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Keywords:

  • Hepatitis B immunoglobulin;
  • lamivudine;
  • liver transplantation;
  • prevention;
  • viral infection

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest Statement
  9. References

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


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest Statement
  9. References

End-stage liver disease secondary to hepatitis B virus (HBV) is the leading indication for liver transplantation (LT) in Asia, especially in China (1). Unfortunately, complete eradication of HBV after LT is rarely possible in these recipients. Reinfection may lead to rapid disease progression or even death (2). In 1980s, HBV-related disease was considered a relative contraindication for LT because of its association with poor survival rate and high HBV recurrence rate (80%) in the absence of prophylactic strategies (3).

Hepatitis B immunoglobulin (HBIG) was the first agent to show efficacy in preventing HBV recurrence. A 1993 European multicenter retrospective study demonstrated that when treatment was continued indefinitely, intravenous (IV) HBIG reduced the 3-year actuarial risk of recurrent HBV infection from 74% to 36% (4). HBIG monotherapy, although effective, has several disadvantages, including high cost, inconvenient administration, adverse effects and the possible development of mutations (5–7). As a result of the shortcomings of HBIG and the introduction of nucleoside or nucleotide analogs, HBIG monotherapy is almost never used for prophylaxis against posttransplant HBV recurrence (8,9).

Lamivudine (LAM) monotherapy became the mainstay of prevention of HBV recurrence after LT in the late 1990s and early 2000. Unfortunately, the initial enthusiasm was tempered by the realization that long-term use of LAM is associated with drug resistance leading to increasing rates of HBV recurrence (10,11).

Previous studies have noted an association of the combination (LAM and conventional high-dose IV HBIG) with encouraging outcomes, that is HBV recurrence rate <10% at 1–2 years of follow-up (12,13). Mechanisms contributing to the efficacy of this regimen may be attributed to the dual effects of reduced production of hepatitis B surface antigen (HBsAg) and decreased rate of escape mutations in the presurface gene/surface gene and polymerase regions. Consequently, for the last decade, this regimen has been the standard of care for preventing posttransplant HBV recurrence. Although LAM combined with high-dose IV HBIG is very effective in preventing recurrent HBV infection, it is very expensive, > $100,000 in the first year posttransplantation and > $50,000 yearly thereafter (14). Other factors including inconvenient administration and unavailability of IV HBIG in some countries limit extensive acceptance of this regimen.

In an attempt to find a regimen that is more cost-effective, convenient and widely accepted, several prophylactic strategies are under investigation. Among these strategies, LAM combined with low-dose intramuscular (IM) HBIG is regarded as one of the most cost-effective regimens. Most commonly, it is given on a fixed monthly schedule. We report our evaluation of the long-term safety and efficacy (mean follow-up, 41.2 ± 22.7 months) of LAM plus HBIG (with individualized dose adjustment) in a large cohort (254 patients).

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest Statement
  9. References

Patients

Since May 2002, liver transplant patients have been using LAM and individualized low-dose IM HBIG combination prophylaxis because of the unavailability of IV HBIG in mainland China. Enrolled patients had HBV-related end-stage liver diseases, and no evidence of coinfection with hepatitis C, hepatitis D or human immunodeficiency virus. Unlike most previous studies, our study excluded patients with hepatocellular carcinoma (HCC). Between May 2002 and December 2009, a total of 261 adult patients underwent deceased donor liver transplantation (DDLT) or living donor liver transplantation (LDLT) for HBV-related benign end-stage liver diseases in our center. The patients were monitored until February 2010 or their death, and their medical records were retrospectively reviewed. All the liver grafts were from brain dead donors or living donors. Living and deceased donations were voluntary and altruistic in all cases, approved by the West China Hospital Ethics Committee, and in accordance with the ethical guidelines of the Declaration of Helsinki.

