Elsevier

Journal of Hepatology

Volume 73, Issue 6, December 2020, Pages 1415-1424
Journal of Hepatology

Research Article
Clinical outcome and hemodynamic changes following HCV eradication with oral antiviral therapy in patients with clinically significant portal hypertension

https://doi.org/10.1016/j.jhep.2020.05.050Get rights and content

Highlights

  • HVPG ≥10 mmHg persists 2 years after therapy in 53–65% of patients with HCV-related cirrhosis despite HCV eradication.

  • Changes in liver stiffness do not correlate with changes in HVPG after a sustained virological response.

  • Baseline HVPG ≥16 mmHg and ascites identify patients with persistent CSPH and risk of decompensation.

Background & Aims

Clinically significant portal hypertension (CSPH), defined as a hepatic venous pressure gradient (HVPG) ≥10 mmHg, persists 24 weeks after sustained virological response (SVR) in up to 78% of patients with HCV-related cirrhosis treated with direct-acting antivirals. These patients remain at risk of decompensation. However, long-term paired clinical and hemodynamic data are not available for this population.

Methods

We conducted a prospective multicenter study in 226 patients with HCV-related cirrhosis and CSPH who achieved SVR after antiviral therapy. Patients with CSPH 24 weeks after end of treatment (SVR24) were offered another hemodynamic assessment 96 weeks after end of treatment (SVR96).

Results

All patients were clinically evaluated. Out of 176 patients with CSPH at SVR24, 117 (66%) underwent an HVPG measurement at SVR96. At SVR96, 55/117 (47%) patients had HVPG <10 mmHg and 53% had CSPH (65% if we assume persistence of CSPH in all 59 non-evaluated patients). The proportion of high-risk patients (HVPG ≥16 mmHg) diminished from 41% to 15%. Liver stiffness decreased markedly after SVR (median decrease 10.5 ± 13 kPa) but did not correlate with HVPG changes (30% of patients with liver stiffness measurement <13.6 kPa still had CSPH). Seventeen (7%) patients presented with de novo/additional clinical decompensation, which was independently associated with baseline HVPG ≥16 mmHg and history of ascites.

Conclusions

Patients achieving SVR experienced a progressive reduction in portal pressure during follow-up. However, CSPH may persist in up to 53–65% of patients at SVR96, indicating persistent risk of decompensation. History of ascites and high-risk HVPG values identified patients at higher risk of de novo or further clinical decompensation.

Lay summary

As a major complication of cirrhosis, clinically significant portal hypertension (CSPH) is associated with adverse clinical outcomes. Herein, we show that CSPH persists at 96 weeks in just over half of patients with HCV-related cirrhosis, despite HCV elimination by direct-acting antivirals. Despite viral cure, patients with CSPH at the start of antiviral treatment remain at long-term risk of hepatic complications and should be managed accordingly.

Introduction

Sustained virological response (SVR) to all-oral direct-acting antivirals (DAAs) is achieved in over 90% of patients with advanced cirrhosis and portal hypertension. Indeed, around 20% of patients on the waiting list for liver transplantation exhibit a clinical improvement after SVR that allows delisting.1,2 However, most of the studies including patients with advanced liver disease have a short follow-up and therefore the long-term impact of viral clearance has not been well characterized.3,4 In this setting, the questions that remain to be answered are to what extent viral eradication is associated with a decreased long-term risk from further complications of cirrhosis, the reliability of non-invasive measures to predict these events, and whether it is possible to predict the individual risk for a personalized clinical follow-up after SVR.

Like other authors, we have shown that SVR in patients with cirrhosis is associated, in the short term, with a reduction in portal hypertension. Our group reported, in a cohort of 226 patients with Child A/B cirrhosis and baseline clinically significant portal hypertension (CSPH) – defined as hepatic venous pressure gradient (HVPG) ≥10 mmHg – that DAA-induced SVR was associated with an HVPG reduction of 2.1 ± 3.2 mmHg at 24 weeks after completing treatment.4 However, 78% of patients still had CSPH at the follow-up evaluation, thus remaining at risk of hepatic decompensation. Other studies have confirmed that when patients with CSPH are considered, only a minority achieve reductions of HVPG below the threshold considered to be protective (10 mmHg).5,6 Preliminary data from another study assessing the effect of interferon-based therapies suggested that by extending the period of observation after SVR, some patients showed additional improvement in liver function and a further reduction in HVPG,7 thus reinforcing the concept that potential improvements in certain aspects of chronic liver disease, such as fibrosis, may take a long time to transpire after SVR. However, in this study, only a minority of patients underwent follow-up HVPG and this was performed at different time points, making it difficult to assess the relationship between long-term HVPG changes and clinical outcomes.

