Elsevier

Journal of Hepatology

Volume 77, Issue 6, December 2022, Pages 1573-1585
Journal of Hepatology

Research Article
Non-invasive tests for clinically significant portal hypertension after HCV cure

https://doi.org/10.1016/j.jhep.2022.08.025Get rights and content

Highlights

  • Post-treatment LSM/platelet count can be used to estimate the probability of CSPH and predict clinical outcomes in cACLD.

  • Patients with cACLD and LSM <12 kPa & PLT >150 G/L (CSPH-excluded; no decompensation risk) may not require portal hypertension surveillance.

  • Patients with cACLD and LSM ≥25 kPa require surveillance/treatment (CSPH-ruled-in; increased decompensation risk).

Background & Aims

Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH; hepatic venous pressure gradient [HVPG] ≥10 mmHg) have predominantly been studied in patients with active HCV infection. Investigations after HCV cure are limited and have yielded conflicting results. We conducted a pooled analysis to determine the diagnostic/prognostic utility of liver stiffness measurement (LSM)/platelet count (PLT) in this setting.

Methods

A total of 418 patients with pre-treatment HVPG ≥6 mmHg who achieved sustained virological response (SVR) and underwent post-treatment HVPG measurement were assessed, of whom 324 (HVPG/NIT-cohort) also had paired data on pre-/post-treatment LSM/PLT. The derived LSM/PLT criteria were then validated against the direct endpoint decompensation in 755 patients with compensated advanced chronic liver disease (cACLD) with SVR (cACLD-validation-cohort).

Results

HVPG/NIT-cohort: Among patients with cACLD, the pre-/post-treatment prevalence of CSPH was 80%/54%. The correlation between LSM/HVPG increased from pre- to post-treatment (r = 0.45 vs. 0.60), while that of PLT/HVPG remained unchanged. For given LSM/PLT values, HVPG tended to be lower post- vs. pre-treatment, indicating the need for dedicated algorithms. Combining post-treatment LSM/PLT yielded a high diagnostic accuracy for post-treatment CSPH in cACLD (AUC 0.884; 95% CI 0.843–0.926). Post-treatment LSM <12 kPa & PLT >150 G/L excluded CSPH (sensitivity: 99.2%), while LSM ≥25 kPa was highly specific for CSPH (93.6%). cACLD-validation-cohort: the 3-year decompensation risk was 0% in the 42.5% of patients who met the LSM <12 kPa & PLT >150 G/L criteria. In patients with post-treatment LSM ≥25 kPa (prevalence: 16.8%), the 3-year decompensation risk was 9.6%, while it was 1.3% in those meeting none of the above criteria (prevalence: 40.7%).

Conclusions

NITs can estimate the probability of CSPH after HCV cure and predict clinical outcomes. Patients with cACLD but LSM <12 kPa & PLT>150 G/L may be discharged from portal hypertension surveillance if no co-factors are present, while patients with LSM ≥25 kPa require surveillance/treatment.

Lay summary

Measurement of liver stiffness by a specific ultrasound device and platelet count (a simple blood test) are broadly used for the non-invasive diagnosis of increased blood pressure in the veins leading to the liver, which drives the development of complications in patients with advanced liver disease. The results of our pooled analysis refute previous concerns that these tests are less accurate after the cure of hepatitis C virus (HCV) infection. We have developed diagnostic criteria that facilitate personalized management after HCV cure and allow for a de-escalation of care in a high proportion of patients, thereby decreasing disease burden.

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.

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  • 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.

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