Early Recurrence Of Hepatitis Research Articles

Whole-genome sequencing reveals the evolutionary trajectory of HBV-related hepatocellular carcinoma early recurrence

Patients with hepatocellular carcinoma (HCC) have poor long-term survival following curative resection because of the high rate of tumor early recurrence. Little is known about the trajectory of genomic evolution from primary to early-recurrent HCC. In this study, we performed whole-genome sequencing (WGS) on 40 pairs of primary and early-recurrent hepatitis B virus (HBV)-related HCC tumors from patients who received curative resection, and from four patients whose primary and recurrent tumor were extensively sampled. We identified two recurrence patterns: de novo recurrence (18/40), which developed genetically independently of the primary tumor and carried different HCC drivers, and ancestral recurrence (22/40), which was clonally related to the primary tumor and progressed more rapidly than de novo recurrence. We found that the recurrence location was predictive of the recurrence pattern: distant recurrence tended to display the de novo pattern, whereas local recurrence tended to display the ancestral pattern. We then uncovered the evolutionary trajectories based on the subclonal architecture, driver-gene mutations, and mutational processes observed in the primary and recurrent tumors. Multi-region WGS demonstrated spatiotemporal heterogeneity and polyclonal, monophyletic dissemination in HCC ancestral recurrence. In addition, we identified recurrence-specific mutations and copy-number gains in BCL9, leading to WNT/β-catenin signaling activation and an immune-excluded tumor microenvironment, which suggests that BCL9 might serve as a new therapeutic target for recurrent HCC. Collectively, our results allow us to view with unprecedented clarity the genomic evolution during HBV-related HCC early recurrence, providing an important molecular foundation for enhanced understanding of HCC with implications for personalized therapy to improve patient survival.

Early Chimerism After Liver Transplantation Reflects the Clinical Course of Recurrent Hepatitis C.

BACKGROUND Human leukocyte antigen (HLA) mismatch is a characteristic feature of post-orthotopic liver transplantation (OLT) hepatitis C. To investigate the importance of donor HLA-restricted immune cells in post-OLT hepatitis C recurrence, we analyzed the frequency of donor chimerism and the clinical course of post-OLT hepatitis C. MATERIAL AND METHODS We analyzed peripheral blood chimerism in 11 HCV-reinfected patients with post-HLA mismatched OLT. Patients were divided into 2 groups: the OLT chronic hepatitis C (CHC) group (n=8), exhibiting active hepatitis C recurrence; and the OLT-persistently normal ALT (PNALT) group (n=3), without active hepatitis. Chimerism was analyzed by flow cytometry using donor-specific anti-HLA antibodies in peripheral blood mononuclear cells from 1-100 days after OLT. Kidney (n=7) and lung (n=7) transplant recipients were also analyzed for comparison. As immune cells from the donor liver might contribute to post-OLT chimerism, the characteristics of perfusates from donor livers (n=10) were analyzed and defined. RESULTS Donor-derived cells were frequently observed in liver and lung transplant recipients. The frequency of donor-derived cells from the B cell subset was significantly higher in peripheral blood from OLT-CHC group than in that of the OLT-PNALT group. B cells, however, were not the predominant subset in the perfusates, indicating that inflow of donor-derived cells alone did not cause the chimerism. CONCLUSIONS Chimerism of B cells is frequent in liver transplant patients with early recurrence of hepatitis C. We propose that monitoring of early chimerism could facilitate early detection of chronic hepatitis C recurrence, although we need more cases to investigate.

Histopathological evaluation of recurrent hepatitis C after liver transplantation: A review

Although the morphological features of hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) have been well established in the last decades, the differential diagnosis still represents a challenge for the pathologist, especially early recurrent hepatitis C vs mild acute cellular rejection. The present review focuses on the role of the pathologist and the pathology laboratory in the management of recipients with recurrent hepatitis C, the usefulness of early and late post-OLT liver biopsies, and the potential role of ancillary techniques (immunohistochemistry and reverse transcription-polymerase chain reaction, RT-PCR). The English literature on the topic is reviewed, focusing on the histopathology, the immunohistochemistry and the use of RT-PCR on HCV-positive post-OLT biopsies. The different histopathological illustrations of early and chronic recurrent hepatitis C are presented, with special focus on the main differential diagnoses and those features with prognostic relevance (cholestasis above all). The usefulness of ancillary techniques are discussed, especially HCV RNA quantitation by RT-PCR. Finally, the usefulness of long-term protocol biopsies is addressed: their usefulness for the study of allograft disease progression is clear, but their meaning in the long term is still debated. The significance of plasma cell infiltrate in HCV-positive allografts, the prognostic weight of graft steatosis, and the impact of donor age in recurrent hepatitis C also represent additional open issues.

