Commentary: Transient Elastography and Fibrosis-4 Index as Predictors of Hepatocellular Carcinoma in Hepatitis C Virus Patients with Sustained Virological Response

^1,2Paula G F da Silva, ³Flávia F Fernandes,¹Cristiane A Villela-Nogueira

¹Clementino Fraga Filho University Hospital, School of Medicine, Hepatology Division, Federal University of Rio de Janeiro, Brazil.

²Bonsucesso Federal Hospital, Department of Hepatology, Rio de Janeiro, Brazil.

³Pedro Ernesto University Hospital, Internal Medicine Department and Obesity Unit (SAI-Ob) Multiuse Clinical Research Center (CePeM), Rio de Janeiro, Brazil.

Abstract

Global data from 2020 estimates that 57 million people have chronic hepatitis C virus (HCV) infection, accounting for 300,000 disease-related deaths and 1.5 million new infections annually¹. In Brazil, from 2000 to 2024, 342,328 confirmed cases of infection were recorded, most of which were chronic².

Follow-up of patients with HCV-related liver disease has advanced considerably over the past two decades³. Studies culminated in the development of direct-acting antiviral (DAA) therapy with high efficacy in achieving sustained virological response (SVR) for both acute and chronic infections^{1, 4}. HCV eradication rates average 90-97%⁵.

The evaluation of patients after SVR demonstrates a reduction in liver stiffness values assessed by transient elastography (TE) and in FIB-4 score; improvement in portal hypertension, as measured by the hepatic venous pressure gradient to values below 10 mmHg; decreased incidence of hepatocellular carcinoma (HCC); lower risk of hepatic decompensation and reduced liver-related mortality^{3, 4, 6, 7}.

Despite the benefits of SVR, individuals with compensated advanced chronic liver disease (cACLD), defined as liver stiffness ≥ 10 kPa, which includes patients with advanced fibrosis (F3) and cirrhosis (F4), remain a challenge in clinical practice because of uncertainty regarding the need for lifelong HCC surveillance⁶. Furthermore, this scenario is becoming increasingly relevant given the growing number of patients achieving SVR, estimated at 1 million worldwide in the next decade⁷.

In general, the Baveno VII and the European and American hepatology guidelines recommend discontinuing surveillance of clinically significant portal hypertension (CSPH) when liver stiffness by TE reduces to values below 12 kPa, in association with a platelet count > 150,000/mm³ and in the absence of other liver damage factors^6-9. Additionally, in patients using non-selective beta-blockers (NSBB) without evidence of CSPH (TE < 25 kPa) and varices on digestive endoscopy, discontinuation of NSBB may be considered^7,9. This unanimity among major world publications regarding discontinuation of CSPH surveillance contrasts with guidance on maintaining routine HCC screening.

HCC risk after SVR is reduced by up to 70% compared with patients without SVR¹⁰. Furthermore, a decreased incidence of HCC is observed in ongoing prolonged follow-up after HCV eradication⁶. However, HCC risk in patients with advanced fibrosis or cirrhosis before SVR still persists for at least 10 years after SVR^{6, 11}. Reported HCC incidence rates in this population range from 0.2% to 2.5%^{6, 11}. Therefore, even patients eligible for discontinuation of CSPH surveillance should not be excluded from HCC screening^{6, 7}.

The main global guidelines – European and American – recommend maintaining routine HCC surveillance for patients with cirrhosis identified before treatment with DAA^{3, 5, 6, 11, 12}. However, only the European and Brazilian guidelines recommend continuing screening for patients with advanced fibrosis (F3) before treatment^{6, 12}. This controversial context and limited evidence on the cost-effectiveness of non-invasive fibrosis tests (NITs), such as the TE and FIB-4 score, evaluated before and/or after antiviral treatment, may be useful for categorizing patients according to their risk of developing HCC.

Pre-treatment TE as an HCC predictor has been analyzed in several publications involving patients with cirrhosis and/or advanced fibrosis, as well as across all stages of fibrosis^13-16. The most recent study demonstrating the predictive value of pre-treatment TE for HCC included 1,075 patients, the majority having advanced fibrosis or cirrhosis¹⁵. This paper showed that a higher pre-treatment TE value, above 15 kPa and especially above 20 kPa, is associated with a greater HCC risk¹⁵. Across the main studies, the median pre-treatment TE value identified as predictive of HCC was 18.7 kPa^13-16.

Post-treatment TE has been evaluated mostly in populations having cACLD^{4, 17-19}. Pons et al. evaluated a cohort of 572 patients with advanced fibrosis or cirrhosis and identified post-treatment values that can aid in risk stratification¹⁷. Individuals with TE < 10 kPa have low risk, while those with TE ≥ 20 kPa have high risk¹⁷. Albumin level assessment is helpful in the intermediate zone (10 to 19 kPa), with albumin < 4.4 g/dL associated with high risk¹⁷. Semmler et al. also identified that TE below 10 kPa or above 20 kPa confers prognostic value¹⁸.