Prophylaxis protocol

Prior to transplantation, LAM therapy (100 mg/day orally) was started in 130 patients with a mean of 31.4 ± 56.2 days (range, 1–366 days). Seven patients were confirmed to have developed tyrosine-methionine-aspartate-aspartate (YMDD) mutants at transplantation, and received HBIG monotherapy or adefovir and low-dose IM HBIG combination therapy after transplantation. The remaining 254 patients received LAM (100 mg/day orally) and 2000 IU IM HBIG (Yuandashuyang Pharmaceutical Co., Ltd., Chengdu, China) in the anhepatic phase, followed by 800 IU daily for the next 6 days and weekly for the rest of 3 weeks in the first postoperative month. The level of serum antibody to hepatitis B surface antigen (anti-HBs) was monitored weekly for the first month, monthly thereafter until stable, and then every 3 months. If the level of anti-HBs was >100 IU/L at the end of the first month, 800 IU per month was administered beginning the second month, if not, 800 IU was administered every 2 weeks. When the serum anti-HBs level still fell below 100 IU/L, the dose was increased to 1200 IU and administered every 2 weeks. An anti-HBs level greater than 100 IU/L on three consecutive occasions in patients receiving the initial dose (800 IU) or on two consecutive occasions in those treated with the adjusted dose was considered to be stable. If serum anti-HBs fell below 100 IU/L after stabilization, additional 800 IU was administered instead of the higher dose.

Immunosuppression

Maintenance immunosuppression consisted of a triple-drug regimen that included tacrolimus or cyclosporine, mycophenolate and prednisone. The dose of tacrolimus was adjusted to maintain serum levels of 7–12 ng/mL for the first postoperative month and 3–7 ng/mL thereafter. Cyclosporine levels were 250–350 ng/mL for the first postoperative month, 100–180 ng/mL for the next 5 months and 50–150 ng/mL thereafter. Prednisone was generally discontinued within 3 months after transplantation.

HBV evaluation

Prior to transplantation, viral markers including HBsAg, hepatitis B surface antibody (HBsAb), hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb), hepatitis B core antibody (HBcAb) and antibody to hepatitis C virus (anti-HCV) were routinely measured using standard commercial assays (Abbott Laboratories, Chicago, IL) as a part of the pretransplant workup for recipients and living donors. Serum hepatitis B virus deoxyribonucleic acid (HBV DNA) was determined using a real-time quantitative polymerase chain reaction (PCR) method, with a limit of detection of 1000 copies/mL. Following LT, liver function profiles were checked daily for the first week, and then weekly for the first month, and monthly thereafter. Serum HBV markers were monitored weekly for the first month, and monthly thereafter, and HBV DNA levels were examined monthly. The monitoring of anti-HBs has been expatiated upon above. HBV recurrence was defined as the reappearance of either HBsAg or HBV DNA in the serum. Studies to determine viral mutation were conducted to identify resistance to LAM or adefovir in the patients with recurrent hepatitis B. Liver biopsies were performed when clinically indicated by an elevation in serum liver enzyme levels.

Statistical analysis

SPSS 13.0 statistical software (SPSS Inc., Chicago, IL) was used to analyze the relevant data. All numerical data are presented as the mean value ± standard deviation or as the median. Survival curves were estimated using the Kaplan–Meier method. The log-rank test for trend was used when comparing survival curves across ordered categories. The Cox proportional hazards model was used to test potential predictors of HBV recurrence after transplantation. Univariate results were reported as hazard ratios with 95% confidence intervals. The variables reaching statistical significance by univariate analysis were then included for multivariate analysis with proportional hazard regression. p < 0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest Statement
  9. References

