Hepatitis B

Hepatitis B is caused by the hepatitis B virus (HBV) which affects the liver and can cause both acute and chronic infections. Many patients present no symptoms during the initial infection.

The following estimates have been calculated for the proportion of infected individuals who develop symptoms:

•   30–50% of those adults infected develop acute icteric hepatitis (McMahon et al. 1985)

•   Over 90 percent of perinatal HBV infections are asymptomatic, while the typical manifestations of acute hepatitis are noted in 5–15 percent of newly-infected young children (1–5 years of age) and in 33–50 percent of older children, adolescents, and adults (Shepard et al. 2006).

We therefore assumed that the range for the symptomatic proportion of new infections was age-dependent (see Table 1).

The duration of acute illness has been estimated at six weeks (Kwong, 2012).

Chronicity rate

There is much evidence of age-related variation in the development rate for chronic HBV infection after acute infection. For example:

•   The likelihood of developing chronic HBV infection is higher in individuals infected perinatally (90%) or during childhood (20–30%), when the immune system is thought to be immature, compared with immunocompetent subjects infected during adulthood (<1%)’ (Fattovich, 2008)

•   The overall chronicity rate for HBV has been estimated at 5–10%, although it is higher in those who were infected perinatally (90%) or during childhood (20%) (Yim & Lok, 2005)

•   More than 90% of infected infants, 25–50% of children infected between and 5 years, and 6–10% of acutely infected older children and adults develop chronic infection (Shepard et al. 2006)

•   About 30% of children aged 1–5 years and 5% of adults develop chronic hepatitis B infection (Pungpadong et al. 2007).

•   Nearly all persons infected perinatally and up to 50% of children infected between the ages of 1–5 years develop chronic hepatitis (NIH, 2008)

•   5% of adults with acute infection develop chronic hepatitis B (Wilt et al. 2008)

•   5-10% of adult patients do not clear the virus and either progress to become asymptomatic carriers or develop chronic hepatitis (WHO 2002)

•   The chronicity rate is approximately 90% for infants in the first year of life, 30% for children infected between the ages of 1 and 4 years and <5% for healthy adults (Edmunds et al. 1993).

In the model, we adopted the age-dependent chronicity rates reported above by Fattovich et al. presented in the results of a systematic review of the literature (2008).

The duration of the chronic carrier stage varies according to the presence or absence of active viral replication, estimated at 4.5 years in the case of active viral replication and 33.24 years in the case of no active replication (Stouthard, 1997). Information on the proportion of chronic hepatitis cases with active viral replication to those without active replication is not available and we chose to set the duration as uncertain, between 4.5 and 33.24 years.

Risk of complications

Fulminant liver failure

Fulminant liver failure occurs in approximately 0.5 to 1.0% of adults with reported acute hepatitis B but rarely in infants and children (Pappas, 1995; Hoofnagle et al. 1995). In the model we specified a range (0.5–1.0%) for this transition probability for all age groups as we were unable to locate specific values for infants and children. However, we modelled the age-specific probability of the case fatality rate based on the observed rates, hence a zero probability of children dying of acute hepatitis (see Table 5).

The case fatality rate (CFR) among patients who develop fulminant liver failure is approximately 20–33% (Bernua et al. 1986; Wai et al. 2005) and this figure was chosen for our model. There were no recent specific European studies stating the frequency and impact of orthotopic liver transplantation (OLT) (Steinmuller et al. 2002) and new antiviral medications (Eisenbach, 2006).

The duration of fulminant liver failure, estimated based on the time from onset of symptoms to encephalopathy, is one to 56 days (Trey and Davidson 1970).

Compensated cirrhosis (CC)

According to Chu (2000), on average, 2.1% of people with chronic HBV infection develop compensated cirrhosis annually. This does not take into account variations due to other effects such as alcohol consumption, diabetes and obesity (in the BCoDE toolkit the yearly rate refers to an Annual Transition Probability, ATP, as opposed to the Lifetime Transition Probability, LTP). However, it is important to consider that individuals who have a severe acute exacerbation complicated by subacute hepatic failure or who have recurrent episodes of acute exacerbations with bridging hepatic necrosis are more likely to develop cirrhosis (Chu, 2000)

Decompensated cirrhosis (DC)

According to a systematic review undertaken by D’Amico et al. (2006. The review undertaken by Fattovich et al. (2008) estimated an annual probability of 3–4% for Europe which we chose for our model.

