The Inherited Diseases of Hemoglobin are an Emerging

Global Health BurdenGlobal Health Burden

Suthat Fucharoen (grsfc@mahidol.ac.th)

Thalassemia Research CenterInstitute of Molecular Biosciences,

Mahidol University, Thailand

Acknowledgements

Prof. Prawase WasiMahidol University,

ThailandSir David Weatherall

Oxford UniversityUK

Contribution of genetic and congenital disorders Contribution of genetic and congenital disorders to infant and childhood mortality

in a typical developed countryin a typical developed country

Global distribution of hemoglobin disorders, in terms of births of affected infants per 1000 births (WHO, 1996)

Gl b l E id i l f H l bi Di dGlobal Epidemiology of Hemoglobin Disorders• Around 7% of the global population carries an

b l h l biabnormal hemoglobin gene

• 300,000-500,000 children are born with clinically i ifi t h l bi di d llsignificant hemoglobin disorders annually

• About 80% of affected children are born in developing countriesdeveloping countries

• About 70% are born with Sickle Cell Diseased th t ith Th l i S dand the rest with Thalassemia Syndromes

• 50-80% of children with SCD die each year in low and iddl i t imiddle income countries

• 50,000-100,000 children with thalassemia major die h i l d iddl i t ieach year in low and middle income countries

Hemoglobin disorders as a common entry pointas a common entry point

‐ They are highly prevalent in many populations

‐ Survival and quality of life can be greatly improves by simple protective measures, such as transfusion programs f  th l ifor thalassemia

‐ Carriers can be detected by cheap and simple h l l d l b d dhematological tests, and carrier couples can be advised prospectively of their risk

‐ Prenatal diagnosis is highly acceptable to couple at risk

Diagnosis registers can be used for service auditg g

‐ Screening strategies and DNA‐based laboratory methods introduced for hemoglobin disorders can be extended to introduced for hemoglobin disorders can be extended to other inherited disorders 

WHO Working Group, 1981  A  B  (L  Ni i ) 8 A P t l ki (Ath G )1.  A. Boyo (Lagos, Nigeria)

