Declining Incidence of Hepatitis C Related Hepatocellular Carcinoma in the era of Interferon-free Therapies

A Population-based Cohort Study

Hamish Innes; Scott A. McDonald; Victoria Hamill; Alan Yeung; John F. Dillon; Peter C. Hayes; April Went; Andrew Fraser; Andrew Bathgate; Stephen T. Barclay; Naveed Janjua; David J. Goldberg; Sharon J. Hutchinson


Liver International. 2022;42(3):561-574. 

In This Article

Abstract and Introduction


Background & Aims: The impact of interferon (IFN)-free therapies on the epidemiology of hepatitis C virus (HCV) related hepatocellular carcinoma (HCC) is not well understood at a population level. Our goal was to bridge this evidence gap.

Methods: This study included all patients in Scotland with chronic HCV and a diagnosis of cirrhosis during 1999–2019. Incident cases of HCC, episodes of curative HCC therapy, and HCC-related deaths were identified through linkage to nationwide registries. Three time periods were examined: 1999–2010 (pegylated interferon-ribavirin [PIR]); 2011–2013 (First-generation DAA); and 2014–2019 (IFN-free era). We used regression modelling to determine time trends for (i) number diagnosed and living with HCV cirrhosis, (ii) HCC cumulative incidence, (iii) HCC curative treatment uptake and (iv) post-HCC mortality.

Results: 3347 cirrhosis patients were identified of which 381 (11.4%) developed HCC. After HCC diagnosis, 140 (36.7%) received curative HCC treatment and there were 202 deaths from HCC. The average annual number of patients diagnosed and living with HCV cirrhosis was approximately seven times higher in the IFN-free versus the PIR era, whereas the number of incident HCCs was four times higher. However, the cumulative incidence of HCC was significantly lower in the IFN-free versus PIR era (sdHR: 0.65; 95%CI:0.47–0.88; P = .006). Among HCC patients, diagnosis in the IFN-free era was not associated with improved uptake of curative treatment (aOR:1.18; 95%CI:0.69–2.01; P = .54), or reduced post-HCC mortality (sdHR: 0.74; 95%CI:0.53–1.05; P = .09).

Conclusions: The cumulative incidence of HCC is declining in HCV cirrhosis patients, but uptake of curative HCC therapy and post-HCC survival remains suboptimal.


Hepatocellular carcinoma (HCC) is a major cause of excess mortality in patients with hepatitis C virus (HCV) infection. From an epidemiological perspective, the number of HCC deaths occurring in a given time period depends on four main factors:

  • Size of the 'at risk' population (For HCC, the major 'at risk' population are people with liver cirrhosis- ie the prevalence of cirrhosis in HCC patients exceeds 80%.[1])

  • Cumulative incidence of HCC among the 'at risk' population (Previous studies suggest the incidence of HCC among patients with HCV-related cirrhosis varies from 1–3 events per 100 person years of follow-up.[2–6])

  • Uptake of HCC curative therapy following an HCC diagnosis (Receiving curative HCC therapy is associated with improved survival,[7] but only patients with early stage HCC are eligible).[1,8]

  • Overall survival following HCC diagnosis (HCC is a leading cause of cancer mortality;[9] Average survival after an HCC diagnosis is less than 1 year.[10])

The arrival of interferon-free (IFN-free) direct acting antivirals (DAAs) from 2014 has not only revolutionised the treatment of chronic HCV infection but also offers new public health opportunities.[11] Whereas older treatments were long, arduous and ineffective, IFN-free therapies are short, tolerable and highly effective.[12,13] It is likely that IFN-free DAAs have already impacted the epidemiological landscape for HCV-related HCC. However, few studies have been able to quantify these changes at a population level, and so the picture remains uncertain. For example, the number of cirrhosis patients with cured HCV has probably increased dramatically in recent years, but precise numbers are not yet known. Similarly, although studies have shown that HCV cure is associated with reduced HCC incidence for cirrhosis patients,[6,14] this does not necessarily mean that HCC incidence is falling at a population level. The situation is complicated because HCV cure is also associated with a reduced risk of competing risk events (i.e. events that preclude the occurrence of HCC, such as death from decompensated cirrhosis), which may mitigate the population impact for HCC. By the same token, there is evidence that HCV cure is associated with improved post-HCC survival[15,16] – but this does not necessarily mean that overall survival at the population level has improved.

A better understanding of how these four aspects of the epidemiological landscape are shifting over time (if at all) is vital for policy makers and practitioners because they provide insight into the drivers of HCC mortality and indicate what innovations are likely to have the biggest impact on reducing deaths going forward (i.e. chemoprevention, risk-stratification for HCC screening, or drug-discovery for late stage disease). The main obstacle to carrying out this analysis is that it requires comprehensive and linkable health registries in order to follow patients from cirrhosis diagnosis through to death. Historical data for patients diagnosed in the era of IFN-based therapies are also essential. Scotland is one of the few settings anywhere in the world with the requisite database and linkage infrastructure to carry out this type of analysis. Thus, the main aim of this study was to determine the trends over a twenty-year period (1999 to 2019) in the aforementioned domains for HCV patients in Scotland.