Clinical Outcomes and Risk Factors of Hepatitis B Virus Recurrence in Patients Who Received Prophylaxis With Entecavir and Hepatitis B Immunoglobulin Following Liver Transplantation

Introduction

Although entecavir (ETV) and hepatitis B immunoglobulin (HBIG) have widely been used for prophylaxis of hepatitis B virus (HBV) recurrence following liver transplantation (OLT), there have been few studies about clinical outcomes and risk factors of HBV recurrence.

Materials and methods

This study retrospectively assessed clinical outcomes and identified risk factors of post-transplant HBV recurrence in 154 patients who received prophylaxis with both ETV and HBIG after OLT.

Results

The median follow-up duration was 28.0 months (range, 1.0–57.8). Post-transplant HBV recurrence occurred in 5 patients (3.2%) without any ETV-resistant mutants. The overall rates of HBV recurrence at 1, 2, and 4 years were 0.6%, 1.6%, and 6.2%, respectively. We found that recurrent hepatocellular carcinoma (HCC) was an independent risk factor of HBV recurrence (hazard ratio = 13.5, 95% confidence interval, 2.4–74.4; P = .006).

Conclusions

Prophylaxis with a combination of ETV and HBIG resulted in a low HBV recurrence rate following OLT without any emergence of ETV-resistant mutants. Recurrent HCC was an independent risk factor of HBV recurrence in patients who received prophylaxis with both ETV and HBIG for prophylaxis following OLT.     

Prophylactic use of low-dose, on-demand, intramuscular hepatitis B immunoglobulin and lamivudine after liver transplantation

The combination of hepatitis B immunoglobulin (HBIG) and antivirals (nucleos[t]ide analogs) has extended the applicability of orthotopic liver transplantation (OLT) for patients with hepatitis B virus (HBV)-related liver disease. However, HBIG administrations have an extremely high cost. Herein, we evaluated our results with low-dose, on-demand, intramuscular HBIG plus lamivudine (LAM) prophylaxis after OLT. The HBV DNA status in 40 patients at the time of OLT determined the treatment: group A (n = 22), HBV DNA (-), no antiviral pretreatment; group B (n = 11), HBV DNA (-), after LAM; group C (n = 3), HBV DNA (+) after LAM (LAM resistance/Adefovir [ADV] unavailable); group D (n = 2), HBV DNA (+), no antiviral pretreatment; and group E (n = 2), HBV DNA (-) after LAM + ADV (LAM resistance/ADV available). Five patients died within 12 months after OLT unrelated to HBV infection. The remaining 35 patients were followed for a median duration of 16 months (range, 6-93 months). Only two recipients from group C, who were transplanted despite LAM resistance + no ADV pretreatment, revealed recurrent HBV infections at 14 and 16 months posttransplantation; they were then treated successfully with ADV as it became available. The third group C recipient had undetectable HBV DNA at 18 months after OLT. The mean cumulative doses of HBIG administered within the first, second, and third years were 34,014, 5258, and 5090 IU, respectively. In conclusion, low-dose, on-demand, intramuscular HBIG plus (LAM +/- ADV) prophylaxis is a safe, efficient, and cost-effective regimen to prevent recurrent HBV infection following OLT. OLT despite untreated LAM resistance may require sustained higher serum HBsAb levels after surgery.     

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.     

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.     

Treatment of hepatitis B and C after liver transplantation. Part 1, hepatitis B

Abstract The outcome of OLT for HBV-related liver disease is dependent on the prevention of allograft re-infection. Over the past decade, major advances have been made in the management of HBV transplant candidates. The advent of long-term hepatitis B immune globulin (HBIG) administration as a prophylaxis against HBV recurrence, and the introduction of new antiviral agents against HBV infection, such as lamivudine (LAM), were a major breakthrough in the management of these patients. Results of OLT for HBV infection are similar to those achieved with other indications. Pre-OLT antiviral treatment such as LAM can suppress HBV replication before OLT and thus decrease the risk of re-infection of the graft. Combination prophylaxis with LAM and HBIG after transplantation highly effectively reduces the rate of HBV re-infection, even in HBV replicative cirrhotic, patients. The optimal HBIG protocol in the LAM era is yet to be defined: dosing of HBIG, routes of administration, and possibility of stopping HBIG. Several antiviral drugs have been developed for the management of HBV infection on the graft, so outcome is currently good.     

