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Keywords:

  • Hepatitis B recurrence;
  • liver transplantation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Liver transplant recipients are at risk of developing recurrent hepatitis B after liver transplantation for hepatitis B virus (HBV)-related liver disease. We evaluated the efficacy of a new hepatitis B prophylaxis regimen involving conversion from at least 12 months of HBIg with lamivudine to combination therapy with an oral nucleoside and nucleotide analog. Between June 2008 and May 2010, a total of 61 liver transplant recipients were converted to a combination of a nucleoside and nucleotide analog. The mean (±standard deviation) follow-up time after conversion was 15.0 (±6.1) months. Recurrent HBV occurred in two (3.3%) patients at 3.1 and 16.6 months after HBIg cessation. The overall person time incidence rate for HBV recurrence after HBIg cessation was 2.7 cases per 100 person-years. The estimate of HBV recurrence was 1.7% at 1 year after HBIg cessation. HBIg cessation a minimum of 12 months after liver transplantation with subsequent combination therapy with a nucleoside and nucleotide analog provides effective prophylaxis against recurrent HBV infection. The clinical implications of HBsAg detection without clinical, biochemical or molecular manifestations of recurrent hepatitis B require further study.


Abbreviations: 
HBeAg

hepatitis B e antigen

HBIg

hepatitis B immune globulin

HBsAb

hepatitis B surface antibody

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

HBV DNA

hepatitis B virus deoxyribonucleic acid

HCC

hepatocellular carcinoma

IM

intramuscular

IV

intravenous

MELD

model for end-stage liver disease

OLT

orthotopic liver transplantation

SD

standard deviation

UCLA

University of California Los Angeles

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

The most commonly accepted strategy for the prevention of hepatitis B recurrence in liver transplant recipients is the combination of lifelong hepatitis B immune globulin (HBIg) and an oral antiviral agent, such as lamivudine (1). This strategy effectively decreases the risk of hepatitis B reinfection in liver transplant recipients, which translates into a patient survival rate that is among the highest of all indications for transplantation (2–4). The overall survival of patients transplanted for hepatitis B virus (HBV)-related cirrhosis, for instance, now exceeds 85% at 1 year and 75% at 5 years (5).

The use of lifelong HBIg for hepatitis B prophylaxis has limitations, namely the high cost, parenteral administration, limited supply, and need for frequent clinic visits and laboratory monitoring (6). Additionally, HBIg is a blood product and its administration could be avoided if a safe nonbiological alternative existed. Regarding cost, intravenous (IV) HBIg can create annual expenses of greater than $100 000 during the first posttransplant year and greater than $50 000 during subsequent years, while intramuscular (IM) HBIg may incur costs of up to $80 000 during the first posttransplant year and greater than $9 000 annually thereafter depending on the administration protocol (7,8). Various methods to reduce the cost associated with lifelong high-dose IV HBIg have been studied and include substitution with IM HBIg (4). Other authors have proposed HBIg cessation with continuation of lamivudine monotherapy, but this is not a widely accepted practice secondary to the concern for HBV breakthrough due to the development of lamivudine resistant viral strains (3,9,10).

Another approach for prevention of recurrent hepatitis B entails HBIg cessation with subsequent administration of a combination of a nucleoside and a nucleotide analog agent. Small case series have demonstrated that combination therapy with adefovir plus lamivudine can effectively prevent hepatitis B recurrence (11–13). Moreover, the use of a combination of oral drugs effectively treats hepatitis B recurrence secondary to escape mutants that occur in patients on HBIg therapy (14,15). The use of a combination of oral drugs would result in potential cost savings of greater than $14 000 over 10 years, as compared to the standard regimens of HBIg with lamivudine (16,17).

