Lavanchy, 2004; Maddrey, 2000; Wright, 2006).

Routes of HBV transmission vary depending on the prevalence of HBV infection (Lavanchy, 2004; Maddrey, 2000). In areas of high endemicity, perinatal transmission is the most common route and the majority of HBV infection is acquired during the preschool years (Lavanchy, 2004; Maddrey, 2000). The lifetime risk of HBV infection is greater than 60% (Lavanchy, 2004; Maddrey, 2000). In areas of intermediate endemicity, most HBV infection occurs in infant or childhood, with lifetime risk of 20-60% (Lavanchy, 2004; Maddrey, 2000). In areas of low endemicity, HBV infection is acquired primarily by horizontal transmission (between individuals) in adolescents or early adulthood, for instance, through intravenous drug use or unprotected sexual transmission (Lavanchy, 2004; Maddrey, 2000). The lifetime risk of acquiring HBV is <20% (Lavanchy, 2004; Maddrey, 2000).

The natural history of HBV infection has three phases including immune tolerance, immune clearance and a residual phase (Lai et al., 2003; McMahon, 2008; Wright, 2006). The first phase of HBV is immune tolerance (Lai et al., 2003; McMahon, 2008; Merican et al., 2000;

In Hong Kong, HCC is the fourth common cancer and the third leading cause of cancer deaths (H. A. Hong Kong Cancer Registry, 2008). In 2006, there were 1745 (1462) new cases (deaths) of liver cancer registered in Hong Kong, representing 7.3% (12.1%) of all cancers in total (H. A. Hong Kong Cancer Registry, 2008). There was a male predominance with a male-to-female ratio of 3:1 (Hong Kong Cancer Registry, 2006), and the age of onset is earlier in males (Department of Health HKSAR, 1998). The age-standardized incidence (mortality) rates for males and females were 29.3 (23.3) and 8.0 (6.7) per 100,000 population, respectively (Hong Kong Cancer Registry, 2006). HBV was significantly contributed to HCC, with 80% of HCC patients found to be hepatitis B carriers (Department of Health HKSAR, 1998). Therefore, HBV infection accounts for the majority of both cirrhosis and HCC

The prevalence of HBV varies notably between and within countries (Custer et al., 2004; Gust, 1996; Lavanchy, 2004, 2005; Maddrey, 2000; Maynard, 1990). It could be categorized as high, intermediate and low HBV endemicity (Custer et al., 2004; Lavanchy, 2004; Maddrey, 2000). In areas of high endemicity, ≥8% are CHB carriers and account for a total of 45% of the global population (Lavanchy, 2004). They include South East Asia, China including Hong Kong, sub-Saharan Africa and the Amazon Basin (Custer et al., 2004; Lavanchy, 2004; Maddrey, 2000). In areas of intermediate endemicity, such as eastern and southern Europe, the Middle East, Japan and part of South America, 2-7% of the population are chronic carriers (Custer et al., 2004; Lavanchy, 2004; Maddrey, 2000). The endemicity of HBV is low in most developed countries, such as North America, Northern and Western Europe and Australia, where less than 2% of the population are chronic carriers (Custer et al., 2004;

Hepatitis B virus (HBV) is present in the blood, saliva, semen, vaginal secretions, menstrual blood, and to a lesser degree sweat, breast milk, tears and urine of infected individuals (Lavanchy, 2004; Wright, 2006). Since HBV is resistant to breakdown outside the body, it is easily transmitted through contact with infected body fluids (Lavanchy, 2004; Wright, 2006). Three modes of HBV transmission have been categorized as: perinatal (from an infected mother to her child), horizontal transmission through mucosal contact with infected blood or bodily fluid secretions and parenteral or percutaneous transmission (such as injection drug use and needlestick injury) (C. J. Chen, Wang, & Yu, 2000; Gust, 1996; Lavanchy, 2004;

Routes of HBV transmission vary depending on the prevalence of HBV infection (Lavanchy, 2004; Maddrey, 2000). In areas of high endemicity, perinatal transmission is the most common route and the majority of HBV infection is acquired during the preschool years (Lavanchy, 2004; Maddrey, 2000). The lifetime risk of HBV infection is greater than 60% (Lavanchy, 2004; Maddrey, 2000). In areas of intermediate endemicity, most HBV infection occurs in infant or childhood, with lifetime risk of 20-60% (Lavanchy, 2004; Maddrey, 2000). In areas of low endemicity, HBV infection is acquired primarily by horizontal transmission (between individuals) in adolescents or early adulthood, for instance, through intravenous drug use or unprotected sexual transmission (Lavanchy, 2004; Maddrey, 2000). The lifetime

The natural history of HBV infection has three phases including immune tolerance, immune clearance and a residual phase (Lai et al., 2003; McMahon, 2008; Wright, 2006). The first phase of HBV is immune tolerance (Lai et al., 2003; McMahon, 2008; Merican et al., 2000;

risk of acquiring HBV is <20% (Lavanchy, 2004; Maddrey, 2000).

worldwide (Perz et al., 2006).

Maddrey, 2000).

Maddrey, 2000; Wright, 2006).

