Clinical outcomes of hepatitis C treatment before and after kidney transplantation and its impact on time to transplant: A multicenter study.

Waitlist time for kidney transplantation is long but may be shortened with the utilization of hepatitis C positive allografts. We retrospectively reviewed the course of 36 hepatitis C positive patients awaiting kidney transplantation at 2 large centers within the same health system, with near-identical care delivery models with the exception of timing of hepatitis C treatment, to determine the impact of timing of hepatitis C treatment on access to transplant, waitlist time, and treatment efficacy and tolerability. The majority of patients had hepatitis C genotype 1a or 1b, and all received direct acting antiviral therapy with 100% treatment response. One patient underwent transplantation in the pretransplant treatment group. The 1-year transplantation rate was 12.5% vs 67.9% (P = .0013) in those treated posttransplantation. The median waitlist time in the posttransplant group was 122 (interquartile range [IQR] 21.5, 531.0) days, which was significantly shorter than the center's regional and national wait time. Pathologic review revealed no difference in allograft quality. Overall treatment related adverse events were not different between the 2 groups. A strategy of posttransplant hepatitis C treatment increased access to transplant and reduced waitlist time. Delaying treatment until after transplant did not appear to adversely affect recipients' kidney allograft or overall survival.

Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II randomized study.

This exploratory phase II study evaluated the safety and efficacy of belatacept in de novo adult liver transplant recipients. Patients were randomized (N = 260) to one of the following immunosuppressive regimens: (i) basiliximab + belatacept high dose [HD] + mycophenolate mofetil (MMF), (ii) belatacept HD + MMF, (iii) belatacept low dose [LD] + MMF, (iv) tacrolimus + MMF, or (v) tacrolimus alone. All received corticosteroids. Demographic characteristics were similar among groups. The proportion of patients who met the primary end point (composite of acute rejection, graft loss, death by month 6) was higher in the belatacept groups (42­48%) versus tacrolimus groups (15­38%), with the highest number of deaths and grafts losses in the belatacept LD group. By month 12, the proportion surviving with a functioning graft was higher with tacrolimus + MMF (93%) and lower with belatacept LD (67%) versus other groups (90%: basiliximab + belatacept HD; 83%: belatacept HD; 88%: tacrolimus). Mean calculated GFR was 15­34 mL/min higher in belatacept-treated patients at 1 year. Two cases of posttransplant lymphoproliferative disease and one case of progressive multifocal leukoencephalopathy occurred in belatacept-treated patients. Follow-up beyond month 12 revealed an increase in death and graft loss in another belatacept group (belatacept HD), after which the study was terminated.

Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies.

BACKGROUND: The goal of hepatorenal syndrome type 1 (HRS-1) treatment is to improve renal function. Terlipressin, a synthetic vasopressin analogue, is a systemic vasoconstrictor used for the treatment of HRS-1, where it is available. AIM: To compare the efficacy of terlipressin plus albumin vs. placebo plus albumin in patients with HRS-1. METHODS: Pooled patient-level data from two large phase 3, randomised, placebo-controlled studies were analysed for HRS reversal [serum creatinine (SCr) value ≤133 µmol/L], 90-day survival, need for renal replacement therapy and predictors of HRS reversal. Patients received intravenous terlipressin 1-2 mg every 6 hours plus albumin or placebo plus albumin up to 14 days. RESULTS: The pooled analysis comprised 308 patients (terlipressin: n = 153; placebo: n = 155). HRS reversal was significantly more frequent with terlipressin vs. placebo (27% vs. 14%; P = 0.004). Terlipressin was associated with a more significant improvement in renal function from baseline until end of treatment, with a mean between-group difference in SCr concentration of -53.0 µmol/L (P < 0.0001). Lower SCr, lower mean arterial pressure and lower total bilirubin and absence of known precipitating factors for HRS were independent predictors of HRS reversal and longer survival in terlipressin-treated patients. CONCLUSIONS: Terlipressin plus albumin resulted in a significantly higher rate of HRS reversal vs. albumin alone in patients with HRS-1. Terlipressin treatment is associated with improved renal function. (ClinicalTrials.gov identifier: OT-0401, NCT00089570; REVERSE, NCT01143246).

Detection of hepatitis C virus replication in peripheral blood mononuclear cells after orthotopic liver transplantation.

