2020 Update to the Consensus Statements on the Diagnosis and Treatment of

Hepatitis B: Special Populations

Hepatology Society of the Philippines (HSP) Hepatitis B Virus (HBV) Consensus

Core Group

Wendell Z. Espinosa, MD, FPCP, FPSG, FPSDE

Jade D. Jamias, MD, FPCP, FPSG, FPSDE
Jenny L. Limquiaco, MD, FPCP, FPSG, FPSDE
Therese C. Macatula, MD, FPCP, FPSG, FPSDE
Karen Sofia M. Calixto-Mercado, MD, DPPS, DPSPGHAN
Janus P. Ong, MD, MPH, FACP, FACG
Edhel S. Tripon, MD, FPCP, FPSG, FPSDE

Hepatology Society of the Philippines

418 Prince David Condominium
#305 Katipunan Ave., Loyola Heights Quezon City
Tel. No.: (02) 9613014
Fax No.: (02) 4361556
E-mail: hepatology2006@gmail.com
Website: http://www.hsp.org.ph
ABBREVIATIONS
ADV adefovir
AASLD American Association for the Study of Liver Diseases
ALF acute liver failure
Anti-HBc hepatitis B core antibody
Anti-HBe hepatitis B e antibody
anti-HBs hepatitis B surface antibody
APASL Asian Pacific Association for the Study of the Liver
ART antiretroviral therapy
CDC Centers for Disease Control and Prevention
CKD chronic kidney disease
CLV clevudine
CTP Child-Turcotte-Pugh
DAA direct-acting antiviral
DNA deoxyribonucleic acid
eGFR estimated glomerular filtration rate
ESPGHAN European Society for Paediatric Gastroenterology Hepatology and Nutrition
ETV entecavir
HAART highly active antiretroviral therapy
HBcAg hepatitis B core antigen
HBeAg hepatitis B e antigen
HBIG hepatitis B immune globulin
HBsAg hepatitis B surface antigen
HBV hepatitis B virus
HCC hepatocellular carcinoma
HIV human immunodeficiency virus
IFN interferon
IgG immunoglobulin G
IgM immunoglobulin M
LAM lamivudine
Ldt Telbivudine
MELD Model for end-stage liver disease
MTCT mother-to-child transmission
NA nucleos(t)ide analogue
NK natural killer
Peg-IFN pegylated interferon
RCT randomized controlled trial
SAE serious adverse event
SVR sustained viral response
TAF tenofovir alafenamide
TDF tenofovir disoproxil fumarate
ULN upper limit of normal
FOREWORD
In 2014, the Hepatology Society of the Philippines published the 2014 Consensus
Statements on the Diagnosis and Treatment of Hepatitis B. However, the Society recognizes
that certain population subgroups of patients with hepatitis B should be given special care due
to conditions that may affect viral kinetics, immune response to infection, the pharmacokinetics
and pharmacodynamics of pharmacotherapy or increase the risk of complications of hepatitis B.
Hence, this Update was developed to provide additional guidance to clinicians in the
management of hepatitis B infection in these special populations.

METHODOLOGY
This update was developed through the initiative of the Hepatology Society of the
Philippines, which created a consensus core group composed of local experts in hepatology.
The members of the core group performed a literature search for all available literature on the
treatment of hepatitis B, with focus on the appropriate treatment according to the various
identified special populations, namely those with acute hepatitis B, those with decompensated
cirrhosis, liver transplant recipients, non-liver solid organ transplant recipients, those receiving
immunosuppressive therapy, those with chronic kidney disease, pregnant patients and children
with hepatitis B. Efficacy and safety data of treatments were extracted and evaluated and
recommendations were developed for treatments with net benefit that are currently available in
the Philippines. Recommendations were discussed and revised until consensus within the core
group was achieved. Recommendations were rated according to an adaptation of GRADE
(Table 1).

Table 1. Grading evidence and recommendations (adapted from GRADE system)

QUALITY OF EVIDENCE
HigH (I) Randomized, controlled trials
Moderate (II) II-1 Controlled trials without randomization
II-2 Cohort or case-control analytical studies
II-3 Multiple time series, dramatic uncontrolled experiments
Low (III) Opinions of respected authorities, descriptive epidemiology
LEVEL OF RECOMMENDATION
Strong Factors influencing the strength of the recommendation
recommendation included the quality of the evidence, presumed patient-
important outcomes, and cost
Weak Variability in preferences and values, or more uncertainty:
recommendation more likely a weak recommendation is warranted
Recommendation is made with less certainty: higher cost or
resource consumption
PATIENTS WITH ACUTE HEPATITIS B

Recommendations
 Patients with severe acute hepatitis B infection should be treated with NAs(Moderate
quality of evidence; strong recommendation)
 Patients with fulminant hepatitis B must be evaluated for liver transplantation (High quality
of evidence; strong recommendation)

The incidence of acute hepatitis B infection has declined dramatically in nearly all countries
since 1992 when the World Health Organization recommended that the hepatitis B vaccine
should be included in all infant immunization programs.1 Moreover, in areas of the world with
low prevalence, acute infection most commonly occurs in nonvaccinated teenagers or adults
who have sexual interactions or share items of personal hygiene or objects to administer illicit
drugs with a chronically infected person. In the vast majority of these cases, the patient is
unaware their partner in these activities has chronic hepatitis B. Patients can also acquire HBV
during medical procedures, either through breaks in universal precautions from health care
workers with chronic hepatitis B or from contaminated medical equipment. Although serologic
testing has been utilized to screen blood products for the presence of HBV for several decades,
the risk of developing acute HBV following a blood transfusion is currently estimated to occur in
1:63,000 units transfused.2
HBV is transmitted by percutaneous or mucosal exposure through infectious blood or body
fluids. Although HBV has been detected in many body fluids, only blood, saliva and semen
appear to contain sufficient levels of virus to be infectious.3
The course of acute hepatitis B is divided into the incubation period andpreicteric, icteric
and convalescence phases over a course of 75 days (range 40–140 days). The onset of
hepatitis B is typically insidious, with nonspecific symptoms of malaise, poor appetite, nausea
and pain in the right upper quadrant of the abdomen. With the onset of the icteric phase,
symptoms of fatigue and anorexia typically worsen. Jaundice can last from a few days to
several months (average of 2–3 weeks).4 Itching and pale stools may occur.
The convalescent phase of hepatitis B begins with the resolution of jaundice. Fatigue may
persist for many months into convalescence. The physical signs of typical acute hepatitis B are
not prominent. Variable degrees of jaundice are present. The only other common physical
finding in a patient with acute hepatitis B is mild and slightly tender hepatomegaly. Mild
enlargement of the spleen or lymph nodes are uncommon.4
Detection of HBsAg along with anti-HBc IgM is the serologic hallmark of acute HBV
infection.5HBsAg appears in serum during the incubation phase, approximately 2 to 6 weeks
before the onset of symptoms.6,7Highly sensitive molecular virologic assays can detect HBV
DNA in the serum during the incubation phase, approximately 10 to 20 days before the
appearance of HBsAg.8 Anti-HBcappears at the onset of symptoms or liver test abnormalities.6,7
Anti-HBc IgM remains detectable for approximately 6 months following the acute exposure.
Thereafter, IgM antibody is lost. IgG anti-HBc remains detectable lifelong.
Patients with acute hepatitis B infection should be considered infectious and capable of
passing HBV to other persons at risk until they develop anti-HBs. Patients with complete
resolution of HBV infection have both anti-HBc and anti-HBs. Over many decades following
acute HBV infection, the level of anti-HBs may decline to levels that are undetectable with
current assays. These patients remain anti-HBc positive as their only marker of previous
exposure to HBV. During the resolution phase,HBeAg is lost prior to HBsAg and anti-
HBeappears before anti-HBs.6,7
About 1% of patients with acute hepatitis B may develop ALF. The risk of developing ALF
with an acute hepatitis B is increased in older individuals and in patients with chronic hepatitis C
and hepatitis D.9-11 Survival without liver transplantation occurs in only about 25% of patients
with ALF secondary to acute hepatitis B. It is therefore imperative that patients with severe
acute hepatitis B be transferred to a liver transplant center for evaluation, management, and
consideration for liver transplantation if indicated and appropriate.
More than 95% of adults with acute hepatitis B do not require specific treatment because
they will fully recover spontaneously. Antiviral treatment is indicated for only those with acute
hepatitis B who have ALF or who have a protracted or severe course, as indicated bytotal
bilirubin >3 mg/dL (or direct bilirubin >1.5 mg/dL), international normalized ratio >1.5,
encephalopathy or ascites. ETV and tenofovir are the preferred antiviral drugs. Treatment
should be continued until HBsAg clearance is confirmed or indefinitely in those who undergo
liver transplantation. Peg-IFN is contraindicated. For those diagnosed with chronic hepatitis B by
failing to clear HBsAg after 6 to 12 months, ongoing management should follow the guidelines
for chronic hepatitis B.12-14
In a study among patients with severe acute hepatitis B patients,LAM caused a greater
decrease in HBV DNA levels but did not cause significantly greater biochemical and clinical
improvement as compared to placebo.14However, in another RCTthat included severe acute
hepatitis patients,LAMshowedstatistically significant improvements in mortality and incidence of
ALF compared with placebo.15
Case reports and case series have reported clinical improvement with the following NAs:
tenofovir monotherapy; include tenofovir withLAM; ETV; ADVwithLAM; and LdT.16-20
Establishing a diagnosis of acute hepatitis B is important, as the majority of adult
patients presenting as acute hepatitis B have reactivation of chronic hepatitis B infection. A
definite history of exposure, positive HBeAg and IgM anti-HBc with low HBV DNA levels and
liver biopsy in doubtful cases can help to establish the diagnosis of acute hepatitis B and
exclude the diagnosis of HBV reactivation. When the distinction between true severe acute
hepatitis B and spontaneous reactivation of chronic HBV infection is difficult, NA treatment
should be administered.21
PATIENTS WITH DECOMPENSATED HEPATITIS B-RELATED CIRRHOSIS

