**2.3.1 Impact of CHB on HRQOL**

384 Hepatocellular Carcinoma – Basic Research

Chronic hepatitis B (CHB) is a chronic debilitating condition that can lead to progressive impairment of physical and mental health as the disease progresses. Improvements in medical and surgical therapies in liver diseases have led to more people living with CHB. HRQOL should be considered an important outcome measures for assessing the impact of CHB and the effectiveness of treatment. The expansion from traditional clinical outcomes to include HRQOL outcomes will enable us to measure modern health care more sensitively (Younossi, 2001). HRQOL is more sensitive in capturing the effect of illness and interventions for those with uncomplicated disease (Bondini et al., 2007; Levy et al., 2008; Nokhodian, Ataei, Kassaian, Adibi, & Farajzadegan, 2009; S C Ong et al., 2008; Tan, Cheah, Teo, & Yang, 2008; Yi, 2006). Furthermore, HRQOL provides additional information for the prioritization of needs among patients with similar clinical severity defined by traditional clinical outcomes. The effect of an intervention on HRQOL has become a very important topic for both consumers and providers of health services (R. C. Martin, Eid, Scoggins, &

The applications of HRQOL measures can be categorized as evaluative, discriminative and predictive (Preedy, Watson, & Lam, 2010; Yacavone, Locke, Provenzale, & Eisen, 2001). Evaluative measures are the most widely used in different populations or patients groups (Preedy et al., 2010). It is used to assess the impact of an illness, effectiveness or side effect of treatment, and quality of healthcare delivery (Preedy et al., 2010; Yacavone et al., 2001). Discriminative measures can be used to differentiate between groups in terms of HRQOL (Preedy et al., 2010; Yacavone et al., 2001). Predictive measures are used to identify people who are at risk or predict service needs for different populations or patient groups (Preedy et al., 2010). HRQOL measures can apply in economic evaluation in relation to treatment (Kanwal et al., 2005; Sun, Qin, Li, & Jiang, 2007; Takeda, Jones, Shepherd, Davidson, & Price, 2007; Veenstra, Spackman, Bisceglie, Kowdley, & Gish,

The World Health Organization (WHO) states that 'health is a state of complete physical, mental and social well-being' (WHO, 1947). Well-being is the subjective perception of an individual's state of living, which has a similar concept as quality of life. It is noted that health is only one of many determinants of a person's quality of life, others include social environment, economy, religion etc. In the context of health services, the focus is on healthrelated quality of life (HRQOL) in an attempt to quantify the net consequence of a disease and its treatment on the patient's perception of his/her ability to live a useful and fulfilling

In the last few decades, there has been an increasing interest in the evaluation of HRQOL in patient groups, including those with chronic liver disease (Foster, Goldin, & Thomas, 1998; J. J. Gutteling, de Man, Busschbach, & Darlington, 2007; Younossi, 2001). The number of articles in gastroenterology on quality of life (QOL) or HRQOL has increased significantly in recent decades (Foster et al., 1998; L. M. Martin et al., 2006; L. M. Martin, Sheridan, & Younossi, 2002; L. M. Martin & Younossi, 2005; Younossi et al., 2001; Younossi, Kiwi, Boparai, Price, & Guyatt, 2000). HRQOL has become standard outcome measure in patients with chronic liver diseases in western countries especially in patients with chronic hepatitis C (CHC) (Chong et al., 2003; Foster, 1999; Foster et al., 1998; Kwan et al., 2008; Spiegel et al.,

2005). It should also become an important outcome measure in CHB patients.

McMasters, 2007; Poon et al., 2001; Yi, 2006).

2008; Yuan, Iloeje, Li, Hay, & Yao, 2008).

life (Schipper, Clinch, & Olweny, 1996).

