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Consensus Guidelines
Foreword
Chronic hepatitis B virus (CHB) infection is a
serious problem that affects over 300 million people
worldwide and is highly prevalent in the AsiaPacific region. In the Philippines, an estimated 7.3
million Filipinos or 16.7% of adults are chronically
infected with HBV, more than twice the average
prevalence in the Western Pacific region.
In view of the above, the Hepatology Society of
the Philippines (HSP) embarked on the development
of consensus statements on the management
of hepatitis B with the primary objectives of
standardizing approach to management, empowering
other physicians involved in the management of
hepatitis B and advancing treatment subsidy by the
Philippine Health Insurance Corporation (PhilHealth).
The local guidelines include screening and
vaccination, general management, indications
for assessment of fibrosis in those who did not
meet treatment criteria, indications for treatment,
I ntroduction
Chronic hepatitis B virus (HBV) infection is a
serious problem that affects over 300 million people
worldwide and is highly prevalent in the Asia-Pacific
region.1-5 In the Philippines, an estimated 7.3 million
Filipinos or 16.7% of adults are chronically infected
with HBV, more than twice the average prevalence
in the Western Pacific region.3,6,7
The course of chronic infection with HBV (i.e.,
immune tolerant, immune clearance, inactive and
reactivation phases) varies and is unpredictable.
Chronic hepatitis B (CHB) ranges from an inactive
carrier state to chronic active hepatitis that may
National Kidney and Transplant Institute
**Paraaque Doctors Hospital
***St. Lukes Medical Center
****The Medical City
*****St. Lukes Medical Center
******University of the Philippines-Philippine General Hospital and
The Medical City
*******Metropolitan Hospital
********University of Santo Tomas Hospital and Chinese General
Hospital
*********National Kidney and Transplant Institute
**********Cardinal Santos Medical Center
*
Jamias J, et al.
Individuals with chronically elevated ALT or AST
Individuals infected with HCV or HIV
Patients undergoing renal dialysis
All pregnant women
Persons needing immunosuppressive therapy
M ethods
The applicability and feasibility of current
international guidelines formulated by the Asian
Pacific Association for the Study of the Liver (APASL),
the European Association for the Study of the Liver
(EASL) and the American Association for the Study
of Liver Diseases (AASLD) on the management of
hepatitis B to the existing healthcare situation in the
Philippines was determined by a thorough review
of the consensus statements conducted by a core
working group composed of nine members (Jamias
J, Bocobo J, Labio ME, Ong J, Wong S, Yu I, Co
A, Macatula T, Go A and Lontok M.) The members
were chosen for their expertise, academic affiliations,
active clinical practice and research in hepatitis B.
Literature searches were performed in Medline, Embase,
and the Cochrane Central Register of Controlled
Trials. Manual searches in bibliographies of key articles
including those published in the Philippine Journal
of Internal Medicine (PJIM) and Philippine Journal
of Gastroenterology were likewise done. Local data
gathering was also performed through a review of
scientific papers submitted by fellows-in-training from
different accredited training institutions of the Philippine
Society of Gastroenterology (PSG).
A Knowledge, Attitudes and Practices (KAP) survey
was also conducted among family physicians, general
internists, infectious disease specialists, gastroenterologists
and hepatologists during the Annual convention of
the Hepatology Society of the Philippines (HSP) last
January 2013. A pre-consensus development conference
was held where the results of the surveys and reviews
were presented and discussed. Important issues were
identified by the core working group for further
deliberations. Following the modified Delphi process,
17 recommendations were proposed by the core
working group for votation. The consensus development
conference proper was held in July 2013 in which
the chairs and training officers or the representatives
from all the training institutions in gastroenterology,
representatives from the Philippine College of Physicians
(PCP), the Philippine Society for Microbiology and
Infectious Diseases (PSMID) and the Philippine Academy
of Family Physicians (PAFP) participated. During the
consensus development proper, voting for each
statement was done as follows: (1) Accept completely;
(2) Accept with some reservation; (3) Accept with
major reservation; (4) Reject with reservation; (5)
Moderate quality
Low quality
Grade Recommendation
Strong
Conditional
(Weak, Discretionary)
C onsensus
Statements
Jamias J, et al.
