does viral cure prevent hcc...

Does Viral Cure Prevent HCC Development

Head, Division of Gastroenterology and Hepatology Director, Institute of Digestive Disease Director, Center for Liver Health Assistant Dean, Faculty of Medicine The Chinese University of Hong Kong

Prof. Henry LY Chan

Lamivudine to reduce HCC in early HBV cirrhosis Controversial in Asian randomized controlled trial

Placebo (n=215) Lamivudine (n=436)

Excluding 5 cases in yr1: HR=0.47; P=0.052

Percentage with diagnosis

Time to diagnosis (months)

Lamivudine

Placebo

P=0.047

10%

5%

Liaw YF et al. N Engl J Med 2004; 351: 1521-31

Meta-analysis NA (lamivudine) can reduce risk of HCC

Total events: 31 (Nucleotide/side analogues), 117 (Placebo/no treatment) Test for heterogeneity: Chi² = 12.57, df = 3 (P = 0.006), I² = 76.1% Test for overall effect: Z = 3.34 (P = 0.0008)

Sung JJ, et al. Aliment Pharmacol Ther 2008;28:1067-77

Adapted from 1. EASL. J Hepatol. 2009;50:227-42. 2. Tenney DJ, et al. EASL 2009. Oral presentation #20. 3. Marcellin P, et al. Hepatology 2009;50(4, Suppl.):532A-3A. 4. Heathcote EJ,

et al. Hepatology 2009;50(4, Suppl.):533A-4A 5. Marcellin P, et al. Lancet 2013;381:468-75.

Entecavir and Tenofovir are the first line NA treatment for CHB

24% 38% 49% 67% 70%

0% 3% 11% 18% 29%

4% 17%

0.2% 0.5% 1.2% 1.2%

0%

1.2%

0% 0% 0%

1.2%

LAM

ADV

LdT

ETV

TDF

Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Drug

Generation

Not head-to-head trials; different patient populations and trial designs

1st

2nd

3rd

0%

Kim R, et al. EASL 2013

HCC in TDF-treated patients - observed vs. predicted

• Progressive divergence between the predicted and observed no. of HCC beyond 3.3 years.

• Standardized incidence ratios – At 2.4 years = 0.94 (95% CI 0.47–1.88) – At 3.3 years = 0.89 (0.48–1.66) – At 5.5 years = 0.55 (0.32–0.94)

6-year follow-up data of 641 patients, 13 cases of HCC 10th HCC case occurred at 3.3 years REACH-B model predicted 11.2 cases at this time point

Estimated annual incidence of HCC in patients based on 5 year FU

1,05% 0,74%

0,54%

3,24%

2,74%

2,26%

0%

1%

2%

3%

4%

Wu et al Hosaka et al Kumada et al

Entecavir/NA* Control

Wu CY, et al. Gastroenterology 2014;147:143-51; Hosaka T, et al. Hepatology 2013;58:98-107;

Kumada T, et al. J Hepatol 2013;58:427-33.

316 316 21595 21595 117

Adj HR 0.23 Adj HR 0.37

*

Propensity score matched

117

Adj HR 0.28

Estimated annual incidence of HCC

Toranomon Hospital cohort: reduction in HCC incidence with ETV greater among cirrhotic patients

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

1 3 5 Treatment duration (years)

50

40

30

20

10

0

0

Cum

ulat

ive

HCC

rate

(%)

Cirrhosis

Log-rank test: P<0.001

79 85 85

79 72 76 65

53 35 54 47

17 ETV Control

No at risk

50

40

30

20

10

0

0 1 3 5

Log-rank test: P=0.440

No Cirrhosis

1.6% 3.6%

2.5% 0%

237 231 231

237 192 201 181

132 66 169 143

27

Control

ETV

ETV Control

No at risk

Treatment duration (years ) Cu

mul

ativ

e HC

C ra

te (%

)

20.9%

4.3%

38.9%

7.0%

Control

ETV

Efficacy of entecavir therapy adjusted for MELD score and maintained viral suppression in cirrhotic patients

Clinical outcomes Hazard ratio 95% CI P values

Hepatic events 0.51 0.34 – 0.78 0.002

HCC 0.55 0.31 – 0.99 0.049

Liver-related mortality 0.26 0.13 – 0.55 <0.001

All-cause mortality 0.34 0.18 – 0.62 <0.001

Wong GLH, Chan HLY, et al. Hepatology 2013;58:1537-47

482 ETV treated (mean 36 months) vs 69 untreated historic control patients (mean FU 114 months) with radiological liver cirrhosis in Hong Kong

Estimated annual incidence of HCC in cirrhotic patients based on 5 year FU

2,76%

3,90%

1,40%

5,28% 4,94%

7,78%

0%1%2%3%4%5%6%7%8%9%

Hong Kong Taiwan Japan

Entecavir/NA* Untreated control

Wong GL, et al. Hepatology 2013;58:1537-47; Wu CY, et al. Gastroenterology 2014;147:143-51;

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

482 69 79 85 3016 2847

HR N/A

Adj HR 0.72 Adj HR 0.55

*


Benefit of NA especially significant among younger, non-cirrhotic and non-diabetic patients

