Hepatitis B Prophylaxis Using Lamivudine and Individualized Low-dose Hepatitis B Immunoglobulin in Living Donor Liver Transplantation

Background

Currently, most available experience concerning prophylaxis against hepatitis B virus (HBV) recurrence after living donor liver transplantation (LDLT) is limited to studies of small size and short follow-up. The objective of this study was to evaluate the efficacy of a prophylactic regimen using lamivudine and individualized low-dose intramuscular hepatitis B immunoglobulin (HBIG) in LDLT.

Methods

We used a database of adult-to-adult right-lobe LDLT procedures performed from June 2002 to April 2012 at our center for HBV-related end-stage liver diseases. Patients were divided into 3 groups: group A, HBV-related decompensated liver cirrhosis; group B, fulminant hepatitis B; and group C, hepatocellular carcinoma (HCC).

Results

During a mean follow-up of 38.3 ± 28.9 months, 8 of 165 (4.8%) recipients developed HBV recurrences. The mean time for HBV reinfection was 15.8 + 11.0 months after transplantation. The overall 1-, 3-, and 5-year HBV recurrence rates were 3%, 7%, and 8.2%, respectively. Both patients with fulminant hepatitis B or HCC seemed to have higher rates of HBV recurrence than those with decompensated liver cirrhosis, albeit not significantly. The independent predictor of HBV recurrence was high HBV DNA level (≥10⁵ copies/mL) at LDLT.

Conclusions

Lamivudine and individualized low-dose intramuscular HBIG provides effective prophylaxis against HBV recurrence after LDLT. Pre-LDLT HBV DNA of ≥ 10⁵ copies/mL was associated with HBV recurrence.     

Analysis of S Gene Mutation of the Hepatitis B Virus in Adult Liver Transplant Recipients Showing Resistance to Hepatitis B Immunoglobulin Therapy

Background

A considerable proportion of recipients of liver transplantations who are presented hepatitis B immunoglobulin (HBIG) monotherapy for hepatitis B virus (HBV) prophylaxis develop HBIG resistance. In this study, we investigated the mutation patterns in the major hydrophilic region (MHR) of amino acid sequences 100 to 160.

Methods

Using the gene sequence analyzer for amino acid sequences 0 to 226 in the S/pre-S region we analyzed blood samples of 15 patients showing HBIG resistance after high-dose HBIG prophylaxis.

Results

Various mutations in the MHR were observed in 14/15 samples: Gly145Arg mutation in 8/13 Adr subtype and 1/2 Ayw subtype samples (60%). The next most common mutation was Gly165Trp in 8/13 Adr subtype but neither of 2 Ayw subtype samples (53.3%). Concurrent antiviral resistance was noted in 5 patients: lamivudine (n = 5), or entecavir (n = 3), but not adefovir, suggesting the occurrence of simultaneous, antiviral cross-resistances. Two patients underwent retransplantation due to the progression of HBV infection despite vigorous antiviral therapy. At diagnosis of HBV recurrence, the mean HBV DNA load was 6.5 × 10⁶ copies/mL; 4 patients showed paradoxical coexistence of anti-HBs and HBsAg. Currently, 2 subjects show low-level HBV DNA replication in peripheral blood, although the other 12 had no DNA replication after prolonged antiviral therapy.

Conclusions

This study suggested that various mutations in the “a” determinant were associated with HBIG resistance. Since treatment failure to rescue antiviral therapy was often associated with delayed detection of HBV recurrence rather than concurrent antiviral resistance, frequent HBV surveillance using more sensitive screening tests, such as HBeAg and HBV DNA polymerase chain reaction assay, seems to be mandatory.     

