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Keywords:

  • entecavir;
  • Hepatitis B immunoglobulin;
  • lamivudine;
  • liver transplantation;
  • recurrence HBV infection;
  • tenofovir

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Source
  8. Disclosure
  9. References
  10. Appendix A1

The combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues [NA(s)] is considered as the standard of care for prophylaxis against HBV recurrence after liver transplantation (LT), but the optimal protocol is controversial. We evaluated the efficacy of the newer NAs with high genetic barrier (hgbNA) [i.e. entecavir (ETV) or tenofovir (TDF)] with or without HBIG as prophylaxis against HBV recurrence after LT. In total, 519 HBV liver transplant recipients from 17 studies met the inclusion criteria and they were compared to those under lamivudine (LAM) and HBIG who had been selected in our previous review. Patients under HBIG and LAM developed HBV recurrence (115/1889 or 6.1%): (a) significantly more frequently compared to patients under HBIG and a hgbNA [1.0% (3/303), p < 0.001], and (b) numerically but not significantly more frequently compared to the patients who received a newer NA after discontinuation of HBIG [3.9% (4/102), p = 0.52]. The use of a hgbNA without any HBIG offered similar antiviral prophylaxis compared to HBIG and LAM combination, if the definition of HBV recurrence was based on HBV DNA detectability [0.9% vs. 3.8%, p = 0.11]. Our findings favor the use of HBIG and a hgbNA instead of HBIG and LAM combined prophylaxis against HBV recurrence after LT.


Abbreviations
ADV

adefovir dipivoxil (ADV);

B

immunoglobulin

ETV

entecavir;

FTC

emtricitabine

HBIG

hepatitis;

HBV

hepatitis B virus

IM

intramuscularly;

IV

intravenously

LAM

lamivudine;

LT

liver transplantation

NA(s)

nucleos(t)ide analogues;

TDF

tenofovir.

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Source
  8. Disclosure
  9. References
  10. Appendix A1

Hepatitis B virus (HBV) related liver disease was considered to be a relative or even absolute contraindication for liver transplantation (LT) in many centers until the introduction of passive immunoprophylaxis with long-term hepatitis B immunoglobulin (HBIG) use in early 1990s, which reduced the re-infection rates after LT and improved prognosis [1, 2]. Later, lamivudine (LAM) was used in both the pretransplant and posttransplant period and further improved the outcome of HBV transplant patients leading to impressive rates of graft and patient survival [3]. Currently, the combination of HBIG and LAM is considered as the standard of care for prophylaxis against HBV recurrence after LT [4]. However, the optimal protocol for post-LT HBV prophylaxis has not been decided, since HBIG has several limitations including high cost, parenteral administration and local or systematic adverse events. In addition, LAM, which is the first and most commonly used oral anti-HBV agent in the LT patients, is not considered as a first-line option for the treatment of chronic hepatitis B because of the progressively increasing rates of viral resistance [4, 5]. Therefore, newer nucleos(t)ide analogues (NAs) are increasingly used in the HBV transplant setting.

Adefovir dipivoxil (ADV) has already been used in clinical practice having a better resistance profile, compared to LAM [2]. In a previous systematic review [6], we showed that patients receiving combinations of HBIG and ADV with or without LAM had significantly lower rates of HBV recurrence than those under HBIG and LAM (2% vs. 6%, p = 0.024), although the former group had significantly more frequently factors favoring HBV recurrence, such as more frequently detectable HBV DNA at LT (70% vs. 39%, p < 0.001) and less frequently indefinite HBIG use (57% vs. 89%, p < 0.0001). In the same review[6], we also observed that HBIG-free ADV prophylaxis (with or without LAM) might be superior to LAM monoprophylaxis and perhaps not inferior compared to HBIG and ADV combined prophylaxis, although such data were available in relatively small numbers of patients with limited follow-up. However, ADV has several drawbacks including high cost, relatively low potency at least in the licensed 10 mg daily dose, risk of viral resistance and risk of nephrotoxicy. The latter is of particular concern in the LT setting because of the concomitant use of the nephrotoxic calcineurin inhibitors and the frequent co-existence of other risk factors for renal impairment, such as diabetes mellitus and arterial hypertension.

Newer and more potent NAs with higher genetic barrier (hgbNA), such as entecavir (ETV) and tenofovir (TDF), are considered as the first-line therapeutic options in patients with chronic hepatitis B including those with decompensated cirrhosis [2]. Although their efficacy and optimal use in combination with HBIG are not well documented in the LT setting, both ETV and TDF have been used in the posttransplant period mainly in an effort to increase the efficacy of post-LT prophylaxis in HBV transplant patients and/or reduce the need for the expensive HBIG preparations at least after the initial postoperative period.

