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      Association of Human Leukocyte Antigen Alleles and Nevirapine Hypersensitivity in a Malawian HIV-Infected Population

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          Human leukocyte antigen genotyping of 272 Malawian HIV patients receiving nevirapine-containing regimens (of whom 117 had nevirapine hypersensitivity) has shown that HLA-C*04:01 increases the risk of Stevens-Johnson syndrome/toxic epidermal necrolysis, with an odds ratio of 5.17 (95% confidence interval, 2.39–11.18).


          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.

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          Most cited references 43

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          HLA-B*5701 screening for hypersensitivity to abacavir.

          Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to abacavir. This double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received abacavir. We randomly assigned patients to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701-positive patients from abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 screening (control group). All patients who started abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to abacavir, we performed epicutaneous patch testing with the use of abacavir. The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001). HLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug. ( number, NCT00340080.) Copyright 2008 Massachusetts Medical Society.
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            Medical genetics: a marker for Stevens-Johnson syndrome.

            Stevens-Johnson syndrome and the related disease toxic epidermal necrolysis are life-threatening reactions of the skin to particular types of medication. Here we show that there is a strong association in Han Chinese between a genetic marker, the human leukocyte antigen HLA-B*1502, and Stevens-Johnson syndrome induced by carbamazepine, a drug commonly prescribed for the treatment of seizures. It should be possible to exploit this association in a highly reliable test to predict severe adverse reaction, as well as for investigation of the pathogenesis of Stevens-Johnson syndrome.
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              HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage.

              A selective advantage against infectious disease associated with increased heterozygosity at the human major histocompatibility complex [human leukocyte antigen (HLA) class I and class II] is believed to play a major role in maintaining the extraordinary allelic diversity of these genes. Maximum HLA heterozygosity of class I loci (A, B, and C) delayed acquired immunodeficiency syndrome (AIDS) onset among patients infected with human immunodeficiency virus-type 1 (HIV-1), whereas individuals who were homozygous for one or more loci progressed rapidly to AIDS and death. The HLA class I alleles B*35 and Cw*04 were consistently associated with rapid development of AIDS-defining conditions in Caucasians. The extended survival of 28 to 40 percent of HIV-1-infected Caucasian patients who avoided AIDS for ten or more years can be attributed to their being fully heterozygous at HLA class I loci, to their lacking the AIDS-associated alleles B*35 and Cw*04, or to both.

                Author and article information

                Clin Infect Dis
                Clin. Infect. Dis
                Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
                Oxford University Press
                1 May 2013
                29 January 2013
                29 January 2013
                : 56
                : 9
                : 1330-1339
                [1 ]Department of Molecular and Clinical Pharmacology, University of Liverpool , United Kingdom
                [2 ]Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi
                [3 ]Department of Biostatistics, University of Liverpool , United Kingdom
                [4 ]Department of Medicine, College of Medicine, University of Malawi , Blantyre
                [5 ]Liverpool School of Tropical Medicine , United Kingdom
                Author notes
                Correspondence: Munir Pirmohamed, MD, PhD, Wolfson Centre for Personalised Medicine, Department of Molecular and Clinical Pharmacology, University of Liverpool, Block A, Waterhouse Bldgs, 1-5 Brownlow St, Liverpool, L69 3GL, UK ( munirp@ ).
                © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.



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