Precision of dynamic modelling for prognosis of prevalence, morbidity and mortality depends on the quality of the data entered and the assumptions made. We have used locally acquired data whenever possible. The critical aspect in HCV pathophysiology is the progressive development of fibrosis towards cirrhosis, and in this aspect, our model also made use of local data. The further development from established cirrhosis is not likely to be very different from that of other cohorts, and the use of estimated transition rates from other studies [
13] should not affect the prognosis measurably.
Our Markov model is based on an assumed low and stable incidence until 2050, whereas other reports estimate a declining or stable incidence [
2]. The observed incidence peak in 2002–2004 in our data is probably a result of increased focus on HCV infection among general practitioners due to our encouragement of diagnosis in that period.
Our cohort is relatively young, and the liver biopsy data has a limited number of observations of severe fibrosis (Ishak grade 4–6). Hence, the estimates generated from these data are less precise regarding progression through high fibrosis stages.
Published data show variable rates of liver fibrosis progression, with 10%–40% developing cirrhosis after 20–35 years of infection [
5,
8,
29]. A large systematic review supports nonlinear fibrosis progression [
8] and other studies have shown that HCV genotype 3 is associated with a faster fibrosis progression [
30‐
33]. Male sex is a reported risk factor for disease progression [
5,
31]. However, we found no effect of sex in the progression of fibrosis, which is also observed in other studies [
34].
Strengths and weaknesses
The strengths of this study are; first, we have reliable data on the HCV-infected subjects in our health region; second, the simulated fibrosis progression in the cohort is based on local data. However, there are apparent weaknesses. First, the number of undiagnosed HCV-infected individuals in the population is unknown. In Sweden, a comparable country regarding HCV epidemiology, it has been suggested that the rate of undiagnosed HCV infection is approximately 20% [
35]. Second, incomplete records regarding confirmation testing has made it necessary to estimate the number of true positive cases, resulting in uncertainty regarding the true prevalence. However, our estimate of 63% true positives among those who only tested positive for anti-HCV is not controversial compared to another reported value of 68% true positive [
36]. Moreover, the significance of RIBA-indeterminate reactions is unclear. Most individuals with indeterminate RIBA have a negative HCV RNA test, which may represent previous exposure to, but spontaneous recovery from HCV [
37]. Authors have shown that approximately half of those with indeterminate RIBA have a resolved HCV infection [
38,
39]. The proportion of RIBA-indeterminate records in our HCV population was low, making the contribution of these records less significant.
Third, the future incidence may be underestimated. Most likely, transmission of HCV will still be mainly by drug abuse, which is an ongoing problem in our region as is the case in the rest of Europe [
40]. On the other hand, the introduction of highly effective, simple, short-term and tolerable therapies has the potential to increase treatment coverage among people who inject drugs. Thus, scaling up treatment in people with a transmission risk could reduce the future incidence and have a major impact on the HCV prevalence [
41]. Fourth, it is documented that both moderate and excessive alcohol intake increase fibrosis progression in patients with HCV [
42,
43]. Presence of concomitant excessive alcohol use was in our study assessed by clinical judgment, and not by a validated questionnaire of drinking habits. We have therefore chosen to omit alcohol use from the model over concerns on the quality of the data. Several other factors have been shown to accelerate the fibrosis progression, like co-infection with hepatitis B virus or HIV, diabetes and obesity [
9]. The prevalence of HBV or HIV co-infections in our HCV population were low, 2.3% and 1% respectively, and therefore not included in the model. Data regarding diabetes and obesity were incomplete and neither included in the model.
Fifth, the exact time of infection is often not known. In individuals with unknown time of infection, we have used the first year of high-risk behavior as the presumed year of transmission, as others have done [
30,
44,
45]. However, it has been reported that the interval between onset of drug injection and HCV infection has lengthened in recent years [
46], which may indicate that the duration of infection could be shorter than estimated in our model of fibrosis progression. If so, our fibrosis model produces a spuriously slow rate of fibrosis progression, making the prognosis relatively conservative.
Sixth, the Markov model assumes that HCC only occurs when liver cirrhosis is established (Ishak 6). However, HCC can develop in lower fibrosis stages in chronic HCV infection [
47,
48]. Finally, regression of fibrosis, cirrhosis and cirrhosis complications is possible after achieving SVR [
49‐
51]. We do not have data to assess the effect of SVR on fibrosis regression, i.e. available pretreatment and post-treatment liver biopsies, and this is another limitation of the model. However, removing subjects achieving SVR from the model can mimic fibrosis regression in non-cirrhotic cases. In patients with cirrhosis, about 60% can regress after SVR [
49,
50], and much less likely in decompensated cirrhosis. In patients with HCV-induced cirrhosis who attain SVR, the risk of HCC declines, but persists [
52,
53]. To reflect that model cases with cirrhosis and SVR still are in risk of cirrhosis complications, we have retained 50% of these in the model.
Implications
HCV is the leading cause of chronic liver disease and cirrhosis and is the main cause of liver transplantation in the Western world [
10]. Although the total number of HCV-infected individuals is estimated to be stable or decline in the future, an increase in liver cirrhosis, liver cancer, hepatic decompensation and liver-related deaths is expected in the coming years.
This assessment is underlined by the World Health Organization (WHO) statement that the burden of HCV disease has been largely ignored as a health priority, and the organization has developed the first-ever global health sector strategy for addressing the viral hepatitis pandemic [
54].
To reduce the future burden of hepatitis C it is necessary to meet the challenge at three levels. First, prophylaxis measures must focus on reducing the transmission rate among active injection drug users. In addition, recent guidelines suggest that treatment should be offered to this group of individuals at high risk of transmitting HCV due to a potential prevention benefit [
55]. Second, HCV infection among apparently healthy subjects must be diagnosed by screening of high-risk groups. Strategies to expand screening beyond high-risk groups should be considered since a substantial proportion of infected are unaware of their status [
56]. Third, antiviral treatment has been offered only to a small percentage of patients, as treatment is hampered by the high cost of the new direct-acting antiviral drugs (DAAs). Based on the unpredictable course of liver fibrosis at the individual level, delaying treatment of patients with early fibrosis stages will increase the risk of liver complications [
11]. DAAs has the potential to reduce the future burden of disease of HCV, but this is restricted by the current treatment levels [
19]. In spite of the high costs of DAAs, several studies show that interferon-free regimens are cost-effective compared to interferon-based regimens [
57‐
61].