In this review, we systematically evaluated all the available data in order to accurately assess the efficacy of the hgbNAs (i.e. ETV or TDF) with or without HBIG as prophylaxis against HBV recurrence after LT. In addition, we documented the rates of HBV recurrence in relation to the different HBIG regimens in patients taking one of the hgbNAs.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Source
  8. Disclosure
  9. References
  10. Appendix A1

Data sources and searches

Medline/PubMed from January 2008 to June 2012 was searched to identify all medical literature included under the terms “hepatitis B recurrence” and “entecavir” or “tenofovir”. In addition, a manual search of all relevant review articles and of the retrieved original studies as well as of the abstracts from the major Hepatology and Liver Transplant congresses during the last 2 years was performed.

Study selection

All studies published in English were included, if they fulfilled all of the following criteria: (1) they were randomized trials or observational cohort studies, (2) they included adult patients who underwent LT for HBV related liver disease, (3) they included patients who received hgbNA(s) (i.e. ETV or TDF) with or without HBIG as prophylaxis from post-LT HBV recurrence, without any restriction on HBIG duration, (4) they reported data on the incidence of post-LT HBV recurrence in relation to antiviral prophylaxis and (5) they defined HBV recurrence as reappearance of HBsAg and/or HBV DNA after LT. In each selected study, only the patients who received hgbNA(s) (i.e. ETV or TDF) alone or in combination with another NA were evaluated, while patients under LAM and/or ADV without hgbNA(s) were excluded. The selected patients were compared with the patients under HBIG and LAM who had been included in our previous systematic review [6]. Literature search was performed by one reviewer (EC), who determined which studies could be potentially included after having screened titles and abstracts. Each study in the list of the preselected papers was evaluated by two independent reviewers (EC, GVP) in order to determine whether it fulfilled all the inclusion criteria.

Data extraction and quality assessment

Data extraction from the finally selected papers was done by one author (EC) according to a predefined form. Any queries in data extraction were arbitrated by discussion with the other author (GVP). Data extracted for selected studies included country and center(s), date of publication, study period, sample size, protocol of HBIG administration, NA(s) prophylaxis, follow up period and number of patients with HBV recurrence. We considered randomized, controlled trials as high-quality evidence, prospective cohort studies as intermediate-quality evidence, and retrospective cohort studies as low quality evidence.

Data synthesis and analysis

We used a descriptive approach to summarize study characteristics and outcome (HBV recurrence in patients receiving antiviral prophylaxis). Quantitative variables were expressed as mean values  ±  standard deviation (SD) and/or median values (range). Chi-square test was used for identification of factors, which were significantly associated with HBV recurrence. Significance testing was two-sided and set to less than 0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Source
  8. Disclosure
  9. References
  10. Appendix A1

In total, 94 articles were initially identified from the literature search, but only 20 studies [7-26] fulfilled the inclusion criteria (Figure Appendix). Of two studies [14, 15] from one center in China with overlapping study periods, only the latest one [14] was included in the analysis. Moreover, there were two other studies [20, 24] from another center in China with overlapping study periods, but we decided to include the oldest one [20], which was published as full paper, because it provided more details on antiviral prophylaxis. Finally, one study, which was published only as an abstract, was excluded because it did not provide separate data on HBV recurrence under hgbNA(s) [26]. Thus, 17 studies [7-14, 16-23, 25] using hgbNA(s) with or without HBIG were included in our analysis. Six studies were from USA [8, 10, 12, 18, 19, 21], three from China [7, 14, 20], two from Spain [13, 16], two from Japan [9, 25] and one study from Netherlands [17], India [23], Taiwan [22] and Greece [11]. Eleven studies evaluated the combination of HBIG with hgbNA(s) [7, 9, 10, 12-14, 16, 18, 19, 22, 25], while eight studies [8, 11, 17-21, 23] evaluated patients under hgbNA(s) after HBIG discontinuation or without any HBIG (Figure 1). There was only one randomized controlled trial [10], while seven were prospective cohort [7, 11, 12, 17, 18, 21, 23] and nine retrospective cohort studies [8, 9, 13, 14, 16, 19, 20, 22, 25].

image

Figure 1. Subgroups of patients under antiviral prophylaxis against HBV recurrence after liver transplantation: 1910 (79%) patients received HBIG and LAM, 304 (12.5%) HBIG and ETV/TDF, 103 (4%) ETV/TDF after HBIG discontinuation and 112 (4.5%) ETV/TDF without any HBIG. HBIG= hepatitis B immunoglobulin; LAM= lamivudine; ETV= entecavir; TDF= tenofovir.

