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Human leukocyte antigen (HLA)-B*5701 allele is associated with abacavir hypersensitivity. Limited data among Asians showed lower rates of HLA-B*5701 compared with Caucasians. In 296 children with HIV in Thailand and Cambodia, the prevalence of HLA-B*5701 was 4.0% (95% confidence interval: 1.6–8.0%) among Thai and 3.4% (95% confidence interval: 0.9–8.5%) among Cambodian children. HLA-B*5701 carriage is not uncommon among Thai and Cambodian children; it is close to the prevalence found in European and higher than the prevalence found in East Asian and African studies.
Abacavir is a nucleoside reverse transcriptase inhibitor with activity against HIV. It has excellent efficacy and a favorable long-term toxicity profile.1 There has been increasing demand for abacavir in first-line and second-line treatment of HIV-infected children in Asia. Abacavir may be preferred to stavudine or zidovudine as part of a nucleoside reverse transcriptase inhibitor backbone in first-line regimens due to its minimal mitochondrial toxicity and lipodystrophy.2 It is also frequently recommended as part of second-line treatment regimens. A key adverse effect of abacavir that limits its use is an immunologically mediated hypersensitivity reaction affecting 5–8% of patients during the first 6 weeks of treatment.3 Abacavir hypersensitivity is strongly associated with the human leukocyte antigen (HLA)-B*5701 allele.4,5 HLA-B*5701 screening is recommended before initiating abacavir to reduce the risk of hypersensitivity reaction.6 A study among HIV-infected patients in the United Kingdom showed differences by race. Among Caucasians, the prevalence was 7.93% (95% confidence interval [CI]: 5.80–10.06%), whereas among Africans, the prevalence was only 0.26% (95% CI: 0.07–0.94%).7 The reported prevalence of HLA-B*5701 in East Asian populations was lower than 0.5% among Koreans8 and Taiwanese.9 We evaluated the frequency of the HLA-B*5701 allele and report the prevalence of abacavir hypersensitivity in HIV-infected Thai and Cambodian children.
This is a substudy of the Pediatric Randomised Early versus Deferred Initiation in Cambodia and Thailand (PREDICT) study study, a randomized study of early versus deferred antiretroviral therapy initiation in children aged 1–12 years in Thailand and Cambodia (NCT 00234091).10 The first-line antiretroviral regimen was zidovudine, lamivudine and nevirapine. Abacavir was used in children with adverse events from zidovudine or used as part of second-line regimen. Clinically suspected abacavir hypersensitivity was defined as occurrences of >2 of the following within 6 weeks after starting abacavir treatment: fever, rash or gastrointestinal, constitutional or respiratory symptoms that disappeared within 3 days after discontinuing abacavir treatment and that could not be explained by other causes.
HLA typing was performed retrospectively from the stored blood samples at the end of the study. High molecular weight genomic DNA was extracted from the peripheral mononuclear cell using QIAGEN kit (Qiagen, Valencia, CA). The concentration of extracted DNA samples was determined by spectrophotometry and stored at −20°C before HLA typing. The HLA-B with 4-digit specificities was determined using Hiseq single-end sequencing of the amplicon/high-resolution technique by Beijing Genomic Institute-Hong Kong Co., Limited, Shenzhen, China.
The study was approved by the Institutional Review Board of all participating sites. The proportion of children who carried HLA-B*5701 and 95% CI was calculated. Statistical analysis was performed using Stata version 11 (StataCorp, College Station, TX).
There were 296 HIV-infected children in this substudy. The median (interquartile range) age was 6 (4–8) years, 42% were male, 177 (60%) were Thai and 119 (40%) were Cambodian. HLA-B*5701 allele was present in 11 children (3.7%, 95% CI: 1.9–6.6%). The prevalence of HLA-B*5701 was 4.0% (95% CI: 1.6–8.0%) among Thai and 3.4% (95% CI: 0.9–8.5%) among Cambodian children.
