Current EPI and a Focus on Therapy of Hepatitis B

Planning for 2015 and beyond

SOTA 2015
Robert Gish
robertgish.com
rgish@robertgish.com
San Diego, CA USA
Medical Director Hepatitis B Foundation
Professor Consultant, Stanford University
Senior Medical Director St Josephs Medical
Center, Phoenix Arizona

Disclosures
Relevant Disclosures to HBV
Consulting : Gilead, Genentech,
Arrowhead, ISIS, Contravir, Enyo,
MedImmune
Stock or stock options: Arrowhead

HBV: Phase I Tests

HBsAg = infection
Anti-HBs = immunity
if anti-HBc is negative

Anti-HBc = exposure

2014
What has the USPHSTF
changed and recommended?
Foreign Born: from endemic regions
Children of parents who are from regions
where HBV has over 2% prevalence
MSM
IVDU
High risk behavior

Yet Are Rarely Screening

How often do you screen Asian/Asian
American patients for chronic HBV?
78% rarely or sometimes screen;
only 10% always screen

100

50

48%
29%
11%

Rarely

Sometimes

Often

11%
4

Always
Source: Pri-Med CME Outcome Data2012

Lack of Knowledge Re:

Isolated Hepatitis B Core Antibody

2/3 of PCPs do not

know how to interpret
HBV lab findings

Source: Pri-Med CME Outcome Data2012

Hepatitis B: The Facts

Hepatitis B is the worlds most

common serious liver infection1
and is a widespread global health
issue
HBV is not curable but controllable
and suppressible
HBsAg clearance is a functional
cure
HBV is 100 times more infectious than
HIV (human immunodeficiency virus)2
10 times more infectious than hepatitis
C3

The virus is transmitted via the

blood and bodily fluids1
Hepatitis B progresses slowly over time
Complications generally involve vague
symptoms or none at all, and are often

1. Hepatitis Australia. Available at http://www.hepatitisaustralia.com/about_hepatitis/hep_b.html. Accessed April 2009;

2. World Health Organization. Hepatitis B Fact Sheet. Available at http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed
April 2009;
3. Ulmer T, et al.(2007) European orientation towards the Better Management of Hepatitis B in Europe .

Hepatitis has 3x the death rate of HIV in the AP

region: yet no significant funding !

Prevalence of HBV:
Global Estimates: note China < 8%; Vaccines work!

HBsAg Prevalence
High (>8%)
Intermediate (2%-7%)
Low (<2%)

Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

Worldwide prevalence of chronic hepatitis B virus

infection among adults aged 19-49 years

Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new
10
estimates of age-specific seroprevalence and endemicity. Vaccine. 2012.30(12):22129.

Global EPI and Impact of HBV

Global impact of CHB

Anti-HBc(+) and at risk for reactivation

New numbers
240M Globally

Mortality from Viral Hepatitis

WPR

Hepatitis B: By The Numbers

More than 350 million or 1 in 20 people worldwide have chronic hepatitis B infection 1
(Compared with the 33 million living with HIV2)

1.46-2.2 million
people in the
United States are
chronically
infected5,6

14 million
in Europe1,4

112 million in AsiaPacific

(93 million people in
China)1,3

200+ million
rest of world1

1.
2.
3.
4.

WHO. Available at: www.who.int/csr/disease/hepatitis/en/;

Ferlay, et al. Globocan 2002, Cancer incidence, mortality and prevalence worldwide, IARC Press, Lyon 2004;
Records of the thematic press conference of the Ministry of Health of the PRC at April 21, 2008, from the website of the Ministry of Health of the People's Republic of China;
Ulmer T, et al. (2007). European orientation towards the better management of hepatitis B in Europe;

5. CDC. Hepatitis B FAQs for Health Professionals. Available at http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm#overview .

6. Gish, Hepatology 2015

New figures from Global Burden of Disease

Survey 2010: Deaths/number of people infected
1,012,873
827,567

Total Asia Pacific

Mortality Figures
304,628
106,729

Viral Hepatitis

Tuberculosis

HIV/AIDS

Malaria

Attribution: Seng Gee Lim AASLD 2013

Outcome of Hepatitis B Virus Infection

by Age at Infection
80

80
60

60

Chronic Infection

40

40

20

20

Older Children
and Adults

1-4 yrs

7-12 mos

1-6 mos

Symptomatic Infection
Birth

Chronic Infection (%)

100

Symptomatic Infection (%)

100

The Increasing Burden of Imported CHB

95% of chronic hepatitis B in the US is imported

1.6 million immigrants in the U.S. are believed to harbor CHB.

The Philippines, China, and Vietnam contributed the most
imported cases

Mitchell T, et al. Plos One 2011; 6:e27717; Kowdley KV, et al. Hepatology. 2012:n/a-n/a.
Hepatitis B on Rise in U.S. Immigrants. http://www.medpagetoday.com/Gastroenterology/Hepatitis/33017. June 1, 2012
Rossi C, Shrier I, Marshall L, et al. Seroprevalence of chronic hepatitis B virus infection and prior immunity in immigrants
and refugees: a systematic review and meta-analysis. PLoS One. 2012;7(9):e44611. Gish Hepatology 2015

HCC:
#
2
cause
of
Cancer
Death
Liver cancer is now the 2nd most common
Worldwide:
HBV isdeath
the #1
cause of HCC
cause of cancer
worldwide

Hepatitis B Disease Progression

> 25% Lifetime Risk

Liver
Cancer
(HCC)

Acute
Infection

Chronic

30-40% of
chronic HBVinfected
individuals2

Cirrhosis

Infection

>90% of infected
children progress
to chronic disease
<5% of infected
adults progress to
chronic disease1

An
ti(+ HB
)
c

Liver
Failure
(Decompensation)

> 15% Lifetime Risk

Torresi J. Gastro. 2000;118:S83-1031;

Moyer LA Am J Prev Med. 1994;10:45-552;
Fattovich G. Hepatology. 1995;1:77-823;
Perrillo RP. Hepatology. 2001;33:424-432.4

Risk for
reactivation

Liver
Transplantation

Death

35-40% Liver related

death

High
Replicative
,
Low
Inflammato
ry
Immune
Trained
High HBV DNA
Normal or low
ALT
HBeAg(+)
High serum levels
of
HBeAg & HBsAg
Mild or no
necroinflammation
No or slow fibrosis
Serum
progression
Decreased
IL-10,
HBV
IL-6,DNA
IL-8 & TNF-
No HBV DNA
mutations

Note: new names and terms

Immune
Clearance
High changing to low
or undetectable HBV
DNA
High decreasing to
normal ALT
Acute or intermittent
hepatitis
Declining HBeAg &
HBsAg
Eventual loss of
HBeAg
High changing to
minimal
necroinflammation
Emergence of core
and
precore mutations

HBsAg
Loss/Occult
Hepatitis B

HBeAg(-)
Chronic
Moderate to high
HBV DNA
High but
fluctuating
ALT
Low HBsAg
levels
Persistent
hepatitis

Necroinflammation
Progressive liver
disease
Immune
clearance
attempts
ineffective

NonReplicat
ive
Low or
undetectable
HBV DNA
HBeAg(-)
Very low
HBsAg
levels
Normal ALT

Serum HBV DNA

phases, alternating
undetectable and
very
low but detectable
Detectable HBV
DNA
in the liver
Intrahepatic
replicationcompetent
HBV genomes such
as
HBV cccDNA
Integrated HBV
DNA

ALT
Normal ALT / Undetectable HBV DNA

Gish AVR 2015

5 Phases in HBV Disease

6 Milestones in Disease Management
Milest Milest Milesto
Milest
Milest
one 1: one 2: ne 3:
one 4:
one 5:
Start
HBV
Cleara
Cleara
HBV DNA HBV DNA level of
DNA
nce This
of is where
HBeAg
nce ofwe
9
>10
declin / anti- decrea
HBsAg
cccDN
would like
our
copies/mL
e of
sed to
HBe
A be
patients to
HBeAg/
HBeAg(+), anti-HBe(-)
HBeAg(-), anti-HBe(+)
HBV
sero- undete
anti-HBe
Low HBV DNA (<2000 IU/mL)
DNA
conve ctable
status
Undetectable
rsion
level of HBV
DNA
HBsAg status

ALT level

Immune low
active

for reduced progression risk

HBsAg+

Immune high
active/clearance

HBsAg-

Inactive
carrier
state

Functional cure

Immune control

Milest
one 6:
Cleara
nce of
cells
with
integr
ated
HBV
DNA
seque
nces

Absolute
cure

HBV Viral Structure

Acute HBV
infection

Perinatal
transmissi
on

Childhood
transmissi
on

High
replicative
low
inflammatory

Immune
clearance /
HBeAg(-)
chronic

Adult
infection

Nonreplicative

Hepatitis
flare

Reactivation

HBsAg loss /
Occult HBV
Gish AVR 2015

Progressive Reduction in HBV DNA

with each phase of Chronicity

Flares
Reactivation

DNA quantification in the serum

HBsAg
seroclearance

Hepatitis B: By The Numbers

If HBV is not treated, in 20-33% of patients, hepatitis B
can cause liver damage leading to cirrhosis, death, liver
transplant and/or liver cancer1
Hepatitis B is responsible for 80% of primary liver cancer
globally, which is almost always fatal2
Historically: Liver cancer was the 3rd highest cause of death by cancer in
men3
Now 2014: Liver cancer is the 2rd highest cause of caner death worldwide 3
Without appropriate treatment or monitoring, 1 in 4 persons with chronic
hepatitis B will die of liver cancer or liver disease
1. WHO. Available at: www.who.int/csr/disease/hepatitis/en/;
2. Hepatitis B Foundation. Hepatitis B and Primary Liver Cancer.
Available at http://www.hepb.org/professionals/hepb_and_liver_cancer.htm. Accessed 4 February 2010;
3. WHO. Cancer Fact Sheet. Available at http://www.who.int/mediacentre/factsheets/fs297/en/index.html.

