Abacavir Hypersensitivity Reaction

1
Abacavir Hypersensitivity Reaction

• Incidence 5
• Most cases within 6 weeks of initiating ABC
  (median 9 d)
• Multi-organ system syndrome, usually with
  symptoms in 2 or more categories
• Fever
• Rash
• GI symptoms (nausea, vomiting, diarrhea,
  abdominal pain)
• Constitutional symptoms (malaise, fatigue,
  achiness)
• Respiratory symptoms (dyspnea, cough, pharyngitis)

2
HLA Haplotype and Abacavir HSR

• Differences in incidence between ethnic groups
  and report of familial predisposition suggested a
  genetic basis
• HLA human leukocyte antigens (major
  histocompatibility antigens)
• Western Australian HIV Cohort Study Odds ratio
  for HSR with HLA B5701 117

Mallal S et al, Lancet 2002359727-32
3
Effect of Genetic Screening on HSR
n 68 n131 n102 n49
Thru 7/05
Rauch A et al, Clin Infect Dis 20064399-102
4
PREDICT-1 Study Design
ABC-containing regimen with HSR monitoring per
standard of care
N 1772 ABC-naïve pts
Exclude if positive test
ABC-containing regimen with prospective
HLA-B5701 screening
Include if negative test
Clinically suspected HSR confirmed by patch
testing. Standard of care arm had retrospective
testing
5
PREDICT-1 Results

• N 1650 evaluable 84 white, 12 black, 18
  antiretroviral naïve
• No skin patch confirmed HSR in screened arm

Mallal S, et al. 4th IAS, 2007, abstr WESS101
6
SHAPE HLA-B5701 screening

• Retrospective case-control study
• Cases Clinically suspected ABC HSR tested for
  HLA-B5701 and skin patch testing
• Controls ABC-tolerant subjects from ABC
  studies, HLA tested

• SPT-positive HSR more likely to have fever,
  constitutional symptoms and gt 3 symptoms than
  SPT-negative patients with HSR

Saag M, et al. 4th IAS, 2007, abstr WEAB305
7
Atazanavir Elimination

• Single 400 mg dose 79 recovered in feces, 13
  in urine
• 7 excreted in urine as unchanged drug (vs. 19
  with indinavir)
• Solubility increases with acidity, similar to
  indinavir
• 3 case reports of nephrolithiasis on ATV/r with
  documented stone analysis published 2006-071-3
• FDA published review of cases4

1Chang HR. N Engl J Med 20063552158-9
2Pacanowski, AIDS 2006202131-2 3Anderson PL et
al, AIDS 2007211060-2 4Chan-Tack KM, AIDS
2007211215-18
8
Atazanavir Nephrolithiasis Spontaneous Case
Reports to the FDA

• 30 cases reported 12/02 - 1/07
• 5 (17) with underlying liver disease (4 HCV, 1
  HBV2 with cirrhosis)
• 5 with h/o nephrolithiasis
• Of 20 with ART information 13 on TDF, 17 on RTV
• Median time on ATV (n 17) 1.7 yrs, range 5
  wks- 6 yrs
• Of 14 with stone analysis 12 with confirmed ATV
• 18 hospitalized, 8 had procedure to remove stone,
  9 d/cd ATV
• Prescribing information temporary
  interruption or discontinuation of therapy may be
  considered

Chan-Tack KM, AIDS 2007211215-18