Due to the cumbersome nature of using HBIg in our patients, and the growing experience of using a combination of a nucleoside and a nucleotide agent, we changed our hepatitis B prophylaxis protocol in patients transplanted for HBV-related disease. This new protocol entails conversion to an all oral antiviral strategy after at least 12 months of IM HBIg concurrently with one nucleoside analog. The aim of the current study is to formally evaluate the efficacy of using a combination of a nucleoside and a nucleotide agent after HBIg cessation for prevention of hepatitis B recurrence after liver transplantation.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Study design

This single-center retrospective study examined 61 patients, who underwent deceased donor orthotopic liver transplantation (OLT) between 1993 and 2009, for end-stage liver disease secondary to hepatitis B and received posttransplant care at the Dumont University of California Los Angeles (UCLA) Transplant Center. Beginning in 2008, these patients were enrolled in a new hepatitis B prophylaxis protocol that involved conversion to dual oral combination therapy with one nucleoside analog (lamivudine or entecavir) and one nucleotide analog (adefovir or tenofovir) after prior administration of standard prophylaxis with at least 12 months of IM HBIg and single agent nucleoside analog therapy. This study was approved by the UCLA Institutional Review Board and was performed in accordance with the declaration of Helsinki.

Hepatitis B prophylaxis protocol

Approximately 85 patients with hepatitis B were actively being followed by the UCLA Liver Transplant Center between 2008 and 2010 and were therefore screened for inclusion in this study. A total of 61 patients were converted to dual combination therapy with one nucleoside analog and one nucleotide analog and met the following inclusion criteria: (1) Had received a minimum of 12 months of IM HBIg with single agent nucleoside analog post-OLT, (2) had undetectable hepatitis B virus deoxyribonucleic acid (HBV DNA) and negative hepatitis B surface antigen (HBsAg), (3) were on a stable immunosuppression regimen without the use of corticosteroids, (4) had stable renal function defined by a creatinine that had not increased by more than 0.5 mg/dL from baseline over the preceding 3 months, (5) had stable hepatic graft function and (6) did not have any episodes of allograft rejection within the past 6 months. Patients with chronic stable renal dysfunction were eligible for inclusion if there had been no acute change in renal function over the prior 3 months. Exclusion criteria included (1) treatment with less than 12 months of HBIg post-OLT, (2) HBV breakthrough while on HBIg evidenced by detectable HBV DNA or detectable HBsAg, (3) current use of corticosteroids for immunosuppression, (4) evidence of liver allograft rejection, (5) patient intolerance of oral antiviral medications, (6) patient's preference not to convert to oral regimen, (7) conversion to a single agent oral antiviral therapy for another research protocol, (8) liver transplantation for a non-HBV-related primary diagnosis and (9) transfer of care to another medical center.

The HBIg immunoprophylaxis regimen has been described previously (18). Specifically, before 1998, patients were administered 10 000 units of IV HBIg during the anhepatic phase, followed by a 7-day course of IV HBIg 10 000 units per day and then 10 000 units per month. After 1998, patients were administered IV HBIg 10 000 units during the anhepatic phase, IV HBIg 2000 units per day during postoperative days 2 through 7 and IV HBIg 2000–10 000 units on postoperative day 20 to keep hepatitis B surface antibody (HBsAb) titers greater than 500 IU/mL. Thereafter, patients were administered IM HBIg 1560 units every 2–4 weeks to maintain HBsAb titer greater than 500 IU/mL at 0–6 months, greater than 250 IU/mL at 6–12 months, and greater than 100 IU/mL after 12 months.

For patients transplanted prior to 1998, hepatitis B prophylaxis consisted of HBIg alone. In the late 1990s and thereafter, with the availability of nucleoside analogs, patients were initiated on dual therapy with HBIg plus one nucleoside analog for hepatitis B prophylaxis. Beginning in 2008, patients were converted to the new dual oral antiviral regimen. For a minimum of 12 months after liver transplantation, patients were administered one nucleoside agent (lamivudine or entecavir) concurrently with HBIg. Three months prior to HBIg cessation, patients were also initiated on one nucleotide analog (adefovir or tenofovir). After 3 months of overlap therapy, consisting of HBIg, a nucleoside analog and a nucleotide analog, HBIg was stopped. Overlap therapy was conducted to ensure patients were tolerant of the dual oral antiviral regimen prior to HBIg cessation. Patients were most commonly maintained on a regimen of lamivudine and tenofovir. The two oral antiviral agents were continued indefinitely. Specifics regarding the protocol for nucleos(t)ide agents of choice during HBIg therapy and after conversion to oral agents alone was dependent on the pretransplant antiviral regimen and is detailed in Table 1. Pretransplant nucleos(t)ide analog resistance was not formally assessed in our patient population.