High Viremia,Prolonged Lamivudine Therapy and Recurrent Hepatocellular Carcinoma Predict Posttransplant Hepatitis B Recurrence†

Hepatitis B virus (HBV) recurrence following orthotopic liver transplantation (OLT) is generally preventable by prophylaxis with hepatitis B immunoglobulin (HBIG) and lamivudine (LAM). However, HBV recurrence sometimes develops despite prophylaxis. This study assessed posttransplant outcomes and identified predictors of HBV recurrence. We analyzed the outcomes of 209 consecutive patients positive for hepatitis B surface antigen who underwent OLT, who received either combination prophylaxis with HBIG and LAM (89.0%) or HBIG monoprophylaxis (11.0%). The median follow‐up was 36.8 months (range, 1.0–84.4). Posttransplant HBV recurrence occurred in 22 patients (10.5%), including 13 patients with drug‐resistant mutations. HBV recurrence was observed in six patients after hepatocellular carcinoma (HCC) recurrence. Independent predictors of HBV recurrence were recurrent HCC (p < 0.001), LAM therapy >1.5 years (p = 0.001) and high HBV DNA titers (≥10⁵ copies/mL) at OLT (p = 0.036). In conclusion, high viremia at OLT and prolonged exposure to LAM should be further stressed as main predictors of HBV recurrence.     

Liver Transplantation in Lymphoma Patients With Hepatitis B Virus Reactivation

Background

Acute-on-chronic liver failure (AoCLF) occurs in lymphoma patients because of hepatitis B virus (HBV) reactivation. We aimed to identify characteristics of patients who underwent liver transplantation (OLT) because of AoCLF that occurred due to HBV reactivation in the setting of lymphoma and to compare these patients with AoCLF patients who did not have lymphoma.

Methods

Twenty patients underwent OLT due to AoCLF between February 2009 and June 2011. Among these patients, five were diagnosed with lymphoma before OLT and assigned to group 1. The remaining patients (n = 15) were assigned to group 2.

Results

Hospitalization after transplantation in group 2 was longer than in group 1 (P = .014). However, there were no differences in other variables between the two groups. The overall survival rate of group 1 was lower than that of group 2, but there was no difference between the two groups (P = .134). With the exception of one patient, the median time from complete remission to liver transplantation in group 1 was 4.5 months (range, 1–15) in group 1. Lymphoma recurrence occurred in one patient 8 months after transplantation.

Conclusion

Our study revealed that OLT is a feasible and effective approach in AoCLF due to HBV reactivation in select lymphoma patients.     

Network meta-analysis on prophylactic regimens against recurrent hepatitis B virus infection after liver transplantation

Background

Previous meta-analyses of non-randomized studies suggested that the hepatitis B immunoglobulin (HBIG) and lamivudine (LAM) combination therapy was significantly better than HBIG or LAM alone in preventing hepatitis B virus (HBV) recurrence after transplantation. However, substantial evidences supporting the superiority of combination therapy are still insufficient. Therefore, we sought to conduct a multiple-treatment comparison to integrate current data which was based on randomized controlled trials (RCTs).

Methods

We searched electronic databases of PubMed, Embase and the Cochrane Library for eligible literatures. Pair-wise meta-analyses were to synthesize studies comparing the same pair of treatments. Appropriate networks for overall and 1-year recurrence rates were established. Bayesian algorithm was used in multiple-treatment comparisons to compare relative effects of all included regimens.

Results

Four RCTs on prophylaxis against HBV recurrence after liver transplantation, involving 162 participants, were included. HBIG mono-therapy, LAM mono-therapy and HBIG plus LAM showed no statistically difference in risk ratios (RRs) in terms of overall HBV recurrence rate in network meta-analysis. Nevertheless, HBIG mono-therapy had potential advantage compared with combination of HBIG and LAM in 1-year HBV recurrence rate [RR 0.00, 95% confidence interval (CI): 0.00 to 0.91] while the rest comparisons revealed no significance. The cumulative probabilities of treatments associated with the highest recurrence were (overall HBV recurrence rate, 1-year HBV recurrence rate): HBIG (18%, 1%), LAM (32%, 42%) and HBIG plus LAM (50%, 57%).

Conclusions

This network meta-analysis based on data from RCTs showed no significant differences among HBIG mono-therapy, LAM mono-therapy, combination of HBIG and LAM in overall HBV recurrence rate after liver transplantation. Further well designed and large-scale RCTs are warranted to clarify these issues.     

Use of Grafts From Anti-HBc–Positive Donors in Liver Transplantation: A 5-Year,Single-Center Experience

Introduction

Liver transplantation (OLT) is the treatment of choice for advanced hepatic disease. The growing gap between waiting list patients and the number of donations has led to acceptance of less than optimal donors. The aim of this study was to evaluate the 5-year experience with anti hepatitis B core antigen (HBc)–positive liver donors.