Although numerous studies have shown significant lower health-related quality of life (HRQOL) scores in patients with chronic liver diseases (CLD), there is relatively little attention on the impact of HRQOL in patients with hepatitis B virus (HBV) because most data come from western populations where CHB is uncommon (J. J. Gutteling et al., 2007; L. M. Martin et al., 2002). In general, studies showed a significant decline in HRQOL in patients with hepatitis C virus (HCV) (Foster et al., 1998; Heitkemper, Jarrett, Kurashige, & Carithers, 2001; Koff, 1999; Kwan et al., 2008; Miller, Hiller, & Shaw, 2001; Spiegel et al., 2005; Strauss & Dias Teixeira, 2006). Only a few papers explored the effect of CHB on HRQOL (Bondini et al., 2007; Levy et al., 2008; Nokhodian et al., 2009; S C Ong et al., 2008; Tan et al., 2008). The first paper on HRQOL of CHB was published by Foster et al in 1998, which evaluated the impact of chronic hepatitis C (CHC) and CHB by a generic measure of HRQOL, the Medical Outcomes Study Short Form-36 (SF-36) Health Survey (Foster et al., 1998). Patients with CHB had significant lower HRQOL scores in mental health and general health perception aspects, but their physical related HRQOL scores were comparable to the healthy control (Foster et al., 1998). The results indicated patients with CHB infection did not have significant lower scores in physical functions but the results were limited by a very small sample of CHB patients (Foster et al., 1998).

Studies with a larger sample size and patients with different stages of CHB are needed in order to provide more precise measures of HRQOL. One study found that CHB patients had similar HRQOL scores to the healthy control group, as measured by both generic (Short Form-36 Health Survey, SF-36) and disease-specific (Chronic Liver Disease Questionnaire, CLDQ) questionnaires (Bondini et al., 2007). CHB patients had lower HRQOL scores in only two (fatigue and worry) out of six CLDQ scales and two (physical functioning and vitality) out of eight SF-36 scales compared to the norm (Bondini et al., 2007). However, health preference values (utility) of CHB patients were lower than the population norm (Bondini et al., 2007).

Recently, two large studies showed that CHB infection had a negative impact on HRQOL (Levy et al., 2008; S C Ong et al., 2008). Asymptomatic hepatitis B (AHB) carriers, CHB patients with impaired liver function (ILF), and compensated cirrhosis (CC) patients had a small to moderate but significant effect on HRQOL, and decompensated cirrhosis (DC) and hepatocellular carcinoma (HCC) patients had the lowest HRQOL scores (S C Ong et al., 2008). Ong et al demonstrated that HRQOL measured by the generic HRQOL measures, the SF-36 Health Survey and EQ-5D, in Chinese AHB carriers was comparable to healthy controls, although those with ILF and CC patients showed a significant reduction in general health and mental health dimensions (S C Ong et al., 2008). Patients with more advanced stages of CHB (DC and HCC) had the lowest HRQOL scores in all dimensions (S C Ong et al., 2008). The results indicated deterioration in physical health while the disease progresses (S C Ong et al., 2008).

Another study by Tan et al showed that hepatitis B carriers in Singapore had good physical and mental health measured by both generic (SF-36 Health Survey) and disease-specific (Hepatitis Quality of Life Questionnaire) HRQOL measures (Tan et al., 2008). There was no significant difference in HRQOL between the 108 hepatitis B carriers in the study and general population, except in social functioning (Tan et al., 2008).

Reviews on the Epidemiology, Quality of Life, and Management of Chronic Hepatitis B (CHB) 387

One study examining the impact of liver cirrhosis found that the presence of cirrhosis was associated with lower HRQOL scores (Bondini et al., 2007). But Dan et al did not find any significant relationship between presence of cirrhosis and HRQOL (A. A. Dan et al., 2008). These two studies only included a small number of patients with CHB infection (Bondini et al., 2007; A. A. Dan et al., 2008). More studies are needed to confirm the relationship

Liver biomarkers, such as alanine transaminase (ALT), was not found to have any significant association with HRQOL (Bondini et al., 2007; Hussain et al., 2001; Miller et al., 2001), though it is an important clinical markers to assess the severity of liver and determine indication for treatment (Fung et al., 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; McMahon, 2006). However, Kondo et al found an association between HRQOL and serum albumin (Kondo et al., 2007), which is a marker

Physical symptoms, for instance, joint pain, muscle cramps, itching and abdominal pain, were also correlated with HRQOL (J. J. Gutteling et al., 2007; Marchesini et al., 2001; Younossi, 2001). Fatigue was also a concern for patients with chronic liver disease (J. J.

