Abstract: One study, which was a randomised, double-blind, controlled, multicentre trial, fulfilled our inclusion criteria. The trial included 1956 adult participants (74% men, with a mean age of 42 years) across 265 centres (medical centres, hospitals, outpatient clinics) in 19 countries around the world who were infected with HIV-type 1 and who had not received abacavir previously. The participants, who had a clinical need for treatment with an antiretroviral-drug regimen containing abacavir, were randomly assigned to undergo prospective human leukocyte antigen (HLA) Class I, locus B, allele 57:01 (HLA-B*57:01) screening (prospective-screening group) before this treatment, or to undergo a standard-care approach of abacavir use without prospective HLA-B*57:01 screening (control group). Participants who tested positive for HLA-B*57:01 were not given abacavir; instead, they received antiretroviral therapy that did not include abacavir. The control group did have retrospective HLA-B*57:01 pharmacogenetic testing. The trial duration was six months. Each participant was observed for six weeks. Assessments were performed at the time of study entry, at baseline (day one of abacavir treatment), and at weeks one, two and six. This study was funded by the manufacturer of abacavir, GlaxoSmithKline. The study did not assess any of our primary outcomes, and it measured none of our secondary outcomes in isolation. However, it did assess an outcome of (characteristically severe) hypersensitivity reaction which included (but was not limited to) our secondary outcomes of HSS and SJS/TEN. The study demonstrated that prospective HLA-B*57:01 screening probably reduces the incidence of hypersensitivity reaction to abacavir. The incidence of clinically diagnosed HSS reaction to abacavir was lower in the screening arm (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.28 to 0.67; 1650 participants; moderate-quality evidence), as was immunologically confirmed HSS reaction (RR 0.02, 95% 0.00 to 0.37; 1644 participants; moderate-quality evidence). A positive result from an epicutaneous patch test performed six to ten weeks after clinical diagnosis provided immunological confirmation. Overall, the study demonstrates a low risk of bias across five out of seven domains. There was a high risk of detection bias because hypersensitivity reactions were diagnosed by the principal investigator at the recruitment site without the use of predefined clinical criteria. Although there was also high risk of attrition bias due to excluding participants with incomplete follow-up from analyses, the authors did undertake a series of sensitivity analyses based on the intention-to-treat population, which demonstrated consistent results with the primary analysis. We rated the study quality as moderate-quality using GRADE criteria. Prospective screening for HLA-B*57:01 probably reduces severe hypersensitivity skin reactions to abacavir in patients positive for HIV-type 1. However, these results are only based on one study, which was at high risk of attrition and detection bias. Our primary outcomes (incidence of severe skin rashes with systemic symptoms, and long-term effects) were not assessed by the trial, and only one of the review’s secondary outcomes was measured (hypersensitivity reaction); thus, we found no evidence relating to hospitalisation, death, or long-term conditions resulting from drug injury. We found no eligible evidence on genetic testing for severe drug-induced skin rash in relation to different drugs and classes of drugs. Further clinical trials based on other drugs, and in different patient populations, would be useful for advising policy changes for improving the prevention of adverse skin reactions to drug treatments.

Plain-language summary: We found only one relevant study. It included 1956 adult participants, of whom 74% were men, who tested positive for HIV-type 1 and were eligible to start highly active antiretroviral therapy including a medication called abacavir. (Antiretrovirals are a drug class used for treating patients with HIV infection.) The age of study participants ranged from 18 to 77 years; the average age was 42 years. The participants were from 19 countries around the world in 265 healthcare centres (e.g. hospitals, clinics). This study investigated whether the following can reduce the rate of serious skin reactions to abacavir: genetic testing for the genetic marker HLA-B*57:01 before prescribing abacavir (i.e. prospective testing) versus no prospective genetic testing for HLA-B*57:01. HLA-B*57:01 is known to be key in developing severe skin reactions to the HIV antiretroviral drug, abacavir. Participants who tested positive for the genotype were not given abacavir; instead, they were given a different antiretroviral therapy. The study lasted six months and each participant was observed for six weeks. GlaxoSmithKline, the company that manufactures abacavir, funded the study. Control participants had HLA-B*5701 pharmacogenetic testing after they had received abacavir as standard of care. Our one included study did not report data for all participants, and clinical assessment of hypersensitivity (HSS) was done at the time of study entry, at baseline (day one) and at weeks one, two and six, without using predefined criteria. These can be important sources of bias and the quality of evidence was therefore judged to be moderate. Available data showed that prospective HLA-B*57:01 screening probably reduces the incidence of hypersensitivity reaction to abacavir (including, but not limited to, our secondary outcomes of hypersensitivity (HSS) syndrome and Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) (i.e. severe and blistering skin reactions caused by medications)). Based on these results, we would expect that out of 1000 people who did not have prospective pharmacogenetic screening (i.e. screening to assess how someone might respond to a particular drug), 78 would experience a hypersensitivity reaction including SJS/TEN (clinical assessment), compared with between 22 and 52 people who did have prospective pharmacogenetic screening to test for HLA-B*57:01. Furthermore, we would expect that out of 1000 people who did not have prospective pharmacogenetic screening (standard care), 27 would experience a hypersensitivity reaction including SJS/TEN (immunologically confirmed), compared with zero participants who had prospective pharmacogenetic screening to test for HLA-B*57:01. A patch test on the skin provided immunological confirmation 6 to 10 weeks after clinical diagnosis. The study did not measure the other outcomes of this review. The evidence is current to July 2018. The included study was rated as being of moderate quality. Some patients were withdrawn from the study and not included in the analyses, and the investigator that diagnosed HSS reactions did not use a predefined clinical criteria of hypersensitivity. These issues caused us to downgrade the certainty of the evidence.