Patients and Methods

All recipients of anti-HBc–positive grafts from January 2005 to December 2010 were evaluated annually after OLT for liver disease etiology, Model for End-Stage Liver Disease (MELD) score, and the presence of hepatocellular carcinoma (HCC) liver biopsy histology and serology for hepatitis B virus (HBsAg, anti-HBs, HBV-DNA), hepatitis C virus, and hepatitis D virus as well as antiviral prophylaxis to prevent de novo HBV.

Results

Among the 249 OLT performed from January 2005 to December 2010, (9.3%) cases used grafts from anti-HBc–positive donors. Etiologics of liver disease among the recipients were HBV (n = 13; 32.5%), HCV (n = 13; 32.5%) or other causes (n = 14; 35%). In 20 of the 40 patients (50%), HCC was found in the explanted organ. Of 40 recipients of anti-HBc–positive grafts 11 died, and 7 (17.5%) required retransplantation. Various regimens were employed as post-transplantation antiviral prophylaxis: (l) Immune globulin (25.8%); (2) Oral antiviral drugs (9.7%); and (3) combined prophylaxis (51.6%) or no treatment (12.9%). No difference was observed in patient or graft survival in relation to the etiology of liver disease, the MELD score, or the presence of HCC at the time of OLT, except graft survival was significantly reduced among recipient who underwent transplantation for non-HBV or non-HCV liver diseases compared with those engrafted due to viral hepatitis (P = .0062). No difference was observed in histologic features (grading and staging) compared with the antiviral prophylactic therapy; the 2 patients (5%) who developed de novo HBV had not received prophylaxis after OLT.

Conclusions

Matching anti-HBc–positive grafts to recipients without HBV infection before OLT, may be especially safe.     

Efficacy and safety of entecavir and/or tenofovir for prophylaxis and treatment of hepatitis B recurrence post-liver transplant

Aims

To establish the efficacy and safety of entecavir (ETV) and/or tenofovir (TDF) in the treatment and prevention of hepatitis B virus (HBV) recurrence after liver transplantation.

Patients and methods

Eight patients (four men) received treatment with ETV and/or TDF after liver transplantation as prophylaxis for HBV recurrence or as posttransplant treatment of HBV. Four liver transplants were in patients with HBV-associated cirrhosis who had received prior nucleos(t)ide analogue treatment until HBV DNA became undetectable. After transplantation, two of these four were treated with ETV + TDF and the other two with just TDF. All received intramuscular hepatitis B immunoglobulins. The reasons for the other four liver transplants were primary biliary cirrhosis in two cases, alcoholic cirrhosis, and hepatitis C virus. Two of the patients were donor anti-HBcAb-positive/recipient anti-HBcAb-negative. They received no anti-HBV prophylaxis so they had a recurrence of HBV. These four patients required treatment with ETV + TDF for the HBV DNA to become negative.

Results

The mean age was 60 (39-67) years. The mean follow-up was 9.5 (3-20) months. The mean follow-up of the patients who received prophylaxis was 8.2 (3-19) months. These had no HBV recurrence. The mean follow-up of the patients who received treatment for HBV recurrence was 12 (3-19) months. ETV combined with TDF was necessary for the HBV DNA to become undetectable because this was not possible using different nucleos(t)ide analogues. There were no significant adverse effects from these drugs and no alteration of renal function during the follow-up period.

Conclusions

Therapy with ETV and/or TDF seems to be efficient and safe when used in the prophylaxis and treatment of HBV recurrence after liver transplantation. They are well tolerated and seem to have no interactions with immunosuppressive medication.     

Effect of Dosage and Type of Hepatitis B Immunoglobulin on Hepatitis Antibody Levels in Liver Transplant Recipients

Background

The current study aimed to evaluate the effect of dosage and type (intramuscular [IM] vs intravenous [IV]) of hepatitis B immunoglobulin (HBIG) on hepatitis antibody level in liver transplant recipients.