Table 1.  Hepatitis B prophylaxis strategy1
Pretransplant therapyPosttransplant HBIg + nucleoside analogPosttransplant nucleoside analog + nucleotide analog
  1. 1All oral antiviral doses corrected for renal function.

  2. Abbreviation: HBIg, hepatitis B immune globulin.

LamivudineHBIg + lamivudineLamivudine + (tenofovir or adefovir)
AdefovirHBIg + lamivudineLamivudine + (tenofovir or adefovir)
EntecavirHBIg + (lamivudine or entecavir)(Lamivudine or entecavir) + (tenofovir or adefovir)
Lamivudine + adefovirHBIg + lamivudineLamivudine + (tenofovir or adefovir)
Entecavir + adefovirHBIg + entecavirEntecavir + (tenofovir or adefovir)
NoneHBIg + lamivudineLamivudine + (tenofovir or adefovir)

Immunosuppression

The immunosuppression regimen used at our institution has been described previously (18). Specifically, the regimen consisted of tacrolimus or cyclosporine, with or without a combination of mycophenolate mofetil, corticosteroids or sirolimus. Patients received peri- and postoperative IV corticosteroids, which were thereafter transitioned to oral prednisone with subsequent tapering as tolerated. Patients were maintained on tacrolimus indefinitely, with conversion to cyclosporine if concerns for side effects such as neurotoxicity arose. Mycophenolate and sirolimus were added as necessary. Immunosuppressive dosing was adjusted according to therapeutic drug levels and renal function.

Surveillance for hepatitis B recurrence

Prior to transplantation, HBsAg, hepatitis B e antigen (HBeAg) and HBV DNA were measured using standard commercial assays. After transplantation, patients were followed closely by the UCLA liver transplant team with careful monitoring for hepatitis B recurrence. Serum HBsAg and HBsAb titers were tested monthly while patients were maintained on combination HBIg plus single agent nucleoside analog therapy. After HBIg cessation, patients underwent regularly scheduled laboratory testing of HBsAg and HBV DNA every 2–3 months. From 1996 until 2004, HBV DNA levels were quantified with the Digene HBV test (Digene Corp., Gaithersburg, MD, USA) and Hybrid Capture II technology (Digene) via a signal amplification hybridization microplate assay. After 2004, HBV DNA levels were tested with the COBAS TaqMan HBV test using real-time polymerase chain reaction amplification (Roche Molecular Systems, Inc., Branchburg, NJ, USA). The primary endpoint of the study was hepatitis B recurrence, defined as the reappearance of HBsAg after HBIg cessation, with or without detectable serum HBV DNA levels.

Statistical analysis

All collected data were entered and stored in commercial spreadsheet software (Excel, Microsoft, Seattle, WA, USA). MedCalc version 11.3.3 statistical software (MedCalc Software, Mariakerke, Belgium) was used to analyze the relevant data. Continuous variables are presented as mean ± standard deviation (SD). Categorical data are presented as the number (percentage).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Demographics

A retrospective review was conducted of 61 patients who underwent liver transplantation for HBV-related liver disease between June 1993 and April 2009. The cohort consisted of 51 males and 10 females with a mean (±SD) age of 58.4 (±11.9) years. These liver transplant recipients were converted to the combination of a nucleoside and a nucleotide agent between June 2008 and May 2010. The mean (±SD) follow-up time after transplantation was 96.8 (±55.3) months. The standard protocol maintained patients on IM HBIg plus single agent nucleoside analog therapy for a minimum of 12 months after liver transplantation, with a mean (±SD) duration of 81.9 (±54.0) months. After HBIg cessation and conversion to dual nucleoside and nucleotide agent combination therapy, the mean (±SD) follow-up time was 15.0 (±6.1) months. Demographic details for the 61 patients are summarized in Table 2. Of the 46 patients with available HBeAg status prior to transplant, 15 (32.6%) patients had a positive HBeAg. Of the 42 patients with available HBV DNA data prior to transplant, 9 (21.4%) patients had detectable HBV DNA with a mean (±SD) viral titer of 3.75 × 107 (±7.87 × 107) IU/mL. Prior to 2004, HBV DNA levels were quantified via a signal amplification hybridization microplate assay, which may have had limited sensitivity thereby accounting for the proportion of patients with positive HBeAg but negative HBV DNA. Of the 22 patients with available hepatitis delta data, 3 (13.6%) patients had hepatitis delta coinfection. Five (8.2%) of 61 total patients had hepatitis C coinfection. None of the patients were co-infected with HIV. The mean (±SD) biological model for the end-stage liver disease (MELD) score was 21.0 (±13.3). Twenty-three (37.7%) patients had hepatocellular carcinoma (HCC) prior to transplant.