Wright, 2006). During this phase, patients are hepatitis B e-antigen (HBeAg) positive and have high levels of serum HBV DNA (ranges between 107-1011 copies/mL) (Lai et al., 2003; McMahon, 2008; Merican et al., 2000; Wright, 2006). However, liver inflammatory disease is minimal or absent, with normal or minimally elevated alanine aminotransferase (ALT) level and minimal histological activity in the liver (Lai et al., 2003; McMahon, 2008; Merican et al., 2000; Wright, 2006). It usually occurs in children and young adults and may last for 10-30 years in Asian patients who acquired HBV infection during the perinatal period (Lai et al., 2003; Merican et al., 2000; Yuen, 2007). Patients in this phase are highly contagious and can transmit the disease easily (Yuen, 2007).

The second phase is immune clearance and it usually occurs when patients are aged between 15-35 years old (Lai et al., 2003; McMahon, 2008; Merican et al., 2000). It is characterized by HBeAg positive, lower level of viral replication (presented by low serum HBV DNA level), evaluated or fluctuating levels of ALT, moderate or severe liver necroinflammation and more rapid progression of fibrosis compared to the previous phase (Lai et al., 2003; McMahon, 2008; Merican et al., 2000). This phase may last for several weeks to several years (Merican et al., 2000). Liver damage has been established and the progression of the disease to a more advanced stage of illness such as cirrhosis depends on the duration of this stage (McMahon, 2008; Wright, 2006; Yuen, 2007).

In the third phase, patients undergo HBeAg seroconversion, with loss of HBeAg and appearance of an antibody to HBeAg, namely anti-HBe (European Association For the study of the liver, 2008; Keeffe et al., 2008; Lai et al., 2003; McMahon, 2008; Merican et al., 2000; Wright, 2006; Yuen, 2007). This phase is usually characterized by very low or undetectable serum HBV DNA levels (usually 103-105 copies/mL), persistent normal ALT level and inactive liver histology with minimal fibrosis (European Association For the study of the liver, 2008; Keeffe et al., 2008; McMahon, 2008; Wright, 2006; Yuen, 2007).

Some patients may progress to the immune phase (phase 4), with clearance of HBsAg and appearance of an antibody to HBsAg (anti-HBs) (Merican et al., 2000). It indicates the development of full immunity to HBV (Merican et al., 2000). Serum HBV DNA tends to become undetectable and risk of re-infection or reactivation is low (Merican et al., 2000). However, this phase is rare in Asian patients, but it may occur in Caucasians at the rate of 1- 2% annually which increase with time (Merican et al., 2000).

Understanding the epidemiology and natural history of CHB infection helps us to prevent HBV infection and to use anti-viral treatment more effectively. There is little benefit to treat patients in phase 1 or phase 3 (Merican et al., 2000). Based on current clinical guidelines, the goal of treatment for CHB is to reduce the risk of disease progression in phase 2, aiming to eliminate the viral replication of HBV (Merican et al., 2000).

Most patients with hepatitis B have no symptoms until they have developed cirrhosis or HCC, both of which are very debilitating conditions that can markedly decrease HRQOL. Patients in the advanced stages of illness often have fatigue, pain, poor appetite, jaundice, ascites, variceal bleeding, and impaired cognitive function(L. M. Martin, Dan, & Younossi, 2006; L. M. Martin & Younossi, 2005), all of which may affect the patient's physical functioning, work, activities of daily living, social functioning and emotions. These domains should be included in the evaluation of the HRQOL of CHB patients. Anti-viral treatments for phase 2 CHB to prevent or delay disease progression not only reduce mortality but can preserve HRQOL through the prevention of morbidity.

Reviews on the Epidemiology, Quality of Life, and Management of Chronic Hepatitis B (CHB) 377

If patients have higher serum HBV DNA levels and increased ALT levels, drug treatment is recommended (Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). A liver biopsy is suggested before receiving drug therapy in order to evaluate the necroinflammatory grade and stage of fibrosis and exclude other reasons of elevated ALT levels (Y F Liaw et al., 2008). The ideal goal of CHB therapy is the complete eradication of HBV but this is still impossible. The short-term goals of CHB treatment include suppression of serum HBV DNA, normalization of ALT, HBeAg seroconversion and improvement in liver histology (European Association For the study of the liver, 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). The ultimate goal of long term treatment is to prevent or delay the onset of liver complications including cirrhosis and HCC, and to prolong survival (European Association For the study of the liver, 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Current clinical guidelines and treatment algorithms focus on the suppression of viral replication to maintain serum HBV DNA at the lowest possible levels (European Association For the study of the liver, 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). This has been shown to prevent and slow the progression to cirrhosis, liver failure or HCC (European Association For the study of the liver, 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009).

Currently, seven drugs are available for management of CHB infection including lamivudine (LVD), adefovir (ADV), entecavir (ETV), telbivudine (LdT), and tenofovir (TDF) and interferon (IFN-α), and pegylated IFN (peg-IFN) (European Association For the study of the liver, 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). The choice of treatment should take into account treatment efficacy, risk of developing drug resistance, long term safety profile, side effects, mode of administration and cost of drug