Treatment of hepatitis B and C after liver transplantation. Part 1, hepatitis B

The outcome of OLT for HBV-related liver disease is dependent on the prevention of allograft re-infection. Over the past decade, major advances have been made in the management of HBV transplant candidates. The advent of long-term hepatitis B immune globulin (HBIG) administration as a prophylaxis against HBV recurrence, and the introduction of new antiviral agents against HBV infection, such as lamivudine (LAM), were a major breakthrough in the management of these patients. Results of OLT for HBV infection are similar to those achieved with other indications. Pre-OLT antiviral treatment such as LAM can suppress HBV replication before OLT and thus decrease the risk of re-infection of the graft. Combination prophylaxis with LAM and HBIG after transplantation highly effectively reduces the rate of HBV re-infection, even in HBV replicative cirrhotic patients. The optimal HBIG protocol in the LAM era is yet to be defined: dosing of HBIG, routes of administration, and possibility of stopping HBIG. Several antiviral drugs have been developed for the management of HBV infection on the graft, so outcome is currently good.     

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.     

Long‐term outcome of patients with lamivudine after early cessation of hepatitis B immunoglobulin for prevention of recurrent hepatitis B following liver transplantation

Yuefeng M, Weili F, Wengxiang T, Ligang X, Guiling L, Hongwei G, Wencai L, Xiaoguang W, Wei M, Zhongyi F. Long‐term outcome of patients with lamivudine after early cessation of hepatitis B immunoglobulin for prevention of recurrent hepatitis B following liver transplantation.
Clin Transplant 2011: 25: 517–522. © 2010 John Wiley & Sons A/S. Abstract: Background: The aim of this study is to examine the efficacy of long‐term prophylaxis with lamivudine (LAM) after a course of post‐operative hepatitis B immunoglobulin (HBIG) in patients who underwent liver transplantation (LT) for hepatitis B virus (HBV)‐related disease. Result: The medical records of HBV‐infected patients who underwent a LT in our institution between July 2001 and May 2005 were reviewed. There were 15 liver transplant recipients who were administered HBIG for <18 months and used LAM as a maintenance prophylaxis regime enrolled in this study. At enrollment, all patients were hepatitis B surface antigen (HBsAg) positive and three patients were HBeAg positive. There were 13 patients who were HBV DNA positive with a mean viral load of 5.4 log copies/mL, and among them, 12 recipients were on antiviral therapy with LAM (100 mg/d orally) for 12–168 d, resulting in HBV DNA negative levels in nine patients prior to their transplant. HBV recurrence post‐LT was noted in two patients who had very high‐HBV DNA levels pre‐LT. Both of these patients showed LAM‐resistant mutation at the time of recurrence. The 11 patients who were HBV DNA negative before LT (low‐risk patients) had no HBV recurrence during a follow‐up at a median of 58 months post‐LT. This included five patients who had intermittent low‐level HBV DNA post‐LT (HBsAg negative), of whom two had YMDD mutation and these two were given adefovir in addition to LAM. Conclusion: Our retrospective study demonstrated excellent long‐term outcomes in the low‐risk patients treated with LAM after a short course of HBIG.     

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.     