Table 2.  Demographics of the 61 total patients
  1. Abbreviations: HBeAg = hepatitis B e antigen; HBV DNA = hepatitis B virus deoxyribonucleic acid; HCC = hepatocellular carcinoma; MELD = model for end-stage liver disease; OLT = orthotopic liver transplantation; SD = standard deviation.

Age, mean ± SD (years)58.4 ± 11.9
Time since OLT, mean ± SD (years)6.8 ± 4.5
Gender
 Male51 (83.6%)
 Female10 (16.4%)
MELD, mean ± SD21.0 ± 13.3
HBeAg positivity pre-OLT (n = 46)15 (32.6%)
HBV DNA pre-OLT (n = 42)
 Positivity9 (21.4%)
 Viral titer, mean ± SD (IU/mL)3.75 × 107± 7.87 × 107
Hepatitis delta positivity pre-OLT (n = 22)3 (13.6%)
Hepatitis C positivity pre-OLT5 (8.2%)
Pre-OLT HCC23 (37.7%)
Post-OLT HCC recurrence1 (1.6%)

Prior to transplant, 37 (60.7%) patients were treated with hepatitis B oral antiviral agents. Posttransplant, all patients were treated with HBIg. HBIg was administered in combination with single agent nucleoside analog therapy after these agents became widely available in the late 1990s. Details regarding specific oral antiviral regimens pre- and posttransplant are included in Table 3. By the conclusion of the study, 60 (98.4%) of 61 total patients were alive, with 1 patient dying 12 months after HBIg cessation due to unrelated causes without evidence of hepatitis B recurrence.

Table 3.  Hepatitis B prophylaxis pre- and post-OLT for the 61 total patients
  1. Abbreviations: HBIg = hepatitis B immune globulin; HBV DNA = hepatitis B virus deoxyribonucleic acid; OLT = orthotopic liver transplantation; SD = standard deviation.

Pre-OLT: Nucleos(t)ide analog therapy
 Lamivudine26 (42.6%)
 Adefovir1 (1.6%)
 Entecavir2 (3.3%)
 Lamivudine + adefovir7 (11.5%)
 Entecavir + adefovir1 (1.6%)
 None24 (39.3%)
Post-OLT: HBIg + single nucleoside analog therapy
   HBIg + lamivudine60 (98.4%)
   HBIg + entecavir1 (1.6%)
Post-OLT: Time on HBIg + single nucleoside analog, mean ± SD (months)81.9 ± 54.0
Post-OLT: Dual nucleos(t)ide analog therapy
 Lamivudine + adefovir19 (31.1%)
 Lamivudine + tenofovir41 (67.2%)
 Entecavir + adefovir1 (1.6%)
Post-OLT: Time on dual nucleos(t)ide analog therapy, mean ± SD (months)15.0 ± 6.1
Post-OLT: Negative HBsAg59 (96.7%)
Post-OLT: Undetectable HBV DNA61 (100%)

Hepatitis B recurrence

Evidence of recurrent hepatitis B occurred in 2 (3.3%) of 61 total transplant recipients, marked by seroconversion from negative to positive HBsAg. In both cases, HBsAg detection was associated with an undetectable HBV DNA, normal liver enzymes and no clinical manifestations of hepatitis B recurrence. These two cases of recurrence occurred at 3.1 and 16.6 months after HBIg cessation, with detailed clinical information presented in Table 4. The overall person time incidence rate for HBV recurrence after HBIg cessation was 2.7 cases per 100 person-years (95% confidence interval, 0.62–7.23). The estimate of HBV recurrence was 1.7% at 1 year after HBIg cessation. All 61 patients maintained undetectable HBV DNA for the duration of the study, and therefore posttransplant nucleos(t)ide analog resistance was not assessed. Importantly, there was no significant decline in renal function, as evidenced by stable creatinine levels, in patients treated with oral antiviral agents including tenofovir. Of the 23 patients with HCC prior to transplant, only 1 patient experienced HCC recurrence posttransplant, without evidence of HBV recurrence.

