Hepatitis C

A total of 20–30% of newly infected individuals develop clinical symptoms of acute hepatitis (e.g. anorexia, abdominal discomfort, nausea, vomiting and jaundice) within 2–24 weeks of exposure (CDC, 2011; Wasmuth, 2010; World Health Organization, 2002). In persons who do develop symptoms of acute hepatitis, the illness lasts between two and 12 weeks (Wasmuth, 2010).

In the model, it was assumed that 20–30% of newly infected individuals develop clinical symptoms of acute hepatitis (CDC, 2011).

Rate of developing chronic hepatitis C

Acute hepatitis C develops into chronic infection in 75.6% (67.3–84.9) of all symptomatic and asymptomatic cases over 20 years old, with the infection resolving in the remaining proportion (Alter & Seef, 1994). The chronicity rate is known to be lower in younger individuals. A recent review of the literature by Alter et al. (2000), has estimated that the rate of spontaneous recovery is 29–45% in those aged under 20 years and this was used for the disease model (chronicity rate: 55–69%).

In the early stages of chronic infection there is a small chance of spontaneous remission. The rate of remission of chronic hepatitis C was set at 0.31 (0.26–0.36)% per year in accordance with the findings of Micallef et al. (2006) (in the Burden of Communicable Diseases in Europe toolkit a yearly rate refers to an Annual Transition Probability, ATP, as opposed to the Lifetime Transition Probability, LTP).

In the absence of spontaneous remission or successful antiviral therapy, chronic infections may progress from mild to moderate hepatitis to liver cirrhosis, with a risk of developing life-threatening sequelae such as decompensated liver disease and hepatocellular carcinoma. Progression to severe liver disease can take 20–40 years. However, progression, which is non-linear, is strongly influenced by cofactors including alcohol intake, HIV or HBV coinfection, gender (male) and an older age at infection (Alberti, 2005; Alter & Seeff, 2000; Freeman, 2003; Lauer & Walker, 2001; Poynard, 2001; Thein, 2008).

Given emerging knowledge of the disease, the most appropriate approach to simulating the progression from chronic infection to cirrhosis would be to specify a model with five health stages, representing the METAVIR fibrosis stages F0–F4, linked by multivariate risk functions. A further possibility could be to represent mild and moderate pre-cirrhotic disease stages. However, for the sake of simplicity and in the context of a burden of disease study in which the objective is to compare a broad spectrum of diseases, a single, chronic hepatitis health outcome was applied.

Risk of complications

Compensated cirrhosis (CC)

The risk of HCV-infected persons developing cirrhosis within 20–30 years is estimated in most studies to be within the range of between 5 and 20%, although some studies give estimates of up to 50% (CDC, 2011; Freeman 2001; Freeman 2003; Lauer & Walker, 2001; Poynard, 1997; Poynard, 2001; Thein, 2008; Wasmuth, 2010). Thein et al. predicted via meta-analysis an average 20-year cirrhosis risk of 16% (95% CI: 14%-19%), and a 30-year risk of 41% (95% CI: 36%–45%), which underlines that the progression to cirrhosis is not a linear process  (Thein et al. 2008).

The annual risk of progressing to compensated cirrhosis was calculated based on the transitional probabilities between the five METAVIR stages of fibrosis, as estimated by Thein et al. (2008), using random-effect meta-analysis applied to non-clinical studies only. The point estimate for the risk of developing compensated cirrhosis from chronic hepatitis, calculated as the inverse of the summed durations in the first four METAVIR stages (each duration in turn was estimated as 1/probability of leaving the METAVIR stage), was 1.9% per year. The disability duration was calculated at 36.5 years; this is the average time taken for 50% of those with chronic hepatitis to exit the compartment: 1-exp(-0.019 * 36.5) = 0.5.

Decompensated cirrhosis (DC)

HCV-associated cirrhosis leads to liver failure and death in about 20–25% of cirrhotic cases. The annual risk of compensated cirrhosis progressing to the decompensated stage (characterised by ascites, bleeding oesophagal varices, or jaundice) is estimated to be 3.9–7% (D'Amico, 2006; Fattovich, 1997; Grieve, 2006; Poynard, 1997; Wasmuth, 2010). In the model, hepatic decompensation was assumed to occur with an annual risk of 3.9 to 12.9 (Dienstag, 2011).

