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 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.     

Subcutaneous administration of hepatitis B immune globulin in combination with lamivudine following orthotopic liver transplantation: effective prophylaxis against recurrence

Prophylaxis against recurrent hepatitis B virus (HBV) infection with hepatitis B immune globulin (HBIG), in combination with antiviral agents such as lamivudine, has allowed transplantation for this condition to become feasible and accepted. Current protocols allow for HBIG administration either intravenously or intramuscularly. To date, there has been no reported experience with the subcutaneous route of post-transplant HBIG delivery. We report our experience of a 60-yr-old man for whom liver transplantation was performed for chronic HBV. HBIG was administered intramuscularly during the anhepatic phase of surgery. The finding of a portal vein thrombosis requiring repeated thrombectomy necessitated chronic anticoagulation. Post-operatively, HBIG was administered subcutaneously, in four separate injections, for a daily dose of 2170 IU along with continued lamivudine dosing. Hepatitis B surface antibody (anti-HBs) titres reached a serum concentration of >500 IU/L by seven d post-transplant and approximately 1000 IU/L by nine d post-transplant. Five months post-transplant, with continued combination of subcutaneous HBIG and lamivudine, there has been no recurrent HBV infection and anti-HBs titres have been at target levels. Our experience suggests that subcutaneous delivery of HBIG may be a feasible consideration when intramuscular/intravenous dosing is not possible.     

Low-dose intramuscular hepatitis B immune globulin and lamivudine for long-term prophylaxis of hepatitis B recurrence after liver transplantation

The combination of lamivudine and hepatitis B immunoglobulins (HBIg) to prevent recurrence of HBV hepatitis has significantly improved the survival of patients transplanted for HBV-related end-stage liver disease. Generally, HBIg are administered intravenously. We evaluated the efficacy, tolerability, and cost savings of long-term intramuscular HBIg and lamivudine in 28 patients (23 men and 5 women), who received liver transplants for acute or chronic HBV-related liver disease. Twelve patients started lamivudine before and 16 at the time of liver transplantation. HBIg were administered intravenously during the first week (50 to 70,000 IU) and intramuscularly thereafter (1200 IU every 3 to 6 weeks) to maintain an HbsAb titer >100 IU/L. Mean follow-up was 20 +/- 13 months. Only one patient experienced HBV recurrence (9 months after transplantation). This patient had failed to follow the scheduled prophylaxis. Cumulative survival at 3 years was 83%. Intramuscular HBIg were well tolerated in all cases. Cost analysis comparing intramuscular vs intravenous HBIg administration showed that 39,490 Euros were saved per patient per year. These preliminary results show that low-dose intramuscular HBIg and lamivudine are efficacious and cost-effective for long-term prophylaxis of hepatitis B recurrence after liver transplantation.     

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.     

Failure of hepatitis B vaccination with conventional HBsAg vaccine in patients with continuous HBIG prophylaxis after liver transplantation.

Hepatitis B vaccination after liver transplantation for hepatitis B-related liver disease has been investigated as an alternative strategy to reinfection prophylaxis with hepatitis B immunoglobulin (HBIG) with conflicting results. In most studies, HBIG treatment was discontinued before vaccination. An outstanding good response was achieved with vaccination under continuous HBIG administration using hepatitis B surface antigen (HBsAg)-based vaccine containing special adjuvants. Both, adjuvants and continuous HBIG administration have been discussed as crucial factors for good response. Twenty-four patients were vaccinated with conventional double dose recombinant vaccine containing 40 microg HBsAg up to 12 times at weeks 0, 2, 4 (cycle 1), 12, 14, 16 (cycle 2), 24, 26, 28 (cycle 3), and 36, 38, 40 (cycle 4). All patients received 2,000 IU HBIG every 6 weeks (4 times intravenously and 4 times intramuscularly). A significant response was defined as reconfirmed increase of anti-HBs-antigen (anti-HBs) unexplained by HBIG administration or lack of anti-HBs decrease below 100 IU/L after discontinuation of HBIG treatment after week 48. Only 2 of 24 patients (8.3%) responded significantly. Anti-HBs started to increase after the seventh vaccination (cycle 3, during intramuscular HBIG administration) in 1 patient and after 12th vaccination (cycle 4, during intravenous HBIG administration) in the other. Maximum anti-HBs levels were >1,000 IU/L in both patients and decreased significantly slower as compared to passive prophylaxis during follow-up. In conclusion, the conventional HBsAg vaccine failed to induce a significant humoral immune response in most patients despite continued HBIG treatment. Further studies should address the question, of whether the use of potent adjuvant systems results in higher response rates.     

