Drug-reaction eosinophilia and systemic symptoms and drug-induced hypersensitivity syndrome.

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DIHS), is a rare, severe cutaneous adverse reaction characterised by fever, rash, lymphadenopathy, eosinophilia and/or other leukocyte abnormalities, and internal organ involvement and often has a relapsing-remitting course despite withdrawal of the drug. The drugs that are most implicated include aromatic anticonvulsants, allopurinol, sulphonamides, antiretrovirals (abacavir and nevirapine), and minocycline. The pathogenesis of DRESS/DIHS is far from clear but probably involves a combination of impaired pharmacokinetics and the accumulation of drug metabolites, the sequential reactivation of the herpesvirus family and genetic susceptibility conferred by the association with certain human leukocyte antigen (HLA) class I alleles. The strong association between abacavir and HLA-B*5701 has enabled pharmacogenetics screening to be employed successfully to minimise the occurrence of hypersensitivity. A prolonged course of oral corticosteroids is required to treat DRESS/DIHS, given the relapsing-remitting nature of the condition with i.v. immunoglobulin and valgangciclovir reserved for refractory or life-threatening cases.

Pathological changes in various organs in HLA-B*57:01 transgenic mice with abacavir-induced skin eruption.

Several patients with cutaneous adverse drug reactions exhibit extracutaneous organ damages, and it becomes severe in a few patients resulting in death due to multiorgan failure. Understanding the sequential changes in various organs in patients with cutaneous eruption following drug administration will help understand disease onset and progression, aiding the development of prevention strategies and interventions. Therefore, we aimed to understand the effects of abacavir (ABC) on various organs in patients with ABC-induced eruptions by evaluating its effects in a mouse model. We found pathological changes in various organs of HLA-B*57:01 transgenic mice (B*57:01-Tg) following oral administration of ABC (20 mg/body/day). B*57:01-Tg exhibited a significant body weight decrease from day 1 of ABC administration, and reddening of the auricle was observed from day 5, and approximately 2/3 mice died by day 7. Histopathological examination revealed severe thymic atrophy after day 3, infiltration of inflammatory cells, predominantly lymphocytes with neutrophils, not only in the skin but also in the liver, kidney, and lung after day 5, and an increased number of lymphocytes with enlarged nuclei and granulocytic hematopoiesis were observed in the spleen after day 5. Blood chemistry revealed that albumin/globulin ratio was below 1.0 on day 5, reflecting a systemic inflammatory response, and the aspartate aminotransferase concentration rose to 193 ± 93.0 U/L on day 7, suggesting that cell damage may have occurred in various organs including liver accompanying inflammatory cell infiltration. These examinations of a mouse model of ABC-induced skin eruption show that disorders in various organs other than the skin should be considered and provide insights into the unexpected early systemic responses dependent on HLA-B*57:01. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00220-1.

Prevalence of the HLA-B*5701 Allele and Abacavir Hypersensitivity in Saudi HIV Patients: A Multicenter Study.

Introduction Human immunodeficiency virus (HIV) incidence and prevalence are increasing in Saudi Arabia, with a total prevalence of 12,000 in 2020. Treatment of HIV patients includes multiple regimens that may involve abacavir (ABC), which is a potent drug for treating HIV and can be used as a single or combined pill. Unfortunately, its use was limited by the known associated hypersensitivity reaction (HSR). A worldwide literature review over the past decades reported that the incidence of ABC-related HSR is 5-8%. Methods The study was a cross-sectional multicentric study involving five governmental hospitals in Saudi Arabia and included all HIV patients who were following in these centers. Results Out of 3082 patients, 1293 were tested for HLA-B*5701. The prevalence for ABC-HSR is 1.59%, with variability among the five hospitals, with the highest in King Fahad Hospital in Hafuf (KFH-H) at 4.00% and the lowest in Dammam Medical Complex (DMC) at 0.49%. In previous studies, HLA-B*5701 associated with ABC-HSR varied among different ethnic groups. Our study showed that two patients developed ABC-HSR clinically while they were both negative for HLA-B*5701. Conclusion The fact that patients with negative genetic testing are still at risk of developing ABC-HSR makes continuing screening for HLA-B*5701 status essential, as the consequences of missing such a life-threatening HSR could be detrimental.

Severe abacavir hypersensitivity reaction in a patient with human immunodeficiency virus infection: a case report.

