Hepatitis B Recurrence: Major Milestones and Current Status

Authors (references)

No. of patients

HBV DNA positive at LT (%)

Prevention of HBV recurrence

Follow-up (months)

HBV recurrence N (%)

Risk factors for HBV recurrence

HBIG regimen

Antiviral

Indefinite high-dose IV HBIG

Markowitz [57]

1 (7 %)

HBIG IV 10,000 IU/month

LAM

0 %

Marzano [54]

HBIG IV 5000 IU/month

LAM

1 (4 %)

LAM-R n = 1

Rosenau [58]

5 (24 %)

2000 IU IV until anti-HBs >100 IU/L

LAM

2 (9.5 %)

LAM-R n = 2

Steinmuller [5]

1500–2000 IU IV until anti-HBs >100 IU/L

LAM

8 %

Faria [18]

21 (41 %)

10,000 IU IV until anti-HBs >150 IU/L (HBV DNA negative at transplant) or >500 IU/L (HBV DNA positive at transplant)

LAM ± ADV or TDV

3 (6 %)

HCC pre-LT

Pre-LT HBV DNA >10⁵ copies/mL

HBIG monoprophylaxis

Han [56]

16 (27 %)

HBIG IV 10,000 IU/month

LAM

0 %

Chun [20]

186

70/167 (32 %)

10,000 IU IV until anti-HBs >350 IU/L

LAM

22 (12 %)

Recurrent HCC

Pre-LT HBV DNA >10⁵ copies/mL

Lamivudine therapy for >1.5 years

Yi [19]

108

43 (40 %)

10,000 IU IV until anti-HBs >350 IU/L

LAM

15 (14 %)

Cumulative dose corticoids

Systemic therapy against HCC

Woo [63]

165

95 (58 %)

HBIG IV 10,000 IU/month during 5 months, HBIG IM 2000 IU biweekly

LAM

7 (4 %)

Pre-transplant Lamivudine therapy for >6 months

LAM-R n = 5

Authors (ref.)	No. of patients	HBV DNA positive at LT (%)	Prevention of HBV recurrence		Follow-up (months)	HBV recurrence N (%)	Risk factors for HBV recurrence
Authors (ref.)	No. of patients	HBV DNA positive at LT (%)	HBIG regimen	Antiviral	Follow-up (months)	HBV recurrence N (%)	Risk factors for HBV recurrence
Indefinite low-dose IM or IV HBIG
Gane [53]	147	125 (85 %)	HBIG IM 800 IU/month	LAM	62	5 (1 % 1 years, 4 % 5 years)	Pre-LT HBV DNA >10⁶ copies/mL
Gane [53]	147	125 (85 %)	HBIG IM 800 IU/month	LAM	62	LAM-R n = 5	Pre-LT HBV DNA >10⁶ copies/mL
Zheng [26]	114	≥10⁵ c/mL (32 %)	HBIG IM 800 IU/month	LAM	20	16 (13.5 % 1 years, 15.2 % 2 years)	Pre-LT HBV DNA >10⁵ copies/mL
Zheng [26]	114	≥10⁵ c/mL (32 %)	HBIG IM 800 IU/month	LAM	20	LAM-R n = 11	Pre-LT HBV DNA >10⁵ copies/mL
Anselmo [59]	89	NA	HBIG IM 1560 IU according to anti-HBs titers	LAM	29	10 (11 %)
Xi [60]	ETV 30	18 (60 %)	HBIG IM 800 IU until anti-HBs >500 IU/L month 3, >300 IU/L month 3–6, > 200 IU/L month 6–12	ETV	NA	0 %
	LAM 90	52 (58 %)		LAM		10 (11 %)
	LAM 90	52 (58 %)		LAM		LAM-R n = 2/4
Jiang [55]	254	53 (21 %)	HBIG IM 8–1200 IU/2–4 week	LAM	41	14 (2.3 % 1 years, 6.2 % 3 years, 8.2 % 5 years)	Pre-LT HBV DNA >10⁵ copies/mL
Jiang [55]	254	53 (21 %)	HBIG IM 8–1200 IU/2–4 week	LAM	41	LAM-R n = 5	Prednisone withdrawal time >3 months
Akyildiz [61]	209	NA	HBIG IM 200–1000 IU/1–4 weeks until anti-HBs >50 IU/L	LAM	18	11 (5.2 %)
Akyildiz [61]	209	NA	HBIG IM 200–1000 IU/1–4 weeks until anti-HBs >50 IU/L	LAM	18	LAM-R n = 5
Cai [64]	ETV 63	NA	HBIG IM 400 IU until anti-HBs >250 IU/L month 3, >100 IU/L >month 3	ETV	ETV 41.2	0 %
	LAM 189			LAM	LAM 38.5	18 (9.5 %)
	LAM 189			LAM	LAM 38.5	LAM-R n = 15
Iacob [65]	42 HDV + 69 %	1 (2 %)	HBIG IV 2500 IU until anti-HBs <50 IU/L	LAM	21	2 (4.8 %)
Subcutaneous HBIG
Di Costanzo [62]	135	NA	HBIG IV 6000 IU/month >12 months post-LT	LAM 87	12	0 %
Di Costanzo [62]	135	NA	HBIG S/C/week 500 IU body weight <75 kg, 1000 IU body weight ≥75 kg	Other 17	12	0 %