2.  A. Cao (Sardinia, Italy)3.  Der kalostian (Beirut, Lebanon)

4   J Hercules (Betheada USA)

8. A. Pantelakis (Athens, Greece)

9. A.Motulsky (Seattle, USA)

10. A. Piel (Geneva, Switzerland)

11 J Rosa (Paris France)4.  J. Hercules (Betheada, USA)

5.  A. Kuliev (Genewa, Switzerland)

6.  D. Loukopoulos (Athens, Greece)

7 B Modell (London UK)

11. J. Rosa (Paris, France)

12. P. Wasi (Bangkok, Thailand)

13. D.J. Weatherall (Oxford, UK)

14 R Williamson (London UK)7. B. Modell (London, UK) 14. R. Williamson (London, UK)

List of relevant documentsList of relevant documents

WHO's Genomic Resource Centre ‐www.who.int/genomics/en

WHO, 1989. Report of the fifth WHO working group on the feasibility study on hereditary disease community control programmes (Hereditaryanaemias) .WHO, Geneva, Switzerland. (WHO/HDP/WG/HA/89.2)WHO    G id li  f  th  M t  f Si kl  C ll Di WHO  G  S it l d (WHO/HDP/SCD/ )WHO, 1991. Guidelines for the Management of Sickle Cell Disease.WHO, Geneva, Switzerland (WHO/HDP/SCD/91.2)WHO, 1993. Report of a joint WHO/TIF meeting on the prevention and control of haemoglobinopathies. WHO, Geneva, Switzerland (WHO/HDP/TIF/WG/93.1)WHO, 1994. Educational materials on prenatal diagnosis for Sickle‐cell disorder. WHO, Geneva, Switzerland (WHO/HDP/EM/PN.SCD/94.2).WHO, 1994. Guidelines for the Control of Haemoglobin Disorders. WHO, Geneva, Switzerland (WHO/HDP/HB/GL/94.1).WHO, 1995. Prevention and Control of Haemoglobinopathies. WHO Bulletin, v73(3):375‐386.WHO, 1997. Inherited Haemoglobin Disorders: an increasing global health problem. WHO Bulletin, v.75 (3):15‐39.WHO, 1999.  Services for the Prevention and Management of Genetic Disorders and Birth Defects in Developing Countries. WHO, Geneva, Switzerland (WHO/HGN/WAOPBD/99.1)WHO, 2000. Primary Health Care Approaches for Prevention and Control of Congenital and Genetic Disorders.WHO, Geneva, Switzerland (WHO/HGN/WG/00.1)WHO  2002  Minutes of a WHO meeting on haemoglobin disorders  WHO  Geneva  Switzerland (WHO/HGN/HB/02 4)WHO, 2002. Minutes of a WHO meeting on haemoglobin disorders. WHO, Geneva, Switzerland (WHO/HGN/HB/02.4)WHO, 2002.  Report of the Advisory Committee on Health Research. Genomics and World Health. WHO, Geneva, Switzerland (ISBN 92 4 154554 2).WHO, 2003. Genetic Approaches to Haemoglobin Disorders and Primary health Care.WHO, Geneva, Switzerland (WHO/HGN/TIF/CONS/03.1)WHO, 2006. Report by Secretariat to Executive Board: Sickle‐cell anaemia. EB117, Doc. EB117/34. WHO, Geneva, Switzerland [ www.who.int/gb ]WHO, 2006. Report by Secretariat to World Health Assembly: Sickle‐cell anaemia. WHA59, Doc.A59/9. WHO, Geneva, Switzerland [ www.who.int/gb ]WHO, 2006. Report by Secretariat to Executive Board: Thalassaemia and Other Haemoglobinopathies. EB118, Doc. EB118/5. WHO, Geneva, Switzerland [  h i / b ][ www.who.int/gb ]WHO, 2006.  Executive Board Resolution on Sickle Cell Anaemia. EB117.R3. WHO, Geneva, Switzerland [ www.who.int/gb ]WHO, 2006. World Health Assembly Resolution on Sickle Cell Anaemia.WHA59.20. WHO, Geneva, Switzerland [ www.who.int/gb ]WHO, 2006. Executive Board Resolution on Thalassaemia and Other Haemoglobinopathies. EB118.R1. WHO, Geneva, Switzerland [ www.who.int/gb ]WHO, 2006. Report  of  a joint  WHO/MOD meeting on Management  of  Birth Defects  and Haemoglobin Disorders.WHO, Geneva, Switzerland.WHO, 2008. Report  of  a joint  WHO‐TIF meeting on Management  of Haemoglobin Disorders.WHO, Geneva, Switzerland., p f j g g f g , ,WHO, 2010. World Health Assembly Resolution on Birth Defects.WHA63.17. WHO, Geneva, Switzerland [ www.who.int/gb

World Health OrganizationEB117 R3 Resolution 2006EB117.R3 Resolution, 2006

World Health OrganizationWHA59.20 Resolution, 2006,

World Health OrganizationEB118.R1 Resolution, 2006,

Resolutions on HemoglobinopathiesResolutions on HemoglobinopathiesThalassaemia and other Haemoglobinopathies U M b St tHaemoglobinopathies

EB118, May 2006 – Resolution EB118.R1Urges Member States: Implement and reinforce national

programs on HB disordersprograms on HB disorders Evaluate the impact of national

programs Intensify the training of all health

professionals Promote community educationy Promote international

cooperation Develop and strengthen medical Develop and strengthen medical

genetic services Support basic and applied

research

Sickle cell anaemiaWHA59, May 2006 – Resolution WHA59.20

research

Resolutions on HemoglobinopathiesResolutions on HemoglobinopathiesThalassaemia and other HaemoglobinopathiesHaemoglobinopathies

EB118, May 2006 – Resolution EB118.R1 Requests the Director-General provide technical support and p pp

advice to national programs expand the training and expertise

of personnelof personnel support the further transfer of

affordable technologiesdrafting guidelines on prevention drafting guidelines on prevention and management

fostering the establishment of regional groups of experts;regional groups of experts;

support needed researchSickle cell anaemiaWHA59, May 2006 – Resolution WHA59.20

NWHO meeting of expertsGeneva, 17-19 May 2006

Priorities:Priorities:• support continued research for the collection and refinement of data relevant for the control of birth defects and hemoglobin disorders

