NEMS Clinic

Long term NUC therapy for HBV

Changing outcomes ?
and HCC surveillance
Robert G Gish MD
Professor Consultant
Stanford University

Relevant Financial Disclosures

Advisory

Board/Speaker Bureau for:

BMS, GILEAD

Outline

Endpoints of therapy

Virological, serological, biochemical results

Histological data

Clinical decompensation, portal hypertension

Hepatocellular carcinoma

Natural History of Hepatitis B Virus Infection

5%-10% of
chronic HBVinfected
individuals1

Liver
Cancer
(HCC)
3%/yr

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

1.
2.
3.
4.

Chronic
Infection

30% of chronic
HBV-infected
individuals1

Cirrhosis

Liver
Transplanta
tion

Death

3%/yr

Liver
Failure
Inactive
carrier

Torresi, J, Locarnini, S. Gastroenterology. 2000.

Fattovich, G, Giustina, G, Schalm, SW, et al. Hepatology. 1995.
Moyer, LA, Mast, EE. Am J Prev Med. 1994.
Perrillo, R, et al. Hepatology. 2001.

(Decomp.)
23% of patients
decompensate
within 5 years of
developing
cirrhosis 3

Chronic HBV is the

6th leading cause of
liver transplantation
in the US 4

Therapeutic strategies for chronic hepatitis B

Short-term "curative" treatment
Follow-up (mo/yrs)

IFN
On treatment
response

HBV DNA < 2000 IU/ml

ALT < UNL
(anti-HBe)

HBsAg
Loss

Long-term "suppressive" treatment

NUC
HBV DNA undetectable by PCR (<10-15 IU)

Years

HBsAg loss

Incidence of Resistance in NUC-nave Patients

*Collation of currently available data not from head-to-head studies
1st generation
80
70
67

Patients (%)

60

2nd generation

49

38

40

29

3rd generation

24

20

18

17

11

3
0

LAM

ADV

LDT

0.2

0.5 1.2
1.2 1.2

ETV

0 0

0 0 0

TDF

adapted from EASL HBV Guidelines, J Hepatol 2012

3-5 years ETV for real life, naive CHB patients

Virological summary
100

99%

96%

n=222

n=418

n=535

Hong-Kong2
(4 years)

Italy3
(5 years)

Thailand4
(5 years)

93%

96%

n=243

Europe1
(3 years)

Patients %

80
60
40
20
0

1) Zoutendijk R et al, Hepatology 2011; 2) Seto WK et al, EASL 2011; 3) Lampertico P et al, EASL 2013;
4) Tanwandee T et al, AASLD 2013

3-5 years ETV for real life, naive CHB patients

Resistance summary
100

93%

96%

99%

96%

1 case

no
resistance

Patients %

80
60

no
resistance

1 case

40
20
n=243

n=222

n=418

n=535

Europe1
(3 years)

Hong-Kong2
(4 years)

Italy3
(5 years)

Thailand4
(5 years)

1) Zoutendijk R et al, Hepatology 2011; 2) Seto WK et al, EASL 2011; 3) Lampertico P et al, EASL 2013;
4) Tanwandee T et al, AASLD 2013

3-5 years ETV for real life, naive CHB patients

Safety summary
100

93%

96%

99%

96%

Patients %

80
60

favourable
safety profile

no serious
adv. events

no adverse
events
no safety
issues

40
20
n=243

n=222

n=418

n=535

Europe1
(3 years)

Hong-Kong2
(4 years)

Italy3
(5 years)

Thailand4
(5 years)

1) Zoutendijk R et al, Hepatology 2011; 2) Seto WK et al, EASL 2011; 3) Lampertico P et al, EASL 2013;
4) Tanwandee T et al, AASLD 2013

Seven years TDF for nave CHB patients

Efficacy summary
Response

HBeAg- Patients
(Study 102)

HBeAg+ Patients
(Study 103)