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The outcomes of patients under hgbNA(s) were compared to those of patients under HBIG and LAM from studies (12, 27–62), which had been included in our previous systematic review [6].

Characteristics of post-LT prophylaxis in patients under HBIG and NA(s)

HBIG and NA(s) combination

In total, 2214 patients received HBIG and LAM or hgbNA(s) (with or without another NA) as prophylaxis from post-LT HBV recurrence. In particular, monotherapy with LAM was used in 1910 (86%) (12, 27–62) and with a hgbNA(s) in 304 (14%) patients [7, 9, 10, 12, 14, 16, 18, 19, 22, 25] (Table 1). Patients who received HBIG and a hgbNA with or without another NA were considered as patients treated with HBIG and a hgbNA and were analyzed together, unless otherwise stated. The characteristics of patients under HBIG and LAM have been described in details in our previous review [6].

Table 1. Published studies using combination of hepatitis B immune globulin (HBIG) and entecavir (ETV) [or tenofovir (TDF)] for prevention of hepatitis B virus (HBV) recurrence after liver transplantation (LT) for HBV related liver disease
Study 1st author, year (Ref no.)Quality of studyPatients (N)Post-LT HBIG: [Anhepatic]/[1st week]/[1st month]NA(s)Mean follow-up, mosHBV DNA assays (lower limit of detection)HBV recurrence n (%)
  1. a

    In one patient, recurrence was associated with no compliance to TDF + FTC.

  2. NA(s) = nucleos(t)ide analogues; RCT = randomized controlled trial (high-quality evidence); PC = prospective cohort study (intermediate-quality evidence); RC = retrospective cohort study (low quality evidence); bDNA = branched DNA; PCR = polymerase chain reaction; LAM = lamivudine; ADV = adefovir; FTC = emtricitabine; NA = not available.

Xi ZF, 2009 [7]PC30[2000 IM] / [1600/day IM until negative HBsAg] / [800/week IM according to antiHBs levels]30 ETVNAPCR (1000 c/mL)0
Degertekin, 2010 [12]PC134 groups: (a) high dose IV HBIG (10 000 IU at anhepatic phase, same for next 6 days, and monthly thereafter; (b) low dose IV HBIG: 3000—6000 IU monthly or 10 000 IU every 2–6 months; (c) intramuscular (IM) HBIG: 1000–1500 IU every 1–2 months; and (d) finite HBIG: HBIG discontinued after a varying periodETV or TDF (with or without LAM or ADV)42PCR (200 c/mL)0
Teperman, 2010 [10]RCT33NA33 TDF + FTC24NA0
Jimenez-Perez, 2010 [13]RC4NA (HBIG was given IM)2: ETV + TDF8.2NA0
    2: TDF   
Cai, 2011 [14]RC63[1000 IM] / [400/day IM] / [400/day IM for another week then according to antiHBs levels]63 ETV41.2PCR (100 c/mL)0
Cambos-Varella, 2011 [16]RC31988–96: [10,000 IV] / [5000/day IV for 5 days] / [5000/month IV]2: ETV;54hybridization1 (33%) under ETV
   1997–2008: [10,000 IV] / [5000/day IV for 5 days] / [4000/month IM for 3 weeks and then 2000/month IM]1: TDF + FTC  (HBV DNA at LT: <12IU/L)
Ahn, 2011 [19]RC1[1000] / [1000/day] / [1000/month for 6 months]1 TDF + FTCNAbDNA1 (100)a
Ishigami, 2011 [9]RC4[10,000 IV] / [10000/day IV until negative HBsAg] / [1000–2000 according to antiHBs levels]4 ETV64NA0
Perillo, 2012 [18]PC60NA60 TDF + FTC18NA0
Hu TH, 2012 [22]RC67NA (HBIG at low dose on67 ETVNANA2 (3)
    demand)   (HBV DNA at LT: NA
Ueda, 2012 [25]RC26[10 000 IV] / [10 000/day IV for 5 days] / [1000 according to antiHBs levels]26 ETV25.1PCR0

Characteristics of post-LT prophylaxis in patients under HBIG and high genetic barrier NA(s)

HBIG administration

Data on the mode and duration of HBIG administration, as well as the dosage and mode of HBIG at anhepatic phase, during the 1st week (day 0 to 7) and during the following 3 weeks (day 8–30) post-LT were evaluated. Details regarding the mode of HBIG administration were available in 131 patients included in all but four studies [10, 12, 18, 22]: 31 of them received HBIG always intravenously (IV), 97 always intramuscularly (IM) and 3 IV for the first period after LT and IM thereafter. Regarding the duration of HBIG administration, data were available in all but four studies [12, 13, 18, 22] including 160 patients: HBIG prophylaxis was given for a finite duration (median 6 months) after LT in 11% (17/160) of patients (Table 2).

