JAC Advance Access originally published online on July 12, 2007
Journal of Antimicrobial Chemotherapy 2007 60(3):599-604; doi:10.1093/jac/dkm243
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Incidence of abacavir hypersensitivity and its relationship with HLA-B*5701 in HIV-infected patients in Taiwan
1 Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan 2 Department of Internal Medicine, National Taiwan University College of Medicine, 1 Jen-Ai Road, Section 1, Taipei 100, Taiwan 3 Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, 1 Jen-Ai Road, Section 1, Taipei 100, Taiwan
* Corresponding author. Tel: +886-2-23123456 ext. 6908; Fax: +886-2-23711574; E-mail: sychang{at}ntu.edu.tw
Received 11 April 2007; returned 8 May 2007; revised 17 May 2007; accepted 8 June 2007
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Abstract |
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Objectives: To describe the incidence of hypersensitivity to abacavir and frequency of human leucocyte antigen (HLA)-B*5701 in HIV-infected Taiwanese persons.
Methods: Medical records of 337 HIV-infected Taiwanese in whom abacavir-containing combination antiretroviral therapy (CART) was prescribed from 1 May 2001 to 31 December 2006 were reviewed, and HLA typing of the patients was performed in 320 patients (232 receiving abacavir and 88 not receiving abacavir) with available blood samples. HLA class I and II polymorphisms were determined by PCR with specific primers. HLA-B*5701 was further confirmed by sequence-based typing.
Results: Of the 337 patients, median CD4 count was 166.5 cells/mm3 (range, 1.0–1914.0) and 83 patients (24.6%) had AIDS-defining opportunistic infections. Thirty-eight patients (11.3%) discontinued abacavir within 6 weeks of starting abacavir-containing CART. Among them, 10 patients had successful abacavir re-challenge and another 11 patients had other specific reasons for abacavir discontinuation. Therefore, 14 patients (4.2%) were classified as cases in whom abacavir hypersensitivity could not be excluded, and 3 patients (0.9%) met the criteria of abacavir hypersensitivity. Of the 320 patients undergoing HLA typing, HLA-A02 was the most common allele and only one individual (0.3%) expressed HLA-B*5701. Along with some differences in allele distributions, there was a significant difference in the genetic frequency of HLA-B57 in our patients compared with those of previous studies in other Chinese populations.
Conclusions: Abacavir hypersensitivity was less frequently encountered in HIV-infected Taiwanese initiating abacavir-containing CART than in Caucasians, which might be explained by the low frequency of the HLA-B*5701 allele.
Keywords: pharmacogenetics , gene frequency , antiretroviral therapy
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Introduction |
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Approximately 5% to 8% of Caucasians with HIV infection who initiate combination antiretroviral therapy (CART) containing abacavir, a nucleoside analogue, have a hypersensitivity reaction,1,2 and such reaction usually occurs within the first 6 weeks of treatment (median time to onset, 11 days) and is characterized by multisystem involvement with presentations of skin rash, fever, constitutional, gastrointestinal or respiratory symptoms.1 Furthermore, re-challenge with abacavir after a hypersensitivity reaction might cause life-threatening hypotension and death.1,3,4 Recently, strong associations between certain specific human leucocyte antigen (HLA) types and abacavir hypersensitivity have been demonstrated in populations mainly consisting of Caucasians.5–7 In addition, prospective employment of routine screening for HLA-B*5701 with subsequent avoidance of abacavir prescription in HIV-infected patients carrying this allele has significantly reduced the incidence of abacavir hypersensitivity.8–11
However, the frequency of HLA-B*5701 varies in different ethnic populations, such as <1% in sub-Saharan African, 1% to 2% in the Mediterranean, 5% to 20% in India, 0% in China and 4% to 10% in Thailand.12,13 Furthermore, published data of the association between HLA-B*5701 and abacavir hypersensitivity in HIV-infected Asian patients are rarely reported.14 In the present study, we aimed to describe the incidence of abacavir hypersensitivity and assess its relationship with HLA-B*5701 in HIV-infected Taiwanese patients who initiated abacavir-containing CART.
