CURRENT

MANAGEMENT OF
CHRONIC HEPATITIS B
PROF. DR. GONTAR A SIREGAR, SP.PD-KGEH
VIROLOGY

• HBV  hepadnavirus family  hepatotropic virus  liver injury

• HBV is also a recognized oncogenic virus that confers a higher
risk of developing HCC
• An estimated 2 billion people have been infected, and more
than 350 million are chronic carriers of the virus.

WHO. Guideline for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. 2015
THE PHASES OF CHRONIC HBV INFECTION
Patient Populations in Chronic Hepatitis B

Immune Immune
Immune clearance Control Precore Mutant
Marker
Tolerant (HBeAg+ (inactive (HBeAg– CHB)
CHB) HBsAg Carrier)
HBsAg + + + +
HBeAg + + – –
Anti-HBe – – + +
ALT Normal  Normal 

HBV DNA
> 105 > 105 < 103 > 103
(copies/mL)

Histology Normal/Mild Active Normal Active

Who should be considered for treatment?
Immune Immune Immune Immune
tolerance clearance control escape

HBeAg+ve HBeAg–ve
< >< >
HBV-DNA

ALT

treat treat
HBeAg +ve Inactive (carrier) HBeAg –ve/+ve active
chronic hepatitis state chronic hepatitis
 GOALS OF THERAPY IN PATIENTS WITH
CHRONIC HBV INFECTION
APASL 2012:
Clinically, the short-term goal APASL 2015:
of treatment is to achieve ‘initial
response’ in terms of
HBeAg seroconversion and/or HBV- Ideal End-Point:
DNA suppression,
HBsAg loss, with or
ALT normalization, and prevention of
hepatic decompensation, without serocon-
and to ensure ‘maintained/sustained version to anti-HBs
response’ to
reduce hepatic necroinflammation and Satisfactory End-
fibrosis during/after point:
therapy. •HBeAg-positive:
sustained anti-HBe
Desirable end- seroconversion
point: •HBV DNA< 2,000
undetectable HBV IU/ml and normal ALT
DNA by a sensitive for HBeAg-negative
PCR assay

Sarin SK, et al. Asian –Pacific clinical practice guidelines on the managmenr of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1-98
TREATMENT CRITERIA FOR CHRONIC
HEPATITIS B
Liver Society HBeAg Positive HBeAg negative
Guidelines HBV DNA ALT HBV DNA ALT
(IU/mL) (IU/mL)

EASL 2012 >2,000 > ULN > 2,000 > ULN

APASL 2015 >2,000 > ULN >2,000 > ULN

AASLD 2015 >2,000 > ULN >2,000 > ULN

Sarin SK, et al. Asian –Pacific clinical practice guidelines on the managmenr of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1-98
Sarin SK, et al. Asian –Pacific clinical practice guidelines on the managmenr of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1-98
 Alogrithm for the management of CHB

Sarin SK, et al. Asian –Pacific clinical practice guidelines on the managmenr of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1-98
DRUGS FOR CHB

• Interferon
• Conventional-IFN
• PEG-IFN
• Nucleos(t)ide analogues
• Lamivudine
• Adefovir
• Entecavir
• Telbivudine
• Tenofovir
PEG-IFN VS. NAS
(PEG-)IFN NAs

Advantages • Finite duration • Potent antiviral effect

• Absence of resistance • Good tolerance
• Higher rates of anti-HBe • Oral administration
and anti-HBs
seroconversion with 12
mo of therapy
Disadvantages • Moderate antiviral effect • Indefinite duration
• Inferior tolerability • Risk of resistance
• Risk of adverse events • Unknown long-term
• Subcutaneous injections safety
FACTORS ASSOCIATED WITH CHOOSING
NUCLEOS(T)IDES AS INITIAL THERAPY
• Favorable predictors of response
• High ALT
• Low HBV DNA (baseline and on treatment)
• Specific patient demographics
• Older people
• Patient preference
• Concomitant HIV infection
• No HCV coinfection
FACTORS ASSOCIATED WITH CHOOSING
INTERFERON FOR INITIAL THERAPY
• Favorable predictors of response
• Genotype A or B > C or D
• Low HBV DNA (baseline and on treatment)

• Specific patient demographics

• Younger people
• Young woman wanting future pregnancy

• Patient preference
• No coinfection with HIV
• Concomitant HCV infection
PREDICTIVE TOOL HBEAG-POSITIVE FOR
PEG-IFN

Chan H, et al, AASLD 2014

PREDICTIVE TOOL HBEAG-
POSITIVE FOR PEG-IFN
PREDICTIVE TOOL HBEAG-NEGATIVE FOR
PEGIFN

Lampertico P et al, AASLD 2014

PREDICTIVE TOOL HBEAG-
NEGATIVE FOR PEG-IFN
 e+
PEG-IFN ALFA-2A MEMBERIKAN KONTROL IMUN MENETAP YANG TERUS
MENINGKAT POST-TREATMENT

Peningkatan serokonversi HBeAg 1 tahun post-treatment

pada 271 pasien dengan HBeAg-positif yang diterapi dengan PEG-IFN alfa-2a
50
42%
serokonversi HBeAg (%)

