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HLA and Pharmacogenomics The Abacavir Story
EFI-ASHI-APHIA Summer School 2013 Stintino
16 – 18 September 2013
Carlo Carcassi
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2
Rx + =
Rx + =
????
Rx + =
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3
Rx + =
Rx + =
Differences in genetic constitution
Rx + =
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4
PHARMACOGENETICS
The study of genetically controlled variations in drug
response
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GENETIC POLYMORPHISMS
Pharmacokinetic Pharmacodynamic
• Transporters • Plasma protein binding • Metabolism
• Receptors • Ion channels • Enzymes • Immune molecules
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Abacavir is a nucleoside reverse transcriptase inhibitor used in
conjunction with other antiretroviral agents in the treatment of HIV
infection.
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Abacavir is generally well tolerated but can cause hypersensitivity in 5% to 8% of patients during the first 6
weeks of treatment
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Hypersensitivity to abacavir is immunologically
mediated, driven by conventional MHC-I
antigen presentation and activation of HLA-
B*5701. Activation of HLA-B*5701 restricted
CD8+ T cells results in the secretion of the
inflammatory mediators TNF-alpha and IFN-
gamma and induces the delayed-type
hypersensitivity reaction
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Reeves et al. HIV Medicine 2006
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Clin Infect Dis. (2008) 46 (7): 1111-1118.
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Clin Infect Dis. (2008) 46 (7): 1111-1118.
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INDIA 5-20%
JAPAN 0%
CHINA 0% (NB 2.5% N.E.
provinces)
UK ~8%
MIDDLE EAST 1-2% (NB 5-7% Ashkenazi Jews)
AUSTRALIA ~8%
US Caucasian
~8% US Asian
~1%
US African-
American ~2.5%
W. EUROPE 5-7%
THAILAND 4-10%*
*THAILAND B*57 carriage: Urban Bangkok 3.6%
Thai Dai Lue (NE Thai) ~11% Southern Thai Muslim 3%
MEDITERRANEAN 1-2%
S. AMERICAN Caucasian
5-7%
US Hispanic
~2%
Subsaharan AFRICA
<1%
HLA-B*5701 carriage frequency
Nolan et al, J HIV Ther 2003; 8(2):36-41
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To recommend screening for HLA-
B*5701 in European populations or of
European origin but not in some Asian
or African populations could be
problematic?
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Ancestry and Disease in the Age of Genomic Medicine N Engl J Med 363;16 October 14, 2010
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N Engl J Med 363;16 October 14, 2010
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Webuye
Kinyawa
N Engl J Med 363;16 October 14, 2010
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Louvre National Gallery
Virgin of the Rocks ( 1495 - 1508 )
Virgin of the Rocks (Madonna and child, San Giovannino and angel) is an oil painting on a panel of 189,5 x 120 cm, executed between
1495 and 1508 by Leonardo da Vinci.