Excess mortality in patients with advanced chronic hepatitis C treated with long-term peginterferon

Abstract

Chronic hepatitis C virus infection can cause chronic liver disease, cirrhosis and liver cancer. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was a prospective, randomized controlled study of long-term, low-dose peginterferon therapy in patients with advanced chronic hepatitis C who failed to respond to a previous course of optimal antiviral therapy. The aim of this follow-up analysis is to describe the frequency and causes of death among this cohort of patients. Deaths occurring during and after the HALT-C Trial were reviewed by a committee of investigators to determine the cause of death and to categorize each death as liver- or nonliver-related and as related or not to complications of peginterferon. Rates of liver transplantation were also assessed. Over a median of 5.7 years, 122 deaths occurred among 1,050 randomized patients (12%), of which 76 were considered liver-related (62%) and 46 nonliver-related (38%); 74 patients (7%) underwent liver transplantation. At 7 years the cumulative mortality rate was higher in the treatment compared to the control group (20% versus 15%, P = 0.049); the primary difference in mortality was in patients in the fibrosis compared to the cirrhosis stratum (14% versus 7%, P = 0.01); comparable differences were observed when liver transplantation was included. Excess mortality, emerging after 3 years of treatment, was related largely to nonliver-related death; liver-related mortality was similar in the treatment and control groups. No specific cause of death accounted for the excess mortality and only one death was suspected to be a direct complication of peginterferon.

Conclusion: Long-term maintenance peginterferon in patients with advanced chronic hepatitis C is associated with an excess overall mortality, which was primarily due to nonliver-related causes among patients with bridging fibrosis.

Figure 1

Overview of the HALT-C Trial, showing flow of the patient cohort from time of randomization, through the 3.5 years of the randomized trial phase, and during the extended follow-up phase showing numbers of deaths.

Figure 2

Cumulative rates of death by fibrosis/cirrhosis stratum in the HALT-C Trial cohort: Kaplan-Meier analysis of 622 patients in the fibrosis stratum (Fibrosis: dotted line) versus 428 patients in the cirrhosis stratum (Cirrhosis: solid line). The vertical line at 3.5 years marks the end of the randomized trial phase.

Figure 3

Cumulative rates of death by randomization group in the HALT-C Trial cohort: Kaplan-Meier analysis of deaths in 517 patients randomized to the treatment group (Trt: dotted line) versus 533 patients randomized to the controls group (Cntl: solid line). The vertical line at 3.5 years marks the end of the randomized trial phase

Figure 4

Cumulative rates of death by fibrosis/cirrhosis stratum and randomization group in the HALT-C Trial cohort: All deaths (A), Liver-related deaths only (B), and Non-liver-related deaths only (C). Kaplan-Meier analysis of deaths in 309 patients in the fibrosis stratum and treatment group (Fib Trt), 313 patients in the fibrosis stratum and control group (Fib Cntl),208 patients in the cirrhosis stratum and treatment group (Cirr Trt), and220 patients in the cirrhosis stratum and control group (Cirr Cntl). The vertical line at 3.5 years marks the end of the randomized trial phase.

Figure 4

Cumulative rates of death by fibrosis/cirrhosis stratum and randomization group in the HALT-C Trial cohort: All deaths (A), Liver-related deaths only (B), and Non-liver-related deaths only (C). Kaplan-Meier analysis of deaths in 309 patients in the fibrosis stratum and treatment group (Fib Trt), 313 patients in the fibrosis stratum and control group (Fib Cntl),208 patients in the cirrhosis stratum and treatment group (Cirr Trt), and220 patients in the cirrhosis stratum and control group (Cirr Cntl). The vertical line at 3.5 years marks the end of the randomized trial phase.

Figure 4

Cumulative rates of death by fibrosis/cirrhosis stratum and randomization group in the HALT-C Trial cohort: All deaths (A), Liver-related deaths only (B), and Non-liver-related deaths only (C). Kaplan-Meier analysis of deaths in 309 patients in the fibrosis stratum and treatment group (Fib Trt), 313 patients in the fibrosis stratum and control group (Fib Cntl),208 patients in the cirrhosis stratum and treatment group (Cirr Trt), and220 patients in the cirrhosis stratum and control group (Cirr Cntl). The vertical line at 3.5 years marks the end of the randomized trial phase.