Interferon (IFN-α) is the first drug used for the treatment of CHB (Lai & Yuen, 2008; Yuen & Lai, 2001). It has to be given by injection which limits its acceptability (Jacobson, 2006). Standard IFN-α has been used for treatment of CHB for more than two decades (Y F Liaw et al., 2008; Marcellin, Asselah, & Boyer, 2005). This treatment stimulates the immune system to eradicate HBV (Ayoub & Keeffe, 2008; Jacobson, 2006; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; Marcellin et al., 2005). The efficacy of standard IFN-α has been demonstrated to be effective in suppression of HBV replication and in inducing remission of liver disease in Western populations (Fung et al., 2008; Jacobson, 2006; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; A. S. Lok et al., 1992; Yuen & Lai, 2001). Peg-IFN, in a newer generation of IFN, has been shown to be superior in terms of HBeAg clearance, normalization of ALT and HBV DNA suppression (Ayoub & Keeffe, 2008; Cooksley et al., 2003; Fung et al., 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; Zoulim & Perrillo, 2008). The advantage of standard IFN-α or peg-IFN is a definite duration of treatment (Ayoub & Keeffe, 2008; Fung et al., 2008; Jacobson, 2006; Lai & Yuen, 2008; Y F Liaw et al., 2008). Long-term effectiveness of standard IFN has shown to be inconclusive (Fung et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; Marcellin et al., 2005; Yuen & Lai, 2001). The efficacy of IFN is limited to CHB patients with high pretreatment ALT levels (Jacobson, 2006; A S Lok & McMahon, 2009), which is uncommon for Asian CHB patients (Fung et al., 2008). Some studies in Japanese and Chinese patients failed to demonstrate a long-term benefit of standard IFN therapy. However, a recent study of Taiwanese patients with a high ALT

**2.2.2 Anti-viral drug treatment** 

(Fung, Lai, & Yuen, 2008).

#### **2.2 Health service needs of CHB patients and HRQOL**

Chronic hepatitis B (CHB) is a chronic disease that can lead to very disabling and even lethal complications, which require different health care services at different stages of the illness.

#### **2.2.1 Monitoring**

Individuals who are chronically infected with HBV require lifetime monitoring of the status of infection and follow-up for the development of liver complications, for instance active chronic hepatitis, cirrhosis and HCC (Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). International guidelines recommend the initial evaluation of patients with CHB infection should include a thorough history, physical examination and laboratory tests to identify the current stage and the phases of HBV infection (Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). We also need to take into consideration family history of HBV and liver cancer, risk factors for co-infection and alcohol consumption (Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Laboratory investigations should comprise HBsAg, HBeAg and anti-HBe, quantification of viral replication by levels of HBV DNA, tests for co-infection with other types of hepatitis (hepatitis C virus and hepatitis D virus), and HIV in high-risk group (Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Liver biopsy should be considered in those infected individuals with elevated ALT or HBV DNA levels (Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Patients should be counseled on preventive measures against transmission of HBV infection through household or sexual contacts (Keeffe et al., 2008; Y F Liaw et al., 2008). Abstinence from alcohol is highly recommended (Keeffe et al., 2008). Negative impacts on psychological, physical and social well being should be considered (Y F Liaw et al., 2008). Previous studies showed that patients with CHB had lower HRQOL scores even in the absence of cirrhosis or cancer (Y F Liaw et al., 2008; S C Ong, Mak, Aung, Li, & Lim, 2008). All infected individuals with HBV infection who are not immuned to hepatitis A should be vaccinated according to Centers for Disease Control and Prevention (CDC) recommendations (Keeffe et al., 2008; A S Lok & McMahon, 2009). After initial evaluation, the frequency and tests of monitoring depends on the stage of illness.

Patients with persistently normal ALT levels often have minimal histological changes and poor response to currently available anti-viral drugs (Y F Liaw et al., 2008). Therefore, no anti-viral drug therapy is recommended for this patient group (Y F Liaw et al., 2008). However, they should be monitored regularly and HCC surveillance may be needed. There is currently no consensus on frequency or type of test for monitoring. The updated Asia-Pacific consensus statements recommends patients with active viral replication should have HBV DNA level, ALT and HBeAg testing every 3 months for the first year and then every 3-6 months, but this is rarely feasible because of limitation in resources (Y F Liaw et al., 2008). The American Association for the Study of Liver Disease (AASLD) guidelines recommend individuals in the immune tolerant phase (stage 2) who are HBeAg-positive but with normal ALT should have ALT and AST tests every 3 months for the first year and then every 6 months (A S Lok & McMahon, 2009). Screening for HCC is particularly important for high-risk group, such as Asian men aged >40 years old or Asian women aged >50 years old, with cirrhosis and family history of severe liver disease (Keeffe et al., 2008; A S Lok & McMahon, 2009).

#### **2.2.2 Anti-viral drug treatment**

376 Hepatocellular Carcinoma – Basic Research

Chronic hepatitis B (CHB) is a chronic disease that can lead to very disabling and even lethal complications, which require different health care services at different stages of the illness.

Individuals who are chronically infected with HBV require lifetime monitoring of the status of infection and follow-up for the development of liver complications, for instance active chronic hepatitis, cirrhosis and HCC (Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). International guidelines recommend the initial evaluation of patients with CHB infection should include a thorough history, physical examination and laboratory tests to identify the current stage and the phases of HBV infection (Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). We also need to take into consideration family history of HBV and liver cancer, risk factors for co-infection and alcohol consumption (Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Laboratory investigations should comprise HBsAg, HBeAg and anti-HBe, quantification of viral replication by levels of HBV DNA, tests for co-infection with other types of hepatitis (hepatitis C virus and hepatitis D virus), and HIV in high-risk group (Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Liver biopsy should be considered in those infected individuals with elevated ALT or HBV DNA levels (Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Patients should be counseled on preventive measures against transmission of HBV infection through household or sexual contacts (Keeffe et al., 2008; Y F Liaw et al., 2008). Abstinence from alcohol is highly recommended (Keeffe et al., 2008). Negative impacts on psychological, physical and social well being should be considered (Y F Liaw et al., 2008). Previous studies showed that patients with CHB had lower HRQOL scores even in the absence of cirrhosis or cancer (Y F Liaw et al., 2008; S C Ong, Mak, Aung, Li, & Lim, 2008). All infected individuals with HBV infection who are not immuned to hepatitis A should be vaccinated according to Centers for Disease Control and Prevention (CDC) recommendations (Keeffe et al., 2008; A S Lok & McMahon, 2009). After initial evaluation,

**2.2 Health service needs of CHB patients and HRQOL** 

the frequency and tests of monitoring depends on the stage of illness.