Patient survival

The clinical features of 254 patients without LAM resistance at transplantation are summarized in Table 1. Twenty-one patients died during the first month following transplantation owing to postsurgical complications (multiorgan failure in 7, primary nonfunction in 3, sepsis in 2, severe pulmonary infection in 4, intraabdominal hemorrhage in 3, and intracranial hemorrhage in 2). Mean follow-up period in the remaining 233 patients was 41.2 ± 22.7 months (range, 1.1–93.4 months). Another 39 patients died during this period. The main causes of those late deaths were graft dysfunction (n = 10, 25.6%), de novo malignancies of other organs (n = 7, 17.9%), sepsis (n = 4, 10.3%), and a few other causes, such as biliary complications, cardiovascular or cerebrovascular accident, renal or respiratory failure, liver abscess, bone tuberculosis and acute severe pancreatitis. The overall 1-, 3- and 5-year survival rates were 85.3%, 77.4% and 76.4%, respectively (Figure 1A). The 1-, 3- and 5-year survival rates were 86.7%, 77.5% and 75.8% in patients with decompensated HBV-related cirrhosis versus 81.2%, 76.4% and 76.4% in patients with fulminant hepatitis B, respectively (p = 0.871; Figure 1B). The 1-, 3- and 5-year survival rates were 84.7%, 77.9% and 77.9% in patients undergoing DDLT versus 87%, 76.5% and 68.8% in those undergoing LDLT, respectively (p = 0.757; Figure 1C). The 1-, 3- and 5-year survival rates in patients with and without posttransplant recurrence were 100%, 92.9% and 77.4%, and 84.4%, 76.4% and 76.4%, respectively (p = 0.325; Figure 1D).

Table 1.  Clinical features of the recipients and donors
Patient characteristicsValue
  1. HBeAg = hepatitis B e antigen; HBV = hepatitis B virus; HBV DNA = hepatitis B virus deoxyribonucleic acid; LT = liver transplantation; LAM = lamivudine; HBsAb = hepatitis B surface antibody; HBcAb = hepatitis B core antibody; MELD = model for end-stage liver disease.

Recipient profiles
 Mean age (years; range)42.8 ± 9.1 (22–68)
 Male gender218 (85.8%)
 MELD score at LT21.8 ± 10.3 (6–59)
Diagnosis
 Decompensated HBV-related cirrhosis190 (74.8%)
 Fulminant hepatitis B64 (25.2%)
 Positive HBeAg68 (26.8%)
 HBV DNA ≥ 105 copies/mL at LT53 (20.9%)
 LAM administration before LT123 (48.4%)
 Mean duration of LAM therapy before LT (days; range)25 ± 37.4 (1–359)
 Posttransplant prednisone withdrawal time >3 months39 (15.4%)
Donor profiles
 Deceased donor number184 (72.4%)
 Living donor number70 (27.6%)
 Mean age (years; range)33.9 ± 8.7 (18–60)
 Male gender214 (84.3%)
 Positive HBsAb44 (17.3%)
 Positive HBcAb4 (1.6%)
image

Figure 1. The overall patient survival curve (A), survival curves in patients with decompensated HBV-related cirrhosis and with fulminant hepatitis B (B), survival curves in patients undergoing DDLT and undergoing LDLT (C), survival curves in patients with and without posttransplant HBV recurrence (D). (B–D, log-rank test).

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HBV recurrence

During the follow-up period, HBV recurred in 14 patients 25.5 ± 17.8 months (range, 3.8–61.3 months) after transplantation. LAM resistance was confirmed in five patients by direct sequencing of the polymerase gene (rtM204V plus rtL180M in all five patients). Details of the 14 cases are listed in Table 2.

Table 2.  Clinical features of the recipients with posttransplant HBV recurrence
 Age (years)GenderPre-LT LAM (days)HBV DNA at LT (copies/mL)HBIG dose adjustment period (months)HBIG regimenPrednisone discontinued within 3 monthsTime until recurrence (months)YMDD mutants at recurrenceOutcome
  1. LT = liver transplantation; LAM = lamivudine; YMDD = thyrosine-methionine-aspartate-aspartate; HBV DNA = hepatitis B virus deoxyribonucleic acid; HBIG = hepatitis B immunoglobulin; ADV = adefovir; ETV = entecavir; M = male; F = female; NA = not available.

  2. 1The two patients did not finish HBIG dose adjustment till HBV recurrence.

