Hepatitis B immune globulin to prevent hepatitis B recurrence after liver transplant: A single-center experience

Abstract

BACKGROUND

Hepatitis B surface antigen (HBsAg) positive liver transplant (LT) recipients are at an increased risk for hepatitis B virus (HBV) recurrence without prophylaxis with hepatitis B immune globulin (HBIG), nucleos(t)ide analogue, or a combination.

AIM

To describe the use of HBIG in HBsAg positive LT recipients and explore the association between HBIG duration and HBV recurrence.

METHODS

We performed a retrospective, single-center cohort study of HBsAg positive LT recipients between January 1, 2016 and July 31, 2023. A descriptive statistical analysis was performed. The primary outcome was HBV virologic recurrence at 12 months post-LT, defined as HBV DNA > 100 IU/mL.

RESULTS

A total of 14 LT recipients (64% males, median age 59 years) were included. Reasons for LT were cirrhosis with hepatocellular carcinoma (n = 5), other complications of cirrhosis (n = 6), and acute liver failure (n = 3). Ten patients received HBIG after LT, with treatment duration ranging from 5 days to 12 months. All patients had HBV DNA < 100 IU/mL by 2 months post-LT. Of the 14 patients, 12 had HBV DNA < 20 IU/mL at either 6 or 12 months post-LT. None of the patients developed HBsAg positivity post-LT.

CONCLUSION

In this small, single-center cohort, shorter durations of HBIG (≤ 6 months) were not associated with HBV recurrence. These findings suggest that time-limited HBIG may be feasible in selected HBsAg-positive LT recipients, but should be interpreted with caution and require validation in larger, prospective studies.

Key Words: Hepatitis B; Liver transplantation; Hepatitis B immune globulin; Post-transplant care; Hepatitis B recurrence

Core Tip: We studied liver transplant (LT) recipients with chronic hepatitis B, who are often given long durations of hepatitis B immune globulin (HBIG) to prevent hepatitis B recurrence, and found that as little as 6 months of HBIG effectively suppressed hepatitis B DNA and prevented recurrence. Our findings have the potential to reduce cost, side effects, and inconvenience for LT recipients with hepatitis B without compromising patient safety.

INTRODUCTION

In the United States, 0.3% of the population has chronic hepatitis B virus (HBV) infection despite the availability of an effective vaccine[1]. Liver transplant (LT) offers definitive treatment of chronic HBV infection associated complications such as decompensated hepatic cirrhosis and hepatocellular carcinoma (HCC)[2]. HBV accounts for 1.8% of LT in the United States, but 5%-7% of LT for HCC[3]. LT recipients with chronic HBV infection, evidenced by hepatitis B surface antigen (HBsAg) positivity, are at high risk for HBV recurrence without prophylaxis; in fact, early literature described HBsAg positivity as a relative contraindication to LT because of the near-universal recurrence of HBV[4]. More recent studies since the advent of modern antiviral therapy have identified risk factors for HBV recurrence, including HBeAg positivity, high levels of HBV DNA prior to transplant, acute liver failure, history of antiviral non-adherence or viral resistance, HCC (particularly outside of Milan criteria), and co-infection with hepatitis D virus (HDV) or human immunodeficiency virus (HIV)[5-7].

To reduce risk of HBV recurrence, several prophylaxis strategies have been employed. At most LT centers, HBsAg positive LT recipients are treated with nucleos(t)ide analogues (NA) pre- and post-LT indefinitely. At many LT centers, individuals with high risk for recurrence are also treated with hepatitis B immune globulin (HBIG), a human derived antibody against HBsAg. HBIG is administered intravenously or intramuscularly. The lack of consensus on the duration of HBIG therapy has incurred a high cost at a questionable benefit. Recent studies demonstrated that HBIG can be discontinued around 12 months post-LT without a high risk for HBV recurrence[4,5]. The aim of this study was to describe the use of HBIG in HBsAg positive LT recipients and explore the association between HBIG duration and HBV recurrence.

