Alfredo Marzano

Prevention of hepatitis B virus recurrence after liver transplantation in cirrhotic patients treated with lamivudine and passive immunoprophylaxis

BACKGROUND/AIMS Treatment with hepatitis B virus immune globulins (HBIG) or lamivudine has reduced the rate of hepatitis B recurrence after liver transplantation to approximately 50%. METHODS To further decrease hepatitis B recurrence, 33 hepatitis B virus (HBV)-related cirrhotic patients were treated with lamivudine before liver transplantation and with lamivudine together with low-dose HBIG (46 500 IU the first month followed by 5,000 lU/monthly) after surgery. RESULTS While on lamivudine, serum HBV DNA level decreased significantly in all patients and in 11 (33%) the Child-Pugh score improved. Twenty-six patients were transplanted. Among the 25 who survived for longer than 12 months, only one (4%) experienced a hepatitis B recurrence over an average follow-up of 31 months, a rate significantly lower (P = 0.0002) than the 50% recurrence rate among a historical control group of 12 patients. However, low-level HBV replication was detected sporadically throughout the follow-up in 64% of patients. CONCLUSIONS Over the medium-term, combined prophylaxis with lamivudine and HBIG significantly decreases the risk of hepatitis B recurrence after liver transplantation. Though low-level HBV infection recurred in two thirds of patients, the pathogenic expression of HBV was prevented.

Reliability of transient elastography for the detection of fibrosis in Non-Alcoholic Fatty Liver Disease and chronic viral hepatitis

BACKGROUND & AIMS Transient elastography (TE) is validated in chronic hepatitis C (CHC) to evaluate hepatic fibrosis; however, limited data are available in chronic hepatitis B (CHB) and non-alcoholic fatty liver disease (NAFLD). This prospective study is aimed to assess the accuracy and the efficacy of TE for the detection of fibrosis in patients with chronic liver disease of different etiology and to evaluate the effect of steatosis on the liver stiffness measurement (LSM). METHODS TE was performed in 219 consecutive patients with chronic liver disease (35% CHC, 32% CHB, and 33% NAFLD) within 6 months of the liver biopsy. RESULTS LSM was related to the fibrosis stage in each group (CHC: p = 0.596, p < 0.001; CHB: p = 0.418, p < 0.001; NAFLD: p = 0.573, p < 0.001), but the correlation was less strong in CHB and NAFLD than in CHC patients. In CHB patients with histological cirrhosis (F4), the median stiffness value was almost two times lower than in patients with severe fibrosis (F3). In NAFLD patients with advanced fibrosis (F3) and severe steatosis (> 33%), the LSM values were lower than expected and were similar to those of patients with initial fibrosis (F1) and fat < 33%. TE underestimated the stage of fibrosis in 75% of patients with F3 and steatosis > 33%. At multiple logistic regression analysis, in CHC and CHB patients, LSM was the only predictive variable of severe fibrosis/cirrhosis (OR = 1.42, p = 0.003 and OR = 1.354, p = 0.003, respectively), while in NAFLD subjects BMI and AST (OR = 1.433, p = 0.002 and OR = 1.053, p = 0.020, respectively) but not LSM were independently related with advanced fibrosis and cirrhosis. CONCLUSIONS This study confirms that TE can be considered a valid support to detect fibrosis in chronic liver disease related to HCV but it should be interpreted cautiously in CHB and NAFLD patients, where host or disease-related factors may modify its accuracy.

Viral load at the time of liver transplantation and risk of hepatitis B virus recurrence

Hepatitis B virus (HBV) recurrence after liver transplantation is significantly reduced by prophylaxis with hepatitis B immune globulins (HBIG) or antiviral drugs in nonreplicating patients and by the combination of both drugs in replicating patients. However, the load of HBV DNA, which defines replicating status in patients undergoing liver transplantation, remains unclear. This study analyzes the correlation between the viral load, tested with a single amplified assay, at the time of liver transplantation, and the risk of hepatitis B recurrence in 177 HBV carriers who underwent transplantation in a single center from 1990 to 2002. Overall, HBV relapsed after surgery in 15 patients (8.5%) with a 5‐ and 8‐year actuarial rate of recurrence of 8% and 21%, respectively. After liver transplantation hepatitis B recurred in 9% of 98 selected subjects treated only with immune globulins and in 8% of 79 viremic patients who received immune globulins and lamivudine (P = NS). A linear correlation was observed between recurrence and viral load at the time of surgery. In transplant patients with HBV DNA higher than 100,000 copies/mL, 200–99,999 copies/mL, and DNA undetectable by amplified assay, hepatitis B recurred in 50%, 7.5%, and 0% of patients, respectively. Overall, a viral load higher than 100,000 copies/mL at the time of liver transplantation was significantly associated with hepatitis B recurrence (P = .0003). In conclusion, spontaneous or antiviral‐induced HBV DNA viral load at the time of surgery classifies the risk of HBV recurrence after liver transplantation and indicates the best prophylaxis strategy. (Liver Transpl 2005;11:402–409.)