(Keeffe et al., 2008; A S Lok & McMahon, 2009).

Patients with persistently normal ALT levels often have minimal histological changes and poor response to currently available anti-viral drugs (Y F Liaw et al., 2008). Therefore, no anti-viral drug therapy is recommended for this patient group (Y F Liaw et al., 2008). However, they should be monitored regularly and HCC surveillance may be needed. There is currently no consensus on frequency or type of test for monitoring. The updated Asia-Pacific consensus statements recommends patients with active viral replication should have HBV DNA level, ALT and HBeAg testing every 3 months for the first year and then every 3-6 months, but this is rarely feasible because of limitation in resources (Y F Liaw et al., 2008). The American Association for the Study of Liver Disease (AASLD) guidelines recommend individuals in the immune tolerant phase (stage 2) who are HBeAg-positive but with normal ALT should have ALT and AST tests every 3 months for the first year and then every 6 months (A S Lok & McMahon, 2009). Screening for HCC is particularly important for high-risk group, such as Asian men aged >40 years old or Asian women aged >50 years old, with cirrhosis and family history of severe liver disease

**2.2.1 Monitoring** 

If patients have higher serum HBV DNA levels and increased ALT levels, drug treatment is recommended (Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). A liver biopsy is suggested before receiving drug therapy in order to evaluate the necroinflammatory grade and stage of fibrosis and exclude other reasons of elevated ALT levels (Y F Liaw et al., 2008). The ideal goal of CHB therapy is the complete eradication of HBV but this is still impossible. The short-term goals of CHB treatment include suppression of serum HBV DNA, normalization of ALT, HBeAg seroconversion and improvement in liver histology (European Association For the study of the liver, 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). The ultimate goal of long term treatment is to prevent or delay the onset of liver complications including cirrhosis and HCC, and to prolong survival (European Association For the study of the liver, 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Current clinical guidelines and treatment algorithms focus on the suppression of viral replication to maintain serum HBV DNA at the lowest possible levels (European Association For the study of the liver, 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). This has been shown to prevent and slow the progression to cirrhosis, liver failure or HCC (European Association For the study of the liver, 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009).

Currently, seven drugs are available for management of CHB infection including lamivudine (LVD), adefovir (ADV), entecavir (ETV), telbivudine (LdT), and tenofovir (TDF) and interferon (IFN-α), and pegylated IFN (peg-IFN) (European Association For the study of the liver, 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). The choice of treatment should take into account treatment efficacy, risk of developing drug resistance, long term safety profile, side effects, mode of administration and cost of drug (Fung, Lai, & Yuen, 2008).

Interferon (IFN-α) is the first drug used for the treatment of CHB (Lai & Yuen, 2008; Yuen & Lai, 2001). It has to be given by injection which limits its acceptability (Jacobson, 2006). Standard IFN-α has been used for treatment of CHB for more than two decades (Y F Liaw et al., 2008; Marcellin, Asselah, & Boyer, 2005). This treatment stimulates the immune system to eradicate HBV (Ayoub & Keeffe, 2008; Jacobson, 2006; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; Marcellin et al., 2005). The efficacy of standard IFN-α has been demonstrated to be effective in suppression of HBV replication and in inducing remission of liver disease in Western populations (Fung et al., 2008; Jacobson, 2006; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; A. S. Lok et al., 1992; Yuen & Lai, 2001). Peg-IFN, in a newer generation of IFN, has been shown to be superior in terms of HBeAg clearance, normalization of ALT and HBV DNA suppression (Ayoub & Keeffe, 2008; Cooksley et al., 2003; Fung et al., 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; Zoulim & Perrillo, 2008). The advantage of standard IFN-α or peg-IFN is a definite duration of treatment (Ayoub & Keeffe, 2008; Fung et al., 2008; Jacobson, 2006; Lai & Yuen, 2008; Y F Liaw et al., 2008). Long-term effectiveness of standard IFN has shown to be inconclusive (Fung et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; Marcellin et al., 2005; Yuen & Lai, 2001). The efficacy of IFN is limited to CHB patients with high pretreatment ALT levels (Jacobson, 2006; A S Lok & McMahon, 2009), which is uncommon for Asian CHB patients (Fung et al., 2008). Some studies in Japanese and Chinese patients failed to demonstrate a long-term benefit of standard IFN therapy. However, a recent study of Taiwanese patients with a high ALT