Year 6

Year 7

Year 6

Year 7

HBV DNA < 400 copies/mL

Intent-to-treat*, (n/N)

81.4%
(281/345)

77.3%
(269/348)

62.5%
(157/251)

60.3%
(149/247)

HBV DNA < 400 copies/mL

On-treatment, (n/N)

99.6%
(283/284)

99.3%
(271/273)

96.8%
(167/169)

99.4%
(159/160)

LTE-TDF (missing = failure; addition of FTC = failure)

Observed (missing = excluded/addition of FTC = included)

No case of TDF resistance

HBeAg loss/seroconversion rates of 55% and 40%, respectively

12% of HBeAg+ patients had confirmed HBsAg loss (10% with seroconversion)
Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use to treat CHB
Marcellin P, et al. AASLD 2013. Washington, DC. #926

10

Seven years TDF for nave CHB patients

Safety summary
By Initial Treatment
Assignment

Total
(N=585)

TDF-TDF
(n=389)

ADV-TDF
(n=196)

AEs leading to drug discontinuation, n (%)

11 (2.8)

2 (1.0)

13 (2.2)

Deaths, n (%)

9 (2.3)

3 (1.5)

12 (2.1)

Serious AEs*, n (%)

5 (1.3)

2 (1.0)

7 (1.2)

Grade 3 or 4 AEs*, n (%)

3 (0.8)

3 (1.5)

6 (1.0)

sCr 0.5 mg/dL above baseline, n (%)

6 (1.5)

4 (2.0)

10 (1.7)

PO4 < 2 mg/dL, n (%)

5 (1.3)

4 (2.0)

9 (1.5)

CrCl < 50 mL/min, n (%)

3 (0.8)

3 (1.5)

6 (1.0)

*Study

drug related

Confirmed

upon retest

Marcellin P, et al. AASLD 2013. Washington, DC. #926

11

Management of HBV Resistance

(Early rescue)
LAM resistance

Switch to TDF (or add ADV)

LDT resistance

Switch to TDF* (or add ADV)

ETV resistance

Switch to TDF* (or add ADV)

ADV resistance

Switch to ETV or TDF (LAM naive)

Switch to ETV (LAM naive + HVL)
Switch to TDF and add a nucleoside (LAM resist.)

TDF resistance**

Switch to ETV (LAM naive)

Add ETV (LAM resistant)*

*the long-term safety of these combinations is unknown

**not seen so far; do genotyping and phenotyping in an expert lab to determine the cross-resistance profile

adapted from EASL HBV guidelines, J Hepatol 2012

Management of HBV Resistance

(Early rescue)
LAM resistance

Switch to TDF (or add ADV)

LDT resistance

Switch to TDF* (or add ADV)

ETV resistance

Switch to TDF* (or add ADV)

ADV resistance

Switch to ETV or TDF (LAM naive)

Switch to ETV (LAM naive + HVL)
Switch to TDF and add a nucleoside (LAM resist.)

TDF resistance**

Switch to ETV (LAM naive)

Add ETV (LAM resistant)*

*the long-term safety of these combinations is unknown

**not seen so far; do genotyping and phenotyping in an expert lab to determine the cross-resistance profile

adapted from EASL HBV guidelines, J Hepatol 2012

5-7 years of ETV or TDF therapy for CHB

Viral suppression in >95% nave/NUC-R patients

HBeAg seroconversion in 40-50%

HBsAg clearance in 1% (20% in selected group)

ALT normalization in ~85%

No major safety issues

Fibrosis regression in 80% of chronic hepatitis

patients and in 75% cirrhotics

Clinical decompensation

Does long-term NUC therapy prevent

decompensation ?

ETV: 3-5 years real life cohort studies in Europe and

Asia (1-4)

TDF: 3-4 years real life cohort studies in Europe (5-6)

1. Wong GL, et al, Hepatology 2013; 2. Zoutendijk R, et al, Gut 2013; 3.Lampertico P, et al,
EASL 2013; 4; Lim et al, Gastroenterology 2014; 5.Lampertico P, et al, AASLD 2013; 6.
Papatheodoridis G et al, AASLD 2013

Does long-term NUC therapy prevent

decompensation ?