BACKGROUND: The presence of hepatitis C virus (HCV) replication in peripheral blood mononuclear cells (PBMCs) remains controversial. We determined the presence of the negative HCV RNA strand in PBMCs from a group of HCV-positive patients before and after liver transplantation. METHODS: Nine patients receiving orthotopic liver transplantation for end-stage HCV-related liver disease were studied. PBMCs were collected on the day of transplantation and 1 month later. The negative HCV RNA strand was detected by highly strand-specific Tth-based reverse transcriptase polymerase chain reaction. RESULTS: All nine patients were positive for the presence of the HCV RNA-positive strand in serum and PBMCs both before and after transplantation. The presence of the negative HCV RNA strand was documented in three PBMC samples after transplantation but in none of the samples collected before transplantation. CONCLUSION: Our results suggest that under circumstances of impaired immunity associated with pharmacological immunosuppression, HCV may be lymphotropic in vivo.

Hepatitis G virus coinfection in hepatitis C virus-infected liver transplant recipients.

BACKGROUND: In this study, we determined the prevalence of hepatitis G virus (HGV) infection in end-stage hepatitis C virus (HCV)-related liver disease and examined the influence of HGV coinfection on the outcome of liver transplantation. METHODS: HGV was detected by reverse transcriptase-polymerase chain reaction and Southern blotting in sera drawn from 159 patients who were known to be HCV infected before transplantation. Patients were followed up for a mean of 28.4 months after transplantation. RESULTS: Forty-one (25.3%) patients were HGV positive and the prevalence of HGV infection was similar for different HCV genotypes. Both HGV-positive and -negative groups had similar survival, recurrence rates, inflammatory activity scores, and degree of fibrosis at the time of recurrence. CONCLUSION: Infection with HGV is common in end-stage HCV-infected patients presenting for liver transplantation. It influences neither the outcome of liver transplantation nor the recurrence of hepatitis in the graft.

Liver transplantation for variceal hemorrhage.

Orthotopic liver transplantation should be considered as a treatment for end-stage liver disease, which provides resolution to all its complications, including portal hypertensive-related bleeding. In the 1990s, variceal bleeding should be controlled primarily with endoscopy and, if this approach fails, with selective surgical shunting in those patients who have good hepatic function and with TIPS in those patients whose hepatic function is marginal and need bridging treatment until transplantation. Decompression of the portal system with either of these approaches allows for liver transplantation with challenges that can be overcome by experienced surgical teams.

Management of portal hypertension-related bleeding.

Although endoscopic sclerotherapy and TIPS remain the primary therapeutic tools in management of acute variceal bleeding, surgical shunts must be considered for low-risk patients with bleeding. OLTx is the only definitive treatment for patients with end-stage liver disease and vascular decompensation. Furthermore, the current prospective multicenter randomized study, funded by the National Institutes of Health and Human Services, will help determine the role of DSRS versus TIPS in cirrhotic patients with good hepatic reserve. This is a necessity in a time in which organ shortages are ever-increasing because of a growing disparity between the number of patients listed for transplantation each year versus the number of suitable organ donors. The various surgical techniques should be applied in different situations based on patients' clinical status at the time of the bleed and whether they are considered candidates for liver transplantation.

Natural history of hepatitis C and outcomes following liver transplantation.

Chronic hepatitis C virus (HCV) infection is common and affects a significant proportion of the population. Chronic HCV-related cirrhosis is the most common indication for liver transplantation (LT) in Australia, the United States (US), and most European countries. Unfortunately, the post-transplant recurrence of HCV is almost a universal phenomenon with approximately 6% to 23% of transplant recipients progressing to cirrhosis at a median of 3 to 4 years post-LT with a cumulative probability of developing graft cirrhosis estimated to reach 30% at 5 years. The 1-year and 3-year actuarial risk of decompensation has been estimated at 42% and 62%, respectively. Similarly, the rate of progression from hepatic decompensation to death is accelerated after LT with a 3-year survival rate of less than 10% in decompensated HCV liver recipients. Ten percent to 25% of the patients with recurrent disease will require re-transplantation within 5 years. Because of the increasing number of patients transplanted for chronic HCV infection and the complexity of factors affecting this population we will present an up-to-date review concerning LT in the setting of HCV infection and cirrhosis with the goal of outlining the natural history, recurrence of infection, risk factors associated with severity of recurrence, treatment strategies for recurrent HCV infection, role of re-transplantation, and de-novo hepatocellular carcinoma.

Selection of different 5' untranslated region hepatitis C virus variants during post-transfusion and post-transplantation infection.

