Hepatocellular Carcinoma Risk in Hepatitis C Stage-3 Fibrosis After Sustained Virological Response With Direct-acting Antivirals

María Sánchez-Azofra; Inmaculada Fernández; María L. García-Buey; Lourdes Domínguez-Domínguez; Conrado M. Fernández-Rodríguez; Antonio Mancebo; Lucía Bonet; Pablo Ryan; Francisco Gea; Antonio Díaz-Sánchez; Marian García-Mayor; Luz Martín-Carbonero; Pilar Castillo; María L. Manzano; Leticia González-Moreno; Federico Pulido; María L. Gutiérrez; José M. Moreno; Irene M. García-Amengual; Guillermo Cuevas; Antonio Guerrero; Miguel Rivero-Fernández; María E. Portales; María L. Montes; Antonio Olveira


Liver International. 2021;41(12):2885-2891. 

In This Article

Abstract and Introduction


Background & Aims: Patients with chronic hepatitis C and stage 3 fibrosis are thought to remain at risk of hepatocellular carcinoma after sustained virological response. We investigated this risk in a large cohort of patients with well-defined stage 3 fibrosis.

Methods: We performed a multicentre, ambispective, observational study of chronic hepatitis C patients with sustained virological response after treatment with direct-acting antivirals started between January and December 2015. Baseline stage 3 was defined in a two-step procedure: we selected patients with transient elastography values of 9.5–14.5 kPa and subsequently excluded those with nodular liver surface, splenomegaly, ascites or collaterals on imaging, thrombopenia or esophago-gastric varices. Patients were screened twice-yearly using ultrasound.

Results: The final sample comprised 506 patients (median age, 57.4 years; males, 59.9%; diabetes, 17.2%; overweight, 44.1%; genotype 3, 8.9%; HIV coinfection, 18.4%; altered liver values, 15.2%). Median follow-up was 33.7 (22.1–39.1) months. Five hepatocellular carcinomas and 1 cholangiocarcinoma were detected after a median of 29.4 months (95% CI: 26.8–39.3), with an incidence of 0.47/100 patients/year (95% CI: 0.17–1.01). In the multivariate analysis, only males older than 55 years had a significant higher risk (hazard ratio 7.2 [95% CI: 1.2–41.7; P = .029]) with an incidence of 1.1/100 patients/year (95% CI: 0.3–2.8).

Conclusions: In a large, well-defined cohort of patients with baseline hepatitis C stage-3 fibrosis, the incidence of primary liver tumours was low after sustained virological response and far from the threshold for cost-effectiveness of screening, except in males older than 55 years.


Hepatitis C virus (HCV) is an independent risk factor for the development of liver fibrosis and the most common cause of hepatocellular carcinoma (HCC) in developed countries.[1] New treatment regimens based on direct-acting antivirals (DAA) achieve high rates of sustained virological response (SVR) irrespective of genotype, stage of liver disease and experience of therapy, with the response remaining durable in 99% of patients.[2,3]

Sustained virological response is associated with a reduction in portal hypertension, improvement in liver dysfunction and regression of fibrosis, which in turn decrease the frequency of liver decompensation, liver-related death and liver transplant.[4,5] In patients with cirrhosis, eradication of HCV also reduces—but does not abolish—the risk of HCC, which has a cumulative annual incidence exceeding the threshold of 1.5%.[6,7] Since this threshold is considered cost-effective for surveillance of HCC,[8] current guidelines from the European Association for the Study of the Liver (EASL), the American Association for the study of liver diseases (AASLD) and the American Gastroenterological Association (AGA) recommend life-long surveillance of HCC in patients with bridging fibrosis and cirrhosis after SVR.[9–13]

Real-world data on the incidence of HCC in patients with baseline stage 3 liver fibrosis (F3) after SVR are limited, as most studies are retrospective with small cohorts and are from the interferon-based treatment era.[14] Furthermore, defining baseline stage 3 liver fibrosis is difficult. Serological indices, such as FIB-4 or APRI, are unable to reliably distinguish between F3 and F4 patients.[15] Transient elastography (TE) is also subject to limitations: the optimal liver stiffness cut-off values used to predict F3 and F4 have wide ranges that overlap.[16] Even liver biopsy can underestimate liver fibrosis or cirrhosis owing to sampling error if the specimen taken is small.[17,18] These limitations are even more marked after SVR, and, in fact, non-invasive tools should not be used to assess fibrosis stage as they are not reliable in this setting.[11,13]

The EASL 2015 guidelines on treatment of hepatitis C stated that patients with cirrhosis and probably also with F3 should be screened for HCC.[19] Despite a low level of evidence, the 2016 and 2018 EASL guidelines consider surveillance of HCC in F3 to be mandatory,[11,20] thus implying a substantial burden both for the patients, who cannot be discharged, and for health systems. Furthermore, this recommendation is very unlikely to be cost-effective in patients with F3 fibrosis.[21]

The results of two prospective studies on this topic were recently published.[22,23] However, both focus on the potential risk of HCC attributed to DAA-induced viral clearance, their follow-up starts at the beginning of treatment (not after SVR) and is short, and both SVR and non-SVR patients are enrolled. Furthermore, in both studies, the main population comprises patients with cirrhosis, and no specific evaluation was made of patients with F3 disease, since it was not possible to draw firm conclusions for this subset as stratification relied exclusively on TE.

We studied the incidence of HCC in patients with well-defined baseline stage 3 liver fibrosis after SVR achieved with DAA and provide evidence on the need to screen for HCC in this population.