Prophylaxis for Hepatitis B Virus Reactivation after Allogeneic Stem Cell Transplantation in the Era of Drug Resistance and Newer Antivirals: A Systematic Review and Meta-Analysis

Abstract

Patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) are at a very high risk of hepatitis B virus reactivation (HBVr). Lamivudine is commonly used as prophylaxis against HBVr in high risk patients undergoing allo-HSCT. Unfortunately, its efficacy is diminishing due to the development of HBV mutant drug resistant strains. With the availability of newer antiviral agents like Entecavir, Telbivudine, Adefovir and Tenofovir, it is important to assess their role in HBVr prophylaxis. A comprehensive search of seven databases was performed to evaluate efficacy of antiviral prophylaxis against HBVr in allo-HSCT patients (PubMed/Medline, Embase, Scopus, Cochrane Library, Web of Science, CINAHL, and ClinicalTrials.gov - June 21, 2017). We identified 10 studies with 2067 patients undergoing allo-HSCT; these primarily evaluated the use of Lamivudine and Entecavir as prophylaxis against HBVr in patients undergoing allo-HSCT because there was little or no data about Adefovir, Telbivudine, or Tenofovir as prophylaxis in this specific patient population. Thus, included studies were categorized into two main prophylaxis groups: Lamivudine and Entecavir. Results of our meta-analysis suggests that Entecavir is very effective against HBVr, although further clinical trials are required to test efficacy of new antivirals and explore the emerging threat of drug resistance.

Introduction

Worldwide, two billion people have evidence of past or present infection with hepatitis B virus (HBV), with the highest prevalence observed in Sub-Saharan Africa and East Asia.¹ HBV can cause acute or chronic liver disease, the latter of which may lead to fibrosis, cirrhosis, end-stage liver disease, or hepatocellular carcinoma.^2,3 Patients with malignancies undergoing chemotherapy and stem cell transplantation are highly susceptible to developing HBV reactivation (HBVr) (Table 1). A meta-analysis performed with data from patients with Non-Hodgkin's Lymphoma receiving rituximab chemotherapy, found that among anti HBc +ive or HBsAg +ive cases, there was a twofold higher rate of HBVr.⁴ In cases of hematological malignancies, especially when a patient is undergoing allo-HSCT, the host's immune system may tip its balance due to the nature of the underlying hematological disease as well as the aggressive treatment used to treat it, both of which may lead to prolonged periods of immunosuppression.⁵ In patients with past HBV infection, during period of immunosuppression, the HBVr rates are highest in HbsAg +ive subset and lowest in those patients who experienced a clinical cure.⁶ Biological cure of HBV infection is defined by loss of covalently closed circular DNA from hepatocytes.⁷ However, clinical cure is defined as loss of HBsAg and seroconversion to anti-HBs. HBVr carries a very high mortality rate when compared with an acute onset HBV infection.

Table 1. Definitions of terminology for HBV reactivation risk stratification.

TERMS	DEFINITION
High Risk (HR) recipients	HBsAg +ve only or HBV DNA quantitative +ve (greater than 2000IU/ml) only, HBsAg +ve but HBV DNA quantitative -ve (less than 2000IU/ml), Anti HBc +ve, Anti HBc +ve and Anti HBs +ve, Prior HBV Vaccination Status Unknown.
High Risk (HR) Donors	Any serology positive i.e HBsAg +ve, Anti HBc +ve, Anti HBsAg +ve or HBV DNA quantitative +ve
Low Risk (LR) recipients	HBV DNA quantitative -ve, Anti HBs +ve, HBsAg -ve, Anti HBc -ve, Anti HBs -ve
Low Risk (LR) Donors	HBV DNA quantitative -ve, HBsAg -ve, Anti HBc -ve, Anti HBs -ve or
Hepatitis B Virus reactivation (HBVr)	Reappearance of serum HBV-DNA or its marked increase (greater than 1 log IU/mL) from baseline with or without acute change in liver function tests (Increase in ALT ≥ 2 times the ULN of <40 IU/L), jaundice, and Anti HBc-IgM +ive.

