Mortality projection in the coming yearsregist2.virology-education.com/2015/1euhep/05_Buti.pdfSmith BD, et al. Ann Intern Med. 2012;157:817‐822. HCV Screening in USA Birth cohort

Mortality projection in the coming years

Maria Buti

Hospital Universitario Valle Hebron. Barcelona, Spain

September 2015Frankfurt

Financial Disclosure Statement

• Consultant for: AbbVie, Bristol-Myers Squibb, Gilead, Novartis, Janssen, and MSD.

The Global burden of liver disease attributable to hepatitis B, hepatitis C, and alcohol: increasing mortality, differing causes

Global Burden of Disease, 2010•HCC deaths, 750,000•Cirrhosis deaths, 1.03 million•Deaths increased from 1.25 to 1.75 million per year

– Increasingly due to HCC– 25% due to HCV– 46% due to HBV

‐ HCV was the predominant cause of liver cancer/cirrhosis deaths in the USA (40/41%) and Western Europe (36/40%), with HBV predominating in China (54/46%) and India (48/35%)

Cowie BC and MacLachian JH. The Liver Meeting 2013; Abstract 23

Lozano et al., The Lancet December 15 2012

If all deaths related to these diseases were directly counted in the main GBD 2010 cause list, hepatitis B would be the 15th ranked cause of death and hepatitis C would be the 25th ranked cause of death.

Percent Change in age‐adjusted liver cirrhosis mortality between 1980 and 2010

HCV-Related Decompensated Cirrhosis and HCC Projected to Rise in the US

• HCV-related decompensated cirrhosis and HCC are rising as manifestations of liver disease in aging population1

• 73.4% of HCV-related deaths occurred among persons 45-64 years of age– Median age was 57 years; ~20 years less than the average lifespan of persons living in the US2,*

1. Davis GL, et al. Gastroenterology. 2010;138:513‐521; 2. Smith BD, et al. MMWR Recomm Rep. 2012;61(RR‐4):1‐32.

Num

ber o

f Cases

1950 1960 1970 1980 1990 2000 2010 2020 2030

160,000140,000120,000100,00080,00060,00040,00020,000

0

Hepatocellular Carcinoma

Decompensated Cirrhosis

Projection based on a dynamic, multicohort, natural history model of data from the CDC, NHANES, and a review of the medical literature, with conservative estimates of disease progression and complications. Model assumes first‐year mortality of 80%‐85% for HCC. *During the period from 1999 to 2007.

Increasing Health Care Costs Associated With Progressive Liver Disease in the Aging HCV‐Infected Population

Razavi H, et al. Hepatology. 2013. Epub ahead of print.

Prevalence(95% CI)

Health Care Cost(95% CI)

While the prevalence of HCV infection is declining from its peak, the incidence of advanced liver disease and associated health care costs continue to rise

Modeling does not take into account any impact of birth cohort screening A system dynamic modeling framework was used to quantify the HCV‐infected population, the disease progression, and the associated cost from 1950‐2030.CI=confidence interval.

Prev

alen

ce (M

illio

n)

Hea

lth C

are

Cos

t (B

illio

n)

Indirect economic costs of HCV

• Data from the 2009 US National Health and Wellness Survey showed patients with HCV were significantly less likely to be employed vs controls (p<0.0001). HCV in the EU population significantly impacts several domains of HRQL (p<0.05)

• DiBonaventura M et al. J Med Econ 2011;14:253–61 DiBonaventura M et al. Eur J Gastroenterol Hepatol 2012;24:869–77

Pat

ient

s (%

)

Absenteeism Presenteeism Overall work impairment

Activity impairment

20

30

10

0

Patients with HCVControls

Mortality projection related to HCV In Europe

Razavi H et al. J Viral hepatitis 2014

Changes in the number of liver transplants, decompensated cirrosis and HCC cases over time

Changes in HCV disease burden over time


Mortality projection related to HCV In Europe


Changes in the number of liver transplants, decompensated cirrosis and HCC cases over time

Changes in HCV disease burden over time


Lee M‐H, et al. J Infect Dis. 2012;206:469‐477.

