Management of chronic liver diseases

1
Management of chronic liver diseases

• Irinel Popescu
• Fundeni Institute of Digestive Diseases and Liver
  Transplantation

2
HCV infection - epidemiology

• Prevalence 180 million persons (3 of the
  population) (underestimated!) (1999-2001)
• More recent data 300 million persons! (2007)
• Incidence 3-4 million persons infected annually
  (a minority is symptomatic 1-3 cases/one million
  persons/year!)

Lee WM, N Engl J Med 1997 337 1733 Lok ASF,
McMahon BJ Hepatology 2001 34 1225 WHO.
Hepatitis C global prevalence. Weekly Epidemiol
Rec 2000 75 18 Anonymous. Global Surveillance
and control of Hepatitis C. J Viral Hepat 1999
6 35 Maria Buti, Advances in the Therapy of
Liver Disease, Barcelona Ars Medica, Sept 2007
263
3
HCV infection - epidemiology

• 70 of chronic hepatitis
• 40 of liver cirrhosis
• 60 of cases of hepatocarcinoma
• 40-50 of LT indications
• Important personal, social, economic implications
  and costs

NIH Consensus Development Conference. Management
of Hepatitis C -2002 June 10-12. Hepatology 2003
4
Global prevalence of HCV infection
EUROPE 22 millions Central and South Est Europe
13 millions
OMS. Wkly Epidemiol Rec. 20007518-19.
5
Natural history of HCV infection
Acute HCV infection
15-20
55-80
Spontaneous Cleareance
Chronic Infection
Chronic hepatitis
70-85
mild
moderate
severe
Cirrhosis
10-20/10-30 years
End-stage
HCC
1-4/year
20/10 years
LTx
Recurrent infection
20 HCV CH/5 years
Death
6
Epidemiologic projection of HCV infection
2000
2010
2020
2040
2030
HCV infection 2.940.678 2.870.391
2.681.556 2.433.709 2.177.089
Cirrhosis 472.103
720.807 858.788 879.747
828.134
Decomp. cirrhosis 65.294 103.117
134.743 146.408 142.732
HCC 7.271
11.185 13.183 13.390
12.528
Death 13.000
27.732 36.483 39.875
39.064
Davis et al. Projecting future complications of
chronic hepatitis C in the United States. Liver
transplantation, 2003
7
Mortality due to liver cirrhosis (standardized
rates)
Ascione, Roche Symp 2006 Poiana Brasov
8
Prevalence of HCV infection in Romania Results of
a nationwide cross-sectional survey (2006-2008)
Geo-historical region Negative Positive Overall Odds Ratio P
Wallachia N 5830 202 6032 1.00 -
Wallachia 96.65 3.35 100.00
Moldavia N 2118 94 2212 1.28 0.052
Moldavia 95.75 4.25 100.00
Transylvania Banat N 4773 129 4902 0.78 0.030
Transylvania Banat 97.37 2.63 100.00
Overall N 12721 425 13146
Overall 96.77 3.23 100.00
Chi2 test 13.2329 Chi2 test 13.2329 Degree of freedom 2 p 0.001
Gheorghe L, Csiki IE, Iacob S, Regep L, J
Gastrointestin Liver Dis 2010 (in press) Grant
Roche Romania
9
What do we know in Romania in 2010?
99.13 genotype 1
19,6 millions1 Romanian population
Moldavia
Transylvania
HCV chronic infection prevalence 3,23 2
Wallachia
633,080 HCV chronic infected people

1. Anuarul Statistic al României(http//
   www.insse.ro/Anuar20200S/CAPITOLE/cap2.pdf 2.
   Gheorghe L et al, submitted

10
Hepatitis C Treatment System in Romania

• Quality of antiviral therapy delivery
• State-of-the-art therapy with pegylated
  interferon and ribavirin is currently prescribed
  for HCV-infected patients for 48 weeks
• Until March 2009 restricted access to therapy
  which prioritized advanced disease/fibrosis,
  younger patients, with high viral load and
  aminotransferases, professional exposure
• From March 2009 an unrestricted access to
  therapy for all eligible HCV-infected patients
  (positive HCV RNA, at least mild hepatitis,
  compensated disease)

11
Hepatitis C Treatment System in Romania

• Quantity of antiviral therapy delivery
• limited funds---low treatment rates------ waiting
  lists
• The access to antiviral therapy is limited by
  restricted reimbursement quantity this results
  in waiting lists (WL) for antiviral therapy
• A certain number of treatment courses are
  negotiated each year by the National Health
  Insurance Agency (NHIA) with the pharmaceutical
  companies (Roche and Schering Plough/Merck)