In the US alone, 8000 allo-HSCTs are performed annually. More than 60% of patients, who are HbsAg +ive prior to transplant, face HBVr. Lamivudine (LAM) is known to prevent HBVr and can be used prophylactically in chronic HBV infected patients undergoing treatment for hematological malignancies. However, the emergence of LAM resistant mutant strains have led to its decreased efficacy.⁸ With the availability of newer antiviral agents such as Entecavir (ETV), Telbivudine (TBV), Adefovir (ADV), and Tenofovir (TDF), it is important to assess their role as prophylaxis in preventing HBVr after allo-HSCT. Currently, there are no updated consensus recommendations regarding the use of these antivirals in the era of LAM drug resistance. Our aim in this review was to comprehensively search and evaluate current medical literature and update clinicians on best evidence-based practices regarding the use of antiviral prophylaxis for hepatitis B reactivation in high risk patients undergoing allogeneic stem cell transplantation.

Methods and Materials

A literature review was performed using methods specified in the PRISMA statement for reporting systematic reviews and meta-analyses⁹ (Fig 1). Controlled vocabulary search terms (MeSH and EmTree), as well as keywords, were used to search the following seven databases for studies that examined hepatitis B reactivation after allogeneic stem cell transplantation: PubMed/Medline, Elsevier/Embase, Elsevier/Scopus, Wiley/Cochrane Library, Thomas-Reuters/Web of Science, EBSCO/CINAHL, and ClinicalTrials.gov. Under supervision of a research librarian (CH), all databases were searched from the date of their inception to the date literature searches were completed on June 21, 2017. Reference lists of, and citations to the articles eventually selected from the database searches, were also screened, as was the reference list of a related, recently published review.¹⁰

Figure 1. Prisma Flow Chart.

Two independent reviewers (AS, AM) initially screened all retrieved titles and abstracts for relevance. The same protocol was used to screen the full text of articles initially selected. Disagreements were resolved by consensus. Inclusion criteria for our review were as follows: (i) Studies with high risk (HR) allo-HSCT recipients and donors (Table 1 Definition of Risk Stratification) (ii) Patients who received allo-HSCT (MUD, MRD, Haplo, Cord) (iii) Patients who received antivirals peri allo-HSCT to prevent HBVr (iv) Low risk (LR) recipients used as a comparison group, who may or may not have received antivirals peri allo-HSCT (Table 1). Case studies, letters, opinions, reviews, including systematic reviews and meta-analyses were excluded as were articles not in English.

To measure study quality, we used a previously validated NIH 14-point scale, with yes or no assigned to each question.¹¹ Studies were categorized into low quality, fair quality, and good quality groups, as per criteria by two independent raters. One author (AS) extracted the data, which was subsequently examined by a second author (SM). The following variables were analyzed: author, year, study design, number of subjects (intervention and control groups), antiviral (agent, dose, duration of treatment), and HBV related outcomes (HBVr or no HBVr). The primary outcome for our review was incidence of HBVr in patients receiving antiviral prophylaxis. According to the American Association for the Study of Liver Disease (AASLD), HBVr is defined as a marked increase in HBV replication (≥ 2 log increase from baseline levels or a new appearance of HBV DNA to a level of ≥ 100 IU/mL) in those with previously stable or undetectable levels.

Results

We found 2560 studies through the database searches. Citation analysis of the most relevant articles revealed an additional two articles. Of the 1264 articles that remained after duplicates were removed, 1183 were excluded because of irrelevance to the topic. Strict inclusion criteria, as outlined above, were applied to the full text of 81 articles. Of these, 10 met the full set of criteria^12-21 and were analyzed in this review. Nine studies were retrospective cohort and one was a prospective cohort with 2067 patients in total, of whom 611 were HR and 1456 were LR. Population size among individual studies ranged from 4 to a maximum of 703 patients. These studies were published in seven different countries, including Australia, China, India, Italy, Japan, Turkey and the United Kingdom between 2002 and 2016. The baseline characteristics are given in Table 2 and 3. Based on the antiviral prophylaxis agent, studies were divided into two groups: LAM prophylaxis and ETV prophylaxis. Duration of planned prophylaxis ranged between 6 and 30 months. All patients underwent allo-HSCT. All patients in the prophylaxis group were given either 100 mg per day LAM or 0.5 mg per day ETV during the peri-transplant period. Random-effects model was applied while doing meta-analysis using comprehensive meta-analysis (CMA) software version 2.