Recommendations
 HBsAg-positive adults with decompensated cirrhosis should be treated with antiviral
therapy indefinitely regardless of HBV DNA level, HBeAg status or ALT level to decrease
the risk of worsening liver-related complications (High quality of evidence; strong
recommendation)
 ETV and tenofovir are recommended as first-line agents (High quality of evidence; strong
recommendation)
 Patients with decompensated Hepatitis-B related cirrhosis must be evaluated for liver
transplantation (High quality of evidence; strong recommendation)
 Surveillance for HCC should continue despite the use of antiviral agents(Moderate quality
of evidence; strong recommendation)

In general, a CTPscore>7isconsideredashepatic decompensation.22 Hepatic

decompensation among chronic HBV carriers is associated with high mortality and has a
reported 5-year survival rate of 14–35%, which is significantly lower than the rate of 80–85%
among those with compensated cirrhosis.23-26However, anti-HBV therapy significantly modifies
the natural history of decompensated cirrhosis, improves liver function and increases survival.
Early intervention with potent antivirals improves virologic and serologic responses in these
patients and maintained virologic response in patients under antiviral therapy leads to better
long-term liver transplant-free survivalcompared to non-responders or untreated patients.27
ETV and tenofovir are the recommended drugs.12,13,21 The licensed entecavir dose for
patients with decompensated cirrhosis is increased to 1 mg once daily (instead of 0.5 mg for
patients with compensated liver disease). However, antiviral therapy may not be sufficient to
rescue all decompensated patients and they should be considered for liver transplantation at the
same time.21The establishment of liver transplant programsface several challenges in
developing countries28, which should be considered when deciding on the best treatment
approach for patients with decompensated liver disease.
The use ofLAM, ADV, and ETV was associated with a decrease in CTP scores of >2
points and normalization of serum ALT. Transplant-free survival varied between 78% and 87%
at 1 year with the various agents. Other beneficial effects with the oral NAs include removal
from the liver transplantation waiting list in 6% of patients receiving ADV, 21% receivingLAM
and 11% treated with ETV. Development of HCC at 1 year was reported in 3%, 7% and 6% of
patients receivingLAM, ADV, and ETV, respectively.29 However, in another study using ETV,
treatment did not entirely eliminate the risk of developing HCC in patients with cirrhosis. Thus,
strict surveillance for HCC is warranted for patients with liver cirrhosis.30
TAF has not been studied in patients with decompensated cirrhosis, thus limiting
recommendations to use this drug in these patients. However, TAF or ETV should be
considered in patients with decompensated cirrhosis who have renal dysfunction and/or bone
disease. The doses of all NAs need to be adjusted in patients with low creatinine clearance (≤50
ml/min). Patients should be monitored closely for the development of adverse effects of antiviral
therapy, such as renal insufficiency and lactic acidosis.12,13,21
 Renal insufficiency is defined as an increase of serum creatinine by >0.5 mg/dL over
baseline. It occurred in 9% (5–17%) of patients treated with ADV and 10% (6–17%) of patients
treated with ETV. In contrast, none of the studies usingLAM reported any instances of renal
insufficiency. In a prospective RCT of LdT andLAM, there was a greater improvement in the
calculated eGFR from baseline among patients treated with LdT as compared toLAM.31 Renal
insufficiency was also reported in 10% of patients treated with ETV in a systematic review.29
Tenofovir was also associated with renal insufficiency in 9% in one study and the need for dose
reductions in three additional patients.32In another study, the incidence of renal insufficiency at 1
year was similar between ETV and TDF.32In another study among HBV-related compensated or
decompensated cirrhosis, there was no significant difference concerning impaired renal function
between ETV and TDF for 2 years.33Because of treatment-related renal safety concerns, renal
function should be monitored regularly, especially high-risk patients such as those with baseline
low eGFR, diabetes mellitus, and those receiving concomitant nephrotoxic drugs.33
Lactic acidosis has been reported to develop with some NAs, particularly ETV, in treated
patients with advanced decompensated cirrhosis (MELD score >20) – although in one analysis,
lactic acidosis and mitochondrial toxicity were reported in only one of the 100 ETV-treated
patients and it resolved despite continuing ETV.22 Therefore, clinical and laboratory parameters
should be closely monitored in this setting.
None of the studies ofLAM reported any SAEs associated with this agent. ADV was
associated with an SAE in 4% of treated patients.34ETV was associated with an SAE in 6% of
treated patients in a pooled analysis of two studies.32 Comparison of ADV and ETV in one
prospective study and of TDF and ETV in another prospective study showed similar rates of
SAEs.22,32
In a systematic review, all the available oral agents can lead to improved virologic,
biochemical and clinical parameters among patients with decompensated HBV cirrhosis at 1
year of follow-up. Furthermore, the use of these agents in decompensated HBV patients was
found to be generally safe and well-tolerated at 1 year. However, the increased incidence of
nephrotoxicity with prolonged ADV therapy and its slower onset of action made it a less
attractive option for this patient population. The increased rates of drug-resistant HBV with
prolonged use ofLAM, ADV, and LdT monotherapy also made these three agents less attractive
for decompensated HBV patients.29 Therefore, although the review found thatETV and TDF had
similar 1-year efficacy toLAM and LdT, the lower rate of drug resistance associated with ETV
and TDF during prolonged use would make them more attractive as initial agents for
decompensated HBV patients who require lifelong treatment.35
Lastly, IFN is not recommended, being poorly tolerated in patients with decompensated
HBV cirrhosis and is also associated with disease flares and worsening liver disease status.36
Peg-IFN is also contraindicated in patients with decompensated cirrhosis because of similar
safety concerns.
PATIENTS WITH EXTRAHEPATIC MANIFESTATIONS OF HEPATITIS B

Recommendations
 Acute and chronic hepatitis B may be associated with extrahepatic manifestations (High
quality of evidence; strong recommendation)
 Viremic HBsAg positive patients with documented extrahepatic manifestations may benefit
from antiviral therapy(Moderate quality of evidence; strong recommendation)
 Plasmapheresis, corticosteroids and or IV IG may be beneficial when used in tandem with
NA treatment for patients with immune-mediated extrahepatic hepatitis B
disease(Moderate quality of evidence; strong recommendation)
 Peg-IFN may worsen immune-related extrahepatic manifestations of hepatitis B(Low
quality of evidence; strong recommendation)

Various extrahepatic syndromes are associated with hepatitis B infection.37These include the
following:
 Polyarteritis nodosa (PAN)
 Glomerulonephritis (membranous, mesangial proliferative or membranoproliferative)
 Serum sickness-like prodrome
 Essential mixed cryoglobulinemia
 Dermatologic manifestations
 Arthritic manifestations
 Neurologic manifestations
 Thyroid dysfunction