Recurrent Hepatitis C Virus Infection and Outcome After Living-Donor Liver Transplant

In living-donor liver transplant recipients with hepatitis C virus infection, outcomes of recurrent hepatitis C virus infection and fibrosis progression are not well documented. We evaluated fibrosis progression, response to pegylated interferon treatment, and long-term graft survival in living-donor liver transplant recipients who had hepatitis C virus infection. In 48 transplant recipients, including 29 recipients who had follow-up liver biopsy ≥ 6 months after transplant, histology and clinical courses were reviewed. Outcomes were evaluated for patients grouped into slow and rapid fibrosis groups. Treatment with pegylated interferon and ribavirin was assessed in 18 patients. Clinical features were similar between recipients with slow or rapid fibrosis. The time interval from transplant to recurrence of hepatitis C virus infection was significantly shorter in the recipients with rapid fibrosis. Recipients with rapid fibrosis had significantly greater confluent necrosis, acidophil bodies, and fibrosis score than recipients with slow fibrosis. Graft survival rates were similar between patients with slow or rapid fibrosis. Cumulative proportion of long-term graft survival was 60% at 7 years after transplant. Sustained virologic response was noted in 5 of 18 patients (28%) who received pegylated interferon and ribavirin. In recipients of living-donor liver transplant with early recurrence of hepatitis C have worse fibrosis progression but graft survival was not affected. Therapy with pegylated interferon and ribavirin achieved sustained virologic response only in a small proportion of the patients.

Concurrent increase in mitosis and apoptosis: a histological pattern of hepatic arterial flow abnormalities in post-transplant liver biopsies

Liver biopsies are critical in managing patients after liver transplantation. One key histological pattern in transplant liver pathology is spotty hepatocyte necrosis without significant lobular inflammation, which is typical of recurrent hepatitis C. Over the past years, we have observed several liver biopsies with a pattern of injury that mimicked the histological findings of early recurrent hepatitis C. This pattern consisted of increased lobular hepatocyte spotty necrosis without significant inflammation, but with the additional finding of numerous concurrent mitotic figures. To better understand this unique pattern of injury, we studied a group of 8 liver biopsies with this pattern and a control group of 22 biopsies with typical recurrent hepatitis C. Hepatocyte apoptosis and mitosis were quantified by counting 10 high-power fields (HPFs). The mean interval between transplantation and biopsy was 62 days in both groups. There was no significant difference between the study and the control groups in portal and lobular inflammation. In contrast, there was more hepatic apoptosis (acidophil bodies) in the study cases than the controls (average of 10.3 vs 2.8 apoptotic bodies/10HPF; P=0.0004). Likewise, there were more mitoses in the study cases than the controls (average 6.3 vs 0.1 /10HPF; P<0.0001). Interestingly, examination of the medical records for the cases with increased apoptosis and mitoses found a very strong association with hepatic arterial problems including thrombosis (N=3), stenosis (1), flow abnormalities consistent with stenosis (3), and arteritis associated with acute rejection (1). In summary, our findings indicate that the histological pattern of concurrent increases in both hepatocyte mitosis and apoptosis in a post-transplant liver biopsy without significant lobular inflammation is strongly associated with hepatic arterial insufficiency and should prompt evaluation of the hepatic artery.

Is Early Recurrence of Hepatitis C Associated With Biliary Anastomotic Stricture After Liver Transplantation?

