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


After a long-term follow-up period, the incidence of HCC in a well-defined cohort of F3 HCV-infected patients with DAA-based SVR proved to be low and far from the cost-effectiveness threshold.

We detected six cases of primary liver tumour, mainly HCC, that is, an incidence rate of 0.47 per 100 patients per year. Patients were diagnosed a median of 29.4 months after SVR, and the baseline TE was below 12 kPa in all cases. All patients were aged over 50 years and none had metabolic syndrome or HIV infection, both of which are risk factors for HCC after SVR.[24,25] The patient with intrahepatic cholangiocarcinoma and progression of TE over time confirmed significant alcohol consumption after being diagnosed. The FIB-4 score did not progress over time. Progression of the FIB-4 score after SVR and, specifically, persistence of a value ≥3.25 after SVR are risk factors for HCC. However, in our cohort, this value was <3.25 at baseline and at diagnosis of the tumour.[26]

The multivariate analysis showed that the composite variable male sex and age >55 years was the only factor that was significantly associated with a greater risk of primary liver tumour. This finding is consistent with data from various studies, which showed that, irrespective of the degree of baseline fibrosis, male sex and age over 50–60 years are risk factors associated with HCC.[27–29] No statistically significant associations were observed for other factors. In particular, we did not analyse fatty liver using ultrasound owing to the reduced reliability of this approach in patients with concomitant liver fibrosis.[30] Nevertheless, risk factors for fatty liver were not associated with an increased risk of HCC.

Specific data on HCC risk in patients with stage 3 liver fibrosis after SVR are scarce. Given the controversial findings in reports on occurrence/recurrence of HCC associated with DAA, Romano et al[22] performed a prospective study to assess the incidence of newly diagnosed HCC after DAA treatment. The authors included 3914 patients, of whom 959 had F3 stage disease, based exclusively on TE. Patients with and without SVR were included, as were patients with chronic hepatitis B and median follow-up was only 17 months. A total of 4 cases were detected, that is an HCC incidence rate of 0.46 per 100 patients per year during the first year of follow-up (95% CI: 0.12–1.17). This fell to 0% during the second year. Piñero et al[23] carried out a prospective study in a Latin-American cohort in order to assess the incidence of HCC associated with DAA treatment. The authors included patients with different stages of liver fibrosis, although only 233 patients had F3 disease, again based exclusively on TE. The median follow-up was 16 months, and patients with and without SVR were enrolled. A total of 30 cases of HCC were reported, only two of which were in F3 patients; the disease had developed over a median time of 7.9 months. Nevertheless, the main population in both studies was cirrhotic, and the study objective was to determine the occurrence/recurrence of HCC potentially associated with DAA. Furthermore, both the study by Romano et al[22] and that of Piñero et al[23] are limited by their short follow-up, the fact that liver diseases other than HCV infection were included, and the inclusion of both SVR and non-SVR patients. Pons et al[31] recently performed a prospective cohort study in which they included patients with SVR after DAA and compensated -advanced chronic liver disease, as per the Baveno VI consensus (liver stiffness ≥10 kPa and Child-Pugh class A). However, since the results reported included values ranging between 10 and 20 kPa (HCC incidence rate 1.7/100 patients per year), no firm conclusions can be drawn on the selective incidence in F3.

Our study is novel in that it assesses the risk of HCC in a specific, well-defined F3 population with SVR achieved with DAA. Our two-step allocation, which excluded patients with results suggesting cirrhosis, enabled us to study stage F3 more accurately, given the considerable uncertainty in the range 9.5–14.5 kPa. In fact, after applying our two-step strategy, about one quarter of the initial study population (23.5%) was excluded owing to signs of cirrhosis and/or portal hypertension, thus highlighting the stringency of our patient selection criteria. Other strengths of our study are its predominantly prospective design, the large sample size, a follow-up of almost 3 years after SVR and good adherence to the screening program (75%). Besides, 18.3% of the cohort were HIV-coinfected, thus enabling us to gather information in this subset of patients. According to our data, this population does not seem to be at increased risk.

The main limitations of our study are those inherent in the definition of F3. Even after our two-step strategy, some F4 patients could have been included in the cohort. Even so, our strategy would still apply for these patients. Another limitation is the duration of follow-up, which ended 3 years after SVR. Nevertheless, the literature indicates that an explosion in the number of cases is unlikely.[14] Finally, the missing data affected very few patients in our cohort (Table 1).

The low incidence of HCC in the total population of F3 patients after SVR is clearly below the threshold considered cost-effective for screening. Nevertheless, while the incidence was below the recommended 1.5% in men older than 55 years screening can in fact be recommended, taking into account the upper limit of the confidence interval and provided the two-step stratification process is applied. Longer follow-up is necessary to determine whether screening should be indefinite or not in these patients. Our two-step study criteria can easily be applied retrospectively in the patients who are currently in the twice-yearly screening program after consulting their baseline data. In contrast, recommendations based on changes in TE values after SVR are limited by the fact that the results are not always available: obtaining them is more expensive, and this approach was not part of standard clinical practice.[11]

In conclusion, we found a low incidence of HCC after SVR in a large cohort of well-defined stage F3 HCV patients assessed using a two-step stratification process. Most cases were detected during the first 3 years of follow-up. The only risk factor associated with the development of HCC was being a man aged more than 55 years. This risk is below the 1.5% cut-off considered cost-effective for surveillance of HCC. According to our results, new screening strategies would be needed in patients with baseline stage 3 fibrosis after SVR.