Dual hepatitis virus infections in liver transplant: case report and a review of the literature

Abstract: Background: Liver transplantation (LT) using grafts from anti‐HBVcore antibody‐positive (anti‐HBVcAB+) donors carry risk for development of hepatitis B virus (HBV) infection. The long‐term course of hepatitis C virus (HCV) patients receiving anti‐HBVcAB+ grafts is poorly understood. Patients and methods: A patient with chronic hepatitis C received an anti‐HBVc+ graft and developed de novo hepatitis B after four months. We describe the 14 HCV patients who received antiHBVc+ grafts and the condition of disease. Results: Hepatitis B was treated successfully with lamivudine. One year later, breakthrough infection developed with a lamivudine‐resistant mutant. Addition of adefovir led to HBV surface antigen to surface antibody seroconversion after two yr, which was maintained long term. Antiviral therapy was discontinued. Liver biopsy revealed minimal histologic changes up to eight yr post‐LT. Survival of 14 recipients of antiHBVc+ allografts and 180 recipients of antiHBVc‐negative grafts was equal (minimum follow up of five yr). Liver biopsies at four yr showed grade 0/1 and stage 0/1 in >70%; only two patients showed bridging fibrosis. A literature review of dual hepatitis virus infection revealed an overall milder course of hepatitis post‐LT. Conclusion: The outcome of HCV patients receiving anti‐HBc+ grafts is good and may be associated with a milder course of recurrent HCV.     

Lamivudine monoprophylaxis for liver transplant recipients with non-replicating hepatitis B virus infection

Background: The aim of this study was to evaluate the efficacy of lamivudine (LAM) monoprophylaxis for patients with non-replicating hepatitis B virus (HBV) infection at orthotopic liver transplantation (OLT). METHODS: Among 128 liver recipients with HBV infection between 1994 and 2004 transplanted at our institution, 60 had non-replicating HBV infection at the time of OLT. Of those, 26 patients received LAM prophylaxis (monoprophylaxis group) and 34 patients received LAM and hepatitis B immunoglobulin (HBIG) prophylaxis (combination group) after OLT. RESULTS: Median follow-up after OLT was 67 and 54 months, for monoprophylaxis and combination groups respectively. One and five yr patient/graft survival were 96/85% and 96/80% in monoprophylaxis group, and 85/79% and 67/55% in combination group. HBV DNA was re-detected or increased >10(5) IU/mL in four patients (15%) at 20-29 month in monoprophylaxis group and six (18%) at 4-35 months in combination group. Recurrent hepatitis was seen in two patients (8%) at 27 and 45 months and monoprophylaxis group and three (9%) at 21-35 months in combination group. The rate of recurrence was not statistically different between two groups. CONCLUSION: LAM monoprophylaxis seemed to be effective for OLT recipients with HBV infection who had non-replicating HBV at transplantation. HBIG administration may play a less valuable role in preventing HBV recurrence in this group of patients.     

Long-term lamivudine monotherapy prevents development of hepatitis B virus infection in hepatitis B surface-antigen negative liver transplant recipients from hepatitis B core-antibody-positive donors

BACKGROUND: Liver transplantation from hepatitis B core-antibody (HBcAb)-positive donors to hepatitis B surface-antigen (HBsAg)-negative recipients has been associated with a risk of hepatitis B virus (HBV) infection in the absence of antiviral prophylaxis. The aim of this study is to assess the efficacy of long-term lamivudine monotherapy to prevent development of HBV infection in HBsAg-negative recipients of liver allografts from HBcAb-positive donors. METHODS: From 315 cadaveric adult liver transplantations performed at our unit between July 1999 and March 2005, 18 recipients (5.7%) received liver allografts from HBcAb-positive donors, 13 of whom were HBsAg-negative pre-transplantation. The recipients consisted of four females and 14 males, age range 28-65 yr (median 49.5 yr). Post-transplantation, HBsAg-negative recipients were administered lamivudine 100 mg daily long term. HBsAg-positive recipients were administered low-dose hepatitis B immunoglobulin (HBIg) and lamivudine according to our usual protocol. Standard post-transplantation immunosuppression was given. Recipients were followed up regularly (range 2-69 months, median 21 months) for development of de novo HBV infection. RESULTS: Ten HBsAg-negative recipients received long-term lamivudine. One patient (HBcAb and HBsAb positive pre-transplant) did not receive lamivudine and, in two patients, lamivudine was discontinued following urgent re-transplantation for primary graft non-function. All 13 of the HBsAg-negative recipients were still alive, with no evidence of HBV infection at the end of follow-up. CONCLUSION: Long-term lamivudine monotherapy was effective in preventing development of HBV infection in HBsAg-negative liver transplant recipients from HBcAb-positive donors.     

