DRUG ALLERGY What have we learned from immunogenetics?

Natacha Santos, Carmen Botelho, Josefina Cernadas HSJ, Dezembro 2010

Adverse Drug Reactions

“A response to a medicine that is noxiuos and unintended, and which occurs at doses normally used in man”

WHO

Type A Augmented pharmacologic effects

Type B Bizarre effects

Typce C Chronic effects

Type D Delayed effects

Type E End-of-treatment effects

Type F Failure of treatment

objectively reproducible symptoms or signs

initiated by exposure to a defined stimulus at a

dose tolerated by normal persons

Hypersensitivity reactions

Immune-mediated Non Immune-mediated

Drug allergy

Drug allergy

Pichler WJ (ed): Drug Hypersensitivity. Basel, Karger, 2007, pp 168–189

Questions? ¨  Aetiology ¨  Phenotypic-specificity

Drug allergy

Drug

Dose

Route of administration

Co-factors

Genetics

Answers?

Pharmacogenetics

“Is the study of variability

in drug response due to

genetic factors, which are

mainly inherited”

Pharmacoproteomics

Pharmacotranscriptomics

Pharmacogenetics

Pharmacometabolomics

Clinical response

Personalized

Prescription

Pharmacogenetics of Drug Allergy

Pharmacokinetics

Pharmacodynamics

Tissue injury and repair mechanisms

Immune system recognition and responsiveness Immunogenetics

Abacavir

“Within the entire abacavir-exposed cohort, presence of HLA-B*5701, HLA-DR7, and

HLA-DQ3 had a positive predictive value for hypersensitivity of 100%, and a negative

predictive value of 97%.” Lancet. 2002 Mar 2;359(9308):727-32

Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4180-5

“HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of

controls. (…) Individuals with abacavir hypersensitivity demonstrated increased

monocyte tumor necrosis factor expression in response to ex vivo abacavir stimulation,

which was abrogated with CD8(+) T cell depletion”

Abacavir

“The cost-effectiveness model demonstrated that depending on the choice of

comparator, routine testing for HLA B*5701 ranged from being a dominant strategy

(less expensive and more beneficial than not testing) to an incremental cost-

effectiveness ratio (versus no testing) of Euro 22,811 per hypersensitivity reaction

avoided.” Pharmacogenetics. 2004 Jun;14(6):335-42

“Detect HLA-B*5701 using allele and group-specific polymerase chain reaction-

sequence-specific primers (PCR-SSP) typing.”

Tissue Antigens. 2005 Jun;65(6):571-4

Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the

prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative

predictive value of 100% and a positive predictive value of 47.9%.

Abacavir

N Engl J Med 2008;358:568-79

Although immunologically confirmed abacavir hypersensitivity reactions are uncommon

in black persons, the 100% sensitivity of HLA-B*5701 as a marker for immunologically

confirmed abacavir hypersensitivity reactions in both US white and black patients

suggests similar implications of the association between HLA-B*5701 positivity and risk

of ABC HSRs in both races. Clin Infect Dis. 2008 Apr 1;46(7):1111-8

Abacavir

FDA ALERT (24/7/2008) “(…) all patients should be screened for the HLA-B*5701 allele before starting or restarting treatment with abacavir or abacavir-containing medications (…)”

EMEA UpDate (24/01/2008) “(…) before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be performed (…)”

Abacavir

¨  Genetic association with large genetic effect size

¨  Valuable in different ethnical groups

¨  Reproducible. High predictive negative values

¨  Impact on clinical outcome in real-world clinical practise

¨  Cost-effectiveness

Carbamazepine

“There is a strong association in Han Chinese between a genetic marker, the human

leukocyte antigen HLA-B*1502, and Stevens-Johnson syndrome induced by

carbamazepine.” Nature. 2004 Apr 1;428(6982):486

“Preliminary results from a European study (RegiSCAR) of 12 carbamazepine-induced

SJS/TEN cases (nine French and three German). Among these only four had a HLA-

B*1502 allele. Remarkably, these four patients had an Asian ancestry, whereas the

others did not as far as we have ascertained.”

Pharmacogenomics J. 2006 Jul-Aug;6(4):265-8

Carbamazepine

“Confirmed the association of HLA-B*1502 with SJS/TEN. By contrast to CBZ-SJS/TEN,

HLA-B*1502 association was not observed in the maculo-papular eruption or

hypersensitivity syndrome groups.”