  3. 2The last dose in the unfinished adjustment period.

  4. 3The patient died of biliary complication.

  5. 4The patient died of lung cancer.

Case 138M16 1.2 × 1055800 IU/2 weeksNo52.4NoRescued with LAM and ADV
Case 250F1024.23 × 106NA11200 IU/2 weeks2Yes 3.8NoRescued with LAM and ADV
Case 355M01.45 × 1034800 IU/2 weeksNo61.2YesRescued with ADV
Case 441M345.75 × 1054800 IU/monthlyNo30.9NoRescued with LAM and ADV
Case 535M15 1.5 × 1054800 IU/2 weeksYes22.7NoDeath3
Case 642M432.43 × 1064800 IU/2 weeksyes30.6YesRescued with ADV
Case 748F64.28 × 1054800 IU/2 weeksNo25YesRescued with ADV
Case 859F05.23 × 1034800 IU/monthlyNo10.6NoRescued with LAM and ADV
Case 944M572.76 × 10551200 IU/2 weeksYes 6.3YesDeath4
Case 1042M134.75 × 1046800 IU/2 weeksNo39.5YesRescued with ETV
Case 1156M12 9.9 × 1044800 IU/2 weeksYes33.2NoRescued with LAM and ADV
Case 1227M93.57 × 1044800 IU/monthlyNo8NoRescued with LAM and ADV
Case 1361M0 9.7 × 104NA11200 IU/2 weeks2Yes 4.8NoRescued with ETV
Case 1447F201.78 × 1054800 IU/monthlyYes28NoRescued with LAM and ADV

The overall 1-, 3- and 5-year posttransplant HBV recurrence rates were 2.3%, 6.2% and 8.2%, respectively (Figure 2A). The 1-, 3- and 5-year HBV recurrence rates were 1.9%, 6% and 8.3% in the patients undergoing DDLT versus 3.3%, 5.6% and 5.6% in those undergoing LDLT, respectively (p = 0.944; Figure 2B). High serum HBV DNA levels at LT resulted in a higher rate of HBV recurrence: The 1-, 3- and 5-year HBV recurrence rates were 3.9%, 16.8% and 20.8% in the patients with HBV DNA ≥ 105 copies/mL versus 1.8%, 2.8% and 3.8% in those with HBV DNA < 105 copies/mL, respectively (p = 0.003; Figure 2C). The 1-, 3-, and 5-year HBV recurrence rates in patients with and without LAM administration before LT were 2.8%, 8.9% and 13%, and 1.8% 3%, and 3%, respectively (p = 0.115; Figure 2D). In addition, the HBeAg status at LT did not influence the posttransplant HBV recurrence rate. The 1-, 3- and 5-year HBV recurrence rates in patients with and without positive HBeAg were 3.2%, 7.9% and 15.1%, and 1.9%, 5.5% and 5.5%, respectively (p = 0.224). Other factors associated with posttransplant HBV recurrence are described further.

image

Figure 2. The overall patient HBV recurrence curve (A), HBV recurrence curves in patients undergoing DDLT and undergoing LDLT (B), HBV recurrence curves in patients with HBV DNA < 105 copies/mL and ≥ 105 copies/mL at LT (C), HBV recurrence curves in patients with and without using LAM before LT (D). (B–D, log-rank test).

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The influence of the HBsAb maintenance cutoff of 100 IU/L on posttransplant HBV recurrence

The serum anti-HBs levels in the first posttransplant year are shown in Figure 3. Adjustment of the HBIG dose was completed in 217 patients 4.3 ± 0.5 months (range, 4–6 months) after transplantation. After dose adjustment, 800 IU of HBIG was administered every month in 94 patients (43.3%) and every 2 weeks in 117 patients (53.9%), and 1200 IU of HBIG was administered every 2 weeks in six patients (2.8%). In other words, low HBsAb level (<100 IU/L) was detected two times in six patients, one time in 117 patients and at no time in the remaining 94 patients during the period of dose adjustment. As of the last follow-up, 12 of the 217 patients had experienced HBV recurrence. No difference in the 1-, 3- and 5-year HBV recurrence rates was observed among patients whose HBsAb level was low twice (16.7%, 16.7% and 16.7%), low once (0%, 4.7% and 8%), and never low (2.2%, 5.4% and 5.4%) (p = 0.438; Figure 4).

image

Figure 3. Monitored serum anti-HBs titers in the first posttransplant year.