Table 2. Efficacy of LAM Prophylaxis in Allogenic HSCT Recipients.

Authors Year Design Place of study	Total (N)	Intervention, Dose, Duration	HPRP	High Risk Recipient(R) HBV Serology\High Risk Donor(D) HBV Serology	Outcomes
Cerva 2016 Retro Italy	High Risk=45 vs. Low Risk=211	LAM 100mg/day (30 mo) vs No Prophy	39\45	(R)Resolved HBV (27), Inactive carrier (3) (D) Resolved HBV (15)	High Risk=2/45(4.4%) HBVr Low Risk=2/211(0.94%) HBVr
Gupta 2016 Retro India	High Risk=7 vs Low Risk=95	LAM 100mg/day or 3mg/kg/day in <12yo (6 mo) vs No Prophy	7\7	(R)Resolved HBV (7) (D) Vaccinated (1)	High Risk =0/7(0%)HBVr Low Risk=20/95(21.05%) HBVr
Giaccone 2010 Retro Italy	High Risk=30 vs Low Risk=87	LAM 100mg/day (40 mo) vs No Prophy	16\30	(R) Resolved HBV (25), Active HBV(2) (D) Active HBV (3)	High Risk= 3/30(10%) HBVr Low Risk=0/87(0%) HBVr
Topcuoglu 2010 Retro Ankara, Turkey	High Risk=23 vs Low Risk=680	LAM 100 mg/day (6-12 mo) vs No Prophy	14\23	(R) Inactive carriers (14) (D) Active HBV (6), Unknown HBV Serology (3)	High Risk= 4/23(17.39%) HBVr Low Risk= 3/680(0.44%) HBVr
Moses 2006 Retro London	High Risk=15 vs Low	LAM 100 mg/day (6 mo) vs No Prophy	8\15	(R) Resolved HBV (8), Inactive carrier(2) (D) Resolved HBV (5)	High Risk= 3/15(20%) HBVr Low Risk= Data not available
Lau 2002 Retro china and Australia	High Risk=20 vs High Risk=20	LAM 100 mg/day (13 mo) vs No Prophy	20\20	(R) Active HBV (20)	High Risk(prophy)=1/20(5%) HBVr High Risk (no prophy) =10/20(50%) HBVr
Shang 2016 Retro China	LAM GROUP High Risk=88 Low Risk=31 ETV GROUP High Risk=75 Low Risk=22	LAM 100mg/day (119) vs. ETV 0.5mg/day (97) (24 mo for both)	LAM= 119\119 ETV= 97\97	LAM Group: (R) Active HBV (88) ETV Group: (R) Active HBV (75)	LAM: High Risk = 28/88(31.81%) HBVr Low Risk = 0/31(0%) HBVr ETV: High Risk = 2/75(2.67%) HBVr Low Risk = 0/22(0%) HBVr

Abbreviations: N= total number of participants, Retro= retrospective study, LAM= lamivudine, mo= months, yo= years old, prophy=prophylaxis, pts= patients, (R)= recipient, (D)= donor, HBV= hepatitis B virus, HBVr= hepatitis B virus reactivation, HPRP= high risk patients received prophylaxis

Table 3. Efficacy of Entecavir Prophylaxis in Allogenic HSCT Recipients.