The proposed mechanisms for these syndromes are typically immunological, including
circulating immune complexes, reactions caused by viral-induced autoantibodies, and/or direct
viral reactions to extrahepatic tissue sites such as the skin, muscle, joints, and kidneys.37,38 Of
these syndromes, the best-described ones are PAN, found more frequently in the first 6 months
of infection, and glomerulonephritis.21,39,40PAN is less common in Asian countries where HBV
infection typically occurs perinatally. Membranous glomerulonephritis (MGN) is the most
common form of hepatitis B-relatedglomerulonephritis, seen in endemic areas and usually
presents as nephrotic syndrome with proteinuria, edema, and hypertension. Both PAN and
MGN are mediated by the presence of circulating immune complexes triggered by viremia.
Although immunosuppression with various agents and plasmapheresis may be used in
the early phases of treatment, controlling viral replication with potent NAs seem to be essential
in the long term for many of these manifestations.40
LIVER TRANSPLANT RECIPIENTS

Recommendations
 Oral antivirals with a high genetic barrier to resistance (i.e., ETV, TDF and TAF) should be
given to patients waiting for a liver transplant to achieve undetectable HBV DNA levels
and reduce the risk of HBV recurrence.(High quality of evidence; strong recommendation)
 Prophylactic antiviral therapy after liver transplant should be given indefinitely.(Moderate
quality of evidence;strong recommendation)
 Among low-risk patients (i.e., with undetectable HBV DNA levels at the time of transplant),
HBIG-free regimens can be used. High potency NAs (i.e., ETV, TDF, TAF) should be
given indefinitely. (Moderate quality of evidence;strong recommendation)
 High-risk patientsshould receive HBIG (e.g., 10,000 IU intravenous HBIG given in the
anhepatic phase followed by short-term (<1 year) intramuscular HBIG administration)
given together with oral antivirals with a high genetic barrier to resistance. (Moderate
quality of evidence;strong recommendation)
 Serial monitoring of HBsAg and HBV DNA is sufficient for HBsAg-negative/anti-HBc
positive recipients who are receiving HBsAg negative/anti-HBc negative liver grafts.
(Moderate quality of evidence; weak recommendation)
 Serial monitoring for HBV in the post-transplant setting includes HBsAg and HBV DNA
every 3 months in the first year and every 6 months thereafter. (Low quality; strong
recommendation)
 HBsAg-negative patients receiving HBsAg-negative/anti-HBcpositive liver grafts should
receive antiviral prophylaxis with either ETV, TDF or TAF. (Moderate quality of
evidence;strong recommendation)

In liver transplant recipients who have chronic hepatitis B, it is important to prevent HBV
recurrence, which can lead to graft loss.12,13,21,41 Treatment against HBV should be started as
soon as diagnosed in decompensated cirrhosis (see Chapter on Decompensated Hepatitis-B
related Cirrhosis), and ideally before transplantation in those who are liver transplant candidates
so that HBV DNA levels can be suppressed at the time of liver transplantation.12,13,21,41,42 HBV
recurrence rates are lowest when HBV DNA levels are not detectable at the time of liver
transplantation.43 The recommended antiviral agents in these patients are ETV and TDF.12,13,21,42
TAF has not been fully evaluated in patients with decompensated cirrhosis or liver transplant
recipients but is the logical drug of choice in treatment-experienced patients and/or those at risk
of bone and kidney disease.13,41 Peg-IFN is not recommended in patients with decompensated
cirrhosis.12,13,41 Antiviral therapy should be continued indefinitely after liver transplantation
because HBV DNA has been shown to persist beyond 10 years after liver transplantation.44
The AASLD and APASL classify HBV-infected liver transplant recipients into low- and
high-risk groups for HBV recurrence after liver transplantation.13,21 Those who have
undetectable HBV DNA at the time of liver transplantation are considered to have a low risk of
HBV recurrence and may be given an HBIG-free prophylactic regimen.13,21 Fung et al showed
that in 265 patients given ETV monotherapy after liver transplant, 92% were negative for HBsAg
and 100% were negative for HBV DNA. HBV DNA level at the time of liver transplantation was
associated with HBsAg seroclearance. An undetectable HBV DNA level at the time of liver
transplant was associated with an HBsAg seroclearance rate of 98% at 1 year after transplant
compared to 92%, 81% and 60% for HBV DNA at transplant of <4 logs IU/mL, >4 to 6 logs
IU/mL and over 6 logs IU/mL, respectively (p<0.001).43
Those who have a high risk of HBV recurrence (Table 2) should receive HBIG in addition
to oral antiviral therapy to reduce the risk of HBV recurrence.13,21,45 However, universal use of
HBIG after liver transplantation is not practical because of the high cost and the inconvenience
of parenteral HBIG administration.21 The availability of potent antiviral agents with high genetic
barrier to resistance (e.g., ETV, TDF and TAF) allows the use of HBIG to be modified after liver
transplantation.41 These modifications, such as low-dose intramuscular HBIG regimens and
shortened-duration HBIG treatment regimens, may be used as alternatives to long-term
intravenous HBIG regimens. The use of low-dose intramuscular HBIG (400 or 800 IU daily for
one week then monthly thereafter) together withLAM 100 mg daily was associated with an HBV
recurrence rate of 4% at 5 years.46 Withdrawal of HBIG after ≤1 year with the continuation of
oral antiviral therapy has been associated with low HBV recurrence rates although drugs with a
high genetic barrier to resistance should be used.45,47,48Another study treated 176 patients with
either ETV or TDF after liver transplantation. Thirty-five (20%) patients had HBV DNA >2,000
IU/mL.HBIG was given at a dose of 10,000 IU intravenously in the anhepatic phase followed by
600–1000 IU/day intramuscularly f for 7 days, weekly for 3 weeks and then monthly to keep
anti-HBs levels >100 mIU/ml for 1 year. HBIG was then stopped at 1 year. HBV recurrence was
observed in only two patients after a mean follow-up of 43 months.49
In the Philippines as well as in many parts of the world where HBV is endemic, many
prospective donors are HBsAg-negative but anti-HBcpositive. HBsAg-negative patients who
receive a liver graft from an HBsAg-negative/Anti-HBcpositive donor are at risk of developing de
novo HBV infection. This risk depends on the anti-HBc and anti-HBs status of the recipient.50
The risk is highest in patients who are anti-HBcnegative and anti-HBsnegative, with a de novo
HBV infection rate of 47.8%. The risk is 13.1% in those who are anti-HBcpositive/anti-
HBsnegative; and lowest (1.4%) in those who are anti-HBcpositive/anti-HBspositive.51Therefore,
the recommendation is to give prophylactic therapy to HBsAg-negative patients receiving
HBsAg-negative/anti-HBc-positive liver grafts using oral antiviral agents.13,50,52 HBIG is not
needed in these cases.Because recipients who are anti-HBcpositive/anti-HBspositive have low
rates of de novo HBV infection after liver transplantation, consideration can be given to serial
monitoring and initiation of antivirals once de novo HBV infection occurs.51,52
HBsAg-negative/anti-HBc‐positive (with or without anti-HBs) liver transplant recipients who
are receiving HBsAg-negative/anti-HBcnegative grafts are at low risk of developing HBV
recurrence and are not deemed to be in need of antiviral prophylaxis.41 Serial monitoring and
initiation of antivirals once de novo HBV infection occurs are sufficient. Serial monitoring for
HBV in the post-transplant setting includes HBsAg and HBV DNA every 3 months in the first
year and every 6 months thereafter.41
TABLE 2. High risk for HBV recurrence after liver transplantation
 High HBV DNA (> 100 IU/mL) at the time of liver transplantation