Natural History and Phases of

Chronic HBV Infection
Childhood
Childhood

Adulthood
Adulthood

>95%
High
High Replicative
Replicative Low
Low Inflammatory
Inflammatory

<5%

HBeAg+
HBeAg+ CHB
CHB

HBeAgHBeAg- CHB
CHB
<15% of HCC associated
with HBV occurs in the
absence of cirrhosis or
advanced fibrosis
AFP, DCP and AFPL3%
will help predict

risk

Inactive
Inactive
carrier
carrier

HCC
HCC
And or
or
And
cirrhosis
cirrhosis

Pungpapong S, et al. Mayo Clin Proc. 2007;82:967-5; Chen DS. J Gastroenterol Hepatol. 1993;8:470-5;
Seeff LB, et al. N Engl J Med. 1987;316:965-70; Lok ASF, McMahon BJ. Hepatology. 2009;50:1-36.

Cumulative rate of Liver Cirrhosis

HBV DNA vs. Liver Cirrhosis :

REVEAL data
Baseline
HBV DNA

No of patients =3,482*

40%

RR

106
10.6
copies/mL
30%

105<106

9.7

104<105
300<104
<300

3.6
2.0
1.0

20%

10%

0%
0

* HBeAg negative n=2960

Iloeje UH, et al. Gastroenterology 2006;130:678-86.

10

11

12

13

Years

HBV DNA vs. HCC : REVEAL Data

.16

Baseline
HBV DNA

No of patients =3,653*

106
copies/mL

Cumulative rate of HCC

.14

RR
6.6

105<106

6.1

.04

104<105

2.3

.02

300<104
<300

1.1
1.0

.12
.1
.08
.06

0
0

*HBeAg negative n=3088

Chen CJ, et al. JAMA 2006;295:65-73.

10

11

12

13

Years

HBV Diagnostic Markers

Serologic Marker Results
HBsAg

Total
AntiHBc

IgM
AntiAnti-HBc HBs

Never infected and no evidence of

immunization

+
+
-

+
+
+

+
-

Acute infection

Immune (immunization)

Interpretation

Chronic infection
Recovered from past infection and not
immune, low level carrier

HBeAg- High infectivity

HBeAb- Low infectivity
Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

Testing Paradigm

Always test: anti-HBc

If anti-HBc +
> does not
need vaccination
>>> risk for reactivation

An Unmet Medical Need

Worldwide, hepatitis B is significantly
Under-diagnosed
Under-treated1
112.6 million
chronic
infections2

5% are
diagnosed3

14 million
chronic
infections1

12% are
diagnosed1

Less than
1%
are treated3

12% are
treated1

1.46 - 2
million
chronic
19%
are
4
infections
diagnosed4
4% are
treated4

Asia-pacific

Europe

1. BMS Market Research. Information available upon request from Bristol-Myers Squibb;
2. Mohamed R, et al. J Gastroenterol Hepatol 2004;19:958-69;
3. Decision Resources. Hepatitis B virus in China Emerging markets study #5; 4. BMS Market Research.

USA

Patients Are Not Asking About HBV

65.4% of the chronically infected
adults were unaware that they
were infected
Only 32% had been referred to
GI/Hep
Only 21% received HBV treatment

One of the most significant factors contributing to poor access to HBV

screening in at risk populations is a lack of appreciation of the
significance of CHB by that at-risk population

Leung W, Heathcote EJ. US Gastroenterol Hepatol Rev 2008;4:24-7.

Lin SY, Chang ET, So SK. Hepatology. 2007;46(4):1034-1040.

Cohen C, et al. J Viral Hepat. 2011;18(6):377-383.

HBV Infection, Diagnosis,

and Care in the United States
(Low to High Estimate)

Number (millions)

1.4-2.2
Million

2.5% to 5%
of the
Total HBV-Infected
Population

400,000600,000

350,000500,000

200,000300,000
50,000

Chronic
HBV Infection

Persons
Aware of
Their Infection

Potentially
Eligible for
Treatment

Entering
Care

Annual HBV
Prescriptions

Modified and updated from : Cohen C, et al. J Viral Hepat. 2010

Historical/ Current

Candidates for Screening for HBV

New Additional
Recommendations (2008-Current)

Persons born in high

endemic areas (>2%
prevalence)
US born persons not
vaccinated as infants whose
parents were born in high
endemic areas (>8%
prevalence)
Men who have sex with men
Persons needing cytotoxic or
immunosuppressive therapy
Persons who have ever
injected drugs
Individuals with chronically
elevated ALT/AST of
unknown etiology

Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

2006
Recommendations
US born children of immigrants

from high-risk areas

Household and sexual contacts of

HBsAg-positive persons

Persons with multiple sexual

partner, or history of STDs

Inmates of correctional facilities

Individuals infected with HIV or

HCV

Patients undergoing dialysis

All pregnant women

Geographic Regions with HBsAg

Prevalence >2%

Africa, Asia, South Pacific (except Australia and New Zealand)

Middle East (except Cyprus and Israel)
Eastern Europe (except Hungary)
Western Europe (Malta, Spain, indigenous populations in
Greenland)
North America (Alaska natives, indigenous populations in
Northern Canada)
Mexico and Central America (Guatemala and Honduras)
South America (Ecuador, Guyana, Suriname, Venezuela, and
Amazon areas of Bolivia, Brazil, Columbia, and Peru)
Caribbean (Antigua-Barbuda, Dominica, Grenada, Jamaica, St.
Kitts-Nevis, St. Lucia, and Turks and Caicos islands)

Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

HBV
Is not curable

New term: (oxymoron)

functional cure
When HBsAg becomes negative

Why treat early ?

Natural History of Chronic HBV Infection
Clinical

Virological

Acute
hepatitis

Chronic
hepatitits

Liver
Cancer

Cirrhosis

HBeAg: HBV DNA

Anti-HBe
HBsAg

Replication

Liver

Integration

Time

Months

Years

in
t
en
v
e
Pr
Yim HJ and Lok AS. Hepatology 2006;43:S173-81.

ion
t
ra
g
te

Decades47

Aiming for True Inactive Carrier

Status and CURE
Milestone
1: Start of
decline of
HBV DNA

Milestone
2: HBeAg/
anti-HBe
seroconversio
n

HBV DNA HBV DNA level

>109
copies/mL
HBeAg/
HBeAg(+), anti-HBe(-)
anti-HBe
status
Undetectable
level of HBV
DNA
HBsAg+
HBsAg status

ALT level

Immune
tolerance

Milestone
3: HBV
DNA
decreased
to
undetecta
ble

HBeAg(-), anti-HBe(+)

Immune clearance

Immune
control

Milestone Milestone
5:
6:
Clearance Clearanc
of cccDNA e of cells
with
integrate
This is where we
d HBV
would like our DNA
patients to besequence
s

Milestone
4:
Clearance
of HBsAg

Low HBV DNA (<2000 IU/mL)

for reduced progression risk
HBsAg-

Inactive
carrier
state

Functional
cure>>>CUR
E

Next Steps in HBV

Management
Use the right NUC to control HBV for the right
patient
Personalized medicine

Help Stop oral (NUC) therapy, current Rx is

indefinite
Choose the correct Nuc for your patient
Pregnancy, Drug resistance, Management, Lactic Acidosis

Safe use of each medicine

Aggressive change dose of HBV Nucs for change in renal
function

Use combination therapy when appropriate

Permanent clearance of HBV
HBsAg clearance: 10% rate now reported with TDF at 5

Endpoints of Antiviral Therapy

Using Continuous Therapy
Clinical endpoints similar to those for
HBeAg-positive
and HBeAg-negative CHB patients
No liver failure
Now
DNA negative in blood, HBsAg clearance in up to
10%,
Decreased rate of HCC
Falling rates of liver transplant
Lower death rates due to HBV

Future
Clear HBsAg in all patients

US FDA dates of Approved

Therapies for CHB
Nucleosides/Nucleotides
Tenofovir

VIREAD

Gilead Sciences

2008

Telbivudine

TYZEKA

Idenix / Novartis

2006

Entecavir

BARACLUDE

Bristol-Myers Squibb

2005

Adefovir dipivoxil

HEPSERA

Gilead Sciences

2002

Lamivudine

EPIVIR-HBV

GlaxoSmithKline

1998

Interferons
Peginterferon alfa-2a

PEGASYS

Roche
Laboratories

2005

Interferon alfa-2b,
recombinant

INTRON A

Schering / Merck

1992

Preferred therapies AASLD

Guidelines

ETV 3-year Clinical Trial HBV DNA

Suppression HBeAg-negative Patients
HBeAg(-) ETV Long-term Cohort (ETV027ETV-901)
95%
93% 94%

ETV-027
94%

80
60
40
20

>60 days
days
Of-treatment
Of-treatment >60

Proportion of patients
with
HBV DNA <300
copies/mL (%)

100

91%

83%
59%

4%

End of Dosing

Baseline

Wk 12

Wk 24

Wk 48

Wk 72

Wk
n 96
67/74

Wk 144
93/99
54/57

4/99

56/95

79/95

84/90

72/77

In the randomised controlled study (ETV-027), patients received 0.5mg ETV. In the 901 rollover study,
patients received 1mg ETV

10 patients
remained
on treatment
at Week 144 of ETV-901 visit had missing PCR samples
Shouval
D, et al.who
AASLD
2008; poster
927.

52

ETV vs LAM: why is LAM

gone?

AGA technical report 2014

53

Korean Cohort: Impact of Entecavir and

Lamivudine on Survival in HBV (19992011)
Entecavir 0.5 mg/day or
lamivudine 100 mg/day
>20 years of age; no prior HCC,
transplant, HCV, HDV, or HIV;
HBV DNA >2000 IU/mL

Death or Transplantation

Single-center cohort of chronic

HBV (n=9615 treatment-nave)

Treatment with entecavir was

associated with
Minimal risk of drug resistance
1.5% verus 50.8%; P<0.001)
Minimal need for rescue therapy
(1.8% verus 39.3%; P<0.001)
Significantly lower risk of death
or transplantation (adjusted
hazard ratio 0.42; P<0.001)

(Propensity-Score-Matched)
Solid lines: cirrhotics
Dotted lines: no cirrhosis
Lamivudine

Cumulative Rates (%)

HR: 0.66
P=0.005
Entecavir

HR: 1.10
P=0.81
Lamivudine
Entecavir

4
Years

Lim Y, et al. Hepatology. 2013;58(suppl 1):223A. Abstract 32.