Impact of Virologic Breakthrough and HBIG Regimen on Hepatitis B Recurrence After Liver Transplantation

The availability of hepatitis B immune globulin (HBIG) and several oral antiviral therapies has reduced but not eliminated hepatitis B virus (HBV) recurrence. We aimed to determine the rate of HBV recurrence after orthotopic liver transplantation (OLT) in relation to virologic breakthrough pre‐OLT and HBIG regimens post‐OLT. Data from the NIH HBV‐OLT database were analyzed. A total of 183 patients transplanted between 2001 and 2007 followed for a median of 42 months (range 1–81) post‐OLT were studied. At transplant, 29% were hepatitis B e antigen (HBeAg) (+), 38.5% had HBV DNA > 5 log₁₀ copies/mL, 74% were receiving antiviral therapy. Twenty‐five patients experienced virologic breakthrough before OLT. Post‐OLT, 26%, 22%, 40% and 12% of patients received intravenous (IV) high‐dose, IV low‐dose, intramuscular low‐dose and a finite duration of HBIG, respectively as maintenance prophylaxis. All but two patients also received antiviral therapy. Cumulative rates of HBV recurrence at 1 and 5 years were 3% and 9%, respectively. Multivariate analysis showed that listing HBeAg status and HBV DNA level at OLT were the only factors associated with HBV recurrence. In conclusion, low rates of HBV recurrence can be accomplished with all the HBIG regimens used when combined with antiviral therapy including patients with breakthrough pre‐OLT as long as rescue therapy is administered pre‐ and post‐OLT.     

Risk-Based Long-Term Screening for Hepatocellular Carcinoma Recurrence After Living Donor Liver Transplantation

Background

This study sought to establish an actual risk-based long-term screening protocol for hepatocellular carcinoma (HCC) recurrence after liver transplantation (OLT).

Methods

The study was a retrospective review of medical records from 334 HCC patients who underwent primary living donor OLT and followed up for at least 5 years.

Results

Overall 10-year patient survival rate was 67.5%, with a 4.8% perioperative mortality. HCC recurred in 68/318 (21.4%) surviving patients over a mean follow-up of 77 months. HCC recurrence was 20.7% at 5 and 22.2% at 10 years. Annual recurrence rates were 11.4%, 6.6%, and 2.0% during the first, second, and third years, respectively. Among patients within Milan criteria, the annual incidence of HCC recurrence was highest during the first 3 years; thereafter only 6 sporadic recurrences were observed during next 8 years. Among subjects beyond Milan criteria, recurrence was common during, but not after 3 years. In 43 patients (63.2%) increased alpha-fetoprotein (AFP) was an initial indication to perform further imaging studies to diagnosis recurrence, whereas they were detected incidentally on protocol screening imaging among another 25 patients (36.8%) in the absence of an AFP rise. There was a close correlation between pretransplant AFP level and AFP increase after HCC recurrence.

Conclusions

Patients beyond the Milan criteria require frequent tumor marker tests and imaging studies over the first 3 years; and those within Milan criteria require 10-years to follow-up primarily with tumor marker tests.     

Low risk of hepatitis B virus recurrence after withdrawal of long-term hepatitis B immunoglobulin in patients receiving maintenance nucleos(t)ide analogue therapy.

Hepatitis B virus (HBV) recurrence rates of 0-16% had been reported in patients maintained on nucleoside analogues (NA) after hepatitis B immunoglobulin (HBIG) discontinuation after orthotopic liver transplantation (OLT). However, follow-up in most studies was short. We aimed to determine the long-term risk of HBV recurrence using this strategy. All HBV patients who received > or =7 doses of intravenous HBIG after OLT, with no HBV recurrence while receiving HBIG, and who eventually discontinued HBIG and were maintained on NA, were included. HBV recurrence was defined as HBsAg-positive or HBV DNA > or =5 log copies/mL on 2 consecutive occasions. Twenty-one patients met the inclusion criteria. Immediate post-OLT prophylaxis was combination HBIG and NA in 15 patients, whereas 6 patients received HBIG monotherapy for 62-109 months before NA was added. HBIG was discontinued a median of 26 (range, 0.2-121) months after OLT. Median follow-up post-HBIG discontinuation was 40 (range, 5-51) months. Only 1 patient, who had 12 months of HBIG and was noncompliant to NA therapy, had HBV recurrence, 34 months after HBIG discontinuation. One patient had HBV DNA of 3.3 log copies/mL 47 and 48 months after HBIG discontinuation but remained HBsAg-negative. Lamivudine-resistant mutations were detected in both patients. Probability of HBV recurrence was 0% and 9% at 2 and 4 years after HBIG discontinuation. Three patients had 1-2 episodes of transiently detectable HBV DNA. All were HBV DNA and HBsAg negative on repeated tests over a period of 2-36 months. Maintenance therapy with NA after discontinuation of long-term HBIG therapy is associated with a low risk of HBV recurrence after OLT in compliant HBV patients.     

