CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations

Daniel F. Carr; Mas Chaponda; Elena M.Cornejo Castro; Andrea L. Jorgensen; Saye Khoo; Joep J. Van Oosterhout; Collet Dandara; Elizabeth Kampira; Francis Ssali; Paula Munderi; David Lalloo; Robert S. Heyderman; Munir Pirmohamed

doi:10.1093/jac/dku315

CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations

Daniel F. Carr, Mas Chaponda, Elena M.Cornejo Castro, Andrea L. Jorgensen, Saye Khoo, Joep J. Van Oosterhout, Collet Dandara, Elizabeth Kampira, Francis Ssali, Paula Munderi, David Lalloo, Robert S. Heyderman, Munir Pirmohamed

Research output: Contribution to journal › Article › peer-review

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Abstract

BACKGROUND:

Nevirapine, an NNRTI used in HIV treatment, can cause hypersensitivity reactions in 6%-10% of patients. In the most serious cases (1.3%) this can manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).

METHODS:

DNA samples were obtained and analysed from a total of 209 adult patients with nevirapine hypersensitivity (57 from a prospective cohort and 152 routine clinic patients) and compared with 463 control patients on nevirapine without any hypersensitivity. The case group included 70 patients with SJS/TEN. All individuals were genotyped for two SNPs in the CYP2B6 gene [c.516G>T (CYP2B6*9) and c.983T>C (CYP2B6*18)] using the TaqMan real-time genotyping platform. The replication cohort comprised 29 controls and 55 nevirapine hypersensitive patients, including 8 SJS/TEN cases.

RESULTS:

An association between the CYP2B6 c.983T>C polymorphism and nevirapine-induced SJS/TEN was observed. In the SJS/TEN group, 30% of individuals possessed at least one c.983T>C versus 16% in the tolerant group [P = 0.006; OR (95% CI) 2.24 (1.27-3.94)]. This association was not significant in the replication cohort [P = 0.075; OR (95% CI) 4.33 (0.80-23.57)]. Combined analysis resulted in an OR of 2.52 (95% CI 1.48-4.20; P = 0.0005) for the association of c.983T>C with SJS/TEN. No association was observed for c.983T>C with other hypersensitivity phenotypes and for CYP2B6 c.516G>T with any hypersensitivity phenotypes.

CONCLUSIONS:

Our data show an association between the c.983T>C polymorphism and nevirapine-induced SJS/TEN. CYP2B6 c.983T>C has a frequency of 5%-10% in a variety of African populations, but is not observed in Caucasians, thus representing an ethnic-specific predisposing factor.

Original language	English
Pages (from-to)	3329-3334
Number of pages	6
Journal	Journal of Antimicrobial Chemotherapy
Volume	69
Issue number	12
DOIs	https://doi.org/10.1093/jac/dku315
Publication status	Published - 1 Dec 2014

Keywords

Adverse drug reactions
Antiretroviral
Pharmacogenetics
Stevens-Johnson syndrome

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/jac/dku315Licence: CC BY

J Antimicrob Chemo 69 3329-3334Final published version, 168 KBLicence: CC BY

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Carr, D. F., Chaponda, M., Castro, E. M. C., Jorgensen, A. L., Khoo, S., Van Oosterhout, J. J., Dandara, C., Kampira, E., Ssali, F., Munderi, P., Lalloo, D., Heyderman, R. S., & Pirmohamed, M. (2014). CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations. Journal of Antimicrobial Chemotherapy, 69(12), 3329-3334. https://doi.org/10.1093/jac/dku315

@article{ce562348f0ef4f53add51a8e481b2bdc,

title = "CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations",

abstract = "BACKGROUND: Nevirapine, an NNRTI used in HIV treatment, can cause hypersensitivity reactions in 6\%-10\% of patients. In the most serious cases (1.3\%) this can manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).METHODS: DNA samples were obtained and analysed from a total of 209 adult patients with nevirapine hypersensitivity (57 from a prospective cohort and 152 routine clinic patients) and compared with 463 control patients on nevirapine without any hypersensitivity. The case group included 70 patients with SJS/TEN. All individuals were genotyped for two SNPs in the CYP2B6 gene [c.516G>T (CYP2B6*9) and c.983T>C (CYP2B6*18)] using the TaqMan real-time genotyping platform. The replication cohort comprised 29 controls and 55 nevirapine hypersensitive patients, including 8 SJS/TEN cases.RESULTS: An association between the CYP2B6 c.983T>C polymorphism and nevirapine-induced SJS/TEN was observed. In the SJS/TEN group, 30\% of individuals possessed at least one c.983T>C versus 16\% in the tolerant group [P = 0.006; OR (95\% CI) 2.24 (1.27-3.94)]. This association was not significant in the replication cohort [P = 0.075; OR (95\% CI) 4.33 (0.80-23.57)]. Combined analysis resulted in an OR of 2.52 (95\% CI 1.48-4.20; P = 0.0005) for the association of c.983T>C with SJS/TEN. No association was observed for c.983T>C with other hypersensitivity phenotypes and for CYP2B6 c.516G>T with any hypersensitivity phenotypes.CONCLUSIONS: Our data show an association between the c.983T>C polymorphism and nevirapine-induced SJS/TEN. CYP2B6 c.983T>C has a frequency of 5\%-10\% in a variety of African populations, but is not observed in Caucasians, thus representing an ethnic-specific predisposing factor.",

keywords = "Adverse drug reactions, Antiretroviral, Pharmacogenetics, Stevens-Johnson syndrome",

