Impact of comorbidities on patient outcomes after interferon-free therapy-induced viral eradication in hepatitis C

Highlights

• A pragmatic algorithm to manage HCV therapy is proposed.

• Charlson index (apart from liver function) reveals the global benefit of the treatment.

• HepCom index can be used for decision-making in the management of patients with HCV.

Background & Aims

Patients with advanced liver fibrosis remain at risk of cirrhosis-related outcomes and those with severe comorbidities may not benefit from hepatitis C (HCV) eradication. We aimed to collect data on all-cause mortality and relevant clinical events within the first two years of direct-acting antiviral therapy, whilst determining the prognostic capability of a comorbidity-based model.

Methods

This was a prospective non-interventional study, from the beginning of direct-acting antiviral therapy to the event of interest (mortality) or up to two years of follow-up, including 14 Spanish University Hospitals. Patients with HCV infection, irrespective of liver fibrosis stage, who received direct-acting antiviral therapy were used to build an estimation and a validation cohort. Comorbidity was assessed according to Charlson comorbidity and CirCom indexes.

Results

A total of 3.4% (65/1,891) of individuals died within the first year, while 5.4% (102/1,891) died during the study. After adjusting for cirrhosis, platelet count, alanine aminotransferase and sex, the following factors were independently associated with one-year mortality: Charlson index (hazard ratio [HR] 1.55; 95% CI 1.29–1.86; p = 0.0001), bilirubin (HR 1.39; 95% CI 1.11–1.75; p = 0.004), age (HR 1.06 95% CI 1.02–1.11; p = 0.005), international normalized ratio (HR 3.49; 95% CI 1.36–8.97; p = 0.010), and albumin (HR 0.18; 95% CI 0.09–0.37; p = 0.0001). HepCom score showed a good calibration and discrimination (C-statistics 0.90), and was superior to the other prognostic scores (model for end-stage liver disease 0.81, Child-Pugh 0.72, CirCom 0.68) regarding one- and two-year mortality. HepCom score identified low- (≤5.7 points: 2%–3%) and high-risk (≥25 points: 56%–59%) mortality groups, both in the estimation and validation cohorts. The distribution of clinical events was similar between groups.

Conclusions

The HepCom score, a combination of Charlson comorbidity index, age, and liver function (international normalized ratio, albumin, and bilirubin) enables detection of a group at high risk of one- and two-year mortality, and relevant clinical events, after starting direct-acting antiviral therapy.

Lay summary

The prognosis of patients with severe comorbidities may not benefit from HCV viral clearance. An algorithm to decide who will benefit from the treatment is needed to manage the chronic HCV infection better.

Introduction

The advent of new direct-acting antivirals (DAAs) has dramatically changed the landscape of hepatitis C (HCV) treatment, by increasing efficacy¹ and safety.² The cure of infection creates a rupture in the natural history of the HCV disease. Indeed, patients achieving sustained virologic response (SVR) showed decreased rates of all-cause mortality, hepatocellular carcinoma (HCC) and decompensated cirrhosis, as well as less need for liver transplantation.³ However, patients with advanced liver fibrosis remain at risk of cirrhosis-related outcomes and patients with severe comorbidities may not benefit from viral clearance. In this setting of excellent results, these factors could be disappointing for physicians, patients, and relatives.

In the past, treatment based on interferon (IFN) did not reach many patients for safety reasons.⁴ Instead, DAA treatment has no specific contraindications according to current European Association for the Study of the Liver (EASL)⁵ and American Association for the Study of Liver Diseases (AASLD)⁶ guidelines, with drug-drug interaction the main concern.⁷ Therefore, theoretically, we could treat all HCV patients irrespective of basal comorbidities, liver disease stage or age. The aim would be to eradicate the virus in patients with mild disease and to improve survival in advanced liver disease. However, many studies have demonstrated that HCV patients showed relevant extrahepatic comorbidities which could limit the impact of the treatment on health status beyond the eradication of the virus.[8], [9] Scores evaluating basal comorbidities include Charlson comorbidity index (Charlson index)¹⁰ and CirCom index¹¹ (adapted for cirrhosis), together with model for end-stage liver disease (MELD)/Child-Pugh, which are able to assess liver dysfunction. The use of these indexes is based on their accuracy and easy interpretation for clinicians. However, it is challenging to integrate this prognostic information into clinical practice. We conducted a prospective study in patients with hepatitis C to assess the impact of the objective measurement of basal comorbidities on health outcomes within the first two years of DAA treatment.