An assessment of patients with CHB should
include
the
evaluation
of
HBV
risk
factors
and related co-infections, alcohol intake, any
family history of HBV infection or HCC, and a
complete physical examination.2,8 Serological markers
for HBV, particularly HBeAg, anti-HBe and HBV
DNA, in conjunction with biochemical (by serum
alanine aminotransferase [ALT]) and other clinical
evidence of liver disease (by liver ultrasound)
are
necessary
for
identifying
the
status
of
HBV infection and assessing the need for and
response
to
treatment. 1,2,8 Because
low
HBsAg
levels may distinguish true inactive carriers from
CHB when HBV DNA and ALT levels are low,
HBsAg quantification is also recommended.13 HBsAg
loss before the onset of cirrhosis has also been
associated with improved outcomes with less risk
of
progression
to
hepatic
decompensation
or
HCC.1
Laboratory examinations (e.g., complete blood
counts
[CBC]
with
platelets,
hepatic
panel,
prothrombin time [PT]) and liver ultrasound are
used
to
assess
liver
status.
Liver
cirrhosis
is
suspected in patients who have a reversal in
the ALT to aspartate aminotransferase (AST) ratio
(<1), a progressive decline in serum albumin
concentrations and/or an increase in -globulins,
and a prolongation in the PT (often with a
decline
in
platelet
counts). 1
Histopathological
confirmation, including the grading and staging of
liver disease by a liver biopsy, should also be
performed if suspected. Furthermore, HCC screening
and surveillance through serum -fetoprotein (AFP)
and liver ultrasound every six months is indicated
for HBV subgroups considered at higher risk for
HCC (see Table III). 1,2,8,13-15
Table III: Definition of terms2,8
HBV INFECTION
Chronic hepatitis B
Immune tolerant
HBV infection
Inactive HBsAg
carrier state
Jamias J, et al.
Resolved hepatitis
B
Reactivation of
hepatitis B
SEROLOGICAL MARKERS
Undetectable
serum HBV DNA
HBeAg clearance
HBeAg
seroconversion
HBeAg
seroreversion
Minimally raised
ALT
Hepatitis flare
Hepatic
decompensation
TREATMENT RESPONSE
Biochemical
response
Virologic response
Maintained
virologic response
Suboptimal
virologic response
Sustained
response
Complete virologic
response
Primary treatment
failure or
non-response
Virologic relapse
Clinical relapse
severe liver disease and increased rates of liverrelated deaths. Patients with CHB should also be
screened for hepatitis A virus antibodies (anti-HAV
IgG) and vaccination is strongly recommended
in hepatitis A virus (HAV) seronegative patients.1,2
Although HBV does not increase the risk of
HAV infection, patients with chronic liver disease
from HBV infection are susceptible to developing
fulminant hepatitis A. 19-23
When to do Liver Biopsy or Assess for Liver Fibrosis
3-1 For patients who do not meet the treatment
criteria (Statement 4), assessment for liver fibrosis is
recommended in patients who aged 40 years and older
OR those with a strong family history of HCC to
evaluate the need for treatment (High quality, Strong).
3-2 Liver biopsy still remains the gold standard for
assessing liver fibrosis [high quality, strong]. However,
transient elastography is an alternative for those who
have contraindications to liver biopsy and those who
desire a non-invasive method (High quality, Strong).
Assessment of liver fibrosis is important in managing
patients with CHB. It serves to determine the extent of
liver damage, rule out other causes of liver disease,
help recognize patients who may benefit from antiviral
therapy, evaluate response to treatment, establish the
best time to start surveillance and stratify the risk
of HCC and hepatic decompensation.1,2,8
Liver biopsy is the gold standard in evaluating liver
fibrosis.1 It is recommended in patients not considered
for treatment with high normal or slightly elevated
ALT levels and in patients >40 years of age.2,8 A
study showed that the risk of complications was
higher when ALT levels were elevated (>0.5x ULN to
2x ULN) due to subtle but chronic, progressive and
permanent immune-mediated liver damage.24 Another
study in Europe revealed that there was no difference
in the stage of liver fibrosis and the incidence of
cirrhosis between patients with normal and elevated
transaminases and that advanced age (40 years)
is the most important risk factor for cirrhosis.25
Although relatively safe, liver biopsy may be
associated with serious complications and is subject
to sampling error and inter-observer variability. Hence,
it is impractical to be done regularly to monitor
patients on antiviral treatment. 1,8 Alternatively, liver
stiffness measurement (LSM) by transient elastography
(TE) is a non-invasive method that may be used.