author = "Carr, \{Daniel F.\} and Mas Chaponda and Castro, \{Elena M.Cornejo\} and Jorgensen, \{Andrea L.\} and Saye Khoo and \{Van Oosterhout\}, \{Joep J.\} and Collet Dandara and Elizabeth Kampira and Francis Ssali and Paula Munderi and David Lalloo and Heyderman, \{Robert S.\} and Munir Pirmohamed",

year = "2014",

month = dec,

day = "1",

doi = "10.1093/jac/dku315",

language = "English",

volume = "69",

pages = "3329--3334",

journal = "Journal of Antimicrobial Chemotherapy",

issn = "0305-7453",

publisher = "Oxford University Press",

number = "12",

}

Carr, DF, Chaponda, M, Castro, EMC, Jorgensen, AL, Khoo, S, Van Oosterhout, JJ, Dandara, C, Kampira, E, Ssali, F, Munderi, P, Lalloo, D, Heyderman, RS & Pirmohamed, M 2014, 'CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations', Journal of Antimicrobial Chemotherapy, vol. 69, no. 12, pp. 3329-3334. https://doi.org/10.1093/jac/dku315

TY - JOUR

T1 - CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations

AU - Carr, Daniel F.

AU - Chaponda, Mas

AU - Castro, Elena M.Cornejo

AU - Jorgensen, Andrea L.

AU - Khoo, Saye

AU - Van Oosterhout, Joep J.

AU - Dandara, Collet

AU - Kampira, Elizabeth

AU - Ssali, Francis

AU - Munderi, Paula

AU - Lalloo, David

AU - Heyderman, Robert S.

AU - Pirmohamed, Munir

PY - 2014/12/1

Y1 - 2014/12/1

N2 - BACKGROUND: Nevirapine, an NNRTI used in HIV treatment, can cause hypersensitivity reactions in 6%-10% of patients. In the most serious cases (1.3%) this can manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).METHODS: DNA samples were obtained and analysed from a total of 209 adult patients with nevirapine hypersensitivity (57 from a prospective cohort and 152 routine clinic patients) and compared with 463 control patients on nevirapine without any hypersensitivity. The case group included 70 patients with SJS/TEN. All individuals were genotyped for two SNPs in the CYP2B6 gene [c.516G>T (CYP2B6*9) and c.983T>C (CYP2B6*18)] using the TaqMan real-time genotyping platform. The replication cohort comprised 29 controls and 55 nevirapine hypersensitive patients, including 8 SJS/TEN cases.RESULTS: An association between the CYP2B6 c.983T>C polymorphism and nevirapine-induced SJS/TEN was observed. In the SJS/TEN group, 30% of individuals possessed at least one c.983T>C versus 16% in the tolerant group [P = 0.006; OR (95% CI) 2.24 (1.27-3.94)]. This association was not significant in the replication cohort [P = 0.075; OR (95% CI) 4.33 (0.80-23.57)]. Combined analysis resulted in an OR of 2.52 (95% CI 1.48-4.20; P = 0.0005) for the association of c.983T>C with SJS/TEN. No association was observed for c.983T>C with other hypersensitivity phenotypes and for CYP2B6 c.516G>T with any hypersensitivity phenotypes.CONCLUSIONS: Our data show an association between the c.983T>C polymorphism and nevirapine-induced SJS/TEN. CYP2B6 c.983T>C has a frequency of 5%-10% in a variety of African populations, but is not observed in Caucasians, thus representing an ethnic-specific predisposing factor.

AB - BACKGROUND: Nevirapine, an NNRTI used in HIV treatment, can cause hypersensitivity reactions in 6%-10% of patients. In the most serious cases (1.3%) this can manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).METHODS: DNA samples were obtained and analysed from a total of 209 adult patients with nevirapine hypersensitivity (57 from a prospective cohort and 152 routine clinic patients) and compared with 463 control patients on nevirapine without any hypersensitivity. The case group included 70 patients with SJS/TEN. All individuals were genotyped for two SNPs in the CYP2B6 gene [c.516G>T (CYP2B6*9) and c.983T>C (CYP2B6*18)] using the TaqMan real-time genotyping platform. The replication cohort comprised 29 controls and 55 nevirapine hypersensitive patients, including 8 SJS/TEN cases.RESULTS: An association between the CYP2B6 c.983T>C polymorphism and nevirapine-induced SJS/TEN was observed. In the SJS/TEN group, 30% of individuals possessed at least one c.983T>C versus 16% in the tolerant group [P = 0.006; OR (95% CI) 2.24 (1.27-3.94)]. This association was not significant in the replication cohort [P = 0.075; OR (95% CI) 4.33 (0.80-23.57)]. Combined analysis resulted in an OR of 2.52 (95% CI 1.48-4.20; P = 0.0005) for the association of c.983T>C with SJS/TEN. No association was observed for c.983T>C with other hypersensitivity phenotypes and for CYP2B6 c.516G>T with any hypersensitivity phenotypes.CONCLUSIONS: Our data show an association between the c.983T>C polymorphism and nevirapine-induced SJS/TEN. CYP2B6 c.983T>C has a frequency of 5%-10% in a variety of African populations, but is not observed in Caucasians, thus representing an ethnic-specific predisposing factor.

KW - Adverse drug reactions

KW - Antiretroviral

KW - Pharmacogenetics

KW - Stevens-Johnson syndrome

U2 - 10.1093/jac/dku315

DO - 10.1093/jac/dku315

M3 - Article

SN - 0305-7453

VL - 69

SP - 3329

EP - 3334

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

IS - 12

ER -

CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations

Abstract

Keywords

UN SDGs

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