 HIV or hepatitis D coinfection

 Lack of access to ETV, TDF or TAF

 Poor compliance with antiviral therapy

 Presence of HBV drug resistance

 HCC at the time of liver transplantation

*Adapted from AASLD13 and APASL21

NON-LIVER SOLID ORGAN TRANSPLANT RECIPIENTS

Recommendations:
 Screening for HBsAg, anti-HBc, and anti-HBs should be part of the evaluation for patients
referred for non-liver solid organ transplant (Moderate quality of evidence; strong
recommendation)
 Patients who are HBsAg-positive and have decompensated liver disease or significant
portal hypertension should be offered liver transplantation in addition to the non-liver solid
organ transplant (Moderate quality of evidence; strong recommendation)
 All patients who are HBsAg-positive undergoing non-liver solid organ transplant should
receive antiviral prophylaxis indefinitely to prevent HBV reactivation (Moderate quality of
evidence; strong recommendation)
 For HBsAg-negative/anti-HBcpositive recipients and recipients of a graft from an HBsAg-
negative/anti-HBcpositive donor, a short course of antiviral prophylaxis (up to 12 months)
immediately after transplant can be considered to decrease the risk of either HBV
reactivation or de novo HBV infection (Weak quality of evidence; conditional
recommendation). Alternatively, careful serial monitoring for HBV reactivation or de novo
HBV infection using serial ALT and HBV DNA every 3 months for at least 1 year post-
transplant may be considered especially in patients who are anti-HBs positive (Weak
quality of evidence; conditional recommendation)

Screening for hepatitis B should be part of the evaluation of patients being considered for
a solid organ transplant other than the liver.13,50,53Screening should include HBsAg, anti-HBc,
and anti-HBs. Those who test negative for HBsAg and anti-HBs should be offered HBV
vaccination.50,52 Those who test positive for HBsAg should undergo evaluation for the presence
and severity of HBV-related liver disease as is done in any patient with chronic hepatitis B.50
Patients with decompensated cirrhosis or those with compensated cirrhosis with
significant portal hypertension should undergo liver transplantation together with transplantation
of the initial non-liver solid organ.13,50 Those without cirrhosis or those with compensated
cirrhosis without portal hypertension can proceed with non-liver solid organ transplantation with
appropriate antiviral therapy to prevent HBV reactivation.50,54
Drugs with high potency and a high genetic barrier to resistance are recommended and
should be given indefinitely.13,50 These drugs include ETV, TDF and TAF.Non-liversolid organ
transplant recipients who are HBsAg-negative but anti-HBcpositive have a low risk of HBV
reactivation posttransplant.50 Either careful serial monitoring or a short course of antiviral
prophylaxis (6–12months) immediately after transplant and close monitoring (every 3 months
thereafter) of ALT and HBV DNA levels are reasonable strategies.13,50
Non-liver solid organ transplant recipients who receive a graft from an HBsAg-
negative/anti-HBcpositive donor have a low risk of developing de novo HBV infection unlike the
situation in liver transplantation.1 This has been best studied in patients for kidney
transplantation, where the risk of developing de novo HBV infection can be as low as 1% or
less.16Those recipients who are anti-HBs positive have the lowest risk for developing de novo
HBV infection. Giving a short course of antiviral prophylaxis (12 months) immediately after
transplant may be considered to further decrease this risk.13,50,52Careful serial monitoring is also
an alternative.
PATIENTS RECEIVING IMMUNOSUPPRESSIVE AND CYTOTOXIC TREATMENT

Recommendation
 HBsAg and anti-HBc (total or IgG) testing should be performed in all patients prior to
initiation of any immunosuppressive, cytotoxic or immunomodulatory therapy (High quality
of evidence; strong recommendation)
 HBsAg-positivepatients should initiate anti-HBV prophylaxis before immunosuppressive or
cytotoxic therapy (Moderate quality of evidence; strong recommendation)
 HBsAg-negative, anti-HBc positive patients could be carefully monitored with ALT, HBV
DNA and HBsAg with the intent of on-demand therapy. Exceptions include patients
receiving B-cell depleting agents(e.g., rituximab) or undergoing stem cell transplantation,
for whom anti-HBV prophylaxis is recommended. (Moderate quality of evidence; strong
recommendation)
 Antiviral prophylaxis should be prescribed continuously until at least 6 months after the
cessation of chemotherapy or immunosuppression, and for at least 12 months after
completion of immunosuppressive therapy for those receiving B-cell depleting agents.
(Moderate quality of evidence; weak recommendation)
 Anti-HBV drugs with a high resistance barrier (ETV, TDF or TAF) are preferred over low-
barrier agents. (Moderate quality of evidence, strong recommendation)
 For patients being monitored without prophylaxis, HBV DNA levels should be obtained
every 1 to 3 months. Patients should be monitored for up to 12 months after cessation of
anti-HBV therapy. (Moderate quality of evidence, weakrecommendation)

Patients with HBV infection are at risk of virus reactivation when immunosuppressive
therapy is initiated for various diseases.55-57Reactivation of HBV replication can lead to
hepatocellular injury, elevated ALT levels, symptoms of acute hepatitis, liver failure and even
death.57Multiple studies have shown that antiviral prophylaxis before initiation of
immunosuppressive treatment can markedly decrease the risk of HBV reactivation.58-63
With increasing recognition of reactivation risk and the availability of effective
prophylactic treatment, interest in appropriate HBV screening before chemotherapy initiation
has grown.56,64The strategy to prevent HBV reactivation includes the identification of patients
with HBV infection prior to immunosuppressive therapy, initiation of prophylactic antiviral
therapy in those at moderate to high risk of reactivation, and close monitoring of patients not
treated prophylactically so that antiviral therapy can be initiated at the first sign of HBV
reactivation.65

DEFINITIONS
HBV REACTIVATION
 A detectable HBV DNA level when they previously had undetectable HBV DNA, or,
 A rise in HBV DNA of more than 2 log10 international units/mL in patients who had
detectable HBV DNA at baseline, or,
 Reverse seroconversion (when a patient previously HBsAg- negative/anti-HBc-positive
becomes HBsAg-positive).
HBV flare
 An abrupt elevation of serum ALT to >5 ULN or a greater than threefold increase in
serum ALT.

HBV-associated liver failure

 Impaired synthetic function (total bilirubin >3 mg/dL or international normalized ratio
>1.5), or,
 Ascites, or,
 Encephalopathy, or,
 Death following HBV-associated liver flare due to HBV reactivation.

SCREENING RECOMMENDATIONS IN THE SETTING OF IMMUNOSUPPRESSIVE OR

CYTOTOXIC DRUGS
The rate of HBV reactivation in patients receiving chemotherapy for solid tumors and
hematologic malignancies without HBV prophylaxis was 4-68% (median 25%); rates vary
according to specific types of cancers.66 Therefore, all candidates for chemotherapy and
immunosuppressive therapy should be screened for HBsAg, anti-HBs and anti-HBc prior to
immunosuppression treatment to institute appropriate prophylactic therapy and/or monitoring.
Screening may also reveal previously unrecognized chronic HBV infection and its liver-related
complications.
Certain approaches to screening for HBV in patients receiving chemotherapy or
immunosuppression include:
 Screen all patients prior to chemotherapy/immunosuppression.67,68
o This strategy would identify patients who would potentially benefit from: (1)
antiviral prophylaxis; (2) HBV serology and HBV DNA monitoring (without
antiviral prophylaxis); (3) immunization against HBV; (4) evaluation for
complications of chronic hepatitis B; or (5) contact tracing of family members for
chronic hepatitis B and their subsequent management.
 Screen only patients in the “high risk” groups according to the CDC.
 Screen only patients who, if serological testing would be positive, would be prescribed
antiviral prophylaxis.

Consideration must also be given to which serological test(s) are to be used for screening.
These include:
 Test HBsAg, anti-HBc and anti-HBs. Test HBV DNA if HBsAg or anti-HBcis
positive (the latter in case of occult HBV infection)
 Test HBsAg, anti-HBc only. The role of anti-HBs in HBV reactivation is unclear.
The role of anti-HBs in screening prior to immunosuppressive therapy has not yet
been established. The presence of anti-HBs does not prevent HBV reactivation, but
anti-HBs may be useful for detecting prior infection in HBsAg negative, anti-HBc
positive patients and in surveillance as the loss of anti-HBs may be a predictor of
HBV reactivation.
  Test anti-HBc only. If positive, proceed to test for HBsAg and HBV DNA.
The risk of HBV reactivation can be classified as high (>10%), moderate (1–10%) or low
(<1%).The cost-effective approach to screening for HBV in patients at risk of HBV reactivation is
unclear. The American Gastroenterological Association recommends HBV serological screening
in patients with “moderate to high risk” according to their risk stratification paradigm (Table
3).67,68

ANTIVIRAL PROPHYLAXIS VS ON-DEMAND TREATMENT

HBsAg-positive patients
 These patients are at high risk of HBV reactivation, especially if their HBV DNA levels
are elevated. They should receive anti-HBV prophylaxis prior to the initiation of
immunosuppressive or cytotoxic therapy. This is supported by threeRCTsthat included
HBsAg-positive, anti-HBcpositive patients receiving anticancer therapy.69-72

HBsAg-negative, anti-HBcpositive patients

 These patients are at a lower risk of HBV reactivation than HBsAg-positive patients.
Depending on their clinical situation and feasibility of close monitoring, they could be
given anti-HBV prophylaxis or monitored with the intent of on-demand anti-HBV therapy
at the first sign of HBV reactivation.
 Patients with rheumatologic conditions receiving biologic therapies, those with
inflammatory bowel disease treated with TNF inhibitors, andthose with psoriasis treated
with biologics or conventional immunosuppressive therapies have been managed
successfully with monitoring without anti-HBV prophylaxis.73-77
 Although lymphoma patients have been successfully managed with close monitoring and
on-demand antiviral therapy while receiving rituximab or conventional anti-cancer
therapy without adverse liver outcomes78,79, prophylaxis is recommended for HBsAg-
negative/anti-HBcpositive patients on B-cell depleting drugs such as rituximab.