• provide practical advice and support for countries wishing to develop medical services for care and prevention of birthservices for care and prevention of birth defects and haemoglobin disorders

• promote human resource capacity• promote human resource capacity development and technology transfer

WHO-TIF Meeting of Experts, Cyprus,November 2007

A proposed 5-year plan of Action1 R i i th t t t f id i l d1: Reviewing the current status of epidemiology and

control services for Hemoglobin (Hb) disorders globally 2: Identification of local and regional problems needs and2: Identification of local and regional problems, needs and

priorities for improving control policies 3: Initiation of Guidelines for the control of Hb disorders4: Supporting the establishment of new and promoting the

services of existing expert centers5: Promotion of the establishment of regional expert

advisory groups6: Fund raising to support programs of control of Hb6: Fund raising to support programs of control of Hb

disorders 7: Development of cost-effective approaches and p pp

interventions for the control of Hb disorders 8: Promotion of the establishment of a World Day for

H l bi Di dHemoglobin Disorders9: Collaboration between potential stakeholders

List of WHA / EB resolutions (in genetics)

WORLD HEALTH ASSEMBLYWORLD HEALTH ASSEMBLY

WHA57.13WHA57.13 22 May 2004 Genomics and world health

WHAWHA5959..2020 27 May 2006 Sickle cell anaemia

WHA63 17WHA63 17 21 May 2010 Birth defectsWHA63.17WHA63.17 21 May 2010 Birth defects

EXECUTIVE BOARDEXECUTIVE BOARD

EB116/3EB116/3 26 May 2005 Control of genetic diseases

EBEB117117.R.R3 3 25 Jan 2006 Sickle cell anaemia

EB118 R1EB118 R1 29 May 2006 Thalassaemia and other EB118.R1EB118.R1 29 May 2006 Thalassaemia and other haemoglobinopathies

‐Thal/Hb E‐Thal 2/Hb E

( ‐Thal)2‐Thal 2Hb E

‐Thal

Hb H Disease ‐Thal 1/ ‐Thal‐Thal/Hb Ec ‐Thal 2‐

‐Thal 1 ‐Thal 1(‐Thal 1)2

Hb Bart’s Hydrops

‐Thal 1/Hb E

Hb Bart s Hydrops

Hb H Disease Hb AEBart,s Disease ‐Thal 1/Hb Ec Hb CS c Hb CS‐‐

Hb Constant Spring(Hb CS)

Hb E(Hb CS) 2 (Hb E) 2

(More than 60 genotypes )

Thailand, 1985

Pune,1Pune,1987

The Thalassemia Situation in CambodiaUntreated thalassemia

May 2005National Pediatric Hospital

19 year old male Hematocrit – 4 %

? Hb E/ thalassaemia? Hb E/ thalassaemia

Prevalence of Thalassemia & H l bi thi i M ldi

38%

Hemoglobinopathies in Maldives 23% 44%

8%

15%

10%Maldives

UNION OF MYANMARUNION OF MYANMAR

Myanmar – Thalassemia(Aung-Than-Batu et al 1968,1971)

• β thalassemia trait 0 5%• β thalassemia trait – 0.5%

• α thalassemia trait - 10%

• HbE trait - 26%

In Myanmar alone, 1‐4.9 per 1000 live birth suffer from severeform of thalassemia (Thalassemia major) (MODELL, 1986) 

Assuming an annual birth rate of 1.4 million, 1400 –7000 new cases of severe thalassemia each and every year in Myanmar 

500 Couples 

HbE thalassemia   HbE‐‐thalassemia,  ONE in every 500 couples are at‐risk 

HbH disease HbH disease TWO in every 500 couples are at‐risk 

Hb Bartʼs Hydrops Fetalis Hb Bart s Hydrops Fetalis NONE in every 500 couples are at‐risk 

(Ne Win et al, 2003 Myan Milit Med; 2005 Ann Rep) 

The distribution and the frequency (%) of thalassemia beta carriers in Indonesiathalassemia beta carriers in Indonesia