Study Author, Year Design, Place of study	Total (N)	Intervention, Dose, Duration	HPRP	High Risk Recipient(R) HBV Serology High Risk Donor(D) HBV Serology	Outcomes
Liao, 2015 Pros, China	High Risk=57 vs Low Risk=105	ETV 0.5mg/day (12 mo) vs No Prophy	57\57	(R) Active HBV (25), Resolved HBV (32)	High Risk=1/57(1.75%) HBVr Low Risk=0/105(0%) HBVr
Aoki, 2014 Retro, Tokyo, Japan	High Risk=4	ETV 0.5mg/day (12.5 mo)	4\4	(R) Active HBV (4)	High Risk=0/4(0%) HBVr
Shang, 2016 Retro, China	LAM GROUP High Risk=88 Low Risk=31 ETV GROUP High Risk=75 Low Risk=22	LAM 100mg/day (119) vs. ETV 0.5mg/day (97) (24 mo for both)	LAM= 119\119 ETV= 97\97	LAM Group: (R) Active HBV (88) ETV Group: (R) Active HBV (75)	LAM: High Risk = 28/88(31.81%) HBVr Low Risk = 0/31(0%) HBVr ETV: High Risk = 2/75(2.67%) HBVr Low Risk = 0/22(0%) HBVr
Tsuji, 2012 Retro, Tokyo, Japan	High Risk=158 vs High Risk=69	LAM 100mg/day (12) ETV 0.5mg/day (146) vs No Prophy	158\158	(R) Resolved HBV (140), Active HBV (18)	High Risk(Prophy)=0/158(0%) HBVr High Risk (No Prophy) =4/69(5.79%) HBVr

Abbreviations: N= Total number of participants, Prosp= Prospective, Retro= Retrospective study, LAM= lamivudine, ETV= entecavir, mo= months, yo= years, Prophy= prophylaxis, pts= Patients, (R)= recipient, (D)= donor, HBV= Hepatitis B virus, HBVr= Hepatitis B virus reactivation, HPRP: High risk patients received prophylaxis

A. Efficacy of Lamivudine prophylaxis against HBV reactivation

This group included seven studies with 323 HR and 1351 LR patients (n= 1674), as summarized in Table 2. Six studies used LAM as prophylaxis for HR patients (n= 104) undergoing allo-HSCT. Only one study used either LAM or ETV as prophylaxis for HR patients (n=163) as prophylaxis. Shang et al ¹⁸ compared both ETV and LAM simultaneously, and thus their data were included in both the LAM and ETV analysis. Duration of LAM prophylaxis ranged from six to 30 months for different studies. Of the 323 HR patients, only 267 patients received prophylaxis. The patients who did not receive any prophylaxis had negative HBV serology, but they were placed in the HR group due to their donors' positive HBV serology. Lau et al ¹⁷ compared HR patients who received LAM prophylaxis with no prophylaxis and found an HBVr rate of 5% and 50% for each group, respectively. Shang et al ¹⁸ reported that HR patients who received LAM prophylaxis (n=88) had an HBVr rate of 31.81%, as compared to the HR patients who received ETV prophylaxis (n=75) who had an HBVr rate of only 2.67%. The cumulative incidence rate of HBVr in their study at 6, 12, and 24 months for LAM prophylaxis was 3.0%, 7.0%, and 24%, and for ETV prophylaxis was 0%, 0%, and 2.0%, respectively. Our analysis for LAM prophylaxis revealed an aggregated HBVr event rate of 11.5% in HR patients (range: 5-30%, 95% CI: 0.046-0.263, p < 0.000, z value = -3.967). Mean follow-up time was 18.7 months (range = 6 to 40 months).

