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The Impact of HBV Therapy on Fibrosis and Cirrhosis This program is supported by an educational grant from Gilead Sciences Jordan J. Feld, MD, MPH Associate Professor of Medicine University of Toronto Hepatologist Toronto Centre for Liver Disease Sandra Rotman Centre for Global Health Toronto, Canada

The Impact of HBV Therapy on Fibrosis and Cirrhosis · The Impact of HBV Therapy on Fibrosis and Cirrhosis ... University of Toronto ... et al. Gastroenterology. 2006;130:678-686

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The Impact of HBV Therapy on Fibrosis and Cirrhosis

This program is supported by an educational grant from Gilead Sciences

Jordan J. Feld, MD, MPHAssociate Professor of MedicineUniversity of TorontoHepatologistToronto Centre for Liver DiseaseSandra Rotman Centre for Global HealthToronto, Canada

About These Slides

§ Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients

§ When using our slides, please retain the source attribution:

§ These slides may not be published, posted online, or used in commercial presentations without permission. Please contact [email protected] for details

Slide credit: clinicaloptions.com

Disclosures

Jordan J. Feld, MD, MPH, has disclosed that he has received funds for research support from Abbott, AbbVie, Gilead Sciences, Janssen, Merck, and Regulus and consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck.

What Happens After HBeAg Loss?

Slide courtesy of Jordan J. Feld, MD, MPH.

Progressive fibrosis may occur more rapidlyin HBV than in HCV infection

HBeAg+ HBeAg- HBeAb+

Progressive fibrosis

InfectionMos-Yrs

HBV DNA

Immune clearanceImmune tolerance

ALT

Slide credit: clinicaloptions.com

§ Virus:– HBV DNA levels

(except for immune tolerant)

– HBeAg positive

– HBV genotype (?)

– C > B > A/D

Risk Factors for Progressive Fibrosis

§ Host:– Male sex

– Increasing age

– Metabolic syndrome

– Alcohol consumption

– Coinfections

– HCV, HDV, HIV

Slide credit: clinicaloptions.com

Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

REVEAL: HBV DNA Level and Risk of Cirrhosis§ Long-term (mean follow-up: 11.4 yrs) cohort study to

determine risk of cirrhosis and HCC in untreated, HBsAg-positive individuals in Taiwan (N = 3582)

Follow-up (Yrs)

Cum

ulat

ive

Inci

denc

e of

Liv

er C

irrho

sis

0.4

0.3

0.2

0.1

00 1 2 3 4 5 6 7 8 9 10 11 12 13

Baseline HBV DNA Level (copies/mL)

Slide credit: clinicaloptions.com

≥ 1 million 100,000-999,99910,000-99,999300-9999< 300

§ Prospective study in same REVEAL cohort (N = 3653)

§ Increased HCC incidence with increasing DNA levels (P < .001)

§ HCC can occur in the absence of cirrhosisChen CJ, et al. JAMA. 2006;295:65-73.

REVEAL: HBV DNA Level and Risk of HCC

Follow-up (Yrs)

Cum

ulat

ive

Inci

denc

e of

HCC

(%)

14

6

4

2

00 1 2 3 4 5 6 7 8 9 10 11 12 13

Baseline HBV DNA (copies/mL)≥ 1 million 100,000-999,99910,000-99,999300-9999< 300

12

10

8

Slide credit: clinicaloptions.com

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

REVEAL: Risk Factors for HCC

Factor Adjusted HR 95% CI P ValueMale sex 2.1 1.3-3.3 .03Age (per yr) 1.09 1.07-1.11 < .001HBeAg positive 2.6 1.6-4.2 < .001Cirrhosis 9.1 5.9-13.9 < .001HBV DNA (copies/mL)§ < 300§ 300-9999§ 10,000-99,999§ 100,000-999,999§ ≥ 1,000,000

1.01.12.36.66.1

Ref0.5-2.31.1-4.93.3-13.12.9-12.7

< .001*.86.02

< .001< .001

*P value for trend.

Slide credit: clinicaloptions.com

Does Therapy Change the Outcome?

Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.

HBV Treatment Reduces Risk of Disease Progression Including Decompensation§ Placebo-controlled, double-blind, parallel group study of pts with chronic HBV

infection and cirrhosis (F4) (N = 651) followed until HBeAg seroconversion or disease progression*

Pts

With

Dis

ease

Pro

gres

sion

(%)

P = .001

25

20

15

10

5

030181260 36

n = 198

n = 173

n = 417 n = 385

n = 43

n = 122

24

Lamivudine

Placebo

Mos*Hepatic decompensation, HCC, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease.