PREFERRED ANTIVIRALS AND DURATION OF TREATMENT

Prophylactic antiviral therapy should be administered to patients with chronic hepatitis B
before the onset of anticancer therapy or a finite course of immunosuppressive therapy
regardless of baseline serum HBV DNA level.80In literature, antivirals were most often given 7
days prior to anti-cancer or immunosuppressive therapy. High potency, high resistance barrier
first-line NAs (e.g., ETV or tenofovir) should be preferred over other NAs, as multiple meta-
analyses have demonstrated reduced reactivation, hepatitis, mortality and anticancer therapy
interruption with these agents.80-82
The most commonly studied and recommended duration of prophylactic antiviral therapy
is 6 to 12 months after discontinuation of anticancer or immunosuppressive
therapy.80Reactivation beyond 12 months has been documentedparticularly for patients who
received anti-CD20 antibody therapy.83-85
Table 4shows a summary of the American Gastroenterology Association guidelines on
the prevention and treatment of hepatitis B reactivation during immunosuppressive drug
therapy.
Table 3. Risk estimates of HBV reactivation according to drug class67,68
Risk estimate of Drug class Drug
HBV
reactivation
High (>10%) Bcell-depleting agents Rituximab (anti-CD20)
Ofatumumab (anti-CD20)
Anthracycline derivatives Doxorubicin
Epirubicin
Corticosteroids (high dose) e.g., Prednisone ≥20 mg for ≥4 weeks
Moderate (1- TNFa inhibitors Infliximab
10%) Etanercept
Adalimumab
Cytokine inhibitors Abatacept (anti-CD80, -86)
Integrin inhibitors Ustekinumab (anti-IL12, -23)
Natalizumab (binds α4-integrin)
Vedolizumab (binds integrin α4β7 [LPAM-1]
Tyrosine kinase inhibitors Imatinib
Nilotinib
Corticosteroids (moderate E. g., Prednisone <20 mg for ≥4 week
dose)
Low (<1%) Corticosteroids (low dose) E. g., Prednisone for <1 week
Corticosteroids (intra-articular)
Traditional Azathioprine 6-mercaptopurine
immunosuppression Methotrexate
Adapted from the American Gastroenterology Association guidelines.67,68
Table 4. Summary on the prevention and treatment of hepatitis B reactivation during immunosuppressive drug
67,68
therapy
Population at risk of Screening test Is antiviral prophylaxis Antiviral drug Monitoring in
HBV reactivation recommended? recommended untreated
for prophylaxis HBsAg (-)/anti-
HBc(+) patients

HBsAg positive HBsAg negative/

anti-HBc positive
High risk of HBV HBsAg and anti- Yes (high Yes (high Drug with high No recommend-
reactivation(>10%) HBc; HBV DNA if quality;strong quality;strong barrier to ation provided
 B-cell depleting serology positive recommendation) recommendation) resistance is
agents Continue at if taking:B-cell favored overLAM
 Anthracycline least6 months depleting agents (moderate
derivatives after completion or anthracycline quality;weak
 High-dose of chemotherapy derivatives. recommendation)
corticosteroids( and at least 12 Continue until .
≥20 mg months for B-cell atleast 12
prednisone for depleting agents. monthsafter
≥4 weeks) completion of
chemotherapy for
B-cell depleting
agents.
Moderate risk of HBsAg and anti- Yes (moderate Yes (moderate Drug with high No recommend-
HBV reactivation(1- HBc; HBV DNA if quality;weak quality;weak barrier to ation provided
10%) serology positive recommendation) recommendation) resistance is
 TNFa inhibitors Continue until at if takingTNFa favored overLAM
 Cytokine or least 6 months inhibitors, (moderate
integrin inhibitors after completion cytokine or quality;weak
 Tyrosine kinase of chemotherapy. integrin inhibitors, recommendation)
inhibitors or tyrosine kinase .
 High-dose inhibitors.
corticosteroids Continue until at
(<20 mg least 6 months
prednisone for ≥4 after completion
weeks) of chemotherapy.
Low risk of HBV Routine screening Not recommend- Not recommend- Not applicable No recommend-
reactivation (<1%) not ed(moderate ed(moderate ation provided
 Traditional recommended. quality;weak quality;weak
immunosuppre Screen for HBV recommendation) recommendation)
ssion as per CDC
 Intra-articular guidelines;
corticosteroids manage
 Systemic accordingly
corticosteroids
for <1 week
67,68
Adapted from the American Gastroenterology Association guidelines.
PATIENTS COINFECTED WITH HEPATITIS B AND HIV

Recommendations
 All HBsAg-positive patients contemplated for antiviral treatment should be screened for
HIV before starting treatment.(Moderate quality of evidence; strong recommendation)
 All HIV-HBV coinfected persons must be started on appropriate ART regardless of CD4
cell count. Both infections should be simultaneously treated using ART that is active
against both viruses to reduce the risk of resistance.(Moderate quality of evidence; strong
recommendation)
 The recommended regimen is TDF/TAF (provided there is no contraindication to tenofovir)
plus emtricitabine/ LAM, plus efavirenz to prevent the selection of HIV-resistant mutants.
(High quality of evidence; strong recommendation)
 LAM, TDF, TAF and ETV should not be used as monotherapy in coinfected patients.
(High quality of evidence; strong recommendation)
 ETV may be a reasonable alternative if needed against HBV in HIV-HBV coinfection, but
only in addition to a fully suppressive HIV ART regimen.(High quality of evidence;
conditional recommendation)
 When coinfected patients are already on ART, drugs that are active against HBV should
not be abruptly discontinued without replacing it with another fully suppressive drug
against HBV.(High quality of evidence; strong recommendation)
 Treatment regimens that include TDF and emtricitabine need renal dose adjustment if
creatinine clearance <50 ml/min. Regimens with TAF and emtricitabine are not
recommended when creatinine clearance <30 ml/min.(High quality of evidence; strong
recommendation)

Studies have shown higher rates of liver-related morbidity and mortality in individuals
with HIV-HBV infection compared with those infected with only one of either virus.86 The
possibility of fibrosis progression, cirrhosis and hepatocellular cancer make it important to give
antiviral regimens that are able to suppress both viruses sufficiently, regardless of current HIV
status and liver histology.
In a meta-analysis of over 12,283 HIV-HBV coinfected patients, there was increased
rates of death in studies done both before and after HAART was commenced.87There is
evidence that HIV infection leads to increased HBV DNA polymerase activity, increased HBV
viral load, and decreased rated of HBeAg seroconversion. The rates of hepatitis B reactivation
and the risk of cirrhosis also increase with coinfection.88-91While there are still conflicting data on
the effect of HBV on the natural prognosis of HIV infection and AIDS-related mortality, several
studies have shown that hepatitis B infection may impair the rise of CD4 while on ART and
increases AIDS-related mortality.92,93 These support the need to suppress both infections during
treatment.
LAM, tenofovir and emtricitabine have activity against both HIV and HBV.LAM
monotherapy should be avoided due to the emergence of resistance; hence a tenofovir-based
treatment is preferred. If available, TAF may be preferable over TDF due to a better kidney and
bone safety profile. Two randomized, controlled non-inferiority studies that included>1,600
patientsfound that equivalent virological success was achieved with TAF and TDF given with
ART, with a significant decrease in creatinine and bone mineral density adverse effects in TAF
vs TDF.94
ETV has been shown to have anti-HIV activity and should not be used without a fully
suppressive anti-HIV regimen as it has been shown to induce the development of the M184T
resistance mutation in both ART-naïve and ART-experienced patients.95
Flares from hepatitis B may occur in the first few weeks of ART treatment due to immune
reconstitution but can also occur when drugs with anti-HBV activity are inadvertently
discontinued when a patient with HIV-HBV coinfection has a change of ART regimen. Due to
the many reasons for increase in ALT levels in patients with HIV (e.g.,drug-induced liver injury,
opportunistic infections, etc.), it is prudent to monitor virologic suppression of HBV periodically,
especially when the cause of ALT elevation is uncertain.13
PATIENTS COINFECTED WITH HEPATITIS B AND C VIRUSES