B. Efficacy of Entecavir prophylaxis against HBV reactivation

This group included a total of four studies (n=609), as summarized in Table 3, with 451 HR patients and 158 LR patients. Four studies used ETV as prophylaxis for HR patients (n=294) undergoing allo-HSCT, and only one study gave ETV to a LR group (n=22). Two studies used either LAM or ETV for HR prophylaxis (n=321). Tsuji et al ²¹ compared a HR population, which received either ETV (n=146) or LAM (n=12) prophylaxis with a group of HR patients who did not receive any prophylaxis (n=69), and found an HBVr rate of 0% vs 5.79%, respectively. Our analysis revealed that the four-study aggregated HBVr event rate with ETV prophylaxis in HR patients (n=282) was 1.9% (range: 0% - 2.67%, 95% CI: 0.007-0.050, p < 0.000, z value: -7.776). Random-effects model was once again applied to this analysis. Mean follow-up duration was 16.1 months (range 12-24 months). The mean duration of follow up for Tsuji et al ²¹ was not clearly stated. Only two of the included studies had LR groups, and among them chemoprophylaxis was used in one study while no prophylaxis was given in the second study.^18,19 Irrespective of prophylaxis use, no HBVr was documented in LR group. Despite the limitation of a retrospective study design, lack of prospective randomized data, and limited numbers of study subjects, ETV prophylaxis appeared to be highly effective against HBVr in this subgroup.

Discussion

Seven drugs are currently approved by the Federal Drug Administration (FDA) for the treatment of chronic hepatitis B (CHB) infection: interferon (INF) (conventional and PEGylated) and five nucleoside/nucleotide analogues (LAM, ETV, TDF, TBV and ADV). Recommendations from leading liver disease associations include the use of INF, ETV, TDF and tenofovir alafenamide (TAF) as initial treatment for chronic HBV infection.^22-25 In treatment-naïve patients, TDF or ETV are generally preferred agents due to their good antiviral activity and low risk of resistance by mutant viral strains.²⁶ TAF is reported to be superior due to its better side effect profile when compared to TDF.^27,28 INFα has limited efficacy (30 to 40 %) and high a incidence of adverse events.²⁹

HR patients undergoing allo-HSCT carry significant risk of HBVr during immunosuppression therapy for Graft Versus Host Disease (GVHD). In patients undergoing chemotherapy for various hematological malignancies, the reported incidence of HBVr is 32.08% to 60%.^30,31 The network meta-analysis by Zhang et al ¹⁰ compared the use of five antivirals for prophylaxis of HBVr in immunosuppressed patients with hematological malignancies and found superior efficacy for ETV (88%) and TDF (90%) when compared to LAM, ADV and TBV. Our meta-analysis focused on efficacy of HBVr prophylaxis specifically among allo-HSCT patients and analyzed data from ten studies in which 611 HR patients received prophylaxis. No studies were available which used TDF, TBV and ADV for HBVr prophylaxis in HR allo-HSCT patients. The aggregated HBVr event rate was 1.9% in the ETV group vs 11.5% in the LAM group.

Data on LAM resistance in patients undergoing allo-HSCT is very limited. Data from other studies using various HR populations suggested that after continuous use of LAM for a few years, the emergence rate of resistant HBV mutant strains was very high (70% after use for four years).^32,33 A multicenter US-Canadian trial studied LAM as HBVr prophylaxis in 77 liver transplant candidates, and discovered that YMDD mutations emerged in 15 (32%) transplant patients and 6 (22%) non-transplant patients.³⁴ In a similar study of liver transplants, 43% of patients were given LAM prophylaxis only and 57% were given combined LAM and hepatitis B immunoglobulin. HBVr in the LAM only prophylaxis group was 15%, whereas HBVr in the combined prophylaxis group was 18%.³⁵

Fung et al ³⁶ used ETV (with a median duration of 5 months) as HBVr prophylaxis in 80 patients undergoing liver transplant due to HBV related complications and at median follow-up of 26 months, there was 91% loss of HbsAg and 98.8% clearance of HBV DNA. Emerging evidence from SOT patients regarding drug resistant strains with LAM use is highlighting the need of testing alternative novel antivirals for patients undergoing allo-HSCT.^34,35,37 The American Society of Transplant (AST) suggests either TDF or ETV should be used in both liver and other solid organ transplant patients with HBV infection because of their high efficacy and low resistance. The antiviral should be given for an indefinite period if patients have active disease (HBsAg +ive or rising PCR for HBV DNA).

