Elsevier

Journal of Hepatology

Volume 72, Issue 3, March 2020, Pages 472-480
Journal of Hepatology

Research Article
Non-invasive prediction of liver-related events in patients with HCV-associated compensated advanced chronic liver disease after oral antivirals

https://doi.org/10.1016/j.jhep.2019.10.005Get rights and content

Highlights

  • Liver stiffness improves after antiviral therapy in most patients.

  • Hepatocellular carcinoma can still occur after antiviral therapy in patients with cACLD.

  • Non-invasive tests at follow-up can stratify the risk of hepatocellular carcinoma.

  • Portal hypertension-related decompensation is rare after treatment in patients with cACLD.

Background & Aims

It is important to know which patients with hepatitis C are likely to develop liver-related complications after achieving a sustained virological response (SVR) to direct-acting antiviral (DAA) therapy. We aimed to describe the incidence of liver-related events in a population of patients with HCV-associated compensated advanced chronic liver disease (cACLD) who achieved SVR and to identify non-invasive parameters that predict the occurrence of liver-related events.

Methods

This 2-center prospective study included 572 patients with cACLD who had been treated with DAAs and had achieved SVR. Patients had liver stiffness measurement (LSM) ≥10 kPa at baseline and had never decompensated (Child-Pugh class A). Laboratory work-up and LSM were performed at baseline and at 1 year of follow-up.

Results

The median follow-up was 2.8 years during which 32 patients (5.6%) presented with a liver-related event. The incidence rate (IR) of portal hypertension-related decompensation was 0.34/100 patient-years. These patients all had baseline LSM >20 kPa, and LSM did not improve during follow-up in 4 out of 5 of them. Hepatocellular carcinoma (HCC) occurred in 25 patients (IR 1.5/100 patient-years). Albumin levels at follow-up (hazard ratio [HR] 0.08; 95% CI 0.02–0.25) and LSM <10 kPa at follow-up (HR 0.33; 95% CI 0.11–0.96) were independently associated with the risk of HCC. Combining both predictors identified 2 groups with differing risk of HCC occurrence: those with LSM ≥20 kPa at follow-up or those with LSM between 10–20 kPa and albumin levels <4.4 g/dl were at the highest risk (IR ≥1.9/100 patient-years). Visual nomograms predicting HCC risk based on LSM and albumin at 1 year of follow-up were constructed.

Conclusion

In patients with HCV-related cACLD who have achieved SVR with DAAs, HCC is the most frequent liver-related event. Both albumin levels and LSM are useful for stratifying patients based on their risk of developing HCC during follow-up.

Lay summary

New oral antivirals can cure chronic hepatitis C infection, however patients with advanced chronic liver disease are still at risk of presenting with liver-related complications. The most frequent complication after oral antiviral therapy in asymptomatic patients with advanced chronic liver disease was liver cancer. The use of simple parameters such liver stiffness and albumin levels after treatment can help to identify patients at higher or lower risk of liver cancer.

Introduction

Direct-acting antivirals (DAAs) have become the new standard of care for patients with chronic hepatitis C virus (HCV) infection, demonstrating high efficacy, with most patients achieving a sustained virological response (SVR) regardless of HCV genotype. Due to their good safety profile, any patient in any stage of chronic liver disease (from mild fibrosis to decompensated cirrhosis) can be treated with DAAs.1 Therefore, it is important to know which patients will be prone to developing liver-related complications, such as hepatocellular carcinoma (HCC) or liver decompensation, requiring lifelong follow-up and which patients can be safely discharged from follow-up.

Several studies have demonstrated that in patients with cirrhosis who have achieved SVR after DAA therapy there is a decrease in liver-related events due to an improvement in liver function and portal hypertension, and a decrease in the incidence of de novo HCC, accompanied by an overall increase in survival rates.[2], [3], [4], [5], [6], [7] These studies have also demonstrated that patients with cirrhosis are at higher risk of complications than those without cirrhosis. However, the variability in the methods used to select and define patients with cirrhosis in different published studies and the heterogeneity of patients included, mixing patients with compensated cirrhosis and decompensated cirrhosis, makes it hard to find predictors to identify high-risk populations and validate the results.