BACKGROUND: Abacavir is a nucleoside reverse transcriptase inhibitor that is used as a component of the antiretroviral treatment regimen in the management of the human immunodeficiency virus for both adults and children. It is efficacious, but its use may be limited by a hypersensitivity reaction linked with the HLA-B*57:01 genotype. HLA-B*57:01 has been reported to be rare in African populations. Because of the nature of its presentation, abacavir hypersensitivity is prone to late diagnosis and treatment, especially in settings where HLA-B*57:01 genotyping is not routinely done. CASE REPORT: We report a case of a severe hypersensitivity reaction in a 44-year-old Kenyan female living with the human immunodeficiency virus and on abacavir-containing antiretroviral therapy. The patient presented to the hospital after recurrent treatment for a throat infection with complaints of fever, headache, throat ache, vomiting, and a generalized rash. Laboratory results evidenced raised aminotransferases, for which she was advised to stop the antiretrovirals that she had recently been started on. The regimen consisted of abacavir, lamivudine, and dolutegravir. She responded well to treatment but was readmitted a day after discharge with vomiting, severe abdominal pains, diarrhea, and hypotension. Her symptoms disappeared upon admission, but she was readmitted again a few hours after discharge in a hysterical state with burning chest pain and chills. Suspecting abacavir hypersensitivity, upon interrogation she reported that she had taken the abacavir-containing antiretrovirals shortly before she was taken ill. A sample for HLA-B*57:01 was taken and tested positive. Her antiretroviral regimen was substituted to tenofovir, lamivudine, and dolutegravir, and on subsequent follow-up she has been well. CONCLUSIONS: Clinicians should always be cognizant of this adverse reaction whenever they initiate an abacavir-containing therapy. We would recommend that studies be done in our setting to verify the prevalence of HLA-B*57:01.

New genetic predictors for abacavir tolerance in HLA-B*57:01 positive individuals.

Abacavir hypersensitivity syndrome (ABC HSS) is strongly associated with carriage of human leukocyte antigen (HLA)-B*57:01, which has a 100% negative predictive value for the development of ABC HSS. However, 45% of individuals who carry HLA-B*57:01 can tolerate ABC. We investigated immune and non-immune related genes in ABC HSS (n = 95) and ABC tolerant (n = 43) HLA-B*57:01 + patients to determine other factors required for the development of ABC HSS. Assignment of phenotype showed that ABC HSS subjects were significantly less likely than tolerants to carry only ERAP1 hypoactive trimming allotypes (p = 0.02). An altered self-peptide repertoire model by which abacavir activates T cells is in keeping with observation that endoplasmic reticulum aminopeptidase 1 (ERAP1) allotypes that favour efficient peptide trimming are more common in ABC HSS patients compared to patients who tolerate ABC. Independently, non-specific immune activation via soluble cluster of differentiation antigen 14 (sCD14) may also influence susceptibility to ABC HSS.

First external quality assurance program of the Italian HLA-B*57:01 Network assessing the performance of clinical virology laboratories in HLA-B*57:01 testing.

BACKGROUND: Since the HLA-B*57:01 allele is strongly associated with abacavir hypersensitivity reaction, testing for the presence of HLA-B*57:01 is mandatory before administration of abacavir. While HLA-B*57:01 testing is usually provided by pharmacogenetics, genetics or blood transfusion services, clinical virology laboratories can be an optimal opportunity for HLA-B*57:01 testing since they receive blood samples for routine HIV monitoring and have the expertise for convenient and less expensive PCR-based point mutation assays. OBJECTIVES: The Italian HLA-B*57:01 Network gathers accredited clinical virology laboratories offering HLA-B*57:01 testing in Italy with the aim to share protocols, test new methods, develop and maintain external quality assurance (EQA) programs. STUDY DESIGN: A panel of 9HLA-B*57:01-positive and 16HLA-B*57:01-negative frozen blood samples were blindly distributed to 10 units including 9 clinical virology laboratories and one reference pharmacology laboratory. Each laboratory was free to use its own routine method for DNA extraction and HLA-B*57:01 testing. RESULTS: DNA was extracted by automated workstations in 6 units and by manual spin columns in 4. Eight units used the Duplicα Real Time HLA-B*57:01 kit by Euroclone and two units used two different PCR homemade protocols. All the 10 units correctly identified all the 25 samples. CONCLUSIONS: The first HLA-B*57:01 EQA program run in Italy showed that clinical virology units are equipped and proficient for providing HLA-B*57:01 testing by inexpensive assays easy to integrate into their routine.

Validation of two commercial real-time PCR assays for rapid screening of the HLA-B*57:01 allele in the HIV clinical laboratory.

The pharmacogenetics approach to screen for the presence of the HLA-B*57:01 allele in HIV-1 infected patients is mandatory to prevent the potential development of hypersensitivity reaction to abacavir treatment. Given the limitations of current genotype methodologies, commercial real-time PCR assays were specifically developed for this purpose, but have not been sufficiently validated and are still not widely used. Here, in the context of the HIV laboratory, we assessed the ability of two commercial kits, the LightSNiP rs2395029 HPC5 assay (TIB Molbiol) and the DuplicαReal-TimeHLA-B*5701 Genotyping kit (Euroclone), to retrospectively detect HLA-B*57:01 positive and negative samples of Israeli HIV-1 infected patients. The LightSNiP rs2395029 HPC5 assay had false-positive results, whereas the DuplicαReal-Time HLA-B*5701 Genotyping kit was highly accurate and could be readily implemented into clinical practice. It is hoped that this study will facilitate the assessment of additional commercial kits for HLA-B*57:01 detection and expand their use in the clinical laboratory. Such studies can likely help the use of abacavir treatment in HIV-1 infected patients.