Recommendations
 All HBsAg-positive patients should be tested for coinfection with HCV.(Low quality of
evidence; strong recommendation)
 HCV treatment should be initiated for all patients with HCV viremia.(High quality of
evidence; strong recommendation)
 HBsAg-positive patients who fulfill the standard criteria for hepatitis B treatmentbased on
ALT and DNA levels(as with mono-infected patients) should be started on NA
treatment.(High quality of evidence; strong recommendation)
 DAA treatment may cause reactivation of hepatitis B and subsequent clinical flares in
HBV-HCV coinfected individuals. Close monitoring with HBV DNA or at least ALTshould
be considered.(Moderate quality of evidence; strong recommendation)
 HBsAg-negative, anti-HBc–positive patientswho are started on DAA should haveALT
levelsmonitored. HBV reactivation should be considered as a cause when there is ALT
elevation. (Moderate quality of evidence; strong recommendation)
 Cirrhotic patients with HBV-HCV coinfection should receive antiviral treatment for both
hepatitis B and C. (Low quality of evidence; strong recommendation)

Due to the similar modes of transmission, coinfection with HBV and HCV is not rare. In
HBV-HCV coinfected patients, the host’s immune system determines the ability of either virus to
replicate in the host, with one virus (usuallyHCV) typically predominating over the other. The
dominant virus responsible for liver disease and liver-related morbidity can be determined by
checking both HBV DNA and HCV RNA. Hepatitis C treatment is an evolving area of study;
hence, standard updated professional guidelines should be followed.96
In 2016, the US Food and Drug Administration issued a warning for patients with HBV-
HCV coinfection on DAAs due to reported cases of HBV reactivation while on DAA
treatment.97,98 Recent studies including systematic reviews have shown that there is a higher
risk of HBV reactivation after DAA treatment compared to what was previously noted in IFN-
based regimens. In a systematic review with a pooled sample of 1,621 patients, reactivation
was noted in 24% (95% CI 19–30%) of HBsAg-positive patients vs only 1.4% in patients with
past hepatitis B (HBsAg-negative, Anti-HBc positive). The risk of reactivation was found to be
higher in patients with HBV DNA levels ≥ 20 IU/mL at baseline.98 Reactivation has also been
reported in cirrhotic individuals with HBV HCV coinfection.99 Reactivation of hepatitis B can be
catastrophic for these individuals and prophylactic HBV treatment may be warranted in this
subset of patients.
More studies need to be done to guide protocols for monitoring and screening for HBV
reactivation in the setting of DAA treatment for HBV-HCV coinfection. The AASLD suggests
monitoring DNA and ALT every 4-8 weeks during and until 3 months after DAA treatment for
HBsAg-positive patients. For patients with past hepatitis B, ALT monitoring at baseline, at end of
treatment and at follow-up is suggested to screen for reactivation.13,97 The EASL, on the other
hand, suggests outright empiric HBV prophylactic treatment with NAs until 12 weeks after
ending DAA treatment.12 In instances that DAAs and tenofovir need to be administered together,
there may be a need to monitor TDF-related adverse events when the drug is used as drug
levels may be increased when coadministered with some DAAs (e.g.,sofosbuvir/ledipasvir or
sofosbuvir/velpatasvir).100
PATIENTS WITH CHRONIC KIDNEY DISEASE

Recommendations
 All candidates for dialysis should be tested for HBsAg, anti-HBs, and anti-HBc before
starting therapy. If HBV seronegative, vaccination is recommended.(Moderate quality of
evidence; strong recommendation)
 For known responders to vaccination, annual determination of anti-HBs titer is
recommended. If the anti-HBs titer is <10 mIU/ml, a booster dose is
recommended.(Moderate quality of evidence; strong recommendation)
 Hepatitis B surveillance using HBsAg and anti-HBs determinationis recommended for
CKD patients on regular hemodialysis. (Moderate quality of evidence; strong
recommendation)
 For patients who are immune to hepatitis with an anti-HBs titer of >100mIU/ml, hepatitis B
surveillance should be done every 6 months.(Moderate quality of evidence; strong
recommendation)
 For patients who are non-immune to hepatitis with an anti-HBs titer of <10mIU/ml,
hepatitis B surveillance should be done every 3 months.(Moderate quality of evidence;
strong recommendation)
 Enhanced surveillance is encouraged for high-risk patients.(Moderate quality of evidence;
strong recommendation)
 CKD patients with chronic hepatitis B should be evaluated for treatment similar to non-
CKD patients. Indications and treatment monitoring are similar to non-CKD patients, as
indicated in sections 4 and 5 of the 2014 HSP Consensus Statement on the Management
of Chronic Hepatitis B.(Moderate quality of evidence; strong recommendation)
 ETV and TAF are the preferred agents for patients with CKD because of better renal and
bone safety profiles.(High quality of evidence; strong recommendation)
 Dosing of antiviral agents should be adjusted based on the eGFR (Table 5). (High quality
of evidence; strong recommendation)

CKD patients on hemodialysis are at highrisk ofchronic hepatitis B because they are
susceptible to nosocomial transmission and occult HBV infection.101 The latter might account for
the potential risk of transmission during hemodialysis and HBV reactivation after kidney
transplantation.
Vaccination is a vital component of preventive healthcare measures among CKD patients
and should not be underutilized because of poor response.102 Special vaccination regimens are
recommended, including double-dose vaccination (40 mg each) in four doses, preferably given
before hemodialysis initiation. Anti-HBs titer determination should be performed every year and
a booster dose of hepatitis B vaccine should be given if antibody titers are below 10 mIU/mL.
Hepatitis B surveillance is recommended for CKD patients on regular hemodialysis.
Enhanced surveillance is encouraged for high-risk patients. These patients include those who
have:103
 Recently injected illicit drugs
 Other blood-borne virus infections
  Unexplained abnormal aminotransferase levels
 Recently received a kidney transplant or blood from a donor known to be infected with
blood-borne viruses
 Sexual partners who inject illicit drugs or have blood-borne virus infections
 Recently received healthcare overseas

Additional parameters complicating the diagnosis and clinical course of chronic hepatitis B
in patients on hemodialysisinclude the minimal or no increase in liver function tests, the lower
viral load levels because of viral clearance by hemodialysis,and the high bleeding risk related to
clotting disorders and intra- dialysis anticoagulant therapies.104,105
Management of HBV patients with CKD requires special consideration, a multidisciplinary
approach, and thorough and regular monitoring of renal function. The administration of NAs has
improved the prognosis of patients with CKD immensely and has prevented HBV recurrence
after kidney transplantation.106 Among CKD patients who are not candidates for kidney
transplantation, antiviral treatment should be reserved for those with active liver disease and
those with significant fibrosis. The dose of NAs should be adjusted according to eGFR, as
shown in Table 5.107
With the advent of NAs, IFN use has been limited to young patients with HBV-related
glomerulopathy without cirrhosis, psychosis or autoimmune disease.108 IFN is poorly tolerated
by patients with CKD, has shown relatively low efficacy, and has set kidney transplant recipients
under the risk of acute rejection. 104 Hence, IFN is contraindicated in patients with CKD.
NAs with high genetic barrier for resistance are the preferred agents for HBV-positive
patients with CKD. In patients with treatment indications for HBV infection, ETV is considered
the first choice, regardless of viremia.107 TAF is likewise a good treatment option because of its
better bone and safety profile compared to TDF. However, studies on the routine use of TAF in
CKD patients are lacking and further research is needed.

