Efficacy and safety of prophylaxis with entecavir and hepatitis B immunoglobulin in preventing hepatitis B recurrence after living-donor liver transplantation

Authors


Dr Yoshihide Ueda, Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Email: yueda@kuhp.kyoto-u.ac.jp

Abstract

Aim:  Hepatitis B recurrence after liver transplantation can be reduced to less than 10% by combination therapy with lamivudine (LAM) and hepatitis B immunoglobulin (HBIG). The aim of this study was to evaluate the efficacy and safety of prophylaxis with entecavir (ETV), which has higher efficacy and lower resistance rates than LAM, combined with HBIG in preventing hepatitis B recurrence after living-donor liver transplantation (LDLT).

Methods:  Twenty-six patients who received ETV plus HBIG (ETV group) after LDLT for hepatitis B virus (HBV)-related end-stage liver disease were analyzed by comparing with 63 control patients who had received LAM plus HBIG (LAM group).

Results:  The survival rates of the patients treated with ETV plus HBIG was 73% after both 1 and 3 years, and there was no statistical difference between the patients in the ETV group and LAM group. No HBV recurrence was detected during the median follow-up period of 25.1 months in the ETV group, whereas the HBV recurrence rate was 4% at 3 years and 6% at 5 years in the LAM group. No patients had adverse effects related to ETV administration.

Conclusion:  ETV combined with HBIG provides effective and safe prophylaxis in preventing hepatitis B recurrence after LDLT.

INTRODUCTION

THE RECURRENCE OF hepatitis B virus (HBV) infection after liver transplantation for HBV-related diseases resulted in poor outcomes before the development of effective prophylaxis with lamivudine (LAM) and hepatitis B immunoglobulin (HBIG). Without the prophylaxis, the majority of patients developed recurrent infections due to HBV in the early phases after liver transplantation, and the recurrence resulted in rapidly progressive liver injury, early graft loss and reduced survival.1–3 The development of prophylaxis dramatically reduced the post-transplant recurrence of hepatitis B and markedly improved prognosis. The most widely used prophylaxis so far has been a combination therapy of LAM and i.v. HBIG.

In the non-transplant setting, the long-term use of LAM resulted in high rates of emergence of resistance to the drug, with rates ranging 14–32% after 1 year and 60–70% after 5 years of treatment. In most cases, the resistance was the result of selection of LAM-resistant mutations in the YMDD motif of the DNA polymerase domain of HBV.4 Moreover, the emergence of HBV strains with mutations that allow escape from hepatitis B surface antibody (anti-HBs) recognition has been reported in patients vaccinated for HBV,5,6 in patients with chronic hepatitis B7,8 and in liver transplant recipients after HBIG administration.9–11 Therefore, the emergence of LAM resistance and HBIG resistance might increase the risk of recurrence during long-term administration of LAM and HBIG, although the rate of HBV recurrence in liver transplant recipients who received prophylaxis with LAM and HBIG for more than 10 years has not been reported to date. At present, several nucleoside analogs are available for the treatment of chronic hepatitis B4. Among them, there is entecavir (ETV), a carbocyclic analogue of 2′-deoxyguanosine, which has been shown to have higher efficacy than LAM in patients with chronic hepatitis B. In addition, ETV has a higher genetic barrier to resistance than LAM. The resistance to ETV requires at least three mutations including rtM204V/I, which causes LAM-resistance, rtL180M, and a mutation at one of the following codons: rtT184, rtS202 or rtM250.4 Therefore, ETV is now used as a first-line therapy in the treatment of chronic hepatitis B worldwide. Data available in the published work suggest that, in transplant recipients, ETV plus HBIG represents a better prophylaxis protocol than LAM plus HBIG for long-term prevention of HBV recurrence after liver transplantation. However, the efficacy and safety of this treatment is largely unknown.

The aim of this study was to evaluate the efficacy and safety of prophylaxis with ETV and HBIG in preventing hepatitis B recurrence after living-donor liver transplantation (LDLT).

METHODS

Patients

WE RETROSPECTIVELY ANALYZED the medical records of 97 patients who underwent LDLT for HBV-related end-stage liver diseases from September 2002 to December 2010. Of these, eight patients were excluded from our study because they had breakthrough hepatitis due to HBV with LAM-resistant mutations and were prescribed LAM plus adefovir before liver transplantation. Accordingly, 89 patients were enrolled in this study.

