icon- folder.gif   Conference Reports for NATAP  
 
  4th IAS (Intl AIDS Society) Conference on HIV Pathogenesis, Treatment and Prevention
Sydney, Australia
22-25 July 2007
Back grey_arrow_rt.gif
 
 
 
Randomized Trials Results Back Gene Screening for Abacavir Reaction: PREDICT 1 and SHAPE Studies
 
 
  4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention
July 22-25, 2007
Sydney, Australia
 
Mark Mascolini
 
PREDICT-1, a randomized, double-blind trial, determined that screening for the genetic marker HLA-B*5701 reliably prevents hypersensitivity reactions to abacavir [1]. Principal investigator Simon Mallal argued that the findings should sweep aside any lingering doubts about making this gene test a routine part of HIV care. A separate study found that HLA-B*5701 screening works as well in blacks as in whites [2].
 
For PREDICT-1 an international team recruited 1956 abacavir-naive people and randomized them to start an abacavir regimen under the standard of care--clinically diagnosed hypersensitivity--or to start abacavir with the standard of care plus HLA-B*5701 screening. In the second group anyone with a positive B*5701 test got excluded, while those with a negative test continued.
 
The trial had two primary endpoints: (1) incidence of clinically suspected hypersensitivity during 6 weeks of observation and (2) incidence of hypersensitivity immunologically confirmed with skin patch testing during 6 weeks of observation. Of the first 100 abacavir-tolerant people through week 6, none had a positive patch test. That meant the specificity of patch testing in spotting the reaction came to 100%.
 
For the primary endpoints Mallal analyzed 1650 people--everyone randomized who started abacavir and either completed the 6-week observation or stopped abacavir early because of diagnosed hypersensitivity. About three quarters of this group were men, 84% were white, and 12% were African in heritage. About 20% started the trial with no antiretroviral experience.
 
None of 802 gene-screened people had patch-test-confirmed hypersensitivity, compared with 27 of 842 people (2.7%) who did not have B*5701 screening. That meant screening lowered the risk of an immunologically confirmed reaction 97% (P < 0.0001). While only 27 of 803 people (3.4%) in the B*5701-screened group had a clinically suspected reaction, 66 of 847 (7.8%) in the control group had clinically suspected hypersensitivity. That meant screening cut the risk of a clinically suspected reaction 60% (P < 0.0001). For immunologically confirmed hypersensitivity, B*5701 had a negative predictive value of 100%. And for clinically suspected hypersensitivity, the gene test had a negative predictive value of 96%.
 
Mallal concluded with two recommendations:
 
- Where validated B*5701 screening is available, clinicians should consider screening any HIV-infected person who has not taken abacavir and for whom an abacavir regimen is being considered.
 
- Where validated B*5701 screening is not available, it is reasonable to begin abacavir with appropriate clinical vigilance.
 
A separate study by the same group determined that gene screening is 100% sensitive for HLA-B*5701 in both whites and blacks [2]. Sensitivity in identifying HLA-B*5701 fell when physicians relied on clinical signals alone to diagnose abacavir hypersensitivity. The Australian team cautioned that "HLA-B*5701 screening may augment clinical management of hypersensitivity but must never substitute for clinical vigilance."
 
References
1. Mallal S, Phillips E, Carosi G, et al. PREDICT-1: a novel randomised prospective study to determine the clinical utility of HLA-B*5701 screening to reduce abacavir hypersensitivity in HIV-1 infected subjects (study CNA106030). 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract WESS101.
 
2. Saag M, Balu R, Brachman P, et al. High sensitivity of HLA-B*5701 in whites and blacks in immunologically-confirmed cases of abacavir hypersensitivity. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract WEAB305.
 
PREDICT-1: a novel randomised prospective study to determine the clinical utility of HLA-B*5701 screening to reduce abacavir hypersensitivity in HIV-1 infected subjects (study CNA106030)
 
Reported by Jules Levin
4th IAS Conference, 22-25 July, Sydney, Australia
 
Mallal S, Phillips E, Carosi G, Molina J-M, Workman C, Toma_ic J, JŠgel-Guedes E, Rugina S, Kozyrev O, Flores Cid J, Hay P, Nolan D, Hughes S, Hughes A, Thorborn D & Benbow A on behalf of the PREDICT-1 study team.
 
Wednesday 25th July 2007
 
Presenter Recommendations
--In clinical settings where validated screening methods are available, clinicians should consider screening for HLA-B*5701 in any HIV-infected patient who has not previously been exposed to ABC and for whom ABC therapy may be considered
--Where screening is not readily available, it is reasonable to initiate ABC with appropriate clinical vigilance
 
Clinical vigilance remains the cornerstone of successful ABC risk management
 
Eligibility Criteria

Key inclusion criteria:
--Naive to ABC
--Pre-study need for ABC treatment
 
Key exclusion criteria:
--Contraindications to ABC
--Known HLA-B*5701 status
 
Double-Blind Study Design
Abacavir-naive subjects randomized to:
--ABC-containing regimen, HSR monitoring according to Standard of Care (control arm), or
--ABC-containing regimen, HSR monitoring according to Standard of Care plus HLA-B*5701 screening (screening arm): HLA-B*5701 positive subjects were excluded; HLA-B*5701 negative subjects continued.
 

wekob-1.gif

1. retrospective high resolution typing
2. prospective high resolution typing
 
Co-Primary Endpoints
Incidence of clinically-suspected ABC HSR during the 6-week observation period --90% power to detect >50% reduction in HSR rate from 7.3 to 3.6%
 
Incidence of immunologically-confirmed (clinical diagnosis plus positive skin patch testing1) ABC HSR during the 6-week observation period
--99% power to detect 80% reduction in HSR rate from 4.6 to 0.91%
1 Assessment by a central independent clinical evaluation committee
 

blind-2.gif

--Immune cell-mediated reaction
--Research tool used to identify patients with immune-mediated abacavir HSR
 

test-3.gif

with-4.gif

Specificity: 100/100 = 100% 95% CI (96.4%, 100%)
Note: all ABC tolerant subjects patch-tested were HLA-B*5701 negative
- The first 100 ABC-tolerant patients through week 6
 
Analysis Populations
 
-- ITT (n=1956) - number of subjects randomised
-- ITT exposed (n=1772) - number of subjects with at least one dose of ABC-containing medication
 
PRIMARY POPULATION FOR ANALYSIS
ITT evaluable (n=1650)
- all randomised patients who started abacavir and either completed the six-week observation period or stopped ABC early due to HSR
 

deomocn-5.gif

odds-6.gif

ScrImp-7.gif

Test 100 subjects:
--Treat 94 subjects at low risk for ABC HSR
--Prevent 4 ABC HSR events
--Inappropriately exclude ABC in 2 subjects
--Open screening may also reduce clinical overdiagnosis of HSR
 
Example shown is based upon PPV calculated from PREDICT-1
 

Results-8.gif