‐thalassemia

1

Batak

3Day

ak

njar

5P’baru

sa

4 2

HbE                

B 3D 0Ban5P

5Kaili

2

M’has

ng 8kasa

r

4nang

19

P’ban

i a

8

M’k

5ngka

8va

ork4

Min

63

1

1Bali

3Su

mba

5

Ba 8Jav

6Alo

5

Bim

a3

Sasa

k

46 4 337

A.S. Sofro & F. Lanni, University of Gajah Mada

4 337

Thalassemia situation in IndonesiaThalassemia situation in Indonesia

1400

Severe thalassemia patients in Jakarta

1200

1400

Type of thalassemias:

800

1000Type of thalassemias:• 52% Beta thalassemia

46% B t /HbE

400

600• 46% Beta/HbE• 2% HbH + others

0

200

1988 1998 20051988 1998 2005

INDONESIAINDONESIAEstimation of new -thalassemia patients

• Population 224 million• Annual birth rate: 2.3%• Carrier frequency 5% - 3,000 new patients/year• Only 3 000 patients registered• Only 3,000 patients registered

The expected number of th l i j ti tthalassemia major patients

Wahidiyat et al 1988Wahidiyat et al., 1988

Southeast/East Asia (2010)

No Country/Region

TotalPopulation (m)

0-thal(%)

+-thal(%)

-thal(%)

Hb E(%)

Hb S(%)Region Population (m) (%) (%) (%) (%) (%)

1 Bangladesh 143.9 0 41 2.5 4.0 02 Bhutan 2.1 0 32 + 4.0 03 DPR, Korea 24 ND ND ND ND ND4 India 1,210.2 0 41 1.6 1.0 1.95 Indonesia 237.4 + 7.7 4.0 1.9 06 Maldives 0.37 0 32 16 1.0 0.17 M anmar 59 1 0 4 32 2 2 25 07 Myanmar 59.1 0.4 32 2.2 25 08 Nepal 28.0 0 32 1.0 3.0 09 Sri Lanka 20.0 0 40.8 2.5 2.5 010 Thailand 64.7 5.0 21 5.3 33 011 Timor-Leste 1.13 ND ND ND ND ND

Grand Total 1,790.9

(Modified from Modell )

Thalassemia diagnosis in different SEARO countries

Country Blood Cell Analyzer

OF Hb Analysis DNA Analysis

Electrophoresis HPLC/LPLC/CE p

Bangladesh (+) - (+) (+) (+) (+)Bhutan ND ND ND ND ND ND

DPR Korea ND ND ND ND ND NDIndia (+) + + (+) + +

Indonesia (+) - + (+) (+) (+)Indonesia (+) + (+) (+) (+)Maldives (+) - + + (+) -Myanmar (+) - (+) - (+) (+)

Nepal ND ND ND ND ND NDSri Lanka + - + (+) (+) (+)Thailand + + + + + +Thailand + + + + + +

Timor-Leste ND ND ND ND ND ND

Thalassemia treatment available in different SEARO countries

Country Blood Transfusion

IronChelation

BM/Stem cell

Transplant

PND NationalProgram

DFO L1 ExjadeBangladesh (+) (+) (+) (+) - - -

Bhutan ND ND ND ND ND ND NDBhutan ND ND ND ND ND ND NDDPR Korea ND ND ND ND ND ND ND

India (+) (+) + + (+) (+) (+)Indonesia (+) (+) (+) (+) - (+) -Maldives + + + + - + +Myanmar (+) (+) + (+) - - -y ( ) ( ) ( )

Nepal ND ND ND ND ND ND NDSri Lanka + + + + - - (+)Th il d ( )Thailand + + + (+) + + +

Timor-Leste ND ND ND ND ND ND ND

Treatment of Thalassemia

1. Conventional Treatment- Blood Transfusion- Iron Chelation

2. Treatment of ComplicationI f ti- Infections

- Heart Failure etc.

2 l bi S i l i2. Hemoglobin F Stimulation4. Cure

- Bone Marrow and Stem CellsTransplantationTransplantation

- Gene Therapy

Estimated Direct Cost for the Management of gOne β‐Thalassemia Major for 30 Years: 2006

Items 1‐10 years 11‐20 years 21‐30 yearsItems 1 10 years 11 20 years 21 30 years

1. Blood transfusion  plus filter/month

2,500 (1 unit) 5,000 (2 units) 7,500 (3 units)

2. Desferrioxamine  Vial/month

5,000 (20 vials) 10,000 (40 vials) 150,000 (60 vials)