Liver Transplantation for Hepatocellular Carcinoma Within Milan Criteria in Patients With Model For End-Stage Liver Disease Score Below 15: The Impact of the Etiology of Cirrhosis on Long-Term Survival

Background

Liver transplantation (OLT) is the gold standard therapy for patients with cirrhosis complicated by hepatocellular carcinoma (HCC) within Milan Criteria (MC). We evaluated the impact of the etiology of the underlying liver disease on long-term outcomes of patients undergoing OLT for HCC within MC having a Model for End-stage Liver Disease (MELD) score < 15.

Methods

From November 2002 to December 2009, we performed 203 primary OLTs from brain-dead donors in recipients with HCC and cirrhosis with biochemical MELD scores below 15. We excluded 31 patients outside MC on the explant pathology of the native liver. The remaining 172 were divided into 3 groups according to the etiology of the underlying cirrhosis: hepatitis C virus-positive (HCV+; n = 78; 45%), hepatitis B virus-positive (HBV+; n = 65; 38%) and other indications (n = 29; 17%). The groups were compared for donor and recipient features, donor-recipient match, and transplant variables. The study endpoint was long-term patient survival.

Results

The groups were similar, except for a greater prevalence of hepatitis B core antibody-positive grafts in the HBV+ group and less frequent HCC bridging procedures in the other indications group. After a median follow-up of 72 months, HCC recurrence was observed in 8 (4.7%) patients (6 HCV+, 2 other indications), 5 of whom died. Overall 5-year patient survival of 82%, revealed significant differences among groups: 98.3% in HBV+, 67.1% in HCV+, and 85.8% in other indications (HBV+ vs other indications: P = .01; HBV+ vs HCV+: P = .0001; HCV+ vs other indications: P = NS). In the HCV+ group, recurrent HCV hepatitis was the most frequent cause of death. Upon multivariate analysis, HBV positivity in the recipient was an independent predictor of better patient survival (hazard ratio = 0.10, 95% confidence interval 0.02–0.64, P = .013).

Conclusions

Etiology of the underlying cirrhosis significantly influenced the long-term survival after OLT of patients with HCC within MC and MELD < 15. It should be taken into account in estimation of survival benefit.     

Laparoscopic Approach for Down-Staging in Hepatocellular Carcinoma Patients Who Are Candidates for Liver Transplantation

Introduction

The aim of this study was to assess the impact of laparoscopic thermoablation (LTA) and laparoscopic resection (LR) as neoadjuvant therapy before orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC).

Methods

From June 2005 to November 2010, 50 consecutive patients affected by HCC with liver cirrhosis were treated with LTA under ultrasound guidance or LR. Of them, 10 patients (mean age, 58.3 ± 5.59 years; male:female, 8:2) underwent OLT. They were mostly Child-Pugh class A (80%).

Results

A LTA of 12 nodules was achieved in 7 patients and an LR of 3 HCC nodules in the other 3 subjects. The mean length of surgery was 163 minutes (range; 60–370). The mean hospital stay was 6.1 days. Transient mild postoperative liver failure was reported in 1 case. Complete tumor necrosis was observed in 10 thermoablated nodules (83.3%) via spiral computerized tomographic scan at 1 month after treatment; the resected patients showed absence of recurrence. All patients underwent OLT after a mean interval of 7 months. The histology of the native liver showed complete necrosis in 9/12 thermoablated nodules (75%); a recurrence at surgical site occurred in 1 patient in the resection group.

