Elsevier

The Lancet

Volume 393, Issue 10179, 6–12 April 2019, Pages 1453-1464
The Lancet

Articles
Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study

https://doi.org/10.1016/S0140-6736(18)32111-1Get rights and content

Summary

Background

Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort.

Methods

We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458.

Findings

Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0–40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2·77, 95% CI 2·07–3·71) and decompensated cirrhosis (3·83, 2·29–6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33–0·70) and hepatocellular carcinoma (0·66, 0·46–0·93), and was not associated with decompensated cirrhosis (1·14, 0·57–2·27).

Interpretation

Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection.

Funding

INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.

Introduction

WHO's Global Hepatitis Report1 states that hepatitis C virus (HCV) has infected 1% of the population worldwide (71 million) and caused approximately 400 000 deaths annually, mainly from cirrhosis and hepatocellular carcinoma. This substantial public health burden can be improved by HCV treatments, because this chronic viral infection is the only one that can be cured, as defined by a sustained virological response.2, 3 Combining two or three direct-acting antivirals targeting viral proteins—eg, NS3/4A protease inhibitors, NS5B polymerase inhibitors, and NS5A replication complex inhibitors—has pan-genotypic efficacy in HCV infection, with a sustained viral response of more than 95% and fair tolerance. Treatment lasts 8–16 weeks depending on baseline factors including stage of fibrosis, genotype, treatment history, and pre-existing resistance-associated variants.4, 5

Findings of observational studies in patients with HCV infection show reduced risk for hepatocellular carcinoma, complications of liver disease, and mortality in patients treated with interferon or direct-acting antivirals who achieve a sustained virological response.6, 7, 8, 9, 10, 11, 12 However, very few studies have compared the clinical outcomes of patients treated and not treated with direct-acting antivirals, as would be done in a randomised trial.13 The findings of a single-centre cohort study showed decreased mortality in patients receiving a combination of paritaprevir, ritonavir, ombitasvir, and dasabuvir, or of sofosbuvir and ledispasvir, compared with untreated patients.14 However, this study did not report the incidence of liver-related events such as liver decompensation or hepatocellular carcinoma, and this information is important because of controversy surrounding a potential increase in risk for hepatocellular carcinoma with direct-acting antiviral treatment.15, 16

Research in context

Evidence before this study

We searched PubMed for reports published in any language between Jan 1, 2012, and Jan 1, 2018, with the MESH terms (“hepatitis C, chronic/drug therapy” OR “hepatitis C, chronic/therapy”) AND (“hepatitis C, chronic/mortality” OR “hepatitis C, chronic/complications”). We searched for evidence of randomised trials or observational studies assessing the risk of mortality, liver cancer, and the complications of liver disease after antiviral treatment with direct-acting antivirals in patients with chronic hepatitis C virus (HCV) infection. We identified a 2017 review of 138 randomised trials assessing the effects of 51 different direct-acting antivirals, indicating that use of these drugs increased the proportion achieving a sustained virological response. However, the review did not reach any conclusions on clinical effects. We only found one additional retrospective cohort study reporting a significant decrease in all-cause mortality in patients receiving either paritaprevir, ritonavir, ombitasvir, and dasabuvir or sofosbuvir and ledipasvir, compared with untreated patients. This study did not report on liver-related mortality or liver-related events (eg, liver cancer or liver decompensation). No existing prospective study has examined the benefits and harms of direct-acting antivirals in chronic HCV infection on liver-related clinical outcomes using time-to-event analyses and by comparison of treated and untreated patients.

Added value of the study

To our knowledge, the ANRS CO22 Hepather cohort study is the first prospective longitudinal study to investigate clinical outcomes associated with direct-acting antiviral treatment in patients with chronic HCV infection, by comparing patients treated with direct-acting antivirals with those untreated with these drugs, irrespective of the status of sustained virological response, with careful control of confounding and indication biases. The adjusted multivariable analyses show that direct-acting antiviral treatment is associated with a rapid decrease in all-cause mortality and the incidence of hepatocellular carcinoma, and that these inverse associations are stronger in patients with cirrhosis.

Implications of all the available evidence

For ethical reasons, a trial with an untreated control arm cannot be undertaken to confirm these findings. We encourage other researchers to do similar comparisons of patients treated with direct-acting antivirals and untreated patients, using existing observational databases. Nevertheless, our results support urgent treatment of patients with advanced liver disease and extension of the follow-up of treated patients with less severe disease to assess the long-term clinical effect of direct-acting antiviral treatment.

The aim of this study was to further clarify the benefits or harms of direct-acting antivirals by comparing the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis in patients treated with direct-acting antivirals and untreated, from the prospective French ANRS CO22 Hepather cohort.

Section snippets

Study design and participants

The ANRS CO22 Hepather cohort is a French national, multicentre, prospective, observational cohort study of patients with active or inactive hepatitis B virus (HBV) or past or present HCV infection, which started in August, 2012.17 The main objectives of the study are to quantify the clinical efficacy and safety of new hepatitis treatments in real life. The anticipated cohort size is 15 000 patients serum-positive for anti-HCV (>90% with existing chronic HCV infection at entry—ie,

Results

Between Aug 6, 2012, and Dec 31, 2015, 14 389 anti-HCV-positive patients had been recruited to the ANRS CO22 Hepather cohort, including 11 870 with chronic HCV infection at entry (figure 1). 95 patients had active HBV co-infection at entry, 653 had a history of hepatocellular carcinoma, 1003 had decompensated cirrhosis, and 326 had undergone liver transplantation; these patients were excluded from this study. A further 148 patients were excluded who had received peginterferon and ribavirin with

Discussion

The findings of this large French cohort study show that direct-acting antiviral treatment is associated with reduced risk for mortality and hepatocellular carcinoma, after adjustment for potential confounding factors. Similar associations were identified in the subgroup of patients with cirrhosis. These inverse associations persisted in the subgroup of patients who achieved a sustained virological response, whereas those who did not achieve a sustained virological response were at higher risk

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    Members of the ANRS-AFEF Hepather Study group are listed at the end of the Article

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