Renal failure in cirrhotic patients: role of terlipressin in clinical approach to hepatorenal syndrome type 2

Objectives Renal failure secondary to hepatorenal syndrome or to organic renal disease occurs frequently in cirrhotic patients with portal hypertension. The present prospective study investigates the usefulness of terlipressin in both the diagnostic and the therapeutic approach to cirrhotics with renal failure. Patients and methods Sixteen patients were studied: 11 with hepatorenal syndrome type 2 (group 1) and five with organic renal disease (group 2). All received terlipressin (1 mg/4 h intravenously) for 7 days. Subsequently, 12 patients (nine from group 1 and three from group 2) underwent a transjugular intrahepatic portosystemic shunt. Results Terlipressin significantly improved renal function (serum creatinine, 1.8 ± 0.8 versus 2.4 ± 0.9 mg/dl; blood creatinine clearance, 53 ± 8 versus 21.3 ± 8.7 ml/min; P < 0.05) in group 1 [8/11 patients (73%) versus 1/5 (20%) of group 2; P < 0.05]. The only patient in group 2 who responded to terlipressin had a mixed renal dysfunction. Renal function improved significantly after transjugular portosystemic shunt in all patients who responded to terlipressin. Conclusions Terlipressin administration significantly improves renal function in cirrhotic patients with hepatorenal syndrome type 2 but not in organic kidney failure. By providing the critical information that a patients kidney function is (or is not) reversible, a trial with terlipressin may be useful when selecting cirrhotic patients with renal failure as candidates for a transjugular intrahepatic portosystemic shunt or liver transplantation.

Patterns of hepatitis delta virus reinfection and disease in liver transplantation.

Twenty-seven carriers of the hepatitis B surface antigen who underwent liver transplantation in Italy and Belgium for terminal Hepatitis delta virus (HDV) cirrhosis were investigated. In 22 of the patients, HDV infection recurred. Two patients died of coexisting HDV and hepatitis B virus (HBV) reactivation. Four patients who died of unrelated causes were found to have HDV without signs of HBV reactivation. Five patients (18%) cleared both HBV and HDV after transplantation with no evidence of hepatitis (mean follow-up, 29 months). In many surviving patients. HDV infection recurred early without signs of HBV reactivation. Disease returned in the 11 HDV-infected patients in whom HBV also recurred. Histological hepatitis did not recur during an interim of 12-33 months in the 5 HDV-infected patients in whom HBV did not return. The overall medium-term survival in patients with HDV who underwent transplantation was 77.7%. Liver transplantation offers patients with HDV a hope of cure from disease despite a high risk of reinfection. In the transplantation setting. HDV can cause subclinical infections without any apparent assistance from HBV; these infections become symptomatic only if and when HBV reactivates. Thus, HDV may not be in itself pathogenic but requires cooperation from HBV to cause the appearance of the disease.

Prophylaxis of hepatitis B virus recurrence after liver transplantation in carriers of lamivudine‐resistant mutants

The combination of lamivudine and hepatitis B immunoglobulin (HBIG) reduces the risk of hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, the efficacy of this strategy and the need for combined therapy with adefovir dipivoxil (ADV) in patients who select lamivudine‐resistant strains (YMDD) before surgery is still unknown. Twenty‐two patients treated with lamivudine (LAM) who underwent LT after YMDD‐mutant selection were studied. In 13 patients, YMDD mutants were associated with an HBV DNA breakthrough greater than 5 log10 (group A: phenotypic resistance), and 11 were treated with ADV to decrease viral load before LT. In the remaining 9 patients who did not experience the viral breakthrough, YMDD mutants were detected only retrospectively in sera stored at the time of LT (group B: genotypic resistance). During 35 months of post‐LT follow‐up, none of the 11 patients of group A treated with ADV before and after surgery (in addition to HBIG and LAM) had HBV recurrence, and neither did any of the 7 subjects of group B treated with LAM before and after transplantation (in addition to HBIG). HBV recurred in 2 patients of group A (untreated with ADV before surgery and transplanted with an HBV DNA exceeding 5 log10) and in 2 subjects of group B (who spontaneously stopped HBIG after surgery). In carriers of YMDD mutants, the risk of post‐LT HBV recurrence is low, provided that preemptive and prophylactic ADV (in addition to LAM and HBIG) treatment is used in highly viremic patients and prophylactic LAM (or ADV) and HBIG therapy is continued in low viremic patients. (Liver Transpl 2005;11:532–538.)