Anti-viral treatment may improve patients' HRQOL (Bernstein, Kleinman, Barker, Revicki, & Green, 2002; S. C. Chang, Ko, Wu, Peng, & Yang, 2008; Kang, Hwang, Lee, Chang, & Lee, 2005; McHutchison et al., 2001; Perrillo et al., 2004; Ware, Bayliss, Mannocchia, & Davis, 1999), but side effects can be a problem (Fung et al., 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Foster et al showed that patients with HCV receiving antiviral treatment of 6-12 months had decreased HRQOL because of side effects (Foster, 1999). Other studies demonstrated a sustained response to treatment was associated with improved HRQOL in patients with HCV infection (Bernstein et al., 2002; S. C. Chang et al., 2008; Kang et al., 2005; McHutchison et al., 2001; Perrillo et al., 2004; Ware et al., 1999).

Socio-demographic factors also play an important role in HRQOL, including age, gender, education levels, marital status and socio-economic status (J. J. Gutteling et al., 2007; L. M. Martin et al., 2002). Previous studies found a significant effect of age and gender on HRQOL in patients with chronic liver disease, including patients with CHC and CHB (J. J. Gutteling et al., 2007; L. M. Martin et al., 2002). Older age was associated with lower HRQOL in patients with chronic liver disease (Afendy et al., 2009; J J Gutteling et al., 2006; Kondo et al., 2007; Sobhonslidsuk et al., 2006; Younossi et al., 2001), but insignificant or positive effect on physical or mental HRQOL (Bianchi et al., 2003; Bondini et al., 2007; A. A. Dan et al., 2008; Hauser, Holtmann, et al., 2004; Hauser, Zimmer, et al., 2004; Hussain et al., 2001; Sumskiene et al., 2006). Consistently, females were more likely to have poorer HRQOL than males (Afendy et al., 2009; Bianchi et al., 2003; A. A. Dan et al., 2008; J J Gutteling et al., 2006; Hussain et al., 2001; Sobhonslidsuk et al., 2006). This pattern is found on the general population as well as patients with CLD (C. L. Lam, Lauder, Lam, & Gandek, 1999; E. T. Lam, Lam, Lo, & Grandek, 2008). Very few data have demonstrated the effect of other sociodemographic factors (Hauser, Holtmann, et al., 2004; Hussain et al., 2001; Sobhonslidsuk et al., 2006), such as education level, marital status and social class/ socio-economic status. Studies showed that level of education was positively correlated with HRQOL (Hussain et

Studies are needed to confirm the effect of anti-viral treatment on HRQOL.

between the severity of liver disease and HRQOL in patients with CHB infection.

of severity of liver disease.

Gutteling et al., 2007; J J Gutteling et al., 2006).

A recent study assessing HRQOL in patients with CHB infection was conducted using a disease-specific HRQOL measure (Chronic Liver Disease Questionnaire) in Iran (Nokhodian et al., 2009). A sample of 61 patients with CHB infection and 60 age and sexmatched healthy control were recruited in this study (Nokhodian et al., 2009). Patients had lower (worse) scores in three out of six CLDQ scales, including fatigue, abdominal and systemic symptoms, as compared to controls (Nokhodian et al., 2009). Surprisingly, CHB patients had a higher score on the worry scale, i.e. less worry, than the control groups (Nokhodian et al., 2009).

Findings from a multi-country study on health preference values found that health states related to CHB infection had significant reduction in HRQOL (Levy et al., 2008). Health preference is a composite HRQOL value that ranges from 0 (death) to 1 (perfect health), with higher scores implying better HRQOL (Brazier, Roberts, & Deverill, 2002). Patients with ILF and CC had a moderate impact on HRQOL with health preference values ranging from 0.68 to 0.80 (Levy et al., 2008). On the other hand, patients with DC or HCC had a stronger impact with health preference values ranging from 0.35 to 0.41 (Levy et al., 2008). Variation in health preference values was found between countries with lower health preference values found in Hong Kong and Mainland China than countries (Levy et al., 2008).