Prophylaxis with ETV or LAM combined with HBIG

Lamivudine plus HBIG therapy was given to all recipients with HBV-related end-stage liver diseases from September 2002 to November 2006, as reported previously.12 From December 2006, we changed the protocol for prophylaxis to ETV plus HBIG. ETV at a dose of 0.5 mg/day or LAM at a dose of 100 mg/day was given before transplantation, usually when the patient was referred to the hospital and scheduled for transplantation. Preoperative ETV or LAM prophylaxis was followed by combination with HBIG after transplantation. The first application of HBIG at a dose of 200 IU/kg body mass was administrated i.v. during the anhepatic phase of LDLT, and repeated every day for the first 5 days post-surgery. HBV serological markers were examined at weekly intervals for the first 2 months after the transplant, then at monthly intervals, and 1000 IU of HBIG was periodically administrated to maintain the serum anti-HBs titers at more than 500 IU/L during the first 6 months and 200 IU/L thereafter throughout the follow-up period.12

Immunosuppression

Tacrolimus and low-dose steroid therapy were administrated to induce immunosuppression in most patients.13 Mycophenolate mofetil was administrated to patients who experienced refractory rejection or required reduction of tacrolimus dose due to adverse events. Patients who received ABO blood-type-incompatible transplants were treated with rituximab, plasma exchange, and hepatic artery or portal vein infusion with prostaglandin E1 and methylprednisolone.14

Diagnosis of HBV activation

Activation of HBV was diagnosed when hepatitis B surface antigens (HBsAg) and/or HBV DNA became positive in the serum of the patients. After LDLT, HBsAg, anti-HBs and serum HBV DNA were measured at least at 3 monthly intervals. Serological HBV markers, including HBsAg, anti-HBs, hepatitis B core antibody, hepatitis B e antigen (HBeAg) and antibodies to HBeAg (anti-HBe), were measured by chemiluminescent enzyme immunoassay (Fuji Rebio, Tokyo, Japan). Serum HBV DNA titer was analyzed using a commercial polymerase chain reaction (PCR) assay (Amplicor HBV Monitor; Roche, Branchburg, NJ, USA). LAM-resistant YMDD mutant virus was detected by the PCR enzyme-linked mini-sequence assay.15

Statistical analysis

Baseline characteristics are shown in Table 1. For continuous variables, medians and ranges are given, and the significance of the data was analyzed with the Wilcoxon rank sum test. For categorical variables, counts are given, and the data were analyzed with the χ2-test. Survival rates and the rates of patients who showed HBV activation after LDLT were estimated using the Kaplan–Meier method and compared using log–rank tests. P < 0.05 was considered significant.

Table 1. Baseline characteristics of 90 patients
 Entecavir + HBIG (n = 26)Lamivudine + HBIG (n = 63) P-value
  • Qualitative variables are shown in number; and quantitative variables expressed as median (range).

  • Wilcoxon rank sum test.

  • χ2-Test.

  • HBeAg, hepatitis B e antigen; HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LDLT, living-donor liver transplantation.

Age (years)55 (33−68)53 (26−64)0.062
Men/women19/746/170.995
Primary disease  0.595
 Acute liver failure6 (23%)9 (14%) 
 Liver cirrhosis, HCC6 (23%)20 (32%) 
 Liver cirrhosis, HCC+14 (54%)34 (54%) 
HBV markers before LDLT   
 HBsAg+24 (92%)61 (97%)0.350
 HBeAg+6 (23%)18 (29%)0.595
HBV DNA before LDLT<2.6 (<2.6–7.6<)3.7 (<2.6–7.6<)0.010
 <2.6 log IU/mL14 (54%)19 (30%)0.024
Follow-up period (months)25.1 (0.2–58.6)70.6 (0.5–109.2)<0.001

RESULTS

Patient characteristics

TWENTY-SIX PATIENTS who received ETV plus HBIG (ETV group) after LDLT for HBV-related end-stage liver disease were included in this study. Baseline characteristics of these patients are listed in Table 1 and compared with those of 63 control recipients who received LAM plus HBIG (LAM group) at our institute already present in our database. The two groups of patients did not differ significantly by age, sex, primary diseases or serological markers for HBV before LDLT. Serum HBV DNA levels before LDLT were significantly lower in the ETV group than in the LAM group. Fourteen of 26 patients (54%) showed less than 2.6 log IU/mL of serum HBV DNA in the ETV group. Median follow-up period was 25.1 months (range, 0.2–58.6) in the ETV group, whereas it was 70.6 months (range, 0.5–109.2) in the LAM group.