The 20–57% case fatality rate for DC was estimated based on the review by D`Amico et al. (20% from the first of two DC stages, characterised by ascites with or without non-bleeding esophageal varices; 57% from the second of two DC stages, characterised by bleeding varices, with or without ascites).

The duration of DC is based on the average waiting time for liver transplants in EU countries which publish their data online (UK and Spain): between 124 and 142 days (NHS, 2014; Matesanz 2009).

Hepatocellular carcinoma (HCC)

The annual rate of developing HCC is 0.1% in asymptomatic HBsAg individuals, and between 0.3 and 1% in patients with chronic hepatitis B, but this rate increases to 2–10% in patients with compensated cirrhosis (Fattovich, 2008; Yim & Lok, 2005; Pungpadong, 2007; Chu, 2000; D’Amico, 2006). Chu and Liaw (2006) and Fattovich (2008) estimated the CC to HCC transition probability to range between 1.5 and 2.2%/year for Europe.

For the model, we adopted Fattovich`s (2008) estimate stemming from an extensive systematic literature review of 0.3% (0.12–0.41) per year to develop HCC from chronic hepatitis B infection and 2.2% (1.71–2.71) per year for the development of HCC from compensated cirrhosis.

In a European setting, Shepherd`s (2006) cost-effectiveness analysis set the annual case fatality rate for HCC to 56%, while Kanwal (2005) set it to 43.3% (20–60). We chose the latter range for our model as it includes Shepherd`s assumption.

Model input summary

Table 1. Transition probabilities and distributions used in the outcome tree

 Health outcome
 (Health state)

Distribution of health states within health outcome

Transition probability

Source/assumption

Symptomatic infection

 

10–50%
See Table 3

Age-dependent
McMahon, 1985; Shepard, 2006

Chronic hepatitis

 

1–90%
See Table 4

Age-dependent
Fattovich, 2008

Fulminant liver failure

 

0.5–1%

Pappas, 1995; Hoofnagle et al. 1995

Fatal cases due to liver failure

 

20-33.3%
See Table 5

Bernau et al. 1986 ; Wait et al. 2005
Assuming different age-specific probabilities based on observed mortality

Compensated cirrhosis

 

2.1%/year

Chu, 2000 (ATP)

Decompensated cirrhosis

 

3-4%/year

Fattovich, 2008 (ATP)

HCC, following

- Chronic hepatitis

- Compensated cirrhosis

 

 

0.3% (0.12–0.41)/year
2.2% (1.71–2.71)/year

 

Fattovich, 2008 (ATP
Fattovich, 2008 (ATP

CFR, following:

- DC
- HCC

 

 

20-57%/year
43.3% (20-60)/year

 

D’Amico, 2006 (ATP)
Kanwal, 2005 (ATP)

Table 2. Disability weights and duration

Health outcome
(Health state)

Disability Weight (DW) (Haagsma, 2015)

Duration

DW

Source: ECDC European Disability Weight Project (2014)

In years

Source/assumption

Symptomatic infection

0.051 (0.039–0.06)

Infectious disease, acute episode, moderate

0.115

Kwong 2012

Fulminant liver failure

0.515 (0.459–0.572)

Terminal phase, with medication (for cancers, end-stage kidney/liver disease)

0.003–0.153

Trey, 1970

Chronic hepatitis

 0.07 (0.057–0.088)

Generic, uncomplicated disease: worry and daily medication

4.5–33.24

Stouthard, 1997

Assuming uncertainty between proportion with active replication and without

Compensated cirrhosis

 0.07 (0.057–0.088)

Generic uncomplicated disease: worry and daily medication

6-10.4

See Table 6

Murray, 1996

Age and gender specific

Decompensated cirrhosis

0.163 (0.136–0.194)

Decompensated cirrhosis of the liver

0.34–039

Assuming average waiting time before liver transplantation in the UK and Spain (NHS and Matesanz 2009)

Hepatocellular carcinoma

0.265 (0.222–0.303)