ETV: 3-5 years real life cohort studies in Europe and

Asia (1-4)

TDF: 3-4 years real life cohort studies in Europe (5-6)

1. Wong GL, et al, Hepatology 2013; 2. Zoutendijk R, et al, Gut 2013; 3.Lampertico P, et al,
EASL 2013; 4; Lim et al, Gastroenterology 2014; 5.Lampertico P, et al, AASLD 2013; 6.
Papatheodoridis G et al, AASLD 2013

Portal hypertension

Changes of esophageal varices (EV) in 107

compensated cirrhotics LAMTDF treated for 12 yrs
> 500 endoscopies over 12 years of NUC treatment

Patients with F1 EV at baseline

(n=27)

Patients without EV at baseline

(n=80)

100

100

83%
80

80

EV regression
60

60

40

40

20

20

EV progression*

EV development*

7%

10%

0
0

12

24

36

48

60

72

84

96 108 120 132 144

12

24

36

48

60

72

84

96 108 120 132 144

Months
* 6 of 7 progressors (86%) had either LMV-R and/or HCC

Invernizzi F. et al, EASL 2014 (poster 1059)

Hepatocellular carcinoma

HBV and HCC features: summary

Complex pathogenesis (single cell event)

Multiple risk factors (host, virus, interactions)

20-75% of HCC HBV-related

Early clinical diagnosis effective but multifocal pattern

possible (latency period)

Poor prognosis, no curative therapy (OLT)

Competitive causes of liver-related death

Risk factors of HBV-related HCC:

Overview
Host-related risk
factors1

Viral risk factors1

Risk factors related to

hostvirus interaction1

Age >40 years

HBV genotype C

Cirrhosis

Asian ethnicity

HCV or HDV infection

High HBV-DNA level

Male gender

PC/BCP HBV variants

Prolonged HBeAg
positivity

Family history of HCC

Chronic aflatoxin
exposure
High alcohol
consumption

Prolonged HBsAg
positivity
High HBsAg level

PC=precore; BCP=basal core promoter.

Created from 1. Fattovich G, et al. Gastroenterol. 2004;127:S35S50; 2. Hosaka T, et al. Hepatology 2012 Dec 5. [Epub ahead of print]
doi: 10.1002/hep.26180.

ETV for NUC-nave chronic hepatitis B patients

HCC rates per year
Duration of ETV therapy: 4-6 years

HCC per year (%)

4
3
2
1.4%

1.4%

1
0

0.6%

0.5%

18/813

2/237

0.7%

Wong
Hosaka
Hong Kong
Japan
(Gastro. 2013) (Hepato. 2013)

n=754

n=878

Cho
Korea
(Gut 2014)

Lim
Korea
(Gastro. 2014)

0.8%
6/209

9/428

Lampertico Papatheodoridis
Italy
Europe
(EASL 2013)
(EASL 2014)

HCC/yr in untreated CHB patients: 0.6% (Asia) and 0.3% (Europe)

(Fattovich G et al, J Hepatol 2008)

ETV for NUC-nave compensated cirrhotics

HCC rates per year
Duration of ETV therapy: 4-6 years
4.1%

4
HCC per year (%)

3.5%

2.7%

2.6%

2.7%

2.0%

2
1
21/247

n=100

Wong
Chen
Hong Kong
Taiwan
(Gastro. 2013) (EASL 2013)

n=378
Cho
Korea
(Gut 2014)

n=860

18/155

8/111

Lim
Lampertico Papatheodoridis
Korea
Europe
Italy
(Gastro. 2014) (EASL 2013) (EASL 2014)

HCC/yr in untreated cirrhotics: 3.7% (Asia) and 2.2% (Europe)