BACKGROUND: Hepatitis C virus (HCV) translation is initiated in a cap-independent manner by an internal ribosome entry site (IRES) located within the 5' untranslated region (5'UTR). Sequence changes in this region could affect translation efficiency and presumably viral replication. AIM: To determine translation efficiency of 5'UTR variants developing during post-transfusion hepatitis C in two immunocompetent subjects and in two immunosuppressed liver recipients with recurrent HCV. METHODS: Sequential samples were screened for 5'UTR changes by single-strand conformation polymorphism followed by cloning and sequencing whenever band pattern suggested sequence changes. 5'UTR variants were tested for IRES activity using a bicistronic dual luciferase expression plasmid transfected into HepG2 and Huh7 cell-lines. RESULTS: In the transfused patients, translation efficiency of 5'UTR variants from early post-transfusion samples was 5.1- to 13.7-fold higher than that of predominant variants found in late follow-up samples. Post-transplant variants in the other two patients had 2.6- to 5.9-fold higher translation efficiency than those present only in pretransplant samples. CONCLUSION: In the immunocompetent host there may be selection of low translation efficiency HCV variants over the course of infection. However, in immunosuppressed subjects the opposite seems to be true as low translation efficiency variants are superseded by high translation efficiency variants.

Clinical significance of elevated alpha-fetoprotein in adults and children.

The aim of the current study is to identify underlying pathology associated with elevated serum alpha-fetoprotein (AFP; >20 ng/ml) among patients referred to a tertiary-care academic medical center with emphasis in liver diseases, hepatobiliary surgery, and liver transplantation. From May 1992 to April 1997, 386 patients (320 adults and 66 children) with elevated AFP (>20 ng/ml) were identified from the Medical Archival System (MARS) database at the University of Pittsburgh Medical Center. The medical records from all these patients were retrospectively reviewed. Radiological, pathological, and biochemical profiles were obtained at the time of documented elevated AFP. These patients included: 218 adults with malignancies, 102 adults without malignancies, 18 children and infants with malignancies, and 48 children and infants without malignancies. Thirty-two percent of adults were found to have raised AFP with liver disease and without hepatocellular carcinoma and 78% had some type of malignancy, predominantly hepatocellular carcinoma. Seventy-three percent of infants and children had elevated AFP without malignancy. Based on our findings, we recommend that all patients (adults, infants and children) with raised AFP of >20 ng/ml should undergo thorough evaluation to rule out malignant disease.

Antitumor effects of interleukin-2 and mismatched double-stranded RNA, individually and in combination, against a human malignant melanoma xenograft.

The antitumor effects of recombinant interleukin-2 (rIL-2) and mismatched double-stranded RNA (dsRNA) were assessed in tissue culture and in a nude mouse model. Mismatched dsRNA did not show a direct antiproliferative effect against the human malignant melanoma cell line, BRO, in tissue culture. However, treatment of the BRO cells with up to 1000 units/ml rIL-2 in culture showed a slight increase in growth rate. Combined rIL-2/mismatched dsRNA treatment also demonstrated a similar slight enhancement of growth. Nude mice bearing subcutaneous tumors were treated by intraperitoneal injection of low doses (5000-20,000 units) of rIL-2 and mismatched dsRNA (500 micrograms). The in vivo tumor growth was significantly inhibited by the combined treatments (P less than 0.05) and survival was significantly increased (P less than 0.05). Measurement of cytotoxicity using splenocytes from treated animals showed significant augmentation of lytic activity against natural killer (NK)-sensitive YAC-1 cells in all rIL-2/mismatched dsRNA treatment groups, compared to the individual treatments or controls (P less than 0.05). Cytotoxicity of the splenocytes against the NK-resistant BRO cells was also augmented in animals treated with mismatched dsRNA and the highest rIL-2 dose utilized here (P less than 0.01). Renal, liver, and hematological toxicity was evaluated by measurement of blood urea nitrogen, creatinine, serum asparrtate aminotransferase, and a complete blood count with differential. There were no significant differences in these parameters in any of the treatment groups. Similarly, no differences in weight of the animals was seen in any treatment group. These results indicate that the combination of low-dose rIL-2 and mismatched dsRNA can potentiate host-mediated antitumor effects, yielding increased survival, without significant toxicity.

Clinical and virologic outcomes of hepatitis B and C viral coinfection after liver transplantation: effect of viral hepatitis D.

