ORIGINAL ARTICLE: HEPATOLOGY INFOGRAPHIC

Management of Hepatitis-B Virus Infection in

Immunocompromised Children: A Single
Center Experience

Pier Luigi Calvo, Michele Pinon, yDominic Dell’Olio, zAndrea Carpino, §Eleonora Biasin,

Antonio Pizzol, jjSilvia Catalano, ôLicia Peruzzi, Caterina Rigazio, Fabio Cisarò,

Anna Opramolla, §#Sebastian Dorin Asaftei, §Paola Quarello, and §Franca Fagioli

ABSTRACT

Objectives: The aims of the study was to expand the pediatric experience on
hepatitis-B virus (HBV) reactivation, a known complication in patients with
hematologic malignancies or on immunosuppression.
Methods: Retrospective appraisal of HBV therapy/prophylaxis in
immunocompromised children, studied from April 2006 to March 2020.
Results: Eighteen HBV-positive patients, 5 girls, median age 11.1 (4.1–17.9)
years were included. Seventeen of 18 were immunosuppressed at HBV-infection
diagnosis. Seventeen were at high risk of reactivation, 1 at moderate risk. Five of
18 had acute hepatitis B as first infection or reactivation, 6 had HBeAg-positive
infection, 1 an HBeAg-negative infection and 6 HBsAg-negative infection.
Median follow-up was 2.7 (0.7–12.5) years. No HBV-related mortality was
observed. Prophylaxis had to be repeated in 1. Lamivudine was used in 6/12
viremic patients and HBV-DNA negativization obtained in 2/6 (33%).
Tenofovir-DF was used in 2/12 and entecavir in 4/12: 100% attained HBV-
DNA negativization. Therapy had to be switched from tenofovir-DF to entecavir
in 1 patient because of renal impairment. Virological breakthroughs were
observed in 1 lamivudine-treated patient, leading to a hepatitis flare; 1
patient on entecavir had a hepatitis flare at immunoreconstitution. Mortality
was 33% in the HBsAg-positive group. Seven prophylactic treatments were
administered to 6 patients with HBsAg-negative infection: tenofovir-DF in 2
HBV-DNA-positive, lamivudine in 5 HBV-DNA-negative, without reverse
HBsAg seroconversion, morbidity or mortality.
Conclusions: There is a residual risk of acute hepatitis B in
immunocompromised children, mortality rate was substantial, potentially
related to the delays in commencing chemotherapy caused by liver
dysfunction. Tenofovir-DF or entecavir are the drugs of choice for HBV
treatment in immunocompromised children.
Key Words: direct-acting antivirals, hepatitis B reactivation, hepatitis B
virus, nucleos(t)ide analogues, prophylaxis
An infographic is available for this article at: http://links.lww.com/
MPG/C161.
(JPGN 2021;72: 597–602)
What Is Known
 Hepatitis-B virus reactivation is a complication of
immunosuppressive therapy in adults and can cause
liver failure.
 Hepatitis-B virus reactivation in adults is preventable
with antiviral drugs.
 Pediatric data are scanty.
What Is New
 There is a residual risk of acute hepatitis B in children
with blood malignancies.
 Tenofovir-diproxil fumarate or entecavir are the drugs
of choice.
 Most patients with HBeAg-hepatitis/infection show a
virological response after immune system recovery:
this may lead to hepatitis flares.
H epatitis-B virus (HBV) infection is a global health problem
and a major cause of chronic liver disease (1). After infec-
tion, the HBV genome enters the hepatocyte nucleus and is repaired
to covalently closed circular-DNA (cccDNA), the template for viral
RNA transcription and viral persistence reservoir. cccDNA remains
highly stable in the nucleus of infected hepatocytes and cannot be
directly targeted by current anti-HBV drugs, making chronic HBV
infection difficult to treat. Stopping treatment or an immune defense
drop may cause reappearance of the virus (2,3). HBV reactivation is
associated with high morbidity/mortality in patients with hemato-
logical malignancy and/or hematopoietic stem cell transplantation

Received June 21, 2020; accepted November 12, 2020.