40
32%
Pasien dengan

30 27%

20

10

72/271 87/271 73/172*

0
EOT Post-treatment Post-treatment
*Year 1 results from a long-term observational 6 bulan 1 tahun
follow-up study (N=73/172) Lau et al. New Engl J Med 2005; Lau et al. EASL 2006
 PEG-IFN ALFA-2B ± LAMIVUDINE SELAMA 52 MINGGU e
HASIL HBSAG CLEARANCE YANG TINGGI 3 TAHUN POST-TREATMENT PADA
PASIEN YANG DITERAPI DENGAN PEG-IFN

Pasien HBeAg-positif diterapi dengan PEG-IFN alfa-2b ± lamivudine selama 52 minggu

50
Pasien yang mencapai HBeAg
30%
Serokonversi HBeAg (%)

40 clearance 6 bulan post-

treatment HBsAg hilang 3
Pasien dengan

31%
29%
30 tahun post-treatment
24%
(N=19/64)
20

10

63/266 77/266 53/172*

0
EOT Post-treatment
(6 bulan) (3 tahun)
* PEG-IFN alfa-2b: N=172 Janssen et al. Lancet 2005; Buster et al. Gastroenterology 2008
PEG-IFN (32 MINGGU) + LAMIVUDINE (52 OR 104 MINGGU) e
SEROKONVERSI HBEAG MENCAPAI 60%
5 TAHUN POST-TREATMENT DENGAN PEG-IFN

85 pasien dengan HBeAg-positif diterapi dengan PEG-IFN (32 minggu)

+ lamivudine (52 or 104 minggu)
100
Serokonversi HBeAg (%)

80

60%
60
Pasien dengan

40 37%

20

0
EOT Post-treatment
(5 tahun)
Wong VW et al. Hepatology 2010
MONITORING OF PATIENTS RECEIVING
NUCLEOS(T)IDE ANALOGUE THERAPY

Time Point Monitoring

 Liver panel
Every 12 wks  Serum creatinine (if receiving TDF
or ADV)
Every 12-24 wks  HBV DNA levels
 HBeAg/anti-HBe (if initially HBeAg
Every 24 wks
positive)
 HBsAg in HBeAg-negative patients
Every 6-12 mos with persistently undetectable HBV
DNA
Lok AS, et al. Hepatology. 2009;50:661-662.
MONITORING OF PATIENTS RECEIVING
(PEG)IFN THERAPY
Time Point Monitoring
During treatment
 Blood counts
Every 4 wks
 Liver panel
 TSH
Every 12 wks
 HBV DNA levels
Every 24 wks  HBeAg/anti-HBe (if initially HBeAg positive)
Posttreatment
 Blood counts
 Liver panel
Every 12 wks during first
 TSH
24 wks
 HBV DNA
 HBeAg/anti-HBe (if initially HBeAg positive)

Lok AS, et al. Hepatology. 2009;50:661-662.

STOP THERAPY IFN

• For conventional IFN, the current recommended duration of

therapy is 4–6 months for HBeAg-positive patients and at least a
year for HBeAg-negative patients
• For Peg-IFN, the recommended duration is 12 months for both
HBeAg-positive and HBeAg-negative patients

APASL , 2012
STOP THERAPY NA
• In HBeAg-positive patients,
• The optimal duration of NA therapy is unknown
• The therapy can be stopped after at least 1 year, but preferably after 3 years of additional
therapy after HBeAg seroconversion with undetectable HBV DNA by PCR and persistently
normal ALT levels.

• In HBeAg-negative patients
• The optimal duration of NA therapy is unknown
• The treatment can be withdrawn
1. After HBsAg loss following either anti-HBs seroconversion or at least 12 months of a post-
HBsAg clearance consolidation period, or
2. After treatment for at least 2 years with undetectable HBV DNA documented on three
separate occasions, 6 months apart.
Sarin SK, et al. Asian –Pacific clinical practice guidelines on the managmenr of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1-98
STRATEGIES TO MANAGE TREATMENT FAILURE
(APASL 2015)
LAM/LdT resistance • Switch to TDF
• Add ADV

LAM then ETV resistance • Switch to TDF

• Add ADV

ADV resistance (no previous LAM) • Switch to ETV

• Switch to TDF

ADV resistance (previous LAM/LdT) • Switch to TDF

• Switch to LAM/TDF

ETV resistance (no previous LAM/LdT) • Switch to TDF

• Add ADV

Multidrug resistance • Swicth to ETV/TDF

• Swicth to Peg-IFN

Sarin SK, et al. Asian –Pacific clinical practice guidelines on the managmenr of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1-98
For HBV DNA suppression rates, ALT normalization rate,
HBeAg seroconversion rate
 there was no difference between Tenofovir and
Entecavir
Nucleotide analogue + Peg-IFN (Combination theray) had
a better efficacy in terms of HBeAg loss, HBD DNA
undetectable rate, HBeAg seroconversion, and HBsAg
loss compared to Nucleotide analogue monotherapy
group at the end of treatment
Patients receiving sequential combination therapy have a
higher rate of HBeAg seroconversion and are more likely
to experience HBsAg clearance than to those continuing
entecavir monotherapy