Liver transplantation for HBV-related cirrhosis in Europe: an ELTR study on evolution and outcomes.

BACKGROUND & AIMS HBV-related chronic liver disease is one of the most common indications for liver transplantation (LT) in Europe. The ELTR database was used to evaluate outcomes and evolution over 20 years (01/1988 and 12/2010). METHODS HBV transplanted patients were analysed according to indication for LT: decompensated cirrhosis (HBVdec) or hepatocellular carcinoma (HBV/HCC). These groups were compared with co-infected patients HBV/HDV (HBDV), HBV/HCV (HBCV), HBV/HDV/HCV (HBDCV); n = 16,664 and with HCV patients (n = 2452) according to LT indication. RESULTS 5912 patients were transplanted for HBV (78% HBVdec, 22% HBV/HCC), with HBV/HCC patients who increased from 15.8% in 1988-1995 to 29.6% in 2006-2010 (p < 0.001). In HBVdec patients, 1, 3, 5, and 10 year patient and graft survival was 83%, 78%, 75%, 68%, and 80%, 74%, 71%, 64%, respectively, significantly better than HBV/HCC (84%, 73%, 68%, 61%, and 81%, 70%, 65%, 58% respectively; p = 0.001 and p = 0.026). In 2006-2010 patient and graft survival significantly improved compared to 1988-1995, both for HBVdec and HBV/HCC (each p < 0.001). A better patient and graft survival was seen in HBV/HCC patients with HBV-DNA(-) compared to HBV-DNA(+) at the time of LT (p < 0.001). Disease recurrence, as cause of death/graft loss, was significantly reduced in recent years compared to the past: currently <1% for HBVdec and 3% for HBV/HCC. CONCLUSIONS Outcomes of LT for HBV have improved in recent years, with disease recurrence being no longer a significant cause of death/graft loss. HBV-DNA at the time of LT seems to influence survival only in HBV/HCC patients.

COBAS AmpliPrep-COBAS TaqMan Hepatitis B Virus (HBV) Test: a Novel Automated Real-Time PCR Assay for Quantification of HBV DNA in Plasma

ABSTRACT Success in antiviral therapy for chronic hepatitis B is supported by highly sensitive PCR-based assays for hepatitis B virus (HBV) DNA. Nucleic acid extraction from biologic specimens is technically demanding, and reliable PCR results depend on it. The performances of the fully automatic system COBAS AmpliPrep-COBAS TaqMan 48 (CAP-CTM; Roche, Branchburg, NJ) for HBV DNA extraction and real-time PCR quantification were assessed and compared to the endpoint PCR COBAS AMPLICOR HBV monitor (CAHBM; Roche). Analytical evaluation with a proficiency panel showed that CAP-CTM quantitated HBV DNA levels in one single run over a wide dynamic range (7 logs) with a close correlation between expected and observed values (r = 0.976, interassay variability below 5%). Clinical evaluation, as tested with samples from 92 HBsAg-positive patients, demonstrated excellent correlation with CAHBM (r = 0.966, mean difference in quantitation = 0.36 log10 IU/ml). CAP-CTM detected 10% more viremic patients and longer periods of residual viremia in those on therapy. In lamivudine (LAM)-resistant patients, the reduction of HBV DNA after 12 months of Adefovir (ADF) was higher in the combination (LAM+ADF) schedule than in ADF monotherapy (5.1 logs versus 3.5 logs), suggesting a benefit in continuing LAM. CAP-CTM detected HBV DNA in liver biopsy samples from 15% of HBsAg-negative, anti-HBcAg-positive graft donors with no HBV DNA in plasma. The amount of intrahepatic HBV DNA was significantly lower in occult HBV infection than in overt disease. CAP-CTM can improve the management of HBV infection and the assessment of antiviral therapy and drug resistance, supporting further insights in the emerging area of occult HBV infection.