(Fattovich G et al, J Hepatol 2008)

HCC rates in ETV treated cirrhotics from Hong Kong

a retrospective study
(482 ETV treated, 55 yrs, 72% HBeAg negative, 80%
naive, 77% compensated)

P=0.036
Untreated
26%

ETV

14%

*cirrhosis was a radiological definition (US)

Wong et al, Hepatology 2013

HCC rates in ETV and LAM treated compensated

cirrhotics from Korea - a PS matched study
Chronic hepatitis without cirrhosis

Compensated cirrhosis

HCC rates/year: ~0.7%

HCC rates/year: ~3.4%

LAM

P=0.46

ETV ~4.7%

~20%

P=0.66
ETV

LAM

Lim YS et al, Gastroenterology 2014

HCC risk in TDF treated CHB patients

Observed vs Predicted HCC in combined analysis

(REACH-B)
Untreated
controls

(N=14)

TDF
SIR = 0.50
95% CI (0.294, 0.837)
1st significant
difference

*Statistically significant at nominal -level of 0.05.

SIR, standardized incidence ratio.

Kim R et al, EASL 2013

HCC in NUC nave TDF treated CHB pts

European multicenter studies
Duration of TDF therapy: 4 years
Chronic hepatitis

Compensated cirrhosis
4%

HCC per year (%)

3.7%

3
2
1

1%
0.4%
6/244

5/302

Lampertico Papatheodoridis
(AASLD 2013)
(EASL 2014)

10/99

10/118

Lampertico
(AASLD 2013)

Papatheodoridis
(EASL 2014)

HCC/yr in untreated Europeans: 0.3% (CHB) and 2.2% (Cirrhosis)

(Fattovich G et al, J Hepatol 2008)

Summary and Conclusion

5-7 years with ETV or TDF:

- >95% viral suppression, 85% normal ALT levels
- Histology: fibrosis/cirrhosis regression in most patients

- Decompensation and portal hypertension prevented

- HCC:

- no reduction in CH without cirrhosis

- no reduction in European cirrhotics
- some reduction in Asian cirrhotics (?)
- surveillance with US and AFP recommended

Treat all cirrhotic patients with HBV !

Start antiviral therapy before cirrhosis develops !!

HBV:
How do we improve HCC
screening
(first test)?
And surveillance = regular
testing

Figure 3. Kaplan-Meier survival analysis stratified according to the TNM-Staging System, 6th
edition (n=395).

op den Winkel M, Nagel D, Sappl J, op den Winkel P, et al. (2012) Prognosis of Patients with Hepatocellular Carcinoma. Validation and Ranking of
Established Staging-Systems in a Large Western HCC-Cohort. PLoS ONE 7(10): e45066. doi:10.1371/journal.pone.0045066
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0045066

Figure 2. Kaplan-Meier survival analysis stratified according to the Child-Pugh-Score (n=365).

op den Winkel M, Nagel D, Sappl J, op den Winkel P, et al. (2012) Prognosis of Patients with Hepatocellular Carcinoma. Validation and Ranking of
Established Staging-Systems in a Large Western HCC-Cohort. PLoS ONE 7(10): e45066. doi:10.1371/journal.pone.0045066
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0045066

For screening and surveillance to be

useful:

Must be a survival benefit There is a

survival benefit for patients when HCC is
diagnosed and treated at early stages versus
patients with more advanced, incidentally
detected tumors

Correlation of Post-Transplantation Pathological Confirmation of Early-Stage Hepatocellular

Carcinoma with Overall Survival (Panel A) and Recurrence-free Survival (Panel B) among 48
Patients with Cirrhosis

Mazzaferro V et al. N Engl J Med 1996;334:693-700

When have financial

incentives been used in
health care ?

