Liver Disease and Thalassaemia George Constantinou.

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


Clinical course of virus related liver disease

4

AcuteHepatitis

Resolution

20 - 40 Years

ChronicHepatitis

Stabilisation

Cirrhosis

CompensatedCirrhosis

DecompensatedCirrhosis(Death)

Liver Cancer


HCV Infection: Worldwide Prevalence

5

WHO. Wkly Epidemiol Rec. 2005


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


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


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”

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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.


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

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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


New Triple Combination Therapy

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InterferonOnce per week - 48 weeks

RibavirinTwice a day - 48 weeks

Telaprevir Three times a day - 12 weeks(Boceprevir)


Thanks to UK Health Professionals & UKTS

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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’


Objective of treatment

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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)


Candidates for the early access programme: triple therapy

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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


Side effects

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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


Conclusion

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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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