While the main effect of hepatitis C virus (HCV) is hepatitis, HCV is also known to cause a variety of systemic immunologic inflammatory abnormalities. The effect of HCV infection on the biliary tract after liver transplantation (LT) is not well understood. The aim of the current study is to determine if recurrence of hepatitis C affects biliary complications after LT, with special reference to late biliary anastomotic strictures (LBAS). A total of 688 consecutive adult LT recipients with a choledochocholedochostomy without T-tube placement between 1990 and 2005 were reviewed. Biliary anastomotic stricture was confirmed by endoscopic retrograde cholangiopancreatography. LBAS was defined as stricture that occurred 30 days or more after LT. Early HCV recurrence was defined as recurrence within 6 months after LT. LBAS occurred in 55 patients (8% of total). Patients with HCV infection had a higher occurrence of LBAS than non-HCV patients (11% vs. 5%, P=0.0093). Among HCV patients, those with early HCV recurrence had an exceedingly high rate of LBAS (16%). In multivariate analyses, early recurrence of hepatitis C (P<0.0001), as well as occurrence of hepatic artery thrombosis (P=0.0018) and prolonged cold ischemic time (P=0.034), were independent risk factors affecting LBAS. Among HCV patients, those with LBAS had a significantly higher hepatitis activity index score (3.1 vs. 1.4, P<0.0001) and fibrosis stage (0.9 vs. 0.4, P<0.0001) as compared to patients without LBAS. Patients with early recurrence of HCV have increased occurrence of late biliary anastomotic stricture after liver transplantation.

Liver transplantation worldwide

Liver transplantation worldwide

Mycophenolic Acid Inhibits Hepatitis C Virus Replication and Acts in Synergy With Cyclosporin A and Interferon-α

Chronic hepatitis C virus (HCV) infection is the leading indication for liver transplantation. Clinical evidence suggests that particular immunosuppressive agents can have an influence on HCV recurrence. Cyclosporine A (CsA) specifically inhibits HCV replication through blocking the viral RNA polymerase enzyme NS5B. In this study, we investigated the effect of mycophenolic acid (MPA) and other immunosuppressants on HCV replication. MPA and other compounds were tested in vitro using an HCV-replication model containing a luciferase reporter gene. At clinically relevant concentrations (1.0-6.0 microg/mL), MPA inhibited HCV replication to approximately 75%. CsA and interferon (IFN)-alpha also showed inhibition in a dose-dependent manner. In these short-term (18 hours) experiments, MPA did not inhibit cell proliferation or induce cell death, which could have accounted for the antiviral effect. In contrast to the antiviral activity of MPA against West Nile virus, the effect of MPA on HCV replication was guanosine independent. When combined, MPA and CsA showed significant synergistic inhibition of replication, reaching maximum inhibition of approximately 90% at the highest doses. Synergistic effects were observed with suboptimal concentrations of IFN-alpha with MPA or CsA. The kinetics of HCV inhibition by MPA, CsA, and IFN-alpha were clearly distinct, with earliest effects seen with IFN-alpha. No specific inhibitory effects were observed with tacrolimus or rapamycin. The immunosuppressive drug MPA is as potent as CsA as an inhibitor of HCV replication. MPA was shown to have a distinct anti-HCV mechanism of action, independent of cell proliferation and guanosine depletion.

Early recurrence of hepatitis C virus infection after liver transplantation

1. Early recurrence of hepatitis C is universal. 2. Typical histopathologic features of hepatitis C virus (HCV) and acute allograft rejection (AAR) exist. 3. Early recurrent HCV may be differentiated from AAR. 4. Liver biopsy plays a role in diagnosing HCV and AAR. 5. Risk factors for recurrent HCV should be known. 6. The natural history of recurrent HCV should be known. 7. The future role of ancillary studies beyond liver biopsy is assessed.

Donor-specific hyporesponsiveness in ELISPOT assay is associated with early recurrence of hepatitis C in liver transplant recipients

Recurrence of hepatitis C in liver transplant recipients is a common event that often leads to loss of the allograft. There are no means to prevent, or even predict, those patients who are more prone to early aggressive recurrence. Therefore there is an increased need for tailored immunosuppression protocols specific to this patient population. Fifteen liver transplant recipients (eight hepatitis C virus [HCV]+; 7 HCV−) were followed for 12–24 months after transplantation. The frequency of donor-specific interferon (IFN)-γ– or interleukin-10–producing lymphocytes was monitored using ELISPOT assays. Of the eight HCV+ recipients, six experienced recurrence within the first year after transplant. All six patients had very low (negligible) frequency of donor-specific IFN-γ precursors; in most cases not higher than the nonstimulated (spontaneous) secretion rate. The other two patients who did not recur exhibited donor-specific IFN-γ reactivity. A significant difference in the frequency of alloantigen-specific T cells was observed between HCV+ recipients and patients with other indications for transplantation. The results of this preliminary study suggest that posttransplant monitoring of the frequency of donor-specific IFN-γ–producing precursors may differentiate a subset of patients at risk for early recurrent hepatitis C and therefore may help to devise treatment strategies for HCV+ liver recipient after transplantation.