It can accurately assess the severity of liver fibrosis
and predict the development of HCC. 1,8,26-28 However,
interpretation of TE results may be difficult in the
presence of severe inflammation associated with high
ALT levels and standardization of LSM optimal cut-offs
Jamias J, et al.
Jamias J, et al.
line agents because they often lead to incomplete
viral suppression due to the development of resistance
in 20% to 75% of patients with long-term use.33-36 The
choice of treatment should be individualized and
should take into account socio-demographic factors
such as affordability, patient and health provider
preference, occupational requirements and the
possibility of pregnancy.
Monitoring During Treatment
6-1 During treatment, serum ALT and HBV DNA levels
should be monitored every three to six months (High
quality, Strong).
6-2 For HBeAg-positive patients, seroconversion should
be monitored every three to six months. For HBeAgnegative patients, HBsAg should be checked every six
to 12 months when HBV DNA level is undetectable.
Renal function should be monitored if ADV or TDF is
used (High quality, Strong).
6-3 For patients on IFN-based treatment, CBC should
be monitored every month and TSH every three months.
Monitoring for other adverse events should be done
(High quality, Strong).
*see Table V on suggested monitoring during and after treatment
Table IV: HBV subgroups at risk for HCC who require surveillance
Asian male hepatitis B carriers over age 405,6
Asian female hepatitis B carriers over age 505
Hepatitis B carrier with a family history of HCC5,7
Cirrhotic hepatitis B carriers5,6
HCV co-infection5,7
Persistent HBV DNA >2,000 IU/mL5,8
HBV genotype C8
Recent evidence suggests that long-term suppression
of viral replication is important in reducing HBV
complications. Monitoring sustained virological response
during and after treatment is essential because of limited
success in achieving durable endpoints for currently
available agents and possible antiviral resistance with
long-term therapy.37 Parameters used to assess treatment
response include decrease in serum HBV DNA level,
loss of HBeAg with or without detection of anti-HBe,
normalization of serum ALT and improvement in liver
histology.1,37 Virological suppression and loss of HBeAg
or HBsAg with or without seroconversion play a major
role in monitoring treatment success and determining
the duration of antiviral therapy (Table V).37
Early viral response may predict the possibility of
sustained response or antiviral resistance.37 Virological
response in patients on IFN-based treatments should be
evaluated at six months. Patients on NAs should be
Jamias J, et al.
after
Treatment
ON TREATMENT
AFTER TREATMENT
HBV DNA
HBeAg, anti-HBe
HBsAg
Every six to 12
months (for HBeAgnegative and once
HBV DNA is undetectable)
Every 12 months
ALT
Creatinine/Phosphate
(ADV/TDF)
Not required
CBC (IFN)
Every month
Not required
TSH (IFN)
Not required
Jamias J, et al.
of
Treatment:
Nucleos(T)Ide
Analogues
Jamias J, et al.
FDA PREGNANCY
CATEGORY
2nd Trimester
% (n/N)
Adefovir
0 (0/43)
0 (0/0)
Not recommended
Entecavir
3 (1/30)
0 (0/2)
Not recommended
Clevudine
Lamivudine
3.1 (122/3,966)
2.8 (178/6,427)
Telbivudine
0 (0/8)
0 (0/9)
Tenofovir
2.2 (27/1,219)
2.1 (15/714)
Mother-to-infant HBV transmission and the potential
risks to the fetus or infant must be discussed with
all women of childbearing age being considered for
HBV treatment.1,8 IFN-based therapy is preferred due
to its finite treatment duration. Additionally, pegIFN has distinct advantages over conventional IFN
therapy because of its once-weekly administration and
possibly better efficacy. 1,2 However, IFN-based therapy
is contraindicated in pregnancy and patients must
Jamias J, et al.
is the preferred treatment (Moderate quality, conditional).