These studies provided some evidence on the negative HRQOL impact of CHB but they are limited by small sample size, inconsistent results and a lack of differentiation between CHB patient types (Bondini et al., 2007; Foster et al., 1998; S C Ong et al., 2008; Tan et al., 2008). Although studies have reported that HCC or cirrhosis patients had poorer overall HRQOL scores compared with the general population (Chong et al., 2003; A. A. Dan et al., 2008; S C Ong et al., 2008), it is still unclear whether patients with asymptomatic, CHB infection with or without ILF have poorer HRQOL than the general population, and whether any significant difference in HRQOL was found among different CHB groups.

An analytic investigation on factors affecting HRQOL enables better targeting of management. Previous studies suggested that biochemical markers, socio-demographic and psychosocial factors did affect HRQOL in patients with CLD but it has not been fully examined in Chinese CHB patients (Afendy et al., 2009; Bianchi et al., 2003; J J Gutteling et al., 2006; Hauser, Schnur, Steder-Neukamm, Muthny, & Grandt, 2004; Hussain et al., 2001; Marchesini et al., 2001; Sobhonslidsuk et al., 2006; Sumskiene, Sumskas, Petrauskas, & Kupcinskas, 2006; Younossi et al., 2001; Younossi et al., 2000). Disease severity, as measured by Child-Pugh scores or stage of CHB illness (asymptomatic, impaired liver function, cirrhosis and HCC), was one of the commonest factors that had a negative relationship with HRQOL (Bianchi et al., 2003; J J Gutteling et al., 2006; Marchesini et al., 2001; Sobhonslidsuk et al., 2006; Sumskiene et al., 2006; Younossi et al., 2001; Younossi et al., 2000). However, some studies did not find any significant effect between HRQOL and disease severity (Hauser, Holtmann, & Grandt, 2004; Hauser, Zimmer, Schiedermaier, & Grandt, 2004). One large cross-sectional study in Singapore found that disease severity was an important determinant of HRQOL of Chinese patients with CHB, controlling for demographic characteristics (S C Ong et al., 2008). Unfortunately, this study did not include some important clinical and co-morbidity variables in regression model, for instance, duration of illness and chronic co-morbidity (S C Ong et al., 2008).

A recent study assessing HRQOL in patients with CHB infection was conducted using a disease-specific HRQOL measure (Chronic Liver Disease Questionnaire) in Iran (Nokhodian et al., 2009). A sample of 61 patients with CHB infection and 60 age and sexmatched healthy control were recruited in this study (Nokhodian et al., 2009). Patients had lower (worse) scores in three out of six CLDQ scales, including fatigue, abdominal and systemic symptoms, as compared to controls (Nokhodian et al., 2009). Surprisingly, CHB patients had a higher score on the worry scale, i.e. less worry, than the control

Findings from a multi-country study on health preference values found that health states related to CHB infection had significant reduction in HRQOL (Levy et al., 2008). Health preference is a composite HRQOL value that ranges from 0 (death) to 1 (perfect health), with higher scores implying better HRQOL (Brazier, Roberts, & Deverill, 2002). Patients with ILF and CC had a moderate impact on HRQOL with health preference values ranging from 0.68 to 0.80 (Levy et al., 2008). On the other hand, patients with DC or HCC had a stronger impact with health preference values ranging from 0.35 to 0.41 (Levy et al., 2008). Variation in health preference values was found between countries with lower health preference values found in Hong Kong and Mainland China than countries (Levy

These studies provided some evidence on the negative HRQOL impact of CHB but they are limited by small sample size, inconsistent results and a lack of differentiation between CHB patient types (Bondini et al., 2007; Foster et al., 1998; S C Ong et al., 2008; Tan et al., 2008). Although studies have reported that HCC or cirrhosis patients had poorer overall HRQOL scores compared with the general population (Chong et al., 2003; A. A. Dan et al., 2008; S C Ong et al., 2008), it is still unclear whether patients with asymptomatic, CHB infection with or without ILF have poorer HRQOL than the general population, and whether any

