Research ArticleNon-invasive tests for clinically significant portal hypertension after HCV cure
Graphical abstract
Introduction
Portal hypertension (PH) is the key driver of hepatic decompensation in patients with advanced chronic liver disease (ACLD).1 Accordingly, interventions that ameliorate PH have been shown to prevent hepatic decompensation in patients who are at risk, i.e., those with clinically significant portal hypertension (CSPH), which is defined by an hepatic venous pressure gradient (HVPG) ≥10 mmHg. In addition to non-selective beta-blockers,1,2 removal/suppression of the primary aetiological factor may lead to substantial reductions in HVPG, thereby decreasing the risk of hepatic decompensation. With the availability of interferon (IFN)-free regimens, sustained virological response (SVR; i.e., HCV cure) is achieved in nearly all patients with chronic HCV infection, despite the presence of pre-treatment ACLD and CSPH.3 Previous studies in patients achieving SVR have reported an amelioration of PH across all pre-treatment HVPG strata.[4], [5], [6], [7], [8], [9] In those with pre-treatment CSPH, HVPG decreases of ≥10% were achieved in 60-63%.[5], [6], [7] However, only the absence/resolution of CSPH eliminates the risk of post-treatment hepatic decompensation, and thus, identifies patients who should be considered for de-escalation of care to avoid unnecessary investigations and costs. The latter has profound economic implications, as the number of individuals who will achieve HCV cure worldwide is expected to exceed 1 million per year for the next decade, with a relevant proportion having compensated ACLD (cACLD).10 On the other end of the disease severity spectrum, those with post-treatment CSPH may remain at considerable risk. Since HVPG measurement is invasive, resource-intensive, and requires considerable expertise,11,12 CSPH risk stratification by non-invasive tests (NITs) is key to individualize post-treatment management in patients with cACLD.13 Platelet count (PLT) and liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) are the most extensively studied NITs for CSPH in patients with cACLD14,15 and have been implemented in clinical practice recommendations for the management of PH with Baveno VI.16 However, their diagnostic ability for CSPH has predominantly been studied in patients with active HCV infection, while investigations after HCV cure are limited and have yielded conflicting results,[5], [6], [7],17 which has led to considerable scepticism regarding their clinical use in this steadily increasing patient population.18
Thus, we conducted a pooled analysis to investigate (i) the diagnostic performance of NITs for CSPH (primary objective) as well as (ii) the relationship between NITs and pre- and post-treatment HVPG and (iii) to validate the derived LSM/PLT criteria against the direct endpoint of hepatic decompensation (secondary objectives).
In addition, we (iv) described the evolution of PH after HCV cure and (v) evaluate the diagnostic utility of NITs for varices and (vi) the relationship between PH and de novo hepatocellular carcinoma (HCC) development.
Section snippets
HVPG-cohort
After removing duplicates, 675 individual patients from 8 cohorts investigating HVPG in patients undergoing HCV treatment (both IFN-containing and IFN-free) were evaluated for inclusion in this pooled analysis (Fig. 1).[4], [5], [6], [7], [8], [9],17,[19], [20], [21], [22] Information on exclusion criteria and patient selection is provided in Fig. 1. Authors of the three additional studies published before 2020 were contacted, however, individual patient data were not provided.[23], [24], [25]
Evolution of PH after HCV cure in the HVPG-cohort
Among 418 patients with paired HVPG measurements, mean BL-HVPG was 14.2 ± 4.8 mmHg, corresponding to 353 (84%) patients with BL-CSPH and 153 (37%) with BL-HVPG ≥16 mmHg.
Median time between EoT and post-treatment HVPG measurement (FU-HVPG) was 28.4 (24–44) weeks (Fig. S2).