Table 2. Characteristics of hepatitis B immune globulin (HBIG) administration in patients who received HBIG and lamivudine (LAM) or HBIG and entecavir (ETV) or tenofovir (TDF) for prevention of hepatitis B virus (HBV) recurrence after liver transplantation (LT) for HBV related liver disease
 HBIG + LAMHBIG + ETV (or TDF)p
HBIG at the anhepatic phase   
 Route   
  Intravenous (IV) administration, n/N (%)918/1723 (53)34/131 (26)<0.001
  Intramuscular administration (IM), n/N (%)596/1775 (34)93/131 (71)<0.001
  IV/IM, n/N (%)209/1775 (11)4/131 (3)0.02
HBIG during the 1st week post-LT   
 Route of HBIG   
  Intravenous administration (IV), n/N (%)896/1757 (51)34/131 (26)<0.001
  Intramascular administration (IM), n/N (%)606/1809 (34)97/131 (74)<0.001
  IV/IM, n/N (%)255/1809 (14)0/131 (0)<0.001
  High dosage (≥10 000 U/day), n/N (%)456/1744 (26)31/194 (16)0.002
HBIG during days 8–30 post-LT   
 Route   
  Intravenous administration (IV), n/N (%)661/1575 (42)31/128 (24)<0.001
  Intramascular administration (IM), n/N (%)625/1627 (38)97/128 (76)<0.001
  IV/IM, n/N (%)289/1627 (18)0/128 (0)<0.001
 Stable dose1043/1627 (64)4/194 (2)<0.001
 High dosage (≥10 000 U), n/N (%)374/1690 (22)1/194 (0.5)<0.001
Indefinite HBIG administration, n/N (%)1600/1773 (90)143/160 (89)0.83

In the anhepatic phase, HBIG was given IV in 34 (26%), IM in 93 (71%) or both IV and IM in 4 (3%) of 131 patients with available data [7, 9, 13, 14, 16, 19, 25] and at high (≥10 000 U) and low (<10 000 U) dosage in 34 (27%) and 93 (73%) of 127 patients with available data [7, 9, 14, 16, 19, 25]. During the 1st week after LT, HBIG was administered IV in 34 (26%) and IM in 97 (74%) of 131 patients [7, 9, 13, 14, 16, 19, 25], while high dosage of HBIG (≥10 000 U/day) was given in 31 (16%) of 194 patients with available such data [7, 9, 14, 16, 19, 22, 25]. Finally, from day 8 to 30, HBIG was given IV in 31 (24%) and IM in 97 (76%) of 128 patients at a median HBIG dose of 1500 (range: 800–10 000) IU [7, 9, 13, 14, 19, 25]. In addition, from day 8 to 30, HBIG was given at a stable dosage in 4 (2%) and according to serum anti-HBs levels [at a median of 500 IU/L (range: 250–500)] in 190 (98%) of 194 patients [7, 9, 14, 16, 19, 22, 25], as well as at low dosage (<10 000 U at any time interval) in all but one of the 194 patients [7, 9, 14, 16, 19, 22, 25] (Table 2).

High genetic barrier NA(s) administration

In 11 studies including 304 patients [7, 9, 10, 12-14, 16, 18, 19, 22, 25], ETV was given in 197 and TDF in 107 patients [alone in 5 and in combination with another NA in 102 [emtricitabine (FTC): 95, LAM: 3, ADV : 2, ETV : 2 patients]. HgbNA(s) were given at dosage adjusted to renal function. ETV had been initiated before LT in 61.5% of patients who received HBIG and ETV after LT, while no data were available for TDF administration before LT. Thirty two (26%) of the 124 patients had detectable HBV DNA at the time of LT [7, 9, 13, 18, 25], while 67 (37%) of 179 patients were ΗβeAg positive before LT [7, 14, 18, 25]. Finally, 13 (10%) of 127 patients were transplanted for HBV acute liver failure (ALF)[7, 9, 13, 14, 25], while there were no available data for patients with HCV or HDV co-infection.