Cancer, diagnosis and primary therapy

0.72–4.48

See Table 7

Murray, 1996

Age and gender specific

Table 3. Hepatitis B infected developing symptoms

Age group

Symptomatic hepatitis B

0

10%

1–4

5–15%

5–80+

30–50%

Table 4. Hepatitis B infected developing chronic hepatitis

Age group

Chronic hepatitis B

0

90%

1–4

20–30%

5–80+

1%

Table 5. CFR age distribution for acute hepatitis observed in Estonia, Germany and the Netherlands 2005–2007

Age groups

CFR

0

0.00

1-4

0.00

5-9

0.10

10-14

0.00

15-19

0.00

20-24

0.14

25-29

0.30

30-34

0.53

35-39

1.27

40-44

1.75

45-49

4.56

50-54

5.81

55-59

5.83

60-64

7.90

65-69

11.86

70-74

11.97

75-79

19.77

80-84

15.67

>85

12.54

All ages

100

Table 6. Duration of compensated cirrhosis

Age group

Duration (years)

 

F

M

0–4

10.4

10.3

5–14

10.4

10.4

15–44

10.2

10

45–59

9.3

8.8

60+

6.5

6

Table 7. Duration of HCC

Age group

Duration (years)

 

F

M

0–14

4.48

4.11

15–44

1.45

2.92

45–59

1.91

2.88

60+

0.72

1.56

References

Alter MJ, Mares A, Hadler SC, Maynard JE. The effect of underreporting on the apparent incidence and epidemiology of acute viral hepatitis. Am J Epidemiol. 1987;125(1):133-9.

Bernuau J, Goudeau A, Poynard T. Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology, vol.6, no. 4, pp. 648–651, 1986

Bernuau J, Rueff B, Benhamou JP. Fulminant and subfulminant liver failure: definitions and causes. Seminars in Liver Disease, vol. 6, no. 2, pp. 97–106, 1986

Christensen PB, et al. Outbreak of Hepatitis B among injecting drug users in Denmark. J Clinical Virology 2001;22(1):133-141.

Chu CM. (2000), Natural history of chronic hepatitis B virus infection in adults with emphasis on the occurrence of cirrhosis and hepatocellular carcinoma. Journal of Gastroenterology and Hepatology, 15: E25–E30.

D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. Journal of Hepatology 2006;44(1):217-31.

Edmunds WJ, Medley GF, Nokes DJ, Hall AJ, Whittle HC. The influence of age on the development of the hepatitis B carrier state. Proceedings Biological Sciences, 1993;253(1337):197-201.

Elhouhari HM, Tamimi TIAR, Carey WD. Hepatitis B virus infection: Understanding its epidemiology, course, and diagnosis. Cleveland Clinical Journal of Medicine 2008;75:881-889.

Eisenbach C, Sauer P, Mehrabi A, Stremmel W, Encke J. Prevention of hepatitis B virus recurrence after liver transplantation. Clin Transplant 2006; 20 Suppl 17: 111–116

Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. [Review] [143 refs]. Journal of Hepatology. 2008 20071204 [Epub ahead of print];48(2):335-52.

Garfein RS, Vlahov D, Galai N, et al. Viral infections in short-term injection drug users: the prevalence of the hepatitis C, hepatitis B, human immunodeficiency, and human T-lymphotropic viruses. Am J Public Health 1996;86:655–661.

Greten TF, Papendorf F, Bleck JS, Kirchhoff T, Wohlberedt T, Kubicka S, et al. Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients. British Journal of Cancer, 2005 May 23;92(10):1862-8.

Haagsma JA, Maertens de Noordhout C, Polinder S, Vos T, Havelaar AH, Cassini A, Devleesschauwer B, Kretzschmar ME, Speybroeck N, Salomon JA. Assessing disability weights based on the responses of 30,660 people from four European countries. Population Health Metrics 2015; 13: 10

Hoofnagle JH, Carithers RL Jr, Shapiro C, Ascher N. Fulminant hepatic failure: summary of a workshop. Hepatology 1995;21:240-252.

Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok ASF. Management of Hepatitis B: Summary of a Clinical Research Workshop. Hepatology 2007;45:1056-1075.

Kanwal F, Gralnek IM, Martin P et al. Treatment alternatives for chronic hepatitis B viral infection: a cost-effectiveness analysis. Annals of Internal Medicine. 2005;142:821-31.