Slide credit: clinicaloptions.com

§ Prospective cohort study in pts with HBV and first-onset complications of decompensated cirrhosis (N = 707)

§ Antiviral therapy improved transplant-free survival over 5 yrs (P = .0098 vs untreated)

HBV Treatment Reduces Risk of Liver Transplant

Jang JW, et al. Hepatology. 2015;61:1809-1820.

Treated,* responder (n = 245)Treated,* nonresponder (n = 178)Untreated (n = 284)

*Treated predominantly with lamivudine (n = 203) or entecavir (n = 198).

Bonferroni-adjusted P < .0003LT-F

ree

Surv

ival

(%)

Mos0 8412 24 36 48 60 72

100

80

60

40

20

0

Slide credit: clinicaloptions.com

Many HBV Treatment Endpoints Indicate None Is Ideal; Need to Use Surrogates§ Complications take yrs to decades to develop—

difficult to use as treatment endpoints§ Instead we use surrogate endpoints:

– Biochemical– Normalization of ALT

– Serologic– HBeAg loss and/or seroconversion for HBeAg positive

HBV– Ideally HBsAg loss and/or seroconversion

– Virologic– Histologic

Slide credit: clinicaloptions.com

§ Open-label study of TDF in pts with chronic HBV infection (N = 585)

1. Buti M, et al. Dig Dis Sci. 2015;60:1457-1464.2. Marcellin P, et al. Lancet. 2013;381:468-475.

Long-term TDF in Pts With HBV: Reversal of Inflammation

Pts

(%)

P < .001P < .001

80%

Knodell Necroinflammatory Score

§ Necroinflammation improved over 5 yrs (n = 348 matched biopsies)[2]

8%

Parameter Outcome at 7 Yrs[1]

Normalized ALT, % (n/N)§ ITT*§ On treatment

57.1 (323/566)80.0 (328/410)

HBV DNA < 29 IU/mL,% (n/N)§ ITT§ On treatment

70.1 (418/596)99.3 (430/433)

HBeAg loss,† % (n/N) 54.5 (84/154)HBe seroconversion,†% (n/N) 39.6 (61/154)

HBsAg loss,† K-M % (95% CI) 11.8 (8.1, 16.9)

HBs seroconversion,†K-M % (95% CI) 9.7 (6.4, 14.6)

*Pts with data missing or FTC added counted as failures.†HBeAg-positive population.

100

80

60

40

20

0Baseline Yr 1 Yr 5

10-14

Slide credit: clinicaloptions.com

7-9 4-6 0-3

Marcellin P, et al. Lancet. 2013;381:468-475.

Long-term TDF in Pts With HBV: Regression of Fibrosis, Cirrhosis§ Overall regression of fibrosis in 51% of pts through 5 yrs

(176/348 pts with matched biopsies)§ Reversal of cirrhosis in 74% of pts through 5 yrs (71/96 pts with

cirrhosis at baseline)Ishak Fibrosis

Score

Pts

(%)

100

80

60

40

20

0

6543210

Baseline Yr 1 Yr 5

38%

39%

12%

63%

P < .001P < .001

Slide credit: clinicaloptions.com

Chang TT, et al. Hepatology. 2010;52:886-893.

Long-term Entecavir in Pts With HBV: Reversal of Inflammation§ Histologic and virologic improvements evaluated by liver biopsy

in HBV pts (N = 69) with ≥ 3-yr cumulative entecavir treatment§ Median time on entecavir: 6 yrs (range: 3-7)

Pts

(n)

Parameter, % (n/N) OutcomeALT ≤ 1 x upper limit of normal 86 (49/57)

HBV DNA < 300 copies/mL 100 (57/57)

HBeAg loss 55 (22/40)

HBe seroconversion 33 (13/40)

HBsAg loss 0 (0/56)

60

50

40

30

20

10

0Baseline Wk 48 Long Term

Slide credit: clinicaloptions.com

Knodell Necroinflammatory Score10-14 7-9 4-6 0-3 Missing

Chang TT, et al. Hepatology. 2010;52:886-893.

