CHRISTIAN MEDICAL COLLEGE, VELLORE, INDIA SINCE: 1900

1
Models for Prophylaxis
Can it be done in
Developing Countries?
6th Global Forum

World Federation of Hemophilia
24th
25th September
Montreal, Canada
CHRISTIAN MEDICAL COLLEGE, VELLORE, INDIA
(SINCE 1900)
Alok Srivastava
Christian Medical College
Vellore, India
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(No Transcript)
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Factor replacement therapy in hemophilia
Outcome at different doses (The Netherlands)
Fischer K, et al. Haemophilia 2001744652
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FACTOR REPLACEMENT THERAPY IN HAEMOPHILIA
OUTCOME AT DIFFERENT
DOSES France Netherlands
Sweden (on demand)
(Intermediate- (High dose
dose
prophylaxis) prophylaxis)

Numbers 116 21 19 Age at study analysis
23 21 16-22 Age at start of
home- treatment 8.9 9.1 NA Age at start of
prophylaxis NA 4.6 2.6 Annual number
of Joint bleeds
16.3 5.3 3 Pettersson score
18.8 6.0
6.5 Orthopaedic joint score 7.7
2.0 2.4 Clotting consumption 1634
1828 3713
(IU kg-¹ year-¹)
van den Berg et al, Haemophilia 2003 9
(Suppl.1) 27-31
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Factor replacement therapy in hemophilia
Outcome at different doses
Sweden Sweden Netherlands Netherlands Netherlan
ds India Brazil Group 1 Group
2 1980 1990 2000 2004 2004 Age 21-35 13-20 20
.3 19.4 19.2 19 18.3 (1525) (1525) (1525)
(1526) (1525.6) Number 25 19 45 46 44 30 13
Age at start of 6.2 2.5 14.7 8.7 4.4 NA NA prophy
lactic treatment (313) (14.5) (12.217.8) (6.61
2) (2.46.2) on full NR NR 64 61 89 NA NA
prophylaxis Number of joint
bleeds/yr 5.2(0.516) 2.6(0.217) 7(2.815) 5(1.1
10.2) 2.2(0.96.5) 6.5(118) 10.4(138) Clinical
score 5.1(015) 1.2(07) NA NA NA 11(026) 10.5(
417) Patients with Petterssons score
(n) 25 19 27 40 44 30 13 Age (range) at
which NR NR 21.3 19.7 20.3 19 18.3 X-rays were
scored (2135) (1320) (16.922.8) (16.224.3) (17
.724.5) (1526) (1525.6) Petterssons
score 18(041) 4.8(022) 17(1133) 17(727) 8(016
) 18(048) 16.3(135) with Petterssons Score
of 0 NR NR 4 10 32 3 NR requiring
orthopaedic NR NR 27 22 9 10 23 surgery An
nual clotting factor 4003300 16005400 4111121 7
691667 15542425 25150 421538 usage
(IU/kg) (855) (1319) (2036) (627)
bleed score Only 10 had surgery, others had
yttrium synoviorthesis
Haemophilia 200410(suppl)2148
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FACTOR REPLACEMENT IN HEMOPHILIA CLASSICAL
PARADIGM FOR PROPHYLAXIS Early recognition (?lt1
years of age) Primary prophylaxis for all -
?Before first bleed / ?After 1-2 bleeds
Large doses - 25-50 iu/kg/dose - 3x
weekly for H-A 2x weekly for H-B - ?Optimum
dose / schedule
Total yearly dose 3000-8000
IU/kg/yr National consumption 5-9
iu/capita Annual cost 150-300 k
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FACTOR REPLACEMENT IN HEMOPHILIA ON DEMAND
TREATMENT Factor infusion as when needed for
bleeds Is the most common prevalent option of
treatment Wide range of dosage reported from
different parts of the world
Total yearly dose 100 - 2500
IU/kg/yr Results in reducing pain, crippling
deformities early mortality. Poor
long-term musculoskeletal outcome even with
significant doses Is such an approach worth
recommending or should other ways be tried when
regular supply of CFC is available at 1-2
IU/capita?
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MUSCULOSKELETAL FUNCTION IN HAEMOPHILIA
(MUSFIH)IN DEVELOPING COUNTRIES-AN
INTERNATIONAL MULTICENTER STUDYStudy Coordinator
Alok SrivastavaClinicalTrials.gov Identifier
NCT00324493
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MUSCULO-SKELETAL FUNCTION IN HEMOPHILIA IN THE
DEVELOPING WORLD (MUSFIH) PATIENT RECRUITMENT
Eligibility criteria 1. Severe hemophilia
(factor assay lt1 activity) between 5-15 years
of age 2. Not have detectable inhibitors by
screening tests at recruitment 3. Be willing to
come for evaluation at least once in 6- 12 months
for 5 years Method Observational study
documenting factor usage and musculoskeletal
outcome (clinical, radiological,
functional) Number of PWH per center
20-30 PWH (Total 200-250)
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MUSFIH study Interim analysis (2008)
Number of patients enrolled (N234)
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MUSFIH study Interim analysis - IIIrd year
Protocol for CFC replacement
CFC (IU/kg/yr) 59.7 555.6
735.3 961.0 993.8 1196.0
1589.1 1794.7 3320.0
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MUSFIH study Interim analysis
Bleeding frequency (annual) / PWH
CFC(IU/kg/yr) 7.2 255.6 282.6
459.8 795.0 930.3 938 1099
1220.9 2132.4
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MUSFIH study Interim analysis
WFH Clinical Joint score vs CFC used (IU/kg/year)
/PWH
N 11 17
38 48 46
56
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Hypothetical correlation between joint scores and
dosage of factor replacement
Dose (IU/kg/yr)
100
No treatment
25100
75
100500
5001000
Joint score
50
Critical level for total functional independence
10002000
20
20003500
Utrecht
gt3500
Malmo
Years
Srivastava A. Br J Haematol 20041271225
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CORRELATION BETWEEN JOINT SCORES AND DOSAGE OF
FACTOR REPLACEMENT
100 75 50 20
Dose (iu/kg/yr)
No treatment
25-100
MUSFIH Study (on going)
100-500
Joint Score
500-1000
Critical level for total functional independence
1000-2000
2000-3500
gt 3500
5 10 15
20 25 30
Years
Dutch-Swedish Outcome Comparison Study (on going)