REVEAL HCV: Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (1991‐2008).Anti‐HCV seronegative (n=18,541); anti‐HCV seropositive (n=1095; detectable HCV RNA: 69.4%). Average follow‐up: 16.2 years.Among extrahepatic causes of death, 68.5% and 69.3% were noncancer deaths for HCV seronegative and seropositive, respectively.*P<.001 for comparison among all 3 groups and P<.001 for HCV RNA detectable vs undetectable.

Follow‐Up (Years)

20

18

16

14

12

10

2

00 2 4 6 8 10 12 14 16 18 20

8

6

4

Follow‐Up (Years)

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18 20

All Causes(n=2394)

Liver Cancer(n=115)

Extrahepatic Diseases(n=2199)

Cumulative Mortality (%

)

Anti‐HCV+, HCV RNA detectable Anti‐HCV+, HCV RNA undetectable Anti‐HCV–

Follow‐Up (Years)

35

30

25

20

15

10

5

00 2 4 6 8 10 12 14 16 18 20

30.1%*

12.8%12.4%

10.4%*

1.6%

0.3%

19.8%*

12.2%11.0%

HCV Viremia Was Associated With Increased Mortality in a Prospective Taiwanese Cohort Study

Can we reduce or prevent mortality by treating HCV patients and is SVR the appropriate surrogate endpoint for that?

Does SVR equal cure of liver disease?

• Viral eradication stops progression of disease• Mild Disease - long-term outcome = pop’n risk

Veldt Gut 2002

286 pts with SVR after IFN therapy

Follow-up post SVR (n=286)

Pro

porti

on o

f pat

ient

s

Time [yrs]

Decompensation/HCC

Survival

Matched generalpopulation

SVRs (n=286)

% s

urvi

val

Time [yrs]

SVR Was Associated With Reduced Long‐Term Risk of All‐Cause Mortality in HCV Patients with cirrhosis

Results of an International, Multicenter Study

van der Meer AJ, et al. JAMA. 2012;308:2584‐2593.

International, multicenter, long‐term follow‐up study from 5 large tertiary care hospitals in Europe and Canada. Patients with chronic HCV infection started an interferon‐based treatment regimen between 1990 and 2003 (n=530).

P<.001

Non‐SVR

SVR

Time (years)

Percen

t

0

10

20

30

0 1 2 3 4 5 6 7 8 9 10

All‐Cause Mortality

Liver-related Mortality and Morbidity 30

LR-M

orta

lity

(%)

20

10

01 2 3 4 5 6 7 8 9 100

Time – in years

30Li

ver F

ailu

re (%

)

20

10

01 2 3 4 5 6 7 8 9 100

Time – in years

Adjusted HR of SVR:0.07 (95%CI 0.03-0.20)

p < 0.001

p < 0.001

SVR

non-SVR


p < 0.001

p < 0.001

SVR

non-SVR

30

HC

C (%

) 20

10

01 2 3 4 5 6 7 8 9 100

Time – in years


p < 0.001

p < 0.001

SVR

non-SVR

Van der Meer JAMA 2012

n=530Median Follow-up 8.4 yrs

Distribution of Clinical Events

non-SVR

SVR

0

10

20

30

40

50

60

Any event Death Liver Failure HCC LR-death/LTx

% w

ith e

vent

30%

7%

33%

2%

22%

4%

30%

2%

9%

50%

169 1001318 1114 767 1033

Van der Meer JAMA 2012

Benefits of SVR: reduction in liver-related disease

Num

ber o

f eve

nts

Mortality Rates and Hospital Episode Rates (Per 100 Person Years) by SVR Status Observed Among 1,215 Post-Treatment HCV Patients in Scotland, 1996-2007

Innes HA et al. Hepatology 2011;54:1547-1558.