肝移植术后HBV再感染的治疗

目的分析肝移植术后乙型肝炎病毒（HBV）再感染患者的抗病毒治疗与乙肝病毒基因变异情况。方法317例HBV相关终末期肝病患者肝移植术后15例单独使用LAM，302例使用小剂量乙肝免疫球蛋白（hepatitis B immune globulin，HBIG）和拉米夫定（lamivudine，LAM）（或adefovir dipivoxil，ADV）联合预防HBV再感染，同时检测HBV血清标志物、血清HBV DNA、YMDD区变异、及肝活检组织乙型肝炎标记物。结果术后LAM组有4例术前HBV DNA阳性患者术后HBV再感染，LAM＋HBIG联合用药组16例HBV再感染，两组术后HBV再感染差异有统计学意义（26．7％VS．5．30％，P〈0．01）。317例患者术后12例发生YMDD变异，发生率为3．79％，再感染病例60％（12／20）。经加用ADV治疗后5例HBV DNA转阴性，4名患者HBV DNA滴度下降，肝功能显著改善，3例发生纤维淤胆性肝炎，2例死亡，1例经再次肝移植治愈。结论小剂量HBIG＋LAM可以有效地预防肝移植术后HBV再感染；在小剂量HBIG＋LAM用药基础上HBV再感染可能产生YMDD（tyrosine，methionine，aspartate，aspartate）变异；ADV可作为LAM耐药后用药，对于发生突破性感染的患者应采取以ADV为主的综合治疗。     

Intramuscular hepatitis B immune globulin combined with lamivudine for prophylaxis against hepatitis B recurrence after liver transplantation.

Immunoprophylaxis using intravenous (IV) hepatitis B immune globulin (HBIG) decreases the recurrence of hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT). However, IV HBIG is expensive, has significant side effects, and is inconvenient to administer. An alternative approach for prophylaxis using intramuscular (IM) HBIG and oral lamivudine was prospectively evaluated in this study. Ten consecutive patients with cirrhosis with HBV infection who underwent OLT were included in this study. Nine of 10 patients received lamivudine, 150 mg/d, for an average duration of 8.6 months before OLT. Two of 10 patients with detectable HBV DNA at the time of OLT received 10,000 U (45 mL) of IV HBIG daily for 7 consecutive days, followed by 5 mL of IM HBIG weekly for the next 3 weeks, then every 3 weeks. The other 8 patients were HBV DNA negative at OLT and received one dose of IV HBIG (45 mL) during surgery, followed by 5 mL of IM HBIG weekly for 4 weeks, then every 3 weeks. All patients received lamivudine, 150 mg/d, after OLT. During a mean follow-up of 15.6 months, 9 of 10 patients achieved a protective hepatitis B surface antibody (HBsAb) titer greater than 200 IU/L and had no evidence of HBV recurrence. One patient failed to develop an adequate HBsAb titer and developed histological and virological evidence of recurrence. One patient died unrelated to HBV recurrence. Our preliminary data suggest that this combination prophylaxis with IM HBIG and lamivudine is effective and potentially cost saving.     

Prophylaxis Against Hepatitis B Recurrence Posttransplantation Using Lamivudine and Individualized Low‐Dose Hepatitis B Immunoglobulin

Although the combination of lamivudine (LAM) and high‐dose intravenous (IV) hepatitis B immunoglobulin (HBIG) is very effective in preventing hepatitis B virus (HBV) recurrence after liver transplantation (LT), the major limitation of this regimen is its high cost. A more cost‐effective, convenient and widely accepted regimen is urgently needed. We evaluated the safety and efficacy of another strategy using LAM and individualized low‐dose intramuscular (IM) HBIG. Between May 2002 and December 2009, a total of 254 adult patients undergoing LT for HBV‐related benign end‐stage liver diseases received this regimen in our center. The mean follow‐up of these patients was 41.2 ± 22.7 months. Their 1‐, 3‐ and 5‐year survival rates were 85.3%, 77.4% and 76.4%, respectively, and 1‐, 3‐ and 5‐year HBV recurrence rates were 2.3%, 6.2% and 8.2%. Fourteen patients experienced posttransplant HBV recurrence. Pretransplant high viral load and posttransplant prednisone withdrawal time were observed to be associated with recurrence. In conclusion, combination therapy with LAM and individualized low‐dose IM HBIG provides a safe and effective prophylaxis against HBV recurrence after LT at about 5% of the cost of conventional high‐dose IV HBIG regimens.     