MATERIALS AND METHODS

This was a retrospective, single-center cohort study of adults (age at least 18 years) with HBsAg positivity prior to LT who underwent LT between January 1, 2016 and July 31, 2023. To minimize selection bias, we included all consecutive patients meeting prespecified inclusion criteria within the study period and derived the cohort from a well-defined clinical database. Participants were ascertained using an internal transplant database, and manual chart review was performed to extract pre-LT characteristics, treatment, and serologies as well as post-LT follow up. Exclusion criteria included dual organ transplants. A descriptive summarization of the data was performed to describe the pre-LT characteristics and post-LT outcomes. The primary outcome was HBV recurrence at 12 months post-LT, defined as HBV DNA > 100 IU/mL; HBsAg seroreversion was not required for the primary endpoint. An institutional protocol guided HBIG dosing according to recurrence risk; however, final decisions were left to provider clinical judgment. Any of the following clinical characteristics were considered to confer higher risk for HBV recurrence and indefinite HBIG was considered: HBV DNA > 10⁵ copies, HCC, HBeAg positivity, prior antiviral drug resistance. HBV DNA was monitored at the time of transplant and at least at 2, 6, and 12 months post-transplant per Organ Procurement and Transplantation Network policy. Missing data were not imputed and were reported as missing. Descriptive statistics were performed. The study was approved by our center’s Institutional Review Board (No. 00114976) and received a waiver of informed consent.

RESULTS

A total of 14 HBsAg positive LT recipients were included. Of these, 9 individuals (64%) were men, and the median age at LT was 59 years. Reasons for LT were HCC (n = 5), decompensated cirrhosis (n = 6), and acute liver failure (n = 3). Comorbidities included co-infection with HDV (n = 1) and HIV (n = 1). Prior to LT, 7 patients were HBeAg positive and 3 patients had HBV DNA > 20000 IU/mL. None had evidence of antiviral resistance prior to LT. Two patients received donor livers with positive hepatitis B core antibody; one of these patients received 5 days of HBIG, the other 6 months, as donor core antibody status does not alter HBIG recommendations in our institutional protocol. The follow up period was 12 months post-LT. No participants were lost to follow up during the study period.

Table 1 shows participant pre-LT characteristics and post-LT outcomes. No participants experienced HBV virologic recurrence. A total of 10 patients (71%) received HBIG post-LT, with treatment duration ranging from 5 days to 12 months. Only 2 patients stopped HBIG before 6 months post-LT (duration of treatment 5 days and 4 months). Four patients did not receive HBIG based on provider assessment of low recurrence risk, consistent with our institutional protocol recommending omission of HBIG in such cases. Three of the 4 patients who did not receive HBIG were HBeAg positive prior to LT. The 3 patients with HBV DNA > 20000 IU/mL prior to LT received variable durations of HBIG (4, 6, and 12 months). All 14 patients were treated with NA (either tenofovir alafenamide, tenofovir disoproxil fumarate or entecavir per provider discretion) post-LT, with 7 receiving tenofovir alafenamide, 7 receiving tenofovir disoproxil fumarate, and 3 receiving entecavir (2 patients were switched from one agent to another). For immunosuppression, all patients received a calcineurin inhibitor (tacrolimus n = 11, cyclosporine n = 3), an antimetabolite (mycophenolate mofetil n = 13, mycophenolic acid n = 1), and prednisone. All 14 patients had HBV DNA < 100 IU/mL by 2 months post-LT, and 13 had HBV DNA < 20 IU/mL at either 6 or 12 months post-LT, with 1 patient missing HBV DNA level at both 6 and 12 months. Nine patients with HBV DNA available at 6 months post-LT had HBV DNA < 10 IU/mL with only one patient having HBV DNA > 10 IU/mL. Among 12 patients with available HBsAg measurements at 2, 6, or 12 months post-LT, no cases of HBsAg positivity were observed (n = 9 at 2 months, n = 5 at 6 months, n = 10 at 12 months). All LT recipients were living with functioning allografts at 12 months. Of the 7 patients with HBsAb titers 12 months post-LT, 3 had titers > 10 mIU/mL suggestive of immunity, whereas 4 patients had titers ≤ 5 mIU/mL, indicating lack of immunity. All 4 patients with low HBsAb titer had suppressed or undetectable HBV DNA, and none received HBIG for 12 months, suggesting effectiveness of NA in patients without immunity even after HBIG withdrawal. A specific washout period after HBIG discontinuation was not mandated prior to HBsAb titers being drawn.

Table 1 Hepatitis B surface antigen positive patient characteristics and post-liver transplant hepatitis B immune globulin treatment outcomes.