NA not available, LT liver transplantation, HBIG hepatitis B immune globulin, LAM lamivudine, ADV adefovir, TDV tenofovir, ETV entecavir, LAM-R resistance mutation(s) to lamivudine, HCC hepatocellular carcinoma, IM intramuscular, IV intravenous

In an effort to find less costly ways of providing HBIG prophylaxis long-term, alternative approaches have been studied including the use of low-dose intramuscular (IM) HBIG [14, 53, 55, 59–61, 64], subcutaneous HBIG [62, 67, 68], withdrawal of HBIG after a finite period or prophylaxis regimens without HBIG.

Combination prophylaxis with low-dose IM HBIG (400–800 IU IM) decreases costs by more than 90 % as compared with an IV regimen, with a recurrence rate as low as 4 % at 4 years [53, 56, 69]. More recently, subcutaneous HBIG initiated 6 months after LT have proven effective as well, with some advantage regarding tolerability and the possibility of self-administration by patients [62, 67, 68]. Degertekin et al. analysed data from 183 patients who had undergone LT between 2001 and 2007 [7]. Patients received combination prophylaxis with antiviral therapy (mostly LAM monotherapy) plus HBIG given either IV high dose (25 %, 10,000 IU monthly), IV low dose (21.5 %, 3000–6000 IU monthly), IM low dose (39 %, 1000–1500 IU every 1–2 months), or for a finite duration (14.5 %, median duration 12 months). Cumulative rates of HBV recurrence at 1, 3, and 5 years were 3 %, 7 %, and 9 %, respectively. A multivariate analysis showed that positivity for HBeAg and a high viral load at transplant, but not the post-transplant HBIG regimen, were associated with HBV recurrence.

Several meta-analyses have compared the use of HBIG, antivirals, or both (Table 2.2) [48, 70–73]. Despite methodological limitations, combination prophylaxis was significantly superior to antivirals or HBIG alone in preventing HBV recurrence, irrespective of the HBV DNA level at transplantation and in reducing overall and HBV-related mortality in some studies. A high HBIG dose (≥10,000 IU/day) vs. a low HBIG dose (<10,000 IU/day) during the first week after LT was associated with a lower frequency of HBV recurrence (3.2 % vs. 6.5 %, p = 0.016).

Table 2.2

Results of meta-analyses comparing combination prophylaxis to HBIG or antiviral monoprophylaxis

Authors (ref.)	Studies	Patients	Results: HBV recurrence, HBV-related mortality
Loomba [72]	6 studies	HBIG + LAM n = 193	HBIG + LAM vs. HBIG:
	1999–2003	HBIG n = 124	– Decrease risk of HBV recurrence 4.1 % vs. 36.1 %
			– Decrease HBV-related mortality: RR = 0.08; 95 % CI (0.02, 0.33)
Rao [70]	6 studies	HBIG + LAM n = 306	HBIG + LAM vs. LAM
Rao [70]	2003–2007	LAM n = 245	– Decrease risk of HBV recurrence: RR = 0.38; 95 % CI (0.25, 0.58)
Katz [71]	20 studies	LAM n = 249	HBIG + LAM vs. HBIG
	(3 RCT)	HBIG n = 351	– Decrease risk of HBV recurrence: RR = 0.28; 95 % CI (0.12, 0.66)
	1999–2007	LAM + ADV = 23	– Decrease HBV-related mortality: RR = 0.12; 95 % CI (0.05, 0.30)
		HBIG + antiviral n = 712	HBIG + LAM and/or ADV vs. LAM and/or ADV
			– Decrease risk of HBV recurrence: RR = 0.31; 95 % CI (0.22, 0.44)
			– Decrease HBV-related mortality: RR = 0.31; 95 % CI (0.09, 1.10)
			HBIG vs. LAM ^a: no statistically significant difference in HBV recurrence and HBV-related mortality
Cholongitas [48]	46 studies	HBIG + LAM and/or ADV n = 2162	HBIG + LAM and/or ADV: HBV recurrence 6.6 %
	(3 RCT)	HBIG + ADV n = 154	HBIG + LAM and/or ADV vs. HBIG: HBV recurrence 6.6 % vs. 26.2 %
	1998–2010	HBIG n = 260	HBIG + LAM and/or ADV vs. LAM and/or ADV: HBV recurrence 6.6 % vs. 19 %
	1998–2010	LAM and/or ADV n = 189	HBIG + LAM vs. HBIG + ADV and/or LAM: HBV recurrence 6.1 % vs. 2 %
Cholongitas [73]	17 studies	ETV or TDV or TDV + FTC and HBIG n = 304	ETV or TDV or TDV + FTC and HBIG: HBV recurrence 1.3 %
	(1 RCT)	ETV or TDV or TDV + FTC and HBIG discontinuation n = 102	ETV or TDV or TDV + FTC and HBIG discontinuation: HBV recurrence 3.9 %
	2009–2012	ETV or TDV or TDV + FTC without HBIG n = 112	ETV or TDV or TDV + FTC without HBIG: HBV recurrence
			– HBsAg + 26 %
			– HBV DNA + 0.9%

