Of the 116 patients who received transplants due to hepatitis C and were followed in our center, 46 satisfied all three inclusion criteria for having recurrent HCV infection post-OLT. Of these 46, 33 (71.7%) were males and the mean (SD) for age was 54.5 (11.2) years. Thirty (65.2%) patients received deceased donor grafts, while 16 (34.8%) received living-related donor grafts. The mean (SD) for donor age was 29.5 (9.8) years and 86% of donors were under the age of 40 years. Twenty-seven patients (58.7%) received transplants at KFSHRC, with the remaining 19 patients receiving transplants abroad, mostly in China, the USA and Germany. Nine (19.9%) patients developed ≥1 episode of acute rejection during follow-up. Clinical, biochemical and virological characteristics of the patients included in our study are shown in .
Clinical, biochemical and virological characteristics of patients with hepatitis C virus recurrence post-liver transplantation atthe time of diagnosis (n=46).
At the time of graft biopsy, 14 (30.4%) patients were treated with either tacrolimus or cyclosporine alone, while the remaining 32 (69.6%) received a combination of drugs, mostly either cyclosporine and mycophenolate mofetil (MMF) or tacrolimus and MMF . Twenty-six (56.5%) patients were taking steroids at the time of biopsy, and only three (6.5%) received IV steroids for treatment of acute rejection episodes. None of our patients received OKT3 or any other anti-lymphocyte preparation.
Upon initial histological examination, 5 (10.9%) patients had grade 0 inflammation, 10 (21.9%) had grade 1, 21 (45.7%) had grade 2, 8 (17.4%) had grade 3 and 2 (4.3%) had grade 4 inflammation. Fibrosis scoring was performed and showed that 14 (30.4%) patients had fibrosis stage 0, 17 (37.0%) stage 1, 10 (21.7%) were stage 2, 4 (8.7%) were stage 3, and only 1 (2.2%) was stage 4 (cirrhosis). The mean (SD) time between transplant and biopsy was 687.8 (1094.1) days. Seventeen (36%) patients had at least one repeat liver biopsy during the follow-up. Six patients showed worsening fibrosis scores, eight were stable and three improved.
Patients who received OLT at KFSHRC (n=27) were similar to those who had OLT abroad (n=19) in demographic, clinical, biochemical, and virological variables. No significant differences were found between patients who received grafts from living-related donors (n=16) compared with patients who received deceased-donor grafts (n=30) in demographic, clinical, biochemical and virological variables except for HCV viral load at the time of biopsy, which was significantly higher in patients who received deceased donor grafts (P=.008).
Twenty-nine patients (63.0%) began peginterferon alfa-2a (40 KD; Pegasys, F. Hoffmann-La Roche, Basel, Switzerland) 135-180 mcg per week subcutaneously and ribavirin (Copegus, F. Hoffmann-La Roche, 800-1200 mg per day orally) therapy for 48 weeks based on their initial histological scores (patients were treated if they had elevated ALT of more than 2 times the upper limit of normal and had grade 2 or more inflammation and stage 2 or more fibrosis on liver biopsy. Of these, 16 (55%) were negative for HCV RNA at the end of therapy and three of these 16 (18.8%) relapsed after the end of treatment, resulting in a sustained virological response of 44.8% (13 of 29). After a mean (SD) follow-up of 38.8 (40.8) months (range, 7.9 to 173 months), 4 patients (in addition to the 1 patient who had cirrhosis at the initial liver biopsy) developed cirrhosis; 7 (15.5%) eventually died of liver failure; 1 died of unrelated causes; and the remainder of the patients were still alive at the time of writing.
Of the 46 patients who had recurrent hepatitis C, 29 (63.0%) were infected with genotype 4. Mean (SD) for age was 54.9 (10.9), 19 (65.5%) were males, 21 (72.4%) received deceased donor grafts and 7 (24.1%) developed ≥1 acute rejection episodes. Upon histological examination of liver biopsy samples from these genotype 4 patients (n=29), 4 (13.8%) patients had grade 0 inflammation, 6 (20.7%) had grade 1, 12 (41.4%) had grade 2, 5 (17.2%) had grade 3, and 2 (6.9%) had grade 4 inflammation. Fibrosis scoring showed that 11 (37.9%) patients had fibrosis stage 0, 9 (31.0%) stage 1, 5 (17.2%) were stage 2, 3 (10.3%) were stage 3, and only 1 (3.4%) was stage 4 (cirrhosis). Univariate analysis showed that there was a significant difference between recurrent HCV patients with fibrosis stage ≥2 compared to those with fibrosis stage 0-1 in the viral load at the time of biopsy (P=.04) (). In addition, there were significant differences in the transplantation-to-biopsy interval (P=.002) and the activity (inflammatory) grade (P=.008). However, multivariate logistic regression analysis of these three variables showed that only the viral load at the time of biopsy was an independent predictor of higher fibrosis stage in patients with HCV-4 recurrence post-OLT (P=.029).
Univariable predictors of hepatic fibrosis in patients with recurrent HCV post-liver transplantation (n=46).
There was no significant difference between patients with HCV-4 and those infected with other genotypes in virological and histological parameters (). More patients (65.6%) with HCV-4 had hypertension than patients infected with other genotypes (30.8%, P=.036). Seventeen (48%) patients received pegylated interferon and ribavirin therapy, nine of whom responded to therapy and two relapsed after the end of the treatment response, resulting in a sustained virological response of 41%. During 38.5 months of follow-up (range, 7.9-170.5 months), 9 patients had a repeat liver biopsy, 5 showed a stable fibrosis score, 2 showed worsening and 2 showed improvement.
Comparison of HCV genotype 4 and other genotypes in 46 liver transplant recipients with recurrent HCV infection.
Eight of the 46 patients (17.4%) died during the follow-up. Of those, 6 were infected with HCV-4; of these, 4 died of severe recurrent cholestatic hepatitis C or chronic graft failure secondary to hepatitis C. No significant difference was found between genotype 4 and non-genotype-4 patients in terms of survival during the follow-up period (). Similarly, survival analyses using Kaplan-Meier curves and the log-rank test were similar in the patients who had DDLT and LDLT as well as among those who had OLT locally and abroad (Figure and ).
Kaplan-Meier survival analysis in genotype-4 patients (green) versus those with other genotypes (blue), P=.297 by logrank test.
Kaplan-Meier survival analysis in patients who received transplantation locally (blue) versus those who were transplanted abroad (green), P=.869 by log-rank test.
Kaplan-Meier survival analysis in patients who received DDLt (blue) versus those who received LDLt (green), P= .778 by log-rank test.