HCC Risk in Caucasian, Chronic HBV Patients

Treated With Entecavir or Tenofovir DF

4.2% at median of 17 months

13.5 new HCC cases/1000 personyears

Strongest HCC risk factors

Chronic HBV with no co-infection, liver

transplantation, or HCC
Initiated either entecavir (43%) or
tenofovir DF (55%)

HCC 5-year incidence

Probability of HCC

Multi-country cohort (Greece, Itlay,

Turkey, Spain, The Netherlands)
(n=1231)

Decompensated liver disease (HR:

2.78; P=0.019), lower platelet count
(HR: 0.97; P=0.002), older age (HR:
1.05; P=0.12)

Asian-based HCC risk scores may not

be applicable to Caucasians with
chronic HBV

Log-Rank P<0.001.

Cumulative Probability HCC

Decompensated
Cirrhosis

29.7%

20.9%

Cirrhosis
2.5%

No Cirrhosis

Time Since Initiation of Treatment

(Years)

Papatheodoridis GV, et al. Hepatology. 2013;58(suppl 1):302A-303A. Abstract 190.

HCC Incidence in Patients Treated

with Long-term ETV
Cirrhosis

50

40Log-rank test: P=0.440

38.9%

28.5%

30

30

20.9%

20

20

11.4%

10

2.6%

4.3%

7.0%

7.0%

ETV

0
0

# at Risk
ETV
79
Control 85

1
3
5
Treatment Duration (Years)
79
85

72
76

No Cirrhosis

50

Control

40Log-rank test: P < 0.001

Cumulative Development
Rates of HCC (%)

Cumulative Development
Rates of HCC (%)

After propensity score matching, significant difference of treatment effect between groups
was seen in patients with cirrhosis (P<0.001), but not in patients without cirrhosis (P=0.440)

53
65

35
54

17
47

10
1.0% 1.6%

0%

# at Risk
ETV 237
Control 231

2.2%
0.8%

0%

3.6%Control
2.5%

1
3
5
Treatment Duration (Years)
237
231

192
201

132
181

66
169

27
143

In comparison to a historical untreated control group, long-term

ETV treatment reduces the incidence of HCC, especially in cirrhotic
CHB patients

Hosaka T, et al. Hepatology, 2013;58:98-107.

Studies 102/103:
Virologic Suppression With TDF at Year 6
Response
HBV DNA < 400
copies/mL
Intent-to-treat*, %
(n/N)

HBeAg- Patients
(Study 102)

HBeAg+ Patients
(Study 103)

Year 5

Year 6

Year 5

Year 6

83
(291/350)

81
(281/345)

65
(160/248)

63
(157/251
)

HBV DNA < 400

99
LTE-TDF (missing = failure/addition of FTC99
= failure)
copies/mL
99.6
97
(167/169
Observed (missing =excluded/addition of FTC = included)
On
treatment , %
(292/295) (283/284) (170/175)
)
(n/N)
80% of 585 patients entering the open-label phase remained on study at Year
*

6; 73% of enrolled patients remained on study

HBeAg loss/seroconversion rates of 50% and 37%, respectively, through 6
years
11% of HBeAg+ patients had confirmed HBsAg loss (8% with seroconversion)
No resistance to TDF was detected through 6 years

Marcellin P, et al. AASLD 2012; abstract 374.

TDF : ITT
Study 102 and 103: Virologic and Biochemical
Suppression at Year 7
HBeAg- (Study 102)
HBeAg+ (Study 103)
77%

Patients (%)

65%

60%
47%

12%
1%

HBsAg Loss
(n=348;247)

ALT Normalization
(n=325;241)

ITT: missing=failure.
Marcellin P, et al. Hepatology. 2013;58(suppl 1):649A. Abstract 926.

HBV DNA
<400 copies/mL
(n=348;247)

Adherence Issues
Virological breakthrough is the first manifestation of
antiviral drug resistance during nucleos(t)ide analogue
treatment of CHB, but not all VBTs are due to drug
resistance.
Adherence should always be considered.
Percent with virological breakthrough

Self-reported adherence
Hongthanakorn C, et al. Hepatology 2011. 52(6): 1854-63; Chotiyaputta W, et al. J Viral Hepat. 2012. 19(3): 205-12

Non-adherence: treatment failure?

Adherence is vital, but may not be

as good as physicians expect

Non-adherence: treatment failure?

Non-adherence can result in
virological breakthrough

Clinicians Need to Recognize

Predictors and Causes of NonAdherence:
Predictors

Reasons

Cultural and health beliefs

Immigration/citizenship status
Health literacy
Literacy in English
Living situation/social support
system
Psychiatric comorbidities
Clinician-patient trust
Access to healthcare and health
insurance
Treatment burden

Chotiyaputta W, et al. J Viral Hepat. 2012. 19(3): 205-12; Giang L, et al. World J Hepatol. 2012. 4(2): 43-49.

Methods
Figure 1: Study Design

HBeAg seroconversion (SC): a positive HBeAb qualitative test with HBeAg

loss

Virologic response (VR): a serum HBV load <1000 IU/mL

Baseline Characteristics

Table 1: Baseline
Characteristics

HBeAg Seroconversion Analysis (n=187)

N

Asian
(n=155)

Non-Asian
(n=32)

ETV

114

93 (60%)

21 (66%)

TDF

73

62 (40%)

11 (34%)

Age (Years)

187

39 12

50 13

Gender (Male)

187

76 (49%)

BMI (kg/m2)

162

Creatinine (mg/dl)

Asian
(n=113)

Non-Asian
(n=32)

98

77 (68%)

21 (66%)

0.79

47

36 (32%)

11 (34%)

<0.001

145

40 13

51 13

<0.001

26 (81%)

<0.001

145

55 (49%)

25 (78%)

0.004

24 5

28 5

0.002

131

25 5

28 5

0.006

142

0.8 (0.7-0.9)

0.9 (0.8-1.1)

0.02

117

0.8 (0.7-0.9)

1.0 (0.9-1.1)

0.002

ALT (IU/ml)

163

46 (33-84)

57 (46-141)

0.02

128

49 (34-81)

62 (45-147)

0.02

Albumin (g/dl)

157

4.1 0.6

3.9 0.5

0.11

127

4.0 0.6

3.8 0.6

0.09

Platelets (K/ml)

148

210 68

197 86

0.35

120

214 67

196 86

0.25

Cirrhosis

185

20 (13%)

4 (12%)

143

15 (14%)

6 (19%)

0.57

HBV viral load (log10

IU/ml)

168

62

72

0.21

132

71

71

0.6

HBV genotype
B
C
Other
Unknown

187

39
60
16
40

(25%)
(39%)
(10%)
(26%)

0
1
21
10

(0%)
(3%)
(66%)
(31%)

Virologic Response Analysis (n=145)

0.55

<0.001
<0.001
<0.001
0.52

145

28
48
15
22

(25%)
(42%)
(13%)
(19%)

Previous treatment
187
145
Nave
73 (47%)
20 (62%)
0.12
67 (59%)
INF
14 (9%)
3 (9%)
1
10 (9%)
LAM
45 (29%)
8 (25%)
0.83
28 (25%)
Otherexpressed
NUC
(52%)
10 (31%)
0.05
44 (39%)
Values
as mean SD, meadian80
(IQR),
or frequency
(%) patients.
Non-Asians
(n=32) in SC analysis:
Caucasian
(23); Black (4);
Hispanic (4); 1
Pacific Islander
(1).
LAM resistance
187
28 (18%)
5 (16%)
145
17 (15%)
Non-Asians (n=32) in VR analysis: Caucasian (24); Black (4); Hispanic (3); Pacific Islander (1).
Jo KJ, et al. AASLD 2013, Washington, DC. Poster 961.

0
2
20
10

(0%)
(6%)
(63%)
(31%)

<0.001
<0.001
<0.001
0.22

23 (72%)
2 (6%)
6 (19%)
8 (25%)

0.22
1
0.64
0.21

5 (16%)

1
64

Figure 2: Cumulative Incidence of HBeAg Seroconversion

Among Asians Versus Non-Asians Treated with ETV or
TDF Monotherapy

65

Figure 3: Cumulative Incidence of Virologic Response

Among Asians Versus Non-Asians Treated with ETV or TDF
Monotherapy

66

Table 3: Multivariate Analysis: Factors Associated

with HBeAg Seroconversion and Virologic Response
Parameter

HBeAg Seroconversion
HR (95% CI)

Drug type (ETV)

Asian
ALT
<40 IU/ml
40-100 IU/ml
>100 IU/ml
HBV viral load
(per log10 increase)
Previous treatment
LAM

0.33 (0.16-0.71)

0.004

Virologic Response
HR (95% CI)

0.33 (0.21-0.53)

<0.001

1.11 (0.67-1.83)

0.69

1
1.73 (0.99-3.01)
4.31 (2.23-8.32)

0.05
<0.001

0.64 (0.55-0.75)

<0.001

0.48 (0.27-0.87)

0.01

Cox proportional hazards regression was used for multivariate analysis.

Parameters with p<0.1 in the univariate analysis were evaluated in the
multivariate analysis
using backward elimination with p>0.05 for removal from the final models
Factors relevant to the study hypotheses, including race, remained in the
final multivaraite analysis to assess the independent association with each
Baseline values.
outcome

Jo KJ, et al. AASLD 2013, Washington, DC. Poster 961.