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Materials and methods |
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Patients
From May 2001 to December 2006, 358 patients were prescribed abacavir as part of their CART from a cohort of ~1550 consecutively enrolled non-haemophiliac HIV-infected persons who received medical care at the National Taiwan University Hospital, the largest referral hospital for HIV inpatient and outpatient care in Taiwan. A standardized case report form was used to record patient demographics, route of HIV infection, history of food or drug allergies, CD4 and CD8 lymphocyte counts, plasma HIV RNA load, AIDS with or without opportunistic infections, concurrent medications within 6 weeks of abacavir use, outcome of abacavir prescription (still used at the end of observation, discontinuation within or after 6 weeks of abacavir use, reasons of abacavir discontinuation, re-challenge of abacavir) and the results of HLA typing. The end of observation was on 12 February 2007 (6 weeks after the last enrolment on 31 December 2006). Eighty-eight HIV-infected patients who did not receive abacavir were recruited as a control group to have their HLA typed for comparison. The study protocol was approved by the Institutional Review Board of the hospital and participants gave written informed consent.
Definite cases of abacavir hypersensitivity were defined as those who had onset of at least two of the following symptoms within 6 weeks of abacavir initiation:5 fever, rash, gastrointestinal symptoms (nausea, vomiting, diarrhoea or abdominal pain), lethargy, malaise, arthralgia, myalgia or respiratory symptoms (dyspnoea, sore throat or cough); resolution of symptoms within 72 h of discontinuation of abacavir; and absence of an alternative likely explanation for the symptoms. Patients with abacavir tolerance were those in whom abacavir had been continued for at least 6 weeks. Patients with abacavir hypersensitivity not excluded were those for whom abacavir hypersensitivity could not be excluded because symptoms in the first 6 weeks of abacavir exposure did not meet diagnostic criteria.5 Patients were categorized as the group of abacavir discontinuation with specific reasons if they had alternative explanations for their early discontinuation (within 6 weeks of initial abacavir use). Patients were excluded from the present study if there were not sufficient clinical data available to assess clinical reaction to abacavir-containing CART or follow-up duration was <6 weeks.
High molecular weight genomic DNA was extracted from peripheral blood mononuclear cells using the Wizard® Genomic DNA Purification Kit (Promega). The concentrations of extracted DNA samples were determined by spectrophotometry and stored at –20°C before HLA typing. The HLA class I and II alleles with two-digit specificities were determined using RELITM SSO typing kits (HLA-A, HLA-B, HLA-Cw, HLA-DRB1, HLA-DQB1 Typing kits; DYNAL BIOTECH) according to the manufacturer's instructions. The HLA-B57 subtypes with four-digit specificities were further determined by sequence-based typing. Because the Taiwanese population is not inbred, we used the assumption of Hardy–Weinberg equilibrium to estimate the gene frequency (GF) for each locus, GF = 1 – 
1 – AF (allele frequency).15 The Hsp70-Hom M493T single nucleotide polymorphism (SNP) was determined using PCR and NcoI restriction fragment-length polymorphism described previously.16
All statistical analyses were performed with SPSS version 12.0 (SPSS, Chicago, IL, USA). Categorical variables were compared by 
2 analysis or Fisher's exact test. Non-categorical variables were compared by the Wilcoxon rank sum test. All comparisons were two-tailed and a P value <0.05 was considered significant.
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Results |
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Among 358 patients initiating abacavir-containing CART during the study period, 21 patients (5.9%) were excluded from further analysis and 337 patients were enrolled in the present study (Figure 1). The demographics of the 337 enrolled patients are shown in Table 1. One hundred and ninety-two patients (57.3%) met the criteria of AIDS, and concurrent AIDS-defining opportunistic infections occurred in 83 patients (24.6%) at abacavir prescription. Thirty-eight patients (11.3%) discontinued abacavir within 6 weeks, and 10 of them had successful re-challenge later (Figure 1). Another one patient stopped abacavir with unknown duration of abacavir use, but resumed it later successfully. Overall, 309 patients (91.7%) were categorized as abacavir tolerant.