HBV recurrence under HBIG and LAM or high genetic barrier NA(s) combined prophylaxis

All patients

HBV recurrence was detected in 6.3% (140/2214) of patients who received HBIG and NA(s) combined prophylaxis during a median follow-up of 30 (range: 8–83) months. Of the 140 patients with HBV recurrence, 22 reported HBIG discontinuation (n = 4)[50, 55], NA(s) discontinuation (n = 14)[19, 54] or poor compliance to HBIG/NA(s) combination prophylaxis (n = 4)[27, 36, 56, 61]. Hence, the rate of HBV recurrence was 5.4% (118/2192) in patients remaining under HBIG and NA(s) prophylaxis after a median of 12 (range 1–40) months after LT.

HBV recurrence developed significantly more frequently in patients under HBIG and LAM (136/1910 or 7.1%) than in patients under HBIG and a hgbNA (4/304 or 1.3%, p = 0.0005) (Table 1). When only patients who remained under HBIG and NA(s) prophylaxis were taken into account, the combination of HBIG and a hgbNA was again superior than the combination of HBIG and LAM (3/303 or 1.0% vs. 115/1889 or 6.1%, p = 0.0004) (Figure 2). The combination of HBIG and hgbNA(s), compared to the combination of HBIG and LAM, was associated with significantly lower HBV recurrence rates using as definition of HBV recurrence either the presence of HBsAg positivity (3/303 or 1.0% vs. 109/1834 or 5.9%, p<0.001) or HBV DNA positivity (1/303 or 0.3% vs. 42/1111 or 3.8%, p = 0.003).

image

Figure 2. Risk of recurrence hepatitis B virus (HBV) infection after liver transplantation (LT) in relation to the type of posttransplant HBV prophylaxis. HBIG = hepatitis B immunoglobulin; LAM = lamivudine; ETV = entecavir; TDF = tenofovir.

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Patients under HBIG and LAM, compared to patients under HBIG and a hgbNA, had similar rates of indefinite HBIG therapy [90% (1600/1773) vs. 89% (143/160), p = 0.83] with numerically shorter post-LT duration of follow-up (mean: 30 ± 17 vs. 37 ± 18 months), but they received more intense HBIG protocol in the anhepatic phase, during the 1st week and during days 8–30 after LT (Table 2). On the other hand, higher proportion of patients who received HBIG and LAM after LT had detectable HBV DNA at LT compared to patients who received HBIG and a hgbNA [39% (503/1263) vs. 26% (32/124), p = 0.003].

Patients under high genetic barrier NA(s)

In patients who received HBIG and hgbNA(s)[7, 9, 10, 12-14, 16, 18, 19, 22, 25], no definitive conclusion could be drawn for the possible impact of HBIG dosage and HBV DNA status at LT on the risk of HBV recurrence, since the numbers of patients in the subgroups were small and the rates of HBV recurrence were very low [1st week post-LT, high (10,000 IU/day) HBIG dosage: 0% (0/31) and lower HBIG dosage 1.8% (3/163)]. Finally, no definite conclusions could be drawn regarding the impact of HBV DNA and HBeAg seropositivity at LT on HBV recurrence which seemed to be minimal, if any, since none of the 124 patients with available data on HBV DNA[7, 9, 13, 18, 25] or of the 179 patients with available data on HBeAg status[7, 14, 18, 25] at LT developed HBV recurrence.

Among the 304 patients who received the hgbNA(s) [7, 9, 10, 12-14, 16, 18, 19, 22, 25], one experienced HBV recurrence after discontinuation of TDF and emtricitabine (FTC)[19]. Thus, 3 (1.0%) of 303 patients who remained under HBIG and hgbNA(s) prophylaxis had HBV recurrence. Among the three patients with HBV recurrence after LT, one had undetectable HBV DNA (<12 IU/L)[16] and two had no detectable YMDD mutants pre-LT[22]. The combination of HBIG and ETV [1.5% (3/197)] had similar antiviral efficacy compared to HBIG and TDF alone [0% (0/5), p = 0.11] or to HBIG and TDF and another NA [0% (0/101), p = 0.52]. The addition of a second NA to the combination of HBIG and ETV or TDF did not affect the rate of post-LT HBV recurrence, which occurred in 3 (1.5%) of 202 patients under HBIG and ETV or TDF and in none of 101 patients under HBIG combined with ETV or TDF plus another NA (p = 0.53) (Figure 2).

