Lamivudine After Hepatitis B Immune Globulin Is Effective in Preventing Hepatitis B Recurrence After Liver Transplantation

The prevention of recurrent hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT) with hepatitis B immunoglobulin (HBIG) is expensive and requires indefinite parenteral administration. Lamivudine is a nucleoside analogue capable of inhibiting HBV replication. The aim of this study is to determine the efficacy of lamivudine in the prevention of recurrent HBV infection after a course of HBIG in patients who were hepatitis B surface antigen (HBsAg) positive and hepatitis Be antigen (HBeAg) negative before OLT. Patients at high risk for recurrent HBV infection (HBeAg positive and HBV DNA positive) were excluded. Thirty HBsAg-positive, HBeAg-negative patients underwent OLT from January 1993 to June 1997. All 30 patients were administered HBIG after OLT and, after 2 years, were given the option of continuing with HBIG or switching to lamivudine. Five patients were excluded: 3 patients were lost to follow-up and 2 patients died of technical complications. Three patients terminated HBIG therapy at 8, 24, and 29 months after OLT, and reinfection with HBV occurred in 1 patient. Six patients elected to continue HBIG therapy for life; 1 patient died of melanoma and the remaining 5 patients are HBsAg negative, with an average follow-up of 73 months. Sixteen patients were converted to lamivudine after a course of HBIG, and all 16 patients are HBsAg negative, with an average follow-up of 51 months after OLT. Five patients have been on lamivudine monotherapy for more than 24 months. These results suggest that lamivudine administered after a posttransplantation course of HBIG can effectively prevent the recurrence of HBV infection in patients who are HBsAg positive and HBeAg negative before OLT. (Liver Transpl 2000;6:434-439.)     

Combination Low-Dose Hepatitis B Immune Globulin and Lamivudine Therapy Provides Effective Prophylaxis Against Posttransplantation Hepatitis B

Although antiviral prophylaxis with lamivudine monotherapy appears to reduce post–liver transplantation recurrence of hepatitis B virus (HBV) infection, breakthrough infections occur in at least 20% of the patients because of the development of drug resistance. Combined lamivudine and intravenous hepatitis B immune globulin (HBIG) therapy (10,000-IU doses) may reduce this risk, but its use is limited by cost (∼US $45,000/yr) and availability. We report the experience at liver transplant centers in Australia and New Zealand in which lamivudine has been used in combination with much lower doses of HBIG than used in conventional HBIG prophylaxis. Lamivudine, 100 mg/d, was administered to hepatitis B surface antigen (HBsAg)–positive candidates on listing for transplantation and was continued posttransplantation. HBIG, 400 or 800 IU, was administered intramuscularly (IM) daily for 1 week from transplantation and monthly thereafter. Thirty-seven HBsAg-positive patients underwent transplantation using this protocol. Thirty-six of these patients were HBV DNA positive by polymerase chain reaction (PCR) or hybridization assay. Thirty-four patients had chronic HBV, 2 patients had hepatitis B and C, and 1 patient had hepatitis B, C, and D. Five patients died within 1 month of transplantation and are not included in the analysis. Mean follow-up in the remaining 32 patients was 18.4 months (range, 5 to 45 months). Treatment was well tolerated, with no significant adverse events. Thirty-one of 32 patients were HBsAg negative, and all 32 patients were HBV DNA negative by PCR at latest follow-up. The cost of treatment was US $967 for lamivudine and between $2,290 and $4,480/yr for IM HBIG. Lamivudine and low-dose HBIG treatment prevents posttransplantation recurrence of hepatitis B and is likely to be more cost-effective than high-dose HBIG regimens.(Liver Transpl 2000;6:429-433.)     

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.     

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.     

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.     

