Flexible and individualized treatment to achieve sustained viral response for recurrent hepatitis C in liver transplant recipients

Summary. Hepatitis C recurrence after liver transplantation is universal and is a major cause of long‐term graft failure. Improving the effectiveness of recurrent hepatitis C treatment is extremely important. We studied 35 anti‐hepatitis C virus (HCV)‐positive patients who underwent liver transplantation. Among the 35 patients, 25 patients had recurrent hepatitis C and received antiviral treatment. HCV RNA load after liver transplantation was increased by 3.68‐fold. The antiviral treatment regimen comprised pegylated‐interferon (180 μg) every 2 weeks and ribavirin at a dose of 200–400 mg every day. The treatment duration was flexible and individualized, and depended on viral response to treatment. The dosage of tacrolimus was decreased gradually to minimize immunocompromise. Median (interquartile) serum level of tacrolimus was 6.9 (6–8.9) ng/mL at initiation of treatment and 3.8 (3.6–5) ng/mL at the end of treatment. One patient (4.0%) was withdrawn from the study, and three patients (12%) died of infection during treatment. At end of treatment, 18 of 25 patients (72%) were negative for serum HCV RNA. After an additional 6 months following the end of treatment, 16 of the 25 patients (64%) had sustained viral response (SVR) and only two patients had HCV relapse. The 1‐year, 3‐year and 5‐year survival rates were 91.4%, 84.5% and 84.5% for all patients and 88.0%, 82.8% and 82.8% for the 25 patients who received antiviral therapy. In conclusion, recurrent HCV infection is an important issue in liver transplantation. The flexible regimen of antiviral therapy and individualized immunosuppressive agents that was applied in this study achieved a SVR rate of 64%.     

Development of hepatic granulomas in patients receiving pegylated interferon therapy for recurrent hepatitis C virus post liver transplantation

Abstract: Infrequently, hepatitis C (HCV) appears to be the cause of hepatic granulomas. Interferon therapy for HCV has been increasingly associated with the development of sarcoidosis.
Aims. We sought to determine the incidence of hepatic granulomas in patients with recurrent HCV post liver transplantation (LT).
Methods. Between 1994 and 2005, 820 patients were transplanted for HCV at our institution. The pathology database was searched for patients having recurrent HCV and granulomas. At Mount Sinai Medical Center, protocol biopsies have been performed for the last 2 years in patients receiving pegylated interferon-α2b and ribavirin (PEG) for recurrent HCV. Review of slides from explanted livers, pre- and post-perfusion biopsies, and all allograft biopsies were evaluated. Lipogranulomas were excluded because of their frequent association with steatosis.
Results. A total of 10,225 liver biopsies were performed on HCV patients, and 25 (0.24%) showed non-caseating epithelioid granulomas. Hepatic granulomas were detected in 14 post-LT HCV patients; 9 patients received PEG. Typically, only 1 lobular granuloma was found. None of these patients had granulomas in the native liver or in any biopsy before interferon therapy; 6/9 patients had undetectable HCV-RNA levels, and 4 had sustained viral response. No other cause for granuloma formation was identified in the 6 patients.
Conclusions. Hepatic granulomas are infrequently found in HCV liver biopsies and rarely found in post-LT biopsies with recurrent HCV. When present, they occur more commonly in patients receiving and virologically responding to PEG therapy. The presence of granulomas in patients with HCV being treated with PEG may not warrant an extensive etiologic work-up for granulomatous hepatitis unless otherwise clinically indicated.     

Clinical significance of antibody against hepatitis B virus core antigen in patients with hepatitis C virus‐related hepatocellular carcinoma

Purpose: We investigated the unsettled issue of whether seropositivity for antibody to hepatitis B core antigen (anti‐HBc) affects characteristics of hepatitis C virus (HCV)‐related hepatocellular carcinoma (HCC). Methods: Antibody status was determined by enzyme immunoassay in 243 patients with this cancer, and associations with clinicopathologic characteristics and outcome were analysed. Serum hepatitis B virus (HBV) DNA was determined by real‐time polymerase chain reaction. Results: Of 235 patients with unequivocal serologic status, 142 were seropositive and 93 were seronegative. Clinicopathologic characteristics and overall cumulative survival rates were comparable between the two groups. However, seropositivity tended to predict poor outcome for patients in Child class B or C (P=0.068), those in tumour‐nodes‐metastasis‐based stage 3 or 4 (P=0.081), those with tumours exceeding 25 mm (P=0.068), and those with a past history of clinical liver disease (P=0.088). Multivariate analysis identified serum albumin, portal vein tumour thrombosis, and tumour size as independent determinants of survival. Serum HBV DNA was below 1.7 log copies/ml in all 40 patients tested. Conclusions: Overall, the clinical features of HCV‐HCC were unaffected by seropositivity for anti‐HBc. Seropositivity tended to worsen prognosis for subgroup with poor hepatic reserve or advanced tumours.     

