Abstract for presentation at 11th International Congress of Human Genetics

Pharmacogenetic investigation of drug-associated adverse events: Hypersensitivity to abacavir

  • Arlene Hughes, GlaxoSmithKline, United States
  • Liling Warren, GlaxoSmithKline, United States
  • Dr Michael Mosteller, GlaxoSmithKline, United States
  • Dr Eric Lai, GlaxoSmithKline, United States
  • Stephen Haneline, GlaxoSmithKline, United States
  • Dr William Spreen, GlaxoSmithKline, United States
  • Cindy Brothers, GlaxoSmithKline, United States
  • Allen Roses, GlaxoSmithKline, United States

    • Abacavir (ABC) is an effective antiretroviral drug used to treat HIV-1 infection. Approximately 5% of patients treated with ABC develop a hypersensitivity reaction (HSR) that in rare cases has proved fatal. The reaction may present with non-specific symptoms; thus, diagnosis can be complicated by concurrent diseases or adverse events from other drugs. A clinical risk management program has successfully reduced the rate of serious outcomes. Performance characteristics for prognostic ABC HSR pharmacogenetic (PG) marker(s) must be extremely high in order to improve upon clinical management, which must remain the basis for diagnosis of ABC HSR; over-reliance on prognostic markers could lead to reduced clinical vigilance and more serious outcomes. Over 500 retrospectively identified subjects with suspected ABC HSR (“cases”) and more than 500 matched, ABC-tolerant subjects have been studied using both candidate gene and genome-wide genotyping approaches. Among 84 markers that demonstrated replicated association with suspected ABC HSR in Caucasians, HLA-B*5701 was most highly associated with ABC HSR (sensitivity=50%, specificity=98%, p=10). No combination of markers exhibited a sensitivity and a specificity greater than those of HLA-B*5701 alone. In non-Caucasians, sensitivity of HLA-B*5701 was 57% in Thai (n=7 cases), 22% in Hispanic (n=63 cases) and 8% in Black subjects (n=50 cases). As retrospective ascertainment of ABC HSR is difficult, the performance characteristics of HLA-B*5701 in reducing ABC HSR are being investigated in a prospective, double-blind, largely European clinical study that compares the ABC HSR rate between a current standard-of-care ABC treatment group and a prospective PG screening group excluding subjects who carry the HLA-B*5701 allele. Because the rate of ABC HSR and the allele frequency of HLA-B*5701 differ between racial groups, alternative study designs may be needed to investigate ABC HSR in non-Caucasian populations.-73

    Conference Organiser - ICMS Pty Ltd