Wu CY, et al. Gastroenterology 2014;147:143-51

Propensity score matched study from Taiwan national database

Non-cirrhotic patients Annual incidence of HCC <1%

0,19%

0,17%

0,37%

0,76%

0,92%

0,0% 0,2% 0,4% 0,6% 0,8% 1,0%

HBV DNA <200 IU/mL

HBV DNA 200–1999 IU/mL

HBV DNA 2000–19,999 IU/mL

HBV DNA 20,000–199,999 IU/mL

HBV DNA ≥200,000 IU/mL

Risk of HCC (average incidence, %)

Modified from Tseng et al. Gastroenterology 2012 and Chan HL. Gastroenterology 2012

ERADICATE-B Study 2,688 non-cirrhoic Taiwanese CHB patients followed for a mean of 14.7 years

Antiviral therapy

Estimated annual incidence of HCC in non-cirrhotic patients based on 5 year FU

0,66% 0,68% 0,50% 0,60%

2,97%

0,72%

0%

1%

2%

3%

4%

Hong Kong Taiwan Japan

Entecavir/NA* Untreated control

Wong GL, et al. Hepatology 2013;58:1537-47; Wu CY, et al. Gastroenterology 2014;147:143-51;

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

1023 355 231 237 18579 18748

HR 0.27

*

From national database, ?under-

labeling of cirrhosis


LSM-HCC Score – combining HBV DNA and cirrhosis for treatment indication

Factors Score Age > 50 years +10 ≤ 50 years 0 Albumin ≤ 35g/l +1 > 35g/l 0 HBV DNA > 200,000 IU/ml +5 ≤ 200,000 IU/ml 0 Liver stiffness ≤ 8.0 kPa 0 8.1-12.0 kPa +8 > 12.0 kPa +14

0,1

1,0

2,5

0,0

0,5

1,0

1,5

2,0

2,5

3,0

0-10 11-20 21-30

Est.

annu

al in

cide

nce

of H

CC (%

)

1555 CHB patients (38% received antiviral therapy) FU 69±9 months 38 patients developed HCC

Modified from Wong GL, et al. J Hepatol 2014;60:339-45

Antiviral therapy

Choice of NA makes a difference? Controversial among cirrhotic patients

0,71% 0,98%

4,10%

1,40%

0,80% 0,50%

4,35% 4,44%

0%

1%

2%

3%

4%

5%

Korean, non-cirrhotic

Japanese, non-cirrhotic

Korean, cirrhotic Japanese, cirrhotic

Entecavir Lamivudine

Lim YS, et al. Gastroenterology 2014;147:152-61 Hosaka T, et al. Hepatology 2013;58:98-107

860 860 878 878 79 49 237 133

P=0.126

P=0.043 P=0.42

P=0.86


Lamivudine resistance: unrescued in Japanese study

HBsAg seroclearance is associated with excellent clinical outcome

Treatment naïve patients on lamivudine (adefovir rescue for resistance) or entecavir Propensity score matched (1:4)

Kim GA, et al. Gut 2014;63:1325-32

VIRGIL ETV study Virologic response is associated with a lower probability of disease progression Retrospective cohort study in 10 large European centers Study population (N=372) Median follow-up 20 (3–51) months 98 patients have liver cirrhosis

0 48 96 144 0

10

20

30

No virologic response

Virologic response (<80 IU/mL)

P=0.05

Hazard rate (HR): 0.29, 95% CI 0.08–1.00

Time at risk (weeks)

Prob

abili

ty o

f eve

nt (%

)

* Composite endpoint: Hepatic decompensation, jaundice, variceal bleeding, ascites or encephalopathy, HCC, death.

Zoutendijk R, et al. Gut 2013 May;62(5):760-5

Virologic remission is an independent factors preventing HCC development in cirrhotic patients under ETV treatment

Non-cirrhotic patients Adjusted HR 95% CI P value Albumin <35 g/L 17.5 2.0-63.4 0.04 Duration of virologic remission ≥24 months 0.6 0.4-1.1 0.08

Cirrhotic patients Adjusted HR 95% CI P value Albumin <35 g/L 7.1 1.8-28.7 0.02 Total bilirubin ≥18 umol/l 5.9 0.5-59.5 0.48 Duration of virologic remission ≥24 months 0.3 0.2-0.7 0.003

1531 CHB patients (69% treatment naïve) on ETV for 42±13 months 332 (22%) had liver cirrhosis

Adjusted for age, gender, albumin, bilirubin, ALT, HBeAg, baseline HBV DNA and HBsAg

Wong GL, et al. Gastroenterology 2013;144:933-44

Cumulative incidence of HCC among incomplete NA responders is higher than complete responders

2,3%

5,9%

11,4%

4,5%

8,6%

18,8%

0%

5%

10%

15%

20%

Year 1 Year 3 Year 5

Cho JY, et al. Gut 2014 (Epub ahead of print)

1378 treatment naïve patients on NA for mean of 42.4 months Liver cirrhosis 32.3% Complete response = HBV DNA <2000 IU/ml