Efficacy and safety of prophylaxis with ETV plus HBIG

Survival rates of the patients treated with ETV plus HBIG estimated by Kaplan–Meier analysis was 73% at both 1 and 3 years (Fig. 1a). There was no difference between the ETV group and the LAM group, in which survival rates were 81% at 1 year, 78% at 3 years and 73% at 5 years. Causes of death in patients in the ETV group were pneumonia (n = 2), sepsis (n = 1), pulmonary hemorrhage (n = 1), cerebral hemorrhage (n = 1), graft liver failure (n = 1) and multiple organ failure (n = 1), none of which were related to ETV. No HBV recurrence was detected in the median follow-up period of 25.1 months in the ETV group, whereas the HBV recurrence rate was 2% at 1 year, 4% at 3 years and 6% at 5 years in the LAM group (Fig. 1b). Three patients in the LAM group had HBV recurrence at 10, 34 and 46 months after LDLT. The emergence of HBV with LAM-resistant mutations in the YMDD motif was confirmed in two of the three patients. HBV mutations of another patient could not be determined because of the low level of serum HBV DNA. As the follow-up period of the ETV group was shorter than that of the LAM group and the HBV recurrence in the LAM group occurred in long-term follow-up after LDLT, the rate of HBV recurrence was not significantly different between the ETV and LAM groups. No patients had adverse events due to ETV administration.

Figure 1.

(a) Post-transplantation survival rates and (b) hepatitis B virus (HBV) recurrence after living-donor liver transplantation in HBV positive recipients who received entecavir and hepatitis B immunoglobulin (HBIG) (solid line), or lamivudine and HBIG (dotted line), estimated by Kaplan–Meier method.

DISCUSSION

IN THIS STUDY, we demonstrated that ETV combined with HBIG provides effective and safe prophylaxis in preventing hepatitis B recurrence after LDLT.

Two studies of patients receiving a combination of ETV and HBIG after liver transplantation have been previously reported.16,17 One study demonstrated that 30 recipients who received ETV plus HBIG prophylaxis had no recurrence of HBV and no adverse effect relating to ETV.17 The other study showed that no HBV recurrence was observed in two recipients with HBV-associated cirrhosis receiving ETV, tenofovir and HBIG.16 Both studies showed the efficacy and safety of prophylaxis with ETV and HBIG in preventing short-term recurrence of HBV after liver transplantation. The current study confirmed their results for longer follow-up periods. Our results showed that prophylaxis with ETV and HBIG has similar efficacy and safety to that with LAM and HBIG, but did not show any further advantage of ETV compared to LAM treatment. Longer follow up might be needed to reveal the difference of HBV recurrence rate. One characteristic of our present report is that all patients in this study underwent LDLT. Our results suggest that prophylaxis with ETV and HBIG in patients after LDLT has similar efficacy and safety to patients after deceased-donor liver transplantation demonstrated in the previous reports.16,17 More recently, efficacy of ETV monotherapy in preventing recurrence of HBV for liver transplant recipients with chronic hepatitis B was reported.18 The study demonstrated that most patients showed disappearance of HBsAg and undetectable serum HBV DNA after liver transplantation without HBIG. Although long-term efficacy of ETV monotherapy needs be confirmed, both our data and previous reports suggest that ETV is an effective and safe antiviral agent in the post-transplant setting.

ACKNOWLEDGMENTS

THIS WORK WAS supported by Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (no. 21229009 and 23590972), Health and Labor Sciences Research Grants for Research on Intractable Diseases, and Research on Hepatitis from the Ministry of Health, Labor and Welfare, Japan, and a grant from Bristol-Myers-Squibb.

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