In clinical practice, the choice of antiviral regimen is based on factors such as prior exposures, drug resistance, potential drug interactions and side effects. Some transplant centers use combination antiviral therapy during the peri-transplant period, including combination ETV and TDF, but there is limited published data to support combination therapy. In cases of non-liver solid organ transplants, patients with chronic HBV should be evaluated by a specialist in the field to determine the need for HBVr prophylaxis.³⁸ TDF has been without resistance after 6 years of use in chronic HBV patients and has shown promising results as chemoprophylaxis for HBVr in liver transplant recipients.³⁹ In the setting of allo-HSCT, there is limited data on chemoprophylaxis with TDF in preventing HBVr post allo-HSCT. A case report of two allo-HSCT patients with GVHD who were given TDF 245 mg per day orally for the treatment of HBVr resulted in a progressive and continual decrease in hepatitis B viral load ⁴⁰.

Some of the limitations of our meta-analysis are directly attributable to the number and quality of studies available for analysis. For example, no randomized controlled trials were found and thus our analysis was limited to retrospective and prospective cohort studies. The overall number of studies included in our analysis was small and many had small sample sizes. Additionally there was significant heterogeneity among patient population, ethnicity, primary diagnoses, conditioning regimens, and prophylaxis duration for patients who were undergoing allogenic HSCT. There were limited data for head-to-head comparison of LAM with ETV or other novel antivirals. The duration for LAM prophylaxis varied among studies, which may account for differences in HBVr rates. We have summarized currently available guidelines and specialty group recommendations available for prophylaxis of HBVr (Table 4). Our project highlights the need for well-designed, prospective clinical trials to establish efficacy of ETV and other novel antivirals for HBVr chemoprophylaxis for patients undergoing allogenic stem cell transplantation.

Table 4. Summary of recommendations and guidelines for prophylaxis of HBV reactivation after solid organ transplantand Hematopoietic stem cell transplantation.