To reduce utilization of health care

resources
Transforming clinical practice
Improving quality of care or reach a
general health target

Chaix-Couturier et al IJQHC 2000

Change in behavior desired

All patients with appropriate risk for
HCC will undergo screening and
surveillance at the appropriate times
When? appropriate risk > 2% per year
rate of developing HCC [from AASLD
guidelines Sherman an Bruix]
How often? 6 months, earlier if there
are abnormal findings, based on
doubling time of most HCC
How? Ultrasound, CT, MRI, serum
testing

For screening and

surveillance:
Should be cost effective
ultrasound
CT
MRI
Serum testing

Cost Averages Around the Country

Abdominal MRI
Baltimore, MD Abdominal MRI Cost
Average
Boston, MA Abdominal MRI Cost
Average

Denver, CO Abdominal MRI Cost

Average
Detroit, MI Abdominal MRI Cost
Average

CT Scan of Abdomen
Baltimore, MD CT Scan of Abdomen Cost

$2,850 Average

Boston, MA CT Scan of Abdomen Cost

$2,925 Average
Denver, CO CT Scan of Abdomen Cost
Average

$2,475

$2,700
$2,250

$2,550

Detroit, MI CT Scan of Abdomen Cost

Average

$2,925 Minneapolis, MN CT Scan of Abdomen Cost

Average

$2,400
$2,250

Minneapolis, MN Abdominal MRI Cost

Average

$2,625 St. Louis, MO CT Scan of Abdomen Cost

St. Louis, MO Abdominal MRI Cost

Average

$2,625 San Diego, CA CT Scan of Abdomen Cost

San Diego, CA Abdominal MRI Cost

Average

$2,325 Cost Average

$2,625

Seattle, WA CT Scan of Abdomen Cost

$2,700 Average

$2,325

Tampa, FL CT Scan of Abdomen Cost

$2,700 Average

$2,100

San Francisco, CA Abdominal MRI

Cost Average
Seattle, WA Abdominal MRI Cost
Average

Average
Average

San Francisco, CA CT Scan of Abdomen

Tampa,
FL Abdominal MRI Cost
http://www.newchoicehealth.com/Directory/Procedure/42/Abdominal%20MRI
$2,475
Average

$2,325
$2,175

Barriers to screening
effectiveness :
limited or outdated knowledge
limited access to appropriate testing
and treatment.
lack of financial incentives
influences above

How to assure screening

and surveillance take place:
Identify all populations at risk
education of specialists and primary
physicians, patients to recognize
when patients require screening and
then surveillance
Incentivize the patient : Make testing
available at minimal or no cost
Incentivize practitioners with
practices with high adherence to

Examples of Randomized studies showing

benefit from financial incentivization
Not new news!
Who

Intervention and
outcome

Results

Ref

Insurers

Advise as to thresholds
that trigger financial
sanctions against provider
for Rx

Reduction of Rx by
physicians when
threshold is known

Hickson et al
Am J Prev Med
1998, 14: 89

Physician
s

Performance based
financial incentive $0.80
-1.60 per immunization

Improved
immunization rate

Kouides et al
Pediatrics
1987, 80:344

From: Effect of Pay-for-Performance Incentives on Quality of Care in Small

Practices With Electronic Health Records: A Randomized Trial
JAMA. 2013;310(10):1051-1059. doi:10.1001/jama.2013.277353

Incentivizing physicians: will it

work?
Must avoid creating conflict between
revenue and quality of care
Remember there are also nonfinancial incentives as well for better
behavior and care

Financial Incentives: Yes

We are human and respond to incentivizes
We want to do well for our patients
incentivize medical professionals to keep
current and adhere to guidelines that should
drive best practices achieves this goal
avoid conflicts of interest
Incentivize patients keep care and testing
affordable and easy to obtain
Saving lives and saving dollars and sharing
some of the savings with providers is
possible if we are good stewards of our
resources

acknowledgements

Pietro Lampertico
Heshem El Serag
Carrie Frenette
Michael Schilsky
Lewis Roberts
Morris Sherman

For all the great slide sharing