Impact of mycophenolate mofetil versus azathioprine on early recurrence of hepatitis C after liver transplantation

The aim of this study was to evaluate the impact of mycophenolate mofetil (MMF) on incidence, delay, severity and clinical course of early recurrent hepatitis C after liver transplantation (LT). A total of 21 hepatitis C virus (HCV)-positive patients after LT were prospectively enrolled in this study. All of them received a quadruple induction cyclosporine A (CsA)-based immunosuppression, augmented by MMF ( n=12) or by azathioprine ( n=9, AZA). MMF tended to delay recurrent disease (50±35 versus 35±35 weeks, P=0.5) with significantly lower levels of aminotransferases ( P<0.05). Furthermore, patients under MMF revealed less severe allograft fibrosis at disease recurrence (stage of fibrosis: 1.5±0.5 versus 2.2±1.2; P=0.07). But stage of fibrosis significantly increased in the MMF-group ( P<0.05) during 6 months of antiviral treatment. Three patients in the MMF-group and none of the controls suffered from severe fibrosing cholestatic recurrent hepatitis C. Initial post-LT administration of MMF tended to delay recurrent hepatitis C and to limit initial HCV-related biochemical and morphological graft dysfunction. But during clinical follow-up, its immunosuppressive capabilities exceeded possible antiviral properties, finally leading to significant progression of graft fibrosis. Thus, concomitant dose reduction of other basic immunosuppressants might be useful in this clinical setting.

LIVING DONOR LIVER TRANSPLANTATION BETWEEN IDENTICAL TWINS FOR HCV LIVER CIRRHOSIS: 2 CASES REPORT

P478 Aims: Hepatitis C virus (HCV)-related disease is the most common indication for liver transplantation. However hepatitis recurs universally at early postoperational period after transplantation. The recurrence of HCV is accelerated in transplant recipients compared with other non-compromised hosts. Immunosuppression is believed to be one of the risk factors for recurrent HCV. We experienced two cases of living donor liver transplantation (LDLT) between identical twins performed without any immunosuppressive therapy including intraoperative bolus steroids. We report the kinetics of serum HCV RNA level and the clinical course of recurrent HCV in completely immunosuppresion free LDLT, which is the clue to understand the natural course of recurrent HCV after liver transplantation without influence of immunosuppression. Methods: Case 1: The patient was a 51-year-old man with the diagnosis of HCV liver cirrhosis and multiple hepatcellular carcinoma. MELD score was 6. Case 2: The patient was a 39-year-old man with the diagnosis of HCV liver cirrhosis. MELD score was 11. In both cases, HCV genotype was 1b. Both recipients received the right lobe graft from their identical twins. Serum was examined for HCV-RNA (Quantitative PCR) and transaminases. When recurrence of hepatitis was histologically proven, antiviral therapy (interferon 2α plus ribavirin) was started. Results: In both cases, the postoperative course was uneventful, however, severe viremia occurred within 2 weeks (shown in figure 1), and the liver biopsy showed recurrent hepatitis one month after transplantation. In case 1, the antiviral therapy was dramatically effective; HCV-RNA was eradicated from blood stream within 2 weeks, and continued to be negative. The liver biopsy at 8 months after transplantation showed no sign of hepatitis. In case 2, serum HCV RNA level has been decreasing to be negative under the antiviral therapy.FigureConclusions: Immunosuppression is believed to exacerbate posttransplant HCV recurrence. However, our cases suggest that the avoidance of immunosuppressants can not prevent early replication of HCV virions or early recurrence of hepatitis. The possible explanations include the complete HLA matching between donor and recipient and graft regeneration as a factor affecting viral replication.

