Early Identification of Recipients With Progressive Histologic Recurrence of Hepatitis C After Liver Transplantation

Abstract

Approximately half of patients undergoing liver transplantation (LT) for hepatitis C virus (HCV) develop histologic evidence of recurrence within the first postoperative year. Early identification of recipients at risk for more severe recurrence of HCV may be useful in selecting patients for antiviral therapy. We determined whether recipients at greatest risk for more severe recurrence of HCV can be identified by pre-and/or early post-LT HCV-RNA levels in serum or tissue. Serum and tissue samples were prospectively collected pre-LT and at 7 days, 4 months, 1 year, and at 3 years posttransplantation from patients undergoing LT for HCV. Hepatitis activity index (HAI) and fibrosis stage (FS) were assessed in all liver biopsies. Forty-seven patients (32 men) were studied. Higher HCV-RNA levels at 4 months post-LT (>10 9 copies/mL, n ‫؍‬ 29) were associated with higher HAI at 1 year and at 3 years post-LT. The HAI seen on protocol biopsies at 4 months correlated significantly with fibrosis stage (FS) at 1 year (r ‫؍‬ .56, P < .001) and 3 years (r ‫؍‬ .53, P ‫؍‬ .002). Higher HCV-RNA levels at 7 days and 4 months post-LT were sensitive (66% and 84%, respectively) and specific (92% and 63%, respectively) in identifying recipients with an HAI greater than 3 at 3 years. End-stage liver disease secondary to chronic hepatitis C infection is the leading indication for liver transplantation in the United States. 1 Approximately 3 million people in the United States are infected with the hepatitis C virus (HCV). 2,3 Although recurrent infection with HCV is almost universal after orthotopic liver transplantation (LT), 4,5 histologic recurrence varies widely from patient to patient. [6][7][8][9][10][11][12] Although the majority of patients who undergo transplantation for hepatitis C do well, it has become increasingly apparent that recurrent disease can be progressive and may adversely affect patient and graft survival. 13 Allograft failure secondary to recurrence of HCV infection is the most common cause of death and retransplantation in the first 5 years after LT. 13 To date, the use of antivirals has had little impact on the course of posttransplant hepatitis C infection because of a combination of poor efficacy and tolerability. [14][15][16][17] In the setting of a chronic and worsening donor-organ shortage, the identification of recipients at greatest risk for more severe recurrence of posttransplant HCV recurrence has become a high priority. To date, viral genotype 1b 7,12,18-20 and higher viral load 13,[21][22][23] have been inconsistently associated with more severe recurrence of HCV after LT. The inconsistency of the reported association of viral load and histologic progression of HCV infection after LT is likely to be caused, at least in part, by differences in study design (e.g., sample handling, quantification methods, histopathologic sampling protocol, and interpretation). In most reports of the impact of viral load and histologic progression, the level of HCV viremia has been assessed in serum rather than in live...

Host and donor risk factors before and after liver transplantation that impact HCV recurrence

“…3,9,13,[25][26][27] In addition, timing of recurrence to progressive disease (early recurrence) also seems associated with a worse prognosis. 28,29 …”

Impact of immunosuppression on immunopathogenesis of liver damage in hepatitis C virus-infected recipients following liver transplantation

“…5 Furthermore, two studies showed that a pulse of methylprednisolone therapy increased serum HCV levels by one log before returning to pre-pulse levels during a 2-week period. 6,16 Thus, at this early stage of infection, additional CS therapy seems to be associated with greater viral loads, which may have important implications concerning HCV-related allograft injury. …”

Sequence variation in the hypervariable region 1 of hepatitis C virus and posttransplantation recurrent hepatitis

“…There is evidence indicating that pre-OLT HCV RNA titers and initial levels of HCV RNA intrahepatic replication are predictive of subsequent liver disease progression. 25,28,33 This argument also is supported indirectly by the efficacy of early treatment in both human immunodeficiency virus and HCV acute infections.…”

“…A greater frequency of hepatitis recurrence was observed in patients with reduced CD4 ϩ T-cell response. 32 Greater levels of intrahepatic and circulating HCV RNA have been detected in patients with hepatitis recurrence, 25,33,34 and greater HVR1 variation has been reported in asymptomatic HCV carriers than in patients with progressive chronic hepatitis. 6 Finally, there is extensive clinical evidence that steroid treatment and stronger immunosuppression regimens negatively affect post-OLT recurrent hepatitis.…”