Non-Liver Related Mortality: SVR is Associated with Improved Renal and Cardiovascular Outcomes in HCV Patients

Hsu et al. Gut 2015

12.384 HCV treated patients without comorbidities were matched with 24768 untreated controls

Non-Liver Related Mortality: SVR is Associated with Improved Renal and Cardiovascular Outcomes in HCV Patients

Hsu et al. Gut 2015

12.384 HCV treated patients without comorbidities were matched with 24768 untreated controls

Multivariate-adjusted Cox regression revealed that antiviral treatment was associated with lower risks of

End Stage Renal Disease (HR 0.15; 95% CI 0.07 to 0.31; p<0.001)Acute Coronary síndrome (HR 0.77; 95% CI 0.62 to 0.97; p=0.026) and ischaemic stroke (HR 0.62; 95% CI 0.46 to 0.83; p=0.001)but unrelated to autoimmunecatastrophes

The Real Problem: Under-diagnosis & Under-treatment

• In wealthy countries - >50% of infected individuals remain undiagnosed!– USA 72%1

– France 44-55%2

• In resource-poor countries – the figures are much more discouraging– Minimal data but very low diagnosis rates

1. Rein Ann Int Med 2012 2. Defossez Eur J Gastro Hep 2008 3. Shah CMAJ 2013

Estimated HCV prevalence, diagnosis rate and treatment uptake

• Prevalencia estimada de la HCC, tasa de diagnóstico y tasa de tratamiento en 2013

Dore GJ, Ward J and Thursz M. Journal of Viral Hepatitis 2014, 21 (Suppl 1): 1‐4.

25

2012 CDC Recommendations for Birth Cohort (1945–1965) Screening

Recommendation 1̶ Adults born from 1945 to 1965 should

receive one‐time testing for HCV without prior ascertainment of HCV risk Grade: strong recommendation Evidence: moderate‐quality

Recommendation 2̶ All persons identified with HCV infection

should receive a brief alcohol screening and intervention as clinically indicated, followed by referral to appropriate care and treatment services for HCV infection and related conditions as indicatedGrade: strong recommendation Evidence: moderate‐quality

Smith BD, et al. Ann Intern Med. 2012;157:817‐822.

HCV Screening in USA

Birth cohort screening (1945-65) is cost-effective

Rein et al Ann Int Med 2012

Davis Gastroenterology 2010

*

34% ↓

68% ↓

~10% ↓

Treatment uptake more important than rate of SVR

Reduction in Liver-Related Death by 2020 with Incremental Treatment

Liver related mortality according to baseline HBV DNA level

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

High Baseline HBV DNA Associated With Increased Risk Of Cirrhosis And HCC

4,5 5,99,8

23,5

36,2

0

10

20

30

40

50

<300 300-9999

10000-99999

100,000-999,999

≥1million

% o

f pat

ient

s

Cumulative incidence of cirrhosisat year 11 follow-up[1] N=3,582

Baseline HBV DNA (copies/mL)

1. Iloeje UH, et al. Gastroenterology 2006;130:678-86.2. Adapted from: Chen C, et al. JAMA 2006;295:65–73.

1,3 1,43,6

12,214,9

0

10

20

30

40

50

<300 300-9,999

10,000-99,999

100,000-999,999

≥1million

% o

f pat

ient

s

Cumulative incidence of HCCat year 13 follow-up[2] N=3,653

Tools for Eradicating HBV Infection

Hepatitis B Vaccine

High virological responses withlong-term ETV or TDF

Response

ETV TDF

HBeAg+ patients Year 51

HBeAg-patients Year 32,a

HBeAg+ patients Year 83

HBeAg-patients Year 83

HBV DNA suppressionb 94%(88/94)

95% (54/57)

98%(159/160)

99%(271/273)

Resistance 1% (n=1) NR 0% 0%

HBsAg loss (seroconversion) NR NR 12.9%

(10.3%)1.1%(<1)

1. Chang TT, et al. Hepatology 2010;51:422–30;2. Shouval D, et al. Hepatology 2008; Poster 927;3. Marcellin P, et al. Med 2014; Abstract 926 4. Lau GKK, et. al. N Engl J Med. 2005;352:2682-95

aETV re-treatment (relapsed <6 monthspost-treatment in ETV-027 study); bTDF: HBV DNA <400 copies/mL, ETV: HBV DNA <300 copies/mL;ETV: entecavir; NR: not reported