Emergency living related liver transplantation for fulminant reactivation of hepatitis B virus after unrelated marrow transplantation

We report a unique case of emergency living related donor orthotopic liver transplantation (OLT) for late fulminant reactivation of hepatitis B virus (HBV) after matched unrelated bone marrow transplantation (BMT) for chronic myeloid leukemia (CML). Cessation of lamivudine after BMT for HBV positive patients may carry risks of late fatal HBV reactivation. Similar to fulminant HBV reactivation in the general population, OLT under resumption of lamivudine can be life saving. In our case, concomitantly molecular relapse of CML at the time of liver failure was also cleared by OLT, possibly via a 'liver-graft vs. leukemia' effect. Liver rejection (graft vs. graft disease) was mild due to inherent immunocompromise of the marrow graft. Hence BMT recipients in stable remission should not be denied the opportunity for life-saving solid organ transplantation. A choice of marrow and liver donors with innate HBV immunity may be needed to give the additional advantage of long-term HBV clearance.     

Prevention of de novo hepatitis B virus infection in living donor liver transplantation using hepatitis B core antibody positive donors

Exclusion of liver grafts from hepatitis B core antibody (anti-HBc) positive donors to prevent de novo hepatitis B virus (HBV) infection after liver transplantation is not feasible in areas highly endemic for HBV virus like Taiwan, where approximately 80% of adults are anti-HBc(+). The efficacy of lamivudine monotherapy to prevent de novo HBV infection after living donor liver transplantation (LDLT) using grafts from anti-HBc(+) donors remains to be elucidated. From June 1994 to August 2000, LDLT was performed in 42 recipients. Twenty-four of the 42 donors were anti-HBc(+) (57%). Pre-transplant HBV vaccination was given to all recipients irrespective of anti-HBc status at monthly intervals for 3 months. Until December 1997, eight recipients received liver grafts from anti-HBc(+) donors without prophylaxis. Since January 1998, prophylaxis with lamivudine monotherapy was given to 16 recipients receiving liver grafts from anti-HBc(+) donors. De novo HBV infection occurred in three of the eight recipients (37.5%) who did not receive prophylaxis, while none of the 16 recipients given lamivudine developed de novo HBV infection after a mean follow-up of 25 months. Two of the three recipients with de novo HBV infection were anti-HBs(-) and one recipient was anti-HBs(+). Lamivudine was well tolerated, and no side effects were noted. These results suggest that lamivudine monotherapy for recipients receiving anti-HBc(+) liver grafts is a simple, relatively inexpensive and effective prophylactic regimen for prevention of de novo HBV infection. The additive protection provided by vaccine-induced or natural immunity is uncertain.     

Liver transplantation for HBsAg‐positive recipients using grafts from HBsAg‐positive deceased donors

This study reports our experience using deceased donor liver grafts from HBsAg‐positive donors. We performed eight cases of liver transplantation (LT) using grafts from deceased HBsAg‐positive donors between November 2005 and October 2010. The median age of donors was 48 years (range: 26–64). HBV DNA in the serum of donors ranged from 44 to 395 IU/ml, but HBeAg in all donors was negative. Preoperative laboratory and liver biopsy samples revealed the absence of definitive cirrhotic features and hepatitis. All recipients showed HBsAg positive preoperatively except one patient with HBsAg(?) status post previous LT for HBV related liver cirrhosis. The median age was 60 years (range: 46–76) at LT. Post‐LT antiviral management consisted of hepatitis B immunoglobulin and antiviral nucleos(t)ide analogues. The median follow‐up period was 25.5 months (range: 14–82). Of eight recipients, two recipients experienced serum HBsAg and HBV DNA disappearance postoperatively. Three recipients died of HBV‐unrelated causes. The remaining five recipients were stable with normal liver function and no marked pathologic changes on follow‐up biopsies. This experience shows that LT using grafts from deceased HBsAg‐positive donors is feasible, and may represent a valuable expansion of the pool of organ donors with appropriate antiviral management and monitoring.     