As liver biopsies are not ideal for a dynamic evaluation of fibrosis due to their invasiveness, non-invasive techniques such as transient elastography (TE) are used instead. Liver stiffness measurement (LSM), assessed by TE, may decrease rapidly during and immediately after DAA treatment, likely because of reduced inflammation, which might lead to overestimation of fibrosis regression. Indeed, in our previous study, 6 months after SVR, 43% of patients with LSM <13.6 kPa (the cut-off ruling out CSPH in patients with active HCV infection4) still had CSPH. Moreover, current guidelines suggest that patients with LSM <20 kPa and a platelet count >150,000/μl have <5% probability of having high-risk esophageal varices (EVs) requiring prophylactic treatment and may therefore avoid endoscopic screening.8 However, data regarding whether these guidelines also apply after HCV elimination are scarce.9

This follow-up report from our prospective study aims at assessing, in a large cohort of patients with HCV-related cirrhosis and CSPH who achieved SVR after treatment with DAA: a) the long-term clinical outcomes and their relationship with HVPG changes, b) the variables associated with CSPH persistence, and c) the predictive value of TE to rule out the presence of CSPH after SVR.

Section snippets

Patients and study design

This is a multicenter long-term follow-up report of a prospective study of consecutive patients with HCV-related cirrhosis undergoing interferon-free antiviral therapy in 6 liver units in Spain [Hospital Clínic (Barcelona), Hospital Sant Pau (Barcelona), Hospital Puerta del Hierro (Madrid), Hospital Ramón y Cajal (Madrid), Hospital Gregorio Marañón (Madrid) and Hospital Marqués de Valdecilla (Santander)]. Inclusion criteria for the study were the presence of CSPH at baseline (baseline HVPG

Hemodynamic changes after SVR in the long term

The initial study cohort comprised 226 patients with CSPH at baseline who underwent follow-up HVPG evaluation at SVR24. Baseline characteristics have been described elsewhere.4 Briefly, median HVPG was 15.6 mmHg (14–19), 78% had HVPG ≥12 mmHg and 41% HVPG ≥16 mmHg. Most patients were Child-Pugh A (79%) and 66 (29%) patients had a history of previous decompensation (multiple decompensations in some patients: ascites n = 51, acute variceal bleeding n = 26; hepatic encephalopathy n = 12). HVPG

Discussion

The development of CSPH is a hallmark in the natural history of cirrhosis because it is associated with a higher risk of hepatic decompensation and an increased risk of HCC and death.[16], [17], [18] Indeed, in a previous study evaluating 213 patients with compensated cirrhosis and CSPH, decompensation occurred in 62 patients (29%) after a median follow-up of 51.1 months16 and in a recent study of 201 patients aimed at assessing the utility of β blockers to prevent decompensation, 16% of

Financial support

XF received support in part by Instituto de Salud Carlos III (PI15/00151), Ministry of Economy and Competitiveness, co-funded by the European Regional Development Fund of the European Union (ERDF, “A way to build Europe”). JCGP received support in part through grants from the Spanish Ministry of Education and Science (SAF-2016-75767-R and PIE 15/00027) and from the “Commissioner for Universities and Research of the Generalitat de Catalunya” (AGAUR SGR 2017). XF and JCGP also received a grant

Authors' contributions

SL, JCGP and XF contributed to the study concept and design. All authors contributed to the acquisition of data. SL, AB, XF and JCGP contributed to the analysis and interpretation of data and drafted the manuscript. All authors contributed to the critical revision of the manuscript for important intellectual content. All authors approved the final manuscript prior to submission.

Conflict of interest

S. Lens has received speaker and consultant fees from Gilead, Abbvie and Janssen. Z. Mariño has acted as a speaker for Abbvie, Gilead, Janssen and is on the advisory board for Gilead and Abbvie. JL. Calleja is a consultant and lecturer for BMS, Gilead Sciences, Abbvie and MSD. X. Torras has received consultancy fees from Gilead, BMS and is a lecturer for Abbvie, Gilead, Janssen and MSD. Agustín Albillos has served as advisor/lecturer for AbbVie, Gilead Sciences, Gore, Griffols, Intercept

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