PEGIFN

HBeAg+ patientswk 72 4

HBeAg-patients WK 725

14% 44%

0% 0%

9% 1.1%

5. Marcellin P, et. al. N Engl J Med. 2004;351:1206-7.

0

20

40

60

80

100

Baseline Year 1 Year 5

Missing6543210

Histological outcomes with TDF treatment: liver fibrosis regression and cirrhosis reversal

• TDF vs ADV for 48 weeks then open-label TDF in HBeAg-and HBeAg+ patients(Studies 102 and 103)

– N=348 had biopsies at baseline and Year 5

– N=96 with cirrhosis

• 74% (71/96) had reversalof cirrhosis

• Only low BMI was associated with fibrosis regression at Year 5

Marcellin P, et al. Lancet 2013;381:468–75

Histologically evaluable patients in the long-term histology cohort;344 patients had biopsies at baseline, Year 1 and Year 5;

BMI: body mass index

Patie

nts

(%)

P<0.001P<0.001

Ishak fibrosis score

100

80

60

40

20

0

Patie

nts

(%)

Baseline Year 1 Year 5

Ishak fibrosis score

IFN-based therapy can result in reduction of HCC vs no treatment

Sung J, et al. Aliment Pharmacol Ther 2008;28:1067–77

Significant reduction in HCC with ETV compared with controls in cirrhotic patients

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

Control ETV LAM

HCC

Treatment duration (years)C

umul

ativ

e H

CC

rate

(%)

0 1 2 3 4 50

20

30

40

50

1011.4%

20.9%

2.6%

28.5%

4.3%

19.7%

7.0%

6

7.0%

22.2%

38.9%

4.8%

12.2%

CirrhosisLog-rank test:ETV vs LAM: P=0.043ETV vs control: P<0.001LAM vs control: P=0.019

No cirrhosis

1.6% 3.6%

2.5%0%

0 1 3 52 4 6

Cum

ulat

ive

HC

C ra

te (%

)

0

20

30

40

50

10

Treatment duration (years)

3.2% 4.9%

Log-rank test:ETV vs LAM: P=0.126ETV vs control: P=0.440LAM vs control: P=0.879

Tools for Eradicating HBV Infection

Hepatitis B Vaccine

Mortality from Hepatocellular Carcinoma Among 6 to 14 Year Old Children: Taiwan (1982-1994)

Chang. NEJM 1997.

0

0,2

0,4

0,6

0,8

1

1982 1984 1986 1988 1990 1992 1994Year

HCC M

orta

lity

per

100,

000

High-risk infant immunization

Routine infant immunization

Thirthy

Chiang C J et al. JAMA 2013

Age and sex-specific mortality and indidence rates of chronic liver disease and HCC for birth cohorts born before and after Hepatitis Bvaccination program in1984 in Taiwan

The National Viral Hepatitis Therapy Program in Taiwan

October 2003 started the program

Oral antiviral for Hep BIFN+RBV for Hep C

By 2011

157,570 Hep B treated61,823 Hep C treated

Aim : To assess the impact of the program on reduction on end‐stage liver disease burden

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

Significant reduction in CLD and HCC mortality through the National Viral Hepatitis Therapy program in Taiwan

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

The age‐gender adjusted rate ratio in 2008‐11 was 0.78 for CLDs and cirrhosis mortality, and 0.76 for HCC mortality using 2003 as the reference period

SummaryMortality projection for Viral hepatitis are country dependent and related

to epidemiology of the infections in every country

Hepatitis B Vaccination is an important tool to decrease HBV related

mortality

Treatment for HCV and HBV can change the predicted mortality only if

specific programs focus on increase screening, treatment uptake and

interferon free regimens are implemented

Documents

Mortality projection in the coming yearsregist2.virology-education.com/2015/1euhep/05_Buti.pdfSmith BD, et al. Ann Intern Med. 2012;157:817‐822. HCV Screening in USA Birth cohort