Table 4.  Clinical information for the two cases of hepatitis B recurrence marked by seroconversion to positive hepatitis B surface antigen
 Case 1Case 2
  1. Abbreviations: HBeAg = hepatitis B e antigen; HBIg = hepatitis B immune globulin; HBV = hepatitis B virus; HBV DNA = hepatitis B virus deoxyribonucleic acid; HCC = hepatocellular carcinoma; MELD = model for end-stage liver disease; OLT = orthotopic liver transplantation.

Age (years)57.461.9
GenderMaleMale
MELD4219
Hepatitis delta coinfectionNoUnknown
Hepatitis C coinfectionNoNo
Pre-OLT: HCCNoNo
Pre-OLT: HbeAgPositiveUnknown
Pre-OLT: HBV DNA (IU/mL)UndetectableUndetectable
Pre-OLT: Nucleos(t)ide analog therapyNoneLamivudine
Post-OLT: HBIg + single nucleoside analogHBIg + lamivudineHBIg + lamivudine
Post-OLT: Time on HBIg + single nucleoside analog (months)142.643.8
Post-OLT: Dual nucleos(t)ide analog therapy after HBIg cessationLamivudine + tenofovirLamivudine + tenofovir, then lamivudine + adefovir
Time to HBV recurrence after HBIg cessation (months)3.116.6
Time to HBV recurrence after OLT (months)145.760.3
Post-OLT HBV DNA (IU/mL)UndetectableUndetectable
Medication complianceYesYes
Follow-up time since HBV recurrence (months)15.56.3
OutcomeAliveAlive

Recurrence case 1 seroconverted to positive HBsAg 3.1 months after HBIg cessation and was not treated with antiviral medication prior to liver transplantation (Table 4). Pretransplant laboratory testing demonstrated positive HBeAg and undetectable HBV DNA, possibly related to the limited sensitivity of HBV DNA microplate assays prior to 2004. Prior to transplant, HCC was not present and the MELD score was 42. HBIg and lamivudine were administered for 142.6 months after transplant. After HBIg cessation, HBV prophylaxis was continued with lamivudine and tenofovir. Case 1 became HBsAg positive 3.1 months after HBIg cessation, with laboratory monitoring over the next 15.5 months demonstrating continued detectable HBsAg. Dual therapy with lamivudine and tenofovir was continued even after HBsAg seroconversion as HBV DNA remained undetectable and liver function enzymes remained within normal limits. Fifteen months after initial seroconversion to detectable HBsAg, case 1 was alive and doing well with no clinical manifestations of hepatitis B recurrence.

Hepatitis B recurrence case 2 seroconverted to detectable HBsAg 16.6 months after cessation of HBIg (Table 4). Prior to transplant, case 2 was on lamivudine monotherapy and had undetectable HBV DNA. The MELD score at the time of transplant was 19 and HCC was not present. HBIg and lamivudine were administered for a total of 43.8 months posttransplant. At the time of HBIg cessation, antiviral agents were administered at doses corrected for renal dysfunction attributed to a combination of tacrolimus toxicity, diabetes and hypertension, with lamivudine dosed every 2 days and tenofovir initiated with doses every 3 days. Renal dysfunction in case 2 did not worsen while on tenofovir but remained stable. After HBsAg detection, case 2 was switched to combination lamivudine dosed every 2 days and adefovir dosed every 3 days in a global attempt to reduce the risk of nephrotoxicity, although the renal dysfunction had preceded tenofovir usage. Subsequent laboratory monitoring over the next 6.3 months demonstrated continued positive HBsAg, with undetectable HBV DNA and normal liver function tests. Liver biopsy was performed and did not show any changes diagnostic of recurrent hepatitis B. Six months after initial HBsAg seroconversion, case 2 was alive, without clinical manifestations of recurrent HBV, and was undergoing renal transplant evaluation.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Currently, the standard of care to prevent hepatitis B recurrent infection after liver transplantation consists of lifelong therapy with HBIg plus lamivudine, a costly and cumbersome regimen. We found that HBIg cessation a minimum of 12 months after transplant with subsequent administration of a combination of a nucleoside and a nucleotide analog agent provides effective prophylaxis against recurrent HBV infection. Specifically, hepatitis B recurrence marked by detectable HBsAg occurred in only 2 (3.3%) of 61 total patients, with a rate similar to that associated with standard regimens of combination lamivudine and IM HBIg (7). Importantly, dual nucleos(t)ide analog prophylaxis prevented the development of measurable HBV replication in these two patients. Additionally, cases of HBsAg detection were associated with normal liver enzymes and no clinical manifestations of hepatitis B recurrence.