Comparison of famciclovir and lamivudine in the long-term treatment of hepatitis B infection after liver transplantation

BACKGROUND: Preliminary results of short-term famciclovir and lamivudine therapy in patients with hepatitis B virus (HBV) infection after liver transplantation revealed promising results. In a retrospective study the efficacy of long-term treatment with these substances was compared. METHODS: A total of 53 HBV-infected adults (48 reinfections and 7 de novo infections) received antiviral treatment. A total of 32 of these patients were treated with famciclovir 3x500 mg, 20 of them were later switched to lamivudine. Fourteen patients received lamivudine, 150 mg/day orally, as first line therapy and 7 patients after failure of famciclovir-prophylaxis. Follow-up time was 8 to 62 months (mean 35 months). Response to therapy (HBV-DNA negative) was compared using Kaplan-Meier estimates. Potential influence factors (HBV-DNA and HBeAg pretransplant, HDV coinfection, pretreatment with famciclovir and immunosuppression) on treatment response were analyzed by log. Rank test (univariate); then a multivariate analysis (Cox multiple stepwise regression model) was applied. RESULTS: A total of 19 and 76% of the patients treated with famciclovir and lamivudine resp. became HBV-DNA negative; 0 and 24% HBsAg negative. Lamivudine was also effective as second line therapy. In a multivariate analysis of all 73 treatment courses, lamivudine treatment and HDV-coinfection were significant factors for better treatment response; regarding only the lamivudine group, negative HBeAg pretransplant was significant. Viral breakthrough after prolonged treatment occurred in 55% (lamivudine) to 80% (famciclovir) of treatment courses but was only accompanied by mild hepatitis. CONCLUSIONS: Lamivudine and famciclovir are potent drugs for the treatment of HBV-infection after liver transplantation. The antiviral capacity of lamivudine is superior even after pretreatment with famciclovir but after prolonged treatment viral breakthrough is often observed.     

Long-term results of hepatitis B immunoglobulin and lamuvidine for hepatitis B prophylaxis after liver transplantation

Purpose

Recurrence of hepatitis B virus after a liver transplantation (OLT) is a risk factor affecting graft and patient survivals. Short-term hepatitis B virus reactivation rates after OLT range between 3% and 15%. Using combination prophylaxis, the outcomes of OLT among patients with liver disease related to hepatitis B virus have improved to levels comparable to those whose disease is not related to hepatitis B virus.

Materials and Methods

Since September 2001, we performed 288 OLT in 282 patients including 74 who had liver failure related to hepatitis B virus among whom 58 were followed for >12 months and analyzed retrospectively. Our protocol included lamivudine (100 mg orally per day beginning the day after surgery) and hepatitis B immunoglobulin (10,000 IU IV during the anhepatic phase, 2000 IU/d IV during the first week after surgery, 2000 IU IV/month from postoperative months 1 to 12). Using our protocol, the anti-hepatitis B surface antibodies (HBsAb) serum titer was maintained up to 100 IU/mL. The female:male ratio was 11:47. The mean age of patients was 43 ± 12.8 years.

Results

Five patients died of causes unrelated to hepatitis B virus. At the time of death, their hepatitis B surface antigens were negative, and serum titers of anti-HBsAb were 45, 35.3, 56.4, 79.6, and 123 IU/mL. Mean follow-up was 46.5 ± 18.9 months (range, 12-79). The hepatitis B surface antigen became positive in 4 patients; the remaining 49 had no evidence of hepatitis B surface antigen. In 18 patients, serum titer of anti-hepatitis B surface antigen was 0; in the remaining 31 patients, it was 69.2 ± 133 IU/mL.

Conclusion

Our combination protocol with hepatitis B immunoglobulin and lamivudine is a safe, cost-saving, and effective treatment for hepatitis B virus prophylaxis after liver transplantation.     

Limited lamivudine and long-term hepatitis B immunoglobulin immunoprophylaxis for prevention of hepatitis B recurrence after liver transplantation

BACKGROUND: No consensus exists concerning dosage and duration of prophylactic hepatitis B immunoglobulin and lamivudine for prevention of hepatitis B recurrence after liver transplantation (LT). METHODS: Lamivudine was discontinued 12 months after LT, maintaining hepatitis B immunoglobulin prophylaxis in eight patients who received lamivudine treatment before LT. RESULTS: At LT, six patients were serum hepatitis B virus (HBV)-DNA negative, whereas two patients had low serum HBV-DNA levels. Hepatitis B surface (HBs) antigen and hepatitis B core antigen stained positively by immunohistochemistry in all hepatectomy specimens. All patients remained recurrence free during the 12 months on combination therapy with normal liver histological examination and negative HBs and HB core staining on biopsy specimens. No relapse occurred after lamivudine withdrawal during a median follow-up of 17.5 months (normal transaminases, negative serum HBs antigen, and HBV-DNA). CONCLUSIONS: Discontinuation of lamivudine 12 months after LT is feasible and safe even in patients with ongoing low viral replication at LT, providing adequate prophylaxis with hepatitis B immunoglobulins.     