HBV recurrence under HBIG and LAM versus high genetic barrier NA(s) alone

Patients under high genetic barrier NA(s) alone after HBIG withdrawal

In four studies [8, 11, 17, 21] including 103 patients, a hgbNA was used after discontinuation of HBIG: ETV was given in 10 (alone in 9 and combined with ADV in 1), and TDF in 93 patients (alone in 10 and combined with FTC in 37 or with LAM in 46 patients; Table 3). During a median follow-up of 24 (range: 11–31) months, 5 (4.8%) of 103 patients had HBV recurrence, but one patient experienced HBV recurrence after discontinuation of TDF and FTC [21]. Thus, 4 (3.9%) of 102 patients who remained under hgbNA(s) prophylaxis had HBV recurrence. The rate of posttransplant HBV recurrence was only numerically but not significantly lower in patients under hgbNA prophylaxis with HBIG discontinuation compared to patients under HBIG and LAM [3.9% (4/102) vs. 6.1% (115/1889), p = 0.52; Figure 2]. At the same time, a hgbNA with HBIG discontinuation was not inferior to the combination of HBIG and a hgbNA [3.9% (4/102) vs. 1.0% (3/303), p = 0.17]. Data on HBV DNA and HBeAg status at LT were available in 45 (45%) of the 103 patients who remained under hgbNA(s) monoprophylaxis [11, 21], but no definitive conclusion could be drawn, since details of HBV DNA and HBeAg at LT in relation to the HBV recurrence were available in only one study [11]. Nevertheless, 3 (75%) of 4 patients with HBV recurrence had undetectable HBV DNA at LT [8, 11]. Finally, 2 (4.5%) of 45 patients were transplanted for HBV-related ALF, while HCV and/or HDV co-infections were present in 2 (4.5%) and 9 (20%) patients, respectively [11, 21].

Table 3. Published studies using newer NA(s) with high genetic barrier [entecavir (ETV) or tenofovir (TDF)] after hepatitis B immune globulin (HBIG) withdrawal, for prevention of hepatitis B virus (HBV) recurrence after liver transplantation (LT) for HBV related liver disease
Study 1st author, year (Ref no.)Quality of studyPatients (N)Time of HBIG withdrawal after LTNA(s)Mean follow-up, mosHBV DNA assays (lower limit of detection)HBV recurrence, n (%)
  1. a

    In one patient recurrence was associated with no compliance to TDF + FTC.

  2. NA(s) = nucleos(t)ide analogues; LAM = lamivudine; FTC = emtricitabine; RCT = randomized controlled trial (high-quality evidence); PC = prospective cohort study (intermediate-quality evidence); RC = retrospective cohort study (low quality evidence); NA = not available.

Saab, 2011 [8]RC42>12 months41 LAM + TDF,15COBAS TaqMan HBV2 (4.7) under LAM + TDF
     1 ETV + ADV  (HBV DNA at LT: undetectable)
Cholongitas,PC24>12 months9 ETV, 10 TDF24COBAS TaqMan HBV1 (4) under ETV
 2012 [11]   5 TDF + LAM (6 IU/mL)(HBV DNA at LT: undetectable)
Wesgrop,PC16≥6 months16 TDF + FTC12NA1 (6.2)
 2012 [17]      (HBV DNA at LT: NA)
Todd, 2012 [21]PC21≥6 months21 TDF + FTC31.1PCR1 (4.7)a
      (25 IU/mL)(HBV DNA at LT: NA)

The type of hgbNA and the use of double antiviral prophylaxis had no impact on the risk of HBV recurrence, since patients under ETV (with or without a nucleotide analogue) had similar rates of HBV recurrence, compared to patients under TDF (with or without nucleoside analogue) [10% (1/10) vs. 3.2% (3/92), p = 0.85]. In addition, patients who remained under prophylaxis with ETV or TDF alone had similar HBV recurrence rates, compared to those with double antiviral (combination of a nucleoside and a nucleotide analogue) prophylaxis [5.2% (1/19) vs. 3.6% (3/83), p = 0.74].

Patients under high genetic barrier NA(s) alone without HBIG (Table 4)

In the four studies [18-20, 23] including 112 patients, a hgbNA was used as post-LT prophylaxis without any HBIG. In particular, for a median of 23 (range: 20–26) months, ETV was given in 81 and TDF in one patient, while details on the type of the hgbNA(s) could not be extracted in 30 patients from one study [23]. Posttransplant HBV recurrence was observed significantly more frequently in the patients who received completely HBIG free prophylaxis based on a hgbNA compared to patients receiving combined of HBIG and LAM prophylaxis using as definition of HBV recurrence the presence of HBsAg positivity [26% (29/112) vs. 5.9% (109/1834), p < 0.0001]. However, if the definition of HBV recurrence was based on HBV DNA detectability (instead of HBsAg positivity), only 1 (0.9%) of 112 patients had HBV recurrence [20], which is numerically but not significantly lower to the recurrence of HBV in patients under HBIG and LAM based on HBV DNA detectability [0.9% vs. 3.8%, p = 0.11] [28, 31, 33, 36, 38, 40, 41, 48, 50, 52]. Again, in this group of patients, the type of NA and the use of double antiviral prophylaxis had no effect on the rates of HBV recurrence.

