Abacavir Hypersensitivity Reaction Reporting Rates During a Decade of HLA‐B*5701 Screening as a Risk‐Mitigation Measure

Abstract

Introduction Human leukocyte antigen (HLA) ‐B*5701 screening identifies patients at increased risk for abacavir ( ABC ) hypersensitivity reaction ( HSR ). Screening was adopted in GlaxoSmithKline and ViiV Healthcare clinical trials in 2007 and human immunodeficiency virus treatment guidelines in 2008. Company meta‐analyses of trials pre– HLA ‐B*5701 screening reported HSR rates of 4–8%. We analyzed the effectiveness of HLA ‐B*5701 screening on reducing HSR rates using clinical trial, Observational Pharmaco‐Epidemiology Research & Analysis ( OPERA ) cohort, and spontaneous reporting data. Methods A meta‐analysis examined 12 trials in 3063 HLA ‐B*5701–negative patients receiving an ABC ‐containing regimen from April 9, 2007, to September 22, 2015. Potential cases were identified using prespecified Medical Dictionary for Regulatory Activities (Med DRA ) preferred terms ( drug hypersensitivity, hypersensitivity, anaphylactic reaction, anaphylaxis ) and adjudicated against a Company ABC HSR case definition. Investigator‐diagnosed cases were identified and rates were calculated. In the OPERA cohort, 9619 patients initiating their first ABC ‐containing regimen from January 1, 1999, to January 1, 2016, were identified. Patients were observed from regimen start until the earliest‐following censoring event: ABC discontinuation, loss to follow‐up, death, or study end (July 31, 2016). OPERA physicians evaluated events against OPERA definitions for definite/probable cases of ABC HSR ; rates were calculated pre‐ and post‐2008. The Company case definition was used to identify spontaneously reported cases for four marketed ABC ‐containing products; reporting rates were calculated using estimated exposure from sales data, through December 31, 2016. Results Suspected ABC HSR rates were 1.3% or less in the meta‐analysis. In the OPERA cohort, the rate was 0.4% among patients initiating ABC post‐2008 versus 1.3% pre‐2008 (p<0.0001). Spontaneous reporting rates were low post‐2008 (54 to 22 cases per 100,000 patient‐years exposure [ PYE ]) versus pre‐2008 (618 to 55 cases per 100,000 PYE ). Conclusions Clinically suspected ABC HSR rates were 1.3% or less in HLA ‐B*5701–negative patients. Recognizing their limitations, data from t...

Drug hypersensitivity in HIV infection

“…In contrast, abacavir hypersensitivity reaction has been largely eliminated in populations where HLA-testing preprescription has been implemented, but still occurs in African populations, but at a low frequency. The low prevalence of the allele in Africans makes testing not to be cost-effective [11]. Increased use of integrase strand transfer inhibitors, and their availability in fixed dose combinations will mean increased exposure to this class of agents.…”

“…The success of HLA-B57 : 01 testing to eliminate abacavir DHS is an exemplar of this model. A recent meta-analysis by Stainsby et al [11] found that post-2008 and the implementation of HLA-B57 : 01 testing prior to abacavir prescribing, there has been near elimination of abacavir DHS. At present there is no other HIV-relevant drug IM-ADRs with genetic markers as favorable as abacavir; although the negative predictive value of HLA C04 : 01 for nevirapine SJS/TEN in African populations appears close to 100% [112], but positive predictive values without other additional genetic markers would make the number needed to test not cost-effective.…”

Mechanistic insights into antiretroviral drug‐induced liver injury

“…Cytochrome P450 and human leucocyte antigen genes that are associated with ART induced adverse reactions HLA-B*5701 polymorphism has been linked with abacavir hypersensitivity in HIV-positive individuals, 75,[80][81][82] while the HLA-DRB1*0101 78 and HLA-B*3505 [83][84][85] was associated with increased risk of developing NVP-driven hypersensitivity reactions. 79,83,[85][86][87] Moreover, HLA-C*0401 allele is associated with hypersensitivity to NVP and is carried across most ethnicities.…”

“…In fact, this has been implemented for abacavir hypersensitivity and has been hailed as a huge success as revealed in a recent metaanalysis by Stainsby and colleagues. 82 1.4 | Molecular mechanisms of ART-driven hepatotoxicity…”

“…90 The granular deposits may rep- is the success that has been achieved by taking a precision medicine approach in dealing with the abacavir hypersensitivity and implementing testing for HLA-B57:01 genotype prior to prescribing the treatment. 82 More pharmacogenetic and pharmacokinetic studies need to be conducted to identify other critical genotypes that may be contributing to the advent of DILI in this vulnerable group of patients, particularly in light of the changing regimens and doses.…”