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Except for the 10 patients who resumed abacavir successfully, the remaining 28 patients who discontinued abacavir within 6 weeks were categorized into three groups: abacavir hypersensitivity (3 patients, 0.9%), abacavir hypersensitivity not excluded (14, 4.2%) and abacavir discontinuation with specific reasons (11, 3.3%). In the group of patients who discontinued abacavir with specific reasons, abacavir was discontinued (median interval from initiation to discontinuation, 26 days; range 1–36 days) because of patient's choice (3 patients), dizziness (2), regimen adjustment (1), structured treatment interruption (1), alopecia (1), eyelid swelling (1), abdominal pain caused by tuberculosis (1), and psychological and gastrointestinal upset (1). The symptoms of patients with abacavir hypersensitivity not excluded were rashes (6 patients), gastrointestinal symptoms with nausea (2) and vomiting (1), and both (1), fever (2), and generalized discomfort (2). All six patients with rashes had concomitant medications, such as efavirenz (2), clindamycin and primaquine (2), sulfamethoxazole/trimethoprim (co-trimoxazole) and nevirapine (1), and co-trimoxazole and carbamazepine (1). One of the two patients with fever also took co-trimoxazole at the same time.
Among the three patients (0.9%) with abacavir hypersensitivity, one (HLA-A02, -A33, -B39, -B58, -Cw07, -Cw10) developed fever, maculopapular rashes, dyspnoea and pneumonitis on day 28 of abacavir use, which resolved after abacavir discontinuation. The second patient (HLA-A*0203, -A33, -B46, -B58, -Cw01, -Cw10) had maculopapular rashes with itching sensation over the trunk, watery diarrhoea and vomiting on day 28 of abacavir use, and these symptoms disappeared after stopping abacavir. In the third case (HLA-A*0203, -A11, -B*1301, -B52, -Cw07, -Cw10), fever and rashes with itching sensation occurred after abacavir use for 10 days and concurrent co-trimoxazole for nocardiosis for more than 3 weeks, and symptoms improved after discontinuation of abacavir and co-trimoxazole. Although he had fever and rash again during the period of co-trimoxazole re-challenge, generalized skin rash and diarrhoea took place on day 15 after he resumed abacavir. No particular alleles were identified to be associated with abacavir hypersensitivity in these three patients.
Three hundred and twenty patients underwent HLA typing, 232 receiving abacavir- and 88 not receiving abacavir-containing CART. Seven HLA-I specificities were present in more than 10% of the study subjects: HLA-A02, HLA-A11 and HLA-A24 at the HLA-A locus; HLA-B60 at the HLA-B locus; and HLA-Cw01, HLA-Cw07, and HLA-Cw10 at the HLA-C locus. There was no significant difference in the allele frequency between the 232 patients initiating abacavir and the 88 not receiving abacavir; only one patient who received abacavir-containing CART had HLA-B*5701. This patient discontinued abacavir 19 days after initial prescription due to rash with concomitant efavirenz use and was grouped as abacavir hypersensitivity not excluded. Because co-occurrence of HLA-B*5701, HLA-DR7 and HLA-DQ3 or HLA-B*5701 and a haplotypic Hsp70-Hom M493T were shown to be predictive of abacavir-induced hypersensitivity,7 further analysis was conducted to analyse the polymorphisms of these regions in our HLA-B*5701 carriers. All the HLA-DR7, HLA-DQ3 and Hsp70-Hom M493T variant markers were present in this patient.
Since the Taiwanese population is not inbred, differences in HLA genetic frequencies have been observed in different ethnic groups of Taiwanese.17,18 The genetic frequencies of the HLA-A, HLA-B and HLA-C of our patients were compared with those of published studies in Taiwanese and the Mainland Chinese populations (Table 2),17–19 and some interesting findings were noted. First, there was no significant difference in the genetic frequencies of HLA class I between our enrolled patients and control patients. Second, the HLA-B57 frequency in our study patients was significantly lower than two of the published studies. Third, there were indeed some significant differences in genetic frequencies of specific alleles between our patients and those of published studies, such as HLA-A02, HLA-A11, HLA-A24, HLA-A30, HLA-A31 and HLA-A33 in the HLA-A locus; HLA-B07, HLA-B13, HLA-B27, HLA-B38, HLA-B39, HLA-B46, HLA-B51, HLA-B52, HLA-B57, HLA-B58, HLA-B60 and HLA-B62 in the HLA-B locus; and HLA-Cw03, HLA-Cw06 and HLA-Cw07 in the HLA-C locus.
