will pharmacogenomic improve hiv...
TRANSCRIPT
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Chonlaphat Sukasem, B. Pharm., MPM. Ph. D.Presented at The 2th National Scientific Conference of HIV/AIDS Laboratory, August 2010
Will Pharmacogenomic Improve HIV Therapeutics?
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Objectives to cover
Brief introduction to Pharmacology and Human genetic variation
Pharmacogenomics (Pharmacology+Genomics)
Current knowledge regarding human genetic variability and responses to HIV therapy (HIV-Pharmacogenomics)
Understand application in clinical setting
To suggest future directions for HIV-Pharmacogenomics
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What determines your risk for ADRs
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หากทานแพยาโปรดแจงใหแพทยและพยาบาล
หากทานแพยาโปรดแจงใหเภสชกร
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กฏหมายคมครองผบรโภค (20 กมภาพนธ 2552)
-การแจงใหผปวยทราบวาการรบประทานยานนๆ อาจกอใหเกดอาการ
ไมพงประสงคจากยา กไมสามารถใชเปนเหตในการทาใหพนผดในกรณทผปวย
เกดอาการแพยา
-การฟองรองในกรณดงกลาว ใหยกเวนคาฤชา
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The genome era of HIV PharmacotherapyTools for initiating antiretroviral therapy in HIV infection
CD4 cell count
Viremia (Viral load)
Clinical symptoms
Viral genetics
(Mutation associated ARVs resistance)
Can host genetic information add something?
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1 22~3,000,000 common SNPs across genome• Representing every gene
P value
1 22
Regions of association
Chromosomal Location
Genome-wide genotyping
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Homozygous 1
Heterozygous
Homozygous 2
Genome-wide genotyping
500,000 to 1,000,000 SNPs/individual
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Genetic Variants
Polymorphism: a common DNA variant (>1% of population) Base substitution, deletion, or insertion Single Nucleotide Polymorphisms (SNPs) Alter function or expression level of protein
C/AC/C
Mutation: a rare DNA variant (<<1% of population)
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เภสชพนธศาสตร:จโนมและเภสชวทยา
Christian M., et al. J Mol Med 2003
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PAST
NOW & FUTRE
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“If it were not for the great variabilitybetween individuals, medicine might as well be a science, not an art.”
(Sir William Osler, pathologist, 1892)
Pharmacogenetics: เภสชพนธศาสตร Rapidly expanding field that will have a major
impact on how we treat diseases:-Help identify who will respond to a specific therapy
-Help identify who is at risk for side effects of treatment
-Help identify the appropriate dosing for individual patients
Why use pharmacogenetics in clinical practice?
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Clinical goals of PGx: Personalized medicine
Avoid adverse drug reactions
Maximize drug efficacy
Select responsive patients
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รายงานอบตการณของการเกดอาการไมพงประสงคจากการใชยา
จากการตดตามปญหาการใชยาในโรงพยาบาลขนาดใหญทวประเทศ
พบผปวยมปญหาแพยา 9%
ทาใหพการ 23% และเสยชวต 11%
เปนปญหาทมความสาคญมากทางการสาธารณสขไทย
-ศนยตดตามอาการไมพงประสงคจากการใชผลตภณฑสขภาพ สานกงานคณะกรรมการอาหารและยา
-http://www.consumerthai.org
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http://www.thaihealth.or.th/node/4868
ศนยเฝาระวงความปลอดภยจากการใชผลตภณฑสขภาพ
สานกงานคณะกรรมการอาหารและยา: สสส. (2523-2550)
แพยาเฉลย จานวน 25,000 รายตอป
เสยชวต 10-20 รายตอป (SJS)
ม 204,417 รายงาน (กลมอาย 7-96 ปเปนผหญง 43.79%)
เสยชวต 269 ราย (8 ตอ 10,000 ราย)
1 ม.ค.-31 ธ.ค.2550 -มรายงานอาการไมพงประสงคจากการใชยาทงสน 46,353 ราย เปนการ
อาการทางผวหนงมากทสด 26,546 ราย -เปนอาการไมพงประสงคทรายแรง 3,227 ราย โดยอาการไมพงประสงค
รายแรงทไดรบรายงานมากทสด คอ ผนผวหนง จานวน 1,560 ครง
-สตเวนส-จอหนสน ซนโดรม จานวน 502 ราย
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DOSE DEPENDENT
DOSE INDEPENDENT
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HIV-Pharmacogenomics???