Role of cytokine gene polymorphism and hepatic transforming growth factor β1 expression in recurrent hepatitis C after liver transplantation

Recurrent hepatitis C virus (HCV) infection after orthotopic liver transplantation (OLT) is nearly universal. Cytokines play an important role in the immune response to viral infection, and cytokine gene polymorphism affects the overall expression and secretion of cytokines. The objective of this study was to define the relationship between cytokine polymorphism and recurrent hepatitis C after OLT. Blood samples were collected from 36 patients at a mean of 44.6±30.4 months after OLT for chronic HCV infection. DNA was extracted from peripheral blood mononuclear cells, and polymerase chain reaction-sequence specific primers (PCR-SSP) analysis was performed on promoter sequences of transforming growth factor β1 (TGF-β 1), interleukin 6 (IL-6) interleukin 10 (IL-10), tumor necrosis factor α (TNF-α) and interferon γ (INF-γ). Liver biopsies performed at diagnosis of recurrent disease were graded with the Knodell score, and hepatic TGF-β 1 expression was determined semiquantitatively by immunohistochemistry. The gene polymorphism of TGF-β 1 was correlated with its expression on hepatocytes and sinusoids. Polymorphism in all studied cytokine genes was correlated with recurrence, and interval to recurrence (>12 or ≤12 months post-OLT), and clinical (ascites, Child–Pugh score and death), biochemical parameters of recurrent HCV (serum alanine aminotransferase (ALT)), INR, albumin, bilirubin), and virological parameters (HCV genotype and load). Biopsies revealed recurrent HCV in 31 patients (86.1%); in 21 (67.7%), the interval to recurrence was 12 months. There was a statistically significant correlation between TGF-β 1 gene polymorphism, i.e., the genetic ability to produce high levels of TGF-β 1, and the intensity of TGF-β 1 staining on hepatocytes ( p=0.003) and sinusoids ( p=0.003), and the degree of fibrosis ( p=0.02). A borderline correlation was found with the presence of ascites ( p=0.07), but not with Child–Pugh score, synthetic liver function tests or HCV genotype and load. The genetic ability to produce low levels of IFN-γ was correlated with recurrent disease ( p=0.015). No such correlation was found for TGF-β 1 gene polymorphism. In conclusion, polymorphism in the TGF-β 1 gene correlates with its in situ hepatic expression in patients with recurrent HCV after liver transplantation. INF-γ, but not TGF-β 1 gene polymorphism, correlates with early recurrent hepatitis C after transplantation. These findings might help to design preemptive prevention therapy in selected patients at risk.

Utilization of Acidophil Bodies in the Diagnosis of Recurrent Hepatitis C Infection after Orthotopic Liver Transplantation

The distinction between acute rejection and early recurrent hepatitis C infection (RHCV) in the setting of orthotopic liver transplantation is often difficult. In liver biopsies acidophil bodies and lobular hepatitis are used to suggest a diagnosis of RHCV over rejection, however, the reliability of this practice has not been established. Because portal tract changes in RHCV and rejection often overlap, we sought to determine whether the degree of hepatocyte acidophil body formation seen on liver biopsies could be used to distinguish between these two conditions. Methods: Quantification of acidophil bodies was performed on liver biopsies in orthotopic liver transplant patients with RHCV (n = 10), non-hepatitis C orthotopic liver transplant patients with uncomplicated rejection episodes (n = 10) and non-transplant patients with chronic hepatitis C infection (n = 10). Hematoxylin and Eosin stained slides from all three groups were randomized and tissue segments 1.0 cm in length and of variable width (0.04–0.13 cm) were examined at 200 × magnification in a blinded fashion by two pathologists in order to quantify the number of acidophil bodies/cm2. Lobular chronic inflammation was also graded on a 0–3+ scale. Results: Liver biopsies taken at the onset of RHCV exhibited 606 ± 101 acidophil bodies/cm2 (mean ± standard error of mean, range 200–1390). These counts were significantly greater (P = .0061, paired 2-tailed t-test) than the 241 ± 53 acidophil bodies/cm2 (range 80–514) for acute rejection, and the 194 ± 21 acidophil bodies/cm2 (range 100–333) for non-liver transplant chronic hepatitis C infection (P = .0013). No difference in lobular inflammation between index RHCV and rejection biopsies was detected. Conclusions: Although there is overlap, on average there are twice as many acidophil bodies in the initial stage of RHCV when compared with acute rejection (average of 55 per linear cm in RHCV versus 21 per linear cm for rejection). Lobular inflammation was not a reliable indicator of the initial onset of RHCV.

Anti-interleukin-2 receptor therapy in combination with mycophenolate mofetil is associated with more severe hepatitis C recurrence after liver transplantation.

