1. Liver Disease and Thalassaemia George Constantinou

2. 2 Causes of liver damage in thalassaemic patients  IRON OVERLOAD  VIRUS C INFECTION  VIRUS B INFECTION  and/or Other infections  Hepatotropic agents, e.g. HGV, GBVC, TTV Iron overload resulting from Blood Transfusions and Hepatitis ⇒ SAFE BLOOD AND EFFECTIVE CHELATION ARE ESSENTIAL Iron overload resulting from Blood Transfusions and Hepatitis ⇒ SAFE BLOOD AND EFFECTIVE CHELATION ARE ESSENTIAL © G. ConstantinouLimassol 25 October 2012

3. 3 CIRRHOSIS FIBROSIS HEALTHY LIVER Progression of Liver Disease © G. ConstantinouLimassol 25 October 2012

4. Clinical course of virus related liver disease 4 Acute Hepatitis Resolution 20 - 40 Years Chronic Hepatitis Stabilisation Cirrhosis Compensated Cirrhosis Decompensated Cirrhosis (Death) Liver Cancer © G. ConstantinouLimassol 25 October 2012

5. HCV Infection: Worldwide Prevalence 5 WHO. Wkly Epidemiol Rec. 2005 © G. ConstantinouLimassol 25 October 2012

6. Prevalence of HCV serum markers 6 Birth Cohort (years of birth) N. of subjects Anti-HCV +Anti-HCV + HCV-RNA + Anti-HCV + HCV-RNA - (1980-1989)6938 (55%)14 (20%)24 (35%) (1970-1979)7873 (93%)44 (56%)29 (37%) (1964-1969)2018 (90%)9 (45%) Overall167129 (77%)67 (40%)62 (37%) (V. Di Marco, M. Capra, et al,) in cohorts of patients with transfusion-dependent thalassaemia born before 1990 © G. ConstantinouLimassol 25 October 2012

7. 7 Hepatitis virus infections in thalassaemic patients Prevalence depends on the quality and safety of the blood as well as, on how endemic the virus is at the local and/or regional level © G. ConstantinouLimassol 25 October 2012

8. Hepatitis C Virus (HCV) infection  Hepatitis C virus is the most common viral infection.  Worldwide 20%-90% of patients with thalassaemia are seropositive for anti-HCV antibodies ( Variation is based on the country’s blood service policy)  Chronic HCV infection is more common in patients who had a large number of blood transfusions before 1990. 8 © G. ConstantinouLimassol 25 October 2012

9. HCV Infection: “The Facts” 9 Estimated global prevalence  3% (170 million persons) Risk of chronicity (variable)75% - 85% (2) Early fibrosis progression rate :Low Risk of cirrhosis: Up to 10% within 20 years; 20% within 30 years (2) Cirrhosis-related mortality: 1% - 5%/year (3) Incidence of HCC (Carcinoma) 1% - 4%/year (2) in patients with cirrhosis: WHO. Hepatitis C. Fact sheet no. 164. 2. CDC. MMWR. 1998;47 (RR-19):1-39. 3. CDC. Hepatitis C slide kit. © G. ConstantinouLimassol 25 October 2012

10. HCV Infection: ‘The Facts’  Estimated global prevalence  Risk of chronicity (variable)  Early fibrosis progression rate:  Risk of cirrhosis:  Cirrhosis-related mortality:  Incidence of HCC in patients with cirrhosis: ~3% (170 million persons) 75%-85% (2) Low Up to 10% within 20 years; 20%within 30 years (2) 1%-5%/year (3) 1%-4%/year (2) WHO. Hepatitis C. Fact sheet no. 164. 2. CDC. MMWR. 1998;47 (RR-19):1-39. 3. CDC. Hepatitis C slide kit.

11. Comparison of virological response 11 46% 0 10 20 30 40 50 60 70 PEG-IFN Virological Response (%) PEG-IFN plus Ribavirin 48% 54% 46% 54% 80 77% 64% p= 0.04 4 weeks 12 weeks Early Virologic Response EVR Rapid Virologic Response RVR 48 weeks 72 weeks End of treatment Virologic response ETR Sustained Virologic Response SVR © G. ConstantinouLimassol 25 October 2012

12. New Triple Combination Therapy 12 Interferon Once per week - 48 weeks Ribavirin Twice a day - 48 weeks Telaprevir Three times a day - 12 weeks (Boceprevir) © G. ConstantinouLimassol 25 October 2012

13. Thanks to UK Health Professionals & UKTS 13  The new triple treatment was not available to Thalassaemia patients during the clinical trials, as the pharmaceutical companies enrolled patients without additional problems; such as transfusion dependent  We set up a group, whose aim was to overcome the pharmaceutical’s exclusion of thalassaemia patients, as the side effects of the drugs relating to anaemia could be well managed.  As a result the 1 st patients enter the treatment under the company’s ‘Compassionate Use Programme’ © G. ConstantinouLimassol 25 October 2012

14. Objective of treatment 14  RNA is non detectable (less than 140 IU/ml) within 4 -8 weeks of treatment  If this does not occur, then the treatment is stopped, as it will not work  This is good news, as you will not have to endure 48 weeks of treatment, if it is not working (unless you are unlucky and the virus develops resistance to Interferon, which will be revealed at the end of the treatment) © G. ConstantinouLimassol 25 October 2012

15. Candidates for the early access programme: triple therapy 15  Patients who had relapsed from previous therapy (Interferon + Ribavirin)  Genotype 1 (Genotype 2 was also included, and it worked)  Patients able to tolerate the many side effects © G. ConstantinouLimassol 25 October 2012

16. Side effects 16  Increase in transfusion frequency ( 50%-70% more)  Requiring increase in iron chelation (30%-50% more)  Loss of weight  Fatigue / Extreme tiredness  Interference with sugar levels if you are diabetic.  Min 2+ days after the interferon injection, you feel as if you are getting the worse cold of your life. (actually more like having been run over by a lorry!)  Psychological anxieties are increased to intolerance levels  Intolerance to daily minor problems increases to frightening levels  Impacts aspects of everyday life due to above © G. ConstantinouLimassol 25 October 2012

17. Conclusion 17  Success rate: Sustained Viral Response (SVR) of non Thalassaemia patients is 65-85 % (Studies?)  So far, 2 Thalassaemia patients have been treated in the UK and a 3 rd has just started  The side effects, are as close to intolerable as can be (similar to the double combination therapy) Future therapies (such as) Daclatasvir & GS-7977 Clinical Trial This is an only, oral therapy, not using Interferon and/or Ribivirin BUT WHAT IS THE ALTERNATIVE ?? © G. ConstantinouLimassol 25 October 2012