Patient characteristics					Serologies at 2 months post-LT			Serologies at 6 months post-LT			Serologies at 12 months post-LT
Age, sex	Reason for LT, co-infection	HBV DNA pre-LT (IU/mL)	HBIG therapy duration (months)	NA post-LT	HBsAg	HBV DNA (IU/mL)	HBsAb titer (mIU/mL)	HBsAg	HBV DNA (IU/mL)	HBsAb titer (mIU/mL)	HBsAg	HBV DNA (IU/mL)	HBsAb titer (mIU/mL)
55, male	Cirrhosis	< 10	Did not receive	TAF	Negative	0	-	Negative	0	-	Negative	0	-
59, male	Cirrhosis, HCC	0	Did not receive	TDF	-	0	-	-	-	-	Negative	0	3
49, male	Cirrhosis, HCC	< 10	Did not receive	TAF	-	0	-	-	0	-	-	0	-
50, male	Cirrhosis, HCC	< 10	Did not receive	TDF	-	0	-	-	-	-	-	0	-
59, female	Acute liver failure	71000000	4	TDF	Negative	10	-	-	-	-	Negative	-	-
58, female	Cirrhosis	0	6	TAF	Negative	0	-	Negative	0	242	Negative	0	19
64, male	Cirrhosis, HIV	1000000000	6	TAF	-	84	-	-	10	-	-	10	-
67, male	Cirrhosis	141	6	TDF	Negative	10	-	Negative	10	-	Negative	10	-
59, male	Cirrhosis	128	6	TDF, entecavir	Negative	20	294	-	0	-	-	-	-
59, male	Cirrhosis, HCC, HDV	0	6	TDF	Negative	0	-	Negative	0	1000	Negative	0	759
46, female	Acute liver failure	7110	6	TAF, TDF, Entecavir	-	19	-	-	0	-	Negative	10	3
60, female	Cirrhosis	214000000	12	Entecavir	Negative	77	14	Negative	18	24	Negative	10	104
48, female	Acute liver failure	1010	6	TAF	Negative	0	-	-	0	-	Negative	0	5
56, male	Cirrhosis, HCC	< 10	5 days (intra-/post-operatively	TAF	Negative	0	791	-	-	-	Negative	0	3

HBsAb: Hepatitis B surface antibody; HBsAg: Hepatitis B surface antigen; HBIG: Hepatitis B immune globulin; HDV: Hepatitis D virus; HCC: Hepatocellular carcinoma; LT: Liver transplant; NA: Nucleos(t)ide analogue; TAF: Tenofovir alafenamide; TDF: Tenofovir disoproxil fumarate.

DISCUSSION

In a small retrospective cohort, we observed that patients receiving HBIG after LT maintained adequate HBV viral suppression at 6 months, suggesting that a shorter duration than is currently utilized at many centers may be feasible. Concurrent use of HBIG and NA in HBsAg positive LT recipients started in the 1990s after discovery that lamivudine was associated with high rate of viral resistance and adding HBIG reduced risk of HBV recurrence[3]. Highly effective NAs were later developed but combination therapy remains the standard of care[2]. Many LT centers, including our own, use pre-LT risk of HBV recurrence to determine duration HBIG therapy. In our cohort, HBIG durations of 12 months or fewer were not associated with HBV recurrence, consistent with prior reports[4,5]. Notably, among patients with low HBV DNA and robust HBsAb titers, shorter durations (2-6 months) were not associated with recurrence; however, these findings should be interpreted with caution given the small sample size and lack of a control group. Further, all patients in the study were treated with NA, which are highly effective at achieving HBV viral suppression, and therefore the specific impact of HBIG on viral suppression could not be ascertained by this retrospective analysis.

This study highlights the potential to reduce unnecessary treatment and cost associated with LT for patients with HBV. This is highly salient given the cost of HBIG, which can be hundreds or up to $1000 per dose[8]. Based on the current published average wholesale price of $189.69 per 312 unit/mL vial, over $2000 would be saved by stopping HBIG at or before 6 months. When accounting for drug administration, facility fees, and lab monitoring, shortening HBIG duration from 12 to 2 months could result in approximately $10000 in cost savings per patient, as well as co-pay savings for patient, reducing financial toxicity of LT. Further, the commonly used intramuscular formulations create logistical barriers including the need for refrigeration and comfort with administration. Taken together, these findings support the need for prospective studies to evaluate risk stratification strategies that may allow for shorter HBIG duration in selected lower-risk patients. Figure 1 presents a proposed treatment algorithm informed by these observations. The limitations of our study include the single-center design, which may limit generalizability, the small sample size, the limited follow up duration, and the retrospective nature of the analysis, including the absence of a control group with longer HBIG durations. We were also not able to assess adherence to HBIG or NA given the study design.

Figure 1 Prevention of hepatitis B virus recurrence in hepatitis B surface antigen positive liver transplant recipients. HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; HBIG: Hepatitis B immune globulin; LT: Liver transplant; NA: Nucleos(t)ide analogue.

CONCLUSION

Fewer than 6 months, and as few as 2 months, of HBIG may provide adequate protection against HBV recurrence in select patients with chronic hepatitis B undergoing LT. Large, multi-center, prospective studies are necessary to determine the long-term safety of a shortened HBIG duration.

ACKNOWLEDGEMENTS

The authors gratefully acknowledge Allison Berryann for assistance with cohort identification.