Studies TDF 102/103:

Observed vs. Predicted HCC Cases
30

Non-cirrhotics

n=482
15
Predicted
Observed
10
SIR = 0.45*
95% CI (0.227, 0.909)

1st significant
difference

Cumulative no. of HCC cases

Cumulative no. of HCC cases

20

All Patients

n=634

25
Predicted
Observed

20
15

SIR = 0.50*
95% CI (0.294, 0.837)

10

1st significant
difference

5
0

48

96

144

192

Week

240

288

336

48

96

144

192

240

288

336

Week

Incidence of HCC in patients on TDF in studies 102/103 was lower

than predicted by the REACH-B model
In non-cirrhotic patients, the effect of TDF becomes noticeable
between 2-3 years of therapy and became statistically (55%
reduction) at 6 years of therapy

Statistically significant at nominal -level of 0.05.

Kim WR, et al. EASL 2013. Oral 43.

68

Differences in Development of
Resistance with Long-term Treatment
in Nuc-nave Patients
Patients with resistance (%)

100

Not head to head trials

Different patient populations and trial designs

90
80

70
65

70
60
50
40
30

53
42
29

24

20
10
0

22

18
11

1.2

Lamivudine1

0.1

Adefovir2 0

0.4
0.41 11.2
Entecavir3-6

Year
Year
Year
Year
Year
Year

4
0 0 0
0 0 0
Telbivudine7,8 Tenofovir9,10

1. Lok ASF, et al. Gastroenterology 2003;125:1714-22; 2. Hadziyannis SJ, et al. Gastroenterology 2006;131:1743-1752; 3. Colonno RJ, et al. Hepatology 2006;44:1656-65;
4. Colonno RJ, et al, Hepatology 2006, 44 (Suppl 1):229; 5. Colonno RJ, et al. J Hepatol. 2007;46(Suppl 1):S294; 6. Tenney DJ et al. Gastroenterology 2009;136(Suppl 1):A865;
7. Telbivudine (Tyzeka) prescribing information; May 2009; Novartis Pharmaceuticals, East Hanover, NJ; 8. Lai CL, Hepatology 2006;44(Suppl 1):222A.
69
9. Tenofovir (Viread) prescribing information; May. 2009; Gilead Sciences, Foster City, CA; 10. Snow-Lampart A et al. Hepatology 2008;48(Suppl 1):745A.

1
2
3
4
5
6

Randomization
1:1

HBeAg(+)
NUC-nave

cccDNA in Patients Treated with ETV:

Study Design
Dosing minimum of 52 weeks (up to 96 weeks)

Baseline biopsy
Hepatic cccDNA
Total hepatic HBV DNA

ETV 0.5 mg, once daily (n=159)

LVD 100 mg, once daily (n=146)
1 endpoint ETV-022
Week 48
Week 48 biopsy
Hepatic cccDNA
Total hepatic HBV DNA

Post-hoc analysis of phase 3, double-blind, randomized, comparative trial of ETV versus LVD (ETV-022) 1
Patients with baseline and Week 48 measurements of total hepatic HBV DNA and
hepatic cccDNA were included

1. Chang TT, et al. N Engl J Med 2006;354:1001-10.

Virologic, Biochemical, and

Histologic Efficacy at Week 48
80

75.9

7067.3 66.4
61.6
60.4
60

Proportion of patients (%)

50
40 36.6

43.1
36.9

ET
V

30
107 53
159 145

96 90
159 146

81
104 20
137 122

10

59 45
137 122

Serum HBV DNA <300 copies/mL

Among patients with paired hepatic HBV DNA measurements. Non-completer = missing
analysis
*ALT < 1.25 ULN. 2-point decrease in Knodell necroinflammatory score with no worsening ( 1-point increase
from baseline) of Knodell fibrosis score. 1-point decrease in Ishak fibrosis score from baseline.

Mean change from baseline

SE log10 copies/HGEq

Change from Baseline at Week 48 in

Total Hepatic HBV DNA and cccDNA
Total hepatic
HBV DNA

Hepatic
HBV cccDNA

ETV

-0.5

LVD

-1.0

-0.9

-1.5
-1.6

-2.0
-2.5

-2.1

-0.7

Difference estimate (95% CI)

-0.2 (-0.3, -0.1)**
P = 0.0033

Difference estimate (95% CI)

-0.5 (-0.6, -0.3)*
P < 0.0001
HGEq, human genome equivalent; SE, standard error.
*Difference estimated using linear regression analysis adjusted for baseline total hepatic HBV DNA level.
**Difference estimated using linear regression analysis adjusted for baseline hepatic cccDNA level.

Scott Bowden, WJG 2015

Conclusions
At Week 48, treatment with ETV was superior to LVD in reducing hepatic
HBV cccDNA and total hepatic HBV DNA from baseline
Lower baseline HBV cccDNA was associated with lower baseline serum
HBV DNA, lower baseline total hepatic HBV DNA, and HBV genotype F
HBV cccDNA reduction at Week 48 was associated with
1)
2)
3)
4)
5)
6)
7)

Lower baseline serum HBV DNA

Lower baseline ALT
Greater on-treatment decrease in serum HBV DNA
Greater decline in total hepatic HBV DNA on therapy
Improvement in Knodell necroinflammatory score
Reduction in ALT
HBeAg loss

Absolute reductions in serum and tissue HBV DNA was associated with
an amplified cccDNA reduction

Scott Bowden, DDW 2013

ETV has a Generally Favourable

Open-label Safety Profile up to 380 Weeks*
Proportion of subjects (%)

100
80

(n=1051)
Median ETV exposure 184 2.8 weeks (range:
1.9380 weeks)

60
40
20

14
4

Drug-related
Grade 34 AEs

Confirmed
Discontinuatio
creatinine
increase
n due to AEs

Adverse

(>0.5 mg/dL from

baseline)
events

Grade 34
lipase
elevation

*49% patients enrolled in ETV-901 had >5 years total ETV treatment (including treatment time in parent
protocols).
Patients in the ETV-901 rollover study received 1-mg ETV.

Manns M, et al. Expert Opin Drug Saf 2012;11:361-8.

TDF has a favourable clinical trial safety

profile up to and beyond 192 Weeks*
Proportion of subjects (%)

100
80
HBeAgve: TDF-TDF (n=235) HBeAgve: ADV-TDF (n=112)
HBeAg+ve: TDF-TDF (n=154) HBeAg+ve:ADV-TDF (n=84)

60
40
20
1

1 2

1
5

1 1
6 6

1
7
2

0 1 0

0 Drug-related Grade 3 or 4 Discontinua

SAE

laboratory AE tion due to

AE

Adverse events

1 <1 <1 2
Confirmed
creatinine
increase
0.5mg/dL

1 2 < 1
1
Confirmed
phosphorus
decrease
<2mg/dL

*On/After week 72, patients with confirmed HBV DNA 400 copies/mL were eligible to add FTC in a fixed dose
combination tablet
Marcellin P et al. AASLD 2010; poster 476; Heathcote EJ, et al. AASLD 2010; poster 477.

76

Renal considerations with NUC

treatment
NUCs are cleared by the kidneys, and appropriate dosing
adjustments are recommended for patients with reduced
creatinine clearance15
Renal dysfunction has been reported with nucleotide usage,
including TDF1,68
Licensing clinical trials have not shown significant signs of
TDF impacting on creatinine clearance in HBV treatment at
Week 1929,10
Case series have shown delta in GFR with ADF and TDF use
There was no difference in renal events with TDF and ETV in
a case controlled study12
However, creatinine clearance rates and 0.5 thresholds may
not provide an accurate assessment of early renal damage 11
1. Viread (tenofovir) SmPC September 2010; 2. Hepsera (adefovir) SmPC June 2009; 3. Baraclude (entecavir) SmPC February 2011;
4. Zeffix (lamivudine) SmPC July 2010; 5. EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009;50:22742;
6. Hepsera (adefovir) SmPC June 2009; 7. Karras A, et al. Clinical Infect Dis. 2003;36:10703; 8. Woodward CL, et al. HIV Med 2009;10(8):4827;
9. Marcellin P et al. AASLD, 2010; poster 476; 10. Heathcote EJ, et al. AASLD, 2010; poster 477;
11. Johnson R, et al. Comprehensive Clinical Nephrology; 2000: 4.15.1-4.15.15; St. Louis, Mosby. 12.Gish JCGH 2012

Protocol for Dose Reductions for Oral HBV

Medications if Changes in Renal Function
Recommended GFR >>> dose adjustments,
although each hepatologist was free to use their own
interpretation of the guidelines in the package insert

>70 mL 7 tablets per week

60-69 mL 6 tablets per week
50-59 mL 5 tablets per week
40-49 mL 4 tablets per week
30-39 mL 3 tablets per week
20-29 mL 2 tablets per week
10-19 mL 1 tablet per week

Gish R, et al. J Clin Gastro Hep 2012

Approved Treatments available

Nucleos(t)ides
Lamivudine
Adefovir
Telbivudine
Entecavir
Tenofovir

Immunomodulators
Standard interferon
Peg-interferon

Current CHB Treatment Strategy

Not for:
Decompensated cirrhosis
ACLF
X
Shor
t
Term
Treatmen
t
indicated

Stopping Rule
Fixed
Duration
IFN
Short
Term
NA

Long Term NA

Based on fixed duration

HBeAg seroconversion

HBsAg clearance

Liaw YF et al. Hepatol Int 2012; 6:531561

Lok AS et al. Hepatol 2009; AASLD Practice Guidelines;
EASL Jury, J Hepatol 201257:167185.

Optimisation of CHB management

Strategy 1
Long Term
Nucleos(t)ides
(NA)
Switch or Add-on
peg-interferon

STOP?

