HLA-Cw8 primarily associated with hypersensitivity to nevirapine

Abstract

We read with interest the report by Littera et al. [1] about human leukocyte antigen (HLA)-dependent hypersensitivity to nevirapine in Sardinian HIV patients. The authors state that high levels of genetic homogeneity and linkage disequilibrium make the Sardinian population particularly suitable for genetic association studies, and they observed a statistically significant association between a nevirapine-hypersensitivity reaction and the HLA-Cw*0802-B*1402 haplotype. In the Sardinian population, however, HLA-Cw*0802 and B*1402 are in such strong linkage disequilibrium that they could not establish which one of these two alleles is primarily associated with the hypersensitivity reaction to nevirapine. Considering that HLA-B14(65) can not be found in the Japanese population, it might be helpful to analyse the patients in our clinic for a determination of the primarily associated HLA allele [2–5]. In our outpatient clinic, a total of 326 HIV-1-infected individuals (309 were Japanese) had given written informed consent for HLA analysis and the study of its association with HIV-1 disease progression and drug-induced adverse events. High resolution typing of the alleles at the HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1 loci had been performed by polymerase chain reaction amplification using sequence-specific primers in all of them. The allele frequency of HLA-Cw8 and HLA-B14 was 13 and 0%, respectively, which is compatible with previous reports of HLA frequency in the Japanese population [2–5]. Forty-three of the analysed patients were on nevirapine treatment or had a history of nevirapine treatment. One of them died of malignant lymphoma 4 weeks after the introduction of nevirapine-containing treatment. In another patient, nevirapine-containing treatment was terminated 17 days after initiation because of granulocytopenia probably induced by co-administered zidovudine. These two patients were excluded from further analysis and the remaining 41 patients were divided into two groups; a nevirapine-hypersensitive group and a nevirapine-tolerant group (Table 1). The nevirapine-hypersensitive group included 11 patients who experienced extensive skin rash (accompanied by fever > 38°C in three) and one patient with chronic hepatitis C who developed nevirapine-induced hepatotoxicity with aspartate aminotransferase/alanine aminotransferase values three times above the baseline. The nevirapine-tolerant group included 29 others who had been treated with nevirapine for a period of more than 6 months and did not develop any hypersensitive reaction [1]. There were no significant differences in age, sex, ethnicity, weight, HIV-1 viral load, CD4 and CD8 cell counts between the two groups (Fisher's exact test for dichotomous variables, Student's t-test for continuous variables). The frequency of HLA-Cw8-positive patients in the nevirapine-hypersensitive group was 42%, which was significantly higher than those of the nevirapine-tolerant group (10%) and the general Japanese population (9–14%) [2–5]. In the nevirapine-hypersensitive group, four patients including one who developed hepatotoxicity had HLA-Cw*0801 and one had HLA-Cw*0803. In the nevirapine-tolerant group, three patients had HLA-Cw*0801. HLA-Cw*0802 was not identified in the patients we analysed. There was no significant difference in the frequency of the other HLA alleles between the two groups.Table 1: Demographics and immunological variables in the nevirapine-hypersensitive group and nevirapine-tolerant group.Considering our data together with that of Littera et al. [1], HLA-Cw8 antigen rather than specific alleles of other genes linked with HLA-Cw*0801 or HLA-Cw*0802 may be primarily associated with a nevirapine-hypersensitivity reaction. Nevirapine or nevirapine metabolite coupled with HLA-Cw8 antigen may be expressed on the cell surface and may induce hypersensitive reactions including skin rash and hepatotoxicities. We totally agree with Littera et al. [1] that a careful choice of drugs in susceptible patients identified by HLA typing would considerably reduce the risk of severe and sometimes life-threatening hypersensitive reactions.