Association of human leukocyte antigen alleles and nevirapine hypersensitivity in a Malawian HIV-infected population.
BACKGROUND
The nonnucleoside reverse transcriptase inhibitor nevirapine is the cornerstone of treatment for human immunodeficiency virus (HIV) in many sub-Saharan African countries. However, nevirapine is associated with a 6%-10% risk of developing a hypersensitivity reaction, with different phenotypes, including the blistering conditions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Our aim was to identify predictive human leukocyte antigen (HLA) markers that are associated with nevirapine hypersensitivity.


METHODS
We identified 117 HIV-infected Malawian adults with nevirapine hypersensitivity (15 drug-induced liver injury [DILI], 33 SJS/TEN, 20 hypersensitivity syndrome, and 46 nevirapine-induced rash plus 3 with both DILI and SJS phenotype) and 155 age-, sex- and ethnicity-matched nevirapine-exposed controls. HLA typing for 5 loci (A, B, C, DRB1, and DQB1) was undertaken using a sequence-based high-resolution protocol. Logistic regression analysis included CD4(+) cell count as a covariate.


RESULTS
HLA-C*04:01 was found to markedly increase the risk for SJS (odds ratio [OR] = 17.52; 95% confidence interval, 3.31-92.80) and all hypersensitivity phenotypes (OR = 2.64; 95% CI, 1.13-6.18) when compared to the baseline rare allele group in a binary logistic regression model. The OR for absolute risk of SJS/TEN associated with carriage of HLA-C*04:01 was 5.17 (95% CI, 2.39-11.18). Positive predictive value was 2.6% and negative predictive value was 99.2%. In addition, a number of alleles within the HLA-DQB1 loci protected against nevirapine-induced hypersensitivity phenotypes.


CONCLUSIONS
Our study has identified HLA-C*04:01 carriage as a risk factor for nevirapine-induced SJS/TEN in a Malawian HIV cohort. Validation of these findings in a larger cohort of patients and mechanistic investigation of the pathogenesis are required.
Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.
Daniel F
DF
Carr
Mas
M
Chaponda
Andrea L
AL
Jorgensen
Elena Cornejo
EC
Castro
Joep J
JJ
van Oosterhout
Saye H
SH
Khoo
David G
DG
Lalloo
Robert S
RS
Heyderman
Ana
A
Alfirevic
Munir
M
Pirmohamed
D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D016022:Case-Control Studies; D004342:Drug Hypersensitivity / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D015658:HIV Infections / Q000188:drug therapy; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D008295:Malawi; D008297:Male; D019829:Nevirapine / Q000009:adverse effects*; D017422:Sequence Analysis, DNA; D055815:Young Adult
D019380:Anti-HIV Agents; D005819:Genetic Markers; D006680:HLA Antigens; D019829:Nevirapine