From the Pediatric Gastroenterology Unit, Regina Margherita Children’s
Hospital, the yRegional Transplant Center, the zDepartment of Pediatrics,
the §Pediatric Onco-Hematology, Stem Cell Transplantation and Cell Ther-
apy Division, Regina Margherita Children’s Hospital, the jjLiver Transplan-
tation Centre, General Surgery 2 U, the ôPediatric Nephrology Unit, and the
#Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Ther-
apy Division, Regina Margherita Children’s Hospital, Azienda Ospedaliera-
Universitaria Citta della Salute e della Scienza, Turin, Italy.
Address correspondence and reprint requests to Pier Luigi Calvo, MD, Pediatric
Gastroenterology Unit, Regina Margherita Children’s Hospital, Azienda
Ospedaliera-Universitaria Cittá della Salute e della Scienza, Piazza Polonia
94 10123, Turin. Italy (e-mail: pcalvo@cittadellasalute.to.it).
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text, and links to the digital files are provided in the
HTML text of this article on the journal’s Web site (www.jpgn.org).
P.L.C. and M.P. are investigators in clinical trials sponsored by Gilead. The
sponsors did neither play any role in the design, methods, data collection or
analyses, nor did they do so in the preparation of the present article.
Copyright # 2020 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0000000000003042

JPGN  Volume 72, Number 4, April 2021 597

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Calvo et al
(HSCT) or immunosuppression after solid organ transplant (SOT)
(4–7).
Two different drug classes are currently available: immu-
nomodulators (alpha-Interferon) and nucleos(t)ide analogues (NA).
Some NA, like lamivudine, have a low genetic barrier to resistance,
others, like tenofovir diproxil fumarate (tenofovir-DF), tenofovir
alafenamide and entecavir, have a high resistance threshold. Lami-
vudine was the first drug to be Food and Drug Administration
(FDA)-approved for use in children 2 years with HBV (8) back in
2001 and remains the least expensive and more widely available
(5,6); tenofovir and entecavir, were later approved for patients ages
12 and 2 years of age, respectively (8–10).
This is a single center retrospective real-life study aimed at
assessing the efficacy of HBV screening and the efficacy and safety
of the available HBV treatment or prophylaxis regimens in immu-
nocompromised children.
MATERIALS AND METHODS
Patients
All children (ages 1–18), admitted between April 2006 and
March 2020 for cytotoxic (CT) biological modifier therapy, allo- or
auto-HSCT (n ¼ 1680) or for SOT (n ¼ 186), were screened for
HBV and enrolled into our study if positive. They were referred
from Venezuela (5 pts), Albania (3 pts), Romania Italy and Ukraine
(2 pts/each), Georgia Kenya Senegal and Syria (1 pt/each). Seven-
teen of 18 patients were already immunosuppressed, 16/18 had
previous CT and blood transfusions.
This study was approved by our institution review board and
carried out according to good clinical practices. Written informed
consent was obtained from all parents or legal guardians. Patient
consent was obtained, wherever appropriate.
Clinical and Laboratory Screening
On admission, all patients had a full physical examination,
abdominal ultrasound, liver disease biochemical assessment (AST,
ALT, GGT, APH, total/conjugated SBR, albumin, INR), HBV
(HBsAg, antiHBs, antiHBc), HCV and HIV markers. Qualitative
real-time polymerase chain reaction (Individual Donor Nucleic Acid
Amplification Testing, ID-NAT) for HBV-DNA, HCV-RNA, and
HIV-RNA was added in immunocompromised oncology patients.
ID-NAT-positive patients were tested for quantitative HBV-DNA/
HCV-RNA and HIV-RNA and screened for Hepatitis Delta infection
with anti-HDV. Acute hepatitis B was diagnosed by its clinical and
biochemical criteria (1); a reactivation was defined as an increase in
HBV-DNA levels or de novo detection of HBV-DNA viremia when-
ever undetectable before the initiation of immunosuppressive treat-
ment (19). It was possible to distinguish a primary infection from a
reactivation only in patients followed at our center at the start of the
oncologic disease or with a complete basal assessment.
Laboratory Methods
