Elsevier

Journal of Hepatology

Volume 64, Issue 6, June 2016, Pages 1224-1231
Journal of Hepatology

Research Article
Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis

https://doi.org/10.1016/j.jhep.2016.01.029Get rights and content

Background & Aims

All oral direct acting antivirals (DAAs) effectively treat chronic hepatitis C virus (HCV) infection, but the benefits in advanced liver disease are unclear. We compared outcomes in treated and untreated patients with decompensated cirrhosis.

Methods

Patients with HCV and decompensated cirrhosis or at risk of irreversible disease were treated in an expanded access programme (EAP) in 2014. Treatment, by clinician choice, was with sofosbuvir, ledipasvir or daclatasvir, with or without ribavirin. For functional outcome comparison, untreated patients with HCV and decompensated cirrhosis who were registered on a database 6 months before treatment was available were retrospectively studied. Primary endpoint was sustained virological response 12 weeks post antiviral treatment (treated cohort) and the secondary endpoint (both cohorts) was adverse outcomes (worsening in MELD score or serious adverse event) within 6 months.

Results

467 patients received treatment (409 decompensated cirrhosis). Viral clearance was achieved in 381 patients (81.6%) – 209 from 231 (90.5%) with genotype 1 and 132 from 192 (68.8%) with genotype 3. MELD scores improved in treated patients (mean change −0.85) but worsened in untreated patients (mean + 0.75) (p <0.0001). Patients with initial serum albumin <35 g/L, aged >65 or with low (<135 mmol/L) baseline serum sodium concentrations were least likely to benefit from therapy.

Conclusions

All oral DAAs effectively cured HCV in patients with advanced liver disease. Viral clearance was associated with improvement in liver function within 6 months compared to untreated patients. The longer term impact of HCV treatment in patients with decompensated cirrhosis remains to be determined.

Introduction

All oral direct acting antiviral (DAA) drugs for patients with chronic hepatitis C virus (HCV) infection have transformed treatment options. High response rates are observed in patients with compensated cirrhosis in clinical trials [1], [2], [3], [4] and in real-life observational studies [5]. Even in patients with decompensated cirrhosis, for whom pegylated interferon (PegIFN) is contraindicated and who otherwise have a poor prognosis, HCV can now be cured safely and effectively [6]. Experience of different DAA combinations in the real world is growing within a number of compassionate use programs [5], [7]. However, virological response with all oral DAAs in decompensated cirrhosis, particularly in HCV genotype 3, is lower than in patients with less advanced liver disease [8], [9]. Remaining uncertainties in treating such patients include the optimal duration of therapy, whether or not the regimen should include ribavirin, and what, if any, clinical benefits accrue to patients with such advanced liver disease following clearance of virus.

Viral eradication in patients with chronic HCV infection has been shown to result in improvements in medium and long term outcomes – assessed both by patient reported quality of life measurements and mortality/morbidity [10], [11], [12]. However, in patients with advanced, decompensated cirrhosis it is uncertain whether treatment and viral clearance is beneficial, and if meaningful functional hepatic recovery is possible. Clearly if treatment were able to reverse liver dysfunction and perhaps avoid the need for transplantation then therapy should be recommended. Therapy, although generally safe, might be associated with adverse events, particularly in unstable patients with advanced cirrhosis [13] and may delay access to transplantation. It is conceivable that patients with decompensated cirrhosis may eliminate virus, stabilise their disease and not progress to a stage where transplantation is indicated. However, they may not recover to any meaningful extent and post therapy, may be left without access to transplantation but with a poor quality of life (so called ‘MELD purgatory’). In the SOLAR study of patients with advanced liver disease infected with HCV genotypes 1 and 4, viral eradication was rapidly associated with an improvement in severity of liver disease scores (MELD scores) [6] but no comparator group was included, and it is unclear whether benefits were related to viral clearance or to improved management of the patients in a clinical trial setting in specialist centres [1], [2], [3].

Here we report on the outcomes of the NHS England expanded access programme (EAP), which treated patients with severe liver disease of all viral genotypes, who were “at significant risk of death or irreversible damage within 12 months due to hepatic or extrahepatic manifestations”. Sofosbuvir combined with the NS5A inhibitors ledipasvir or daclatasvir, with or without ribavirin, was used for a fixed duration of 12 weeks and patients were enrolled in the UK hepatitis C registry – HCV Research UK. To address the question of whether antiviral therapy is beneficial in unselected patients with decompensated cirrhosis infected with all HCV genotypes, we examined the functional outcomes of patients with equivalent disease stage, who enrolled into the same registry for at least 6 months prior to the start of EAP, and hence were not able to receive HCV treatment for at least 6 months of follow-up. We show that HCV treatment improves outcomes and we present a model to predict those patients who are likely to derive most benefit from therapy.

Section snippets

Study design and patients

For treated patients this was a prospective, observational cohort study. Patients enrolled in the HCV Research UK registry who received antiviral therapy as part of the EAP between 1 April 2014 and 11 November 2014 were studied. Eligible patients were those at significant risk of death or irreversible damage from HCV infection within 12 months, irrespective of genotype. Criteria for inclusion were decompensated cirrhosis – ascites, variceal bleed or encephalopathy (past or current), Child Pugh

Treatment cohort

A total of 480 patients received therapy as part of the EAP between the start of the programme (1 April 2014) to 11 November 2014; 467 patients consented to provide data to the HCV Research UK database (Fig. 1). At treatment initiation 409 (88%) patients had decompensated cirrhosis and/or Child Pugh score ⩾7; 44 (9%) had undergone liver transplantation with aggressive HCV recurrence without decompensation. The remaining 14 (3%) patients were treated for extrahepatic indications. Table 1 and

Discussion

The efficacy of all oral antiviral regimens in the management of patients with compensated liver disease due to chronic HCV infection is now established [1], [2], [3], [4] and data on patients with decompensated cirrhosis are emerging [5], [6], [7], [14]. In this study we examined a fixed, 12 week, duration course of antiviral therapy in a large heterogeneous group of patients with decompensated cirrhosis or life-threatening complications of HCV infection, and we compared outcomes to an

Financial support

This study received funding from NHS England; Medical Research Foundation and Gilead; Bristol-Myers Squibb.

Conflict of interest

Professor Foster has received speaker and consultancy fees from AbbVie, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Idenix, Janssen, Merck, Novartis, Roche, Springbank; Professor Irving has received speaker and consultancy fees from Roche Products, Janssen Cilag and Novartis, educational grants from Boehringer Ingelheim, MSD and Gilead Sciences, and research grant support from GlaxoSmithKline, Pfizer, Gilead Sciences and Janssen Cilag; Dr Agarwal has received speaker and

Authors’ contributions

The study was designed and led by GRF, WI and KA. MC, BH, SV managed patients in the study, collated the data and assisted in the analysis. 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 and DCM led the recruitment and data collection. All authors participated in data analysis and participated in the preparation of the manuscript.

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These authors contributed equally as joint first authors.

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