Table 5. Dosage adjustment of NAs according to creatinine clearance.107

CrCL LAM LdT ADV ETV TDF TAF
(mL/min)
≥50 100 mg/day 600 mg/day 10 mg/day 0.5 mg/day 245 mg/day 25 mg/day
30-49 50 mg/day 600 mg 10 mg every 0.25 mg/day 245 mg 25 mg/day
nd nd nd
every 2 day 2 day every 2 day
10-29 25 mg/day 600 mg 10 mg every 0.15 mg/day 245 mg 25 mg/day
rd rd rd
every 3 day 3 day every 3 to
th
4 day
<5-10 or 10 mg/day 600 mg 10 mg every 0.5 mg/week 245 25 mg/week
rd
hemodialysis every 3 to week mg/week
th
4 day
*In patients undergoing hemodialysis, all agents should be given once weekly after an HD session.
** For LAM, resistance, dosage of ETV is doubled.
RECOMMENDATIONS FOR DRUG RESISTANCE

Recommendations
 For resistance toLAM, LdT or CLV, add-on ADV, TDF or TAF therapy (High quality of
evidence;strong recommendation) OR switching to TDF or TAF is indicated (Moderate
quality of evidence;strong recommendation)
 For resistance to ADV, add-on ETVOR switching to ETV, TDF or TAF is indicated
(Moderate quality of evidence;strong recommendation)
 For resistance to ETV, add-on ADV or TDF or TAF (Moderate quality of evidence;strong
recommendation) OR switching to TDF or TAF is indicated (Moderate quality of
evidence;strong recommendation)
 For resistance to both ADV AND eitherLAM, LdT or CLV, switching to ETV plus TDF, or to
TDF or TAF alone, is indicated (Moderate quality of evidence;strong recommendation).
 For resistance to any NA, switching to IFN-based therapy may be considered (Moderate
quality of evidence;strong recommendation).
 Management of drug resistance in the treatment of HBV is complex. Referral to a
specialist is recommended.(Low quality of evidence; strong recommendation).\

Drug resistance is identified by an initial non-response to treatment or virological

breakthrough in the presence of established treatment compliance.23Ideally, drug resistance
testing is performed to tailor rescue therapy but may not be feasible in resource-limited settings.
Alternatively, add-on treatment or switching to different antivirals is guided by available cross-
resistance data.109
Among antiviral agents,LAM yields the highest year-on-year rates of HBV resistance in
treatment-naive patients.23ETV and TDF have the lowest documented resistance rates although
data for TDF is limited.110
In patients withLAM resistance, add-on ADV enhances viral suppression, prevents
virologic breakthrough and is more effective than switching to ADV alone.111,112Moreover,LAM
plus ADV was significantly better than ETV monotherapy (1 mg/day) inenhancing viral
suppression and reducing virologic breakthrough rates.113However, ETV may still be offered to
patients not amenable to other antivirals. Switching to TDF monotherapy has been shown to be
effective forLAM or ADV resistance.114ETV plus TDF should be considered for patients resistant
to combined nucleoside and nucleotide analogs.
IFN-based treatment has also been used for patients with NA resistance. A 48-week
course of peg-IFN versus continuous ADV treatment in HBeAg-positive patients withLAM
resistance showed that peg-IFN was superior to ADV in inducing HBeAg seroconversion after
72 weeks (or 6 months after peg-IFN treatment) (p=0.01). However, only 10.6% of peg-IFN
treated patients had HBV DNA <80 IU/mL versus 22.5% in ADV-treated patients during the
same time period.115
TAF, similar to TDF, is a phosphonate prodrug of tenofovir. It has enhanced antiviral
potency with improved renal and bone safety profile compared to TDF. Moreover, TAF has
greater plasma stability than TDF, allowing more efficient delivery of the active metabolite
intracellularly at much lower doses.116,117In vitro, TAF has shown potent activity againstLAM-
resistant and ETV-resistant recombinants, with mean changes in half-maximal effective
concentration (EC50) values of less than two-fold compared with wild-type virus.118 Pooled
analysis of phase III studies on TAF showed that majority (89.2%) of patients had wild-type virus
at baseline and that the number of patients with resistance mutations associated with other NSs
was small.119
PREGNANT WOMEN WITH CHRONIC HEPATITIS B INFECTION

Recommendations
 All pregnant women should be screened for hepatitis B. (Moderate quality of evidence;
strong recommendation).
 Infants born to chronic hepatitis B mothers should receive timely prophylaxis with HBIG
and the first dose of HBV vaccine within 12 hours of birth. (Moderate quality of evidence;
strong recommendation).
 Pregnant women with HBV DNA >200,000 IU/mL should receive antiviral therapy during
the third trimester up to the first 6 weeks postpartum, if started solely for MTCT.
Monitoring should still be done after discontinuation of antivirals. (Moderate quality of
evidence; strong recommendation).
 Preferred agents for use in pregnant women with chronic hepatitis B are LAM, LdT and
TDF are considered safe for pregnancy, with TDF being the preferred agent. (Moderate
quality of evidence; strong recommendation)
 The mode of delivery should still be guided by obstetric indications rather than HBV
infection status. (Low quality of evidence; strong recommendation).
 Breastfeeding should not be withheld. (Low quality of evidence; strong recommendation).

Vertical or MTCT is still the predominant mode of HBV spread in hyperendemic areas of
the world (>8% prevalence of HBsAg seropositivity) such as Asia and the South Pacific.120-
122
The Philippines has an HBsAg seroprevalence of 16.7%, classifying it as one of these
hyperendemic countries.123
Screening for HBVinfection during pregnancy identifies seropositive women, whose
neonates are at highest risk of perinatal spread.124Preventing vertical transmission heavily
depends on prenatal screening of pregnant women for HBsAg. Those identified to be positive
will need to do further tests, such as HBeAg, ALT, HBV,and DNA, the latter being the most
important predictor of perinatal transmission.125,126Infants born to chronic hepatitis B mothers
need to receive timely prophylaxis with HBIG (0.5 mL intramuscularly) and the first dose of HBV
vaccine within 12 hours of birth.127This combination of passive and active immunization
decreases the rates of MTCT from 90% to 10%.127,128
Despite immunoprophylaxis, 10–30% of infants born to chronic hepatitis B mothers with
HBV DNA levels >200,000 IU/ml still acquire HBV. Therefore, pregnant women with HBV DNA
>200,000 IU/mL should receive antiviral therapy during the third trimester (week 28 onward) to
further reduce the chances of perinatal transmission.13,122,129 Threatened preterm labor,
prolonged uterine contractions and a previous child in whom immunoprophylaxis had failed are
also indications for initiating antiviral treatment. This antiviral treatment should be continued for
the first 6 weeks postpartum, if started solely for MTCT.122 Monitoring should still be done after
discontinuation of antivirals.
LAM, LdT, andTDF are considered safe for pregnancy, with TDF being the preferred
agent. As of late, there is still no published safety profile for TAF in pregnant women.12,130
Pregnant patients without active or advanced chronic HBV infection can have their
antiviral treatment deferred until after childbirth.
 Data on the benefit of doing a Cesarean section for chronic hepatitis B mothers are
conflicting and nonconclusive. To date, the recommendations for the mode of delivery should
still be guided by obstetric indications rather than HBV infection status.13
Breastfeeding has significant maternal and infant benefits and does not seem to
increase HBV transmission risk from mother to child. Hence, breastfeeding should not be
withheld. Antivirals, if necessarily taken postpartum, are minimally excreted in breast milk and
are not likely to cause significant toxicity.12,13
Figure 1 summarizes the management of chronic hepatitis B in pregnant women.13,131

Figure 1. Management of Chronic Hepatitis B in Pregnant Women13,131

Adapted from American Association for the Study of Liver Diseases13 and Ayoub and Cohen
(2016)131
CHILDREN WITH CHRONIC HEPATITIS B