拉米夫定预防肝移植术后乙型肝炎病毒再感染的研究

目的 探讨和评价拉米夫定预防原位肝移植术后乙型肝炎病毒（HBV）再感染的效果。方法 41例患者，术前诊断为肝炎后肝硬化（失代偿期）者22例，慢性重型肝炎并肝炎后肝硬化（失代偿期）者12例，慢性重型肝炎者7例，其中HBVDNA阳性16例。41例患者均采用背驮式原位肝移植，术前15例给予拉米夫定治疗，术后41例患者均服用拉米夫定。结果 10例患者术后出现HBV再感染，其中9例为YMDD变异毒株感染，术后1、2年的HBV再感染率分别为9．8％（4／41）、24．4％（10／41）。术前血清HBVDNA阴性者术后HBV再感染率（12．0％，3／25）明显低于HBVDNA阳性者（43．8％，7／16）。术前长期服用（超过6个月）拉米夫定者和未服用拉米夫定者术后HBV再感染率分别为66．7％、23．1％，均明显高于术前短期（未超过6个月）服用拉米夫定者（0，P〈0．05）。结论 术前服用拉米夫定可降低乙型肝炎患者肝移植后HBV再感染率，但服药时间不宜超过6个月；长期、单一的应用拉米夫定易导致病毒变异而出现耐药毒株感染。     

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.     

Liver transplantation in Asian patients with chronic hepatitis B using lamivudine prophylaxis

OBJECTIVE: To report the results of liver transplantation in 31 Asian patients with chronic hepatitis B using lamivudine prophylaxis in an open-label study. SUMMARY BACKGROUND DATA: Chronic hepatitis B is a prevalent cause of end-stage liver disease in Asia, but the results of liver transplantation in these patients are poor. METHODS: Thirty-one Asian patients with chronic hepatitis B underwent liver transplantation using lamivudine prophylaxis (100 mg daily). Twenty-three (74%) patients had detectable serum hepatitis B envelope antigen (n = 18) or hepatitis B virus DNA (n = 11) before treatment, and seven had associated hepatocellular carcinoma. Lamivudine was continued indefinitely after transplantation, and hepatitis B immune globulin was not used. RESULTS: The actuarial patient and graft survival rates were 84% and 81%, respectively. Five patients died of causes unrelated to hepatitis B, and 26 patients were alive at a median follow-up of 16 months (range 6-47) after transplantation. One (3.8%) patient developed recurrent hepatitis B resulting from viral breakthrough at week 53 and survived after retransplantation using adefovir and hepatitis B immune globulin treatment. The remaining 25 surviving patients had no biochemical or histologic evidence of recurrent hepatitis, and serum hepatitis B virus DNA remained negative by polymerase chain reaction. In six patients, hepatitis B surface antigen (HBsAg) persisted or reappeared in serum. Among 19 patients who became negative for HBsAg from 5 to 431 days after transplantation, 13 developed anti-HBsAb that lasted a median of 6 months (range 1-21). None of the seven patients with hepatocellular carcinoma developed recurrent tumor. CONCLUSIONS: Asian patients with chronic hepatitis B may achieve a good outcome after liver transplantation using lamivudine prophylaxis.     

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.     

Additional interferon alpha for lamivudine resistant hepatitis B infection after liver transplantation: a preliminary report

Resistance formation is a major problem in antiviral treatment of hepatitis B recurrence after liver transplantation. One possible therapeutic approach is an antiviral combination therapy with synergistic drugs. Four patients who were transplanted for chronic hepatitis B were analyzed retrospectively. All patients had reinfection of the graft and breakthrough of hepatitis B virus (HBV) during consecutive famciclovir and lamivudine monotherapy. Subsequently a combination therapy of lamivudine and interferon alpha 2a (3 times 3 million units weekly) was initiated. Addition of interferon markedly reduced viral replication rate in all patients. Three patients became HBV-DNA negative despite lamivudine resistance, but only two had a sustained response. No patient seroconverted to anti-HBe or lost HBsAg, but all patients showed a normalization of alanine aminotransferase and aspartate aminotransferase levels. No severe complications, and especially no rejection episodes occurred. Therefore lamivudine combined with interferon might be used for the therapy of hepatitis B reinfection after liver transplantation.     

Efficacy of lamivudine for the treatment of hepatitis B virus infection after liver transplantation in children

BACKGROUND: There is at present very little information about hepatitis B virus (HBV) infection in children after liver transplantation. This is the first study to assess the safety and efficacy of lamivudine in this patient population. METHODS: We describe three children aged 5-14 years who underwent liver transplantation for fulminant hepatitis A, hyperoxaluria, and cystic fibrosis. Despite adequate immunoprophylaxis, two of the children who were serum hepatitis B surface antigen-positive before transplantation (HBV DNA-negative by hybridization) had a reactivation of the disease, and one had a de novo HBV infection, at 12-18 months after transplantation. Lamivudine 3 mg/kg was administered on a compassionate-use basis for 14-36 months. RESULTS: After 1 month of therapy, HBV DNA disappeared from the serum in all patients by hybridization and in two patients by polymerase chain reaction. In all three children, alanine transaminase levels normalized. One child developed lamivudine resistance after 22 months with no evidence of hepatic decompensation. Repeated liver histological studies revealed progression of hepatic fibrosis in one child. All children remained serum hepatitis B surface antigen- and hepatitis B e antigen-positive. No adverse effects of the drug were noted. CONCLUSION: Lamivudine is beneficial and well tolerated in children with HBV infection after liver transplantation.