การกนยาอยางสมาเสมอ (Adherence) ในผตดเชอเอชไอวเปน
สงสาคญมาก
อาการขางเคยงจากการกนยาเปนปจจยสาคญตอการกนยา
อยางสมาเสมอ
Trevor Hawkinsa, 2010
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HypothesisIndividuals carrying risk genetic markers (GR) will discontinue
the initial treatment more frequently/earlier than individuals without
577 individuals starting first line ART 2004-2007
0 60 120 180 240 300 3600
102030405060708090
100without GRwith GR
50671
No. at Riskwithout GRwith GR
45859
43251
41144
38038
347 30535
50.2%
31.2%
aHR = 1.76 (CI95%: 1.18 - 2.63)Pa= 5.65 x 10-3
29
Time to discontinuation (days)
Glo
bal d
isco
ntin
uatio
n (%
)
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b)
0 60 120 180 240 300 3600
20
40
60
80
100without GRwith GR
28.6%
13.6%
aHR = 1.61 (CI 95%: 0.67 P = 0.286
Time to discontinuation (days)
TDF
disc
ontin
uatio
n (%
)b)
0 60 120 180 240 300 3600
20
40
60
80
100without GRwith GR
28.6%
13.6%
aHR = 1.61 (CI 95%: 0.67 P = 0.286
Time to discontinuation (days)
TDF
disc
ontin
uatio
n (%
)b)
0 60 120 180 240 300 3600
20
40
60
80
100without GRwith GR
N t Ri k
71.2%
28.1%
aHR = 3.43 (CI95% 1.48 - 7.9P = 0.004
Time to discontinuation (days)
EFV
disc
ontin
uatio
n (%
)b)
0 60 120 180 240 300 3600
20
40
60
80
100without GRwith GR
N t Ri k
71.2%
28.1%
aHR = 3.43 (CI95% 1.48 - 7.9P = 0.004
Time to discontinuation (days)
EFV
disc
ontin
uatio
n (%
)
0 60 120 180 240 300 3600
20
40
60
80
100without GRwith GR
46.5%
33.1%
aHR = 1.28 (CI95%: 0.53 - 3.1P = 0.587
Time to discontinuation (days)
LPV
disc
ontin
uatio
n (%
)
0 60 120 180 240 300 3600
20
40
60
80
100without GRwith GR
46.5%
33.1%
aHR = 1.28 (CI95%: 0.53 - 3.1P = 0.587
Time to discontinuation (days)
LPV
disc
ontin
uatio
n (%
)
b)
0 60 120 180 240 300 3600
20
40
60
80
100without GRwith GR
t Ri k
62.5%
18.9%
aHR = 6.10 (CI95%:2.78 - 13.3
P = 6.00 x 10- 6
Time to discontinuation (days)
ATV
disc
ontin
uatio
n (%
)
b)
0 60 120 180 240 300 3600
20
40
60
80
100without GRwith GR
t Ri k
62.5%
18.9%
aHR = 6.10 (CI95%:2.78 - 13.3
P = 6.00 x 10- 6
Time to discontinuation (days)
ATV
disc
ontin
uatio
n (%
)
Tenofovir Efavirenz
Lopinavir/r Atazanavir/r
Renal toxicity CNS
HyperbillirubinemiaHeart disease
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Host genetic variation- ARVs
Hypersensitivity reaction syndromes
Hepatotoxicity Central nervous system S/E Hyperbilirubinemia Peripheral neuropathy Lipodystrophy Hyperlipidemia Pancreatitis Renal toxicity
Valerio Tozzi, 2010
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Associations between Allelic Variants and HIV Treatment ResponseReaction Drugs Gene
Hypersensitivity Abacavir HLA-B*5701, hsp70-hom
(Lancet 2002:359,727 & 1121; PNAS 2004:101,4180)
Hyperbilirubinemia Indinavir, UGT-1A1 (Gilbert’s)Atazanavir
(PNAS 2001:98,12671; ICAAC 2002)
Lipoatrophy NRTI TNF-α promoter(AIDS 2002:16,2013; AIDS 2003:17,121)
Rash/Hepatitis/Fever Nevirapine HLA-DRB1*01(AIDS 2005:19,97)
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DRUGS WITH GENETIC MARKERS
*Efavirenz
Atazanavir
Lopinavir
Tenofovir
**Abacavir
**Nevirapine
INTERMEDIATE PHENOTYPE
High plasma levels
Increased bilirubin
Increased lipid levels
Phosphaturia, glucosuria, etc…
CLINICAL EFFECT
CNS toxicity
Gilbert syndrome
Cardiovascular diseases Renal toxicity
Hypersensitivity
Hypersensitivity
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Pharmacogenetic markers•Selecting appropriate drug •Treatment choice
DOSE-INDEPENDENT
ADRs type B