^aIn two out of three studies, LAM was given after pretreatment with HBIG (1 week or 6 months)

RCT randomized-controlled trial, HBIG hepatitis B immune globulin, LAM lamivudine, ADV adefovir, ETV entecavir, TDV tenofovir, FTC emtricitabine

The role and the safety of newer nucleos(t)ide analogs (i.e., ETV or TDV) have not yet been adequately evaluated [60, 73–75]. In a recent systematic review, the combination of HBIG and a newer nucleos(t)ide analog was superior to the combination of HBIG and LAM in reducing the risk of HBV recurrence (1 % vs. 6.1 %, p = 0.0004) [73].

The use of IV HBIG has limitations, namely the high cost, parenteral administration, limited supply, need for frequent clinic visits and laboratory monitoring, lower effectiveness in patients with high levels of HBV replication before LT (HBIG monoprophylaxis ), and the potential selection of HBsAg escape mutants (HBIG monoprophylaxis). The intramuscular (IM) route of administration is a cost-effective alternative to IV HBIG. Subcutaneous injections improve quality of life by offering greater independence and home self-administration may contribute to decrease costs by avoiding the need for day hospitals. HBIG has a satisfactory safety record and adverse events observed have usually been minor. Hypersensitivity reactions or even anaphylaxis rarely occur following HBIG administration and can be controlled with antihistamines or steroids.

HBIG Discontinuation

Indefinite combination therapy with HBIG plus a nucleos(t)ide analog may not be required in all liver transplant recipients. The replication status of the patient prior to the initiation of antiviral therapy and at the time of LT should guide prophylaxis. Alternative strategies to consider, especially in patients without detectable HBV DNA prior to transplantation, are the discontinuation of HBIG after a defined period of time and continuing treatment with antivirals alone.

Studies of hepatitis B vaccination as an alternative to long-term HBIG in LT recipients showed that successful hepatitis B vaccination and discontinuation of HBIG are feasible only in a small group of selected patients but the optimal vaccine protocol has not been established [76–84].

Another strategy is HBIG withdrawal after a defined period of combination prophylaxis (Table 2.3) [9, 10, 85–93]. In a study of 29 patients, high-dose HBIG and LAM were used in the first month, and patients were then randomized to receive either LAM monotherapy or LAM plus IM HBIG at 2000 IU monthly [85]. None of the patients developed HBV recurrence during the first 18 months but later recurrences developed in 4 patients after 5 years of follow-up related with poor LAM compliance [86]. An alternative approach is to switch from HBIG/LAM to a combination of antiviral agents. In a randomized prospective study, 16 of 34 patients receiving low-dose IM HBIG/LAM prophylaxis were switched to ADV/LAM combination therapy, whereas the remaining patients continued HBIG/LAM [88]. At a median follow-up of 21 months post-switch, no patient had disease recurrence, although one patient in the ADV/LAM group had a low titre of HBsAg in serum but was repeatedly HBV DNA negative. The same group has recently reported the outcome of 20 patients receiving LAM + ADV initiated at the time of listing and continued after LT [92]. Eight hundred IU of IM HBIG were given immediately after LT and daily during 7 days. After a median follow-up of 57 months post-LT, only one patient became HBsAg positive (HBV DNA negative ) at the time of HCC recurrence. Recently, Teperman et al. evaluated the use of a combination of TDV with Emtricitabine after HBIG discontinuation [91]. In this study, subjects were treated with a combination of Emtricitabine/TDV and HBIG for 24 weeks and then randomized to continue this regimen (n = 19) or to discontinue HBIG (n = 18). At 72 weeks post-randomization, only one patient in the Emtricitabine/TDV group had a transient detectability of HBV DNA related to poor compliance. Several studies demonstrated cases of seroconversion to positive HBsAg associated with undetectable HBV DNA (Table 2.3) [87–89, 92]. A proposed mechanism for this is that HBsAg was being produced at low levels during HBIG therapy and became detectable after HBIG cessation. Longer follow-up of these patients is necessary to determine whether they will clear HBsAg or whether they are at future risk of viral breakthrough. Duration of HBIG in HBIG withdrawal strategies is variable across centers and has not yet been established (Table 2.3). Drug compliance during long-term antiviral therapy may be a very important issue for transplant patients who have a lifelong risk of HBV recurrence.