P=0.028

Complete responders (n=1132)

Incomplete responders (n=246)

Incidence of HCC

5 year cumulative HCC in HBeAg-negative pts Complete NA responders > inactive carriers

N 5-year cumulative incidence P

No cirrhosis Complete responder 316 6.9% <0.001

Inactive carrier 884 0.8%

Cirrhosis Complete responder 223 15.3% <0.001

Inactive carrier 130 6.0%

Cho JY, et al. Gut 2014 (Epub ahead of print)

HBeAg-negative complete responders have higher baseline HBV DNA (5.52 vs 1.82 log IU/ml) , ALT and baseline cirrhosis (41% vs 13%) than inactive carriers

Primary non-response from treatment naïve CHB to entecavir 0.5mg daily NOT predictive of maintained response

Yang et al Korea

Bang et al Korea

N 1254 355

HBeAg positive 55% 58%

Primary non-response 1.2-1.3% 1.7%

Primary non-response <2 log reduction at month 6 (AASLD); <1 log reduction at month 12 (EASL)

Yang YJ, et al. Hepatology 2014;59:1303-10; Bang SJ, et al. Dig Dis Sci 2013;45:600-5.

FU (months) 54 8-36

Undetectable HBV DNA 100% 100%

Partial response from treatment naïve CHB to entecavir 0.5mg daily Predictive of maintained response at 3 years

Wong et al Hong Kong

Bang et al Korea

Kwon et al Korea

Ko et al Korea

N 440 355 227 128

HBeAg positive 36% 58% 65% 66%

Partial response 23.5% 17.7% 28.2% 14.1%

Partial response = > 1 log reduction but detectable HBV DNA at month 12

Wong GL, et al. Aliment Pharmacol Ther 2012;35:1326-35; Bang SJ, et al. Dig Dis Sci 2013;45:600-5; Kwon DH, et al. Gut Liver 2013;7:712-8; Ko SY, et al. Scand J Gastroenterol 2012;47:1362-7.

UD HBV DNA

Month 24 NA 31% 45% NA

Month 36 58% 45% 74% NA

Tenofovir is effective to suppress HBV DNA in ETV suboptimal responder

14 patients (12 HBeAg-positive) on ETV for 65.4 (26-126 weeks) 12 patients treatment naïve, 1 LMV exposed, 1 pegIFN exposed HBV DNA 7.55 (5.30-9.40) log copies/ml

Pan CQ, et al. J Viral Hepat 2012

TDF is equally effective as TDF+ETV for ETV partial responders

Complete viral suppression

ETV+ADV (n=5)

TDF (n=6)

ETV+TDF (n=31)

6 months 20% 83% 83%

12 months 20% 100% 97%

42 patients on entecavir with incomplete viral suppression with no drug resistance All Asian, 95% HBeAg positive HBV DNA at time of switch = 3.32±0.74 log IU/ml Rescue treatment 14 (3-30) months; one patient has complete viral suppression by ETV+TDF at month 3 and other have treatment >6 months

Yip B, et al. Dig Dis Sci 2012;57:3011-6.

Combination of tenofovir and emtricitabine improves viral suppression in HBeAg-positive patients with high viral load

Univariate analysis Multivariate analysis

Non-responders

N=25

Responders N=82

p-value Odds ratio 95% CI

Female, n (%) 5 (20) 46 (56) 0.002 6.0 1.9-18.2

Baseline HBsAg, mean log10 4.88 4.69 0.010

TDF/FTC treatment, n (%) 7 (28) 47 (57) 0.012 3.9 1.4-11.1

Baseline HBV DNA, mean log10 9.26 9.13 0.036

HBeAg +ve pts with high HBV DNA and normal ALT (n=126)

TDF 300 mg (n=64)

TDF 300mg + FTC 200mg (n=62)

1:1 Randomization Response = HBV DNA < 69

IU/ml at week 192

Chan HL, et al. Gastroenterology 2014; 146:1240-8.

14/19 (74%) HBV DNA <400 copies/mL

At Week 240/last visit

57/641 (9%) eligible to add FTC to TDF at/after Week 72

19/57 (33%) remained on TDF monotherapy

38/57 (67%) added FTC to TDF

24/38 (63%)

HBV DNA <400 copies/mL At Week 240/last visit

Studies 102/103: Adding FTC does not improve viral suppression vs Maintaining TDF Monotherapy

All subjects analyzed with >400 copies/mL had no TDF resistance detected.

Marcellin P, et al. AASLD 2011. Oral 238.

Summary • There is sufficient data to suggest antiviral therapy can reduce the

risk of HCC in Asian cirrhotic patients – Annual incidence of HCC – 1.4% - 3.9%

• Conflicting data on benefit of antiviral therapy among non-cirrhotic

patients – Annual incidence of HCC – 0.5% - 0.7%

• Complete viral suppression can improve HCC prevention

• Only 58%-74% partial responders at 1 year have complete HBV DNA

suppression at 3 years

• Tenofovir switch is effective for entecavir partial responders

does viral cure prevent hcc...

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