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Pharmacogenomics marker: Dose-independent**
HLA HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB1
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• Nucleoside reverse-transcriptase inhibitor, used in the treatment of HIV
• Has shown efficacy, few drug interactions, and a favorable long-term toxicity profile
• Most important adverse effect of ABC that limits its use is an immunologically mediated hypersensitivity reaction affecting 5 - 8% of patients during the first 6 weeks of treatment
Abacavir:ABC
Mallal S et al. N Engl J Med 2008;358:568-579
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Incidence of Hypersensitivity Reaction to Abacavir
PPV= Positive predictive valueNVP=Negative predictive value
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NVP HLA-B* 3505, Chanrtarangsu et al, 2008d4t HLA-B* 4001, Wongsomboonsiri, et al, 2010
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Pharmacogenetic markers•Predicting appropriate drug levels•Treatment choice
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Pharmacogenomics marker : Dose-dependent
A. Ultra-rapid metabolizers (UM) B. Extensive metabolizers (EM) C. Intermediate metabolizers (IM) D. Poor metabolizers (PM) or Slow metabolizers (SM)
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Host Genetics and Efavirenz
Efavirenz (EFV) is the second line regimen for HIV-1 infection
CNS side effects are common with EFV
EFV plasma clearance is slower in blacks than in whites. (Barrett 2002, Pfister 2003, Ribaudo 2004)
One study suggested earlier virologic failure on EFV in blacks than in whites. (Wegner 2002)
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Efavirenz Metabolism by CYP2B6
Ward et al. J Pharmacol Exp Ther 2003:306,287.
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Cou
nt
0
5
10
15
20
25
30
35
log10 EFV AUC (µg*h/ml)
0.5 1.0 1.5 2.0 2.5 3.0 3.5
Cum
ulat
ive
Freq
uenc
y
1
10
30
50
70
90
99
99.9
99.99
Cou
nt
0
5
10
15
20
25
30
35
log10 EFV AUC (µg*h/ml)
0.5 1.0 1.5 2.0 2.5 3.0 3.5
Cum
ulat
ive
Freq
uenc
y
1
10
30
50
70
90
99
99.9
99.99
Distribution of Efavirenz AUC valuesRotger et al. Clin Pharm Ther 2007
Extensive metabolizer
Slow metabolizerRapid metabolizer
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GG GT TT GG GT TT GG GT TT0
50
100
150
200
250
all subjects African-American
European-American
CYP2B6 G516T genotype
efav
irenz
AUC
0-24
h
(mic
rog.
h.m
L-1)
CYP2B6 G516T (Exon 4) andEfavirenz Plasma Levels
Haas et al, AIDS 2004;18:2391
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Nevirapine Liver Toxicity
Nevirapine (NVP) can cause hepatotoxicity
NVP is metabolized by CYP2B6, not known to be a substrate for P-glycoprotein
We explored MDR1, CYP2B6, CYP3A4, and CYP3A5 SNPs and NVP hepatotoxicity
Haas et al, 12th CROI, 2005
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MDR1 Polymorphism and Nevirapine Hepatotoxicity: FTC-302 and ACTG Collaboration
CC CT TT0
20
40
60
80
100 Hepatotoxicity casesControls
(RR=0.30; P=0.016)
MDR1 position 3435
prop
ortio
n
Haas et al, 12th CROI, 2005
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LPV ETA1-CL
-1.1 -1.0 -0.9 -0.8 -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6
Num
ber o
f ind
ivid
uals
0
5
10
15
20
25
30
35
40
45
50
55
Prob
it
1
10
30
50
70
90
99
99.9
99.99
Low Outliers (n=121)
Extreme (>P85%) (n=92)
Cases Controls
Lopinavir/r Pharmacokinetic-Genetics
Lubomirov et al.