Kim WR, Brown RS, Terrault NA, El-Serag H. Burden of liver disease in the United States: summary of a workshop. Hepatology 2002; 36: 227-242

Kwong JC, Ratnasingham S, Campitelli MA, Daneman N, Deeks SL, et al. (2012) The Impact of Infection on Population Health: Results of the Ontario Burden of Infectious Diseases Study. PLoS ONE 7(9): e44103. doi:10.1371/journal.pone.0044103

Levine OS, Vlahov D, Nelson KE. Epidemiology of hepatitis B virus infections among injecting drug users: seroprevalence, risk factors, and viral interactions. Epidemiol Rev 1994;16:418–36

Levine OS, Vlahov D, Koehler J, et al. Seroepidemiology of hepatitis B virus in a population of injecting drug users. Association with drug injection patterns. Am J Epidemiol 1995;142:331–41.

Liaw YF (2009) Natural history of chronic hepatitis B virus infection and long-term outcome under treatment. Liver international Vol. 29; pp 100-107.

Lok ASF, McMahon (2007) Chronic Hepatitis B. Hepatology Vol. 45; pp 507 - 539

Matesanzemail R, de la Rosa G. Liver transplantation: The Spanish experience. Digestive and Liver Disease Supplements. Volume 3, Issue 4 , Pages 75-81, December 2009.

McMahon BJ, Alward WL, Hall DB, Heyward WL, Bender TR, Francis DP, et al. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. The Journal of Infectious Diseases, 1985 Apr;151(4):599-603.

McMahon BJ (2005). Epidemiology and natural history of Hepatitis B. Seminars in liver disease. Vol. 25. Supplement 1.

Murray CJL, Lopez AD. World Health Organization, World Bank, Harvard School of Public Health. Global health statistics: a compendium of incidence, prevalence and mortality estimates for over 200 conditions. Geneva: World Health Organization; 1996.

Murray CJL, Lopez AD. The Global Burden of Disease - A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Cambridge: Harvard School of Public Health on behalf of the World Health Organization and the World Bank; 1996.

National Health System (NHS), UK. http://www.nhs.uk/conditions/Liver-transplant/Pages/Introduction.aspx. Website visited on 31 July 2014

National Institutes of Health (2008) NIH Consensus Development Conference Statement on Management of Hepatitis B. NIH Consensus and State-of-the-Science Statements Volume 25, Number 2. October 20–22, 2008

Pungpapong S, Kim WR, Poterucha JJ. Natural history of hepatitis B virus infection: an update for clinicians. Mayo Clin Proc 2007; 82:967–975.

Shepard CW, Simard EP, Finelli L, Fiore AE, Bell BP (2006) Hepatitis B virus infection: Epidemiology and vaccination. Epidemiological Reviews; Vol. 28; pp 112-125

Shepherd J, Jones J, Takeda A et al. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation. [Review] [136 refs]. Health Technology Assessment (Winchester, England). 2006;10(28):iii-iiv.

Stouthard M , Essink-Bot M, Bonsel G, Barendregt J, Kramers P. 1997. Disability weights for diseases in the Netherlands. Rotterdam, Department of Public Health, Erasmus University.

Trey C, Davidson CS. The management of fulminant hepatic failure. In: Popper H, Schaffner F, eds. Progress in liver disease. Volume 3. New York: Grune & Stratton, 1970:282-98

Wai CT, Fontana RJ, Polson J, Hussain M, Shakil AO, Han SH, et al. Clinical outcome and virological characteristics of hepatitis B-related acute liver failure in the United States. J Viral Hepat 2005; 12: 192-198

Wilt TJ, Shamliyan T, Shaukat A, Taylor BC, MacDonald R, Yuan J-M, et al. (2008) . Management of Chronic Hepatitis B. Evidence Report/Technology Assessment No. 174. (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 09-E002. Rockville, MD. Agency for Healthcare Research and Quality. October 2008.

WHO (2002) Hepatitis B; WHO/CDS/CSR/LYO/2002.2:Hepatitis B

WHO (2001) Introduction of Hepatitis B vaccine into childhood immunization services

Yim HJ, Lok ASF. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology 2006; 43:pp 173–S181.