Pharmacogenetic (PG) investigation of hypersensitivity to abacavir
Background: Abacavir (ABC) is an effective antiretroviral drug. Approximately 5% of patients treated with ABC develop a hypersensitivity reaction (HSR) that in rare cases has proved fatal; a clinical risk management program has successfully reduced the rate of serious outcomes. Symptoms of HSR may overlap with other syndromes; thus, diagnosis can be complicated by concurrent diseases or adverse events from concomitant drugs. Performance characteristics for prognostic ABC HSR PG marker(s) must be extremely high in order to improve upon clinical management, which must remain the basis for diagnosis and management of ABC HSR; over-reliance on prognostic markers could lead to reduced clinical vigilance and more serious outcomes.
Methods: Over 500 retrospectively identified subjects with presumed ABC HSR (“cases”) and more than 500 matched, ABC-tolerant controls have been studied using both candidate gene and genome-wide genotyping approaches.
Results: Among 84 markers that demonstrated replicated association with presumed ABC HSR in Caucasians, HLA-B*5701 was most highly associated with presumed ABC HSR (sensitivity=50%, specificity=98%, p=10 E-73). 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). No combination of markers exhibited a sensitivity and a specificity greater than those of HLA-B*5701 alone.
Conclusions: A strong association between presumed ABC HSR and HLA-B*5701 carriage was confirmed in this analysis. 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, multicenter 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 among racial groups, alternative study designs may be needed to investigate ABC HSR in non-Caucasian populations.
AIDS 2006 - XVI International AIDS Conference
"M.Mosteller, et al.
Pharmacogenetic (PG) investigation of hypersensitivity to abacavir.
AIDS 2006 - XVI International AIDS Conference: