INTRODUCTION:Severity of recurrent hepatitis C virus (HCV) infection in liver transplant recipients (LTR) is variable and the influence of different factors, including the administration of antiviral therapy in the long-term outcome is controversial. METHODS:We analyzed the outcome of a cohort of HCV-infected LTR who were transplanted in our institution. Patients were divided into 2 groups (severe and non-severe HCV disease) depending on the presence of a fibrosis score of F ≥ 2 in the Scheuer index and/or fibrosing cholestasic hepatitis (FCH) in a graft biopsy. Risk factors were studied using logistic regression analysis. Survival of patients was estimated using Kaplan-Meier plots. A total of 146 patients were followed for a mean of 58 months. RESULTS:Fifty-six (34%) patients developed severe HCV disease and showed shorter survival (P < 0.024). Donor age (odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.02-1.06) and pre-transplant viral load (VL) >10(6) UI/mL (OR: 3.5; 95% CI: 1.42-10.61) were the only factors associated with severe HCV infection. Over-immunosuppression (OR: 2.3; 95% CI: 1.2-4.41) was specifically associated with the development of FCH. Overall, patient survival in recipients who received a full course of anti-HCV therapy was higher than in patients who did not complete antiviral therapy (P = 0.004) or received no treatment (P = 0.007). Patients with non-severe HCV infection have a higher probability of receiving a full course of antiviral therapy (P = 0.033). CONCLUSION:In conclusion, donor age, pre-transplant VL, and over-immunosuppression were associated with the long-term development of severe HCV recurrence in liver grafts. Administration of a full course of antiviral therapy was associated with better survival.

BACKGROUND:Hepatitis C (HCV) is among the most common causes of end-stage liver disease worldwide. The donor shortage leads us to consider alternative organ sources such as HCV-positive donors. The outcomes of these transplants must be evaluated thoroughly since there is universal recurrence of disease among HCV-positive liver transplant recipients.METHODS:From January 2005 to April 2011, we performed 143 liver transplants (OLT) to treat end-stage liver disease secondary to HCV infection. Thirteen patients (9,1%) received livers from HCV-positive donors. A control group consisted of 130 HCV-positive patients who underwent OLT during the same period with organs from HCV-negative donors. Donor HCV status was assessed by 2 tests: HCV antibodies and viral load. Not only recipient and graft survivals were analyzed, but also frequency, timing and severity of hepatitis recurrence.RESULTS:Among 143 transplants performed in HCV-positive recipients during a 6-year period from January 1, 2005, to April 30, 2011, 9.1% of patients received an organ from an anti-HCV-positive donor, 72.7% of whom showed a negative viral load. The vast majority (80%) of our patients suffered hepatitis during their follow-up, 22.4% of which were severe cases.CONCLUSIONS:No significant difference in patient or graft survival was observed between the 2 groups. A high percentage of grafts with initial positive serology for HCV showed no viral replication. Grafts from HCV-positive donors can be considered to be a safe, effective source for liver donation.

Kidney transplantation from hepatitis C virus (HCV) antibody positive donors (HCVD+) into HCV antibody positive recipients (HCVR+) is controversial. We implemented this policy in our units in 1990. Herein, we report the long-term safety of this strategy. From March 1990 to March 2007, 162 HCVR+ received a kidney from HCVD+ (group 1) and 306 from HCVD- (group 2) in our units. Mean follow-up was 74.5 months. Five-and 10-year patient survival was 84.8% and 72.7% in group 1 vs. 86.6% and 76.5% in group 2 (p = 0.250). Three deaths in group 1 and two in group 2 were liver-disease related. Five- and 10-year graft survival was 58.9% and 34.4% versus 65.5% and 47.6% respectively (p = 0.006) while death-censored graft survival was 69% and 47% versus 72.7% and 58.5% (p = 0.055). Decompensated chronic liver disease was similar: 10.3% versus 6.2%. Cox-regression analysis could not identify the donor's HCV serology as a significant risk factor for death, graft failure and severe liver disease in HCVR+. In conclusion, long-term outcome of HCVR+ transplanted with kidneys from HCVD+ seems good in terms of patient survival, graft survival and liver disease. HCVD+ was not a significant risk factor for mortality, graft failure and liver disease among HCVR+. These data strongly suggest that the use of kidneys from HCVD+ in HCVR+ is a safe long-term strategy that helps to prevent kidney loss.

BACKGROUND/AIMS:Hepatitis C-related liver disease is the main indication for liver transplantation in many centers. Viral RNA remains after transplantation in almost 100% of the patients, and more recent reports show a graft hepatitis rate of about 90%. The progression of this hepatitis seems to be quicker than in the nontransplant setting.METHODOLOGY:From June 1989 to October 2000, 197 adult patients had 213 for HCV-related liver disease at our institution. Basal immunosuppression consisted of a triple therapy with cyclosporine, azathioprine and steroids, or dual therapy with tacrolimus and steroids. None of the patients was treated with antivirals after liver transplantation.RESULTS:Pure HCV-related cirrhosis was the indication for liver transplantation in 114 patients, another 14 with hepatocellular carcinoma, 8 associated metabolic diseases, 43 high alcohol intake, 4 hepatitis B, 5 cholestatic diseases, and 3 other diseases. Six patients out of the 197 transplanted in this period were already grafted before this time, and had their first retransplantation of the liver after 1989 (their first liver transplantation was done when HCV was not known). Sixteen additional retransplantation procedures were done in the period considered. Hepatitis was diagnosed in 84.3% of the grafts biopsied later than 90 days after liver transplantation (118/140), and in 92.9% if it was done after one year (92/99). Cirrhosis was diagnosed in 21 grafts at a mean time of 1004.7 days, 21.2% of the grafts biopsied after 1 year and 28.6% after 2 years. Nine grafts in 8 patients were diagnosed as fibrosing cholestatic hepatitis. Patient actuarial survival was 80.9%, 69.7%, 67.5% and 50.6% at 1, 3, 5 and 10 years. Liver failure and hepatoma recurrence were the cause of death in 42.4% of the patients. Actuarial graft survival was 75.2%, 64.9%, 63.5% and 48.6% at 1, 3, 5 and 10 years, and was significantly affected by Child stage (B vs. C, P = 0.004). When compared to 228 non-HCV- infected patients with chronic parenchymatous disease, these had an almost significantly better patient survival (P = 0.0577), but a nonsignificant difference in graft survival. Graft loss related to liver causes was 17.6% in HCV+ patients 14.6% in HCV- patients. Liver causes of death were 14.0% in HCV+ patients and 4.8% in HCV-patients (P = 0.002).CONCLUSIONS:HCV infected liver transplantation recipients present very often graft hepatitis, which may progress to advanced stages in a quite short interval. Mid-term patient and graft survival is comparable to those of non-HCV recipients, but causes of death related directly to liver disease are more common in HCV+. This makes one think that long-term prognosis (more than 10 or 15 years) will be worse in HCV patients.

Dominguez-Gil, Beatriz1; Munoz, Miguel Angel1; Campistol, Jose Maria2; Andres, Amado1; Fuertes, Antonio2; Oppenheimer, Federico2; Bruguera, Miguel2; Castellanos, Gregorio1; Rodicio, Jose Luis1; Pereira, Brian J.G.3; Morales, Jose Maria1 Author Information

BACKGROUND/AIMS:We compared the response to interferon-alpha 2a in 35 patients with antibody to HBeAg (anti-HBe) and 20 patients with HBeAg in serum, and histological features of chronic hepatitis B.METHODOLOGY:Patients were treated with 4.5-6 MU of interferon-alpha 2a, three times a week for 12 months, and followed for 30.8 +/- 13.5 additional months.RESULTS:All of them had elevated serum levels of aminotransferases and positive test for hepatitis B virus-DNA in serum. Patients with anti-HBe-positive chronic hepatitis were older and had higher serum aminotransferase levels than HBeAg-positive patients, but no differences were seen between both groups with respect to sex, history of acute hepatitis, mode of transmission of the infection or histological appearance before interferon therapy. Serum levels of alanine transaminase became normal and hepatitis B virus-DNA undetectable by PCR at the end of therapy in 25 (71%) of anti-HBe-positive patients and in 10 (50%) of HBeAg-positive patients (P > 0.05). Although 10 (29%) of the anti-HBe-positive and none of the HBeAg-positive patients relapsed, no significant difference was seen in the rate of sustained response (43% vs. 50%, respectively). The histological improvement was similar in both groups.CONCLUSIONS:The results of this study indicated that biochemical, virological and histological response to 12-month interferon-alpha 2a therapy was similar in patients with anti-HBe antibody than in patients with the classical HBeAg-positive of chronic hepatitis B.

We report a patient who acquired hepatitis C virus (HCV) infection at cardiac transplantation, developing fibrosing cholestatic hepatitis (FCH) with early liver failure and a fatal outcome. FCH is a recently described clinicopathological entity characterized by a cholestatic pattern of serum liver enzyme abnormalities, a progressive course leading to liver failure, and a pathological picture defined by periportal fibrosis, neutrophilic infiltrates and signs of histological cholestasis. Although it was initially described secondary to hepatitis B virus infection, it has also been recently related to HCV infection. Some histopathological features consistent with azathioprine hepatotoxicity like cholestasis, perisinusoidal fibrosis, veno-subocclusive lesions and nodular regenerative hyperplasia were also observed in this case. Therefore, a direct cytopathic effect of HCV and the concurrent pathogenic role of azathioprine hepatotoxicity may be involved in the development of this complication of transplantation.

We designed a prospective study to assess the time course and evolution of hepatitis C virus (HCV) infection in 152 patients who underwent a liver transplantation (LT) in our institution. Forty-four recipients (29%) were infected by HCV after transplantation: 40 who developed recurrent infection after LT and four who acquired infection during or after LT. No differences were found in survival actuarial rates at 1, 2, and 4 years after transplantation for patients infected by HCV vs. noninfected ones. Graft hepatitis occurred in 66% of HCV-infected recipients: 18 developed chronic active hepatitis (10 of them with intense fibrosis) and 2 developed cirrhosis during the follow-up. Infection by the HCV-1b genotype was found in 79% of the infected recipients and in 100% of those in whom histologic evolution was worst. Fourteen grafts were lost in 44 HCV-infected recipients, in comparison with 12 in 108 HCV-negative patients (P = .007), mostly because of chronic rejection. HCV infection did not affect life expectancy in the midterm follow-up for LT patients. However, it was often associated with the occurrence of early and severe graft hepatitis and with a higher incidence of graft loss due to chronic rejection.

735 The use of kidneys from HCV positive donors remains controversial. We have previously shown that 80% HCV RNA negative recipients from HCV RNA positive donors tested positive for HCV RNA after transplantation. Therefore, in 1993 we restricted these organs to HCV RNA positive recipients. We present now the experience of a single hospital using this policy comparing the results with those obtained with a control group of HCV positive patients who received kidneys from HCV negative donors in the same period July 1993-June 1997.TableNotably the incidence of acute hepatitis was low, nobody died by liver failure and survival figures were excellent without differences with the control group. In conclusion, although superinfection is possible, our results suggest that transplantation of kidneys from HCV positive donors into HCV RNA recipients could be the best alternative to use these kidneys avoiding organ loss. Matching HCV RNA genotype could be the next step to improve this policy.

Severe hepatitis C virus (HCV)-related fibrosing cholestatic hepatitis leading to early liver failure has been reported only exceptionally. Of 259 HCV-infected renal transplant (RT) patients in one hospital unit, four (1.5%) are described, representing the first series of this particular post-RT disease. Patient mean age was 55.7 yr. Three were men. All had pretransplant, hepatitis B surface antigen-negative and were anti-HCV antibodies positive. Three of them showed pretransplant mild liver enzyme abnormalities, and all received kidneys from HCV-negative donors. All were on steroids, cyclosporine, and azathioprine (AZA). The clinical pattern appeared early after RT (mean, 11.5 mo). In three patients, hyperbilirubinemia (6.5 to 20 mg/dl) and high alkaline phosphatase levels (428 to 859 IU/L) were observed. Also, in all subjects, high gamma glutamyl transpeptidase levels (639 to 4270 IU/L), mild aspartate aminotransferase and alanine aminotransferase abnormalities, and serum HCV RNA were observed. Liver biopsy revealed diffuse fibrosis, leukocyte infiltrates, and different degrees of cholestasis, with typical signs of HCV hepatitis in only one patient. Two patients developed subfulminant liver failure and died 2 and 3 mo after biopsy, respectively. One patient also suffered hepatic failure, receiving a liver transplant. The fourth is alive on dialysis awaiting a combined kidney and liver transplant. It is concluded that fibrosing cholestatic hepatitis is a new, early, and severe complication after RT in HCV(+) patients, which appears in patients with ongoing HCV infection under AZA therapy, despite a nonaggressive immunosuppressive protocol. Both HCV and AZA could play a concurrent role in the pathogenesis of this severe complication after RT.

Background. Hepatitis C virus (HCV) infection has been described in association with various types of glomerular diseases, usually type I membranoproliferative glomerulonephritis and rarely membranous glomerulonephritis (MGN). In this article, we describe the first series of MGN exhibited in renal transplant patients and associated with HCV infection. Methods. From January 1980 to December 1994, 2045 kidney transplantations were performed in our renal transplant units. A retrospective analysis demonstrated an overall 20% prevalence of HCV virus-positive patients; 409 transplanted patients were HCV positive (ELISA and RIBA). Results. Fifteen patients developed an allograft MGN (3.66%) 24 months after renal transplantation. MGN appeared in the form of significant proteinuria (>1.5 g/24 h) with stable renal function. In all cases, graft biopsy demonstrated a thickening of the capillary wall, subepithelial electron-dense deposits, and IgG and C3 diffuse granular deposits along the basal membrane. Ten cases were considered de novo, two cases were considered recurrent MGN, and three cases were considered undetermined because the primary renal disease was chronic glomerulonephritis. All patients showed negative antinuclear antibodies and cryoglobulins, normal complement, and negative rheumatoid factors. During follow-up (an average of 2 years), 12 patients developed a progressive worsening of renal function, with increased serum creatinine and persistent proteinuria; 8 of the 12 patients returned to dialysis. Of the remaining three cases, two patients showed partial remission of nephrotic syndrome after high doses of steroids, and one patient persisted with stable renal function and proteinuria (<2 g/24 h.). Conclusions. In summary, HCV is preferentially associated with MGN in renal transplant patients, rather than with membranoproliferative glomerulonephritis as in the normal adult population. MGN associated with HCV infection has a similar clinical picture and outcome to posttransplant idiopathic de novo MGN, with persistent massive proteinuria and progressive deterioration of renal function.