Outcomes of hepatitis B virus recurrence after liver transplantation

The introduction of high doses of hepatitis B immune globulin (HBIG) and lamivudine for liver transplantation (OLT) prophylaxis has reduced the risk of hepatitis B recurrence and improved the survival of patients transplanted for hepatitis B virus (HBV)-related liver disease. But, posttransplant prophylaxis strategies to treat the recurrence of HBV have not yet been standardized. We analyzed 23 patients with HBV recurrence among 340 HBV-associated liver transplants performed from September 1996 to April 2004 (6.7%). Nine patients underwent deceased donor OLT and 14, living donor OLT. Mean follow-up was 37 months. Seroconversion after recurrence was observed in 6 of 23 patients (26%). Mean time to HBV recurrence tended to be shorter among the seroconversion (+) patients compared to seroconversion (-) patients (10 months vs 19.7 months; P = .062). Seroconversion rate after HBIG and lamivudine combination therapy for patients with HBV recurrence was 37.5% and time to seroconversion after HBV recurrence was 1.7 months. Seroconversion was best achieved when the pretransplant HBV DNA level was high and HBeAg was positive. Also, seroconversion rate was increased when HBV DNA level was low and the alanine transferase level high at the time of recurrence and when the time to recurrence after transplantation was short. Seroconversion after HBV recurrence, which was observed in 26%, may be increased in selected cases. Accordingly, aggressive treatment should be undertaken after HBV recurrence.     

Clinical outcomes of liver transplantation for HBV-related hepatocellular carcinoma: data from the NIH HBV OLT study

Han SH, Reddy KR, Keeffe EB, Soldevila‐Pico C, Gish R, Chung RT, Degertekin B, Lok ASF. Clinical outcomes of liver transplantation for HBV‐related hepatocellular carcinoma: data from the NIH HBV‐OLT study.
Clin Transplant 2011: 25: E152–E162. © 2010 John Wiley & Sons A/S. Abstract: Background: Hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) is an indication for orthotopic liver transplantation (OLT) in patients with tumor stage within the United Network for Organ Sharing criteria. The number of patients listed for HBV‐related HCC is increasing, while the number of patients listed for HBV‐related cirrhosis is declining presumptively because of the availability of more effective oral nucleos(t)ide analogues. This study presents the final, long‐term outcome of patients transplanted for HBV‐related HCC in the National Institutes of Health (NIH) HBV OLT Study Group. Results: Ninety‐eight patients (52.4%) in the NIH HBV OLT cohort underwent OLT for HBV‐related HCC. With a mean follow‐up of 36.5 months post‐OLT, 12 (12.2%) patients developed recurrence of HCC. Multivariate analysis did not find a statistically significant role of gender, tumor stage at OLT, pre‐OLT HCC treatment, recurrence of HBV, or duration of HCC diagnosis pre‐OLT in predicting HCC recurrence. Serum alpha‐fetoprotein (AFP) level >200 ng/mL at transplant was found to be statistically significant in predicting HCC recurrence (p = 0.003). HCC recurrence was significantly associated with decreased post‐OLT survival. Conclusion: HCC is the most common indication for OLT in patients with chronic hepatitis B in the era of more effective oral antivirals. Serum AFP at the time of OLT is significantly associated with HCC recurrence.     

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.)     

Virologic and Clinical Outcomes of Hepatitis B Virus Infection in HIV‐HBV Coinfected Transplant Recipients