Use of combined treatment of hepatitis B immune globulin and lamivudine as prevention of hepatitis B virus recurrence in liver allograft

Antiviral prophylaxis with lamivudine appears to reduce hepatitis B virus (HBV) infection after liver transplantation, although recurrence of infection occurs in at least 20% of the patients because of the development of drug resistance. Treatment for HBV reinfection with lamivudine pretransplantation and posttransplantation together with hepatitis B immunoglobulin could abolish recurrence of HBV infections following liver transplantation. We report the experience at our center in which lamivudine has been used in combination with low doses of immunoglobulin. Lamivudine (100 mg/d) was administered to liver transplant candidates for at least 4 weeks before transplantation and was continued posttransplantation indefinitely. Immunoglobulin was administered intramuscularly (10,000 IU at time of liver transplantation; 1,000 IU for 1 week; 1,000 IU weekly the first month; and 1,000 IU monthly thereafter). Lamivudine and low-dose immunoglobulin administration prevents posttransplantation recurrence of hepatitis B with 100% efficiency; it is well tolerated and is less cost-effective than high-dose immunoglobulin regimens.     

Antiviral treatment for hepatitis B virus recurrence following liver transplantation

The purpose of this study was to identify the factors associated with the recurrence of hepatitis B virus (HBV) following liver transplantation (LT) for HBV‐related disease and to recognize the outcome of treatment for HBV recurrence with oral nucleos(t)ide analogues. Six hundred and sixty‐seven LTs were performed for HBsAg‐positive adult patients in our institute from 1996 to 2010. HBV prophylaxis was performed by hepatitis B immunoglobulin (HBIG) monotherapy or HBIG and entecavir combination therapy. There were 63 cases (11.4%) of HBV recurrences during a median follow‐up of 51 months. The median time to HBV recurrence was 22 months. A preoperative HBV DNA load of more than 10⁵ IU/mL, HBIG monotherapy, and hepatocellular carcinoma in the explant liver were independent risk factors for HBV recurrence following LT in multivariate analysis. Patient survival at 10 yr was 54.2% for HBV‐recurrent patients. Among patients with HBV recurrence, HBsAg seroclearance was achieved in 13 patients (20.6%), but HBsAg seroclearance did not affect survival in these patients after the recurrence of HBV (p = 0.28). The recurrence of HBV led to graft failure in six cases. HBV recurrence should be prevented by strict management of pre‐transplant HBV viremia and an effective post‐transplant HBV prophylaxis.     

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.     

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。     

Liver transplantation for chronic hepatitis B infection with the use of combination lamivudine and low-dose hepatitis B immune globulin.

Current protocols for prophylaxis against allograft reinfection after liver transplantation for chronic hepatitis B virus (HBV) infection include the administration of large doses of hepatitis B immune globulin (HBIG), with considerable associated economic costs. Monotherapeutic prophylaxis with lamivudine has been complicated by the development of resistant strains of HBV. We studied the effectiveness of a posttransplantation prophylaxis protocol using combination lamivudine and low-dose HBIG in 7 consecutive patients with chronic HBV infection, 4 of whom were serum HBV DNA positive before pretransplantation lamivudine therapy. All patients were serum HBV DNA negative at transplantation and received lamivudine, 100 mg/d, posttransplantation. HBIG, 2170 IU, was administered intramuscularly intraoperatively and daily for 14 days. Maintenance HBIG therapy consisted of 2170 IU intramuscularly twice weekly, tapered to every 2 to 4 weeks by 12 months posttransplantation. Target serum HBIG (HBV surface antibody) titers were less than 500 IU/L for 6 months, then greater than 300 IU/L until 12 months posttransplantation. Induction serum HBIG titers were determined daily in 5 patients, and both serum HBIG and hepatitis B surface antigen were determined every 4 weeks in all patients. One patient died 61 days posttransplantation; the surviving patients (n = 6) were followed up for a mean of 532 days (range, 395 to 648 days). No patient has developed allograft reinfection. In the induction period, a target HBIG titer of greater than 500 IU/L was not achieved until a mean of 6.8 days (range, 5 to 10 days). In the maintenance period, all patients achieved the target HBIG titer. This suggests combination lamivudine and low-dose HBIG is effective in preventing allograft reinfection by HBV.     

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.     