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image

Figure 4. Posttransplant HBV recurrence rate of recipients with low HBsAb levels (<100 IU/L) for two times, recipients with low HBsAb level for one time, and recipients with no low HBsAb level during the HBIG dose adjustment period (log-rank test).

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Then, we compared the outcomes of LT recipients with HBsAb level below 100 IU/L to those with HBsAb level above 100 IU/L after the adjustment period. HBsAb level dropped below 100 IU/L after the period of dose adjustment in 71 (32.7%) of the 217 patients. The drop in HBsAb level below 100 IU/L had no effect on recurrence. The 1-, 3- and 5-year recurrence rates were not influenced by this drop (0%, 8.9% and 13.9% in patients with HBsAb level below 100 IU/L and 2.1%, 3.2% and 3.2% in patients with HBsAb level above 100 U/L; p = 0.114; Figure 5).

image

Figure 5. Posttransplant HBV recurrence rate of recipients with and without HBsAb level below 100 IU/L after the HBIG dose adjustment period (log-rank test).

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Risk factor analysis for posttransplant HBV recurrence

In univariate analysis, the significant risk factors for HBV recurrence were high viral load with serum HBV DNA level ≥ 105 copies/mL at LT and posttransplant prednisone withdrawal time (>3 months; Table 3). In multivariate analysis, the two variables were also found to be independent predictive factors for posttransplant HBV recurrence (Table 4).

Table 3.  Univariate analysis for posttransplant HBV recurrence
 Hazard ratio95% CIp-Value
  1. CI = confidence interval; LAM = lamivudine; YMDD = thyrosine-methionine-aspartate-aspartate; LT = liver transplantation; HBV DNA = hepatitis B virus deoxyribonucleic acid; HBeAg = hepatitis B e antigen; HBsAb = hepatitis B surface antibody.

Age1.0350.981–1.0920.210
Male gender2.3730.743–7.5810.145
Diagnosis (fulminant hepatitis B vs. decompensated HBV-related cirrhosis)1.3510.792–2.3040.269
Pretransplant LAM administration2.4660.772–7.8730.128
Duration of pretransplant LAM therapy (days)1.0040.996–1.0120.293
HBV DNA at LT (≥ 105 vs. < 105 copies/mL)4.3141.495–12.4550.007
Serum positive HBeAg at LT1.9080.661–5.5020.232
Prednisone withdrawal time (> 3 vs. ≤ 3 months)2.0681.211–3.5320.008
HBsAb level < 100 IU/L after dose adjustment period2.4690.783–7.7900.123
Positive HBsAb in donor0.9830.219–4.4100.982
Table 4.  Multivariate analysis for posttransplant HBV recurrence
 Hazard ratio95% CIp-Value
  1. CI = confidence interval; LT = liver transplantation.

  2. 1Patients with serum HBV DNA level ≥ 105 copies/mL at LT.