12
Hepatitis C Treatment System in Romania

• The antiviral therapy is fully reimbursed NHIA
  reimbursed 100 of PegIFN costs and 25 of RIBA
  costs (the companies are currently supporting 75
  of RIBA costs). There are no bureaucratic hurdles
  in the reimbursement process excepting the WLs
• Patients receive reimbursed treatment on the
  following criteria
• Time spent on the WL
• Severity of the disease, professional exposure,
  age (children and adolescents), oncologic
  co-morbidities requiring chemotherapy
• Retreatment is reimbursed for a limited of
  relapsers and not reimbursed for non-responders
  since 2010

13
Hepatitis C Treatment System in Romania

• The diagnosis, recommendation, and follow-up is
  performed by specialists (gastroenterologists/infe
  ctious diseases specialists)
• Patients are referred monthly from the local WL,
  according to the above mentioned criteria for
  national validation and access to therapy
• A central NIHA database allows to registry and
  follow-up the patients ever receiving reimbursed
  antiviral therapy in Romania
• Within the National Program for Therapy in
  Chronic Diseases, chronic hepatitis compete with
  other chronic diseases (psychiatric,
  rheumatologic, or dermatologic) for the same
  category of NHIA funds

14
European treatment rates specific to each country
indicating the number of treated patients with
PegInterferon for 100 prevalent cases of HCV
2008
2005 lt1
Lettmeier B, Muhlberger N. et al, J Hepatol 2008
49 528536
15
First National Awareness and Prevention Campaign
on Hepatitis C
(Find about C Find out why)

• Articles in press gt 150, since April 2007
• TV advertise
• More than 10 million people have seen the ad at
  least once
• In total, the ad was seen 44 million times
• TV news 15
• 12 pages of references on hepatita C / afla
  de C on Google in Romanian language
• More than 27,000 people visited www.afladec.ro
• More than 1,000 people called the toll-free
  number

16
Ministry of Health and NHIA actions

• Screening program for chronic diseases initiated
  by the Ministry of Health in 2007 large numbers
  of patients with increased ALT have been
  discovered and further referred to a specialist
  for HCV HBV screening
• Screening programs in high risks groups
• 100 increase of the CHC reimbursed therapy
  courses in 2008 vs 2006 (5,200 vs 2,600)

17
Efficiency of Peg-IFN?2a/2bribavirin in Romanian
patients with chronic hepatitis C Clinical
Practice
Gheorghe L, Iacob S, et al. J Gastrointestin
Liver Dis 2007 Gheorghe L, Grigorescu M, Iacob S
et al. Rom J Gastroenterol 2005
18
Evolution of chronic hepatitis C treatment
Discovery of hep C
PegIFN alfa 2b plus RIBA
Protease inhibitors
IFN alfa 2a
IFN alfa 2b plus RIBA
PegIFN alfa 2a plus RIBA
IFN alfa 2b
1989
1991
1992
1998
2001
2002
2011
2010
19
Evaluation of preventable liver-related deaths,
including HCC due to antiviral therapy (estimated
according to Romanian program of antiviral
therapy approval)
Interval Yearly mean no. of patients with chronic hepatitis C Yearly mean no. of patients with chronic hepatitis C Yearly mean number of liver related deaths Yearly mean number of liver related deaths
2010 - 2012 105666 105666 5700 5700

SVR No. patients treated with antiviral therapy Percent of patients with hep C treated with antiviral therapy Preventable yearly deaths due to antiviral therapy Percent of yearly preventable deaths due to antiviral therapy from the total number of liver-related deaths
50 4200 3.97 75 1.31
50 2000 1.89 35 0.62
50 8000 7.57 143 2.51
75 4200 3.97 112 1.97
75 8000 5.69 213 3.74
Yet unpublishet data
20
HBV infection - epidemiology

• 350 million people around the world are
  chronically infected with HBV
• ?75 of them reside in the Asia-Pacific region
• increased risk of developing hepatic
  decompensation, cirrhosis and HCC
• main indication for LT in Asia
• 1525 deaths due to HBV-related liver disease

Liaw Y, J Hepatol 2009
21
HBV infection - epidemiology

• universal HBV vaccination in newborns in Asian
  countries since 1984
• universal HBV vaccination in newborns in Romania
  since 1995

22
Global prevalence of HBV infection
Dienstag JL, NEJM 2008
23
Decreasing HBV prevalence and acute incidence due
to HBV vaccination