BACKGROUND We wanted to investigate the influence of viral genotype on the severity of liver injury and response to interferon and whether the level of viremia differs in accordance with genotype, severity of liver disease, and response to interferon in patients with hepatitis C virus (HCV) infection. METHODS We studied 118 patients with HCV-related liver disease. HCV genotypes were determined with a line probe assay, and serum HCV RNA levels with a competitive reverse transcription polymerase chain reaction assay. RESULTS HCV type 1b was the most prevalent genotype (88%). It was present in 100% of cirrhotic patients, with or without hepatocellular carcinoma (HCC), but only in 78% of patients with chronic hepatitis (P < 0.001). The response to interferon was better in patients infected with non-1b HCV genotypes (P = 0.002). In a multivariate analysis non-1b HCV genotypes and a low hepatic fibrosis correlated with a favorable response to interferon. Among patients with chronic hepatitis those infected with HCV type 1b were older (P < 0.001), and age was the only independent factor associated with HCV type 1b. Viremia levels differed neither between genotypes nor in response to interferon and was significantly lower in patients with cirrhosis and HCC. CONCLUSIONS HCV 1b was associated with more severe liver disease and a worse response to interferon therapy. Non-1b genotypes and a lower liver fibrosis were the only independent predictors of a favorable response to interferon. Levels of HCV viremia differed neither among different genotypes nor in response to interferon and decreased with advanced liver disease.

BACKGROUND/AIMS:Human autologous liver transplantation is possible due to an adequate suppression of the body's immune response. This also causes a higher hepatitis infection rate, making hepatitis prevention very important.MATERIALS AND METHODS:We describe our experience with hepatitis B virus vaccination in 140 adult liver transplant recipients, transplanted from 1986 to 1994 with more than one year of follow-up. Excluded were those who had hepatitis B surface antigens or antibodies to those antigens before the transplant. The vaccination schedule was 0-1-2 months with a double dose of recombinant vaccine.RESULTS:The total response rate (surface antigen antibodies > 10 U) was 40% (56/140); the rate was 47.7% in men and 26% in women. At the end of the study, only 17.1% (24/140) of the patients had antibodies > 10 U. The response rate was higher in patients with antibodies to hepatitis B core antigen (66.6%) than in those lacking antibodies (31.7%), and more long lasting (42.4% vs 11.2%). The response rate in 116 patients with booster doses was 12.9%. Six correctly vaccinated patients (4.28%) acquired new hepatitis B virus infections after the operation.CONCLUSIONS:The total response rate in these patients is much lower than in the general population, and there is a rapid decline of titers, probably due to immunosuppression. The role of booster doses in these patients should be clarified.

BACKGROUND:Recent development of an assay based on the hybridization of the amplification product obtained by polymerase chain reaction (PCR) of the RNA of hepatitis C virus (HCV) with specific probes for each viral genotype ("reverse-hybridization"), has permitted to have a rapid, simple and reproductible technique to identify the different genotypes of HCV. The identification of HCV genotypes seems to be important given their different pathogenic capacity and response to interferon therapy.METHODS:We prospectively studied 221 patients with HCV infection defined by the detection of viral RNA in serum by "nested-PCR". HCV genotype was determined by "reverse-hybridization" using specific oligonucleotide-probes for each genotype corresponding to the 5, UTR.RESULTS:HCV 1b genotype was predominant in 221 patients studied (180/221, 81%), followed by 1a (10%) and by 3 and 4 (4% respectively). Two patients presented mixed infection (1a/1b). No case of infection by genotypes 2 and 5 was found. The predominance of 1b genotype was more evident in adults than in children (83 vs 62%) (p < 0.05).CONCLUSIONS:HCV 1b is the predominant genotype among our patients with hepatic disease induced by HCV. The reverse-hybridization assay is a simple and rapid technique that permit the identification of the most important genotypes of hepatitis C virus.