Cost-effective and safe ambulatory long-term immunoprophylaxis with intramuscular instead of intravenous hepatitis B immunoglobulin to prevent reinfection after orthotopic liver transplantation

BACKGROUND: Hepatitis B (HBV)-infected patients receive an anti-HBs immunoprophylaxis [hepatitis B immunoglobulin (HBIG) titre of more than 100 IU/L] in combination with lamivudine to prevent reinfection after orthotopic liver transplantation (OLT). In comparison with intramuscular (i.m.) HBIG, costs for intravenous (i.v.) HBIG are found to be extremely high. We therefore studied patients' outcome (i) after a switch from i.v. to i.m. HBIG and (ii) the outcome after the patients were initially treated with i.m. HBIG after discharge from the hospital. METHODS: (i) Six outpatients were switched from 2000 IU i.v. HBIG (Hepatect) administered every 2 wk to 2000 IU i.m. HBIG (Hepatitis-B-Immunoglobulin Behring) given once a month. (ii) Six other outpatients were directly treated with i.m. HBIG every 4 wk after OLT. All patients also received 100 mg lamivudine/d. RESULTS: Patients switched from i.v. to i.m. HBIG had stable anti-HBs titres (i.v. HBIG: 180 +/- 37 IU/L vs. i.m. HBIG: 173 +/- 23 IU/L). Patients directly treated with i.m. HBIG also had sufficient anti-HBs titres (176 +/- 31 IU/L). Intramuscular application of HBIG was well tolerated by all patients and no side-effects were observed in patients receiving i.m. HBIG. In comparison with the protocol using i.v. HBIG, the costs of i.m. treatment were 60% lower. CONCLUSION: Long-term administration of i.m. HBIG saves up to 60% of the usual costs for i.v. prophylaxis of HBV reinfection in patients after OLT. In combination with lamivudine, long-term i.m. HBIG therapy is as efficient as i.v. HBIG treatment, but its lower costs clearly favour its use in preventing HBV reinfection after OLT.     

Prevention of de novo hepatitis B infection in recipients of hepatic allografts from anti-HBc positive donors.

BACKGROUND: The shortage of donor organs occasionally mandates the use of hepatic allografts from anti-HBc+ donors in recipients who are susceptible to de novo hepatitis B virus (HBV) infection. The efficacy of hepatitis B immune globulin and lamivudine to prevent de novo HBV infection in anti-HBs negative recipients of allografts from anti-HBc+ donors has not been investigated. METHODS: After liver transplantation with an allograft from a donor positive for anti-HBc, recipients who were anti-HBs-, HbsAg- received hepatitis B immune globulin (HBIG) 10,000 IU i.v. daily for 7 days and monthly for 6 months. After 6 months, 1000 IU of HBIG was given IM. every 2 weeks for 18 months. Patients transplanted after 4/1/97 were given lamivudine 150 mg daily starting postoperative day 1. RESULTS: Between 8/14/96 and 6/10/98, 264 orthotopic liver transplants were performed and 16 anti-HBs-, HbsAg- patients received an hepatic allograft from a donor positive for anti-HBc. HBIG mono-therapy was administered to one patient. HBIG and lamivudine combination therapy was administered to 15 patients. Of the 16 patients, 8 were positive only for anti-HBc before transplant, and 8 were naive (anti-HBs-, anti-HBc-). The single patient who received HBIG monotherapy became HbsAg+ at 6 months. All patients receiving combination therapy with HBIG and lamivudine have remained HbsAg-. The average follow-up is 459 days (range 170-754). Two patients died from unrelated causes. CONCLUSIONS: Combination therapy with HBIG and lamivudine may prevent de novo HBV infection in anti-HBs-, HbsAg- recipients of hepatic allografts from anti-HBc+ donors.     