Strategy 2
Peg-interferon +
NA
Long term
NA

Strategy 3
Peginterferon

Therapeutic Signposts for Chronic

Hepatitis B
signposts

HBeAg positive CHB

Start
Rx

Reduce
serum
HBV DNA

Normal
ALT

HBeAg
loss

AntI-HBe
Seroconversion

Goals of Tx
qHBsAg

HBsAg
Loss/SC

~?%
HBeAg negative CHB
Start
Rx

Reduce
serum
HBV DNA

Normal
ALT

Liver
inflammation and fibrosis
Adapted from Naumov, EASL 2006

PCR
negative

qHBsAg

HBsAg
Loss/SC

Prevent
Cirrhosis
Liver
failure
HCC
Improve
survival

Interferon
Short fixed duration therapy
No Renal toxicity
Ideal for patients with high ALT and medium
to low DNA
Has stopping rules and continuation rules
Combined with NUCS: up to 15-20% HBsAg
loss
Chance of DNA suppression long-term is less
than 20%
HBsAg loss is 10%
Same as with Nuc therapy

qHBsAg: Biomarker for

Hepatitis B
Natural Course
Different phases1,2,3
Inactive HBsAg Carrier3,4,5
Risk for HCC6
HIV co-infection7

HBsAg
PEG-IFN:
Personalisation of
11-15
10
treatment
1. Jaroszewicz J, et al., J Heaptol 2010;52:514-22;
2. Nguyen T, et al., J Hepatol 2010;52:508-13;
3. Brunetto MR, et al.,
NUCs:
Prediction
of HBsAg loss8Adapted from: Chan
et al., J Hepatol 2011;55:1121-31.

Gastroenterology 2010;139:48-90;
4. Manesis EK, et al., AASLD 2010; abstract 483; 5. Martinot-Peignoux M, et al., AASLD 2010; abstract 992; 6. Lee JH, et al.,
AASLD 2011; abstract 1095;
7. Jaroszewicz J, et al., Plos One 2012;7: e43143; 8. Wursthorn et al., Hepatology 2010;52:1611-20; 9. Jaroszewicz J, et al.,
Antiviral Ther 2011;16:915-24;
10. Zoutendijk R, et al., JID 2011;204:415-8 & 2012;206:974-80; 11. Moucari R, et al., Hepatology 2009;49:1151-7;
12. Brunetto MR, et al., Hepatology 2009;49:1141-50; 13. Sonneveld et al., Hepatology 2010;52:1251-7;
14. Rijckborst V, et al., Hepatology 2010;52:454-61; 15. Rijckborst V, et al., J Hepatol 2012;56:1006-11.

HBsAg Quantification/HBV DNA Quantification

HBsAg quantification and HBV DNA quantification provide
complementary information

Peg-interferon

HBsAg
=
marker of
Immunological response

Oral antiviral agents

(NAs)

HBV DNA
=
marker of
Virus replication

HBsAg quantification is an additional

information to HBV DNA quantification!
Brunetto MR. Editorial. J Hepatol 2010;52:475-7.

Two Concepts for Response-guided Therapy

Approach Based on HBsAg Levels

Identify responders (PPV)

Identify non-responders (NPV)

Continue therapy

Change strategy

Motivate the patient

Stop PEG-IFN
(or add on an NA?)

Track success
The earlier the better
86

HBsAg Reduction at Week 24 of PEG

INF can Predict of Future HBsAg
Clearance

45%
43%
Among HBeAg-negative patients
who achieved HBsAg decline
10% from baseline at Week 24
of treatment*

achieved HBV DNA

10,000 copies/mL
at 1 year post- treatment
(N=29/67)

SUSTAINED
IMMUNE CONTROL

*56% of patients achieved HBsAg decline 10% at week 24

Marcellin P, et al. APASL 2010.

of those achieved HBsAg

clearance at 5 years
post-treatment (N=13/29)

NIDDKD Cohort: HBsAg Loss

by Mode of HBeAg Clearance

Treatment-induced HBeAg
clearance (n=51)

Probability of HBsAg Loss by

Mode of HBeAg Clearance

Cumulative incidence of HBeAg

loss per year (P=0.02)
Spontaneous: 1.6%
Nucleoside analog induced: 4.4%
Interferon induced: 6.3%

Most significant predictors of

HBsAg loss
Mode of HBeAg loss
Race

Probability of HBsAg Loss

Interferon related: 86%

Interferon-Related
HBeAg Loss (n=19)

Nucleoside
Analog-Related
HBeAg Loss (n=2)

Spontaneous Loss
of HBeAg (n=8)

0
NIDDKD: National Institute of Diabetes and Digestive
and Kidney Diseases.

Abdalla A, et al. Hepatology. 2013;58(suppl 1):627A. Abstract 883.

10

Years

15

20

25

HBsAg Loss in HBeAg-Positive and

HBeAg-Negative Patients

Patients (%)

15%

10%
8%
5%
3.0%
1.5%

Lamivudine
52 weeks

1%

Adefovir
5 Years

Entecavir
96 weeks

Tenofovir DF Telbivudine
4 years
52 weeks

Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org.

Heathcote EJ, et al. Hepatology. 2010;52(suppl):556A-557A. Abstract 477.
Gish RG, et al. J Viral Hepatitis. 2010;17:16-22.

PegIFN
72 weeks

PegIFN
+ LAM
72 weeks

On-treatment HBsAg Decline can Distinguish

Between Relapsers and Responders
In HBeAg-negative patients
Non-Responders (N=18)

3.5

HBsAg (Log IU/mL)

HBV DNA (Log copies/mL)

Sustained responders* (N=12)

5
4
3
2
1
0

Relapsers (N=18)

2.5
2
1.5
1
0.5

BL

W12

W24

PEGASYS treatment

W48

W72

W96

Follow-up

*HBV DNA undetectable by PCR 1 year post-treatment

Moucarir R, et al. Hepatology 2009;49:1151-7.

BL

W12

W24

PEGASYS treatment

W48

W72

W96

Follow-up
90

Elastography: Enhancing Performance to

Predict Cirrhosis in HBV Patients using
Different Cut-off Values

In this way, liver biopsy can be avoided in approximately

62% of patients with normal ALT and
58% of patients with elevated ALT
Chan HL, et al. J Viral Hepat 2009;16:36-44.

REACH B
Risk Calculator for HCC Risk Estimation
Generation of risk calculator
Database of REVEAL study
population-based cohort
3,584 patients, age 30-65 years
HBsAg (+), anti-HCV (-)
No cirrhosis
HBV DNA measured at study entry
No antiviral therapy
Median follow-up of 12 years
131 HCC developed

Yang HI, et al. Lancet Oncol 2011;12:568-74.

Development Cohort:
Multivariate Cox Proportional Hazards Model
Hazard ratio (95%
CI)

coefficient

p value

Risk
score

Sex
Female
Male

1.00
2.2 (1.4-3.4)

1.00
0.78798

1.64 (1.48-1.87)
..
..
..
..
..
..
..

0.49295
..
..
..
..
..
..
..

1.00
1.5 (1.0-2.2)
2.6 (1.5-4.4)

1.00
0.38823
0.96311

1.00
2.3 (1.3-3.8)

1.00
0.81308

..
0.0004

0
2

Age (years)
Per 5 years
33-34
33-39
40-44
45-49
50-54
55-59
60-65

0.0001
..
..
..
..
..
..
..

1
0
1
2
3
4
5
6

ALT (U/L)
15
15-44
45

..
0.0559
0.0003

0
1
2

HBeAg
Negative
Positive

0
2

HBV DNA level (copies per mL)

300 (undetectable)
1.00
1.00
..
0
300-9999
1.1 (0.4-2.9)
0.11648
0.8063
0
6
ALT=alanine aminotransferase. HBV=hepatitis B virus. *The risk score attributed to HBV DNA 10 copies per mL was less Than that for HBV DNA of
10000-99999
3.7
(1.6-8.5)
1.31467
0.0017
3
100000-999999 copies per mL because most patients with HBV DNA 106 copies per mL were also HBeAg positive, thus sharing the associated higher
100000-999999
9.7
(4.4-21.3)
2.27028
0.0001
5
score for this
category.
106
8.1 (3.5-19.0)
2.09258
0.0001
4*
Yang HI, et al. Lancet Oncol 2011;12:568-74.

Validation Cohort: ROC Curves for Risk of

Developing HCC and Predicted vs Observed HCC
Overall validation cohort

1.0

1.0

0.8

0.8

0.6
3-year HCC risk

0.4

(AUROC=0.811, 95% CI 0.790-0.831)

5-year HCC risk

(AUROC=0.796, 95% CI 0.775-0.816)

0.2

Non-cirrhotic validation cohort

Sensitivity

Sensitivity

10-year HCC risk

0.6
3-year HCC risk

0.4

(AUROC=0.902, 95% CI 0.884-0.918)

5-year HCC risk

(AUROC=0.783, 95% CI 0.759-0.806)

0.2

10-year HCC risk

(AUROC=0.769, 95% CI 0.747-0.790)

(AUROC=0.806, 95% CI 0.783-0.828)

0
0

0.5

0.5

1-specificity

1.0

1.0

Kaplan-Meier
observed HCC risk

Kaplan-Meier
observed HCC risk

1-specificity

0.1
0.01
3 year
5 year
10 year

0.001

0.0001
0.0001

0.001

0.01

0.1

Mean risk-score predicted HCC risk

0.1
0.01
3 year
5 year
10 year

0.001

0.0001
0.0001

0.001

0.01

0.1

Mean risk-score predicted HCC risk

ROC=receiver operating characteristics. HCC=hepatocellular carcinoma. AUROC=area under receiver operating characteristic
curve.
Yang HI, et al. Lancet Oncol 2011;12:568-74.

HBV Reactivation Following

Rituximab-Containing Chemotherapy

HBsAg negative, anti-HBc positive

HBV DNA <10 IU/mL
No concomitant liver disease or
prior HBV treatment
Reactivation: HBV DNA >10 IU/mL
regardless of HBsAg status
Follow-up: 36.6 months

Cumulative Rate of
HBV Reactivation

Single-center cohort with a

variety of hematologic diagnoses
(n=62) (2011-2013)

High rate of reactivation

Majority occurred within the first
6 months (86.7%)
Presence of low anti-HBs levels
was not protective against HBV
reactivation

9-Month Cumulative
Rate: 29.3%

Probability of HBV Reactivation (%)

Seto W, et al. Hepatology. 2013;58(suppl 1):224A. Abstract 34.

