Elsevier

Journal of Hepatology

Volume 65, Issue 4, October 2016, Pages 741-747
Journal of Hepatology

Research Article
Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis

https://doi.org/10.1016/j.jhep.2016.06.019Get rights and content

Background & Aims

Direct-acting antivirals have become widely used for patients with chronic hepatitis C virus infection with decompensated cirrhosis. Virological responses are excellent and early improvements in liver function, at least in a proportion of patients, have been observed but the longer term impact of viral clearance on end-stage liver disease complications is unclear.

Methods

Prospective study of patients with decompensated cirrhosis who received 12 weeks of all-oral direct-acting antivirals through the English Expanded Access Programme. Endpoints were deaths, liver transplantation, hepatocellular carcinoma, serious decompensation events, sepsis or hospitalisations, and MELD scores between start of therapy to 15 months post-treatment start. An untreated cohort of patients was retrospectively studied over 6 months for comparison.

Results

Amongst 317/406 patients who achieved sustained virological response at 24 weeks post-treatment, there were 9 deaths (3%), 17 new liver cancers (5%), 39 transplantations (12%) and 52 with serious decompensations (16%), over 15 months.

When compared to the first six months from treatment start and to untreated patients, there was a reduction in incidence of decompensations [30/406 (7%) in months 6–15 and 72/406 (18%) in months 0–6 for treated patients vs. 73/261 (28%) in untreated patients]. There was no significant difference in liver cancer incidence (10/406 (2.5%) in months 6–15 and 17/406 (4%) in months 0–6 for treated patients vs. 11/261 (4%) in untreated patients).

Conclusions

This study suggests that antiviral therapy in patients with decompensated cirrhosis led to prolonged improvement in liver function, with no evidence of paradoxical adverse impact nor increase in liver malignancy.

Lay summary

This is a report of a large group of patients in England who have hepatitis C virus (HCV) infection with advanced liver disease. They have been treated with new anti-HCV drugs, which cured the infection in the majority. This study looks at their outcomes a year following treatment, in terms of deaths, cancers and other complications of advanced liver disease. We conclude that in most patients anti-HCV treatment is beneficial even in advanced liver disease.

Introduction

All-oral, interferon (IFN)-free direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection has allowed successful treatment of patients with advanced liver disease. Worldwide, large numbers of HCV-infected patients with decompensated cirrhosis have received antiviral therapy and although sustained virological response (SVR) rates are slightly reduced compared to patients with compensated disease, over 80% of treated patients still achieve viral clearance. Early analysis of patients who responded to therapy showed associated improvements in MELD and Child-Pugh scores [1], [2], [3], [4], although some concerns have been expressed that the rate of malignancy may not change or may, paradoxically, increase [5], [6]. Previous studies of IFN-based therapies have demonstrated that HCV clearance improves liver fibrosis, even in cirrhosis [7]. Moreover, patients who achieved SVR had reduced mortality, complications of cirrhosis and hepatocellular carcinoma compared to untreated patients or those who failed to achieve SVR [8], [9], [10]. However, such studies involved patients with relatively ‘early’ cirrhosis and it remains unclear whether these long term benefits will be seen in patients treated for more advanced disease. Although there is little data on long term outcomes, international guidelines recommend that patients with decompensated cirrhosis should be urgently treated with IFN-free DAA therapy, regardless of eligibility for liver transplantation [11], [12].

Chronic HCV infection is the main indication for liver transplantation in the Western world, and universally recurs causing accelerated disease progression in the liver graft. Given the shortage of donor organs and costs of liver transplantation, DAA treatment may reduce the need for transplantation in patients with advanced cirrhosis and allow alternative uses for scarce organs. Pooled analysis of over 800 patients with decompensated cirrhosis showed that 60% of patients had an improvement in MELD score from baseline following therapy, but 23% deteriorated, at post-treatment weeks 4 to 12 [13]. The magnitude of improvement varied with a median of 2 MELD points. It is unclear whether this early change is clinically meaningful. Perhaps more importantly, minor reductions in MELD may adversely affect access to liver transplantation, if a patient no longer meets transplant criteria but is insufficiently improved with a reduced quality of life (so called ‘MELD purgatory’). In such cases, therapy may not be beneficial.