Hepatitis B (HBV) and C viral (HCV) dual-infection-associated liver disease is an uncommon indication for liver transplantation. The clinical and virologic outcomes in such patients have not been well studied. We retrospectively studied 13 patients with hepatitis B surface antigen (HBsAg) and antibody to HCV positivity who underwent orthotopic liver transplantation (OLT) and survived at least 30 days post-OLT. Antibody to hepatitis delta virus (HDV) was negative in 8 patients (group I) and positive in 5 patients (group II). Eleven of the 13 patients received standard hepatitis B immune prophylaxis, and they all remained HBsAg negative. All group I patients were HCV RNA positive after transplantation; in contrast, all group II patients were HCV RNA negative. Serum alanine aminotransferase levels were elevated in 88% (7 of 8) of the patients in group I compared with 20% (1 of 5 patients) in group II. None of the patients had graft loss from chronic rejection or recurrent hepatitis. Three patients had unsuspected hepatocellular carcinoma in the explant. We conclude that among liver transplant recipients with HBV and HCV coinfection, HDV infection is associated with the suppression of HCV replication and mild inflammatory activity after OLT.

Outcome of liver transplantation in hepatitis C virus-infected patients who received hepatitis C virus-infected grafts.

BACKGROUND & AIMS: The present organ shortage has brought into question the suitability of hepatitis C virus (HCV)-positive grafts. This study reviewed the outcome of such transplantations in our institution. METHODS: Twenty-three HCV-positive patients who underwent orthotopic liver transplantation (OLT) for end-stage liver disease with HCV-positive grafts in 1992-1995 were studied. Only patients who survived more than 30 days were included in the analysis. Control group included 169 patients who underwent transplantation for HCV-related cirrhosis and received HCV-negative organs. RESULTS: Patients who received HCV-infected organs had a cumulative survival rate of 89% and 72% at 1 and 5 years, respectively, vs. 88% and 73% for the control group (NS). There was no difference in graft survival, incidence of cirrhosis, mean hepatitis activity index score, fibrosis, or mean activity of serum transaminases. There was a trend toward lower incidence of recurrent hepatitis C in the study group compared with control (21% vs. 23% at 1 year and 47% vs. 64% at 5 years; NS). Patients in whom the donor strain became predominant after transplantation had significantly longer disease-free survival than patients who retained their own HCV strain (P < 0.003). CONCLUSIONS: HCV-infected livers transplanted into HCV-infected recipients do not appear to convey a worse outcome in the initial years after OLT than HCV-negative grafts.

Distribution of infecting hepatitis C virus genotypes in end-stage liver disease patients at a large American transplantation center.

The distribution of hepatitis C virus (HCV) genotypes was studied in 202 anti-HCV-positive liver transplant candidates with end-stage liver disease. HCV sequences were successfully amplified from 185 patients: In the first 100, the genotype was determined by direct sequencing in the NS5 region, and in the remaining 85, type-specific primers were used for genotyping. Eighty-five patients (46.0%) were infected with type 1a HCV strains, 52 (28.1%) with type 1b, 14 (7.6%) with type 2b, 13 (7.0%) with type 4, 5 (2.7%) with type 3a, 2 (1.1%) with type 2a, and 1 (0.5%) with type 2c. Thirteen HCV-positive patients (7.0%) could not be genotyped. The relatively low prevalence of genotype 1b in this population of end-stage liver disease patients speaks against postulated higher pathogenicity of this genotype.

The influence of hepatitis C virus genotypes on the outcome of liver transplantation.

BACKGROUND: The aim of this study was to report the influence of hepatitis C virus (HCV) genotypes and HLA matches on the outcome of liver transplantation, hepatitis recurrence, and progression to cirrhosis after transplantation. METHODS: HCV genotypes were determined from pretransplantation sera and/or liver explant tissues from 202 patients with HCV-related end-stage liver disease. One hundred fifty patients with known infecting genotype for whom posttransplantation biopsy specimens were available or who had normal results of liver injury tests constituted the group analyzed. Patients were followed up for up to 4.5 years. Hepatitis activity index scores at the time of disease recurrence were used to assess disease activity. Cirrhosis was diagnosed by using histological evidence. The number of HLA matches with respect to A, B, DR, and DQ loci was determined. RESULTS: The rates of hepatitis recurrence were 25% and 75% at 1 year and 4 years, respectively; Kaplan-Meier survival analysis did not reveal significant differences between the infecting genotypes with respect to overall rates of survival or recurrence of hepatitis. At hepatitis recurrence, hepatitis activity index scores did not differ between the genotype groups. The distribution of infecting genotypes among the 7 patients who developed cirrhosis is reflective of pretransplantation distribution. Neither HLA site-specific nor total matches affected the rates of survival or disease recurrence. CONCLUSIONS: The infecting HCV genotype had no influence on the incidence or severity of recurrent hepatitis, rate of survival, or development of cirrhosis. HLA matching does not influence transplantation outcome for HCV-related disease.