Long-term Entecavir in Pts With HBV: Regression of Fibrosis, Cirrhosis§ Regression of fibrosis (≥ 1-point decrease in Ishak score) in 88% of

pts (50/57 pts with matched biopsies and baseline Knodell scores ≥ 2)

§ Reversal of cirrhosis in 4/10 pts with cirrhosis at baseline (median decrease in Ishak score: 3 points)

n = 57 matched biopsies

6

5

4

3

2

1

0

Missing

50

40

30

20

10

0Baseline Wk 48 Long

Term

60

Pts

(n)

Ishak Fibrosis Score

Slide credit: clinicaloptions.com

HCC Incidence in Pts With Chronic HBV Infection

1. Wong GL, et al. Hepatology. 2013;5:1537-1547.2. Wu CY, et al. Gastroenterology. 2014;147:143-151.3. Hosaka T, et al. Hepatology. 2013;58:98-107.

13.8

482 69

26.4

6.62

19.08

21,595

7.0

38.9

79 85

aHR: 0.31(95% CI: 0.27-0.53)

aHR: 0.55(95% CI: 0.31-0.99)

Slide credit: clinicaloptions.com

Nucleos(t)ide analoguesControl

0

10

20

30

40

n =

Hong Kong[1]

(Cirrhosis only)Taiwan*[2] Japan[3]

(Cirrhosis only)

5-Yr

Cum

ulat

ive

Inci

denc

e of

H

CC

21,595

*Incidence rates include cirrhotic pts (13.6% of pts had cirrhosis at baseline) and noncirrhotic pts.

HCC Incidence in Pts With Chronic HBV Infection but Without Cirrhosis

1. Wong GL, et al. Hepatology. 2013;5:1537-1547.2. Wu CY, et al. Gastroenterology. 2014;147:143-151.3. Hosaka T, et al. Hepatology. 2013;58:98-107.

0

3.3984 355

3.05-Yr

Cum

ulat

ive

Inci

denc

e of

H

CC

2.5 3.6237 231

10

20

30

40Greater benefit in pts with cirrhosis

n =

Slide credit: clinicaloptions.com

Nucleos(t)ide analoguesControl

Hong Kong[1]

(No cirrhosis)Taiwan*[2] Japan[3]

(No cirrhosis)*Incidence rates include cirrhotic pts (13.6% of pts had cirrhosis at baseline) and noncirrhotic pts.

6.62

19.08

21,59521,595

aHR: 0.31(95% CI: 0.27-0.53)

Cho JY, et al. Gut. 2014;63:1943-1950.

Is HBV Suppression the Same as Inactive Disease?§ Retrospective cohort study of

treatment-naive pts with HBV starting oral nucleos(t)ide analogues (n = 1378) vs HBeAg-negative pts with inactive CHB (n = 1014)

– Group receiving nucleos(t)ide analogues divided by continuous viral suppression (complete vs incomplete responder)

§ Spontaneous control better than treatment

Complete responders

Inactive CHB

P < .001

Cum

ulat

ive

Inci

denc

e of

HC

C (%

)Mos

60

50

40

30

20

10

00 12 24 36 48 60 72

Pts at Risk, nNUC CRInactive CHB

11321014

848918

564724

497594

380469

128304

1980

Slide credit: clinicaloptions.com

Reduction in HCC Mortality Through National Viral Hepatitis Therapy Program§ Pts receiving treatment for chronic hepatitis after start of program in 2003 in Taiwan:

157,570 (HBV) and 61,823 (HCV)§ Reduced rate of HCC mortality in all age cohorts by 5-8 yrs after introduction of national

therapy program

Chiang CJ, et al. Hepatology. 2015;61:1154-1162.

30-39 40-49 50-59 60-69

1.00 1.00 1.00 1.00 0.98

0.8

0.6

0.4

0.2

0

Sex-

Adj

uste

d H

CC

M

orta

lity

Rat

e R

atio

0.93*

0.79†

1.00.88*

0.66†

0.92*

0.76† 0.77†

2000-20032004-20072008-2011

Age Group (Yrs)*P < .01 vs 2000-2003.†P < .005 vs 2000-2003.

Slide credit: clinicaloptions.com

§ Retrospective study comparing prognostic performance of TE vs FIB-4 serological biomarker score to identify risk of HCC in pts with CHB (N = 1308)

§ TE was more accurate than FIB-4 at identifying low HCC risk

Kim SU, et al. Medicine (Baltimore). 2016;95:e3434.

Identifying Risk of HCC: Transient Elastography vs Biomarkers

Yrs

TE

Cum

ulat

ive

Inci

denc

e

0.4

0.3

0.2

0.1

070 1 2 3 4 5 6

LSM ≤ 8 kPa8 < LSM ≤ 13 kPa13 < LSM ≤ 18 kPa18 < LSM ≤ 23 kPaLSM > 23 kPA

Yrs

FIB-4

Cum

ulat

ive

Inci

denc

e

0.4

0.3

0.2

0.1

070 1 2 3 4 5 6

FIB-4 < 1.251.25 ≤ FIB-4 < 1.701.70 ≤ FIB-4 < 2.40FIB-4 ≥ 2.40

Slide credit: clinicaloptions.com

Based on This . . .Whom and How Should We Treat?