• HBsAg prevalence in children lt 15years ? from
  9.8 in 1984 to 0.7 in 1999 and 0.5 in 2004 in
  Asia
• China reduced HBsAg prevalence to lt1 among
  children lt5 years and has prevented an estimated
  16-20 million HBV carriers through hepatitis B
  vaccination of infants
• In order for the HBV carrier rate to approximate
  zero, universal vaccination programs need to
  continue for at least 21 years

Liaw Y, J Hepatol 2009 Liang X, Vaccine 2009 Su
FH, Chang Gung Med J. 2007
24
Prevalence of HBV infection in Romania Results of
a nationwide cross-sectional survey (2006-2008)
Geo-historical region Negative Positive Overall Odds Ratio P
Wallachia N 5699 325 6024 1.00 -
Wallachia 94.60 5.40 100.00
Moldavia N 2101 100 2201 0.84 0.123
Moldavia 95.46 4.49 100.00
Transylvania Banat N 4751 151 4902 0.56 0.0001
Transylvania Banat 96.92 3.08 100.00
Overall N 12551 576 13127
Overall 95.61 4.39 100.00
Chi2 test 34.6684 Chi2 test 34.6684 Degree of freedom 2 p 0.001
Gheorghe L, Csiki IE, Iacob S, Regep L (not
published yet) Grant Roche Romania
25
Significantly increased prevalence of HBsAg in
persons aged 40-60 years
Age groups (years) Negative Positive Overall Odds Ratio P
18 - 29 N 1990 69 2059 1.00 -
18 - 29 96.65 3.35 100.00
30 - 39 N 2669 101 2770 1.09 0.582
30 - 39 96.35 3.65 100.00
40 - 49 N 2491 130 2621 1.50 0.007
40 - 49 95.04 4.96 100.00
50 - 59 N 3099 206 3305 1.92 0.0001
50 - 59 93.77 6.23 100.00
60 N 2302 70 2372 0.88 0.446
60 97.05 2.95 100.00
Total N 12551 576 13127
Total 95.61 4.39 100.00
Chi2 test 49.4418 Chi2 test 49.4418 Freedom degree 4 P 0.0001
Gheorghe L, Csiki IE, Iacob S, Regep L (not
published yet) Grant Roche Romania
26
Significantly increased prevalence of HBcAb in
persons aged gt30 years
Age groups (years) Negative Positive Overall Odds Ratio P
18 - 29 N 1726 343 2069 1.00 -
18 - 29 83.42 16.58 100.00
30 - 39 N 2233 533 2766 1.20 0.016
30 - 39 80.73 19.27 100.00
40 - 49 N 1820 799 2619 2.21 0.0001
40 - 49 69.49 30.51 100.00
50 - 59 N 1963 1324 3287 3.39 0.0001
50 - 59 59.72 40.28 100.00
60 N 1389 970 2359 3.51 0.0001
60 58.88 41.12 100.00
Total N 9131 3969 13100
Total 69.70 30.30 100.00
Chi2 test 629.6602 Chi2 test 629.6602 Freedom degree 4 P 0.0001
Gheorghe L, Csiki IE, Iacob S, Regep L (not
published yet) Grant Roche Romania
27
Choosing therapies in chronic hepatitis BA
chronic hepatitis B patient might be a life long
patient!
Treatment of chronic HBV infection is a complex
task that requires individualized assessment!
Start therapy in the right patients at the right
time so that the response endpoint can be
achieved earlier hence, shortening the duration
of therapy!
28
Worldwide costs studies in treating HBV patients
USA (USD) China (USD) Australia (AUS) Taiwan (NT) Europe (EUR)
Chronic hepatitis B 761 142 1233 4905 1093-3396
Compensated cirrhosis 227 185 1394 6574 1134-3997
Decompensated cirrhosis 11459 1702 11961 36621 5292-8842
HCC 7533 4741 11753 95741 3731-9352
LT 86552 1144392 199725 25165-84568
LT care gt12months 12560 23160
Lee TA, J Clin Gastroenterol 2004Zhiqiang G, J
Clin Gastroenterol 2004 Butler JR, J Clin
Gastroenterol 2004 Hsieh CR, J Clin
Gastroenterol 2004 Brown RE, J Clin
Gastroenterol 2004
29
National Transplant Agency

• A national transplant network
• Established the protocol of diagnosis and
  declaration of the brain death
• Established the conditions for the removal of the
  organs from the deceased donor
• Mass-media campaign to explain the brain death
  and to promote organ and tissue donation

30
National Program of Organs, Tissues and Cells
Transplantation

• Immunologic and virusologic testing of potential
  donors and recipients
• Coordination of transplant activities
• Maintaining in physiologic conditions the brain
  dead donors
• Transplant procedures
• Providing medication for posttransplant status
• Management of the National Transplant Registry