肝移植术后乙型肝炎复发的预防和治疗

目的探讨拉米夫定联合低剂量乙型肝炎（乙肝）免疫球蛋白（HBIG）预防肝移植术后乙肝复发的效果及乙肝复发后的治疗。方法对2000年12月至2003年5月因乙肝相关性终末期肝病和（或）合并肝细胞癌于我院接受肝移植手术并经随访的11例患者进行回顾性分析。所有患者均接受拉米夫定联合低剂量HBIG预防乙肝复发方案。观察术后近期乙肝转阴情况、术后较远期乙肝复发情况以及乙肝复发后的治疗情况。结果（1）所有患者HBsAg、HBeAg、HBV-DNA均于术后1-4d转为阴性,术后1周所有患者对HBIG均有反应,HBsAb滴度水平逐渐上升;（2）所有患者于观察期内生存情况均良好,对患者HBsAb滴度水平定期进行监测结果示大部分患者HBsAb滴度水平与预期治疗水平基本符合;（3）1例患者于术后25个月乙肝复发,通过改用阿德弗韦并加大HBIG用量,基本得到控制。结论拉米夫定联合低剂量HBIG预防肝移植后乙肝复发疗效确切,而且可显著降低治疗费用。     

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.     

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.     

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.     

Prevention of and Treatment for Hepatitis B Virus Infection After Liver Transplantation in the Nucleoside Analogues Era

Post-transplant prophylaxis with hepatitis B immune globulin (HBIG) has significantly reduced hepatitis B virus (HBV) recurrence rates, but it is rather ineffective in patients with pretransplant viremia. Moreover, long-term HBIG administration is very expensive and may be associated with emergence of escape HBV mutants. Lamivudine has been widely used in the management of HBV transplant patients. Pretransplant lamivudine lowers HBV viremia, decreasing the risk of post-transplant HBV recurrence, but to try and minimize development of resistant HBV strains, it should start within the last 6 months of the anticipated transplantation timing. Preemptive post-transplant lamivudine monotherapy is associated with progressively increasing HBV recurrence rates, but combined therapy with lamivudine and HBIG at relatively low dosage is currently the most effective approach in this setting, even in HBV-DNA-positive patients, who also receive lamivudine in the pretransplant period. The most frequent therapy for post-transplant HBV recurrence is lamivudine, but the increasing resistance rates represent a rather challenging problem. Adefovir dipivoxil and entecavir are currently the most promising agents for lamivudine-resistant HBV strains. All these advances in anti-HBV therapy have made HBV liver disease an indication for liver transplantation irrespective of viral replication status, a complete turn around from 10 years ago.     

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

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

Entecavir Combined With Short-term Hepatitis B Immunoglobulin in Preventing Hepatitis B Virus Recurrence in Liver Transplant Recipients

BackgroundThe combination of nucleoside analogs and long-term hepatitis B immunoglobulin (HBIG) is considered to be the standard regimen for preventing hepatitis B virus (HBV) recurrence after liver transplant (LT). However, long-term use of HBIG causes many adverse effects. The aim of this study was to evaluate the effect of nucleoside analogs entecavir combined with short-term HBIG in preventing HBV recurrence after LT.MethodsThis retrospective study assessed the effect a combination of entecavir and short-term HBIG in prophylaxis of HBV recurrence among 56 LT recipients who had undergone the procedure because of HBV-associated liver disease at our center between December 2017 and December 2021. All patients received entecavir treatment combined with HBIG for the prevention of hepatitis B recurrence, and HBIG treatment was withdrawn within 1 month. The patients were followed up to determine levels of hepatitis B surface antigen, antibody to hepatitis B surface antigen (HBsAb), and HBV-DNA and the recurrence rate of HBV.ResultsOnly 1 patient appeared positive for hepatitis B surface antigen at 2 months post-LT. The overall HBV recurrence rate was 1.8%. The HBsAb titers of all patients gradually decreased over time, with a median of 376.6 IU/L at 1 month post-LT and a median of 13.47 IU/L at 12 months post-LT. During the follow-up period, the HBsAb titer of the preoperative HBV-DNA–positive patients remained at a lower level than that of HBV-DNA–negative patients.ConclusionsEntecavir combined with short-term HBIG can exert a good effect for the prevention of HBV reinfection post-LT.