An analytic investigation on factors affecting HRQOL enables better targeting of management. Previous studies suggested that biochemical markers, socio-demographic and psychosocial factors did affect HRQOL in patients with CLD but it has not been fully examined in Chinese CHB patients (Afendy et al., 2009; Bianchi et al., 2003; J J Gutteling et al., 2006; Hauser, Schnur, Steder-Neukamm, Muthny, & Grandt, 2004; Hussain et al., 2001; Marchesini et al., 2001; Sobhonslidsuk et al., 2006; Sumskiene, Sumskas, Petrauskas, & Kupcinskas, 2006; Younossi et al., 2001; Younossi et al., 2000). Disease severity, as measured by Child-Pugh scores or stage of CHB illness (asymptomatic, impaired liver function, cirrhosis and HCC), was one of the commonest factors that had a negative relationship with HRQOL (Bianchi et al., 2003; J J Gutteling et al., 2006; Marchesini et al., 2001; Sobhonslidsuk et al., 2006; Sumskiene et al., 2006; Younossi et al., 2001; Younossi et al., 2000). However, some studies did not find any significant effect between HRQOL and disease severity (Hauser, Holtmann, & Grandt, 2004; Hauser, Zimmer, Schiedermaier, & Grandt, 2004). One large cross-sectional study in Singapore found that disease severity was an important determinant of HRQOL of Chinese patients with CHB, controlling for demographic characteristics (S C Ong et al., 2008). Unfortunately, this study did not include some important clinical and co-morbidity variables in regression model, for instance, duration of

significant difference in HRQOL was found among different CHB groups.

illness and chronic co-morbidity (S C Ong et al., 2008).

groups (Nokhodian et al., 2009).

et al., 2008).

One study examining the impact of liver cirrhosis found that the presence of cirrhosis was associated with lower HRQOL scores (Bondini et al., 2007). But Dan et al did not find any significant relationship between presence of cirrhosis and HRQOL (A. A. Dan et al., 2008). These two studies only included a small number of patients with CHB infection (Bondini et al., 2007; A. A. Dan et al., 2008). More studies are needed to confirm the relationship between the severity of liver disease and HRQOL in patients with CHB infection.

Liver biomarkers, such as alanine transaminase (ALT), was not found to have any significant association with HRQOL (Bondini et al., 2007; Hussain et al., 2001; Miller et al., 2001), though it is an important clinical markers to assess the severity of liver and determine indication for treatment (Fung et al., 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009; McMahon, 2006). However, Kondo et al found an association between HRQOL and serum albumin (Kondo et al., 2007), which is a marker of severity of liver disease.

Physical symptoms, for instance, joint pain, muscle cramps, itching and abdominal pain, were also correlated with HRQOL (J. J. Gutteling et al., 2007; Marchesini et al., 2001; Younossi, 2001). Fatigue was also a concern for patients with chronic liver disease (J. J. Gutteling et al., 2007; J J Gutteling et al., 2006).

Anti-viral treatment may improve patients' HRQOL (Bernstein, Kleinman, Barker, Revicki, & Green, 2002; S. C. Chang, Ko, Wu, Peng, & Yang, 2008; Kang, Hwang, Lee, Chang, & Lee, 2005; McHutchison et al., 2001; Perrillo et al., 2004; Ware, Bayliss, Mannocchia, & Davis, 1999), but side effects can be a problem (Fung et al., 2008; Keeffe et al., 2008; Y F Liaw et al., 2008; A S Lok & McMahon, 2009). Foster et al showed that patients with HCV receiving antiviral treatment of 6-12 months had decreased HRQOL because of side effects (Foster, 1999). Other studies demonstrated a sustained response to treatment was associated with improved HRQOL in patients with HCV infection (Bernstein et al., 2002; S. C. Chang et al., 2008; Kang et al., 2005; McHutchison et al., 2001; Perrillo et al., 2004; Ware et al., 1999). Studies are needed to confirm the effect of anti-viral treatment on HRQOL.