Transplantation of hepatitis B surface antigen–positive livers into hepatitis B virus–positive recipients and the role of hepatitis delta coinfection

The scarcity of liver donors requires consideration of grafts from sources not previously used. Allografts from hepatitis B surface antigen (HBsAg)‐carriers without a significant liver disease have been proposed for liver transplant recipients with hepatitis B virus (HBV)‐related cirrhosis and hepatocellular carcinoma (HCC). Combination prophylaxis schemes against HBV post‐liver transplantation (LT) recurrence are currently available; the efficacy of those schemes in HBV‐related cirrhosis and HCC must be assessed. This report describes the allocation of HBsAg‐positive grafts in three HBsAg‐positive recipients, with HBV‐related cirrhosis and evolving HCC lesions, two of them with hepatitis Delta virus (HDV) coinfection. Patients were administered anti‐hepatitis B immunoglobulins (HBIGs) and lamivudine in order to prevent HBV recurrence. In spite of anti‐HBV prophylaxis, HBV infection did persist after LT in all patients (no serum clearance of HBsAg). HBV replication assessed by serum HBV deoxyribonucleic acid (DNA) presence was detected in the first month after LT in the 3 recipients. A prompt HDV reinfection with a clinical and histological pattern of hepatitis was observed in the 2 HBV / HDV coinfected recipients. In 1 of them, an evolving chronic hepatitis required a second LT. The non‐HDV–infected patient showed an uneventful follow‐up, but the lack of the neutralizing effect of HBIGs and the high risk of escape mutants forced the addition of adefovir‐dipivoxil to lamivudine, in order to prevent viral variants and hepatitis recurrence. In conclusion, allografts from HBsAg‐positive donors in HBsAg‐positive recipients are associated with the persistence of the HBsAg after LT due to the failure of HBIG prophylaxis, even if lamivudine does inhibit virion production. This condition favors HDV replication and HDV hepatitis recurrence in coinfected patients. The allocation of HBsAg‐positive grafts in HBsAg‐positive recipients could be justified only in recipients without HDV coinfection and a combined prophylaxis with lamivudine and adefovir‐dipivoxil is currently the best way to manage escape mutants in these recipients. (Liver Transpl 2005;11:922–928.)

Occult hepatitis B virus infection in HBsAg negative patients undergoing liver transplantation: Clinical significance

Occult Hepatitis B virus (o‐HBV) infection has been reported in HB surface antigen (HBsAg)‐negative liver donors whose risk of transmitting HBV justifies a specific prophylaxis in liver recipients. The clinical significance of o‐HBV infection in HBsAg‐negative recipients and their need for prophylaxis is unknown. Liver samples collected during surgery from 23 HBsAg‐negative patients (9 liver donors and 14 recipients) and 20 HBsAg‐positive recipients (controls) were studied by polymerase chain reaction with an independent set of primers mapping the core and surface HBV genes. Intrahepatic HBV DNA was detected as core and surface genes in all the HBsAg‐positive recipients, in none of the HBsAg‐negative donors and in 9/14 (64%) of the HBsAg‐negative recipients (2 HCV negative, 7 HCV positive). The intrahepatic amount of HBV was significantly lower in HBsAg‐negative than in HBsAg‐positive livers (median values 1.36 Log10/μg DNA vs. 3.66 Logs, p<0.0001, core gene, and 1.13 vs. 6.21 Logs p<0.0001, surface gene). No HBV DNA was detected in plasma from o‐HBV recipients; one of them tested positive in lymphocytes. No correlation was found between o‐HBV and serologic markers of previous HBV exposure, response to vaccination, acute rejection, hepatitis D and G virus‐infections. None of o‐HBV carriers experienced a de novo hepatitis B after transplantation (median follow‐up: 477 days). Occult HBV is frequent in HBsAg‐negative liver recipients. It is not associated with increased episodes of acute rejection, coinfection with hepatotropic viruses, different responses to HBV vaccination, or the development of de‐novo hepatitis B. In o‐HBV infection a particular virus‐host interaction can explain the low intrahepatic HBV content and the lack of extrahepatic HBV replication, thus justifying the low risk of hepatitis B reactivation, in absence of specific prophylaxis, once the recipient liver is removed. (Liver Transpl 2004;10:356–362.)