ALT was determined by standard methods (normal values
<33 IU/L). HBV markers (HBsAg, HBsAb, HBeAg, HBeAb, anti-
HBc IgM), anti-HCV, anti-HDV, and anti-HIV antibodies were
tested by immunoenzymatic assays (EIA; Abbott Diagnostic
Inc., Chicago, IL). ID-NAT for HBV/HCV/HIV was performed
with Cobas Amplicore (Roche Molecular System, Branchburg, NJ,
USA) until 2010, then with Procleix Ultrio Elite assay (Grifols
Diagnostic Solutions Inc. Emeryville, CA USA). HBV-DNA viral
load was determined by PCR (Amplicor HBV, Monitor; Roche).
Polymerase mutants were identified by a commercially available kit
(Inno-LiPa HBV DR, Innogenetics N.V.).
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JPGN  Volume 72, Number 4, April 2021
Treatment
Treatment was instituted in HBV-infected patients with acute
hepatitis-B or HBsAg-positive infection, prophylaxis in HBsAg-
negative patients.
Until May 2009, lamivudine was the only antiviral drug used
in our hospital, thereafter tenofovir-DF and, later, entecavir were
used as off-label drugs until approved by the national drug agency
(AIFA). Tenofovir-DF was initially preferred based on our experi-
ence in treating HIV. From 2012 onwards, we mostly used entecavir
(Fig. 1).
Drug dosages were: lamivudine 3 mg/kg (max 100 mg),
tenofovir-DF 8 mg/kg (max 300 mg), and entecavir 0.015 mg/kg
(max 0.5 mg), administered orally once a day.
HBV-DNA titres were checked at 3 and 6 months after
antiviral therapy discontinuation.
Both children and parents were given simple instructions on
how to recognize drug side effects emphasizing the importance of
reporting any concomitant comorbid condition and/or intercurrent
illness that might require treatment.
Follow-up
Patients with positive HBV markers and/or HBV-DNA were
checked for liver disease activity and severity, HBV markers and
quantitative HBV-DNA at each follow-up appointment and treat-
ment-related symptoms were assessed. Parents controlled therapy
compliance.
Efficacy Assessment
According to EASL recommendations (11), treatment
responses were defined as follows: virological response (HBV
undetectable by PCR with a detection limit of 10 IU/mL), primary
nonresponse (less than 1 log10 decrease in serum HBV-DNA after
3 months of therapy), partial virological response (a decrease in
HBV-DNA of more than 1 log10 IU/ml but detectable HBV-DNA
after at least 12 months), virological breakthrough (if HBV DNA
increased by >1 log10 IU/mL from lowest value on-therapy), HBV-
resistance to NA(s) (characterized by selection of HBV variants),
hepatitis flare (a 3-fold increase in ALT associated with viral
replication).
Statistical Methods
Descriptive statistics were reported as median, minimum
(Min), and maximum (Max) values and as percentages.
RESULTS
Eighteen immunocompromised children had 19 therapeutic
or prophylactic treatment courses for HBV infection (Fig. 1).
One patient had 2 prophylactic courses at 2 stages of his
oncologic disease.
Sample Description
Thirteen boys (72%)/5 girls (28%), median age 11.1 (4.1–18)
years. Seventeen of 18 were immunosuppressed at first observation
and HBV infection diagnosis; 1 was diagnosed at liver transplant
assessment. After therapy completion, 11 of them returned abroad,
where treatment, continuation, when recommended, was often
unfeasible. Median follow-up was 2.7 (0.7–12.5) years.
Sixteen of 18 were immunocompromised because of blood
malignancies (10 treated by allo-HSCT, 3 by auto-HSCT, 2 by CT,
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JPGN  Volume 72, Number 4, April 2021 Managing HBV Infection in Immunocompromised Children

HBsAg-positive patients HBsAg-negative patients FDA

12 children (3 F) 6 children (2 F) APPROVAL
Median age 11 (4.1-18) years Median age 13 (6.5-15) years
GROUPS ALT 14-77 UI/mL
and patient 1 patient was treated twice, at two stages of infection
characteristics Acute hepatitis B Chronic hepatitis B infection 2001:
5 children (1 F)
Median age 11.7 (4.1-14.2) years LAMIVUDINE
HBeAg-pos infection HBeAg-neg infection
ALT 73-1200 UI/ml 6 children (2 F) 1M APPROVED ≥ 2
HBV-DNA >20.000 IU/mL Median age 10.9 (5.6-13) years 5.2 years YEARS OLD
IgM-antiHBc >1.2 s/c ALT 29-54 UI/mL ALT 29
HBV-DNA >107 IU/mL HBV-DNA 2988 IU/mL