Reviews on the Epidemiology, Quality of Life, and Management of Chronic Hepatitis B (CHB) 379

treatment with ADV up to 5 years results in significant histologic, virologic and biochemical improvement (Hadziyannis et al., 2005). Currently, ADV is primarily used in patients who have developed resistance to LVD (Fung et al., 2008; Zoulim & Perrillo, 2008). Some studies have shown the addition of ADV to LVD rather than switchover to ADV monotherapy produced a lower rate of resistance to ADV (Lampertico et al., 2007; Manolakopoulos et al., 2008; Rapti, Dimou, Mitsoula, & Hadziyannis, 2007; van der Poorten et al., 2007; Zoulim & Perrillo, 2008). Other studies have shown that ADV monotherapy in patients with LVDresistant was as effective for HBV DNA suppression as combination therapy (Fung et al., 2007; Fung et al., 2008; Y F Liaw et al., 2008; Peters et al., 2004). Most guidelines recommended to add on ADV in LVD-resistant patients in order to minimize the development of ADV-resistance and maintain HBV DNA suppression in the long term (European Association For the study of the liver, 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). ADV has a higher genetic barrier than LVD resulting in lower rates of resistance (Fung et al., 2008). The cumulative incidence of ADV-resistance is 29% after 5 years of treatment in patients with HBeAg negative and about 20% in HBeAg positive patients (Hadziyannis et al., 2006; A S Lok & McMahon, 2009). According to a large trial, ADV in 10-mg doses was well tolerated and had similar safety profile as placebo (Hadziyannis et al., 2006). However, renal abnormalities were reported with 30 mg of ADV (Marcellin et al., 2003). Continued treatment of ADV up to 5 years induces a reversible increase in serum creatinine of more than 0.5 mg/dL (Hadziyannis et al., 2006). Therefore, renal function should be monitored regularly and closely (A S Lok & McMahon, 2009).

Entecavir (ETV) is the third oral nucleoside analog licensed for CHB (Lai & Yuen, 2008). It was superior to LVD and ADV in rates of histologic, biochemical and virologic responses, irrespective of HBeAg status (T. T. Chang et al., 2006; Lai et al., 2002; Lai et al., 2006; Leung, 2008). In a viral kinetic study ETV showed a more dramatic decline in HBV DNA levels than ADV (Y F Liaw et al., 2008). After 2 years of ETV treatment, no virological breakthrough from ETV resistance has been found (Fung et al., 2008; Lai & Yuen, 2008; Y F Liaw et al., 2008). The rate of resistance to ETV was very low at 1.2% in treatment-naïve patients after 5 years (Ayoub & Keeffe, 2008; European Association For the study of the liver, 2008; Lai & Yuen, 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; Nguyen & Keeffe, 2009). ETV has demonstrated to be effective in LVD-resistant patients, but was associated with a lower response rate and a higher resistance rate of 39.5% after 4 years (Ayoub & Keeffe, 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; Nguyen & Keeffe, 2009). Therefore, LVD should be discontinued when patients are switched to ETV in order to reduce the risk of ETV resistance (Fung et al., 2008; A S Lok & McMahon, 2009). ADV addon therapy may be better than ETV switching therapy for patients with LVD-resistance (Fung et al., 2008; Keeffe et al., 2008; A S Lok & McMahon, 2009). ETV therapy is best given

Telbivudine (LdT) is more potent than LVD and ADV in HBV DNA suppression (H. L. Chan et al., 2007; Keeffe et al., 2008; Lai et al., 2005; A S Lok & McMahon, 2009). A phase III controlled trial showed that 60% of patients who received LdT had an undetectable HBV DNA level compared to those who received LVD (40%) after 2 years of treatment (Keeffe et al., 2008; Y. F. Liaw et al., 2009). Resistance rate increases dramatically after one year of LdT to 25.1% in HBeAg positive and 10.8% in HBeAg negative patients after 2 years of treatment (Y F Liaw et al., 2008; A S Lok & McMahon, 2009). LdT was well tolerated when used as a monotherapy and has a similar safety profile to LVD (Keeffe et al., 2008; Leung, 2008; A S Lok & McMahon,

to treatment naïve patients (Leung, 2008).

pretreatment level has shown a beneficial effect on reduction of liver-related complications, for instance, cirrhosis and HCC (Fung et al., 2008). The occurrence of adverse event is the main concern. Standard IFN and peg-IFN have similar side effect profiles but is less common in peg-IFN (A S Lok & McMahon, 2009). The most common side effect is influenza-like symptoms consisting of fever, chills, headache, malaise and myalgia (Jacobson, 2006; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Other side effects comprise fatigue, anorexia, weight loss and hair loss (Y F Liaw et al., 2008). Patients receiving IFN should have regular follow-up for mood deterioration (Jacobson, 2006). Recently, studies have focused on combination or sequential therapy with LVD (Y F Liaw et al., 2008). No superior effects have been found with combination therapy of IFN and lamivudine (LVD) (Jacobson, 2006; Y F Liaw et al., 2008). It reduced the risk of developing resistance.