 H it l   3. Hospital care 1 day/month

2,000 2,000 2,000

4. Other: Lab  1,000 1,000 1,0004tests/month

5. Total cost/month 10,500 18,500 26,500

6. Total cost/year 126,000 222,000 318,000

7. Total cost/10 years 1,260,000 2,220,000 3,180,000

Grand total 6,660,000 Baht (150,000 Euro )

(1 Euro = 44 Baht) (Leelahavarong P et al 2010) 

Thalassemia in ThailandThalassemia in Thailand‐Thalassemia (‐thal1 and ‐thal2) 20 ‐ 30%

Hb Constant Spring (�-thal 2 like effect ) 1 ‐ 8%

� Th l i 3 9%�-Thalassemia 3 ‐ 9%

Hemoglobin E 10 ‐ 53%

Total number of thalassemic patients and the number of Total number of thalassemic patients and the number of births per year (total births = 800,000/year)births per year (total births = 800,000/year)

Diseases Couple at risk (per year)

Birth (per year)

Living patients

Homozygous � thalassemia 828 207 2 070Homozygous �-thalassemia 828 207 2,070�-Thalassemia/Hb E 12,852 3,213 96,390Hb Bart,s hydrops fetalis 3332 833 0Hb Bart s hydrops fetalis 3332 833 0Hb H disease 22,400 5,600 336,000

Total 39,412 9,853 434,460, , ,

Modified from Fucharoen S. and Winichagoon P., 1988

Comparison of the cost of treatment and and prevention ofsevere thalassemia in 1000 pregnant women in Thailand

Prevention Expected No. Birth

Treatment(av. life= 30 yrs)

Hb Bart’s hydrops fetus

48,280 B(US$ 1379) 2

42,500 B(US$ 1 214)fetus (US$ 1379) 2 (US$ 1,214)

Beta thalassemic 48,280 B **26,400,000 BDisease* (US$ 1379) 4# (US$ 754,285)

(* include both homozygous beta thalassemia and beta thal/HbE,#1 homozygous beta thalassemia and 3 beta thal/HbE , ** cost per case 6 660 000 B)** cost per case = 6,660,000 B)

C l PC l PControl ProgramControl Program

Strategy

1 • Treatment of Existing Cases

Strategy

1 g

• Prevention Birth of New Cases2 • Prevention Birth of New Cases

Preliminary data on serum ferritin in ADULT and pediatric patients after 6mths of GPO-L-ONE-2

3 mths 6mthsAverage s erum ferritin reduction after 6 mths of DFP

- 57.6 - 20.6- 934 -1260

Pediatrics

Adults-200

01 2 3

Average dose in ped. = 75-80 MKD

Average dose in adult = 50-55 MKD-600

-400

ng/m

L)

-1000

-800SF (n

-1400

-1200

0 3mths 6mths0 3mths 6mths

pediatrics (n=33) adults (n=30)

Prevention of Thalassemia

Screening Counseling

General

Screening Counseling

GeneralPremarital

PreconceptionalPrenatalPostnatal

-Screening test:- MCV/OF- DCIP

-Diagnostic test:- Hb typing- genotyping- DCIP - genotyping

Immunochromatographic Strip Test for -Thalassemia

3 h 4 R d lt1. 0.1 ml. blood

+ hemolysis t

2. Insert strip, leave 2 min.

3. wash 4. Read result

3 minutesagent

Tongsong T, Wanapirak C,Sirivatanapa P, Sanguansermsri T, Sirichotiyakul S, Piyamonkol W, Chanprapaph P.

Prenatal control of severe thalassemia: Chiang Mai strategy

Prenat Diagn 2000; 20: 229-234

Hb Bart’s Hydrops Fetalis

20 191920

11

15 Hydrops

10

23

5

0 0 0 0 00

‘94 ‘95 ‘96 ‘97 ‘98 ‘99 ‘00 ‘01 ‘02 ‘03

Wanapirak C. et al, 2004

New registration for thal majorNew eg s o o jo

6

5

6

4

5

CMU h i l33

CMU hospital

1

2

0 0 0 0 0 0 0 00

ʻ94 ʻ95 ʻ96 ʻ97 ʻ98 ʻ99 ʻ00 ʻ01 ʻ02 ʻ0394 95 96 97 98 99 00 01 02 03Wanapirak C. et al, 2004

