HLA-B*5701 and Abacavir

Alec WalkerOctober 2014

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Part I. Discovery

Association between presence of HLAB*5701, HLA-DR7,

and HLA-DQ3 and hypersensitivity to HIV-1 reverse-

transcriptase inhibitor abacavir

S Mallal, D Nolan, C Witt, G Masel, A M Martin, C Moore, D Sayer, A Castley, C

Mamotte, D Maxwell, I James, F T Christiansen

Lancet 2002; 359: 727–32

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Living with Cost and Benefit

Background The use of abacavir—a potent HIV-1 nucleoside- analogue reverse-transcriptase inhibitor—is complicated by a potentially life-threatening hypersensitivity syndrome in about 5% of cases. Genetic factors influencing the immune response to abacavir might confer susceptibility. We aimed to find associations between MHC alleles and abacavir hypersensitivity in HIV-1 positive individuals treated with abacavir.

1. Why use abacavir, ever?2. How would knowledge of a predictor of

hypersensitivity affect the cost-benefit profile?

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Translating into Formal Structure

Methods MHC region typing was done in the first 200 Western Australian HIV Cohort Study participants exposed to abacavir. Definite abacavir hypersensitivity was identified in 18 cases, and was excluded in 167 individuals with more than 6 weeks’ exposure to the drug (abacavir tolerant). 15 individuals experienced some symptoms but did not meet criteria for abacavir hypersensitivity. p values were corrected for comparisons of multiple HLA alleles (pc) by multiplication of the raw p value by the estimated number of HLA alleles present within the loci examined.

3. What is the study design (e.g. cohort, case-control, case-crossover, cross-sectional, other?)

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What is the Risk Associated with …

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Which Genotype?

4. (Note that Predictive Value = Risk .) How do you balance Sensitivity (displayed) and

Predictive Value in choosing a criterion?

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GraphicalPresentation

5. What does this chart convey that the tabulations miss?

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Many Comparators

6. What information do other comparators offer? Do they tell you about risk?

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Part II. Assessment

Prospective Genetic Screening Decreases the Incidence of Abacavir Hypersensitivity Reactionsin the Western Australian HIV Cohort Study

A. Rauch, D. Nolan, A. Martin, E. McKinnon, C. Almeida, and Simon Mallal

Clinical Infectious Diseases 2006;43:99–102

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Design: Screen All Patients Treat with Abacavir only Those Who are Negative

Any symptoms

Hypersensitivity

7. Why does screening reduce the occurrence of symptoms other than those of hyper-sensitivity?

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When HLA-B*5701 Patients Were Treated with Abacavir

Of the 9 ART-naive, HLA-B*5701–positive patients identified by genetic screening, 1 patient started abacavir treatment before the review of HLA results. This 48-year- old white man subsequently developed a typical abacavir hyper-sensitivity reaction, characterized by the development of a widespread maculopapular rash, fever, and constitutional symptoms 6 days after commencing abacavir therapy.

Of the 14 ART-experienced, HLA-B*5701–positive patients who were screened, 2 started abacavir therapy. In 1 case, HLA test results were not reviewed before drug prescription, and 1 patient made an informed choice to initiate abacavir therapy because … of previous treatment complications) ... Both of these white patients experienced abacavir hypersensitivity reactions….

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What More Information is Needed?

An RCT of abacavir screening was undertaken. Suggest: Exposure measure Outcomes Necessity for blinding Generalizability Ethical justification

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Mallal S, et al for the PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008 Feb 7;358(6):568-79

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Exposures

Prospective HLA-B*5701 pharmacogenetic screening followed by combination active antiretroviral therapy that included abacavir (the prospective-screening group), or

Combination active antiretroviral therapy that included abacavir, followed by retrospective HLA-B*5701 pharmacogenetic screening (the control group).

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Endpoints

Risk of clinically diagnosed hypersensitivity reaction to abacavir during the 6-week observation period

Risk of immunologically confirmed hypersensitivity reaction (defined as a clinically diagnosed reaction that was confirmed by a positive result on epicutaneous patch testing 6 to 10 weeks after clinical diagnosis).

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Endpoints

Note that the clinically diagnosed events that were not confirmed were fewer in the prospective screening group (27 or 3.4% vs. 43 or 5.1%). Why? Granting that these are unrelated to HLA-B*5701, would you still count this difference as an effect of screening?

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Ethics, revisited

“The strength of the existing evidence, the availability of patch testing as a research tool for the identification of patients who could have had a hypersensitivity reaction, and widespread acknowledgment that definitive prospective data are required to include HLA-B*5701 screening in the standard of care provide the rationale for our study.”

The justification rests on a belief that the observational data were not definitive. Do you agree?

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From the 9/11/2013 labelhttp://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist

Thank You!