HCV and HDV co-infections are transmitted in the
same manner as HBV. There is an increased risk of
developing fulminant hepatitis, liver cirrhosis and HCC in
HBV patients with HCV and/or HDV co-infections.1,8,82-87
Management of hepatitis co-infections is complex and
requires close monitoring. The predominant infection
needs to be determined by measuring the level of
viremia for both hepatitis B and C. In HCV-dominant
dual infections, HCV responds well to peg-IFN plus
ribavirin. However, rebound HBV infection and acute
hepatitis B flares may occur after elimination of HCV.8892
Referral to a specialist experienced in managing
hepatitis co-infections is advised.
Patients Co-Infected With HIV
12-1 For patients with HBV-HIV co-infection, comanagement with an infectious disease specialist is
strongly recommended (Low quality, Strong).
12-2 Antiretroviral therapy (ART) containing TDF and
LAM plus EFV is the therapy of choice for those
with CD4 T-cell count 500 cells/mm 3 or those with
severe chronic liver disease regardless of CD4 count
(Low quality, Strong).
12-3 If TDF cannot be safely used, alternative
regimen includes: ETV plus AZT/LAM/EFV (High quality,
Strong), ADV or LdT plus AZT/LAM/EFV (Low quality,
Conditional).
12-4 If the CD4 count is >500 cells/mm 3 and ART is
not indicated but meet the criteria for HBV therapy,
TDF plus LAM-containing regimen is preferred (Moderate
quality, Conditional).
HIV infection is associated with higher HBV-related
morbidity and mortality and HIV treatment can cause
immune reactivation and HBV flares.1,93 Referral and
co-management with an infectious disease specialist
is recommended.
CD4 count should be evaluated every six months.
Treatment for both HIV and HBV is indicated in
patients with CD4 T-cell counts 500 cells/mm 3 or
those with severe chronic liver disease regardless of
CD4 count.93 Several NAs have activity against both
HBV and HIV, but sensitivity and resistance profiles
for HBV and HIV differ. Thus, treatment entails careful
selection of antiviral combinations that avoid selection
of HIV- or HBV-resistant strains.
The 2013 World Health Organization (WHO)
recommendations and the 2014 Department of Health
(DOH) Revised Antiretroviral Therapy (ART) Guidelines
support TDF/LAM/EFV therapy as first-line treatment
10
Jamias J, et al.
peg-IFN was superior to ADV in inducing HBeAg
seroconversion after 72 weeks (or six 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.112
Patients on Immunosuppression or Chemotherapy
15-1 Screening for HBsAg and anti-HBc should be
done in all patients being evaluated for any form of
immunosuppression or chemotherapy. If HBsAg-positive,
HBV DNA determination must be done and prophylactic
therapy with nucelos(t)ide analogues started before or
together with chemotherapy to prevent HBV reactivation
[high quality, strong]. Depending on the HBV DNA level
and duration of immunosuppression or chemotherapy,
ETV or TDF (Moderate quality, Strong). LAM may also
be used (Moderate quality, Conditional).
15-2 For those with isolated anti-HBc-positivity, HBV DNA
determination should be done to test for occult HBV
infection particularly in those who will receive biologic
agents (e.g., rituximab) and steroid-containing regimens.
For those with detectable HBV DNA, prophylactic
treatment is recommended (Moderate quality, Strong).
15-3 For those on prophylactic therapy, treatment
should be continued for six to 12 months postimmunosuppression/chemotherapy (Moderate quality,
Strong).
15-4 For those who meet treatment criteria (Statement 4)
prior to immunosuppression or chemotherapy, treatment
should be continued until appropriate endpoints are
met (Statement 9) (High quality, Strong).
15-5 Monitoring of HBV DNA and ALT should be done
every three to six months while on treatment and
upon discontinuation of treatment (High quality, Strong).