HVPG decreased in 333 patients (80%), remained stable in 23 (5.5%) patients, and increased in 62 (14.8%), resulting in a mean FU-HVPG of 11.8 ± 5.4 mmHg. The median absolute difference between BL-HVPG and FU-HVPG was −2.5 (−4.3
Discussion
In this pooled analysis, we have synthesized the data of individual studies to provide robust information on the relationship between NITs and HVPG after HCV cure. We have developed clinically useful tools for estimating the probability of CSPH and established that NITs are capable of excluding and ruling-in CSPH in the majority (i.e., 59.3%) of unselected patients with cACLD who have achieved SVR. The same criteria may be applied for non-invasive risk stratification. Finally, our pooled
Financial support
This work was supported by a grant from the Medical Scientific Fund of the Major of the City of Vienna (No. 17035) as well as the Andrew K. Burroughs short-term training fellowship of the European Association for the Study of the Liver.
Authors’ contributions
Study concept and design (G.S., S.L., J.C.G.-P., and M.M.), acquisition of data (all authors), analysis and interpretation of data (G.S., S.L., E.M., J.C.G.-P., and M.M.), drafting of the manuscript (G.S., S.L., J.C.G.-P., and M.M.), critical revision of the manuscript for important intellectual content (all authors).
Data availability statement
Data are available from the corresponding authors upon reasonable request.
Conflict of interest
G.S. received travel support from Gilead. S.L. received grant support from Gilead and served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, and MSD. E.L.M. received grant support from Novartis. A.B. has nothing to disclose. E.A. has nothing to disclose. E.L. has nothing to disclose. L.T. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, Bayern, Janssen, and W. L. Gore & Associates, and received travel support from AbbVie,
Acknowledgements
We would like to acknowledge the contributions of Stefanie Hametner-Schreil, and Rainer Schöfl (Ordensklinikum Linz Barmherzige Schwestern) as well as Michael Schwarz, Caroline Schwarz, and Michael Gschwantler (Klinikum Ottakring) to the external cACLD-validation-cohort.
References (40)
- et al.
Prevention of first decompensation in advanced chronic liver disease
Clin Liver Dis
(2021) - et al.
Beta blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial
Lancet (London, England)
(2019) - et al.
Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension
J Hepatol
(2016) - et al.
Scaling up prevention and treatment towards the elimination of hepatitis C: a global mathematical model
Lancet (London, England)
(2019) - et al.
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension
J Hepatol
(2015) - et al.
Clinical outcome and hemodynamic changes following HCV eradication with oral antiviral therapy in patients with clinically significant portal hypertension
J Hepatol
(2020) - et al.
Effect of sustained viral response on hepatic venous pressure gradient in hepatitis C–related cirrhosis
Clin Gastroenterol Hepatol
(2007) - et al.
BAVENO VII - renewing consensus in portal hypertension: report of the Baveno VII Consensus Workshop: personalized care in portal hypertension
J Hepatol
(2022) - et al.
HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease
J Hepatol
(2022) - et al.
Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study
Lancet (London, England)
(2013)
Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis
Gastroenterology
The diagnostic accuracy of Fibroscan for cirrhosis is influenced by liver morphometry in HCV patients with a sustained virological response
J Hepatol
Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis
Gastroenterology
Interferon-free regimens for chronic hepatitis C overcome the effects of portal hypertension on virological responses
Aliment Pharmacol Ther
Association between severe portal hypertension and risk of liver decompensation in patients with hepatitis C, regardless of response to antiviral therapy
Clin Gastroenterol Hepatol: Off Clin Pract J Am Gastroenterol Assoc
Effects of all-oral anti-viral therapy on HVPG and systemic hemodynamics in patients with hepatitis C virus-associated cirrhosis
Gastroenterology
Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy
Hepatology (Baltimore, Md)
Portal pressure and liver stiffness measurements in the prediction of fibrosis regression after sustained virological response in recurrent hepatitis C
Hepatology (Baltimore, Md)
Persistence of clinically significant portal hypertension after eradication of hepatitis C virus in patients with advanced cirrhosis
Clin Infect Dis: Off Publ Infect Dis Soc Am
The clinical use of HVPG measurements in chronic liver disease
Nat Rev Gastroenterol Hepatol
Cited by (0)
Author names in bold designate shared co-first authorship.
- †
G.S. and S.L. contributed equally to the work.
- ‡
J.C.G-P. and M.M. share the corresponding and last author position.