2005:
ENTECAVIR
TREATMENT: 2007 2012 2012 2006-07 2011-17 2011 2012-17 2012-17
TDF ETV LAM
APPROVED ≥ 16
Year starting therapy and LAM ETV TDF LAM TDF
drug 3 pts 1 pt 1 pt 3 pts 3 pts 1 pt 5 pts HBV-DNA neg 2 pts HBV-DNA pos
YEARS OLD

8/12 pts (66%) 6/6 pts (100%)

HBV-DNA
2014:
NEGATIVIZATION
2 NEG TENOFOVIR
NEG NEG 3 POS 3 NEG NEG
1 POS APPROVED ≥ 12
YEARS OLD

TREATMENT 2014 2009

CHANGE ETV 1 TDF 2014:
Year/drug/cause nephrotoxicity VBT ENTECAVIR
APPROVED ≥ 2
YEARS OLD

1 Alive Alive Died 2 Alive 3 Alive Alive 6 Alive

OUTCOME 2 Died 1 Died
at last follow-up
Alive/Deceased Median follow-up 3.7 (0.7-7.2) years Median follow-up 2.6 (0.8-12.5) years Median follow-up 2.6 (0.8-12.5) years
Mortality 60% (3/5) Mortality 14% (1/7) Mortality 0% (0/6)

FIGURE 1. A visual summary of the study, showing patient characteristics, HBV infection diagnosis, treatments, HBV-DNA negativization,
treatment changes, and outcomes. On the right, a timeline of FDA approval of anti-HBV drugs for the pediatric age. ETV ¼ entecavir, LAM ¼
lamivudine, TDF ¼ tenofovir, VBT ¼ virological breakthroughs.

and 1 by CT associated with rituximab); 2 had received a SOT (1
kidney transplant, 1 liver transplant). None had clinical or echo-
graphic signs of cirrhosis or portal hypertension.
At baseline, 12/18 patients were HBsAg-positive: 5 had
acute hepatitis B, 6 HBeAg-positive infection, 1 HBeAg-negative
infection. The remaining 6/18 had HBsAg-negative infection.
Patient characteristics are illustrated in Figure 1 (5–11).
Children With Acute Hepatitis B
It was impossible to determine whether 4/5 acute hepatitis B
patients had a new infection or a flare-up because of their disease or
chemotherapy in active carriers. 3 patients had acute lymphoblastic
leukemia (ALL) (1 in complete remission/2 in the fourth relapse), 1
acute myeloblastic leukemia (AML) in the first complete remission, 1
rhabdomyosarcoma in the first complete remission). Four received
HSCT (3 allo-HSCT, 1 auto-HSCT), the fifth (Italian, multiple blood
transfusions) had primary infection, due either to nonresponse to
vaccination or a reduction in antiHBs titres under chemotherapy.
positive (antiHBc and HBV-DNA were not performed) and his
results were misinterpreted as if he had been vaccinated. He
probably had a HBV reactivation but a new infection cannot be
excluded (5,11–13).
Children With HBsAg-negative Infection
Four of 6 HBsAg-negative patients had undetectable HBV-
DNA (antiHBc-positive  antiHBs-positive, HBV-DNA-negative)
(14). The fifth patient had 2 different HBV infection profiles during
2 different phases of his disease: HBsAg-negative infection with
HBV-DNA positivity (HBV-DNA 22-40 IU/mL) at 14.9 years and a
negative HBV-DNA at 18. The sixth patient was HBsAg-negative
with repeatedly positive HBV-DNA (4437 IU/mL), with negative
serological markers. Underlying pathology was: 1 LMA, 3 ALL
(first-second-third relapses), 1 type-III glycogen storage disease, 1
aplastic anemia, 1 hyper-IgM syndrome. Four received HSCT (3
allo-HSCT, 1 auto-HSCT), 1 was treated with CT only and 1 had
liver-transplant.