Active Immunization to Prevent De Novo Hepatitis B Virus Infection in Pediatric Live Donor Liver Recipients

This study aims to evaluate the efficacy of HBV vaccination as an alternative preventive measure against de novo HBV infection in pediatric living donor liver transplantation (LDLT). Sixty recipients were enrolled in this study. Thirty received grafts from anti-HBc(+) donors, and another 30 received grafts from anti-HBc(-) donors. HBV vaccine was given pretransplant to every candidate. Posttransplant, lamivudine was routinely given to recipients receiving anti-HBc(+) grafts for about 2 years. Forty-seven (78%) recipients achieved high levels of anti-HBs titer (>1000 IU/L). Two (3.3%) recipients developed de novo HBV infection where one received an anti-HBc(-) graft and another received an anti-HBc(+) graft. Both recipients were in the lower anti-HBs titer group (<1000 IU/L). The incidence of de novo HBV infection was significantly higher in the lower titer group (15.4% vs. 0%, p = 0.04). The median follow-up period was 51 months in recipients with anti-HBc(-) grafts and 57 months in those with anti-HBc(+) grafts. Active immunization is an effective method to prevent de novo HBV infection. It can result in high levels of anti-HBs titer (>1000 IU/L) which may prevent de novo HBV infection in pediatric patients with efficient primary vaccination undergoing LDLT.     

Natural History of Patients with Recurrent Chronic Hepatitis C Virus and Occult Hepatitis B Co-Infection after Liver Transplantation

It is uncertain whether occult hepatitis B virus co-infection will hasten progressive liver disease in chronic hepatitis C patients after liver transplantation. This study evaluated fibrosis progression and severe fibrosis in 118 consecutive hepatitis B surface antigen-negative patients with virological and histological evidence of recurrent chronic hepatitis C infection co-infected with occult hepatitis B virus after liver transplantation. HBV DNA was detected from serum at the time of recurrent chronic hepatitis C infection by polymerase chain reaction. Each subject underwent a repeat liver biopsy 5 years post-liver transplantation. Occult hepatitis B virus co-infection was present in 41 of the 118 (34.7%) patients. At 5 years post-liver transplantation, 13 of the 41 occult hepatitis B virus co-infected patients compared with 16 of the 77 patients without occult hepatitis B virus co-infection developed fibrosis progression (31.7% vs. 20.8%, respectively, p = 0.39). Eight of 41 the occult hepatitis B virus co-infected patients compared with 13 of the 77 patients without occult hepatitis B virus co-infection had severe fibrosis (19.5% vs. 16.9%, respectively, p = 0.97). In conclusion, occult hepatitis B virus co-infection in patients with recurrent chronic hepatitis C infection was not associated with accelerated fibrosis progression or severe fibrosis after liver transplantation.     

Risk of de novo hepatitis in liver recipients from hepatitis-B core antibody-positive grafts - a systematic analysis

Skagen CL, Jou JH, Said A. Risk of de novo hepatitis in liver recipients from hepatitis‐B core antibody‐positive grafts – a systematic analysis.
Clin Transplant 2011: 25: E243–E249. © 2011 John Wiley & Sons A/S. Abstract: Many transplant programs utilize liver grafts from hepatitis‐B core antibody (HBcAb)‐positive and hepatitis‐B surface antigen (HBsAg)‐negative donors. However, there is risk for de novo hepatitis B (DNH) in recipients of these grafts. We reviewed 26 studies reporting the rates of DNH in recipients receiving HBcAb‐positive liver grafts. Four hundred and sixty‐two donor–recipient pairs were included to evaluate the risk of DNH stratified by the recipient’s immune status to hepatitis B and type of prophylactic therapy given, if any. The rate of DNH was highest (58%) in the stratum of hepatitis‐B (HBV) naïve recipients who did not receive prophylaxis. In HBV naïve recipients, prophylactic therapy (lamivudine and/or hepatitis‐B immunoglobulin – HBIG) reduced DNH to 11% (odds ratio [OR] = 11.1, 95% CI 4.98–25, p < 0.0001 for DNH without prophylaxis). Recipients with hepatitis‐B surface antibody (HBsAb) positivity had DNH rates of 18% without prophylaxis and 0% with prophylaxis (OR = 9.2, 95% CI 1.1–83.3, p = 0.039). Recipients with both HBsAb and HBcAb positivity had DNH rates of 4% without prophylaxis and 3% with prophylaxis (p = 1.00), while recipients with HBcAb positivity alone had DNH rates of 14% without prophylaxis and 3% with prophylaxis (p = 0.21). There was no significant difference between the types of HBV prophylaxis received whether lamivudine, HBIG or both. However, in the subgroup who received HBIG alone, rates of DNH were higher after cessation of HBIG prophylaxis compared to DNH rates with indefinite HBIG (p = 0.0002). In summary, the risk of DNH is highest for HBV naïve liver recipients from HBcAb‐positive donors. Recipients who are HBV naïve as well as those recipients with isolated HBsAb positivity derive significant benefit from HBV prophylaxis after transplantation with a HBcAb‐positive graft. The ideal prophylactic regimen for prevention of DNH is unclear, but based on our analysis of the literature, antivirals alone may suffice. More data are needed with the newer antivirals for hepatitis B.     