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Prophylactic CFC replacement therapy Hypothetical
model Country A Total population - 50
million No. of PWH _at_100/million 5000 60
with severe hemophilia (sPWH)- 3000 Total CFC
available at 1iu/capita 50 million iu CFC for
sPWH (90 of total) 45 million iu Total CFC
/ PWH / year 15,000 iu Total weekly dose
300 iu (for 50 weeks / year)
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Prophylactic CFC replacement therapy Hypothetical
model In reality this will be higher, as among
sPWH 1.In most developing countries 25-75 of
total number detected 2.10 with
clinically mild phenotype 3.10 with
persistent inhibitors They will NOT be on
such prophylaxis Amount available iu/patient
could be double or more of the iu/capita
calculation in most developing countries
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Prophylactic CFC replacement therapy Hypothetical
model Children between 2-15 years 15-45kg
(Average Wt 30kg) I. With CFC at 1
iu/capita Prophylaxis _at_ 300iu / week Once
weekly dose 10 iu/kg (500iu/kg/yr) Twice
weekly dose 5 iu/kg
II. If CFC available at 2 iu/capita Prophylaxi
s _at_ 600iu / week Once weekly dose 20 iu/kg
(1000iu/kg/yr) Twice weekly dose 10 iu/kg
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STUDIES DESCRIBING OUTCOME OF LOWER DOSES OF
FACTOR REPLACEMENT FOR ACUTE HAEMARTHROSES
Srivastava BJH 2004 12712 - 25
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Availability of CFC Selected countries

• Colombia 0.89Macedonia 0.9Brazil 0.96
• Turkey 1.13Uruguay 1.19Kazakhstan 1.26Bulgaria
  1.27Serbia 1.43Venezuela 1.47Iran
  1.51Azerbaijan 1.52Latvia 1.92

• Chile 2.12Argentina 2.19Costa Rica 2.27Japan
  2.51Korea 2.52
• Portugal 3.19Russia 3.44Greece 3.49

Data - Courtesy WFH Global Survey, 2008
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The PHACTEM STUDY (to be initiated)
Courtesy P. Fiorentini, LFB, France
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FACTOR REPLACEMENT THERAPY IN HEMOPHILIA -
POSSIBILITIES IN DEVELOPING COUNTRIES THE
EVIDENCE SUGGESTS THAT ON-DEMAND THERAPY OVER A
WIDE RANGE DOES NOT SIGNIFICANTLY ALTER
LONG-TERM MUSCULOSKELETAL OUTCOME IU / CAPITA
OF CFC DOES NOT NECESSARILY REFLECT THE ACTUAL
AMOUNT AVAILABLE / PWH IN DEVELOPING
COUNTRIES POSSIBLE TO CONSIDER PROPHYLAXIS AT
LOW-DOSES TO BEGIN WITH AT THE QUANTITIES
AVAILABLE IN MANY DEVELOPING COUNTRIES THE
FIRST CHALLENGE IS TO CONVINCE HEALTH CARE
AUTHORITIES, PHYSICIANS AND PATIENTS THAT THIS
IS POSSIBLE WORTH ATTEMPTING THE LOGISTICS
OF DELIVERY OF SUCH AN APPROACH WILL THEN NEED
TO BE ESTABLISHED IN THESE COUNTRIES