A
small percentage of HIV positive people taking abacavir (Ziagen,
also a component of the fixed-dose combination pills Epzicom
and Trizivir) experience a potentially
life-threatening hypersensitivity reaction characterized by skin rash, fever,
and respiratory and gastrointestinal symptoms. Most studies suggest that the incidence
is around 5%, but this varies among racial/ethnic populations.
Recent
studies have shown that individuals with a specific genetic variation known as
HLA B*5701
are much more likely to develop abacavir hypersensitivity, and a genetic test
to predict which patients are at risk for the reaction is currently under development.
Now,
researchers from British Columbia report in the June 1, 2007 issue of Clinical
Infectious Diseases that a simple, inexpensive screening test that can be
combined with routine HIV drug resistance testing may offer a potential alternative
to expensive HLA typing
The researchers based their assay on an observed
correlation between the presence of the HLA B*5701 variation and an associated
HIV resistance mutation, a cytotoxic T-lymphocyte escape variation occurring at
reverse transcriptase (RT) codon 245.
The association was investigated
in 392 HIV positive, antiretroviral-naive adults who were starting HAART
for the first time. The relationship between the codon 245 variation and premature
abacavir discontinuation was then assessed in a larger cohort of 982 individuals
treated with the drug. Associations between HLA-B*5701 and the codon 245 variant
were determined using Fisher's exact test or the chi2 test.
Results
•
A
very strong association was observed between HLA B*5701 and RT codon 245 variation.
•
Only
1 of 24 subjects (4.2%) with HLA B*5701 harbored HIV with the clade B wild-type
amino acid 245V, compared with 278 of 368 subjects (75.5%) who did not have HLA
B*5701 (P < 0.001).
•
The
sensitivity and specificity of the codon 245 substitution for predicting the presence
of HLA B*5701 were 96% and 75%, respectively.
•
The
positive predictive value was 99.6%, indicating that almost everyone with HLA
B*5701 would have the codon 245 mutation.
•
However,
the negative predictive value was low, at 20%, indicating that many people with
the codon 245 mutation would not have HLA B*5701.
•
The
association remained robust even after antiretroviral treatment was administered
(negative predictive value 100%; n=269).
•
Among
the 982 abacavir-treated individuals, the codon 245 substitution were predictive
of premature abacavir discontinuation (P = 0.02).
Conclusion
"As
HIV RT sequence is incidentally obtained as a part of routine drug-resistance
testing, the examination of sequence variation at RT codon 245 could be adopted
as a simple, low-cost screening method to identify individuals who could be safely
treated with abacavir and/or who could benefit from HLA characterization,"
the authors concluded.
British Columbia Centre for Excellence in HIV/AIDS,
University of British Columbia, Vancouver, Canada.
06/15/07
Reference CK
Chui, ZL Brumme, B Yip, and others. A simple screening approach to reduce B*5701-associated
abacavir hypersensitivity on the basis of sequence variation in HIV reverse transcriptase.
Clinical Infectious Diseases 44(11): 1503-1508. June 1, 2007.
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