Long‐term outcomes of direct acting antivirals in post‐transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis

Long‐term functional outcomes of sofosbuvir‐based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post‐transplant hepatitis C virus (HCV) recurrence. Seventy‐three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24‐week sofosbuvir with ribavirin±pegylated interferon or interferon‐free sofosbuvir‐based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82‐112) weeks. Twelve of 73 (16.4%) died (10 non‐FCH, 2 FCH) and two underwent re‐LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non‐FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow‐up, MELD and Child‐Turcotte‐Pugh scores improved both in non‐FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short‐treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long‐term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child‐Turcotte‐Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals‐based treatments for severe post‐transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long‐term survival. The setting of severe HCV recurrence may require the identification of “too‐sick‐to‐treat patients” to avoid futile treatments.     

Conversion to mycophenolate mofetil for modulating recurrent hepatitis C in liver transplant recipients

BACKGROUND: The aim of this study was to analyze the influence of cyclosporine A (CsA) taper in conjunction with mycophenolate mofetil (MMF) therapy on recurrent hepatitis C virus (HCV) in liver transplant patients. PATIENTS AND METHODS: Nineteen liver recipients with serologically and morphologically confirmed recurrent HCV were included in this study. After MMF introduction up to a maximum dose of 2000 mg/day, CsA dose was significantly tapered. In the control group immunosuppression remained unchanged. Allograft function and morphology, viral loads, and renal function were analyzed continuously. RESULTS: MMF treatment was well tolerated without risk of rejection. Allograft fibrosis progressed in 6 patients of the MMF group (66.6%) and none (0%) of the controls at 12-month biopsy (P=0.005). Moreover, aminotransferases and viral loads increased slightly in the MMF-treated patients. Renal function improved significantly (serum creatinine: 239.3+/-90.2 micromol/L vs. 175.8+/-46.0 micromol/L; P=0.008) in the treatment group, while deteriorating (serum creatinine: 156.8+/-44.6 micromol/L vs. 214.8+/-120.1 micromol/L; P=0.06) in the controls. CONCLUSION: MMF introduction allows a safe CsA taper in HCV-positive liver transplant patients and results in significant improvement of renal function. However, there seems to be a risk of marked progression of HCV-induced allograft injury.     

Clinical characterization of patients developing histologically‐proven fibrosing cholestatic hepatitis C post‐liver transplantation

Aim: Fibrosing cholestatic hepatitis C (FCH) post‐liver transplantation (LT) is an uncommon disorder with extremely poor outcome. Using stringent histological criteria, we sought to identify cases of FCH to better characterize its incidence, clinical features and outcomes. Methods: From January 1991 to December 2007, 973 LT for hepatitis C virus (HCV) were performed at our center. Using the pathology database, 51 cases with a provisional diagnosis of FCH were identified. FCH was diagnosed histologically by cholestasis accompanied by thin periportal fibrous septa, ductular reaction and mild inflammation. Results: FCH was reconfirmed in 24 recipients; seven had concurrent biliary problems. Twenty‐seven cases were excluded; biopsy was unavailable in nine cases, 15 did not meet the histological criteria of FCH and three had missing clinical information. All received deceased donors at a mean age of 64.4 years (15/17 aged >50 years). Mean time from LT to FCH was 7.6 months with 16 of 17 diagnosed within 1 year of LT. At diagnosis, mean viral load was 14.4 million IU/mL, bilirubin 16.2 mg/dL, aspartate aminotransferase 262 IU/mL, alanine aminotransferase 192 IU/mL and alkaline phosphatase 299 IU/mL. All 17 patients died or required re‐LT a mean of 7.8 months after the FCH diagnosis. Conclusion: FCH occurs infrequently and is typified by hyperbilirubinemia, donor age of more than 50 years, extremely high HCV RNA and specific histological changes occurring within the first several months post‐LT with extremely poor patient and graft survival. Histology alone is not reliable for the diagnosis of FCH, especially in the setting of recurrent HCV with concurrent biliary problems.     