Lamivudine (LVD) is a nucleoside analog and the first oral anti-viral drug licensed since 1998 for the treatment of CHB infection (Ayoub & Keeffe, 2008; Lai & Yuen, 2008). It has an excellent safety profile (Ayoub & Keeffe, 2008; Fung et al., 2008; Jacobson, 2006; Leung, 2008; Y F Liaw et al., 2008) and is the least expensive of all nucleoside analogs approved for the treatment of CHB (Dan, Aung, & Lim, 2008; Zoulim & Perrillo, 2008). It is effective in suppressing HBV DNA, normalizing ALT and HBeAg seroconversion (Dienstag et al., 1999; Fung et al., 2008; Lai et al., 1998; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Previous studies showed that LVD led to significant histological improvement and reduction in the progression of liver fibrosis (Ayoub & Keeffe, 2008; Dienstag et al., 1999; Lai et al., 1998; Leung, 2008). Long-term LVD therapy reduces the risk of developing cirrhosis and HCC in precirrhotic/cirrhotic and non-cirrohotic patients (Y. F. Liaw et al., 2004; Yuen et al., 2007). Duration of LVD therapy remains controversial in HBeAg negative CHB patients (A S Lok & McMahon, 2009). For patients who are HBeAg positive, LVD can be stopped 6-9 months after HBeAg seroconversion (A S Lok & McMahon, 2009). Hepatic flares, defined as increased serum ALT levels to ≥ 5 times upper normal limit, may develop on stopping LVD and result in hepatic decompensation (Fung et al., 2008; Y F Liaw et al., 2008). Earlier studies demonstrated about 50% of the patients achieved a sustained response after stopping LVD treatment (Y F Liaw et al., 2008). In one of the studies by Chan et al, 89 Chinese CHB patients with HBeAg negative received two years of LVD treatment resulted in 56% complete response (defined as normalization of ALT and HBV DNA level of < 104 copies/mL) (Y F Liaw et al., 2008). The response was sustained in 26% of patients 6 months after stopping LVD treatment (Y F Liaw et al., 2008). The main drawback of LVD is development of drug resistance (Jacobson, 2006; Y F Liaw et al., 2008; Nguyen & Keeffe, 2009; Yuen & Lai, 2001; Zoulim & Perrillo, 2008). According to a recent review, LVD drug resistance rates are approximately 50% after 3 years and 76% after 8 years (Ayoub & Keeffe, 2008; Fung et al., 2008; Leung, 2008; Nguyen & Keeffe, 2009; Yuen et al., 2007). The incidence of drug resistance increased with the duration of therapy (Ayoub & Keeffe, 2008; Fung et al., 2008; Jacobson, 2006; Leung, 2008). Benefits induced by LVD therapy are reduced once drug resistance occurs (Fung et al., 2008; Jacobson, 2006). However, even those who develop LVD-resistance, their treatment outcome is still better than untreated patients.

Adedovir (ADV) is the second oral nucleoside analog approved for CHB and has been shown to be effective, irrespective of HBeAg status or LVD-resistance (Hadziyannis et al., 2006; Hadziyannis et al., 2003; Lampertico et al., 2005; Leung, 2008; Marcellin et al., 2003). Although ADV has fairly slow action compared with other oral anti-viral treatments (in terms of HBAg seroconversion, normalization of ALT and suppression of HBV DNA),

pretreatment level has shown a beneficial effect on reduction of liver-related complications, for instance, cirrhosis and HCC (Fung et al., 2008). The occurrence of adverse event is the main concern. Standard IFN and peg-IFN have similar side effect profiles but is less common in peg-IFN (A S Lok & McMahon, 2009). The most common side effect is influenza-like symptoms consisting of fever, chills, headache, malaise and myalgia (Jacobson, 2006; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Other side effects comprise fatigue, anorexia, weight loss and hair loss (Y F Liaw et al., 2008). Patients receiving IFN should have regular follow-up for mood deterioration (Jacobson, 2006). Recently, studies have focused on combination or sequential therapy with LVD (Y F Liaw et al., 2008). No superior effects have been found with combination therapy of IFN and lamivudine (LVD) (Jacobson, 2006; Y F Liaw et al., 2008). It

Lamivudine (LVD) is a nucleoside analog and the first oral anti-viral drug licensed since 1998 for the treatment of CHB infection (Ayoub & Keeffe, 2008; Lai & Yuen, 2008). It has an excellent safety profile (Ayoub & Keeffe, 2008; Fung et al., 2008; Jacobson, 2006; Leung, 2008; Y F Liaw et al., 2008) and is the least expensive of all nucleoside analogs approved for the treatment of CHB (Dan, Aung, & Lim, 2008; Zoulim & Perrillo, 2008). It is effective in suppressing HBV DNA, normalizing ALT and HBeAg seroconversion (Dienstag et al., 1999; Fung et al., 2008; Lai et al., 1998; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Previous studies showed that LVD led to significant histological improvement and reduction in the progression of liver fibrosis (Ayoub & Keeffe, 2008; Dienstag et al., 1999; Lai et al., 1998; Leung, 2008). Long-term LVD therapy reduces the risk of developing cirrhosis and HCC in precirrhotic/cirrhotic and non-cirrohotic patients (Y. F. Liaw et al., 2004; Yuen et al., 2007). Duration of LVD therapy remains controversial in HBeAg negative CHB patients (A S Lok & McMahon, 2009). For patients who are HBeAg positive, LVD can be stopped 6-9 months after HBeAg seroconversion (A S Lok & McMahon, 2009). Hepatic flares, defined as increased serum ALT levels to ≥ 5 times upper normal limit, may develop on stopping LVD and result in hepatic decompensation (Fung et al., 2008; Y F Liaw et al., 2008). Earlier studies demonstrated about 50% of the patients achieved a sustained response after stopping LVD treatment (Y F Liaw et al., 2008). In one of the studies by Chan et al, 89 Chinese CHB patients with HBeAg negative received two years of LVD treatment resulted in 56% complete response (defined as normalization of ALT and HBV DNA level of < 104 copies/mL) (Y F Liaw et al., 2008). The response was sustained in 26% of patients 6 months after stopping LVD treatment (Y F Liaw et al., 2008). The main drawback of LVD is development of drug resistance (Jacobson, 2006; Y F Liaw et al., 2008; Nguyen & Keeffe, 2009; Yuen & Lai, 2001; Zoulim & Perrillo, 2008). According to a recent review, LVD drug resistance rates are approximately 50% after 3 years and 76% after 8 years (Ayoub & Keeffe, 2008; Fung et al., 2008; Leung, 2008; Nguyen & Keeffe, 2009; Yuen et al., 2007). The incidence of drug resistance increased with the duration of therapy (Ayoub & Keeffe, 2008; Fung et al., 2008; Jacobson, 2006; Leung, 2008). Benefits induced by LVD therapy are reduced once drug resistance occurs (Fung et al., 2008; Jacobson, 2006). However, even those who develop

