Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

12 Applying Pharmacogenomics in Therapeutics
Among seven international laboratories, specificity and sensitivity of detecting the
HLA-B*5701 allele via PCR sequencing were 100% and 99.4%, respectively. 68 In
studies where patients were diagnosed with an abacavir HSR based on symptom
presentation, the sensitivity of the HLA-B*5701 test was 46–78%. 64,69,70 In contrast,
that sensitivity was up to 94–100% in patients with an immunologically confirmed
(via skin patch testing) abacavir HSR. 65,71,72 There is suggestion that the discrepancy
of lower estimates of test sensitivity was the inclusion of non-abacavir-related
HSR. 73 However, the specificity of the HLA-B*5701 test is 90–100%, regardless of
whether abacavir HSR is based on symptom presentation or immunologic confirmation.
64,65,69–72 Pooled data from three study populations reported a positive predictive
value and a negative predictive value of 82% (95% confidence interval [CI]: 71–90%)
and 85% (95% CI: 81–88%), respectively. 64,69,70 This suggests a high genetic penetrance
of the HLA-B*5701 allele in predisposing patients to abacavir HSR. 70
Several guidelines provide guidance for whether patients should be tested for the
HLA-B*5701 allele prior to initiation. According to the US Department of Health
and Human Services, 74 screening for HLA-B*5701 prior to initiation of abacavir is
recommended. If a patient is positive for the HLA-B*5701 allele, abacavir should
not be recommended. 74 The Infectious Diseases Society of America (IDSA) has also
recommended HLA-B*5701 testing prior to initiating abacavir to reduce the risk
of an HSR. Patients positive for the HLA-B*5701 should not be treated with abacavir.
75 In July 2008, the US FDA updated the black box warning in the prescribing
information 76 to recommend screening for the HLA-B*5701 polymorphism prior
to starting abacavir treatment. Screening is also recommended prior to reinitiation
of abacavir in patients of unknown HLA-B*5701 status who have previously tolerance
abacavir. 77 The benefits of testing for that allele and the potential detection of a
potentially life-threatening HSR clearly outweigh the risk of testing.
In at least two pharmacoeconomic studies, testing for the HLA-B*5701 polymorphism
has been shown to be cost-effective according to the high risk of
abacavir-induced HSR. 70,78 Some publications have demonstrated the feasibility of
implementing such a testing program for abacavir, which involves education and
training of staff and continual monitoring. 63,79,80
TOXICITY: CARBAMAZEPINE
Clinical Case
TL is a 30-year-old Chinese American male with newly diagnosed complex partial
seizures who presents to the clinic for evaluation. He has not previously been treated
with an antiepileptic drug, and the neurologist is considering starting carbamazepine.
TL has no known drug allergies, and his other medical history is pertinent for
hypertension and seasonal allergies. His medications include losartan and loratadine.
Background
Carbamazepine is an anticonvulsant that is indicated for partial and generalized
seizures, trigeminal neuralgia, and bipolar disorder. 30,81 The exact mechanism