It is also important to note that currently most of the asymptomatic patients with advanced fibrosis or cirrhosis are diagnosed by elastographic methods such transient elastography and not by liver biopsy. So in many of these cases, the exact stage of the disease is suspected, but unconfirmed. For this reason, the Baveno VI consensus defined patients with liver stiffness measurement (LSM) ≥10 kPa and no prior decompensation as having “compensated advanced chronic liver disease” (cACLD).8 This patient population is of particular interest because, although they have never decompensated, approximately 80–90% of them have portal hypertension and up to 50–60% have clinically significant portal hypertension (CSPH).9 It would probably be easier to identify low-risk groups for liver-related events in this cACLD population, where some patients have an initial degree of advanced liver disease and higher odds of improving with therapy, than to identify them in mixed cirrhotic populations (Child-Pugh class A-B) affected by more advanced disease (with a higher proportion of CSPH and a greater risk of complications), in whom mechanisms of hepatocarcinogenesis might already have been initiated.

The aim of the present study was to describe the incidence of liver-related events in a population of patients with HCV-associated cACLD who achieved SVR after DAA therapy, and to identify non-invasive parameters (serological and elastographic) to predict the occurrence of liver-related events.

Section snippets

Patients and methods

This is a prospective cohort study from 2 tertiary hospitals (Hospital Universitari Vall d’Hebron and Hospital Clinic) from Barcelona, Spain. All adult patients (≥18 years old) who started DAA therapy for HCV infection between January 1st, 2015 and March 31st, 2016 were assessed for participation in the study. The inclusion criteria were: i) suspected cACLD defined by LSM ≥10 kPa and no prior decompensation (ascites, variceal bleeding, hepatic encephalopathy or jaundice) according to Baveno VI

Study population

A total of 1,563 patients in both centers who started DAA therapy between January 1st, 2015 and March 31st, 2016 were evaluated for eligibility. SVR was confirmed in 1,518 patients (97.1%) and finally, a total of 572 patients with cACLD were included in the study (Fig. 1). The baseline characteristics of the patients included are described in Table 1. The mean age of the patients included was 63.7 years and 49.3% were male. Most patients had HCV genotype 1 (85.8%) and 78.1% patients were

Discussion

The main findings of the present study, in a cohort of patients with HCV-associated cACLD who achieved SVR after DAA therapy, were that the incidence of liver-related events was relatively low, with de novo HCC being the most frequent complication, and that using simple non-invasive predictors (albumin and LSM at follow-up) we could identify 2 patient groups with a differing risk of HCC during follow-up.

Several studies have demonstrated that in patients who achieve SVR after DAA therapy, the

Financial support

MP is a recipient of a Río Hortega grant from Instituto de Salud Carlos III, Spain. SRT received a grant from Instituto de Salud Carlos III, Rio Hortega program CM17/00015, and an Initiation research grant from the Catalonian Society of Digestology and the Emili Lentag end-of-residency prize from Hospital Clínic de Barcelona. SL was supported by a grant from Hospital Clinic. XF received support by Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement (grant 2017 SGR 1753)

Conflicts of interest

ZM is an advisor for Gilead and Abbvie. VV is a speaker for Intercept and an advisor for Promethera. SL has received speaker/advisory fees from Abbvie, Gilead, Janssen and MSD. MB is an advisor and speaker for Gilead, MSD and Abbvie. XF has served as advisor for AbbVie and Gilead. BM has received lecture fees from Gilead and Bayer and is an advisor for Bayer.

Please refer to the accompanying ICMJE disclosure forms for further details.

Authors’ contributions

Study concept and design: MP, JG. Patient enrollment and acquisition of data: MP, SRT, JIE, ZM, VV, SL, MB, SA, XF, BM, JG. Analysis and interpretation of data: MP, BM, JG. Drafting of the manuscript: MP, JG. Critical revision of the manuscript: SRT, JIE, ZM, VV, SL, MB, SA, XF, BM. All the authors approved the final draft which is being submitted.

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