31
Liver transplant indications
USA 1992-2007
Korea
32
LT indications in Romania 200 patients (adults
and children)April 2000- October 2009
LT indication Patient No
HBVHDV cirrhosis 32
HCV cirrhosis 31
HBV cirrhosis 28
HCC 25
Primitive/secondary biliary cirrhosis 16
Wilson disease 13
Alcoholic cirrhosis 10
Biliary atrezia 7
Glicogenosis 5
Congenital liver fibrosis 3
HBVHCV cirrhosis 3
Ductopenia 2
Others 15
Popescu I et al, Chirurgia 2010
33
Characteristics of 372 adult patients with
cirrhosis on WL for LT
Variable Blood type O Blood type A Blood type B Blood type AB
No () patients 113 (30.4) 172 (46.2) 61 (16.4) 26 (7)
Mean age (?SD) (years) 47.5 10.9 46.1 11 47.3 11.1 44.6 10.7
Gender (males) 64.6 57 50.8 53.8
Underlying liver disease () Viral hepatitis Autoimmune Alcoholic Other 75.2 5.3 11.5 8 71.5 9.3 12.2 7 67.2 13.1 8.2 11.5 76.9 3.8 11.5 7.7
Deceased (no,) 40 (35.4) 37 (21.5) 14 (23) 4 (15.4)
Median waiting time on WL (months) 22.3 28.9 28.1 31
Iacob S,Popescu I. Chirurgia 2009
34
Frequency of cirrhosis complications in 372
patients on WL
Iacob S,Popescu I. Chirurgia 2009
35
Management of cirrhosis complications
Hepato-renal syndrome
Spontaneous bacterial peritonitis
1-2mg/4h terlipressin Albumin 1g/kgbw first
day followed by albumin 20-40g/day, 15 days
Cefotaxime Albumin 1.5g/kgbw first day followed
by albumin 1g/kgbw, day 3
Refractory ascites repeated paracentesis
Albumin 6-8g/liter of fluid removed
Ortega R, Hepatology 2002 Sort P, NEJM
1999 Runyon A, Hepatology 2004
36
Estimated costs for treatment of these
complications on WL in Romania

• 50 ml albumin 20 (10g albumin) ? 40Eur
• 1mg terlipressin ? 24Eur

Hepato-renal syndrome
Refractory ascites
? 47 patients
? 85 patients
2160Eur for terlipressin 15 days
5 paracentesis/month

? 3 bottles of albumin/paracentesis
1400Eur for albumin 15 days
? 600Eur/month
37
Waiting list mortality in Romania (adults)
Global rate of mortality while on WL (2001-1 June
2010) 44.7
Median survival 43.4 months 5 years mortality
60.8 2 years mortality 36.7 1 year mortality
25.3 6 months mortality 13.9
38
Survival following LT in Romanian Program
1 year post-LT median survival 84.2 2 years
post-LT median survival 82.3 5 years post-LT
median survival 75
39
Estimated liver-related deaths (including HCC)
that can be prevented by LT in Romania
Interval Mean annual number of liver-related death Mean annual number of liver-related death Mean annual increase of death number Mean annual increase of death number
2009-2015 5890 5890 3.5 3.5
Mean annual no of LT Mean annual required donors Required donor (ppm inhabitants)/ year Deaths prevented annually Annual rate of deaths prevented by LT
First year survival rate 85 First year survival rate 85 First year survival rate 85 First year survival rate 85 First year survival rate 85
30 46 2.2 3 0.56/1000 deaths
40 62 2.9 4 0.75/1000
50 77 3.7 6 0.93/1000
75 115 5.5 8 1.40/1000
100 154 7.3 11 1.87/1000
150 231 11.0 17 2.80/1000
200 308 14.7 22 3.74/1000
Yet unpublishet data
40
Conclusions

• Recent epidemiologic data are valuable for a
  better understanding of the burden of the disease
  and developing appropriate preventive strategies
  and programs to control the spread and
  consequences of HCV/HBV infection in Romania
• Strategies to increase the number of treated
  patients limited funding ? campaigns to bring to
  knowledge ? improving detection ? increase of the
  prescribed therapy ? positive pressure on
  authorities ? increase of the reimbursed
  therapies/year

41
Conclusions

• Need for improved access to antiviral therapy for
  patients with chronic hepatitis C/B in order to
  decrease the number of related cirrhosis and its
  complications
• decrease of costs and liver related
  mortality
• Need for strategies to increase the donors number
  for LT in order to decrease liver related
  mortality (organ donation card)