Specialty	Recommend		ations and guidelines for prophylaxis of HBV reactivation after organ transplantation.
NCCN 2.2017	Prophylaxis indication		If HbsAg +ve, HBV DNA quantitative +ve or anti HBc +ve but HbsAg -ve and anti HBs +ve, consult Infectious Disease to determine possible antiviral prophylaxis. If HbsAg +ve and/or HBeAg +ve titers are high or increasing HBV DNA quantitative viral load, consider delay in transplant and antiviral therapy should be given for 3-6 months before conditioning.
	Recommended Agents		Lamivudine 100mg/day PO, Entecavir 0.5mg/day PO (nucleoside-treatment-naïve with compensated liver disease) or 1mg/day PO (In lamivudine refractory or known lamivudine resistant patients) (Preferred), Tenofovir DF 300mg/day PO (Preferred)
	Role of Vaccine		3 doses of HBV vaccine strongly recommended 6-12 months following HSCT. HBV vaccination strongly recommended in HBV naïve patients i.e. HbsAg -ve, anti HBs -ve and anti HBc -ve.
	Monitoring schedule		Both donor and recipient should be screened for HBV, HCV and HIV before undergoing HSCT. Monitor all Allo-HSCT patients at least 6-12 months post-transplant.
AASLD	Prophylaxis indication		HBsAg (+) HBV DNA ≥ 2000 U/mL, HBsAg (+) HBV DNA < 2000 U/mL, HBsAg (-) antiHBc (+) [Close mon/treat if HBV DNA (+) or rituximab/stem cell transplant]
	Recommended Agents		LAM (LdT) preferred Entecavir / Tenofovir
	Role of Vaccine		For HBsAg (-) antiHBc (-) antiHBs (-)
	Monitoring schedule		Every 1-3 mo/treat if HBV DNA (+) for HBsAg (-) antiHBc (+)
ASCO 2015	Prophylaxis indication		HBsAg +ve, HBsAg-negative/anti-HBc–positive patients anticipated to receive B cell– depleting agents, for 6 – 12 months. Insufficient data to determine the optimal strategy for HBsAg-negative/anti-HBc–positive patients receiving therapies not known to cause a high risk of reactivation. For this latter group of patients, the panel suggests monitoring of HBV DNA and ALT levels approximately every 3 months during therapy and initiation of on-demand antiviral therapy if there is evidence of HBV reactivation
	Recommended Agents		Recommended but not specified, Lamivudine (drug resistance issues) and Entecavir (preferred)
	Role of Vaccine		Not Specified
	Monitoring schedule		Monitor HBsAg-negative/anti-HBc–positive patients for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during therapy and start antiviral therapy promptly if HBV reactivation occurs
AGA	Prophylaxis indication		Only for reactivation group moderate risk (1-10%) and high risk (more than 10%) and no prophylaxis to low risk (less tha 1%) group.
	Recommended Agents		Entecavir, potentially tenofovir are preferred and may be superior to lamivudine due to drug resistance.
	Role of Vaccine		Not Specified
	Monitoring schedule		Not Specified
AGIHO of DGHO 2016	Prophylaxis indication		HBsAg +ve / anti-HBc +ve and HBV DNA quantitative +ve recipients / anti-HBc +ve and HBV DNA quantitative -ve recipients, HBV DNA quantitative +ve donors (antivirals up to 6 months post-HSCT)
	Recommended Agents		Lamivudine 100 mg/day, Entecavir 0.5–1.0 mg/day, Tenofovir 245 mg/day
	Role of Vaccine		Not Specified
	Monitoring schedule		HBV-DNA until anti-HBs +ve and HBV-DNA -ve
AST 2013	Prophylaxis indication		Donor HbsAg +ve, Anti HBc IgM +ve, Anti HBc IgG +ve and Recipient Anti HBs +/-ve
	Recommended Agents	Lamivudine 100mg/day PO and HBIG 20,000 units/dose I/V, Lamivudine 100mg/day PO and Adefovir 10mg/day PO, Entecavir 0.5mg/day PO and Tenofovir 300mg/day PO ± HBIG 20,000units/dose I/V.
	Role of Vaccine	Vaccination as stratagem to discontinue HBIg or antivirals not advised.
	Monitoring schedule	HbsAg +ve Liver transplant recipients need indefinite treatment.
5th ECIL 2013	Prophylaxis indication	All HBsAg +ve, Anti HBc +ve, HBV serology -ve recipient with Anti HBc +ve donor (Duration of antivirals: up to 12 months post HSCT)
	Recommended Agents	Choice of treatment depends upon HBV DNA levels and anticipated duration of use: a) HBV DNA < 2000 IU/mL: any antiviral can be used b) HBV DNA > 2000 IU/mL: entecavir(0.5mg/day) or tenofovir (245 mg/day) c) use greater than 12 months = entecavir(0.5mg/day) or tenofovir (245 mg/day).
	Role of Vaccine	Consider vaccinating seronegative HBV patients.
	Monitoring schedule	All patients should be screened for HBV (HBsAg, anti-HBc, HBV DNA quantitative -DNA, anti-HBs, Check for HDV if HBsAg +ve) and if viral hepatitis is suspected should undergo expert liver evaluation before HSCT/chemotherapy. Monitor HBV DNA and ALT every 3 months. Screen HSCT Donors for HBV (HBsAg, anti-HBc, HBV DNA quantitative -DNA, anti-HBs).
CIBMTR, NMDP, EBMT, ASBMT, CBMTG, IDSA, SHEA, AMMI,	Prophylaxis indication	HbsAg +ve, Anti HBc +ve or HBV DNA +ve recipient or HBV DNA +ve donor.
	Recommended Agents	Lamivudine (100 mg/day up to 6 months post HSCT in recipient), Entecavir (at least 4 weeks or until HBV DNA -ve for donor).
CDC Published in ASBMT 2009	Role of Vaccine	All HBV -ve recipients with HBsAg +ve donors should be vaccinated preferably before chemotherapy for the initial 2 doses 3 to 4 weeks apart followed by a third dose 6 months later which should be given ideally before HSCT. Give HBIG (0.06 ml/kg) prior to stem cell infusion If: vaccination is impractical pre-transplant or Anti-HBs titer is 10 IU/L post vaccination. Revaccinate recipients, after immune recovery, with 1 to 3 doses of hepatitis B vaccine who's Anti-HBs titer fail to rise but remain seronegative post-transplant.
	Monitoring schedule	Monitor ALT monthly for first 6 months if at the time of harvest both donor and harvest cells are HBV DNA -ve. If ALT start rising, test recipient for HBsAg or HBV DNA. Anti-HBs levels should be monitored every 3 months and reduction in its titer should prompt HBV DNA testing. After discontinuation of antivirals, biweekly testing with ALT and HBV DNA quantitative should be done to detect rebound HBVr and hepatitis. Perform liver biopsy in patients with active HBV (HBsAg +ve/HBV DNA quantitative +ve) because pre-existing cirrhosis can increase treatment related mortality. Test both Recipient and donor before transplant using following assays: HBsAg, anti-HBs, anti-HBc. If HBsAg and Anti HBc return +ve, do further testing by HBV DNA quantitative. Avoid transplant from HBsAg +ve or HBV DNA quantitative +ve donors to HBV-naïve recipients however, it is not absolutely contraindicated.