Recommendations
 Treatment is indicated for children with HBeAg-positive chronic hepatitis B and
persistently elevated ALT with moderate to severe inflammation and fibrosis (High quality
of evidence; strong recommendation)
 Treatment is indicated for children with HBeAg-negative chronic hepatitis B infection and
persistently elevated ALT with moderate to severe inflammation and fibrosis (High quality
of evidence; strong recommendation)
 Treatment is indicated for children with chronic hepatitis B infection and compensated
cirrhosis (High quality of evidence; strong recommendation)
 Treatment is indicated for children with chronic hepatitis B infection and decompensated
cirrhosis(High quality of evidence; strong recommendation)
 Liver biopsy is recommended to establish liver histology prior to commencing anti-viral
treatment for chronic hepatitis B infection in children (High quality of evidence; strong
recommendation)
 In children with chronic hepatitis B, antiviral therapy may be started without a prior in the
following conditions: decompensated cirrhosis; HBeAg-positive, > 20,000 IU/ml HBV DNA
and ALT 2x ULN for >12 months; and HBeAg-negative, > 2,000 IU/ml HBV DNA and
persistent ALT 2x ULN(Moderate quality; strong recommendation)
 Tenofovir and ETV are first-line antivirals for children with chronic hepatitis B infection
requiring treatment (Moderate quality; strong recommendation)
 Lifelong post-treatment monitoring for SVR, clinical decompensation and adverse effects
of treatment is recommended in children with chronic hepatitis B(Moderate quality; strong
recommendation)

Management of chronic hepatitis B in children requiresspecial attention.Many aspects of

care remain unproven, such as the long-term effectiveness of anti-viral treatment in preventing
liver cirrhosis orHCC.Data on treatment in children are more recent compared to
adults.Although IFN has been used for chronic HBV infection in children in the 1980s, it is only
recently that NAs have been approved.As such, the optimal duration and adverse effects of
treatment remain unclear.Guidelines for the management of chronic hepatitis B in children have
been published by a consensus group from the United States as well as ESPGHAN, AASLD
and APASL to guide practitioners in the management of hepatitis B in children, given the
limitations in clinical evidence.21,132-134
Treatment in children impacts the prevalence of cirrhosis and HCC, both in adults and
children.These complications are reported in children at a rate of 0.6-3.8% and 0.01-2.8%,
respectively.135-144Identified risk factors for HCC specific to children include early HBeAg
seroconversion, presence ofcirrhosis,male sexand pre-S2 deletion mutants.136,138,142,145-147In a
nationwide multicenter survey of children with chronic HBV infection in Japan, HCC was
diagnosed in children as young as 9 years old, with a reported median age of 15 years.144
The natural course of illness of chronic hepatitis B in the pediatric agegroup has
peculiarities.Treatment is not indicated during the immune-tolerant phase, which may be
prolonged in children, sometimes lasting >3 decades following vertical transmission.132Maternal
HBeAgtransferredtransplacentallyhas been postulated to induce tolerance to HBeAg of the
helper T cells of the infected infant.148
In children, treatment is recommended for a prolonged immune-reactive phase and during
the reactivation phase (HBeAg negative, Anti-HBc/anti-HBs positive chronic hepatitis B) since
necroinflammation exists at these times with resulting progression of liver disease.133 Children
with chronic hepatitis B-related cirrhosis require treatment even with normal ALT levels and
without the need for liver biopsy.21,23
In the pediatric age group, chronic hepatitis B infection may coexist with another primary
liver condition.This situation should be considered in the following circumstances:(1) HBeAg-
positive with intermediate or low viral load and persistent elevation of ALT for any duration; (2)
HBeAg-negative with low viral load and persistently elevated ALT; and (3) HBeAg-negative with
intermediate to high viral load and ALT elevated ≤2x ULN.Once other primary liver disease
conditions are ruled out, treatment for chronic hepatitis B infection may commence as indicated
by a liver biopsy showing moderate to severe inflammation and significant fibrosis.21
A liver biopsy remains a useful tool in the determination of treatment indication in
children with chronic hepatitis B.Hence, a liver biopsy is recommended prior to antiviral
treatment. However, no liver biopsy is required in HBeAg-positive chronic hepatitis B with high
viremia and ALT>2x ULN persisting for 12 months andHBeAg-negativechronic hepatitis B with
HBV DNA >2,000 IU/ml and persistent ALT >2x ULN.21Decompensated cirrhosis is an indication
for treatment that requires no liver histologic analysis.132,133The use of non-invasive tests such
as APRI,transient elastography (e.g.,FibroScan) or FibroTest is not yet recommended for
children.42
Table 6 summarizes the indications for the treatment of children with hepatitis B, as
recommended by guidelines.
Treatment should be considered for children with a family history of HCC or cirrhosis,
even if mild histologic changes are mild, because of the increased risk of HCC.21
The goals of treatment in children include sustained HBeAg seroconversion,
undetectable serum HBV DNA, ALT normalization, histologic improvement and regression of
liver fibrosis. Conventional IFN-alpha, LAM, ADV, ETV, and TDF have all been evaluated for
safety and efficacy in children. Antiviral drugs with a high genetic barrier to resistance (i.e.,
tenofovir or ETV) are recommended first-line treatments for both adults and children by the
World Health Organization. LAM, ADV, and LdT are not recommended because of the low
barrier to resistance.42IFN-alpha was superior to placebo in maintaining SVR and ALT
normalization in a systematic review and meta-analysis that included children with HBeAg-
positive chronic hepatitis B.149 A phase IIIb open-label study of peg-IFN alfa-2a monotherapy
started in 2012 will be completed in 2021.150
Although lifelong NAs treatment is recommended in adults with cirrhosis, the duration of
treatment in children is unclear. In children, NAs are recommended until the therapeutic
endpoint of HBeAg seroconversion is achieved. Thereafter, consolidation therapy for 12 months
is given to prevent virological relapse. For HBeAg-negative chronic hepatitis B, prolonged NA
treatment is given and HBsAg loss is the therapeutic target to address the high relapse
rate.21The IFN-alpha treatment recommendation is finite at 24 weeks.
Following treatment, monitoring of children is recommended every 3 months for at least
1 year to detect recurrent viremia, ALT flares, and clinical decompensation.134
 Table 6. Indications for the treatment of children with chronic hepatitis B
Serum HBV ALT Duration Liver histology Ruled out
DNA IU/mL primary liver
disease?
HBeAg (+) Child
21
APASL 2015 2000-20,000 Persistently 6 months* Moderate or severe Yes
elevated inflammation &
fibrosis
>20,000 1-2x ULN >1 year Moderate or severe Not
inflammation & recommended
fibrosis
>20,000 >2x ULN >1 year Not recommended
US Consensus > 2000 1.5x ULN or 6 months Moderate or severe -
132
2010 60IU/L inflammation &
133
ESPGHAN 2013 fibrosis
HBeAg (-) Child
21
APASL 2015 <2000 Persistently 3-6 months* Moderate or severe Yes
elevated inflammation &
fibrosis
>2000 1-2x ULN 3-6 months* Moderate or severe Yes
inflammation &
fibrosis
>2000 >2x ULN 3-6 months* Not recommended Not
recommended
133
ESPGHAN 2013 > 20,000 1.5x ULN 12 months Moderate or severe -
inflammation &
fibrosis
US Consensus >2000 1.5x ULN or 60 12 months Moderate or severe -
132
2010 IU/L inflammation &
fibrosis
* Implied but not directly stated.
 Table 7 summarizes the dosing and monitoring of drugs used to treat chronic hepatitis B in
children.

Table 7. Details of pharmacotherapy for chronic hepatitis B in children

Drug Dose Monitoring Remarks

Tenofovir 300 mg once daily Nephrotoxicity; decreased ≥12 years old; weight at least
bone mineral density 35 kg; for NA treatment-naive
possible & LAM-refractory

ETV Dose (mL) of 10 High genetic barrier to drug ≥2 years old; weight at least 1
mg/0.5 mL solution by resistance but resistant 0kg; for NA treatment-naive
bodyweight (kg): variants reported to be
10 to 11 kg: 3 mL slightly higher in children
>11 to 14 kg: 4 mL than in adults
>14 to 17 kg: 5 mL
>17 to 20 kg: 6 mL
>20 to 23 kg: 7 mL
>23 to 26 kg: 8 mL
>26 to 30 kg: 9 mL
>30 kg: 10 mL

Interferon-alpha 5–10 million units per No resistance; serious Contraindications:

square meter, 3x potential adverse effects decompensated cirrhosis,
weekly for 6 months cytopenia, autoimmune
disorders, cardiac or renal
failure, transplanted patients
Adapted from Sokal EM, Paganelli M, Wirth S, et al. Management of chronic hepatitis B in childhood: ESPGHAN clinical
practice guidelines: consensus of an expert panel on behalf of the European Society of Pediatric Gastroenterology,
Hepatology and Nutrition. J Hepatol 2013;59:814-29 and World Health Organization (2015). Guidelines for the
prevention, care, and treatment of persons with chronic hepatitis B infection.
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