LVD-resistance, their treatment outcome is still better than untreated patients.

Adedovir (ADV) is the second oral nucleoside analog approved for CHB and has been shown to be effective, irrespective of HBeAg status or LVD-resistance (Hadziyannis et al., 2006; Hadziyannis et al., 2003; Lampertico et al., 2005; Leung, 2008; Marcellin et al., 2003). Although ADV has fairly slow action compared with other oral anti-viral treatments (in terms of HBAg seroconversion, normalization of ALT and suppression of HBV DNA),

reduced the risk of developing resistance.

treatment with ADV up to 5 years results in significant histologic, virologic and biochemical improvement (Hadziyannis et al., 2005). Currently, ADV is primarily used in patients who have developed resistance to LVD (Fung et al., 2008; Zoulim & Perrillo, 2008). Some studies have shown the addition of ADV to LVD rather than switchover to ADV monotherapy produced a lower rate of resistance to ADV (Lampertico et al., 2007; Manolakopoulos et al., 2008; Rapti, Dimou, Mitsoula, & Hadziyannis, 2007; van der Poorten et al., 2007; Zoulim & Perrillo, 2008). Other studies have shown that ADV monotherapy in patients with LVDresistant was as effective for HBV DNA suppression as combination therapy (Fung et al., 2007; Fung et al., 2008; Y F Liaw et al., 2008; Peters et al., 2004). Most guidelines recommended to add on ADV in LVD-resistant patients in order to minimize the development of ADV-resistance and maintain HBV DNA suppression in the long term (European Association For the study of the liver, 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). ADV has a higher genetic barrier than LVD resulting in lower rates of resistance (Fung et al., 2008). The cumulative incidence of ADV-resistance is 29% after 5 years of treatment in patients with HBeAg negative and about 20% in HBeAg positive patients (Hadziyannis et al., 2006; A S Lok & McMahon, 2009). According to a large trial, ADV in 10-mg doses was well tolerated and had similar safety profile as placebo (Hadziyannis et al., 2006). However, renal abnormalities were reported with 30 mg of ADV (Marcellin et al., 2003). Continued treatment of ADV up to 5 years induces a reversible increase in serum creatinine of more than 0.5 mg/dL (Hadziyannis et al., 2006). Therefore, renal function should be monitored regularly and closely (A S Lok & McMahon, 2009).

Entecavir (ETV) is the third oral nucleoside analog licensed for CHB (Lai & Yuen, 2008). It was superior to LVD and ADV in rates of histologic, biochemical and virologic responses, irrespective of HBeAg status (T. T. Chang et al., 2006; Lai et al., 2002; Lai et al., 2006; Leung, 2008). In a viral kinetic study ETV showed a more dramatic decline in HBV DNA levels than ADV (Y F Liaw et al., 2008). After 2 years of ETV treatment, no virological breakthrough from ETV resistance has been found (Fung et al., 2008; Lai & Yuen, 2008; Y F Liaw et al., 2008). The rate of resistance to ETV was very low at 1.2% in treatment-naïve patients after 5 years (Ayoub & Keeffe, 2008; European Association For the study of the liver, 2008; Lai & Yuen, 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; Nguyen & Keeffe, 2009). ETV has demonstrated to be effective in LVD-resistant patients, but was associated with a lower response rate and a higher resistance rate of 39.5% after 4 years (Ayoub & Keeffe, 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; Nguyen & Keeffe, 2009). Therefore, LVD should be discontinued when patients are switched to ETV in order to reduce the risk of ETV resistance (Fung et al., 2008; A S Lok & McMahon, 2009). ADV addon therapy may be better than ETV switching therapy for patients with LVD-resistance (Fung et al., 2008; Keeffe et al., 2008; A S Lok & McMahon, 2009). ETV therapy is best given to treatment naïve patients (Leung, 2008).