Conclusions

Laparoscopic ultrasound can be used in potential OLTs candidates to accurately stage HCC in advanced cirrhosis with minimal morbidity. LTA and LR proved to be safe and effective techniques for HCC patients, representing a valid “bridge” to OLT.     

An Efficacy and Cost-Effectiveness Analysis of Combination Hepatitis B Immune Globulin and Lamivudine to Prevent Recurrent Hepatitis B After Orthotopic Liver Transplantation Compared With Hepatitis B Immune Globulin Monotherapy

Orthotopic liver transplantation (OLT) for hepatitis B virus (HBV) infection was limited until recently by poor graft and patient outcomes caused by recurrent HBV. Long-term immunoprophylaxis with hepatitis B immune globulin (HBIG) dramatically improved post-OLT survival, but recurrent HBV still occurred in up to 36% of the recipients. More recently, combination HBIG and lamivudine has been shown to effectively prevent HBV recurrence in patients post-OLT. The aim of the current study is to determine long-term outcome and cost-effectiveness of using combination HBIG and lamivudine compared with HBIG monotherapy in patients who undergo OLT for HBV. A retrospective chart review identified 59 patients administered combination HBIG and lamivudine and 12 patients administered HBIG monotherapy as primary prophylaxis against recurrent HBV. Lamivudine, 150 mg/d, was administered orally indefinitely. HBIG was administered under a standard protocol (10,000 IU intravenously during the anhepatic phase, then 10,000 IU/d intravenously for 7 days, then 10,000 IU intravenously monthly) indefinitely. A decision-analysis model was developed to evaluate the potential economic impact of prophylaxis against HBV with combination therapy compared with monotherapy. Recurrent HBV was defined as the reappearance of hepatitis B surface antigen (HBsAg) after its initial disappearance post-OLT. In the combination-therapy group, no patient redeveloped serum HBsAg or HBV DNA during mean follow-ups of 459 and 416 days, respectively. In the monotherapy group, 3 patients (25%) had reappearance of HBsAg in serum during a mean follow-up of 663 days. Combination therapy resulted in a dominant, cost-effective strategy with an average cost-effectiveness ratio of $252,111/recurrence prevented compared with $362,570/recurrence prevented in the monotherapy strategy. Combination prophylaxis with HBIG and lamivudine is highly effective in preventing recurrent HBV, may protect against the emergence of resistant mutants, and is significantly more cost-effective than HBIG monotherapy with its associated rate of recurrent HBV. (Liver Transpl 2000;6:741-748.)     

Expression Pattern Analysis of Hepatocellular Carcinoma Tumor Markers in Viral Hepatitis B and C Patients Undergoing Liver Transplantation and Resection

Background

This study was conducted to compare the expression patterns of serum alpha-fetoprotein (AFP) and proteins induced by vitamin K absence or antagonist-II (PIVKA-II) in hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) and resection at a high-volume single institution.

Methods

First, 663 liver transplant recipients with HCC were selected. They were divided into hepatitis B virus (HBV) (n = 628) and hepatitis C virus (HCV) groups (n = 35). Their medical records were retrospectively reviewed. Second, another cohort of 2709 patients who underwent HCC resection included 2258 HBV, 143 HCV, and 308 non-HBV non-HCV (NBNC) patients.

Results

In the transplantation group, pretransplantation AFP level >20 ng/mL was observed in 42.5% of HBV patients and 60% of HCV patients (P = .042). PIVKA-II level >40 mAU/mL was observed in 30.6% of HBV patients and 42.9% of HCV patients (P = .127). In the resection group, a preoperative AFP level >20 ng/mL was observed in 51.7% of HBV patients and 43.3% of HCV patients (P = .052). PIVKA-II level >40 mAU/mL was observed in 59.7% of HBV patients and 56.6% of HCV patients (P = .47). Preoperative AFP level >20 ng/mL and PIVKA-II level >40 mAU/mL were observed in 35.7% and 61% of NBNC patients, respectively. Receiver-operator characteristic curve analyses revealed that the expression pattern of PIVKA-II in patients with elevated AFP level was not predictable and vice versa, regardless of background liver diseases.