An abacavir-containing regimen was administered to 30 patients during the study period. The HLA status was performed retrospectively after study had ended; therefore, HLA status was not known at the time of abacavir initiation. However, none of 30 children who received abacavir carried HLA-B*5701. One child (3.3%; 95% CI: 0.8–17.2%) developed clinically suspected abacavir hypersensitivity. Abacavir had been substituted for zidovudine in his antiretroviral regimen because he developed anemia after using a zidovudine-containing regimen for 7 weeks. On day 3 of abacavir administration, he developed high-grade fever, sore throat and cough (but no rash or no myalgia) leading to drug discontinuation due to clinically suspected hypersensitivity. Symptoms resolved within 3 days. He was subsequently found to have HLA*B5101 and HLA*B1801, but not HLA-B*5701.
This is the first report of HLA-B*5701 frequency in HIV-infected children in Thailand and Cambodia. The prevalence of 3.4–4.0% is lower than that in Caucasians,7 but higher than that reported in East Asians (including Koreans, Taiwanese and Japanese). Park et al reported that none of 534 Korean patients carried HLA-B*5701.8 Sun et al found only 1 (0.3%) HLA-B*5701 carrier of 320 Taiwanese patients.9 Saito et al showed that none among 371 Japanese patients carried HLA-B*5701.11 The previous report from 49 Thai adults showed that HLA-B*5701 allele was found in 3.1% of study population.12
The purpose of prospective HLA-B*5701 screening is to identify patients at greatest risk of abacavir hypersensitivity than to predict which patients will definitely develop a hypersensitivity reaction. A double-blinded study to determine the benefit of screening HLA-B*5701 before treatment with abacavir to reduce the incidence of hypersensitivity reaction found that 39% of patients who had HLA-B*5701 tolerated abacavir during the 6-week observation period without evidence of hypersensitivity reaction. However, the negative predictive value of HLA-B*5701 for patch test–positive abacavir hypersensitivity was found to be 100%.6 Screening for HLA-B*5701 has been found to be cost effective in developed countries.13,14 One of the obstacles for screening for HLA-B*5701 in developing countries is laboratory cost. Low cost techniques, such as polymerase chain reaction sequence-specific primer-based genotyping, may make screening feasible in resource-limited settings15 Whether or not HLA-B*5701 screening has been performed, clinical training on early detection of the clinical symptoms of abacavir hypersensitivity, especially in the first 6 weeks of treatment, should be emphasized. Abacavir should be immediately discontinued in any patient who develops clinical signs and symptoms consistent with hypersensitivity and rechallenge is contraindicated.
This study has some limitations. First, there were only 30 patients who actually received abacavir, which is too small to determine the actual rate of clinically diagnosed abacavir hypersensitivity in Thai and Cambodian children. Furthermore, none of them carried HLA-B*5701. Second, we did not perform epicutane-ous patch testing in the patient with clinically diagnosed abacavir hypersensitivity; therefore, we could not confirm whether he had immunologically confirmed hypersensitivity.
This study suggests that carriage of HLA-B*5701 is not uncommon among Thai and Cambodian children. Early detection of abacavir hypersensitivity reaction through close clinical monitoring remains important whether or not HLA-B*5701 screening has been performed.
The study was funded by the Commission of Higher Education, Bangkok, Thailand, TREAT Asia/amfAR, the Foundation for AIDS Research through the ViiV Healthcare Paediatric Innovation Seed Fund and the National Research University Project of Commission of Higher Education and the Ratchadapisek Somphot Endowment Fund (HR 1161A-55). TP is supported by the grants from the Senior Researcher Scholar, Thai Research Fund. KR is supported by the grants from the Senior Researcher Scholar, Thai Research Fund; and the Professional Research Team Strengthening Fund, BIOTEC, Bangkok, Thailand. JA and KR received consultation or speaker honoraria from ViiV Health Care (Middlesex, UK).
The authors thank the participants and their families who participated in the study. The authors also thank Dr. Nattiya Hirankarn for her advice in conducting the study. The authors also thank Dr. Annette Sohn for her advice in preparing the English manuscript.
The authors have no other funding or conflicts of interest to disclose.