Table 4. Published studies using newer NA(s) with high genetic barrier [entecavir (ETV) or tenofovir (TDF)] without any hepatitis B immune globulin (HBIG), for prevention of hepatitis B virus (HBV) recurrence after liver transplantation (LT) for HBV related liver disease
Study 1st author, year (Ref no.)Quality of studyPatients (n)NA(s)Mean follow- up, mosHBV DNA assays (lower limit of detection)HBV recurrence, n (%)
  1. NA(s)= nucleos(t)ide analogues; RCT = randomized controlled trial (high-quality evidence); PC = prospective cohort study (intermediate-quality evidence); RC = retrospective cohort study (low quality evidence); NA = not available.

Ahn, 2011 [19]RC1TDFNAbDNA0
Fung, 2011[20]RC80ETV26COBAS TaqMan HBV18 (22.5) (based on HBsAg positivity)
     (35 copies/mL)(HBV DNA at LT: undetectable in 3 of 18 patients)
Wadhawan, 2011 [23]PC30ETV ± TDF20NA11 (37) (based on HBsAg positivity)
      (HBV DNA at LT:<2,000 IU/mL)
Perillo, 2012 [18]RC1ETVNAPCR (50IU/mL)0

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Source
  8. Disclosure
  9. References
  10. Appendix A1

The current strategy to prevent HBV recurrence after LT is based on the combined use of HBIG and a NA, usually LAM, which results in a low rate of HBV recurrence [4]. Three recent meta-analyses [63-65] and our systematic review [6] have shown that HBIG and LAM combination achieve significantly lower HBV recurrence rates compared to HBIG or LAM monoprophylaxis. In addition, the combination of HBIG and ADV with or without LAM seemed to be more effective than the combination of HBIG and LAM, as HBV recurrence developed in 2% and 6% of patients respectively (p < 0.05), although the patients under the former combination had more frequently detectable HBV DNA at LT and less frequently indefinite HBIG use [6]. The superiority of HBIG and ADV combination could be attributed to the better long-term efficacy of the antiviral agent(s) (ADV with or without LAM compared to LAM alone) against both wild type and LAM resistant HBV strains [6]. However, ADV has several drawbacks including its modest antiviral suppressive effect, moderate chance of drug resistance and potential renal toxicity [66]. In addition, ADV is more expensive than more recent NAs. For these reasons, ADV monotherapy is not considered as a first line option for patients with chronic hepatitis B, and it is currently being replaced by the recently approved TDF [67].

The hgbNAs, ETV and TDF, are considered as the first-line agents for oral antiviral therapy in chronic hepatitis B due to their high potency and minimal or no risk of viral resistance [2]. These agents are currently used in the LT setting in many transplant centers, but their impact on HBV recurrence after LT has not been adequately evaluated to date. In this review, we systematically compared the efficacy of the combination of HBIG and a hgbNA (ETV or TDF with or without another NA) with the efficacy of the most common prophylactic regimen HBIG and LAM. The major limitations of our study are the lack of randomized controlled trials (all but one were cohort studies) and the great heterogeneity in the HBIG regimens used in different centers. These limitations, however, exist for the data of both HBIG with hgbNA(s) and HBIG with LAM prophylaxis. According to our findings, HBV recurrence developed significantly more frequently in patients under HBIG and LAM than under HBIG and a hgbNA. Even when only patients who remained under HBIG and NA(s) prophylaxis were taken into account, the combination of HBIG and a hgbNA was again superior than the combination of HBIG and LAM (1.0% vs. 6.1%, p = 0.0004), although the latter patients received significantly more frequently HBIG intravenously and at higher dosages during the first month after LT (Table 2). A higher proportion of patients who received HBIG and LAM had detectable HBV DNA at LT compared to patients who received HBIG and a hgbNA probably due to the higher efficacy of these agents in the pretransplant setting. Nevertheless, when only the patients under HBIG and LAM with undetectable HBV DNA at LT were considered [6], the combination of HBIG and a hgbNA provided again superior protection against HBV recurrence (1.0% vs. 4.0%, p = 0.03).

Given the very low number of patients with HBV recurrence under HBIG and a hgbNA, no definitive conclusion could be drawn for the possible impact of the HBIG regimen, HBV DNA status at LT and other pretransplant or posttransplant factors on the risk of post-LT HBV recurrence.

The combination of HBIG and ETV or TDF achieved almost negligible rates (<2%) of post-LT HBV recurrence and therefore the addition of another NA in such combinations does not seem possible to offer additional benefit, at least in the vast majority of HBV transplant patients.