12

24

36

48

60

Months

72

84

96

Highest Risk Patients>10%*

HBsAg +
Anti-HBc +
Anti-HBs -

Initiate Prophylaxis
Viremia

High Risk Characteristics:

Patients with HBV DNA (>2000IU)
HBeAg positive
*In highest risk patients more
frequent assessment may be
necessary

Assess for
HBV Viremia
(DNA PCR)

HBsAg Anti-HBc +
Anti-HBs - (or +)
HBsAg Anti-HBc Anti-HBs +

NO Viremia

Monitor
aminotransferases
and
HBV DNA monthly

STOP
Initiate Prophylaxis

Moderate Risk Patients 1-10%*

*Actions taken assume a 2-5% risk of
reactivation with HBsAg neg/anti HBc
positive patients

HBsAg +
Anti-HBc +
Anti-HBs HBsAg Anti-HBc +
Anti-HBs - (or +)
HBsAg Anti-HBc Anti-HBs +

NO Viremia

Monitor
aminotransferases
and
HBV DNA
q 2 months
Initiate Prophylaxis

STOP
HBsAg +
Anti-HBc +
Anti-HBs -

Low Risk Patients <1%*

*Actions taken assume very low risk of
HBV reactivation. Includes population
with no cost justification for baseline
virologic monitoring. However, HBsAg
testing should be performed for
investigation of abnormal
aminotrasnferases

Viremia

Assess for
HBV Viremia
(DNA PCR)

Assess for
HBV Viremia
(DNA PCR)

Viremia

NO Viremia
Aminotransferases
(ALT)

Abnormal

HBsAg Anti-HBc +
Anti-HBs - (or +)

Monitor
aminotransferases
q 3 months

Normal
STOP

HBsAg Anti-HBc Anti-HBs +

STOP

Consider
Immunization if
Anti HBs -

Figure 1. Proposed Algorithm for HBV Reactivation Treatment and Monitoring. Patients may be categorized into low, medium, or high risk dependent upon baseline
characteristics and proposed agents. In medium and high risk populations serologic screening with HBsAg, anti-HBc, and Anti-Hbs can be performed. Serologic screening
should be performed in those at low risk with unexplained abnormal aminotransferases.

Gastro 2015

Specific (Special) Populations:

Immune tolerant patients: NNT is too high with current
data to justify treatment
Occult HBV (defined as anti-HBc (+) and HBsAg(-)
Risk of cancer: no intervention yet justified
Risk of reactivation: high risk demanding prophylaxis
Rituximab, StCTx, BMTx, ablative therapies

Children
Use of INF and approved nucleos(t)ides to treat selected patients

Pregnancy
Use first line, category B drugs (TDF) during 3rd trimester if HBV DNA
>10^6

FHF or AoC: treat HBV with oral therapies while waiting

for HBV DNA
Test all at risk patients for delta hepatitis
Advanced liver disease

Can Chronic Hepatitis B be

cured/eradicated?
Current paradigm: chronicity is for life
What is eradication?
Occult HBV exists
Residual cccDNA after HBsAg loss

Functional Cure HBsAg

loss/seroconversion
Absolute or
Absence of cccDNA in
body
complete cure
Zeisel MB, et al. Gut 2015;epub ahead of print (state of the art ANRS workshop on HBV cure)
Zoulim, Cold Spring Harb Perspect Med 2015;5:a021501

Is a Functional Cure possible?

Natural: HBsAg Seroclearance in Asymptomatic
Carriers: Long-Term Follow-Up

N=1965 HBeAg+
asymptomatic adult
carriers
The cumulative
probabilities of HBsAg
seroclearance were 8.1%
after 10 yrs, 24.9% at 20
yrs and 44.7% at 25 yrs

50

Cumulative propability (%)

45
40
35
30
25
20
15
10

HBsAg seroclearance
5
correlated positively with
0
age at entry (P<0.0001)
0
and sustained remission
of hepatitis (P<0.0001)
and marginally
Chu,
Liaw. Hepatology
significantly
with2007;45:1187-1192:
male

10

15

20

Years after entry

25

30

We Need Therapies to Attack: HBV

Replication: @ cccDNA Pathway
Spherical &
Filamentous HBsAg

HBeAg

Mature HBV
virion

Uncoating
GOLGI
ER

Precore

Nuclear
Transport

iRNA

viralRNA

Surface

RC-DNA

Translation
Transcription

Core
Polymerase

Reverse
Transcription
Immature
Nucleocapsid

RC-DNA

Intracellular Conversion Pathway

Mature
Nucleocapsid

RC-DNA

New Therapies 2015 and beyond

New therapies en-route

Anti-Sense: DNA like molecules ISIS

iRNA: Modified RNA Arrowhead
Uptake inhibitors blocking entry Myclurdex
Capsid formation inhibitors: block release
and cccDNA formation Various
Block RNAaseH Various
Block histone modifications Various

HBV Treatment Strategies

Therapeutic targets

T-cell responses

Recovery of HBV-specific T-cell

responses

Humoral responses
Robust anti-envelope neutralizing
responses

Innate immunity
Suppression through cytokine- and APCmediated mechanisms

Block
Viraemia

Viral particles cause (re)infection

Antigen load (HBe, HBs)

Subviral particles overhaul
host immune system

cccDNA
Master template causes persistence

Boost

Courtesy of Seng Gee Lim

VACCINATE !

Regional and Country Specific Polices

action plans, peer review publications, technical working groups,
white papers, buy in from NGO, patients and patients advocates

Concluding Points
There are currently 7 approved therapies for CHB and
determination of which therapy to use includes careful
consideration of duration of treatment, stopping rules, drug
efficacy, side effects, and potential for antiviral resistance
with the nucleos(t)ide analogs
There is no cure: so what is next ?
Functional cure ? S Ag clearance
New treatments: clear capsid and cccDNA

iRNA
Capsid inhibitors
Anti-Sense
Entry inhibitors
RNAase H target

TEST VACCINATE TREAT SURVEILLANCE

Launch of the WHO guidelines for

prevention, care and treatment of
persons with chronic hepatitis B
infection

Outline of presentation
Why WHO HBV guidelines are needed?
WHO guidelines process
Key recommendations and rationale

Use of NITs for staging of liver disease

Who to treat?
What treatment to use? (First and Second-Line)
How to Monitor? (ART, toxicity, HCC)
When to stop?
Prevention

Implementation of the guidelines

108

Background

Chronic HBV infection (CHB)

significant cause of morbidity and
mortality:
240 million persons with CHB
Up to 30% develop complications
cirrhosis and HCC
45% of HCC + 30% of cirrhosis due
to HBV
686,000 annual deaths
Global programme on infant HBV
immunization has led to significant
decrease in prevalence.

Deaths due to HBV

1000
800
600
400
200
0

Acute Hepatitis B
HBV - Hepatocellular Carcinoma
HBV - cirrhosis
100

Very limited HBV testing and low levels

of treatment coverage in LMICs
80
60
40
20

HepB 3
HepB birth
dose

Lack of hepatitis B management

guidelines
for
resource-limited
.Ott J. et al. Vaccine
2012.
& Murray, C. et al The Lancetsettings
2014
WHO Position Paper. 2012
2013 Global
HB3 = 81%
BD = 38%

Why does the world need WHO hepatitis B

treatment guidelines?
Existing HBV Guidelines

AASLD 2009
APASL 2012
EASL 2012
NICE 2013

Some similarities and some

differences in .
Indications for treatment
Choice of antiviral drug
HCC surveillance

Emphasis on high-income countries

and settings with access to HBV
testing

Distinctive features of WHO guidelines

Feature

WHO Guideline

Other Guidelines

TARGET
AUDIENCE

National Programme
managers

Treating clinicians

SETTINGS

Low and middle

High income
income countries
countries
Generalised/Concent
rated epidemic
setting
Poor access to liver
biopsy, and HBV DNA
testing

EVIDENCEBASED GRADE
APPROACH
Feasibility, equity,

Variable use of
evidence-based
framework

resource use
considered
APPROACH

The Public health

Individualised

The Public health approach and health

equity
Lessons learnt from ARV scale-up:
The public health approach seeks
to:
Simplified and
and standardized
standardized
Simplified
approaches to
to ensure
ensure the
the widest
widest
approaches
possible access
access to
to high-quality
high-quality services
services
possible
at the
the population
population level
level
at
Strike a
a balance
balance between
between implementing
implementing
Strike
the best-proven
best-proven standard
standard of
of care
care and
and
the
what is
is feasible
feasible on
on a
a large
large scale
scale in
in
what
resource-limited
settings equity and
resource-limited
settings
Promotion
of health

human rights so that:

Expanded access
access is
is fair
fair and
and equitable
equitable
Expanded
Priority for
for treatment
treatment given
given to
to those
those
Priority
most in
in need
need
most
In environment
environment free
free of
of stigma
stigma and
and
In
discrimination
discrimination

WHO guidelines development process

1. Constitute Guideline Development
Group

2. Formulate questions (PICO

format)
3. Conduct systematic reviews of
data
4. Evaluate quality of evidence
(GRADE)
5. Formulate recommendations
Disseminate, Adapt, Evaluate. 6
113

1. Guidelines Development Group

membership

22 members

50% low and middle

income countries

Civil Society
representation

Declaration of conflicts of
interest

12 Systematic reviews and two network

meta-analyses along Continuum of Care
Who should undergo
hepatitis serologic testing?
What assays to use?
What screening
approaches should be
used?

AWARENES
S

TESTING

How to assess
stage of liver
disease?
Who needs
treatment?

REFERRAL

Care and prevention

What interventions to
slow progression of
liver disease?
Vaccination, alcohol
cessation
What interventions to

DISEASE
STAGE
ASSESSMEN
T

How to monitor for

treatment
response?
How to monitor for
drug toxicity?
How to monitor for
HCC?
TREATMEN
T

MONITORI
NG

Who to treat and

when?
What medicine to
use?
When to stop?