Conclusions

This study indicates that serum AFP and PIVKA-II may be expressed variably regardless of the types of background liver disease. Further large-volume multicenter studies are needed to evaluate the possibility of the etiology-dependent expression of tumor markers.     

Urgent Liver Transplantation for Chemotherapy-Induced HBV Reactivation: A Suitable Option in Patients Recently Treated for Malignant Iymphoma

Background

Hepatitis B (HBV) reactivation induced by chemotherapy is a problem currently encountered in the management of malignancies. HBV reactivation occurs particularly in patients who were not checked for HBV status, and therefore have not undergone antiviral prophylaxis. HBV reactivation may ultimately lead to fulminant liver failure (FLF). Liver transplantation (OLT), the only remaining effective treatment option, is generally denied for subjects with a recent history of malignancy.

Case Reports

We described retrospectively three cases of FLF caused by HBV reactivation in two men and one woman undergoing rituximab-containing chemotherapy for malignant lymphomas: follicular, diffuse large B-cell and lymphoplasmacytic types. The two men reactivated after eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone and the one woman after 13 cycles of rituximab monotherapy; their hematologic disease was in remission. All three patients were hepatitis B surface antigen (HBsAg)-positive with high HBV DNA levels. Neither man had been screened for HBV before chemotherapy; the woman had been treated with lamivudine (LAM) experiencing an HBV flare-up due to emergence of LAM resistance. All patients fulfilled King's College criteria for urgent OLT upon admission to the transplant center and underwent an urgent OLT. Their hemato-oncologic prognosis was considered to be favorable. All three patients are alive (54, 46, and 37 months post-transplantation), tumor-free and HBsAg negative on a standard HBV prophylaxis regimen: hepatitis B immunoglobulin and LAM + adefovir or tenofovir.

Conclusions

Before chemotherapy appropriate prophylaxis for HBV reactivation should always be administered to at-risk patients. However, if reactivation with FLF occurs, OLT should not be generally denied. The prognosis of the hematologic malignancy should be assessed; OLT should be considered for patients in remission with a favorable long-term prognosis, for our data suggest acceptable survival.     

Telbivudine Prophylaxis for Hepatitis B Virus Recurrence After Liver Transplantation Improves Renal Function

Introduction

Renal impairment after liver transplantation represents an important issue in the management of transplantation patients, particularly when those subjects may need prophylaxis for fungal or viral infection. Herein we report our experience with 12 transplantation patients receiving telbivudine 600 mg/d while on the waiting list, followed by treatment for 18 months after liver transplantation, showing an improvement on their renal function during the follow-up period.

Methods

Our series consisted of men with hepatitis B virus (HBV)–related end-stage liver disease. The viral load decreased rapidly while on the waiting list once the patient was started on antiviral treatment. Those subjects were compared with 12 patients on lamivudine prophylaxis. All patients were evaluated for liver and renal function, immunosuppression trough levels, and creatine phosphokinase (CPK) before liver transplantation (T0) and at 3, 6, 12, and 18 months (T3, T6, T12, T18).

Results

All patients received a calcineurin inhibitor immunosuppression-based regimen. Creatinine clearance (Modification of Diet in Renal Disease) was 67 mL/min at T0, with a statistically significant improvement after month 6 compared with those on lamivudine and with the value at the beginning of the prophylaxis (Mann-Whitney U test P < .05). Neither CPK nor transaminase serum levels increased throughout the study period. Once HBV DNA was cleared while on the waiting list, it remained negative throughout the follow-up period.

Conclusions

Telbivudine prophylaxis for HBV is safe and effective, without any significant deleterious effect on the liver; on the contrary, it seems to improve renal function after liver transplantation through 18 months. Further studies and larger series are warranted to confirm these findings.     