High viral load at LT15.066 1.735–14.7940.003
Prednisone withdrawal time (> 3 months)2.2911.321–3.9720.003

Cost for HBIG in the prophylaxis protocol

In the follow-up period, 199 patients used HBIG for more than 1 year and 170 patients used it for more than 2 years. The median HBIG consumption in the first and second posttransplant year was 25,200 IU and 19,200 IU (i.e. $4,076 for the first year, $3,106 per annum thereafter), respectively. In addition, the median cost of monitoring HBsAb level was about $21 for the first year and $9 per annum thereafter.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest Statement
  9. References

Combination prophylaxis with LAM and low-dose IM HBIG is currently being investigated extensively, and the prophylactic effect reported by many studies is encouraging (15–17). However, almost all of these studies included patients with HCC. Since the survival of patients with HCC is more likely to be shorter because of tumor recurrence, we expected that including such patients would result in an inaccurate evaluation of the prophylactic effect. Our study therefore excluded these patients. Most commonly, LAM with low-dose IM HBIG combination therapy is given on a fixed monthly schedule. The rationale is that the fixed regimen may sustain a protective level of HBsAb after LT. However, levels of HBsAb tend to differ among patients owing to inter-individual differences. Consequently, the level in some patients remains too low. Taking into consideration inter-individual differences, our regimen (tailored to the each patient) may be a more reasonable approach.

The large cohort (254 cases) and long follow-up (a mean of 41.2 ± 22.7 months) of this study are enough to evaluate the potential predictors of posttransplant recurrence. Moreover, the exclusion, by the present study, of patients with HCC to avoid selection bias should result in a more accurate risk factor analysis for recurrence. Two factors (high viral load at LT and prednisone withdrawal time after LT) were observed to be associated with posttransplant HBV recurrence in our study.

Some studies have reported that pretransplant HBV DNA level affects recurrence (15,17,18). Our results further reinforce this point. To reduce the impact of this risk factor, LAM can be used to lower the pretransplant high viral load. Villeneuve et al. (19) and Yao et al. (20) have reported that in HBV DNA-positive cases, HBV DNA became undetectable after 6 months of LAM therapy. But in practice, the duration of LAM therapy before LT varies dramatically among patients, because it largely depends on the predictability of transplant timing and the choice of antiviral therapy. So the goal of reducing the HBV DNA level sufficiently prior to transplantation may not be achieved in every recipient. Furthermore, increased duration of LAM therapy before LT has been linked to the occurrence of YMDD mutation, which confers resistance to LAM (21–23). Fortunately, patients with YMDD mutants can now be successfully treated with alternative drugs, such as adefovir. To ensure a low HBV DNA level at LT, Marzano et al. (24) added adefovir while continuing LAM as rescue therapy. As soon as HBV DNA levels fell below 105 copies/mL, patients were placed back on the waiting list for LT.

In earlier studies, prednisone played an important role in HBV replication (25–27). Prednisone can stimulate viral replication by influencing the glucocorticoid responsive enhancer region of the HBV genome. As a consequence, the rapid removal of prednisone from the immunosuppressive regimen has been proposed to minimize the risk of HBV recurrence after LT. However, no studies, to the best of our knowledge, show that this regimen produces a better outcome, although at many centers early withdrawal of prednisone from the immunosuppressive regimen of recipients is practiced. In our center, prednisone is generally discontinued within 3 months after transplantation. When indicated by a fluctuation in serum bilirubin or liver enzyme index, the duration of prednisone therapy will be extended beyond 3 months. Prednisone was used beyond 3 months in 39 of our patients (17 using 800 IU HBIG monthly, 17 using 800 IU every 2 weeks, 2 using 1200 IU every 2 weeks, and 3 dying or experiencing recurrence before completion of dose optimization). The prednisone withdrawal time (>3 months) has been found to be associated with posttransplant HBV recurrence in univariate and multivariate analysis. However, it may be arbitrary to confirm this relationship by the retrospective study. Prednisone may be a surrogate marker for some other factors. Therefore, it is very worthwhile to further investigate the influence of prednisone withdrawal time on HBV recurrence in long-term, randomized, controlled, prospective trials.