Concerns remain about applying this protocol to patients with chronic stable renal dysfunction. As recurrence case 2 seroconverted to detectable HBsAg while on oral antivirals dosed for renal dysfunction, there remains concern that dosing reduction may have contributed to HBsAg emergence. Therefore, renal dysfunction may represent a contraindication to the suggested protocol for HBIg withdrawal. Furthermore, we did not study the interaction between hepatitis delta, hepatitis C and pretransplant hepatitis B viremia on the risk of hepatitis B breakthrough on our protocol. Thus, the conversion to oral antivirals may be best applied to low-risk patients with undetectable HBV DNA prior to transplant. Overall, in patients with stable renal function, dual therapy with nucleoside and nucleotide analogs effectively prevents HBV recurrence following HBIg cessation and is associated with undetectable HBV DNA even in the presence of HBsAg seroconversion.

Renal toxicity remains a concern of long-term usage of oral antiviral drugs for HBV. While this study demonstrated no significant change in renal function in patients on oral antiviral therapy during the follow-up period of 15.0 (±6.1) months, studies with longer durations of follow-up should be conducted to further evaluate concerns for renal toxicity. In patients converted to dual oral antiviral therapy, it is prudent to frequently monitor renal function, especially in those taking other nephrotoxic drugs and in those with chronic stable renal dysfunction.

Hepatitis B prophylaxis with dual nucleoside and nucleotide analog therapy has been investigated by only a small number of studies to date. Angus et al. found that combination adefovir plus lamivudine, compared with combination HBIg plus lamivudine, provides equivalent protection against recurrent hepatitis B, with only 1 out of 16 patients in the adefovir group seroconverting to positive HBsAg with undetectable HBV DNA (11). Similarly, Lo et al. studied a small cohort of patients after liver transplantation and demonstrated no hepatitis B viral breakthrough after treatment with lamivudine plus adefovir, with 2 of 16 patients having detectable HBsAg but undetectable HBV DNA and no biochemical evidence of recurrence (12). Nath et al. found that only 1 of 14 liver transplant recipients treated with lamivudine and adefovir prophylaxis developed detectable HBsAg with hepaptitis B viremia (13). However, the patient developed no clinical complications, and had liver enzymes. Additionally, recent studies have demonstrated increasing experience with using tenofovir plus emtricitabine after HBIg cessation to effectively prevent hepatitis B recurrence (19). These prior studies demonstrate low rates of HBV reinfection, findings similar to our study. However, prior studies examining HBV recurrence in patients on dual nucleoside and nucleotide analog therapy have been limited by the small number of patients. Our study of 61 total patients represents the largest study thus far evaluating the efficacy of hepatitis B prophylaxis with dual nucleoside and nucleotide analogs after HBIg cessation.

Interestingly, both our study and prior studies demonstrated multiple cases of seroconversion to positive HBsAg associated with undetectable HBV DNA (11,12). A prior proposed explanation for this is that HBsAg was being produced at low levels while on HBIg therapy and became detectable after HBIg cessation with the concurrent fall in HBsAb titers (11). Longer-term follow-up of patients who seroconvert to positive HBsAg is necessary to determine whether they will eventually clear HBsAg or whether they are at future risk for virologic breakthrough and clinical recurrence. Risk factors for recurrent hepatitis B while on HBIg therapy have been described previously and include age greater than 60 years at OLT, pre-OLT HCC, HCC recurrence after OLT, and pre-OLT and post-OLT systemic chemotherapy (18). Studies involving larger cohorts of patients are needed to fully elucidate the potential risk factors leading to hepatitis B recurrence after HBIg cessation. Additionally, the clinical implications of HBsAg detection without biochemical, clinical or molecular manifestations require further study.