Table 2.3

Prevention of HBV recurrence after liver transplantation with HBIG discontinuation and long-term antiviral therapy

Authors (references)	No. of patients	HBV DNA positive at LT (%)	Prevention of HBV recurrence	Duration of HBIG	Follow-up (months)	HBV recurrence N (%)
Buti [85, 86]	29	0	Randomized trial	1 months	83	1/9 (11 %) in the LAM + HBIG group
			HBIG + LAM then LAM (n = 20) vs. LAM + HBIG IM 2000 IU/month (n = 9)			3/20 (15 %) in the LAM group (poor compliance to LAM)
						Transient detection of HBV DNA n = 6
Wong [87]	21	20 %	HBIG ± LAM then LAM or ADV	median 26 months	40	HBV DNA+, HBsAg + (LAM-R) n = 1 (5 %) (poor compliance to LAM)
		HBV DNA >5 log copies/mL				HBV DNA +, HBsAg—(LAM-R) n = 1
						Transient detection of HBV DNA n = 3
						Transient detection of HBsAg n = 1
Neff [90]	10	0	HBIG + LAM, then LAM + ADV	6 months	31	0
Angus [88]	34	20 %	Randomized trial	>12 months	21	0/18 in HBIG + LAM group
Angus [88]	34	20 %	IM HBIG + LAM then HBIG + LAM (n = 18) vs. ADV + LAM (n = 16)	>12 months	21	1/16 (6 %) in ADV + LAM group (HBsAg+, HBV DNA−)
Saab [89]	61	21 %	IM HBIG + LAM then LAM or ETV + ADV or TDV (3 months of overlap therapy)	>12 months	15	2/61 (3.3 %) (HBsAg+, HBV DNA−)
Teperman [91]	37	47 %	Randomized trial	Median 3.4 years + 24 weeks	22	0
Teperman [91]	37	47 %	At a median of 3.4 years post-LT, HBIG + TDV-emtricitabine 24 weeks then HBIG + TDV-emtricitabine vs. TDV-emtricitabine	Median 3.4 years + 24 weeks	22	0
Gane [92]	20 + 10	65 %	IM HBIG + LAM + ADV then LAM + ADV	7 days	57	0
Gane [92]	20 + 10	65 %	IM HBIG + LAM + ADV then LAM + ADV	7 days	57	Transient detection of HBsAg in a patient with concomitant HCC recurrence
Nath [93]	14	79 %	IV HBIG + LAM then LAM + ADV	7 days	14.1	1 (7 %)
Lenci [9]	30	0	HBIG + LAM ± ADV were withdrawn after liver biopsy specimens were negative for total and cccDNA	NA	29	5/30 (17 %)
						HBV DNA+, HBsAg + n = 1
						Transient detection of HBsAg n = 4

NA not available, LT liver transplantation, HBIG hepatitis B immune globulin, LAM lamivudine, ADV adefovir, ETV entecavir, TDV tenofovir, LAM-R resistance mutation(s) to lamivudine, IM intramuscular, IV intravenous

An ultimate approach was to evaluate the safety of complete and sustained prophylaxis withdrawal in LT recipients at a low risk of HBV recurrence. Lenci et al. evaluated a cohort of 30 patients treated with a combination of HBIG and LAM (± ADV) for at least 3 years [9]. Using the absence of intrahepatic total HBV DNA and cccDNA as a guide, HBIG and then antiviral therapy was withdrawn. After a median of 28.7 months off all prophylactic therapy, 83 % of the cohort remained without serologic recurrence of HBV infection. Five patients developed HBsAg recurrence but only one patient was HBV DNA positive. In the other patients, HBsAg positivity was transient. The ability to measure total HBV DNA and cccDNA in a liver biopsy has limitations: this strategy requires sequential liver biopsies and assays for quantification of total HBV DNA and cccDNA are not standardized.

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