Hashimoto's encephalopathy after interferon therapy for hepatitis C virus in adult liver transplant recipient accompanied by post‐transplant lymphoproliferative disorder related to Epstein–Barr virus infection

T. Hori, F. Oike, K. Hata, M. Nishikiori, Y. Ogura, K. Ogawa, Y. Takada, H. Egawa, J.H. Nguyen, S. Uemoto. Hashimoto's encephalopathy after interferon therapy for hepatitis C virus in adult liver transplant recipient accompanied by post‐transplant lymphoproliferative disorder related to Epstein–Barr virus infection
Transpl Infect Dis 2010: 12: 347–352. All rights reserved Abstract: A 55‐year‐old woman underwent living‐donor liver transplantation (LDLT). She had no history of autoimmune diseases. Spleen was preserved. Steroids were withdrawn at 3 months after LDLT. Epstein–Barr virus (EBV) infection occurred at 3.5 years after LDLT. Recurrent hepatitis C virus infection was confirmed at 4.5 years after LDLT, and pegylated interferon was introduced. Diagnosis of EBV‐positive post‐transplant lymphoproliferative disorder (PTLD) was made at 4.8 years after LDLT, and tacrolimus (Tac) was stopped completely. Then, unconsciousness, convulsion, and cervical stiffness appeared suddenly. Electroencephalography, cerebrospinal fluid analysis, and image studies revealed normal or only nonspecific findings. The patient was in a state of exhaustion; therefore, steroid pulse therapy (SPT) was attempted. Surprisingly, her general condition, including consciousness disturbance, was improved markedly, and Hashimoto's encephalopathy (HE) was suspected, based on this reaction to SPT. Elevations of anti‐thyroglobulin antibody and anti‐thyroid peroxidase antibody were confirmed. After withdrawal of Tac, and treatment with acyclovir and steroids, EBV‐positive PTLD and HE improved, although they recurred at 5.1 years after LDLT. SPT improved only neurological symptoms. Molecular‐targeted therapy was given for recurrent PTLD, based on analysis of sampling specimens. This therapy was effective, but tumor lysis syndrome occurred, and the patient died at 5.3 years after LDLT.     

Healthcare-associated hepatitis C virus transmission among patients in an abdominal organ transplant center

Background. De novo hepatitis C virus (HCV) infection among transplant patients is rarely recognized but can have severe consequences. We investigated the scope, source, and mode of HCV transmission within a transplant center after incident HCV infection was identified in 2 patients who had liver transplantation in late 2006.
Methods. Patients were interviewed, and transplant logs, medical records, and staff practices were reviewed to identify opportunities for HCV transmission. Infection via receipt of blood or organs was evaluated. Molecular epidemiology was used to determine the relatedness between persons with incident and chronic HCV infection.
Results. HCV from infected blood or organ donors was ruled out. Among the 308 patients who underwent transplant in 2006, no additional incident HCV infections were identified. Eighty-five (28%) had pre-transplant chronic HCV infection; 13 were considered possible HCV source patients based upon shared days on the inpatient unit, nursing assignment, or invasive procedures in common with incident HCV case-patients. Viral isolates from 1 HCV source patient and 1 incident case-patient were found to be highly related by quasispecies analysis, confirming patient-to-patient HCV transmission. Possible modes of transmission identified were the improper use of multidose vials, sharing of blood-contaminated glucometers, and touch contamination.
Conclusion. Sporadic transmission or endemic levels of HCV transmission might be overlooked in a setting with high HCV prevalence, such as liver transplant units, where multiple, repeated opportunities for patient-to-patient HCV transmission can occur. Surveillance through pre- and post-transplant screening is necessary to identify incident HCV infection in this setting. Constant, meticulous attention must be paid to maintaining aseptic technique and good infection control practices to eliminate HCV transmission opportunities.     

Mortality predictors in liver transplant recipients with recurrent hepatitis C cirrhosis.

BACKGROUND/AIM: Recipients of orthotopic liver transplant for hepatitis C (HCV) invariably develop recurrent disease. The risk factors for death and retransplantation following the development of cirrhosis from HCV are unclear. The aim of this study was to identify predictors of survival in liver transplant recipients who develop cirrhosis from recurrent HCV. METHODS: We reviewed records of patients who underwent liver transplantation for cirrhosis due to HCV between January 1990 and December 2001. Prognostic factors of patient survival following the development of recurrent cirrhosis were identified through multivariate analysis. RESULTS: During the study period, 511 patients underwent transplantation for HCV cirrhosis. Of these, 65 patients (13%) developed biopsy proven recurrent cirrhosis from HCV; 43 (8%) were relisted for transplantation, and 24 (5%) underwent retransplantation. The overall Kaplan-Meier patient survival rates after the histologic diagnosis of cirrhosis at 1 and 5 years were 66% and 30%, respectively. A multivariate Cox proportional hazards model showed patients with higher last (i.e. at follow-up or prior to retransplantation) International normalized ratio (INR) values (hazard ratios (HR)=2.02, 95% confidence interval 1.26, 3.24, P<0.01) to have an increased risk of death. CONCLUSION: Our results suggested survival was decreased after the diagnosis of cirrhosis from recurrent HCV. Higher INR was associated with an increased risk of death following the development of cirrhosis.     