The efficacy of HBIG discontinuation or even the use of HBIG-free prophylaxis in HBV transplant patients has been challenging and controversial. Unfortunately, good data to definitely address these issues are not available. In a relatively small number of patients (n = 102) followed for a median of 24 months, the use of hgbNA(s) prophylaxis after HBIG discontinuation seemed not to be inferior to the combination of a newer NA with HBIG (3.9% vs. 1.0%, p = 0.17), but also not to be superior to the combination of HBIG and LAM when the definition of HBV recurrence is based either on HBsAg positivity (3.9% vs. 5.9%, p = 0.52) or HBV DNA positivity (0% vs. 3.8%, p = 0.08). In these small patient subgroups with HBIG discontinuation, the type of the hgbNA (ETV or TDF) and the use of a single or two oral antiviral agents had no effect on HBV recurrence.

In the patients (n = 112) who received HBIG-free prophylaxis with hgbNA(s), posttransplant HBV recurrence was observed significantly more frequently compared to the combination of HBIG and any NA(s) including LAM (26% vs. 5.4%, p < 0.0001), if HBV recurrence was based on the presence of HBsAg seropositivity. It should be noted, however, that only one of these 29 patients had detectable HBV DNA and all had normal liver function tests without any impact on their outcomes [20, 23]. Given the current availability of potent NAs with negligible risk of long-term viral resistance, the clinical significance of HBsAg seropositivity in HBV transplant patients is unknown. The prognosis of nontransplant chronic hepatitis B patients who maintain HBV DNA undetectability under NA(s) is excellent particularly if they had not developed cirrhosis before treatment [68]. However, the long-term outcome of HBsAg-positive, HBV DNA negative transplant patients under oral antivirals but also under immunosuppressive agents needs further study. Interestingly, in a recent study [69], (20%) of 25 HBV transplant patients who discontinued any anti-HBV prophylaxis became HBsAg-positive, but none of them experienced any clinically relevant event and three eventually cleared HBsAg and achieved seroconversion to anti-HBs without any therapeutic intervention. Thus, in case of HBIG-free post-LT HBV prophylaxis, the definition of HBV recurrence might be reconsidered, as HBsAg seropositivity alone in patients under hgbNA(s) may not have any clinical impact on the long-term graft and patient survival.

Long-term drug compliance may arise as an important issue in HBV transplant patients under hgbNA(s) prophylaxis alone, as such patients feel well but remain at life-long risk of HBV recurrence. This is supported by the findings in the study by Buti et al. [28], in which three (75%) of the four patients with HBV recurrence had poor drug compliance. Hence, close monitoring of HBV transplant recipients on NA(s) prophylaxis would be needed to confirm adherence and to promptly detect HBV recurrence, allowing the early introduction of proper therapeutic interventions to suppress HBV replication.

All liver transplant recipients should undergo careful renal function monitoring because of the use of calcineurin inhibitors [2]. Based on the available data from seven studies [8, 10, 11, 13, 18, 19, 21], the use of hgbNA(s) for a median of 24 months had no significant impact on renal function in all but one study [21]. In the latter [21], (14%) of the 21 patients under the combination of TDF and FTC developed reversible acute renal failure within 16–21 months, but only one of them had possible TDF/FTC-induced acute tubular necrosis on renal biopsy. Finally, one study [11] found no difference in renal function (evaluated by glomerular filtration rate using 51Cr-EDTA) between 9 patients under nucleoside and 15 under nucleotide analogues followed for a median of 24 months. Of course, longer safety data for the hgbNAs are needed in the HBV transplant setting.

In conclusion, our findings favor the use of HBIG and a hgbNA instead of HBIG and LAM combined prophylaxis against HBV recurrence, as such a strategy further increases the efficacy of post-LT prophylaxis in HBV transplant patients achieving negligible rates of HBV recurrence. The use of ETV or TDF can be effectively combined with lower HBIG dosages even at the early post-LT period. Further studies are required to decide whether, when and perhaps in which subgroups HBIG can be discontinued in patients under a hgbNA. Similarly, the efficacy and effectiveness of HBIG-free prophylaxis based on hgbNA(s) should be evaluated initially in well-designed clinical studies and subsequently in clinical practice.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Source
  8. Disclosure
  9. References
  10. Appendix A1

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Source
  8. Disclosure
  9. References
  10. Appendix A1

Appendix A1

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Source
  8. Disclosure
  9. References
  10. Appendix A1
image

Figure 3. Study flow diagram. Newer nucleos(t)ide analogue (NA) with high genetic barrier: entecavir or tenofovir.

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