Updated AASLD Guidelines: When to Treat

Terrault NA, et al. Hepatology. 2016;63:261-283.

HBeAg Positive HBeAg NegativeHBV DNA,

IU/mLALT Histologic

DiseaseHBV DNA,

IU/mLALT Histologic

DiseaseAny > 2 x ULN N/A Any > 2 x ULN N/A

> 20,000 Any Any > 2000 Any AnyAny Any Cirrhosis Any Any Cirrhosis

Do not stop treatment in HBeAg-negative pts with cirrhosis

Changes to guidance:

§ Lower threshold for treating HBeAg-negative pts

§ Treat all pts with cirrhosis regardless of HBV DNA

Slide credit: clinicaloptions.com

AASLD Guidelines: Initial Treatment

Terrault NA, et al. Hepatology. 2016;63:261-283.

Treatment Preferred NotesEntecavir Yes (unless previous history

of lamivudine resistance)High potency, high genetic barrier to resistance

Tenofovir Yes High potency, high genetic barrier to resistancePegIFN Yes Less safe in pts with cirrhosisAdefovir No Low genetic barrier to resistanceLamivudine No Low genetic barrier to resistanceTelbivudine No Low genetic barrier to resistance

§ Treatment with antivirals does not eliminate the risk of HCC, and surveillance for HCC should continue in persons who are at risk

Slide credit: clinicaloptions.com

TAF vs TDF in Pts With HBV Infection: Efficacy§ Multicenter phase III studies in pts with chronic HBV infection

(N = 1298), including pts with compensated cirrhosis

1. Seto WK, et al. AASLD 2016. Abstract 67. 2. Chan HL, et al. EASL 2016. Abstract GS12. 3. Buti M, et al. EASL 2016. Abstract GS06.

HBeAg-Positive Pts[2]

(N = 873)HBeAg-Negative Pts[3]

(N = 425)Outcome, % TAF TDF P Value TAF TDF P ValueHBV DNA < 29 IU/mL at Wk 72[1] 71.6 71.9 .78 92.6 92.1 .84

ALT normalization at Wk 48§ Central laboratory criteria*§ AASLD laboratory criteria†

7245

6736

.18.014

8350

7532

.076<.001

HBeAg§ Loss at Wk 48§ Seroconversion at Wk 48

1410

128

.47

.32

HBsAg§ Loss at Wk 48§ Seroconversion at Wk 48

<1<1

<10

.52

.22

Slide credit: clinicaloptions.com

*ULN for men, ≤ 43 U/L (≤ 35 U/L if age ≥ 69 yrs); for women, ≤ 34 U/L (≤ 32 U/L if age ≥ 69 yrs).†ULN for men, ≤ 30 U/L; for women, ≤ 19 U/L.

TAF vs TDF in Pts With HBV Infection: Safety§ Multicenter phase III studies in pts with chronic HBV infection

(N = 1298), including pts with compensated cirrhosis

1. Seto WK, et al. AASLD 2016. Abstract 67. 2. Agarwal K, et al. AASLD 2016. Abstract 1844. 3. Izumi N, et al. AASLD 2016. Abstract 1904.

Outcome TAF TDF P Value

Mean change in BMD at Wk 72, %[1]

§ Hip§ Spine

-0.16-0.57

-1.86-2.37

< .001< .001

Median change in serum creatinine at Wk 48, mg/dL[2] 0.01 0.02 .012Median change in eGFR at Wk 48, mL/min[2] -1.2 -5.4 < .001

Mean change in FibroTest score at Wk 48[3]

§ HBeAg-positive pts§ HBeAg-negative pts

-0.07-0.05

-0.04-0.03

.007

.028

Slide credit: clinicaloptions.com

Summary

§ HBV is a very dynamic disease§ Fibrosis may progress quickly both in HBeAg-positive and

HBeAg-negative disease§ Antiviral therapy can:

– Suppress HBV DNA– Reduce inflammation—ALT and HAI– Reverse fibrosis– Reduce the risk of HCC and liver-related events

§ New agents have similar efficacy on surrogate endpoints and a better safety profile

Slide credit: clinicaloptions.com

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