HLA­B genetic variants and Adverse Drug Reactions 

HLA-B in immune responses (drug hypersensitivity): Part of MHC Family codes for MHC I. On all nucleated cells
responsible for presenting peptides to T cells. Constantly peptides breaking down and some presented – recognized as self or
foreign. Many HLA genes/highly polymorphic > 1.5k HLAB alleles IDd. Codominant. Matching imp in GVHD.
Heterodimer.
3 signals to activate T-Cell immune response: Sig 1 MHC -> CD8+ T cell. (2 = CD28 on T to B7 on APC loss =
hyposensponsive anergy, Sig 3 = CK signals that dictate T cell development).
Type IVc Hypersens rxn. Antigens cause T cell activation, release CK and recrut effector cells (macrophages, eosinophils).
4 subtypes – Macrophage (I), eos(II), t cells (III), neutrophils (IV). Onset > 72h = tuberculin rxn, usually skin. Drug
causes = maculopap rashes to drugs, bullus exanthems, pustular exanthems.
Abacavir: HIV HAART. HLA-B*57.01. Med time to HSR 11 days. Fever, rash, GI, fatigue, resp (cough, dyspnea). ~20%
SW Asian are carriers. 5-7% EU.Polymorph do not affect pk/pd of abacavir, carrier w/at least one copy of HLA-B*57:01
have risk drug-induced hypersensitivity. Symp w/time if continued. CI if symp resolve w/ d/c. Hapten Hypothesis.
b/c co-dominant, results are either positive or negative. PREDICT-1 Study showed NO HSR with HLA-B*5701
negative pts. ~50% predictability with immunologically confirmed hypersens,
Screen all naïve pts, if positive, not recc unless absolutely need to, if testing not available, sufficient
monitoring & counsel. 94% pts without gene will not get HSR.
MHC in HSR:
I - Hapten / Pro Hapten Model: proposes that drug or drug metabolite binds covalently to a host protein which then undergoes
intracellular antigen processing to generate a pool of chemically-modified peptides. When presented in the context of HLA
these modified peptides are recognized as foreign by T cells and elicit an immune response. Examples of this model include
allergy to penicillin and reactive metabolites of sulfamethoxazole (nitroso-sulfamethoxazole)
II - The Pharmacological Interaction With Immune Receptors (p-i) Model: postulates that the offending drug binds, non-
covalently, to either the T-cell receptor (TCR) or HLA protein in a peptide-independent manner to directly activate T cells.
This model has been hypothesized to explain T-cell reactivity that is labile (i.e., reactivity is abrogated by washing drug from
the surface of antigen presenting cells) and/or is observed within seconds of drug exposure, a time course too short for
intracellular antigen processing
III - Altered Peptide Repertoire Model: Drug occupies a position in the peptide binding groove of the HLA protein changing
the structure of the binding cleft and therefore the peptide specificity of the HLA risk allele. The neo-epitopes displayed as a
result of altered binding specificity are recognized as foreign by the immune system and therefore elicit a T-cell response
CBZ and HLA-B*57:02: In 2004, 44 pts w/CBZ-induced SJS IDd to have HLA-B*57:01 vs control group. Usually happen
within 4-10 days of initiation. Primarily in Han Chinese. WITH THE HAN POPULATION, NEGATIVE HLA-
B*57:02 HAS A 100% PREDICTIVE VALUE.
CPIC: Avoid CBZ in naïve pts if alt available, > 3 mo = extremely low risk regardless of status.
Phenytoin and HLA-B*57:02: Phenytoin SJS extremely low in EU/African pop, Asian . 1-10% South Asian.African 1%,
EU 0-1%. In contrast to CBZ, the absence of HLA-B*57:02 CANNOT completely rule out PHT-induced HSR as
specificity is 87.2%. Do not use unless > 3 mo. Co-dom. Caution w/X-sensitive reagents ex. Oxcarbazepine.