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Discussion |
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Our present study showed the occurrence of abacavir hypersensitivity (0.9%) was lower in HIV-infected patients in Taiwan when compared with that (5% to 8%) in Western countries.1,2 In addition, the incidence of abacavir hypersensitivity not excluded was also lower (4.2%) in our patient population than that (8.6-10.2%) in other countries without routine screening for HLA-B*5701.8,11 Besides, the proportion of patients carrying HLA-B*5701 was only 0.4% in our patients initiating abacavir (0.3% in 320 HIV-infected patients with HLA typing), which was much lower than that (7.3% to 12.2%) in Caucasians.8–11 Although one patient with abacavir hypersensitivity not excluded had HLA-B*5701 in the present study, none of the three patients who met the clinical criteria of abacavir hypersensitivity had this variant. Because only one patient had all the HLA-DR7, HLA-DQ3 and Hsp70-Hom M493T variant markers, it is difficult to reach a conclusion regarding the association between these HLA alleles and abacavir hypersensitivity from our observations. However, further studies might be needed to explore whether other specific genes are responsible for abacavir hypersensitivity in our population of ethnic Chinese, since abacavir hypersensitivity did occur in patients without these HLA alleles.
Studies of prospective screening for HLA-B*5701 prior to initiation of abacavir have illustrated significant reduction in the incidence of abacavir hypersensitivity, from 6.2–12.2% to 0–2.0%,8–11 in Caucasians. Hughes et al.20 also demonstrated that such practice appears to be cost-effective in terms of healthcare resources. However, application of routine HLA-B*5701 testing to other racial populations raises concerns because of lack of such an association of HLA-B*5701 and abacavir hypersensitivity in black Africans.21,22 It is worth noting that few Asians were enrolled in these studies8–11,23 although Mosteller et al.14 has demonstrated comparable sensitivity (57% versus 50%) of HLA-B*5701 in Thai subjects (7 enrolled cases) and Caucasians (444 enrolled cases). Therefore, our study provided a missing piece of information with respect to incidence of abacavir hypersensitivity in 337 ethnic Chinese and prevalence of HLA-B*5701.
As compared with Caucasians in prior studies,8–11 Chinese populations have a lower frequency of HLA-B*5701.17–19 Different genetic frequency of specific alleles between our data and prior published reports existed (Table 2),17–19 and such observations might result from our limited sample size or simply reflect the complex ethnic nature of Taiwanese. Nevertheless, our patients had significantly lower genetic frequency of HLA-B57 than other Chinese populations, which might explain the low incidence of abacavir hypersensitivity in the present study. Based on the above findings, we might conclude that HLA-B*5701 is not a common allele in Taiwanese, and utilization of routine testing for HLA-B*5701 might not be a sensitive or specific method to reduce the risk associated with abacavir hypersensitivity in Taiwan.
Because diagnosis of abacavir hypersensitivity depends mainly on clinical criteria, concurrent medications and opportunistic infections could potentially confound physicians’ judgement given the possibly life-threatening result of abacavir continuation or re-challenge. Among 337 enrolled patients in our present study, 57.3% of them were in the stage of AIDS and one-fourth (24.6%) had concurrent opportunistic infections necessitating concurrent medications at abacavir prescription. When episodes of suspected abacavir hypersensitivity occurred, seven (50%) of the 14 patients with abacavir hypersensitivity not excluded had concomitant use of medications which might be responsible for the symptoms. Besides, abacavir hypersensitivity does occur in our patients and Caucasians with negative HLA-B*5701.10 Such circumstances emphasize the importance of clinical vigilance in dealing with the reactions in HIV-infected patients who are treated with abacavir in the setting where the frequency of abacavir hypersensitivity is lower and no sensitive or specific biomarker is available to identify persons at risk.
Our study is limited by retrospective study design and a small sample size. However, we provide valuable experience of abacavir use and association of abacavir hypersensitivity and HLA-B*5701 in HIV-infected Taiwanese patients. In conclusion, our findings suggest that abacavir hypersensitivity is less frequently encountered in HIV-infected Taiwanese than in Caucasians, which might be explained by the low frequency of HLA-B*5701.
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No funding has been received for the present study.
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None to declare.
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References |
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