Without transplantation the prognosis is poor. The five-year survival rate with decompensated liver cirrhosis is roughly 50% (Planas, 2004). One report based on a small study population (n=65) estimated the annual mortality rate at 12.9% (Fattovich et al. 1997), but higher values were reported in the systematic review by D’Amico et al. (2006) (20% 1-year mortality from the first stage of DC; 55% from the second DC stage, which is indicated by bleeding varices with or without ascites). The estimated annual risk of death from DC was set to within a range of 13–38.5% (Fattovich, 1997; Grieve, 2006; D’Amico, 2006); the upper bound was calculated as the mean of the rates for the two DC stages reported by D’Amico et al (2006).

Duration of DC is based on average waiting time for liver transplant in the UK and in Spain which are represented as an average duration (142 days, NHS and 124 days, Matesanz 2009).

Hepatocellular carcinoma (HCC)

In contrast to hepatitis B, development of primary liver cancer, or hepatocellular carcinoma (HCC), is rare in patients with chronic hepatitis C who do not have cirrhosis (Lauer & Walker, 2001; Spengler, 2010; Wasmuth, 2010; WHO, 2002). Once cirrhosis is established, the risk of hepatocellular carcinoma is estimated to be 1–4% per year (Fattovich et al. 1997; Lauer & Walker, 2001). Studies modelling the natural course of hepatitis C have assumed annual risks of around 1.5% (Grieve et al. 2006; Siebert et al. 2003).

HCC is an outcome that can occur after either the compensated or decompensated cirrhosis stages. The annual risk of developing HCC following either CC or DC was set to 3%, based on the estimate by D’Amico et al. (2006).

Studies modelling the natural course of hepatitis C have assumed annual case fatality rates (CFR) due to liver cancer ranging widely from 43–86% (Grieve, 2006; Siebert, 2003; Wong, 2000). This variation might be a consequence of stage and treatment-specific survival rates, and other underlying conditions including alcohol consumption, diabetes or obesity, where the higher estimate is used to simulate a situation without early diagnosis and effective treatment. In the model, this CFR is set to 48.9%/year, based on the 1-year survival rate (Kwong, 2012).

Other complications

Fulminant hepatic failure due to acute HCV infection is considered to be very rare (CDC, 2011; Lauer & Walker, 2001; Wasmuth, 2010; World Health Organization, 2002) except in cases of HBV coinfection (Chu, 1999). Fulminant liver failure and death was reported to occur in approximately 0.1% (2/1536) of adults with reported (notified) acute hepatitis C (Bianco, 2003). Due to this condition being extremely rare, no health outcome was specified in the outcome tree.

Model input summary

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

 Health outcome
 (Health state)

Distribution of health states in health outcome

Transition probability

Source/assumption

 Symptomatic infection

20–30%

 

CDC, 2011

 Chronic hepatitis

 

> 19yr: 75.6% (67.3–84.9)
< 20yr: 55–69%

Alter, 1994; Alter, 2000
Age dependent

 Remission from chronic hepatitis

 

0.31 (0.26–0.36)%/year

Micallef, 2006 (ATP)

 Compensated cirrhosis

 

1.9%/year

Modelled from Thein, 2008 (ATP)

 Decompensated cirrhosis

 

3.9–12.9%/year

Dienstag, 2011 (ATP)

 HCC, following
       - Compensated cirrhosis

       - Decompensated cirrhosis

 


3.0%/year
3.0%/year


D'Amico, 2006 (ATP)
D'Amico, 2006 (ATP)

 CFR, following:
      - Decompensated cirrhosis
      - Hepatocellular carcinoma

 


13–38.5%/year
48.9%/year


Fattovich, 1997; Grieve 2006; D’Amico 2006 (ATP)
Kwong, 2012 (ATP)

Table 2. Disability weights and duration

Health outcome
(Health state)

Disability Weight (DW) (Haagsma, 2015)

Duration

DW

Label

In years

Source

Symptomatic infection

0.051 (0.039–0.06)

Infectious disease, acute episode, moderate

0.038–0.23 

CDC, 2011; Wasmuth, 2010; World Health Organization, 2002

Chronic hepatitis

 0.07 (0.057–0.088)

Generic uncomplicated disease: worry and daily medication

36.5

Modelled from Thein, 2008

Compensated cirrhosis

 0.07 (0.057–0.088)

Generic uncomplicated disease: worry and daily medication

6-10.4
See table 3

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 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 4

Murray, 1996
Age and gender specific

Table 3. 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 4. Duration of hepatocellular carcinoma

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

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