High Genetic Barrier Nucleos(t)ide Analogue(s) for Prophylaxis From Hepatitis B Virus Recurrence After Liver Transplantation: A Systematic Review

The combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues [NA(s)] is considered as the standard of care for prophylaxis against HBV recurrence after liver transplantation (LT), but the optimal protocol is controversial. We evaluated the efficacy of the newer NAs with high genetic barrier (hgbNA) [i.e. entecavir (ETV) or tenofovir (TDF)] with or without HBIG as prophylaxis against HBV recurrence after LT. In total, 519 HBV liver transplant recipients from 17 studies met the inclusion criteria and they were compared to those under lamivudine (LAM) and HBIG who had been selected in our previous review. Patients under HBIG and LAM developed HBV recurrence (115/1889 or 6.1%): (a) significantly more frequently compared to patients under HBIG and a hgbNA [1.0% (3/303), p < 0.001], and (b) numerically but not significantly more frequently compared to the patients who received a newer NA after discontinuation of HBIG [3.9% (4/102), p = 0.52]. The use of a hgbNA without any HBIG offered similar antiviral prophylaxis compared to HBIG and LAM combination, if the definition of HBV recurrence was based on HBV DNA detectability [0.9% vs. 3.8%, p = 0.11]. Our findings favor the use of HBIG and a hgbNA instead of HBIG and LAM combined prophylaxis against HBV recurrence after LT.     

Clinical Outcomes of Pneumocystis carinii Pneumonia in Adult Liver Transplant Recipients

Purpose

Pneumocystis carinii pneumonia (PCP) is an opportunistic infection associated with morbidity and mortality in solid-organ transplant recipients. We retrospectively assessed the characteristics and outcomes of liver transplant (OLT) recipients with PCP compared with those of patients with severe non-P carinii pneumonia (non-PCP) who required intensive care with mechanical ventilation.

Methods

During the 2-year period between January 2008 and December 2009, 43 adult OLT recipients had severe pneumonia requiring mechanical ventilation; of these, 8 (19%) had PCP. During this period, routine antibiotic prophylaxis was administered for the first 6 months after OLT.

Results

The median period from OLT to development of PCP was 9.5 months (range, 1–67); the 1-year incidence was 0.9%. The 6 and 6 to 12-month incidences of non-PCP were 4.2% and 0.3%, respectively, and those of PCP were 0.3% and 0.6%, respectively. Four of 8 patients (50%) in the PCP group had a recent history of a rejection episode. PCP was associated with a higher incidence of prior antirejection treatment. There were no significant differences between PCP and non-PCP groups in age, gender, preoperative Model for End-stage Liver Disease score, primary diagnosis, graft type, and total number of rejection episodes.

Conclusions

These results indicate that the risk of PCP in OLT recipients is closely related to strong immunosuppressive treatment for acute cellular rejection episodes, suggesting the importance of PCP prophylaxis in these patients. Because most patients developed PCP at around 1 year, it may be advisable to prolong routine post-OLT PCP prophylaxis for 12 months, especially among patients receiving antirejection treatment.     

Hepatitis B prophylaxis in hepatitis B-negative recipients transplanted with donor grafts positive for hepatitis B core antibodies

Background and aims

Use of grafts from hepatitis B (HBV) core antibody (HBcAb⁺) individuals is a routine transplant practice. Herein, we have reported the results of 20 HBV-negative patients transplantated with a HBcAb-positive liver grafts in order to access the efficacy of HBV prophylaxis using immunoglobulin (IE) and antiviral drugs.

Methods

From January 2004 to December 2009, we performed 168 liver transplantations including 38 HBcAb-positive grafts (22.6%) in 18 cases of HBV-positive recipients and 20 HBV-negative recipients. Histological data obtained from these last 20 grafts during retrieval showed an Ishak 1 score in three and no fibrosis in the other cases. HBV prophylaxis included infusion of 10,000 UI IG during the anhepatic phase and every 24 hours for the first 7 days irrespective of the antibody titer as well as lamivudin (100 mg) administred daily. Once discharged, outpatient management provided modulated IG infusions according to when the antibody titer was lower than 400 UI.

Results

No patient displayed an HBV infection. The overall survival was 80%. Two patients died within the first month after transplantation due to septic complications; one patient succumbed at 24 months after transplantation because of a lymphoproliferative malignancy and another died due to an aggressive hepatitis C virus recurrence at 6 months post transplant.

Conclusion

By using appropriate anti-HBV prophylaxis, HBcAb-positive grafts can be used safely for HBcAb-negative recipients.