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:
3050% 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 515 percent of newly-infected young children (15 years of age) and in 3350 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 (2030%), 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 510%, although it is higher in those who were infected perinatally (90%) or during childhood (20%) (Yim & Lok, 2005)
More than 90% of infected infants, 2550% of children infected between and 5 years, and 610% of acutely infected older children and adults develop chronic infection (Shepard et al. 2006)
About 30% of children aged 15 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 15 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 (0.51.0%) 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 2033% (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 DAmico et al. (2006. The review undertaken by Fattovich et al. (2008) estimated an annual probability of 34% for Europe which we chose for our model.
The 2057% 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 210% in patients with compensated cirrhosis (Fattovich, 2008; Yim & Lok, 2005; Pungpadong, 2007; Chu, 2000; DAmico, 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% (0.120.41) per year to develop HCC from chronic hepatitis B infection and 2.2% (1.712.71) 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% (2060). 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 |
Distribution of health states within health outcome |
Transition probability |
Source/assumption |
Symptomatic infection |
|
1050% |
Age-dependent |
Chronic hepatitis |
|
190% |
Age-dependent |
Fulminant liver failure |
|
0.51% |
Pappas, 1995; Hoofnagle et al. 1995 |
Fatal cases due to liver failure |
|
20-33.3% |
Bernau
et al. 1986 ; Wait et al. 2005 |
Compensated cirrhosis |
|
2.1%/year |
Chu, 2000 (ATP) |
Decompensated cirrhosis |
|
3-4%/year |
Fattovich, 2008 (ATP) |
HCC, following - Chronic hepatitis - Compensated cirrhosis |
|
0.3%
(0.120.41)/year |
Fattovich,
2008 (ATP |
CFR, following: - DC |
|
20-57%/year |
DAmico,
2006 (ATP) |
Table 2. Disability weights and duration
Health
outcome |
Disability Weight (DW) (Haagsma, 2015) |
Duration |
||
DW |
Source: ECDC European Disability Weight Project (2014) |
In years |
Source/assumption |
|
Symptomatic infection |
0.051 (0.0390.06) |
Infectious disease, acute episode, moderate |
0.115 |
Kwong 2012 |
Fulminant liver failure |
0.515 (0.4590.572) |
Terminal phase, with medication (for cancers, end-stage kidney/liver disease) |
0.0030.153 |
Trey, 1970 |
Chronic hepatitis |
0.07 (0.0570.088) |
Generic, uncomplicated disease: worry and daily medication |
4.533.24 |
Stouthard, 1997 Assuming uncertainty between proportion with active replication and without |
Compensated cirrhosis |
0.07 (0.0570.088) |
Generic uncomplicated disease: worry and daily medication |
6-10.4 See Table 6 |
Murray, 1996 Age and gender specific |
Decompensated cirrhosis |
0.163 (0.1360.194) |
Decompensated cirrhosis of the liver |
0.34039 |
Assuming average waiting time before liver transplantation in the UK and Spain (NHS and Matesanz 2009) |
Hepatocellular carcinoma |
0.265 (0.2220.303) |
Cancer, diagnosis and primary therapy |
0.724.48 See Table 7 |
Murray, 1996 Age and gender specific |
Table 3. Hepatitis B infected developing symptoms
Age group |
Symptomatic hepatitis B |
0 |
10% |
14 |
515% |
580+ |
3050% |
Table 4. Hepatitis B infected developing chronic hepatitis
Age group |
Chronic hepatitis B |
0 |
90% |
14 |
2030% |
580+ |
1% |
Table 5. CFR age distribution for acute hepatitis observed in Estonia, Germany and the Netherlands 20052007
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 |
04 |
10.4 |
10.3 |
514 |
10.4 |
10.4 |
1544 |
10.2 |
10 |
4559 |
9.3 |
8.8 |
60+ |
6.5 |
6 |
Table 7. Duration of HCC
Age group |
Duration (years) |
|
|
F |
M |
014 |
4.48 |
4.11 |
1544 |
1.45 |
2.92 |
4559 |
1.91 |
2.88 |
60+ |
0.72 |
1.56 |
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