New registration for thal/Hb ENew registration for thal/Hb E

77

5 56

7

5 5

4

5 CMU hospital

23

4

1

2

11

2

0 0 0 00

ʻ94 ʻ95 ʻ96 ʻ97 ʻ98 ʻ99 ʻ00 ʻ01 ʻ02 ʻ0394 95 96 97 98 99 00 01 02 03Wanapirak C. et al, 2004

Case Registration (year)g (y )

40CMU MOPH

353130

3540

3126 24 22 22

25 2421

2530

ber

Hb E/beta-thal22 22

1511

21

111520

Num

b Hb E/beta-thalbeta-Thal major

11 9

3

11 10 95 4 35

10

3300

93 94 95 96 97 98 99 00 01 02YearYear

N i l P h P i dNational Program on the Prevention and Control of Thalassemia in Thailand

(Starting: 1994)

University Thalassemia Foundationof Thailandof Thailand

Ministry of Public Health

Thalassemia in Developing Countries1. Many communicable diseases

2. Poverty

 Li it d d t    f   d l k  f d t  3. Limited data on frequency and lack of data on economic issue

4. Lack of awareness: government/NGO

5. Ethical, social, religious and legal issues

ELSI and Thalassemia1. Should thalassemia be treated in poor 

t ?country?

2  Lack of education2. Lack of education

3. Social and religious issues3 g

4. Government and social policy on PND

5. Lack of regulatory/ethics organization

Global Control of Hemoglobinopathies

1. North-south or north-south-south university partnershipspartnerships

2. Identification of local mutations3. Training and technology transfer4. National control program established5 Future: Regional network to be established5. Future: Regional network to be established

Country Report1 Australia (John Prior)1. Australia (John Prior) 2. Bangladesh (Syed Khairul Amin)3. Cambodia (Sam Vuthy, Robyn Devenish)3. C bod (S Vu y, oby eve s )4. China, Guangxi (Chen Ping)5. China, Hong Kong (Vivian Chan) Prawase Wasi

Mahidol University

6. India (Roshan Colah)7. Indonesia (Iswari Setianingsih)8 Laos (Douangdao Souk Aloun)8. Laos (Douangdao Souk Aloun)9. Malaysia (Elizabeth George) 10. Maldives (Naila Firdous) Sir David Weatherall( )11. Myanmar (Sann Sanda Khin) 12. Singapore (Hai Yang Law)

Oxford University

13. Sri Lanka (Shanthimala de Silva)14. Taiwan (Ching-Tien Peng)15 Thailand (Vichai Tienthavorn)15. Thailand (Vichai Tienthavorn) 16. Vietnam (Lam Thi My)

Alan BittlesEdith Cowan University

ASIAN NETWORK FOR THALASSAEMIA CONTROL

Miracle Grand Hotel

Bangkok, July 2-4, 2005

Organizers:- Thalassemia Research Center, Mahidol University, y- Department of Maternal and Child Health,

Ministry of Public Health, Thailandy ,- Thalassemia Foundation of Thailand

Asian Network for Thalassemia Control

July 4, 2005Miracle Grand HotelBangkok, Thailand

Conclusion:1. We have common problemsp2. Magnitude of problems is not well established in some countries 3. Different levels of knowledge and technologyin member countries4. Heterogeneity of disease severity

Proposed a Twin Center Concept:Bridge countries with knowledge and technology

to the one that just getting start.

Questions:Questions:How to get start? Where is the fund?

Proposes:

1) Set up Regional Working Group on Hemoglobinopathies(RWGH)(RWGH)2) Provides partial support to run the RWGH3) Have a regular annual meeting of the working group, rotate to all member countries4) The annual meeting should be mainly sponsored by local

t ( ith ti l t f SEARO)government (with partial support from SEARO)5) The RWGH can help local organizer (of annual meeting) toorganize education symposium or laboratory workshop fororganize education symposium or laboratory workshop forthe local people (administrators, doctors, technicians, nurses)6) The RWGH will help to develop lab manual (for diagnosis), GCP guidelines, etc.7) The RWGH will help training of personals (doctor, nurse, technicians counselor etc )technicians, counselor etc.)

SEARO should work in collaboration with other regions