Use of immune function test in monitoring immunosuppression in liver transplant recipients

Immune function test (Immuknow^?) is a measure of cell‐mediated immunity based on peripheral CD4⁺ T cell adenosine triphosphate activity (desired range, 225–525 ng/mL). We evaluated the role of immune function test (IFT) in monitoring and adjustment of immunosuppression in orthotopic liver transplant (OLT) recipients. A total of 289 IFTs were obtained from 171 patients from March 2007 to June 2008. Graft/patient status was classified as stable, serious infection, or malignancy. IFT levels were analyzed with duration of follow‐up after OLT, graft/patient status, and the presence of hepatitis C (HCV) infection. The mean age was 54 ± 14 yr, with 62% men. The median follow‐up was 65 (2–249) months. Mean IFT levels were significantly lower in patients who were <24 months than in those ≥24 months post‐OLT (220 ± 19.5 vs. 257 ± 11.3 ng/mL, p = 0.03). Clinically stable patients had higher IFT levels than those with serious infection or malignancy (254 ± 11.1 vs. 162.5 ± 23.9, p < 0.001). HCV‐infected patients had lower IFT levels than uninfected patients (206.7 ± 15.7 vs. 273 ± 12.0 ng/mL, p < 0.001). Immunosuppression was reduced in 58 patients with IFT levels <225 ng/mL, and 90% maintained stable graft function after a median follow‐up of 22 (1–39) months. IFT may be a useful tool in monitoring and lowering of immunosuppression in long‐term OLT recipients.     

Kidney Transplantation from Hepatitis B Surface Antigen Positive Donors into Hepatitis B Surface Antibody Positive Recipients: A Prospective Nonrandomized Controlled Study from a Single Center

The number of patients on renal transplant waiting list is increasing rapidly in many countries, exacerbating the shortage of organs. We conducted a study to evaluate the safety and efficacy of deceased-donor kidney transplantation from hepatitis B surface antigen (HBsAg)-positive (+) donors into hepatitis B surface antibody (anti-HBs)-positive (+) recipients. Sixty-five patients received grafts from HBsAg(+) donors, and 308 subjects received grafts from HBsAg-negative(−) donors. Posttransplantation, recipients with HBsAg(−) grafts or HBsAg(+) grafts received 400 U of hepatitis B immunoglobulin once and twice, respectively. The seven recipients who received grafts from hepatitis B virus (HBV) DNA(+) donors were treated with hepatitis B immunoglobulin 400 U weekly for 3 months and lamivudine 100 mg daily for 6 months. All patients were monitored for liver function and hepatitis B viral status. The follow-up period was 38.7 ± 15.4 months. Although two recipients developed de novo HBV infection, neither patient developed severe liver dysfunction nor died. The incidence of liver injury (39/65 vs. 207/308, chi-square test, p > 0.05) and survival (log-rank test, p > 0.05) did not differ between the groups. We conclude that anti-HBs(+) recipients receiving HBsAg(+) grafts did as well as those receiving HBsAg(−) grafts.     

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.     

