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.     

Prevalence and risk factors associated with hepatitis C among Brazilian male patients with haemophilia: A long‐term follow‐up

People with haemophilia represent a population with a high prevalence of HCV infection due to the use of blood components and plasma‐derived clotting factor concentrates before the introduction of viral‐inactivating procedures (in the 1980s) and screening for HCV (in the 1990s). About 80% of HCV‐infected patients have chronic HCV infection, and at least 20% develop end‐stage liver disease. The aim of the study was to assess current anti‐HCV positivity in a large cohort of Brazilian haemophilia patients and to determine associated factors with HCV exposure. The study retrospectively analysed medical records of all male haemophilia patients attended the main public referral blood centre in Belo Horizonte, Brazil, from January 1985 to January 2015. Sociodemographic, epidemiological and serological characteristics were collected of all participants tested for anti‐HCV. Among 724 patients enrolled in the study, anti‐HCV was positive in 259 resulting in a seroprevalence of 35.8% (95% CI: 32.3%‐39.3%). Factors independently associated with previous exposure to HCV were as follows: age older than 30 years, moderate to severe haemophilia, detection of inhibitor at least once in lifetime and previous exposure to hepatitis B virus (HBV) infection or HIV infection. Otherwise, exclusive previous use of inactivated clotting factors resulted in a significant decrease in the chance of positivity for anti‐HCV. At the end of cohort period, patients with positive anti‐HCV had a 3‐fold higher risk of death. This study showed that hepatitis C infection remains a critical problem for Brazilian haemophilia patients and reinforced the need to unify efforts to eradicate it.     

No increased mortality from donor or recipient hepatitis B‐ and/or hepatitis C‐positive serostatus after related‐donor allogeneic hematopoietic cell transplantation

Limited data exist on allogeneic transplant outcomes in recipients receiving hematopoietic cells from donors with prior or current hepatitis B (HBV) or C virus (HCV) infection (seropositive donors), or for recipients with prior or current HBV or HCV infection (seropositive recipients). Transplant outcomes are reported for 416 recipients from 121 centers, who received a human leukocyte antigen‐identical related‐donor allogeneic transplant for hematologic malignancies between 1995 and 2003. Of these, 33 seronegative recipients received grafts from seropositive donors and 128 recipients were seropositive. The remaining 256 patients served as controls. With comparable median follow‐up (cases, 5.9 years; controls, 6.7 years), the incidence of treatment‐related mortality, survival, graft‐versus‐host disease, and hepatic toxicity, appears similar in all cohorts. The frequencies of hepatic toxicities as well as causes of death between cases and controls were similar. Prior exposure to HBV or HCV in either the donor or the recipient should not be considered an absolute contraindication to transplant.     

Long‐term morbidity and mortality in a Canadian post‐transfusion hepatitis C cohort: Over 15 years of follow‐up

The Federal Government of Canada established a $1.1 billion compensation programme in 1999 to support individuals who acquired hepatitis C virus (HCV) through blood products between January 1986 and July 1990. We aimed to describe the morbidity and mortality of this unique post‐transfusion cohort (n = 4550) followed for over 15 years from 2000 to 2016. The age‐standardized mortality rates were compared with that of the Canadian general population and HCV cohorts from other countries. We evaluated all‐cause mortality using Kaplan‐Meier survival curves and HCV‐related and unrelated mortality using competing risk models. The age‐standardized all‐cause and HCV‐related mortality rates per 10 000 person‐years were 127 (95% CI: 117‐138) and 76 (95% CI: 69‐85) for males, and 77 (95% CI: 69‐87) and 43 (95% CI: 37‐51) for females, respectively. The risk of death of the post‐transfusion cohort was almost twice as high as the Canadian general population (rate ratio = 1.8; 95% CI: 1.7‐1.9). All‐cause, HCV‐related and HCV‐unrelated mortality were 20%, 12% and 8%, respectively at 15 years of follow‐up. By comparison, HCV‐related mortality rates per 10 000 person‐years for population‐based HCV cohorts varied from 18 and 11 in Australia to 65 and 43 in Scotland for males and females, respectively. We reported long‐term follow‐up data for the largest post‐transfusion cohort in the literature. The all‐cause mortality rates were markedly higher than that of the Canadian general population. We also showed that HCV‐related mortality were greater compared to other HCV cohorts. This suggests that continued efforts to identify and treat post‐transfusion HCV are warranted.     