Whether the anti-HBs levels achieved by low-dose IM HBIG are adequate to prevent HBV recurrence is controversial. Roche et al. (28) found that the risk of HBV recurrence was much higher after low-dose HBIG than after high-dose HBIG. A high titer of anti-HBs (>500 IU/L) was believed to ensure prophylaxis, even in HBV DNA-positive patients. On the other hand, some centers have reported encouraging results using low HBsAb level. Karademir et al. (29) gave 1200–2000 IU IM HBIG on-demand when the anti-HBs titer fell below 100 IU/L after transplantation. In a median follow-up period of 16 months, 2 of 40 recipients experienced HBV recurrence. Anderson et al. (30) in 2007 gave HBIG indefinitely with the interval of injections adjusted to maintain the anti-HBs titer at or above 100 IU/L. Unlike the protocol in the former study, their protocol called for a switch to IV HBIG in patients who were unable to maintain an anti-HBs level of 100 IU/L. HBV recurrence occurred in 1 of 17 patients at the end of the follow-up period. However, these studies were limited by the small number of patients or short duration of follow-up. In addition, they did not investigate whether patients with anti-HBs titer below 100 IU/L were at an increased risk for HBV recurrence, in other words, whether the maintenance cutoff of 100 IU/L was really meaningful. To answer this question, we preliminarily examined whether the HBsAb maintenance cutoff of 100 IU/L affected posttransplant HBV recurrence. No difference was observed between patients with anti-HBs level above 100 IU/L and patients with anti-HBs level below 100 IU/L (Figure 5). Apparently, the HBsAb level necessary to prevent HBV recurrence still needs to be determined. Therefore, more prospective, controlled trials should be conducted for this purpose.

In this series, 5 cases (43.8%) of YMDD mutant HBV were detected in the 14 recipients who experienced recurrence during the follow-up period. Compared with other studies (68.8% by Zheng et al. (17), 100% by Gane et al. (15)), the rate of YMDD mutation appears to be lower in our patients. Reasons for this may include (1) reduced rate of escape mutation in the YMDD region due to the synergistic actions of combination therapy, (2) shorter duration (a mean of 25 ±37.4 days) of LAM treatment before LT and (3) our immunosuppressive regimen. Immunosuppression has a great influence on the development of YMDD mutation, which confers resistance to LAM. The LAM resistance was detected in 15% of immunocompetent patients within the first treatment year compared with 45% in immunosuppressed patients (31,32). Hence, we may have reason to believe that our immunosuppression protocol (i.e. low drug concentration and rapid prednisone withdrawal), to some extent, contributes to lowering the rate of YMDD mutation after transplantation. In addition, the immunosuppressive regimen may also increase the survival of patients experiencing HBV recurrence. In our 14 patients with HBV recurrence after transplantation, all except two patients who died of causes unrelated to recurrence were alive at the last follow-up. However, further studies to confirm this encouraging survival rate are needed.

LAM combined with individualized low-dose IM HBIG is very cost-effective. The first- and second-year costs of IM HBIG in our patients were $4,076 and $3,106, respectively, or about 5% of the cost of conventional high-dose IV HBIG regimens. Moreover, our prophylactic strategy led to lower 1-, 3- and 5-year recurrence rates (i.e. 2.3%, 6.2% and 8.2%, respectively). These results are equal to or even superior to the results in patients using conventional high-dose IV HBIG plus LAM (12,13,33).

In conclusion, this single-center large-cohort retrospective study demonstrated that LAM combined with individualized low-dose IM HBIG provides a safe and effective prophylaxis against HBV recurrence after LT at about 5% of the cost of conventional high-dose IV HBIG regimens. The major limitation of this study is its retrospective nature. Some factors observed to be associated with posttransplant HBV recurrence in our study, such as posttransplant prednisone withdrawal time, still need further verification by large prospective, controlled trials. In addition, further studies are needed to define the protective HBsAb level necessary to prevent posttransplant HBV recurrence.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest Statement
  9. References

This work was supported by a grant from the National Science and Technology Major Project of China (2008ZX10002-026).

Funding sources: This work was supported by a grant from the National Science and Technology Major Project of China (2008ZX10002-026).

Conflict of Interest Statement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest Statement
  9. References

None of the authors have any conflict of interest to declare with regard to the content of this article.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest Statement
  9. References