Children With HBeAg-positive and HBeAg- Treatment Description

negative Infection
Six of 7 patients with HBeAg-positive/HBeAg-negative
infection (6 HBeAg-positive/1 negative infection) had blood malig-
nancies, 1 non-Hodgkin lymphoma (first relapse), 4 ALL (2 first
remission, 2 first relapse), 1 Burkitt lymphoma (second relapse); 3
were treated with allo-HSCT at first relapse, 3 with CT only. The
remaining patient (HBeAg-positive) was on postkidney transplant
immunosuppression; at transplant he had been HBsAg-ve/antiHBs-
Treatment depended on what drugs were available at admis-
sion (Fig. 1): tenofovir-DF was used off-label in 6 patients, ente-
cavir off-label in 2 and in 3 as approved therapy. The time-lapse
between starting HBV-therapy and CT/HSCT differed: median 140
(36–418) days in acute hepatitis, median 25 (1–243) days in
HBeAg-positive/HBeAg-negative infection, median 29 (0–90) days
in HBsAg-negative infection. Seventeen of 18 patients were at high
risk of HBV reactivation, 1 at moderate risk.

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Calvo et al
The 5 acute hepatitis B patients were given lamivudine (3
patients, 2007), tenofovir-DF (1 patient, 2012), or entecavir (1
patient, 2012). 3/7 with HBeAg-positive/negative infection were
given lamivudine (2006–2007), median age 11.1 (10.9–12.9) years,
1/7 tenofovir-DF (2011, age 5.2 years), and 3/7 entecavir (in 2011,
2012, 2017), median age 8.6 (5.6–17.9) years. Lamivudine was used
in 4/6 patients with HBsAg-negative infection who had undetect-
able HBV-DNA, median age 10.6 (12.8–18) years and tenofovir-DF
in a child with detectable HBV-DNA (13.8 years). The sixth patient
had 2 different infection profiles during different disease stages:
when HBV-DNA positive (14.8 years, HBV-DNA 22–40 UI/mL)
he was given tenofovir-DF and lamivudine when HBV was unde-
tectable (18 years).
End Points
Mortality
None of our patients on treatment/prophylaxis died of HBV-
related liver disease. Four of 18 (22%) died during the observation
period: 3/5 (60%) of acute hepatitis B patients, 1/7 (14%) with
HBeAg/HBeAg-negative infection, all after HSCT and 3 with graft-
versus-host disease (GVHD). No death was observed in HBsAg-
negative children, despite the comparability of underlying disease
severity and treatment aggressiveness (Fig. 1).
Virological Response
In HBsAg-positive patients, virological response was
achieved in 100% on 2 tenofovir-TF and 4 entecavir-treated patients
but only in 2/6 (33%) lamivudine-treated children: both had acute
hepatitis and low viremia. HBV-DNA negativization was obtained
after a median of 1.9 (0.08–4.8) years. There were no primary
nonresponders. Nine of 12 patients were partial virological respond-
ers: 4/6 on lamivudine, 1/2 tenofovir-DF, and 4/4 entecavir. HBV-
DNA negativization took more than a year also in the patient where
tenofovir was added to lamivudine for virological breakthrough.
Virological Breakthrough and Hepatitis B Virus
Resistance to Nucleos(t)ide Analogues
Virological breakthroughs were documented in 2 HBeAg-
positive chronic infection patients on lamivudine. One had a
hepatitis flare at immunoreconstitution, 7 months after CT discon-
tinuation: ALT were >10 times the upper reference limits, IgM-
antiHBc-positive, without HBeAg seroconversion. The other had a
virological breakthrough 12 months after CT discontinuation:
tenofovir-DF was then added, leading to HBV-DNA negativization.
HBV variants (polymerase mutants) were detected in both (5–8).
Hepatitis Flares
Hepatitis flares were evidenced in 2 patients. In the patient on
lamivudine and virological breakthrough 7 months after CT dis-
continuation and in a HBeAg-positive chronic infection patient on
entecavir, 2.5 months from allo-HSCT, after cyclosporine had been
suspended. Both patients were still viremic, with ALT levels >10 to
30 times upper limits of normal and were IgM-antiHBc-positive.
HBeAg/HBsAg Seroconversion
HBeAg loss with antiHBe seroconversion was observed in 8/
12 patients, all achieved HBV-DNA negativization. AntiHBs sero-
conversion was observed in 4 patients, 3 with acute hepatitis and 1
with an HBeAg-positive infection.
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JPGN  Volume 72, Number 4, April 2021
Therapy and Prophylaxis Duration
Antiviral therapy is continued in all HBsAg-positive patients
still under our care, whatever their HBeAg response and HBV-DNA
