PharmacologyTier 1Medical Sciences concept

HLA associations with drug hypersensitivity (pharmacogenomics)

Core concept

HLA-restricted drug hypersensitivity is a T-cell mediated (type IV) reaction where the drug alters the peptide repertoire presented by a specific HLA allele
Three proposed models
- Hapten - drug covalently binds a peptide -> neoantigen
- p-i concept - drug binds the TCR/HLA directly, non-covalently, no processing needed
- Altered peptide repertoire - abacavir binds within the *HLA-B57:01 F pocket**, changing which self-peptides are presented -> the immune system sees "new self"
Consequence: the allele is necessary but not sufficient - high negative predictive value, modest positive predictive value

Allele	Drug	Reaction	Population
*HLA-B57:01**	Abacavir	Hypersensitivity syndrome	All - screening mandatory
*HLA-B58:01**	Allopurinol	SJS/TEN, DRESS	Han Chinese, Thai, Korean (much higher carriage)
*HLA-B15:02**	Carbamazepine	SJS/TEN	Han Chinese, Thai, Malay, South Asian
HLA-A*31:01	Carbamazepine	DRESS, maculopapular	European, Japanese
HLA-B*57:01	Flucloxacillin	Cholestatic DILI	European
HLA-B*13:01	Dapsone	Dapsone hypersensitivity	Chinese, Southeast Asian
HLA-DRB1*15:01	Amoxicillin-clavulanate	DILI	European
HLA-B*38	Sulfamethoxazole, clozapine	SJS/TEN, agranulocytosis

Abacavir screening is the model - HLA-B*57:01 negative predictive value ~100%
- PREDICT-1: screening abolished immunologically confirmed hypersensitivity
- Reaction = fever, rash, GI upset, malaise; worsens with each dose, and rechallenge is fatal - never rechallenge
Allopurinol - risk also rises with starting dose and renal impairment
- Start at 50-100 mg daily and titrate; do not start at 300 mg, and do not start during an acute flare
- Test HLA-B*58:01 before allopurinol in high-prevalence ancestry where testing is available
Carbamazepine - test HLA-B*15:02 before starting in patients of Han Chinese or Southeast Asian ancestry
Reaction risk is HLA-dependent; drug metabolism is not - these are immunological, not pharmacokinetic, associations

Ancestry changes the pre-test probability, so the drug choice should change with it - this is the practical point
- Southeast Asian patient needing an anticonvulsant -> avoid carbamazepine or test first (valproate or levetiracetam instead)
- Han Chinese patient needing urate lowering -> consider febuxostat, or test
Any severe cutaneous adverse reaction -> stop the drug, document the allergy explicitly with the reaction type, and never rechallenge
- Distinguish SCAR (SJS/TEN, DRESS, AGEP) from a benign maculopapular rash - the label determines a lifetime of prescribing
DRESS - eosinophilia, fever, facial oedema, organ involvement, 2-8 weeks after starting, and relapses on steroid taper
Allopurinol hypersensitivity syndrome carries ~20-25% mortality - the reason for slow titration

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