In our cohort of 425 patients with cACLD, pre- and 1-year post-treatment TE ≥ 20 kPa were identified as stratification tools for HCC²⁰. This conclusion was based on AUROC analysis, which showed similar and acceptable values for pre- and post-treatment [0.70 (95% confidence interval (CI): 0.57-0.80) and 0.70 (95% CI: 0.58-0.81), respectively, p=0.97]²⁰. Subsequently, we developed four Cox survival regression models, evaluating pre- and post-treatment TE separately and as continuous or categorical variables²⁰. Both pre- and post-treatment TE were independently associated with HCC development during follow-up²⁰. The decision to perform the analysis individually was due to several factors. First, pre-treatment TE values may be influenced by hepatic inflammation related to active viral infection, which can increase liver stiffness measurements^{6, 21}. Therefore, a value that could overcome this limitation was sought. Second, there is a lack of uniformity in the timing of TE assessment across current publications. Third, TE is not universally available worldwide. Consequently, patients who had the opportunity to perform this NIT at only one point (pre- or post-treatment) could also use the results of this tool at any time to improve their risk stratification.

The dynamics of liver stiffness during follow-up in cACLD patients who achieved SVR is a controversial subject, evaluated by some authors^{13, 16, 18, 22}. Studies involving the largest cohorts did not identify an association between reductions or maintenance/increases in liver stiffness post-treatment and HCC prediction^{13, 18}. However, Alonso et al. presented a 25.5% variation in liver stiffness after 1 year of treatment as a marker of HCC development in a cohort of 933 patients with advanced fibrosis and cirrhosis¹⁶. Ravaioli et al. detected a 30% reduction as a protective factor²².

In our cohort, we did not identify 1-year post-treatment TE reduction of 20% and 25% as HCC protective factors, as demonstrated by some authors^{13, 18, 20}. This result corroborates the rationale for the American guideline, which states that a reduction in TE predominantly reflects a decrease in hepatic inflammation rather than a regression of fibrosis²³.

The FIB-4 score has been more frequently evaluated across cohorts encompassing a wide spectrum of fibrosis stages than TE, largely due to its widespread availability in clinical practice^{16, 24-29}. Pre-treatment assessment of this biomarker showed that values > 3.25 confer a higher risk of developing HCC^{24, 25}. This result was also identified for patients with cACLD²⁸. However, several studies have highlighted the prognostic value of post-treatment FIB-4 as a predictor of HCC^{16, 26, 27}. Tamaki et al. evaluated a cohort of 3823 patients in which FIB-4 ≥ 3.25 is an HCC predictor at any time point during follow-up after SVR²⁷. However, FIB-4 delta over follow-up has not shown to predict HCC in a cohort of 229 individuals with cirrhosis evaluated by Nicoletti et al.²⁹.

In our cohort, 1-year post-treatment FIB-4 score ≥ 3.25 AUROC performs slightly better than pre-treatment, in agreement with the main publications [0.76 (95% CI: 0.74-0.82) and 0.78 (95% CI: 0.71-0.85) respectively]²⁰. However, comparison of the curves showed similar performance (p=0.47)²⁰. Therefore, we performed a Cox regression analysis separately for pre- and post-treatment, using continuous or categorical variables²⁰. This individual analysis of the FIB-4 score was motivated by the same factors that justified the separate analysis of TE: the presence of inflammation at pre-treatment and the lack of consensus on the optimal timing for biomarker application. Despite its wide availability, it is worth examining the optimal cutoff points in the two main moments of individual assessment (pre- and post-treatment) to expand the range of risk categorization. Our results show that a FIB-4 score ≥ 3.25, both before and 1 year after the end of treatment, is useful for stratifying risk²⁰. In addition to this result, the reduction in FIB-4 score was not associated with a protective effect, consistent with the hypothesis of improved inflammation rather than fibrosis^{6, 20}.

A relevant observation from our analyses is that percentual reductions in TE and FIB-4 score during follow-up do not, in isolation, provide consistent prognostic information²⁰. Thus, even with a decrease in these parameters, patients who maintain TE values ≥ 20 kPa and FIB-4 score ≥ 3.25 remain at significant risk of developing HCC²⁰. These findings suggest maintaining surveillance regardless of the magnitude of improvement in liver stiffness.

This finding can be explained by the current difficulty in clearly distinguishing the contribution of inflammation to the degree of liver stiffness, since we do not perform liver biopsies to stratify liver fibrosis and, inflammation in any case^{6, 23, 30}. It is possible that part of the pre-treatment elevated values may predominantly reflect the inflammatory component and misrepresent the true degree of liver fibrosis^{6, 23, 30}. Furthermore, this inflammatory element is associated with liver carcinogenesis that persists after SVR¹⁰. On the other hand, post-treatment elevated values may mainly reflect residual liver fibrosis with little or no influence from inflammation^{6, 23}. Thus, the results suggest that both pre- and post-treatment assessment of TE or FIB-4 score may be useful for risk stratification, expanding the clinical applicability of these markers and potentially reducing costs associated with serial assessments.

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