Liver Disease and Thalassaemia
George Constantinou
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
© G. Constantinou
Limassol 25 October 2012
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Progression of Liver Disease
FIBROSIS
HEALTHY LIVER
CIRRHOSIS
© G. Constantinou
Limassol 25 October 2012
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Clinical course of virus related
liver disease
Resolution
Acute
Hepatitis
Stabilisation
Chronic
Hepatitis
Compensated
Cirrhosis
Cirrhosis
Liver
Cancer
Decompensated
Cirrhosis
(Death)
20 - 40 Years
© G. Constantinou
Limassol 25 October 2012
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HCV Infection: Worldwide Prevalence
WHO. Wkly Epidemiol Rec. 2005
© G. Constantinou
Limassol 25 October 2012
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Prevalence of HCV serum markers
in cohorts of patients with transfusion-dependent thalassaemia
born before 1990
Birth Cohort
(years of birth)
N. of
subjects
Anti-HCV +
Anti-HCV +
HCV-RNA +
Anti-HCV +
HCV-RNA -
(1980-1989)
69
38 (55%)
14 (20%)
24 (35%)
(1970-1979)
78
73 (93%)
44 (56%)
29 (37%)
(1964-1969)
20
18 (90%)
9 (45%)
9 (45%)
Overall
167
129 (77%)
67 (40%)
62 (37%)
(V. Di Marco, M. Capra, et al,)
© G. Constantinou
Limassol 25 October 2012
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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. Constantinou
Limassol 25 October 2012
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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.
© G. Constantinou
Limassol 25 October 2012
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HCV Infection: “The Facts”
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)
in patients with cirrhosis:
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.
© G. Constantinou
Limassol 25 October 2012
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HCV Infection: ‘The Facts’
 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 in patients
with cirrhosis:
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.
Comparison of virological response
p= 0.04
80
70
77%
77%
64%
60
40
54%
54%
50
46%
48%
46%
30
20
10
0
PEG-IFN
PEG-IFN plus Ribavirin
Early Virologic Response EVR
4 weeks
Rapid Virologic Response RVR
12 weeks
© G. Constantinou
End of treatment
Virologic response ETR 48 weeks
Sustained
Virologic Response SVR
Limassol 25 October 2012
72 weeks
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New Triple Combination Therapy
Interferon
Once per week - 48 weeks
Ribavirin
Twice a day - 48 weeks
Telaprevir Three times a day - 12 weeks
(Boceprevir)
© G. Constantinou
Limassol 25 October 2012
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Thanks to UK Health Professionals
& UKTS
 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 1st patients enter the treatment under
the company’s ‘Compassionate Use Programme’
© G. Constantinou
Limassol 25 October 2012
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Objective of treatment
 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. Constantinou
Limassol 25 October 2012
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Candidates for the early access
programme: triple therapy
 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. Constantinou
Limassol 25 October 2012
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Side effects
 Min 2+ days after the
 Increase in transfusion
interferon injection, you
frequency (50%-70% more)
feel as if you are getting
 Requiring increase in iron
the worse cold of your life.
chelation (30%-50% more)
(actually more like having been
run over by a lorry!)
 Loss of weight
 Psychological anxieties are
 Fatigue / Extreme tiredness
increased to intolerance
levels
 Interference with sugar
levels if you are diabetic.  Intolerance to daily minor
problems increases to
frightening levels
 Impacts aspects of
everyday life due to above
© G. Constantinou
Limassol 25 October 2012
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Conclusion
 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
3rd 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. Constantinou
Limassol 25 October 2012
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