negativity, as HBsAg loss, rather than a stable HBeAg negativiza-
tion, became our aim, 2 are still on ETV after 4.8 and 5.3 years and 1
on TNF after 11. Although all patients are HBsAg-positive, 2/3
have seroconverted to antiHBe. Lamivudine was stopped in 1
patient who became antiHBs-positive after a hepatitis flare,
6 months after immunosuppression withdrawal; entecavir was
stopped in another at stable antiHBe seroconversion as he returned
home abroad, where the drug was unavailable.
Prophylaxis in HBsAg-negative patients was continued for at
least 6 months after stopping immunosuppression (CT or cyclo-
sporine), up to 12 to 18 months, whenever feasible, in patients on
high-risk treatment. HBV-DNA testing was performed at 3 and
6 months after antiviral therapy discontinuation.
Adverse Effects
Tenofovir-DF was substituted by entecavir in 1 patient after
achieving virological response as renal function declined to stage 2
CKD (eGFR ¼ 75 ml/min/1.73 m2, with low serum phosphate
2.82 mg/dL as sign of tubular damage), with a reversion of adverse
effects.
DISCUSSION
HBV reactivation concomitant to immunosuppression is an
increasingly recognized clinical problem associated with significant
morbidity and mortality. HBV reactivation is a complication of
chemotherapy and immunosuppression and of the new biologicals
increasingly used in onco-hematology, rheumatology, dermatology,
and gastroenterology (4–7,12). Pediatricians should be alerted to
this problem as their use is on the increase; despite recommenda-
tions made by many international organizations (4,6,11,15–17),
omission of HBV screening remains a problem. Original pediatric
data are scarce and even consensus recommendations must be
extrapolated from adult studies (18,19).
Our study analyzes a single center 14-year retrospective
experience of HBV screening, prophylaxis or treatment and
HBV monitoring in immunocompromised children. Early detection
of HBV infection requires testing for HBV markers at disease
diagnosis rather than later when immunosuppression is started.
Patients arrived to our attention without having been screened
for HBV infection even if they came from high HBV prevalence
countries (20–22).
Baseline screening should encompass HBsAg, antiHBs,
antiHBc testing, and we suggest that HBV-DNA determination
become part of the protocol in children with hematologic malig-
nancies as serology alone may be misleading in heavily immuno-
suppressed patients. A patient with occult infection had repeatedly
positive HBV-DNA, whilst other markers were negative: only
during follow-up did antiHBs and antiHBc become positive. Test-
ing for antiHBc should be mandatory. A kidney-transplant patient
was interpreted as having been vaccinated although he had an occult
infection; this mistake led to HBV reactivation when immunosup-
pression without prophylaxis was commenced. Anti-HBsAg titers
should be checked and vaccination performed with an accelerated
schedule, even if the decision to use antiviral prophylaxis cannot be
based on antiHBs titres when antiHBc is present (6,21–26). Our
experience evidences a residual risk of HBe-positive hepatitis,
which is not related to HBsAg escape, also in vaccinated children
when treated for malignancy. Immune-suppressive, cytotoxic, or
biological modifier therapies should not be postponed because of
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JPGN  Volume 72, Number 4, April 2021
HBV and antiviral therapy should preferably be started a week
earlier or in concomitance (11,19). There were no HBV-related
deaths in our treated children but the high mortality (60%) observed
in our acute hepatitis B patients may be potentially related to delays
in instituting treatment of the underlying disease because of
liver dysfunction.
Unfortunately, lamivudine remains the drug used in low and
middle-income countries as it is available and affordable (5,7,27).
Its use may, however, induce emergence of lamivudine-resistant
HBV strains in a significant number of patients. Lamivudine
resistance rates of 20% at 1 year and 30% at 2 years have been
reported in nonimmunocompromised adults (27,28), 19 to 40% at
52 weeks in children (8,29) and may be higher in immunosup-
pressed patients (30). Four of 6 HBsAg-positive patients on lami-
vudine had a partial response. Tenofovir-DF rescue therapy was
added to lamivudine treatment for nonresponders or
virological breakthroughs.
Tenofovir-DF treatment (5 patients, 1 previously on lami-