The pathogenesis of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is poorly understood, but the cellular immune response is likely to have a major role. Daclizumab, an interleukin-2 receptor (IL-2R) antibody that blunts T-cell activation, leading to a decreased risk for cellular rejection, is used frequently in transplant recipients. The aim of this study is to evaluate the effect of daclizumab therapy on the incidence and severity of recurrent HCV. Forty-one liver transplant recipients (21 patients, HCV positive; 20 patients, HCV negative) at high risk for neurological or renal complications of calcineurin inhibitors were administered daclizumab, mycophenolate mofetil (MMF), and steroids in the early post-LT period, followed by tacrolimus and a steroid taper. All patients were followed up prospectively for graft function and disease recurrence with protocol liver biopsies day 7, month 4, and yearly. Compared with patients without HCV, patients with HCV administered daclizumab had greater 4-month serum alkaline phosphatase, total bilirubin, and alanine aminotransferase (ALT) levels. These biochemical differences resolved by 12 months, except for persistent elevation of ALT levels. Compared with a well-matched HCV control population, patients with HCV administered daclizumab were more likely to have an earlier onset of hepatitis, jaundice, and greater histological activity. Recurrent hepatitis progressed more rapidly in the daclizumab group; 45% developed advanced disease within 1 year. HCV viral load in the daclizumab group was significantly greater at both 4 months and 1 year. Results of this study suggest that the use of adjuvant IL-2R antibodies in combination with MMF in the early peritransplantation period may be associated with early recurrence of hepatitis C and more rapid histological progression of disease.

Serum hepatitis C virus RNA levels and histologic findings in liver allografts with early recurrent hepatitis C.

Histopathologic features of early recurrent hepatitis C after orthotopic liver transplantation (OLTx) may be modified by immunosuppressive therapy or complicated by other conditions. Hepatitis C virus (HCV) RNA level usually increases after OLTx, but its correlation to histologic findings is not clear. To evaluate the histologic findings of early recurrent hepatitis C in liver allografts and its correlation to serum HCV RNA level. We studied 14 patients who underwent OLTx for chronic HCV infection. Thirty liver biopsy specimens and HCV RNA levels of 22 corresponding plasma samples obtained during the first 6 months following OLTx were analyzed. The control group (9 patients, 25 biopsy specimens) was chosen at random from patients with chronic liver disease other than HCV who were undergoing OLTx, and all tested negative for HCV RNA by polymerase chain reaction after OLTx. Statistically significant pathological features of early recurrent HCV infection were the number of acidophilic bodies, piecemeal necrosis, lymphocyte predominance in the portal tracts, and fibrous septum. These findings and histologic activity index scores increased with time after OLTx. The HCV RNA levels determined by branched DNA assay showed no significant correlation with histologic features. However, patients with higher histologic activity index scores tended to have higher RNA levels. Liver biopsy specimens are helpful for the diagnosis or confirmation of early recurrent hepatitis C in liver allografts, but serial biopsy specimens are sometimes required for definite diagnosis. The HCV RNA levels are usually higher in patients who display signs of more severe liver damage.

Serum hepatitis C virus RNA levels and histologic findings in liver allografts with early recurrent hepatitis C.

Abstract Background.—Histopathologic features of early recurrent hepatitis C after orthotopic liver transplantation (OLTx) may be modified by immunosuppressive therapy or complicated by other condi...

DACLIZUMAB (ZENAPAX) IS EFFECTIVE IN PREVENTION OF ACUTE REJECTION IN LIVER TRANSPLANTATION ONLY IN COMBINATION WITH CALCINEURIN INHIBITORS.