Abbreviations: National comprehensive cancer network (NCCN), Infectious Diseases Working Party of the German Society for Hematology and Medical Oncology (AGIHO/DGHO), European Conference on Infections in Leukemia (ECIL), Center for International Blood and Marrow Transplant Research (CIBMTR), The National Marrow Donor Program(NMDP), The European Blood and Marrow Transplant Group (EBMT), The American Society of Blood and Marrow Transplantation (ASBMT), American gastroenterology association (AGA), The Canadian Blood and Marrow Transplant Group (CBMTG), The Infectious Diseases Society of America (IDSA), The Society for Healthcare Epidemiology of America (SHEA), The Association of Medical Microbiology and Infectious Diseases Canada (AMMI), The Centers for Disease Control and Prevention (CDC).

In conclusion, patients undergoing allo-HSCT need to be routinely screened during the pre-transplant period to be stratified into HR and LR for HBVr. HR patients should receive effective prophylactic antiviral agents during the peri-transplant phase to lower the HBV DNA load before transplantation and to decrease the risk of HBVr after transplantation. Planned monitoring of HBV DNA by PCR and immune markers of HBVr after transplantation should be routinely performed. LAM is associated with high resistance rates, but resistance data is not well documented in the hematopoietic stem cell transplant population. Furthermore, there is little or no published data about the efficacy of Adefovir, Telbivudine, and Tenofovir as HBVr prophylaxis in this specific patient population. However, based on the currently available published data in allo-HSCT patients, ETV is an effective prophylactic agent against HBVr.

Figure 2. Efficacy of LAM prophylaxis in preventing HBV reactivation among allo-HSCT patients.

Figure 3. Efficacy of ETV prophylaxis in preventing HBV reactivation among allo-HSCT patients.

Highlights.

• Efficacy of prophylactic Entecavir against HBV reactivation in allogenic stem cell transplant recipients is very promising.

• Prolonged Lamivudine use is associated with drug resistance but resistance data is not well documented in the hematopoietic stem cell transplant population.

• Aggregated data reveals the rate of HBV reactivation with Lamivudine prophylaxis is inferior when compared to efficacy of prophylactic Entecavir.

• Our project highlights the need for well-designed, prospective clinical trials to establish efficacy of tenofovir and other novel antivirals for HBV chemoprophylaxis for patients undergoing allogenic stem cell transplantation.

Abbreviations

ADV

Adefovir

allo-HSCT

Allogenic hematopoietic stem cell transplantation

ETV

Entecavir

HBVr

HBV reactivation

anti HBc

Hepatitis B core antibody

anti HBs

Hepatitis B surface antibody

HBsAg

Hepatitis B surface antigen

HBV

Hepatitis B virus

HR

High risk

INF

Interferon

LAM

Lamivudine

LR

Low risk

PCR

Polymerase chain reaction

TBV

Telbivudine

TDF

Tenofovir

TAF

Tenofovir alafenamide