Use of hepatitis B core antibody-positive donors in orthotopic liver transplantation

HYPOTHESIS: Hepatic allografts from donors positive for antibody to hepatitis B core antigen (anti-HBc) frequently transmit hepatitis B virus (HBV) infection to recipients. Therefore, most transplantation centers will not use these organs for orthotopic liver transplantation (OLT). Although it is expensive and not always efficacious, hepatitis B immune globulin (HBIG) has been used routinely for indefinite periods to prevent HBV infection in liver allograft recipients. We assessed the effectiveness of long-term use of a nucleoside analog, lamivudine, in preventing HBV transmission by anti-HBc-positive allografts. DESIGN: Retrospective study. SETTING: A tertiary care center. PATIENTS: Twelve patients received hepatic allografts from anti-HBc-positive donors at Loyola University Medical Center, Chicago, between February 23, 1998, and March 13, 2001. INTERVENTION: All patients received 10 000 U/d of intravenous HBIG for 7 days. In addition, they received 300 mg/d of lamivudine in divided doses. Their liver biopsy specimens were tested for HBV DNA, hepatitis B surface antigen (HBsAg), and hepatitis B core antibody (HBcAb). Serum samples from the donor and recipient were tested for HBcAb, HBV DNA, and hepatitis B surface antibody (HBsAb). MAIN OUTCOME MEASURE: The incidence of HBV infection in recipients who received HBcAb-positive donor livers and lamivudine prophylaxis. RESULTS: All recipients were anti-HBc negative before OLT. Five of the recipients had HBsAb titers greater than 150 U at the time of OLT. Three of the donor livers were HBV DNA positive and 2 were hepatitis B core antigen positive at the time of OLT. Donor serum was HBcAb positive in all 12 donors. None of the recipients have become infected with HBV with a follow-up of 2 to 38 months. CONCLUSION: Perioperative use of HBIG combined with long-term use of lamivudine can prevent HBV infection in recipients who receive hepatic allografts from HBcAb-positive donors.     

Lamivudine or lamivudine combined with hepatitis B immunoglobulin in prophylaxis of hepatitis B recurrence after liver transplantation: a meta-analysis

There is a controversy over whether the different outcomes of prophylaxis of hepatitis B virus (HBV) recurrence are attributable to different treatments. A systematic review and a meta-analysis were conducted to evaluate lamivudine monotherapy and combined therapy of lamivudine and hepatitis B immunoglobulin (HBIG) in HBV infected liver recipients. A fixed effects model was used for statistical pooling of relative risks (RR) for the different outcomes. Six articles (551 patients) fulfilled the inclusion criteria. Statistically significant differences were observed between lamivudine monotherapy and lamivudine + HBIG therapy in hepatitis B recurrence [ P  < 0.0001; RR = 0.38; 95% CI (0.25, 0.58)], YMDD mutant [ P  = 0.002; RR = 0.40; 95% CI (0.23, 0.72)] and hepatitis B recurrence in HBV-DNA positive patients before orthotopic liver transplantation [ P  < 0.00001; RR = 0.31; 95% CI (0.21, 0.45)]. No significant differences were observed in patient survival [ P  = 0.59; RR = 1.02; 95% CI (0.95, 1.09)], graft survival [ P  = 0.56; RR = 1.02; 95% CI (0.95, 1.09)] and diseases leading to death between the two groups [HBV recurrence leading to death: P  = 0.05; RR = 0.47; 95% CI (0.22, 1.02); hepatocellular carcinoma recurrence leading to death: P  = 0.13; RR = 0.34; 95% CI (0.09, 1.36)]. In conclusion, combination of lamivudine and HBIG can effectively decrease the recurrence rate of HBV and the incidence of YMDD mutant, but it can not improve patient survival and graft survival significantly. Well-designed large-sample trials are needed to evaluate the efficiency of combined therapy of lamivudine and HBIG in prophylaxis of HBV recurrence in liver graft recipients.     

Advanced donor age increases the risk of severe recurrent hepatitis C after liver transplantation

The association between donor age and the severity of recurrent hepatitis C and, whether there is any donor age above which severity of recurrence increases significantly, were analyzed. A total of 131 liver grafts of hepatitis C virus (HCV)‐infected recipients were selected for the study. Distribution of donor age was compared between grafts with and without severe recurrence. The risk of developing severe recurrence as well as the hepatitis‐free, severe hepatitis‐free and HCV‐related graft survival was compared between different donor age groups. Mean donor age was higher for grafts with severe recurrence (P = 0.007). The risk of developing severe recurrence within 2 years post‐transplant increased with donors aged ≥50 years (RR = 1.34) and donors aged ≥70 years (RR = 1.61). Five‐year severe hepatitis‐free survival rates decreased progressively when donor age was over 50 years (P < 0.001). The study shows 50 and 70 years as the donor age cut‐off points above which the evolution of HCV‐infected recipients worsens.     