Telbivudine (LdT) is more potent than LVD and ADV in HBV DNA suppression (H. L. Chan et al., 2007; Keeffe et al., 2008; Lai et al., 2005; A S Lok & McMahon, 2009). A phase III controlled trial showed that 60% of patients who received LdT had an undetectable HBV DNA level compared to those who received LVD (40%) after 2 years of treatment (Keeffe et al., 2008; Y. F. Liaw et al., 2009). Resistance rate increases dramatically after one year of LdT to 25.1% in HBeAg positive and 10.8% in HBeAg negative patients after 2 years of treatment (Y F Liaw et al., 2008; A S Lok & McMahon, 2009). LdT was well tolerated when used as a monotherapy and has a similar safety profile to LVD (Keeffe et al., 2008; Leung, 2008; A S Lok & McMahon,

Reviews on the Epidemiology, Quality of Life, and Management of Chronic Hepatitis B (CHB) 381

Although there are several published guidelines for HCC screening, there is no consensus regarding screening for HCC (Bruix et al., 2005; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; Omata et al., 2010). A recent AASLD practice guideline has been published and recommended that HBV carriers at high risk should be screened with ultrasound (US) every 6-12 months and alpha-fetoprotein (AFP) alone if US is not available (A S Lok & McMahon, 2009). Ultrasound and AFP are currently two commonly used screening tests for HCC (A S Lok & McMahon, 2009). High risk group is defined as Asian men aged >40 years old, Asian women aged >50 years old, those with cirrhosis or family history of severe liver disease, with persistent or intermittent ALT elevation and/or high HBV DNA level >2000 IU/mL (A S Lok & McMahon, 2009). On the other hand, the latest Asia-Pacific consensus suggested that only male HBV carriers aged 40 or above with cirrhosis or family history of serious liver disease should be screened with US and AFP every 3-6 months (Y F Liaw et al., 2008). In general, HCC screening should be considered for patients with cirrhosis. However, it remains unclear whether screening for HCC in an asymptomatic population has beneficial outcomes, what is the best screening strategy and

The Hong Kong Government provides healthcare service to patients with HBV infection, but resources are limited and management has to be prioritized according to the severity of the illness. For patients found to be CHB carriers, the frequency of monitoring and types of

In Hong Kong, lamivudine (LVD), adefovir (ADV) and entecavir (ETV) are the standard antiviral drugs used for the treatment of CHB (Fung et al., 2008). Interferons are of doubtful use for Chinese patients (Fung et al., 2008). Telbivudine (LdT) is seldom used because of its cost and high resistance rate (Fung et al., 2008; Zoulim & Perrillo, 2008). The long-term effect of tenofovir (TDF) is unknown (Keeffe et al., 2008; Lai & Yuen, 2008; Y F

Anti-viral drugs are expensive and the government provides subsidy for patients with cirrhosis and HCC only in public service. Most CHB patients with impaired liver function (ILF) need to pay for their full drug cost and HBV DNA assay. The costs of anti-viral treatment range from HKD 1,000 to HKD 3,000 per month depending on the drug choice (Yeo B, 2008). Patients' willingness to pay may influence treatment options which also affects the duration of treatment, effectiveness, drug resistance and side effects. Many patients cannot afford or are not willing to pay for treatment even though it is recommended by physicians. There is no policy on hepatitis B screening (Hong Kong (China). Dept. of Health., 1998), which is not routinely provided by the public service.

Free printed information on hepatitis is available from the Department of Health to educate the public about the prevention of spread of the disease, indication for treatment and treatment options (Department of Health). Primary care doctors or specialists can easily distribute these printed information to their patients during the consultation but this not often done because time is limited and the evaluation of disease pathology and its

whether screening is cost-effective.

Liaw et al., 2008).

complication take top priority.

**2.2.4 Health services for CHB in Hong Kong** 

laboratory tests differed by the severity of their diseases.

2009). Increase in creatine kinase levels (a level of >7 times upper limit of normal (ULN)) was more commonly found in patients receiving LdT than LVD (7.5% vs. 3.1%) (Leung, 2008; Y F Liaw et al., 2008). However, it improved spontaneously with continued drug therapy. Cases of reversible myopathy and peripheral neuropathy have been reported (Leung, 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Although LdT is more potent than LVD, its high resistance rate and cost limit its use as the first line treatment for CHB (Keeffe et al., 2008; Leung, 2008; Y F Liaw et al., 2008; Zoulim & Perrillo, 2008).

Tenofovir (TDF) is an oral anti-viral drug and has been approved for the treatment of CHB in 2008 (Ayoub & Keeffe, 2008; A S Lok & McMahon, 2009). It belongs to the same family of nucleotide analogs as ADV (Ayoub & Keeffe, 2008; Keeffe et al., 2008; A S Lok & McMahon, 2009; Zoulim & Perrillo, 2008). It has been shown to be more potent than ADV particularly in early suppression of HBV (Ayoub & Keeffe, 2008; Keeffe et al., 2008; Lai & Yuen, 2008; Leung, 2008; Marcellin et al., 2008). In a phase III clinical trial in HBeAg positive patients, TDF resulted in a significantly higher percentage of patients with undetectable HBV DNA levels compared with ADV (76% vs. 13%) after 48 weeks (Ayoub & Keeffe, 2008; Y F Liaw et al., 2008; Marcellin et al., 2008). No resistance mutations associated with TDF were found at week 48 and 72 (Ayoub & Keeffe, 2008; Keeffe et al., 2008; Lai & Yuen, 2008; Leung, 2008). The incidence of adverse events was similar in TDF and ADV (Ayoub & Keeffe, 2008; Keeffe et al., 2008). The incidence of ALT flares (>2 times baseline values) was higher in patients receiving TDF than those with ADV (11% vs. 4%) (Keeffe et al., 2008). Studies are still ongoing for long-term efficacy and safety.
