531 ReseaRch aRticle ISSN 1462-2416 10.2217/PGS.09.6 © 2009 Future Medicine Ltd Pharmacogenomics (2009) 10 (4), 531–540 TNF , LTA, HSPA1L and HLA-DR gene polymorphisms in HIV-positive patients with hypersensitivity to cotrimoxazole Sulfamethoxazole (SMX) in combination with trimethoprim (TMP) is known as cotrimoxa- zole and is the drug of choice for the prophy- laxis and treatment of opportunistic infections in immunosuppressed patients, including those with HIV [1] . In high-income countries, the most common opportunistic disease in patients with HIV is Pneumocystis jirovecii pneumonia where cotrimoxazole prophylaxis has been the standard of care for many years. In resource-poor nations, however, the main causes of morbidity and mortality in patients with HIV include TB, parasitic enteritis and bacterial infections. In Africa, cotrimoxazole prophylaxis has been demonstrated to reduce mortality and hospital admissions in patients with dual TB and HIV infection by up to 50% [2,3] . Based on such evidence of clear patient benefit, the WHO has issued guide- lines which recommend that all HIV-positive individuals in the resource-limited settings should receive cotrimoxazole [4] . The use of cotrimoxazole has been associated with hypersensitivity reactions in both HIV- negative and HIV-positive patients. In patients without HIV, hypersensitivity reactions to cotri- moxazole occur at a frequency of 3–8%; by con- trast, in HIV-positive patients, such reactions are much more common (30–50%) [5–7] . It is thought that in the majority of patients the reaction is mediated by the sulphonamide moiety rather than TMP [8] . The mechanisms of hypersensitivity to SMX are thought to be multifactorial. However, clinical manifestations and immunohistochemical factors are strongly suggestive of an immune pathogenesis [9] . This has been further emphasized by the finding of T cells that recognize SMX [10] . Ex vivo stud- ies have shown that SMX and its metabolites induce specific human leukocyte antigen (HLA) class I and II-restricted CD8 and CD4 T-cell responses [11,12] . Inflammatory cytokines, and in particular TNF- a, play an important role in the patho- genesis of drug hypersensitivity. Several studies have shown the presence of TNF- a in skin biopsies and in the blister fluid of patients with toxic epidermal necrolysis (TEN), the most serious form of drug hypersensitivity [13,14] . The gene ( TNF ) that encodes TNF- a is located on chromosome 6 within the HLA class III region of the highly polymorphic MHC. Genes within all three classes of the MHC region have previously been associated with drug-induced hypersensitivity in HIV- positive and HIV-negative patients [15–21] . The Aims: Sulfamethoxazole in combination with trimethoprim (cotrimoxazole) is used for prophylaxis and treatment of several opportunistic infections in HIV-infected patients. It is associated with a high incidence of hypersensitivity reactions, which is thought to have an immune basis. Genetic polymorphisms in MHC are known to predispose to hypersensitivity reactions to a structurally diverse group of drugs in HIV-positive patients. The aim of the study was to determine whether functional polymorphisms in TNF , LTA, HSPA1L and HLA-DRB1 genes influence the risk of cotrimoxazole hypersensitivity in HIV-infected patients. Methods: We genotyped 136 HIV-positive patients with (n = 53) and without (n = 83) cotrimoxazole hypersensitivity using a combination of PCR-based techniques, including PCR-restriction fragment length polymorphisms, PCR-sequence specific oligonucleotides and real-time PCR. Genotypes and the haplotype frequencies were analyzed using the c 2 test in the Haploview and CLUMP programs. Results: No statistically significant difference in SNP or haplotype frequencies were found in HIV-infected sulfamethoxazole hypersensitive patients compared with controls. Conclusion: Our data show that MHC polymorphisms are not major predisposing factors for cotrimoxazole hypersensitivity, although we cannot exclude a minor contribution. An environmental factor (i.e., HIV infection) seems to predominate over any of the genetic factors so far investigated in increasing the risk of cotrimoxazole hypersensitivity. KEYWORDS: adverse drug reactions n cotrimoxazole n HIV n HLA n hypersensitivity n MHC region n polymorphisms n sulphametoxazole Ana Alirevic 1 , F Javier Vilar 2 , Mohammed Alsbou 1 , Ansar Jawaid 3 , Wendy Thomson 4 , William ER Ollier 4 , Clive E Bowman 5 , Olivier Delrieu 6 , B Kevin Park 1 & Munir Pirmohamed 1† † Author for correspondence: 1 Department of Pharmacology & Therapeuics, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, Merseyside, L69 3GE, UK Tel.: +44 151 794 5549; Fax: +44 151 794 5540 ; munirp@liv.ac.uk 2 North Manchester General Hospital, Manchester, UK 3 AstraZeneca, Cheshire, UK 4 University of Manchester, UK 5 University of Reading, UK 6 Pharmacogenomics Innovaive Soluions, High Wycombe, UK For reprint orders, please contact: reprints@futuremedicine.com