Heart Transplantation Outcomes in Patients With Hepatitis C Virus Infection: Potential Impact of Newer Antiviral Treatments After Transplantation
More than 185 million people worldwide, including more than 4 million in the U.S., are infected with the hepatitis C virus (HCV).1 Because of the indolent nature of the disease, actual prevalence is underestimated.2,3 Detection of HCV in people already infected is estimated to continue to increase over the next decade.4 Although primary manifestations of the disease are the result of liver damage, HCV infection is a systemic illness. In a study of more than 19,000 patients, HCV infection was identified as an independent risk factor for development of heart failure.5 In the U.S., prevalence of HCV infection in patients with heart failure is reported to be as high as 15%, much higher than the general population prevalence of 1.8%.6 When first identified in 1989, HCV infection was considered incurable. Clinical trials have since found a steady improvement in outcome, and now the disease is considered curable in up to 90% of cases.7
Clinical outcomes of heart transplantation (HTx) historically have been inferior in patients with HCV infection.8,9 The authors hypothesized that the literature on HTx outcomes has not accounted for the improvements in HCV infection treatment options that have occurred since the 1990s. In the study reported here, United Network of Organ Sharing (UNOS) data on adult HTx was used to evaluate clinical outcomes of HCV infection over 4 treatment eras.
Material and Methods
The authors analyzed UNOS data on adult HTx from January 1991 to March 2014. Two groups were created: patients with HCV infection (HC+) and noninfected patients (HC–). Eligible patients were aged > 18 years. Hepatitis C virus status was defined with antibody testing at time of HTx. Patients with multiorgan transplantation or with hepatitis B virus or HIV infection were excluded. For comparison of post-HTx survival, the 23-year study period was divided into 4 eras reflecting the evolution in HCV infection treatment options in the U.S. (Table 1). The first medication was interferon α (IFN-α), which was used alone (first era, 1991-1997) and then with the newly introduced ribavirin (second era, 1998-2000). The combination of IFN-α and ribavirin increased sustained virologic response rates, but the rates of adverse effects (AEs), such as cytopenia and depression, were high, and many patients could not tolerate the extended (48-week) regimen.10,11
Peginterferon, a long-acting IFN introduced in 2001, significantly increased adherence to 2-drug treatment for HCV infection, and its use in combination with ribavirin marked the third era (2001-2010). The fourth era (2011-2014) began with the introduction of direct-acting antiviral agents and their remarkable results. Since 2014, direct protease inhibitors without IFN found a dramatic impact on HCV treatment: fewer AEs, shorter treatment (24 weeks), and high (> 90%) sustained virologic response.7,12,13
Statistical Analysis
Categoric variables were analyzed with the χ2 test or the Fisher exact test and are reported as percentages. Continuous variables were analyzed with the Student t test or the Wilcoxon rank sum test and are reported as means, medians, and SDs. Statistical significance was set at P < .05. Survival curves were plotted with the Kaplan-Meier method, and comparisons made with log-rank tests. Analysis was performed with SAS Version 9.3 (Cary, NC).
Results
Between January 1991 and March 2014, adult HTx was performed 36,589 times, including 778 times (2.1%) in patients with HCV infection. There was no significant difference in percentage of HC+ patients who underwent HTx over the 4 treatment eras (first, 2.1%; second, 2.9%; third, 2.1%; fourth, 1.6%) (Table 2). Mean patient age for the HC+ and HC– groups was comparable. Percentage of African American patients was higher in the HC+ group than in the HC– group (18.9% vs 15.0%), as was percentage of patients of other race (11.2% vs 9.2%; P = .0008).
Regarding indications for HTx, ischemic (and nonischemic) cardiomyopathy was similar in prevalence between the 2 groups, but the “other” heart failure etiologies (congenital heart disease, valvular heart disease, postpartum cardiomyopathy, restrictive heart disease) were more prevalent in the HC+ group (12.9% vs 9.7%; P = .013). The HC+ group also had higher rates of tobacco use history (42.2% vs 40.1%; P = .002) and hypertension (23.1% vs 20.9%; P = .014). Mean (SD) bilirubin level at time of transplantation for the HC+ and HC– groups was comparable: 1.12 (1) mg/dL and 1.11 (1) mg/dL, respectively (P = .707). Of the heart donor variables (Table 3), only tobacco use history was significantly higher in the HC+ group (23.5% vs 19.8%; P = .008).
Survival Data
Mean (SD) overall follow-up was 6.2 (5.3) years (median, 5 years; range, 0-23.3 years) for all patients; 5.6 (4.3) years (median, 5.05 years; range, 0-23.2 years) for HC+ patients; and 6.2 (5.3) years (median, 6.1 years; range, 0-23.2 years) for HC– patients.
HC+ patients’ survival rates were 82.5% (1 year), 64.4% (5 years), and 42.1% (10 years), and HC– patients’ rates were 87.2% (1 year), 73.4% (5 years), and 54.7% (10 years). The HC+ group’s inferior survival at 1, 5, and 10 years was statistically significant (P < .0002) (Table 4).
During the first era (1991-1997), HC+ patients’ survival rates were 81.0% (1 year), 73.3% (2 years), and 61.4% (5 years), and HC– patients’ rates were 85.0% (1 year), 80.6% (2 years), and 70.3% (5 years) (P < .05). During the second era (1998-2000), HC+ patients’ rates were 79.1% (1 year), 74.6% (2 years), and 62.0% (5 years), and HC– patients’ rates were 85.4% (1 year), 81.7% (2 years), and 72.0% (5 years) (P < .05). During the third era (2001-2010), HC+ patients’ rates were 83.6% (1 year), 78.6% (2 years), and 66.8% (5 years), and HC– patients’ rates were 88.4% (1 year), 84.6% (2 years), and 75.4% (5 years) (P < .05).