Post‐transplant recurrent hepatitis C: immunohistochemical detection of hepatitis C virus core antigen and possible pathogenic implications

Introduction: The mechanisms by which severe cholestatic hepatitis develops after liver transplantation are not fully understood. Reports on immunohistochemical distribution of hepatitis C virus (HCV) antigens are still scarce, but recently, HCV immunostaining was suggested for early diagnosis of cholestatic forms of recurrent hepatitis C in liver grafts. After purification, Rb246 pab anticore (aa1‐68) yielded specific, granular cytoplasmic staining in hepatocytes. Signal amplification through the Envision‐Alkaline Phosphatase System avoided endogenous biotin and peroxidase. Aims/Methods: Rb246 was applied to liver samples of explants of 12 transplant recipients, six with the most severe form of post‐transplantation recurrence, severe cholestatic hepatitis (group 1) and six with mild recurrence (group 2). We also assessed immuno‐reactivity at two time‐points post‐transplantation (median 4 and 22 months) in both groups. HCV‐core Ag was semiquantified from 0 to 3+ in each time point. Serum HCV‐RNA was also measured on the different time points by branched DNA. Results: In the early post‐transplant time point, one patient had a mild staining (1+), two patients had a moderate staining (2+) and the other three had no staining in group 1, compared with five patients with no staining (0) and one patient with mild staining (1+) in group 2. Late post‐transplant liver samples were available in nine patients, and two out of four samples in group 1 showed a mild staining, compared with no staining patients in five patients in group 2. Strikingly, on the explant samples, HCV immunostaining was strongly positive in group 1, and mildly positive in group 2. Two out of five samples showed 3+ staining, and three samples showed 2+ staining in group 1; two out of five samples showed no staining, two samples showed 1+ staining and one sample showed 2+ staining in group 2. Serum HCV‐RNA was significantly higher in group 1, on both time‐points post‐transplantation. HCV‐core Ag was not directly associated with serum HCV‐RNA on the different time points. Conclusion: These preliminary results suggest that strong HCV immunostaining in the explant is predictive of more severe disease recurrence.     

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.     

Ten‐year follow‐up analysis of chronic hepatitis C patients after getting sustained virological response to pegylated interferon‐α and ribavirin therapy

There is little data on the long‐term follow‐up outcomes of chronic hepatitis C patients achieving sustained virological response (SVR) after treatment with peglylated interferon‐α plus ribavirin. We prospectively investigated the overall clinical, biochemical, virological and histological outcomes in a ten‐year cohort study of 325 patients with chronic hepatitis C achieving SVR to pegylated interferon‐α and ribavirin therapy. Patients underwent consistent clinical, biochemical and virological evaluation every six months, and patients with pretherapy Ishak fibrosis score ≥2 were invited to accept a second liver biopsy at the last follow‐up. Liver biopsy specimens were evaluated using Ishak's scoring system. At the end of follow‐up, five patients developed decompensated liver cirrhosis. One patient (0.3%) with pretherapy cirrhosis was diagnosed with hepatocellular carcinoma (HCC). A total of 305 patients (94%) had normal serum ALT and AST levels during the entire period of follow‐up. Twenty‐seven patients (8%) had conclusive evidence of virological relapse. Among the 117 patients with paired pretherapy and long‐term follow‐up biopsies, 96 (82%) had a decreased fibrosis score. Ninety‐nine (79%) had a decrease in combined inflammation score. Thirty‐seven (32%) had normal or nearly normal livers on long‐term follow‐up biopsy. SVR achieved with PEG‐IFN‐α and RBV combination therapy is durable, while late virological relapse may still occur in some patients. Clinical outcomes for patients who obtain SVR are excellent, although the patients with cirrhosis are still at a low risk of hepatocellular carcinoma.     

Removal from liver transplantation list of a hepatitis C virus‐HIV co‐infected patient after successful treatment with sofosbuvir and daclatasvir

We present a human immunodeficiency virus‐infected patient with severe decompensated hepatitis C virus‐related cirrhosis awaiting liver transplantation (LT) who received a 24‐week course of interferon/ribavirin‐free antiviral treatment with sofosbuvir and daclatasvir on a compassionate basis. Rapid viral suppression was associated with progressive improvement of his liver function tests. The patient achieved a sustained virological response and concomitant clinical improvement, which prompted removal from the LT list 12 weeks after the end of treatment.     

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.