Monitoring HBV status is warranted in
immunocompromised states since HBV reactivation occurs
in 20% to 50% of HBV carriers on immunosuppression
therapy. HBV-related liver mortality rates range from 5%
to 30%.2,113 Enhanced HBV replication and reactivation
can occur with chronic steroid treatment, cancer
chemotherapy, hematopoietic stem cell transplantation
or organ transplantation.114,115 It can also occur with
rituximab therapy and possibly other emerging biological
response modifiers (BRMs) (e.g., alemtuzumab) which
cause B- or T-cell depletion.116-123
Screening for HBsAg and anti-HBc is indicated
when chemo- or immunosuppressive therapy is being
considered. High viral load is a significant risk factor
and baseline HBV DNA testing should be performed
11
Jamias J, et al.
in patients who test positive for HBsAg or anti-HBc. 8
While HBV DNA levels guide treatment, chemotherapy
should not be delayed while awaiting HBV DNA results.
HBV antiviral treatment alongside immunosuppressive
therapy is advised for patients who meet HBV treatment
criteria (see Statement 4) and should be continued
until adequate endpoint parameters are achieved (see
Statement 9). IFN-based therapy is not recommended
because it may cause further bone marrow suppression
or hepatic flares.2
Prophylactic antiviral therapy should be administered
to HBsAg-positive carriers.1,2,8 It is also recommended
for occult HBV infections (i.e., HBsAg-negative patients
who are anti-HBc-positive and have detectable HBV
DNA), particularly in patients on BRMs or steroidcontaining regimens.8,124 Less commonly, HBV reactivation
or seroreversion may develop during or shortly after
completion of chemotherapy in patients with isolated
anti-HBc but with otherwise undetectable HBV DNA
at baseline. 2,8,125 Hence, HBV DNA and ALT should
be closely monitored every three to six months and
antiviral treatment initiated when there is documented
elevation in ALT and HBV DNA.
Prophylactic treatment should be given before or
with immunosuppressive treatment and maintained for
six to 12 months after completion.1,2 HBV DNA level
and the anticipated duration of immunosuppression
therapy determine the choice of prophylactic agent.
LAM, being the most extensively studied prophylactic
agent in this setting, can be used in most cases
and has been shown to reduce the risk of HBV
reactivation and HBV-related mortality.8,113,114,126 However,
because of the higher incidence of LAM resistance,
NAs with a high barrier of resistance (i.e., ETV or TDF)
are considered in patients with high HBV DNA levels
(>2000 IU/mL) or those requiring prolonged or lifelong
immunosuppression (i.e., organ transplantation ).1,8
Patients with Acute Hepatitis B
16-1 For patients with HCC and detectable HBV DNA,
treatment with a nucleos(t)ide analogue (preferably
with ETV or TDF) should be initiated before any
therapy for HCC is considered (High quality, Strong).
16-2 For patients with HCC and decompensated
liver disease, treatment with a nucleos(t)ide analogue
(preferably with ETV or TDF) should be initiated
(High quality, Strong).
HBV reactivation can occur following HCC liver
resection, especially with baseline HBV DNA >104
IU/mL.127 It has been shown to significantly reduce
postoperative recovery of liver function, increase
liver failure rates, and worsen three-year diseasefree and overall survival rates. 128,129 A prospective
12
with
Hepatocellular
Carcinoma
Acknowledgements
The Hepatology Society of the Philippines wishes
to thank the following for their invaluable contribution
to the development of the 2014 Philippine Consensus
Statements on the Management of Chronic Hepatitis
B: The Consensus Group Dr. Jose D. Sollano
Jr.(HSP Past President/UST), Dr. Erlinda V. Valdellon
(HSP Past President/UERMM), Dr. Marilyn O. Arguillas
(HSP Past President/Davao Doctors), Dr. Evelyn B. Dy
(HSP, Manila Doctors) , Dr. Ernesto R. Que (HSP,NKTI),
Jaime G. Ignacio (HSP), Dr. Felix M. Zano (PGH),
Dr. Jane R. Campos (HSP), Dr. Ian Homer Y. Cua
(HSP), Dr. Rontgene M. Solante (PSMID), Dr. Limuel
Anthony Abrogena (PAFP), Dr. Marie Yvette C. Barez
(PCP), Dr. Vanessa H. de Villa (Liver Center, Medical
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