Impact of anti-hepatitis Bc-positive grafts on the outcome of liver transplantation for HBV-related cirrhosis

BACKGROUND: The present scarcity of organ donors requires consideration of grafts from sources not previously used. Several studies have addressed the use of grafts from donors who have antibodies to the hepatitis B core antigen (anti-HBc+). The aim of this study was to evaluate the impact of the use of anti-HBc+ grafts in patients transplanted for hepatitis B virus (HBV)-related cirrhosis. METHODS: Recipients of first hepatic transplants from donors with antibodies to HBV were identified retrospectively. All patients who had serology suggestive of active HBV and were negative for hepatitis C and D were included in the analysis. The Kaplan-Meier method was used to assess the actuarial recurrence-free survival on patients with graft survival longer than 1.5 months. The stepwise Cox regression model was used to identify independent predictors of HBV recurrence. RESULTS: One thousand seven hundred seventeen first liver transplants were performed at the Thomas E. Starzl Transplantation Institute from September 1, 1990, to December 31, 1999. HBV was the cause of cirrhosis in 112 patients (6.5%). Thirty-three patients had coexistent viral infection (23 HCV and 10 HDV). Fourteen donors (17.2%) were positive for HBV markers, with nine anti-HBc+ and with five both anti-HBc+ and anti-HB surface-positive; of these, 13 anti-HBc+ organ recipients had long-term survival. Nine (69.2%) of these cases were reinfected versus 20 (35.7%) in the group that received grafts from HBV- donors (P<0.05, Fisher's exact test). The mean time to reinfection was shorter in the anti-HBc+ group (2.9 yr vs. 6.4 yr, P<0.005). There were no statistical differences in graft or patient survival between the two groups. HBV prophylaxis with combined lamivudine and hepatitis B immunoglobulin (HBIG) significantly reduced the reinfection rate (P<0.03). Hepatitis Be (Hbe) antigen-positive recipients trended to faster reinfection (not significant). Cox regression analysis revealed that both anti-HBc graft donor status (RR, 2.796; P=0.020) and combination of lamivudine/HBIG (RR, 0.249; P=0.021) are independently associated with reinfection. CONCLUSIONS: The use of anti-HBc+ liver grafts does not affect graft or patient survival. However, patients who receive these organs are 2.5 times more likely to develop HBV recurrence. Lamivudine and HBIG combination decreases HBV recurrence 4-fold.     

Impact of donor age on survival and fibrosis progression in patients with hepatitis C undergoing liver transplantation using HCV+ allografts.

Studies have suggested that the use of hepatitis C virus (HCV)-positive (HCV+) donor allografts has no impact on survival. However, no studies have examined the effect that HCV+ donor histology has upon recipient and graft survival. We evaluated the clinical outcome and impact of histological features in HCV patients transplanted using HCV+ livers. We reviewed all patients transplanted for HCV at our institution from 1988 to 2004; 39 received HCV+ allografts and 580 received HCV-negative (HCV-) allografts. Survival curves compared graft and patient survival. Each HCV+ allograft was stringently matched to a control of HCV- graft recipients. No significant difference in survival was noted between recipients of HCV+ livers and controls. Patients receiving HCV+ allografts from older donors (age > or =50 yr) had higher rates of graft failure (hazard ratio, 2.74) and death rates (hazard ratio, 2.63) compared to HCV- allograft recipients receiving similarly-aged older donor livers. Matched case-control analysis revealed that recipients of HCV+ allografts had more severe fibrosis post-liver transplantation than recipients of HCV- livers (P = 0.008). More advanced fibrosis was observed in HCV+ grafts from older donors compared to HCV+ grafts from younger donors (P = 0.012). In conclusion, recipients of HCV+ grafts from older donors have higher rates of death and graft failure, and develop more extensive fibrosis than HCV- graft recipients from older donors. Recipients of HCV+ grafts, regardless of donor age, develop more advanced liver fibrosis than recipients of HCV- grafts.     