Pathogenesis and diagnosis of delayed-type drug hypersensitivity reactions, from bedside to bench and back.

Drug hypersensitivity reactions (DHR) have been present since the advent of drugs. In particular T-cell mediated delayed-type hypersensitivity reactions represent a heterogeneous clinical entity with a diverse pathogenesis and result in a considerable burden of morbidity and mortality not only driven by the reactions themselves but also by the use of alternatives which are sometimes less effective or even more dangerous. Diagnostic procedures rely on clinical history, skin testing and potential provocation testing, whereas validated in vitro diagnostic procedures are still lacking for most of them. Recent work in the field of pharmacogenomics combined with basic scientific research has provided insights in the pathogenesis of abacavir and carbamazepine hypersensitivities linked with certain human leucocyte antigen risk alleles. Nevertheless, important scientific questions on how other DHR arise and how host-drug interactions occur, remain unanswered. Recent work indicates an intricate relation between host, drug and pathogens in severe cutaneous and systemic reactions and provides more insights in the role of regulatory T-cells and viral reactivation in these reactions. In this review we focus on type IV delayed-type DHR, and address recent advances in the pathogenesis, pharmacogenomics, and diagnosis of these reactions with an emphasis on the understandings arising from basic research.

The frequency of HLA-B(∗)57:01 and the risk of abacavir hypersensitivity reactions in the majority population of Costa Rica.

HLA-B(∗)57:01 is a well-known and cost-effective pharmacogenetic marker for abacavir hypersensitivity. As with other HLA alleles, there is widespread variation in its frequency across populations. The Costa Rica Central Valley Population (CCVP) is the major population in this country. The frequency of HLA-B(∗)57:01 in this population has not been described yet. Thus, our aim was to determine the frequency of this allele in the CCVP. 200 unrelated healthy volunteer donors born in the CCVP were typed. HLA-B(∗)57-positive samples identified by HLA intermediate resolution typing methods were further typed by SBT to high resolution. An HLA-B(∗)57:01 carrier frequency of 5.00% was determined in this sample. This frequency is relatively high in comparison to reports from other populations in Latin America. These results suggest that there is a considerable frequency of HLA-B(∗)57:01 in the CCVP and that pharmacogenetic testing for HIV+ patients who are going to receive abacavir-based treatment should be considered in this country.

Diagnostic accuracy of HLA-B*57:01 screening for the prediction of abacavir hypersensitivity and clinical utility of the test: a meta-analytic review.

AIM: To determine diagnostic accuracy of HLA-B*57:01 testing for prediction of abacavir-induced hypersensitivity and to quantify the clinical benefit of pretreatment screening through a meta-analytic review of published studies. METHODS: A comprehensive search was performed up to June 2013. The methodological quality of relevant studies was assessed by the QUADAS-2 tool. The pooled diagnostic estimates were calculated using a random effect model. RESULTS: Despite the presence of heterogeneity in sensitivity or specificity estimates, the pooled diagnostic odds ratio to detect abacavir-induced hypersensitivity on the basis of clinical criteria was 33.07 (95% CI: 22.33-48.97, I(2): 13.9%), while diagnostic odds ratio for detection of immunologically confirmed abacavir hypersensitivity was 1141 (95% CI: 409-3181, I(2): 0%). Pooled analysis of risk ratio showed that prospective HLA-B*57:01 testing significantly reduced the incidence of abacavir-induced hypersensitivity. CONCLUSION: This meta-analysis demonstrates an excellent diagnostic accuracy of HLA-B*57:01 testing to detect immunologically confirmed abacavir hypersensitivity and corroborates existing recommendations.

HLA-B*5701 genetic screening among HIV-1 infected patients in Hong Kong: is this a practical approach in Han-Chinese?

Abacavir hypersensitivity is associated with the presence of human leukocyte antigen (HLA)-allele B*5701. However, the cost and workload of routine HLA-B*5701 pretreatment screening is relatively heavy. This study aimed to determine the prevalence of the HLA-B*5701 allele in the HIV-positive population under care in Hong Kong. Blood samples from 1264 HIV-1 infected patients in Hong Kong were collected between 2007 and 2011 for this study. HLA-B*5701 screening of the study group was determined by in-house polymerase chain reaction (PCR) followed by confirmation using the AlleleSEQR(®) HLA-B PCR/Sequencing Kit (Celera Corporation for Abbott, San Francisco, USA). HLA-B*5701 carriers were identified among 3% of Caucasians, 1% of non-Chinese Asians and 0.5% of Han-Chinese in Hong Kong. Our findings revealed that HLA-B*5701 pretreatment screening might not be necessary for the local Han-Chinese population due to its low prevalence.