Abstract
Background: The antiretroviral nevirapine is associated with hypersensitivity reactions in 6%–10% of patients, including hepatotoxicity, maculopapular exanthema, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).Objectives: To undertake a genome-wide association study (GWAS) to identify genetic predisposing factors for the different clinical phenotypes associated with nevirapine hypersensitivity.Methods: A GWAS was undertaken in a discovery cohort of 151 nevirapine-hypersensitive and 182 tolerant, HIV-infected Malawian adults. Replication of signals was determined in a cohort of 116 cases and 68 controls obtained from Malawi, Uganda and Mozambique. Interaction with ERAP genes was determined in patients positive for HLA-C*04:01. In silico docking studies were also performed for HLA-C*04:01.Results: Fifteen SNPs demonstrated nominal significance (P < 1 × 10−5) with one or more of the hypersensitivity phenotypes. The most promising signal was seen in SJS/TEN, where rs5010528 (HLA-C locus) approached genome-wide significance (P < 8.5 × 10−8) and was below HLA-wide significance (P < 2.5 × 10−4) in the meta-analysis of discovery and replication cohorts [OR 4.84 (95% CI 2.71–8.61)]. rs5010528 is a strong proxy for HLA-C*04:01 carriage: in silico docking showed that two residues (33 and 123) in the B pocket were the most likely nevirapine interactors. There was no interaction between HLA-C*04:01 and ERAP1, but there is a potential protective effect with ERAP2 [P = 0.019, OR 0.43 (95% CI 0.21–0.87)].Conclusions: HLA-C*04:01 predisposes to nevirapine-induced SJS/TEN in sub-Saharan Africans, but not to other hypersensitivity phenotypes. This is likely to be mediated via binding to the B pocket of the HLA-C peptide. Whether this risk is modulated by ERAP2 variants requires further study.
Highlights
Nevirapine, an NNRTI used for HIV1 infection is effective[2] as part of combination antiretroviral therapy, but causes hypersensitivity in 6%–10% of patients.[3,4] This can manifest in various ways, ranging from nevirapine-induced rash (NIR), hypersensitivity syndrome (HSS) to severe blistering skin reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)[5] (1–2 per 1000 exposed individuals[6])
Our own previous study within a subset of patients from the Malawian HIV population described in this paper identified an association between HLA-C*04:01 and nevirapine-induced SJS.[21]
We have investigated whether there is any interaction between HLA-C*04:01 in SJS/TEN patients and the endoplasmic reticulum aminopeptidase genes (ERAP1 and ERAP2), which have been shown to modulate the risk of various immune diseases, in particular ankylosing spondylitis.[22]
Summary
Nevirapine, an NNRTI used for HIV1 infection is effective[2] as part of combination antiretroviral therapy, but causes hypersensitivity in 6%–10% of patients.[3,4] This can manifest in various ways, ranging from nevirapine-induced rash (NIR) (i.e. a maculopapular exanthema without any systemic manifestations), hypersensitivity syndrome (HSS) to severe blistering skin reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)[5] (1–2 per 1000 exposed individuals[6]). Our own previous study within a subset of patients from the Malawian HIV population described in this paper identified an association between HLA-C*04:01 and nevirapine-induced SJS.[21]. The antiretroviral nevirapine is associated with hypersensitivity reactions in 6%–10% of patients, including hepatotoxicity, maculopapular exanthema, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