Grading of Recommendation
Assessment, Development and Evaluation
By outcome:
Quality of
Evidence

Strength of
Recommendati
on

Strong or Conditional
depends on:

116

High quality
Moderate
Low
Very low

Quality of evidence
Balance of benefits and
harms
Values and preferences
Resource use
Feasibility

CHAPTERS: ALONG THE CONTINUUM 6

OF CARE

Evidence Summary,
Summary, Rational
Rational for
for
Evidence
Recommendation, Balance
Balance of
of Benefits
Benefits and
and
Recommendation,
Harms, Resource
Resource Use,
Use, Value
Value &
& Preferences,
Preferences,
Harms,
Research Gaps
Gaps
Research

Tables, Boxes
Boxes for
for Clinical
Clinical
Tables,
Points, Figures,
Figures, Checklists
Checklists
Points,
& Algorithms
Algorithms
&

HBV Guideline Recommendations (2015)

TOPIC
Staging/ noninvasive test
(NIT)
Who
to
treat

First line
treatment
Treatment
failure
Treatment
discontinuation

RECOMMENDATION
APRI preferred NIT to assess for the presence of cirrhosis

Decompensated cirrhosis or cirrhosis (clinical criteria or

APRI score >2), regardless of ALT levels, HBeAg, or HBV
DNA.
No cirrhosis but persistently abnormal ALT levels +/ongoing HBV replication, (HBV DNA >20,000 IU/mL or
HBeAg +ve).
Drugs with a high barrier to resistance (TDF or ETV).
ETV in children aged 2-11 years.
Switch to TDF if evidence of resistance to 3TC, ETV, ADF,
TBV.
Never discontinue in persons with cirrhosis.

If no cirrhosis, discontinuation on case-by-case basis

(persistent HBeAg and/or HBsAg loss or undetectable HBV
DNA)
On or pre-treatment: ALT + HBV DNA (HBsAg, HBeAg +
Monitoring
APRI pre-treatment) annually. More frequent monitoring
(treatment
with cirrhosis.
response/toxicit
118

y)

Assessment of baseline renal function prior to treatment

 Find the New 2015 WHO HBV Guidelines on http://www.who.int/hiv/pub

/hepatitis/hepatitis-b-guidelines/en/

Use of Non-Invasive Tests for

Assessment of Liver Disease
Stage

120

Use of NITs to assess for

cirrhosis: Recommendations

Important for decisions on

prioritising who needs
treatment
Liver biopsy considered
impracticable in low income
settings
RECOMMENDATION

APRI

AST, platelets

FIB-4

Age, AST, ALT,

platelets

FibroTest

5 serum markers

FibroScan Transient
elastography
STRENGTH EVIDENCE
QUALITY

APRI is the preferred NIT to assess for

presence of cirrhosis (APRI score >2 in
adults) in resource-limited settings.
Transient elastography or FibroTest may
preferred NIT in settings where they are
available and cost is not a major
constraint.

Conditional

Low

EVIDENCE
Systematic review
review of
of 79
79 studies
studies on
on
Systematic
diagnostic performance
performance of
of NITs
NITs
diagnostic
SE Asia,
Asia, 22 SSA;
SSA; 22 HIV,
HIV, 11 38
38
SE
children
))children

RATIONALE

Use of
of APRI
APRI and
and TE
TE
Use

APRI: tests
tests widely
widely available,
available, low
low cost,
cost, and
and
APRI:
simple to
to interpret
interpret
..simple
TE: higher
higher PPV,
PPV, but
but high
high equipment
equipment cost
cost
TE:
FIB-4 not
not for
for cirrhosis;
cirrhosis; FibroTest
FibroTest
FIB-4
patented and
and more
more expensive
expensive
patented

Use of
of APRI
APRI single
single high
high cut-off
cut-off >2
>2
Use

Simpler and
and easier
easier to
to interpret
interpret
Simpler
Low cut-off
cut-off has
has high
high false-positive
false-positive rate
rate
Low
Missed cirrhosis
cirrhosis cases
cases but
but meet
meet other
other
Missed
treatment eligibility
eligibility criteria
criteria
..treatment

Conditional recommendation
recommendation
Conditional

All NITs:
NITs: Low
Low PPV
PPV for
for cirrhosis,
cirrhosis, esp
esp APRI
APRI
..All
High specificity
specificity (>85%)
(>85%) Fibroscan
Fibroscan ++ APRI
APRI
High
(high cut-off)
cut-off)
(high

Low PPV
PPV for
for all
all NITs
NITs
Low
Very limited
limited data
data from
from SSA
SSA
Very
Impact of
of intercurrent
intercurrent
Impact
illness/comorbidities
illness/comorbidities

WHO TO TREAT
AND
NOT TREAT?

123

Who to treat?
RECOMMENDATION

As a priority, treat all with clinical evidence of

compensated or decompensated cirrhosis (or
APRI score >2 in adults), regardless of age,
HBeAg status, ALT or HBV DNA levels.
If no evidence of cirrhosis (or APRI score 2 in
adults):
Treat if >30 years, and persistently
abnormal ALT levels and high level HBV
replication (HBV DNA >20 000 IU/mL),
regardless of HBeAg status.

STRENGTH

Strong

Strong

EVIDENCE
QUALITY
Moderate

Moderate

Who not to treat but monitor?

RECOMMENDATION

Treatment is not recommended in persons

without clinical evidence of cirrhosis (or APRI
score 2 in adults): and persistently normal ALT levels
and low levels of HBV replication (HBV DNA
<2000 IU/mL), regardless of HBeAg status or
age.

STRENGTH
Strong

EVIDENCE
QUALITY
Low

Continued monitoring is necessary in all persons with CHB,

including:
persons without cirrhosis 30 years, HBV DNA levels >20 000 IU/mL
but persistently normal ALT levels;
HBeAg-negative persons without cirrhosis 30 years, with HBV DNA
levels fluctuating 2000-20 000 IU/mL, or intermittently abnormal ALT
levels

EVIDENCE
Two systematic
systematic reviews
reviews
Two
Identifying HBeAg+/HBeAg+/- at
at high
high and
and low
low
Identifying
risk of
of HCC
HCC and
and cirrhosis
cirrhosis
risk

22 observational
observational studies
studies (4
(4
22
population-based)
population-based)
SE Asia,
Asia, Europe,
Europe, N.
N. America;
America; 11
SE
HIV
HIV

Impact of
of treatment
treatment in
in advanced
advanced liver
liver
Impact
disease (4
(4 studies)
studies)
disease

RATIONALE
Treat as
as priority
priority those
those with
with cirrhosis
cirrhosis
::Treat
High risk
risk of
of life-threatening
life-threatening
High
complications
complications

Treatment can
can halve
halve disease
disease
Treatment
progression and
and deaths
deaths ++ fibrosis
fibrosis
progression
regression
..regression
Targeting treatment
treatment is
is costcost- effective
effective
Targeting
Treatment safe
safe even
even with
with
Treatment
decompensated cirrhosis
cirrhosis
decompensated

Treat: those
those without
without cirrhosis
cirrhosis
Treat:
Consistent evidence
evidence of
of increased
increased
Consistent
HCC and
and cirrhosis
cirrhosis risk
risk (age,
(age, ALT,
ALT,
HCC
HBV DNA)
DNA)
HBV
Uncertainties in
in specific
specific thresholds
thresholds
Uncertainties
Abnormal ALT
ALT level
level varies
varies by
by lab
lab -Abnormal
Age >30
>30 yr
yr based
based on
on Asian
Asian pop
pop -..Age

Where HBV DNA not available

RECOMMENDATION

STRENGTH

EVIDENC
E
QUALITY

TO TREAT

Conditional

Low

Conditional

Low

adults without evidence of cirrhosis

(or APRI score 2), consider
treatment based on persistently
raised ALT levels alone, regardless
of HBeAg status.
** where other common causes of persistently
raised ALT such as impaired glucose tolerance,
dyslipidaemia and fatty liver have been excluded.

TO NOT TREAT BUT MONITOR

Antiviral therapy is not recommended

In HBeAg-positive persons without
cirrhosis aged 30 years and
persistently normal ALT levels.

WHAT TREATMENTS TO
USE?

128

What treatment to use?

FIRSTLINE

RECOMMENDATION

STRENGTH

EVIDENCE
QUALITY

NAs with a high barrier to drug resistance

(tenofovir or entecavir) are recommended in all
adults, adolescents and children (12 years) in
whom antiviral therapy is indicated.

Strong

Moderate

Strong

Moderate

- Entecavir is recommended in children 211

years.
FIRSTLINE

NAs with a low barrier to resistance

(lamivudine, adefovir or telbivudine) can lead to
drug resistance and are not recommended.

