Effect of Nonviral Factors on Hepatitis C Recurrence After Liver Transplantation

Four million Americans are infected with hepatitis C virus (HCV), a prevalence double that of the human immunodeficiency virus (HIV) and hepatitis B (HBV) combined.1 Of patients with chronic infection, 20% will progress to cirrhosis over 10 to 20 years, making HCV the most common cause of chronic liver disease in the United States, the major cause of hepatocellular cancer, and the leading indication for orthotopic liver transplantation (OLT).2–4 Risk factors for disease progression include age, obesity, alcohol intake, and coinfection with HBV and/or HIV.5 HCV virologic factors, including recognition of 6 genotypes with over 100 subtypes, do not appear to contribute to progression but do affect response to therapy.6 Unfortunately, recurrence of HCV infection in the allograft is immediate and universal after OLT.7 However, the natural history of recurrent HCV disease after OLT is variable, with approximately 20% of recipients progressing to graft cirrhosis within 5 years of transplant.8 Overall, HCV disease is more aggressive in OLT recipients than in patients whose immunity is intact.9 Enhanced disease progression is multifactorial and probably depends upon interactions among host, donor, viral, and external factors, although these relationships remain controversial and poorly defined. Recent reports suggesting that grafts from living related donors fare worse than those from unrelated cadaver donors in HCV recipients have implied an immunologic role as well.10 The diagnosis of recurrent HCV disease, as opposed to reinfection, is based on biochemical graft dysfunction and histologic findings on liver biopsy. Recent data suggest that the frequency and severity of HCV disease recurrence after OLT are accelerating.11–13 This is an ominous finding, given that retransplantation for recurrent HCV has significantly worse outcome than primary OLT in most recipients.9 Identifying recipients at risk for rapid recurrence would be especially helpful when considering treatment with the currently available antiviral agents either as prophylaxis or therapy. Most studies examining HCV recurrence have focused on viral characteristics, while little is published on the impact of host, donor, or perioperative factors. Interestingly, in the much larger immunocompetent population with HCV infection, the most powerful predictors of disease severity are those related to the host, while viral factors such as genotype and HCV RNA level have been shown to play a lesser role in determining outcome. We have previously examined nonviral factors that contribute to overall patient and graft survival in OLT for HCV.14 The present study was undertaken to determine whether these factors might contribute specifically to rapid HCV recurrence following OLT.