Upload
doreen-brown
View
237
Download
0
Tags:
Embed Size (px)
Citation preview
Liver Disease and Thalassaemia
George Constantinou
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. Constantinou Limassol 25 October 2012
3
CIRRHOSIS
FIBROSISHEALTHY LIVER
Progression of Liver Disease
© G. Constantinou Limassol 25 October 2012
Clinical course of virus related liver disease
4
AcuteHepatitis
Resolution
20 - 40 Years
ChronicHepatitis
Stabilisation
Cirrhosis
CompensatedCirrhosis
DecompensatedCirrhosis(Death)
Liver Cancer
© G. Constantinou Limassol 25 October 2012
HCV Infection: Worldwide Prevalence
5
WHO. Wkly Epidemiol Rec. 2005
© G. Constantinou Limassol 25 October 2012
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) 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,)
in cohorts of patients with transfusion-dependent thalassaemia born before 1990
© G. Constantinou Limassol 25 October 2012
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
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
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. Constantinou Limassol 25 October 2012
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. Constantinou Limassol 25 October 2012
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.
Comparison of virological response
11
46%
0
10
20
30
40
50
60
70
PEG-IFN
Viro
logi
cal R
espo
nse
(%)
PEG-IFN plus Ribavirin
48%54%
46%
54%
8077%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. Constantinou Limassol 25 October 2012
New Triple Combination Therapy
12
InterferonOnce per week - 48 weeks
RibavirinTwice a day - 48 weeks
Telaprevir Three times a day - 12 weeks(Boceprevir)
© G. Constantinou Limassol 25 October 2012
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 1st patients enter the treatment under the company’s ‘Compassionate Use Programme’
© G. Constantinou Limassol 25 October 2012
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. Constantinou Limassol 25 October 2012
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. Constantinou Limassol 25 October 2012
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. Constantinou Limassol 25 October 2012
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 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