We recently published data on the virological and clinical outcomes of patients with decompensated cirrhosis treated on the English Expanded Access Programme (EAP) with 12 weeks of sofosbuvir and a NS5A inhibitor with or without ribavirin [14]. Consistent with other studies, the majority of patients successfully achieved viral clearance associated with MELD improvements by post-treatment week 12. To assess the impact of antiviral therapy in patients with decompensated cirrhosis, the study compared treated patients to a retrospective cohort of patients with decompensation who were untreated for 6 months prior to the availability of DAAs. Treated patients had fewer decompensations, reduced deterioration in MELD, and overall adverse events, although there were no significant differences in rates of death, liver transplantation or hepatocellular carcinoma [14]. To address the longer term benefits of successful HCV clearance, here we report the outcomes in the same patient cohort followed-up for one year after completion of therapy.

Section snippets

Patients and methods

Patients who received DAA therapy through the English EAP were enrolled into the HCV Research UK (HCVRUK) registry for prospective data collection. Patients who started treatment between 1 April and 11 November 2014 were studied. Details of the EAP treatment and patient selection criteria were previously published [14]. In brief, treatment consisted of 12 weeks of sofosbuvir with ledipasvir or daclatasvir, with or without ribavirin. Treatment choice was according to local multidisciplinary

Patient population

A total of 480 patients received antiviral therapy through the EAP between the start of the programme on 1 April 2014 to 11 November 2014 – 467 (97.3%) patients consented to provide data to the HCVRUK registry and 406 (87%) patients had decompensated cirrhosis and/or Child-Pugh score ⩾B7, without previous liver transplantation, at treatment start. Sixty-one (13%) patients were treated for extrahepatic HCV disease or aggressive HCV recurrence in liver grafts.

Table 1 shows the demographics and

Discussion

The availability of highly effective all-oral antiviral regimens for patients with chronic HCV infection has transformed the treatment options for infected patients and most patients can now achieve viral clearance. For patients with advanced liver disease it is unclear whether viral eradication is beneficial and there are some reports suggesting that it may be harmful. Indeed, the definition of benefit following viral clearance, whether it is patient survival, access to transplantation or

Financial support

This study was supported by NHS England; Medical Research Foundation (Grant reference C0365); Gilead; Bristol-Myers Squibb.

Conflict of interest

Dr Cheung is funded by the National Institute for Health Research Doctoral Research Fellowship; Professor Mutimer has received honoraria from Gilead Sciences, AbbVie, Bristol-Myers Squibb, MSD and Janssen. Dr Agarwal has received speaker and consultancy fees from AbbVie, Achillion, Astellas, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis; Professor Foster has received speaker and consultancy fees from AbbVie, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb,

Authors’ contributions

The study was designed and led by GRF and WI. MC, BH, SV managed patients in the study, collated the data and assisted in the analysis. MC and AW performed the data and statistical analysis. WI and JM supervised sample collection, data management and assisted with study design and implementation. DJM, AB, WG, DCM and KA led the recruitment and data collection. All authors participated in data analysis and participated in the preparation of the manuscript.

Acknowledgements

The authors would like to thank the patients, their families and all participating study studies for contributing data to this study. We are also grateful to HCV Research UK, in particular Elizabeth Holtham and Jennifer Benselin for collecting and collating data. HCV Research UK was supported by the Medical Research Foundation (grant reference C0365). AW was supported by the MRC-funded STOP-HCV consortium. We would like to acknowledge NHS England, Gilead Sciences and Bristol-Myers Squibb for

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    After removal of duplicates, the literature search yielded 2461 articles. We reviewed 152 articles in full-text and performed data extraction for 31 articles5,16-45 that included patients with cirrhosis and 11 articles19,21,22,28-30,34,35,43-45 that included patients without cirrhosis. The screening and article inclusion/exclusion process are shown in Figure 1.

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