SECON
D-LINE

In persons with confirmed or suspected antiviral

Strong
resistance (i.e. history of prior exposure or
primary non-response) to lamivudine, entecavir,
adefovir or telbivudine, a switch to tenofovir is
recommended.
- Use of entecavir is not recommended

Low

EVIDENCE

RATIONALE

Systematic reviews
reviews
Systematic
Three in
in Rx
Rx nave
nave
Three

Comparative studies:
studies: 77 existing
existing
- Comparative
reviews (49
(49 trials)
trials)
reviews
Long-term effectiveness
effectiveness and
and
- Long-term
safety of
of entecavir/tenofovir
entecavir/tenofovir (n=12)
(n=12)
safety
HIV coinfection
coinfection (n=23)
(n=23)
- HIV

One in
in Rx
Rx experienced:
experienced: 11 existing
existing
One
review (5
(5 RCTs,
RCTs, 33 non-RCTs)
non-RCTs) and
and 77
review

Most effective
effective therapies
therapies to
to achieve
achieve
Most
undetectable HBV
HBV DNA
DNA and
and ALT
ALT
undetectable
normalization (reviews
(reviews and
and NMA)
NMA)
normalization
High genetic
genetic barrier:
barrier: very
very low
low rates
rates of
of
High
drug resistance
resistance
drug
Safe and
and effective
effective in
in children
children and
and
Safe
pregnancy
pregnancy

Drug

RCTs
RCTs

Network meta-analyses
meta-analyses
Network
RCTs (eAg+);16
(eAg+);16 RCT
RCT (eAg-)
(eAg-) 21
21
RCTs

Evidence
Evidence
Potent inhibitors
inhibitors of
of HBV
HBV replication
replication
..Potent

% HBV DNA <300c/ml

NA naive

NA
experienced

Tenofovir

94.1% (74.798.9)

89% (51.8-98.2)

Entecavir

64.5% (49.180.5)

21.4% (10.044.6)

Strong operational/programmatic
operational/programmatic advantages
advantages
Strong
ADF+LMV
36.9% (12.331.3% (13.470.3)pill
60.8)
Convenient one
one
pill once
once aa day
day
Convenient

RCTs (eAg+)
(eAg+) and
and 66 RCT
RCT (771
(771 eAg
eAg -)
-) 77
RCTs

ADF
(14.8Well
tolerated -33.4%
- low
low rates
rates of
of side-effects;
side-effects;
Well
tolerated
61.2)
minimal requirement
requirement for
for toxicity
toxicity monitoring
monitoring
minimal
LMV
38.7%
Simplifies drug
drug procurement
procurement (HIV
(HIV programmes)
programmes)
Simplifies

Affordability
Affordability

HOW TO MONITOR?
- Monitoring for disease
progression and treatment
response
- Monitoring for renal toxicity
- Monitoring for HCC

131

How to monitor for disease

progression/
treatment response and toxicity?
RECOMMENDATION

STRENGTH

EVIDENCE
QUALITY

MONITO
R IN ALL

At least annually:
ALT level (and AST for APRI), HBsAg,
HBeAg, and HBV DNA levels
NITs: (APRI score or FibroScan) to assess for
presence of cirrhosis (if no cirrhosis at
baseline);
Adherence monitored regularly and at each
visit, if on treatment.

Strong

Moderate

TOXICIT
Y

Measurement of baseline renal function

and assessment of baseline risk for renal
dysfunction should be considered in all
persons prior to initiation of antiviral therapy.

Condition
al

Very Low

Renal function should be monitored

annually in persons on long-term tenofovir
or entecavir therapy, and growth monitored
carefully in children.

EVIDENCE

RATIONALE

No studies
studies directly
directly compared
compared
No
different monitoring
monitoring strategies,
strategies,
different
frequency or
or assays
assays (renal
(renal
frequency
toxicity)
..toxicity)

Limited evidence
evidence base
base to
to guide
guide
Limited
optimal strategies/
strategies/ frequency
frequency of
of
optimal
monitoring
monitoring

Indirect evidence
evidence from
from cohort
cohort
Indirect
studies on
on disease
disease progression
progression
studies
existing systematic
systematic reviews
reviews 44
existing
RCTs and
and 33 cohort
cohort studies
studies 22
RCTs
Indirect evidence
evidence from
from long-term
long-term
Indirect
follow-up studies
studies on
on renal
renal AEs
AEs
follow-up
tenofovir, 44 entecavir
entecavir 88
tenofovir,
None in
in children
children
None

At least
least annual
annual monitoring
monitoring
At
Multiple trials
trials show
show
::Multiple
High rates
rates of
of sustained
sustained HBV
HBV
High
suppression
suppression
Low rates
rates of
of drug
drug resistance
resistance
Low
Low renal
renal toxicity
toxicity (0.3%-2%)
(0.3%-2%)
Low
at 55 years
years
at

Annual monitoring,
monitoring, ifif good
good
Annual
adherence and
and low
low renal
renal risk
risk
adherence
More frequent
frequent monitoring
monitoring ifif
More
higher risk
risk of
of progression
progression or
or
higher
adverse events
events
adverse

How to monitor for HCC?

Recommendation

STRENGTH

EVIDENCE
QUALITY

Routine surveillance for HCC with abdominal ultrasound and

alpha-fetoprotein testing every six months is recommended for:
with cirrhosis, regardless of age
persons
or other risk factor
persons with a family history of HCC
without clinical evidence of
persons
cirrhosis (or APRI score 2)
- aged over 40 years (lower age may
apply according to regional incidence of
HCC) and
- HBV DNA level >2000 IU/mL

Strong

Low

Strong

Low

Conditiona
l

Low

EVIDENCE
How to
to screen?
screen?
How
Systematic review
review of
of different
different
Systematic
screening strategies
strategies
screening
studies (2
(2 RCTs
RCTs and
and 33
88 studies
economic evaluations)
evaluations)
economic

Who to
to screen?
screen?
Who
Systematic review
review of
of predictors
predictors of
of
Systematic
HCC
HCC
22 observational
observational studies
studies (4
(4
22
population-based)
population-based)

RATIONALE

vs. >6
>6 monthly
monthly US
US ++ AFP
AFP 66
vs.
Reduced disease-specific
disease-specific
Reduced
mortality (by
(by 50%)
50%) and
and detection
detection
mortality
of early
early HCC
HCC
of

High risk-groups
risk-groups for
for
High
screening
::screening
Presence of
of cirrhosis,
cirrhosis, family
family
Presence
history of
of HCC
HCC and
and age
age
history

When to stop?
RECOMMENDATION

STRENGTH

EVIDENCE
QUALITY

LIFELONG
THERAPY

All persons with cirrhosis (based on

clinical criteria or APRI score >2 in adults)
require lifelong treatment, and should not
discontinue antiviral therapy, because of
the risk of reactivation, which can cause
severe acute-on-chronic liver injury.

Strong

Low

CONSIDER

Discontinuation of NA therapy may be

considered exceptionally in:

Condition
al

Low

DISCONTIN
UE

persons without evidence of cirrhosis (based on

absence of clinical criteria or APRI score <2 in
adults);
and who can be followed carefully long term for
reactivation;
and if evidence of HBeAg loss and seroconversion
to anti-HBe and at least one additional year of
treatment;
and in association with persistently normal ALT
levels and persistently undetectable HBV DNA
levels.

The road ahead..

Dissemination and Implementation

Regional
Dissemination and
country dialogue in
adaptation and
implementation
Additional WHO guidance
regarding on Screening
and testing

IMPLEMENTATION CONSIDERATIONS FOR

COUNTRIES

Infrastructure/service delivery
Integration with HIV, TB, NCD
programmes
Public health approach
Staffing and human resources
Training and mentorship
Laboratory facilities
AST, ALT, HBV DNA
Drugs and diagnostic supplies
Generic drugs available at low cost
Pooled procurement
Costs and Funding
Public and private

What could be the impact?

IMPACT
) Incidence, Mortality(

Modelling of impact of

World

integrated treatment +
prevention package on incidence
and mortality

Incidence of New Chronic Carriage of HBV

Millons

8
6
4
2

Based on high coverage for:Infant vaccination + universal access to

0
2010

2020

2030

2040

2050

2060

2070

2080

2060

2070

2080

2060

2070

2080

Number of Persons Living With Chronic Infection

250
Millons

blood and injection safety + harm reduction

Scale-up of diagnosis and treatment

Status Quo
Infant Vacc
Infant Vacc + PMTCT
Infant Vacc + PMTCT + Treatment
Infant Vacc + PMTCT + Treatment + Cure

200
150
100
50
0
2010

Feasible targets by 2030?

2030

2040

2050

HBV Deaths
Thousands

90% reduction in new cases of

chronic infection
65% reduction in HBV deaths
13M deaths averted, 6M cancers

2020

1200
800
400
0
2010

2020

2030

2040

2050

Acknowledgments
Special thanks to all the external experts who contributed as members of the Guideline
Development Groups, the Peer Review panel and to those who contributed to the
GRADE systematic reviews and supporting evidence which informed the guidelines
process.

Chairs: Olufunmilayo Lesi (University of Lagos, Nigeria) and Brian McMahon (Alaska
Native Tribal Health Consortium USA). Methodologist: Nandi Siegfried (South African
Cochrane Centre)

Guidelines Development Group: Priya Abraham; Avelin F Aghokeng; Isabelle AndrieuxMeyer; Joan Block; Milagros Davalos Moscol; Manal Hamdy El-Sayed; Charles Gore; Kwang
Hyub Han; Jidong Jia; Ahmed Khatib; Giten Khwairakpam; Karine Lacombe; Nancy Leung;
Anna Lok; Ponsiano Ocama; Huma Qureshi; Lewis Roberts; Edna Strauss; Ali Sulaiman;
Mark Thursz; Cihan Yurdaydin. Writer: Geoff Dusheiko

External peer review group Adele Benzaken; Nikoloz Chkhartishvili; Serge Eholie;
Shaffiq Essajee; Silvia Franceschi; Nina Grundmann; Margaret Hellard; Karen Kyuregyan;
Seng Gee Lim; David Muljono; Samuel So; George Siberry; Mark Sonderup; Vincent
Soriano; Mihai Voiculescu; Gilles Wandeler

Systematic reviews: Ivan Sol, David Rigau Comas (Centre Cochrane Iberoameric,
Spain); Victoria Wakefield, Charlotta Karner (BMJ Technology Assessment Group, London,
UK); Emmanouil Tsochatzis (, UCL and Royal Free Hospital, UK); Grammati Sarri, Jill
Parnham (National Clinical Guideline Centre [NCGC], Royal College of Physicians, UK)

WHO Steering Committee, Philippa Easterbrook, Stefan Wiktor, Tatsuya Yamashita,

Marco Vitoria, Nathan Shaffer, Jessica Markby, Annette Verster, Anita Sands, Ana Maria
Henao Restrepo, Selma Khamassi, Ying-Ru Lo.

Other WHO staf: Susan Norris; Ioannis Hodges-Mameletzis, Sarah Hess,, Zainab
Hussain, Nick Walsh Naoko Obara.

Thank you

Stefan Wiktor WHO

Stephen Locarnini
Fabian Zoulim
Ed Gane
Gene Schiff
Seng Gee Lim
Bob Perrillo
Tim Block
Henry Chan
Harry Janssen
MF Yuen
And all of my HBV Gurus