Date Published: January 16, 2019
Publisher: BioMed Central
Author(s): Karam Mounzer, Ricky Hsu, Jennifer S. Fusco, Laurence Brunet, Cassidy E. Henegar, Vani Vannappagari, Chris M. Stainsby, Mark S. Shaefer, Leigh Ragone, Gregory P. Fusco.
HLA-B*57:01 screening was added to clinical care guidelines in 2008 to reduce the risk of hypersensitivity reaction from abacavir. The uptake of HLA-B*57:01 screening and incidence of hypersensitivity reaction were assessed in a prospective clinical cohort in the United States to evaluate the effectiveness of this intervention.
We included all patients initiating an abacavir-containing regimen for the first time in the pre-HLA-B*57:01 screening period (January 1, 1999 to June 14, 2008) or the post-HLA-B*57:01 screening period (June 15, 2008 to January 1, 2016). Yearly incidence of both HLA-B*57:01 screening and physician panel-adjudicated hypersensitivity reactions were calculated and compared.
Of the 9619 patients eligible for the study, 33% initiated abacavir in the pre-screening period and 67% in the post-screening period. Incidence of HLA-B*57:01 screening prior to abacavir initiation increased from 43% in 2009 to 84% in 2015. The incidence of definite or probable hypersensitivity reactions decreased from 1.3% in the pre-screening period to 0.8% in 2009 and further to 0.2% in 2015 in the post-screening period.
Frequency of HLA-B*57:01 screening increased steadily since its first inclusion in treatment guidelines in the United States. This increase in screening was accompanied by a decreasing incidence of definite or probable hypersensitivity reactions over the same period. However, a considerable proportion of patients initiating abacavir were not screened, representing a failed opportunity to prevent hypersensitivity reactions. Where HLA-B*57:01 screening is standard of care, patients should be confirmed negative for this allele before starting abacavir treatment.
Abacavir, a nucleoside reverse transcriptase inhibitor (NRTI), was approved by the FDA in December 1998. It has since become widely used in combination with other antiretroviral agents to achieve viral suppression and immunologic improvement in patients with HIV infection [1–5]. While abacavir is believed to have a lower propensity for causing mitochondrial toxicity than other NRTIs , it has also been linked to potentially fatal hypersensitivity reactions (HSR). Hypersensitivity is an extreme form of adaptive immune response occurring when the immune system reacts inappropriately to certain antigens, and may lead to inflammatory reactions and tissue damage . Abacavir is thought to induce HSR by altering the repertoire of self-peptides presented to T-cells, resulting in an immune response. This is heightened in patients carrying HLA-B*57:01 due to a direct, metabolism-independent and non-covalent interaction of abacavir with HLA-B*57:01 [8–11].
To the best of our knowledge, this is the first evaluation of HLA*B-57:01 screening practices and changes in HSR incidence in a clinical setting in the United States. In the OPERA® cohort, before the screening test was available, the overall definite or probable HSR incidence was 1.3%. HLA*B-57:01 screening increased steadily after its introduction in June 2008, from 43% screened in 2009 to 84% in 2015. This expansion of screening was accompanied by an important decrease of HSR incidence in the same period from 0.8% in 2009 to 0.2% in 2015.
Expanded HLA*B-57:01 screening in clinical practice has been associated with fewer patients experiencing abacavir-associated hypersensitivity reactions in the OPERA® cohort. However, 16% of patients initiating abacavir in 2015 had not been screened beforehand. This gap indicates a potential for further reducing the risk of HSR by improving clinical practices. Indeed, where HLA-B*57:01 screening is standard of care, patients should be confirmed negative for this allele before starting abacavir treatment, as recommended in clinical guidelines.