vudine) in HBV-DNA positive patients (3 low viremic) obtained a
100% HBV-DNA negativization rate. In a trial (9), 52 HBV-
infected adolescents (91% HBeAg-positive, 60% previously on
lamivudine) were treated with tenofovir-DF: HBV-DNA negativi-
zation was achieved in 89% at 72 weeks, without significant renal
toxicity, even if 6 in the tenofovir-DF group had a slight increase in
creatine levels than the 2 in the placebo group. One of our patients,
previously on CT, was shifted from tenofovir-DF to entecavir at
HBV-DNA negativization, because of renal dysfunction (31) and
had complete renal normalization. Tenofovir-DF therapy was not
associated to detectable resistance after 8 years of treatment (32).
We have no experience with Tenofovir alafenamide that reportedly
has lower nephrotoxicity and a higher bone safety score (33).
Entecavir has good long-term safety and efficacy and a high
HBV-DNA negativization rate (34–37). A 49% virological
response at 1 year of treatment and 64% after 2 years, with a
cumulative probability of entecavir resistance of 0.6% and 2.6%
respectively, were reported (10). Thirty-one immunosuppressed
children with cancer (34) had a high virological response to
entecavir (67.7% at 1 year, 83.9% at 2, and 90% at 4 years),
30% HBeAg seroconverted and 2 had a virological breakthrough, 1
at 96 weeks and another at 192 weeks. The 4 children on entecavir
had a high viremia at presentation but all achieved HBV-DNA
negativization, even if they were still HBV-DNA-positive after 1
year’s treatment and at immunoreconstitution, risking a
hepatitis flare.
Prophylaxis with lamivudine in HBsAg-ve/HBV-DNA-neg-
ative patients was effective in preventing viral reactivation. As
suggested by a recent ESPGHAN position paper (19), drugs with a
better resistance barrier should be used. Lamivudine might still
have a residual role in HBsAg-neg/HBV-DNA-negative patients
when prophylaxis is life-long (as in SOT) and if concerns for drug
cost and availability are preeminent (29,30). In the presence of
HBV-DNA viremia, also HBsAg-negative patients ought to com-
mence tenofovir-DF or entecavir, whilst lamivudine is contraindi-
cated so as to avoid inducing resistant mutants.
Antiviral prophylaxis in HBsAg-positive/negative patients
should be continued for at least 6 months after stopping immuno-
suppression and for at least 12 months when B-cell-depleting-
agents have been used (5,6,11,17,19), the aim being to obtain
HBV-DNA negativization before immunoreconstitution to avoid
a hepatitis flare. Two HBeAg-positive patients on lamivudine/
entecavir, who suspended immunosuppressive therapy, developed
a severe hepatitis at immunoreconstitution.
Optimal duration of antiviral prophylaxis in HSCT or SOT
recipients is still controversial (5–7,11,17,19,23). Long-term anti-
viral prophylaxis may need to be considered at the clinician’s
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Managing HBV Infection in Immunocompromised Children
discretion as these patients are at risk of HBV reactivation for
years after the transplant (38). Current consensus advises suspend-
ing antiviral drugs in HBsAg/HBeAg-negative patients once a
stable antiHBe seroconversion has been achieved. An alternative
strategy of continuing therapy until antiHBsAg seroconversion was
achieved was chosen for our locally resident patients, even if it has
not been proven to accelerate antiHBs seroconversion (11–17).
HBsAg-negative/antiHBc-positive/HBV-DNA-positive patients
who had a SOT received continuous prophylaxis.
CONCLUSIONS
There is a risk of acute hepatitis B, as first infection or
reactivation even in countries with a low HBV prevalence that may
increase overall mortality in children with cancer.
All children should be screened for HBV-infection by
HBsAg, antiHBs, antiHBc serology before starting immunosup-
pression and we suggest adding a sensitive HBV-DNA test for
children with cancer. Antiviral therapy/prophylaxis with tenofovir
or entecavir should be started as early as possible. Entecavir may
have a better safety profile when nephrotoxic drugs are concomi-
tantly used. HBV-DNA negativization may take more than a year in
most immunosuppressed patients, with a risk of hepatitis flare at
immunoreconstitution or when cyclosporine is discontinued
after HSCT.
Acknowledgment: The authors wish to thank Mrs. Barbara
Wade for her linguistic advice.
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