Pharmacogenet Genomics. 2006 Apr;16(4):297-306

FDA ALERT (12/12/2007) “(…) Patients with ancestry from areas in which HLA-B*1502 is present should be screened for the HLA-B*1502 allele before starting treatment with carbamazepine(…)”

Allopurinol

 ”In Han Chinese, the HLA-B*5801 allele was present in all (100%) 51 patients with allopurinol-severe cutaneous

adverse reactions, but only in 20 (15%) of 135 tolerant patients.”

Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4134-9

“All of the 27 (100%) allopurinol-induced SJS/TEN patients who were examined carried HLA-B*5801 whereas

only seven (12.96%) of the control patients had this allele. The positive predictive value and the negative

predictive value of the HLA-B*5801 allele was 1.52 and 100%, respectively.”

“A strong association between allopurinol-induced severe cutaneous adverse reactions and HLA-B*5801 was

observed in a Han Chinese population with high frequency of this allele, whereas only a moderate association

was observed in populations with low frequency (i.e. European and Japanese).”

Pharmacogenet Genomics. 2009 Sep;19(9):704-9

Late Hypersensitivity reactions

Abacavir DHS HLA-B*5701

Allopurinol SJS/TEN HLA-B*5801

Amoxicilin/clavulanic acid Hepatitis HLA-DRB1*1501

Carbamazepine SJS/TEN HLA-B*1502

HLA-B*5901

HLA-A*0206

MPE HLA-E/HLA-A*3101

Efavirenz Skin rash HLA-DRB1*01

Flucloxacilin Hepatitis HLA-B*5701

Lamotrigine SJS/TEN HLA-B*1502

HLA-B*38

Nevirapine Skin rash HLA-B*3505

HLA-DRB1*01

Hepatitis HLA-Cw8 and HLA-B14(65)

Oxcarbazepine SJS/TEN HLA-B*1502

Phenitoin SJS/TEN HLA-B*1502

Why HLA?

CD8+ T cells in skin biopsies of patients

Elevated tumor necrosis factor-a (TNFa) and interferon-gamma (IFNg)

Positive skin-patch test

Betalactams

“In a chinese population, significant differences of E237G

genotype were observed between patients with positive

benzylpenicillanyl (BPA), phenoxomethylpenicilloyl (PVO) or

ampicilloyl (APO)-IgE and control group. The E237G

variant of the FcepsilonRIbeta gene is involved in the

development of penicillins allergy”

Allergy. 2004 Dec;59(12):1326-32

Betalactams

“Among atopic (french) subjects, we found two distinct

significant associations between immediate beta-

lactam allergy in women and the Ile75Val variant of

IL-4Ralpha gene, and two linked IL-10 promoter gene

polymorphisms, -819C>T and -592 C>A.”

Allergy. 2006 Aug;61(8):921-7

In an Italian population, the combination of the less

frequent allele of the IL13 R130Q polymorphism with

any of the predominant homozygous genotypes of the

three polymorphisms of IL4RA was more significantly

associated with the risk of betalactam allergy than

any polymorphism considered alone

Betalactams

Pharmacogenet Genomics. 2006 Oct;16(10):713-9

NSAIDs

Aspirin-exacerbated respiratory disease

•  HLA-DPBI*0301

•  LTC4S

•  ALOX5

•  CYSLT

•  PGE2

•  TBXA2R

•  TBX21

J Clin Pharm Ther. 2008 Oct;33(5):465-72.

NSAIDs

Aspirin-intolerant urticaria

•   HLA-DB1*0609

•  ALOX5

•  FCER1A

•  HNMT

J Clin Pharm Ther. 2008 Oct;33(5):465-72.

Drug-allergy pharmacogenetics

¨  Insight of the mechanisms of immune-mediated diseases

¨  Clinical importance - screening

Except for abacavir, carbamazepine and allopurinol, there is no clear evidence that

genetic factors dominate over environmental factors such as concomitant disease

Drug-allergy pharmacogenetics

Enhanced and cheaper genetic technologies

Better patient phenotyping

International database access

Multigenic / whole genome approach

Functional and epigenetic studies

The future?

§  EUDRAGENE

§  Human Genome Project

§  1000 Genomes Project.

§  REGISCAR

§  Pharmacovigilance Working Party

§  EUDRAVIGILANCE

§  PROTECT

§  International Serious Adverse Event Consortium

Taylor made therapy