Liver transplantation (LT) is the treatment of choice for end‐stage liver disease, but is controversial in patients with human immunodeficiency virus (HIV) infection. Using a prospective cohort of HIV‐hepatitis B virus (HBV) coinfected patients transplanted between 2001–2007; outcomes including survival and HBV clinical recurrence were determined. Twenty‐two coinfected patients underwent LT; 45% had detectable HBV DNA pre‐LT and 72% were receiving anti‐HBV drugs with efficacy against lamivudine‐resistant HBV. Post‐LT, all patients received hepatitis B immune globulin (HBIG) plus nucleos(t)ide analogues and remained HBsAg negative without clinical evidence of HBV recurrence, with a median follow‐up 3.5 years. Low‐level HBV viremia (median 108 IU/mL, range 9–789) was intermittently detected in 7/13 but not associated with HBsAg detection or ALT elevation. Compared with 20 HBV monoinfected patients on similar HBV prophylaxis and median follow‐up of 4.0 years, patient and graft survival were similar: 100% versus 85% in HBV mono‐ versus coinfected patients (p = 0.08, log rank test). LT is effective for HIV‐HBV coinfected patients with complications of cirrhosis, including those who are HBV DNA positive at the time of LT. Combination HBIG and antivirals is effective as prophylaxis with no clinical evidence of HBV recurrence but low‐level HBV DNA is detectable in ～50% of recipients.     

Prevention of hepatitis B recurrence after liver transplantation using lamivudine or lamivudine combined with hepatitis B Immunoglobulin prophylaxis.

The aim of our study was to determine the outcomes of liver transplant recipients receiving either lamivudine (LAM) monotherapy or LAM combined with low-dose intramuscular (IM) hepatitis B Immunoglobulin (HBIG) therapy. We performed a retrospective review of the medical records of patients that had had liver transplantation in a single center for HBV-related liver diseases from December 1999 to June 2004. A total of 165 patients received LAM monotherapy (51 patients) or combined prophylaxis (114 patients) post-liver transplantation (LT) with a mean follow-up of 20.13 months. Hepatitis B relapsed in 21 patients of the hepatitis B surface antigen (HBsAg) carriers who received LAM monotherapy, with a 1- and 2-yr actuarial risk of 27.4% and 39.7%. Recurrence occurred in 16 patients of 114 patients receiving the combined prophylaxis, with a 1- and 2-yr recurrence rate of 13.5% and 15.2% (P = 0.024). A total of 25 cases (67.6%) with YMDD mutants were detected in all the 37 patients, 14 cases (66.7%) in the monotherapy group and 11 cases (68.8%) in the combination group. In conclusion, LAM and low-dose intramuscular HBIG treatment demonstrates a better result than LAM monotherapy, as prophylaxis against post-LT reinfection of the graft, but the safety and efficacy as a substitution for high-dose intravenous HBIG with LAM needs to be investigated further.     

Intramuscular hepatitis B immunoglobulin (HBIG) and nucleosides for prevention of recurrent hepatitis B following liver transplantation: comparison with other HBIG regimens

High titer hepatitis B immunoglobulin (HBIG) has significantly reduced the recurrence of hepatitis B virus (HBV) infection after liver transplantation. We compared our experience with intramuscular (IM) HBIG prophylaxis to our earlier outcomes with intravenous (IV) HBIG and other regimens. Methods: One hundred and twenty-three patients with acute or chronic hepatitis B underwent liver transplant at the Baylor Regional Transplant Center between July 1985 and July of 2005. Of these, 63 (43%) received long-term low-dose IM (n = 17) or high-dose IV (n = 46) HBIG. All patients in IM group also received a nucleoside before and after transplant. These patients were compared with those transplanted earlier who received either no prophylaxis (n = 16) or HBIG on day zero and one only (n = 44). Results: HBV recurrence was significantly lower in patients who received long-term HBIG [9/38 (23.7%) for IV and 1/17 (5.9%) for IM] compared with patients who received no treatment (8/11; 72.7%) or only two doses of HBIG (32/40; 80.0%). Two-yr actuarial survivals were 89%, 88%, 54%, and 64%, respectively. Patients on long-term HBIG by either parenteral route survived as well as patients transplanted for other indications. Post-transplant recurrence of hepatitis B in the long-term HBIG groups was usually controlled by intensifying antiviral therapy. Conclusion: Long-term low-dose IM and high-dose IV HBIG are equally efficacious with similar survival and early hepatitis recurrence rates. Graft loss is usually avoidable when recurrence is discovered early and aggressively treated. The IM route is preferable to IV administration due to its ease of administration and lower cost.     

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.     

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.