Prediction of significant liver fibrosis in kidney transplant patients with chronic hepatitis C virus infection: the TX‐3 index

Summary. HCV infection is highly prevalent among kidney transplant (KT) recipients. The natural history and management of these patients are controversial. We sought to assess the diagnostic value of noninvasive markers of liver fibrosis in KT HCV‐infected patients. This cross‐sectional study included 102 KT individuals with positive HCV‐RNA. Bivariate and multivariate analyses were used to identify variables associated with significant fibrosis (METAVIR ≥ F2). Significant fibrosis was observed in 20 patients (20%). Time after transplantation, AST level, and platelet count were identified as independent predictors of significant fibrosis. Based on the regression model, a simplified index was devised. The AUROC for the TX‐3 model was 0.867 ± 0.081 (0.909, when adjusted by DANA). Values ≤4.0 of TX‐3 showed a NPV of 97% and scores >9.6 exhibited a PPV of 71%. If biopsy indication was restricted to scores in the intermediate range of TX‐3, this could have been correctly avoided in 68% of cases. The APRI score provided a correct diagnosis in only 47 individuals (46%) and exhibited lower diagnostic indices for both cutoffs, as compared to the TX‐3 index. Comparison of AUROCs showed a trend towards superior diagnostic accuracy for TX‐3 over APRI, although the difference between AUROCs did not reach statistical significance (0.867 ± 0.053 vs 0.762 ± 0.066, respectively, P = 0.064). In conclusion, significant liver fibrosis can be reliably predicted in KT HCV‐infected subjects by simple and widely available parameters. If additional studies confirm our results, this model might obviate the requirement for a liver biopsy in a significant proportion of those patients.     

Successful treatment of hepatitis C virus infection with direct‐acting antivirals during hematopoietic cell transplant

Current guidelines recommend that hepatitis C virus (HCV) infection be treated completely prior to hematopoietic cell transplantation or delayed until immune reconstitution after transplantation to avoid drug‐drug interactions and treatment interruption. However, these recommendations were informed by outcomes using treatment with ribavirin and pegylated interferon. We report the first case of successful treatment of HCV using direct‐acting antivirals during hematopoietic cell transplantation. This case study suggests that treatment of HCV concurrent with hematopoietic cell transplantation for malignancy may be the best option for some patients in whom it is unsafe to delay treatment for either disease.     

Successful treatment of donor‐derived hepatitis C infection in a lung transplant recipient

Data are limited regarding the use of direct‐acting antivirals for treatment of hepatitis C infection post lung transplant, especially in a donor‐derived infection. We present a case of a lung transplant recipient with donor‐derived hepatitis C that was successfully treated with a 12‐week regimen of simeprevir and sofosbuvir. This case reiterates the importance of screening recipients of increased‐risk donor organs for disease transmission and the value of early therapy.     

Successful heart‐kidney transplantation from a Hepatitis C viremic donor to negative recipient: One year of follow‐up

Every year the number of patients waiting for a heart transplant increases faster than the number of available donor organs. Some potential donor organs are from donors with active communicable diseases, including hepatitis C virus (HCV), potentially making donation prohibitive. The advent of direct‐acting antiviral agents for HCV has drastically changed the treatment of HCV. Recently, these agents have been used to treat HCV in organ donor recipients who acquired the disease from the donor organ. We report a case of heart‐kidney transplantation from an HCV viremic donor to HCV negative recipient with successful treatment and sustained virologic response.     

Aggressive Epstein‐Barr virus‐negative B‐cell post‐transplant lymphoproliferative disorder in a hepatitis C‐negative liver transplant recipient who received a hepatitis C‐positive graft: Implications for D+/R− hepatitis C virus seroconversion

Post‐transplant lymphoproliferative disorder (PTLD) is an uncommon, but well‐described complication after liver transplantation. Most recently, Hepatitis C virus (HCV) has been implicated in the development of PTLD. A HCV‐negative 62‐year‐old man with autoimmune hepatitis received a HCV nucleic acid amplification test‐positive liver graft from a 73‐year‐old brain‐dead donor (D+/R?). After his recovery from the operation, the patient was treated for HCV and achieved an undetectable viral load. He was readmitted 6 months after transplant with a spontaneous perisplenic hematoma, weight loss, failure to thrive, low‐grade fevers, and abnormal liver function tests. He had a rapid clinical deterioration and expired shortly after admission. His liver biopsy demonstrated EBV‐negative monomorphic B‐cell PTLD. Our case is the first to report an aggressive early‐onset EBV‐negative monomorphic B‐cell PTLD in a HCV D+/R? liver transplant. This case illustrates the paucity of knowledge on HCV seroconversion and its involvement in EBV‐negative monomorphic B‐cell PTLD development.