88 Daclizumab is a humanized monoclonal antibody directed against the ∝ chain of the IL-2 receptor. Previous studies have demonstrated its efficacy in preventing rejection in renal transplantation. Its efficacy has been associated with a paucity of adverse effects, including a lack of neuro- and nephrotoxicity. Currently, we have reviewed our experience with the use of daclizumab in liver transplant recipients. Thirty-two patients were given daclizumab as induction therapy in the setting of hepatic transplantation. Seven of these patients were enrolled in a prospective, IRB approved pilot study to determine the efficacy of induction with daclizumab in conjunction with corticosteroids and mycophenolate mofetil (MMF) WITHOUT the use of calcineurin inhibitors (C.I.). These patients were given two perioperative doses of daclizumab (1 mg/kg in the operating room and 1 mg/kg on postoperative day 1). The recipients were also given MMF 1500 mg po bid, and methylprednisolone. The other twenty-five patients had various indications for daclizumab including preexisting renal insufficiency (n=17), a desire to avoid MMF (n=3), neurologic conditions (n=2), and others (n=3). The period of follow up ranged from 1 to 12 months. Results: The prospective pilot study was halted after the first seven patients were enrolled because of an unacceptably high rate of rejection (7/7=100%). Of note, in this study, a significant proportion had severe steroid resistant rejection (4/7=57%), with two patients not responding to OKT3. Three patients also had a histologic finding of centrilobular necrosis, vascular or antibody mediated rejection. After their rejection episodes, these patients were all eventually started on a calcineurin inhibitor. In this study, the C.I. was given at a mean of 36 days postop. One patient died with recurrent hepatitis C and chronic rejection, and another has been relisted for transplant because of chronic rejection. Of note, the daclizumab levels and saturation of IL-2 receptors on peripheral blood lymphocytes were suboptimal in these patients. Overall, 16/32 patients (50%) had at least one biopsy proven episode of rejection. Interestingly, in five of these cases of rejection (31%), centrilobular ballooning and necrosis was seen. Excluding the seven pilot study patients that originally did not receive calcineurin inhibitor, 9/25 (36%) had at least one episode of rejection. In the recipients that suffered from rejection (n=16), the mean number of days postoperatively that calcineurin inhibitor was given was 23 days. In the recipients (n=16) that did not suffer from rejection, calcineurin inhibitor was given at an average of 5 days post op. Conversely, in patients who received their first dose of C.I. beyond postoperative day 8 had a rejection rate of 91% (10/11) vs. those patients receiving C.I. within eight days post transplant whose rejection rate was 29% (6/21). In the patients with renal insufficiency, the rejection rate was 35% (6/17 patients). None of these patients had steroid resistant rejection, and were easily treated with corticosteroids and increased C.I. dosing. Significant infectious complications were rare, and included 2 cases of invasive CMV, and 2 cases of early recurrent hepatitis C. Conclusions: Daclizumab used with the above dosing regimen in the absence of C.I. appears ineffective and possibly predisposes patients to steroid resistant rejection. However, it can be used safely and effectively in patients with preexisting or postoperative renal dysfunction in conjunction with low doses of C.I. given within the first week postoperatively.

Serum HCV RNA levels and histological findings in early recurrent hepatitis C in liver allografts: [formula omitted] Stratton-Popper Dept. of Pathology and Depts. of Surgery∗ and Internal Medicine #, The Mount Sinai Medical Center, New York, NY

Serum HCV RNA levels and histological findings in early recurrent hepatitis C in liver allografts: [formula omitted] Stratton-Popper Dept. of Pathology and Depts. of Surgery∗ and Internal Medicine #, The Mount Sinai Medical Center, New York, NY

Severe or multiple rejection episodes are associated with early recurrence of hepatitis C after orthotopic liver transplantation

Recurrent hepatitis C causes significant morbidity after liver transplantation. Because immunosuppression is associated with enhanced viral replication, we postulated that clinical recurrence of the disease may be associated with augmented immunosuppression for rejection. In 96 patients with hepatitis C who received liver transplants, we recorded the interval from transplantation to recurrence, the episodes of steroid-resistant rejection (SRR) requiring OKT3, the number of rejection episodes, and the use of OKT3 induction. Recurrence was diagnosed based on elevated transaminases and characteristic histology. Hepatitis C recurred in 43 of 96 patients. Fifteen of 21 patients (71.4%) who previously had SRR had recurrence, versus 28 of 75 patients (37.3%) who either had no SRR (72 patients) or had it after recurrence was diagnosed (3 patients) (P < .01). Mean time to recurrence was 127 +/- 31 days in the 15 patients who had had SRR versus 246 +/- 42 days in the other 28 patients (P = .02). Recurrence and number of rejection episodes were clearly associated: 6 of 33 patients (18.2%) with no rejection had recurrence (P < .05), versus 11 of 26 patients (42.3%) with one rejection episode (P < .05) and 26 of 37 (70.2%) with more than 1 episode (P < .05). OKT3 induction was used in 15 patients; 9 of 15 patients had recurrence (ns) at 337 +/- 95 days. Of 72 patients who initially received triple immunosuppression, 30 patients had recurrence at 186 +/- 25 days (P = .05). Nine patients received primary FK506; 4 had recurrence at 68 +/- 14 days.(ABSTRACT TRUNCATED AT 250 WORDS)