Socio-demographic factors also play an important role in HRQOL, including age, gender, education levels, marital status and socio-economic status (J. J. Gutteling et al., 2007; L. M. Martin et al., 2002). Previous studies found a significant effect of age and gender on HRQOL in patients with chronic liver disease, including patients with CHC and CHB (J. J. Gutteling et al., 2007; L. M. Martin et al., 2002). Older age was associated with lower HRQOL in patients with chronic liver disease (Afendy et al., 2009; J J Gutteling et al., 2006; Kondo et al., 2007; Sobhonslidsuk et al., 2006; Younossi et al., 2001), but insignificant or positive effect on physical or mental HRQOL (Bianchi et al., 2003; Bondini et al., 2007; A. A. Dan et al., 2008; Hauser, Holtmann, et al., 2004; Hauser, Zimmer, et al., 2004; Hussain et al., 2001; Sumskiene et al., 2006). Consistently, females were more likely to have poorer HRQOL than males (Afendy et al., 2009; Bianchi et al., 2003; A. A. Dan et al., 2008; J J Gutteling et al., 2006; Hussain et al., 2001; Sobhonslidsuk et al., 2006). This pattern is found on the general population as well as patients with CLD (C. L. Lam, Lauder, Lam, & Gandek, 1999; E. T. Lam, Lam, Lo, & Grandek, 2008). Very few data have demonstrated the effect of other sociodemographic factors (Hauser, Holtmann, et al., 2004; Hussain et al., 2001; Sobhonslidsuk et al., 2006), such as education level, marital status and social class/ socio-economic status. Studies showed that level of education was positively correlated with HRQOL (Hussain et

Reviews on the Epidemiology, Quality of Life, and Management of Chronic Hepatitis B (CHB) 389

advantages and disadvantages. Table 1 presents the characteristics of these disease-

 HQLQ CLDQ LDQOL HBQOL CLD-QOL Author Bayliss et al Younossi et al Granlnek et al Spiegel et al Lee et al Year 1998 1999 2000 2007 2007 Country USA USA USA USA Korea # of items 69 29 111 31 27 # of scales 13 6 20 6 5

No Yes Yes Yes No

Health distress Abdominal Concentration Stigmatization General

Limitations Systemic Memory Vulnerability Uncertain

Health distress

Psychological well-being

Anticipation anxiety

Effects of LD Vitality Emotional

Specific symptoms

status

Social function

Fatigue 8 scales from SF-36

Activity Symptoms of LD

Health distress Worry Quality of social Transmission

Sleep

Loneliness

Hopelessness

Stigma of LD

Sexual

The Chronic Liver Disease Questionnaire (CLDQ) is the first disease-specific HRQOL measure for evaluating patients with chronic liver disease (CLD) developed by Younossi et al (Younossi et al., 1999). The CLDQ has 29 items generated by patients with chronic liver disease, hepatologists, and a review of literature (Younossi et al., 1999). The CLDQ has six scales measuring fatigue, activity, emotional function, abdominal symptoms, systemic symptoms and worry (Younossi et al., 1999), which captures the important problems associated with CHB infection and its complications. It is scored with six domain and one summary scores (Younossi et al., 1999). This short measure can be completed in less than 15 minutes, a criterion for assuring a good response rate (Cella & Tulsky, 1990; McColl,

Emotional function

Table 1. Characteristics of Disease-specific HRQOL Measures

specific HRQOL measures.

Scales 8 scales from SF-36

 Positive wellbeing

somnolence

Sleep

Total score

al., 2001; Sobhonslidsuk et al., 2006). Data from Hussain et al found there was weak correlation between level of education and physical HRQOL (Hussain et al., 2001). On the other hand, another study proved that patients with lower education level had significant lower mental HRQOL scores (Sobhonslidsuk et al., 2006).

Chronic co-morbidity also affected HRQOL in patients with chronic liver disease (Hauser, Holtmann, et al., 2004; Hauser, Zimmer, et al., 2004; Hussain et al., 2001). Hauser et al examined 94 patients with CHC attending a liver clinic and showed that psychiatric comorbidities was one of important determinant of mental component summary (MCS) score of SF-36 (Hauser, Zimmer, et al., 2004). The number of active co-morbidities was associated with the SF-36 physical component summary (PCS) score (Hauser, Zimmer, et al., 2004).