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Manolio Nat Genet 2009
Dyslipidemia as common genetic trait
Rotger et al. 2009
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Clinical Issues
Pharmacogenomics may hold the potential to improve efficacy and safety in prescription, but complex factors affect their clinical success
Jai Shah, BMJ 2004
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Human Genetics• SNPs• Haplotypes• Sequencing
Expression Profiling• Specific transcript levels• Total RNA profiling
Proteomics• Specific biochemical
markers• Protein profiling
Phenotype• Drug response
• Disease
Prediction
Pharmacogenomics
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Qing Ma, Future Drug, 2008
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2010
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Establishment of Clinical Utility
Practice guideline and/or consensus statement inclusion
Government endorsement: policy statements
Payer policy statements - Insurance and managed care
Lab and tests available
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Potential Modifiers of TestAdoption Curve Access to test (laboratory and/or specimen requirements) Regulatory Approval Reimbursement limitations Physician group involved
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Regulatory Factors Impacting Test Adoption; FDA approval key to assay adoption
FDA drug labeling changes and test kit approvals have not resulted in test uptake
Warfarin, UGTA1A, Cytochrome P450 chip,
Tests with established clinical utility have been adopted prior to specific FDA action
HLA-B*5701 • Abacavir drug labeling
update July 2008
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Lai Goldman: Genet Med, 2008
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เภสชพนธศาสตรเพอคณภาพชวตคยไทยทดขน
เภสชพนธศาสตรชวยประหยดงบประมาณดานการรกษาโรคดวยยาเพอใหม
งบประมาณเพยงพอสาหรบการรกษาประชาชนคนรากหญาอยางทวถง
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Take Home Messages
Personalized medicine has begun to pay off• Targeted therapies • Risk reduction strategies
In the future, multiple opportunities exist to• Prevent or predict ADRs• Improve medication management• Reduce health care costs• Improve pace of drug discovery/clinical trials
Multiple challenges to implementation still remain• Clinical science• Public policy
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หองปฏบตการเภสชพนธศาสตรและการรกษาเฉพาะบคคลLaboratory for Pharmacogenomics and Personalized Medicine
From Bench to Bedside
PGx testing at Ramathibodi hospital
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นาเทคโนโลยเภสชพนธศาสตรเขามาชวยคดกรองผปวยกอนการใชยา เพอสนบสนนใหเกดการรกษาท
เหมาะสมเฉพาะบคคล ลดโอกาสเกดผลขางเคยงทรนแรงซงบางรายอาจเปนอนตรายถงชวต โดยมงเนน
ในกลมโรคทเปนปญหาทางสาธารณสขของประเทศไทย อาท ผตดเชอเอชไอวหรอผปวยเอดส โรคหลอด
เลอดและหวใจ โรคเลอดจางธาลสซเมย เปนตน เพอสงเสรมใหผปวยมคณภาพชวตทดขนและลดคาภาระ
คาใชจายในระดบบคคล องคกร และประเทศ
หองปฏบตการเภสชพนธศาสตรและการรกษาเฉพาะบคคล
Laboratory for Pharmacogenomics and Personalized Medicine
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การตรวจวนจฉยทเปดบรการ
การตรวจวนจฉยทางเภสชพนธศาสตรเพอเปลยนหรอเลอกใชยา I. HLA polymorphisms
• 1. การตรวจหายน HLA B*5701 กอนการจายยา Abacavir (The XVI International AIDS Conference,http://www.thebody.com/content/art16156.html)
• 2. การตรวจหายน HLA B*1502 กอนจายยา Carbamazepine Man CB, Kwan P, Baum L, Yu E, Lau KM, Cheng AS, et al. Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia. 2007 May;48(5):1015-8.
• 3. การตรวจหายน HLA B*5801 กอนจายยา Allopurinol Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, Lin YL, Lan JL, Yang LC, Hong HS, Chen MJ, Lai PC, Wu MS, Chu CY, Wang KH, Chen CH, Fann CS, Wu JY, Chen YT. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A. 2005; 102: 4134-9.
• 4. การตรวจหายน HLA B* 3505 กอนจายยา Nevirapine
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การตรวจวนจฉยทเปดบรการ
การตรวจวนจฉยเภสชพนธศาสตรเพอการปรบขนาดยาI. ตรวจหา CYP 450 polymorphisms
1. การตรวจหายน CYP 2B6 polymorphisms
CYP2B6*1 (516G/785A/1459C), CYP2B6*4 (785G),
CYP2B6*5 (1459T), CYP2B6*6 (516T/785G)
และ CYP2B6*7 (516T/785G/1459T)
2. การตรวจหายน CYP 2D6 polymorphisms
CYP2D6*2-*7, CYP2D6*9, CYP2D6*10
3. การตรวจหายน CYP2C9 polymorphisms
CYP2C9*2 CYP2C9*3 (VKORC1 )
4. การตรวจหายน CYP2C19 polymorphisms
CYP2C19*2 และ CYP2C19*3
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DNA Chip/ Micro Array: Mapping 10K, 50K, 100K, 500 K Array
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Case study: All-in-One assay
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Result and interpretation
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เราใหบรการ……….แมนยาถกตองตามหลกวชาการ (Reliability)
เราใหบรการ………….ดวยประสทธภาพระดบมออาชพ (Professionality)เราใหบรการ ………….ดวยความรวมมอรวมใจของทกภาคสวน (Co-operation)
International standards; GLP, GCP, ISO 15189 and CLIA
หองปฏบตการเภสชพนธศาสตรและการรกษาเฉพาะบคคล
Laboratory for Pharmacogenomics and Personalized Medicine
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The next frontier
http://www.ipadrblog.com/BlindMenandElephant.jpg