Impact of HLA-compatibilities in patients undergoing liver transplantation for HBV-cirrhosis

Liver transplantation (OLT) for end-stage chronic hepatitis-B-virus (HBV) infection is frequently complicated by HBV recurrence. In the present study we investigated whether human leucocyte antigen (HLA)-matching influences the outcome after OLT. In a retrospective analysis we reviewed 84 recipients of liver transplants for end-stage HBV-cirrhosis and complete HLA-typing for outcome after OLT. Follow-up ranges from 1 to 110 months (median = 55.6 months). Immunosuppression consisted of Cyclosporin A (CsA)-based quadruple induction therapy or Tacrolimus-based induction protocols. Immunoprophylaxis with hepatitis B immunoglobulin was started at OLT and continued long-term. Actuarial 1- and 5-yr graft survival figures were 90.5 and 80.4%, respectively. Hepatitis-B recurrence was responsible for 15 of 20 (75%) graft failures. We observed a significantly improved graft survival in patients with more HLA-A, -B compatibilities (p = 0.02), whereas the degree of HLA-DR compatibilities did not influence the outcome. The occurrence of HBV-reinfection was significantly lower in HLA-A, -B matched grafts (p < 0.05). Additionally, graft survival was prolonged in patients with HBV-reinfection and 1 or 2 HLA-B compatibilities when compared with patients with HBV-reinfection and a complete HLA-B mismatch (p = 0.02). In conclusion, this retrospective analysis shows that more HLA-A, -B compatibilities seems to be associated with an improved graft survival in patients after OLT for end-stage HBV infection.     

Serum globulin levels in predicting the extent of hepatic fibrosis in patients with recurrent post-transplant hepatitis C infection

Abstract:  The progression of HCV-related disease is particularly aggressive in the post-transplantation setting. Recipients with recurrent HCV infection undergo repeated liver biopsies in order to estimate disease progression. A strong association was found between serum immunoglobulins levels and hepatic fibrosis in non-transplanted patients with chronic HCV infection. The aim of this study was to determine if serum globulin and immunoglobulins levels can predict the extent of fibrosis in patients with recurrent HCV infection. The records of 45 patients (mean age 51.6 ± 10.5 yr; 53.3% men) with biochemical, serologic, virologic, and histological evidence of recurrent HCV infection were reviewed. Recurrence developed after a median interval of 11.7 months (range: 3–106); in 14 patients (31.1%), the recurrent infection was severe. The mean duration of follow-up was 51.4 ± 35.4 months. A total of 96 liver biopsies were performed. The mean fibrosis score increased significantly with an increase in the number of biopsies (p < 0.0001, r = 0.44). On multivariate analysis, the only predictors of severe fibrosis were serum levels of globulin (OR: 5.97, 95% CI: 1.82–19.53; p = 0.0004) and IgG (OR: 1.003, 95% CI: 1.001–1.006; p = 0.018). On linear regression analysis, for each 0.5-g/dL increase in serum globulin level, there was a 0.22-point increase in fibrosis stage. In conclusion, serum levels of globulin and IgG can serve as a noninvasive marker of the extent of hepatic fibrosis in patients with post-transplant recurrent HCV infection, thus avoiding the need for repeated liver biopsies. These findings, if confirmed, have important implications for the prevention and treatment of fibrosis in this patient group.     

Liver Transplantation for Hepatitis B and C Virus-Related Cirrhosis: Mid-Term Results

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is almost universal; cirrhosis develops in up to 30% of cases. Currently there is interest in the midterm outcomes of HCV patients with concomitant hepatitis B virus (HBV) infection among OLT recipients. We therefore retrospectively analyzed our database of patients who underwent OLT for HCV-HBV-related cirrhosis. Between April 1992 and December 2008, 350 patients underwent OLT, including 20 (5.7%) transplanted for HBV-HCV cirrhosis. We assessed patient and graft survivals at 1 and 5 years, as well as the progression of fibrosis. Protocol liver biopsies were available yearly after OLT. The survival curves were analyzed by the Kaplan-Meier approach and chronic hepatitis evaluated according to the Ishak scoring system. At a median follow-up of 68.4 ± 53 months, the 1- and 5-year patient and graft survival rates were 80% and 70%, respectively. The 5-year fibrosis progression rate was 0.17 ± 0.08 units of fibrosis. The only patient who developed histologic cirrhosis within 10 years of follow-up showed a lamivudine-resistant HBV recurrence. Patients transplanted for HBV-HCV coinfection showed a lower fibrosis progression rate compared with HCV monoinfected subjects.