In our study, the two most commonly used hepatitis B prophylaxis regimens were lamivudine combined with either adefovir or tenofovir. These regimens combined the use of nucleoside and nucleotide analogs, classes of medication with differing mechanisms of action and without cross-resistance, to provide an effective barrier for the development of multi-drug resistant HBV. In particular, recent studies of combination lamivudine and adefovir therapy have shown lower rates of virologic breakthrough and improved biochemical response marked by lower HBV DNA, as compared to adefovir monotherapy (20). Additionally, the utility of a combination of nucleoside and a nucleotide agent is demonstrated in patients who develop HBV recurrence despite HBIg and lamivudine therapy with subsequent viral suppression after adefovir and lamivudine treatment (14).

The use of dual nucleoside and nucleotide analog therapy is cost effective as compared to standard regimens involving lifelong HBIg administration. The annual cost for adefovir and lamivudine has been estimated to be greater than $8000, as compared to a yearly cost of greater than $13 000 for low-dose IM HBIg plus lamivudine, representing an annual savings of over $5000 when administering dual nucleos(t)ide analog therapy (11). Other studies have found significant potential cost savings ranging from $14 000 to $139 000 over 10–15 years when administering dual nucleos(t)ide analog therapy as compared to regimens involving IM HBIg (7,17).

In addition to the pharmacoeconomic advantage of avoiding the use of parenteral HBIg for hepatitis B prophylaxis, there are also quality of life advantages. Administration of HBIg requires frequent blood tests to assess HBsAb titers as well as monthly clinic visits for HBIg administration. Contrastingly, oral medications require less frequent clinic visits, although the need to monitor renal function with blood tests remains. Additionally, compliance with HBIg administration is a concern, with reported noncompliance rates of up to 15% (3), whereas noncompliance with oral adefovir has been reported to be as low as 1% (21).

Limitations of this study include its retrospective design and short-term follow-up and are important factors to take into account when drawing conclusions. Due to the retrospective nature of the study, we were unable to maintain homogeneity in all baseline clinical characteristics such as pre-OLT antiviral regimen, pre-OLT HBV DNA, HBeAg status and coinfection with hepatitis delta or hepatitis C. This is clinically relevant as many of these factors may affect posttransplant hepatitis B recurrence risk. Therefore, when generalizing our conclusions, it may be most prudent to initially apply them to a population at low risk of hepatitis recurrence such as those with undetectable HBV DNA at the time of transplant and without viral coinfections. Additionally, as our patients were followed for a mean of 15 months after conversion to oral antivirals, we are unable to draw conclusions for outcomes after this time period. Other limitations of our study include lack of a control group, as all eligible patients at our center were converted to dual nucleoside and nucleotide analog therapy. Additionally, this study was only performed at a single center. Larger, prospective, multi-center controlled trials, with longer follow-up periods, are needed to further examine the efficacy of combination nucleos(t)ide therapy for hepatitis B prophylaxis. Nevertheless, this study is one of the largest of its kind, and our results are consistent with those of previous studies demonstrating the efficacy of dual nucleoside and nucleotide analog therapy in preventing HBV recurrence. This study provides adequate preliminary data to warrant future-related studies.

In conclusion, this single-center retrospective study demonstrated that HBIg cessation a minimum of 12 months after liver transplantation with subsequent dual nucleoside and nucleotide analog therapy provides an effective prophylaxis against recurrent HBV infection. The use of regimens that do not require lifelong HBIg administration will have important implications in the future cost effectiveness of posttransplant health care. Overall, the low rates of HBV recurrence coupled with the lower cost and ease of administration of dual nucleoside and nucleotide analog therapy may lead to a change in the national standard of care for prevention of hepatitis B recurrence in liver transplant recipients.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

The authors would like to thank the liver transplant coordinators who provide uncompromising care and dedication to liver transplant recipients, as well as Kelvin Nguyen for administrative assistance.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

The authors of this manuscript have the following conflicts of interest to disclose as described by the American Journal of Transplantation: Dr. Francisco Durazo is a speaker for Genentech and Salix. Drs. Sammy Saab and Steven Han are consultants and are on the speakers bureau for Bristol-Myers-Squibb and Gilead Pharmaceuticals. The manuscript was not prepared or funded by a commercial organization.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References