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48th Annual ICAAC / IDSA 46th Annual Meeting
October 25-28, 2008
Washington, DC
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Substitution of Nevirapine (NVP) for Efavirenz (EFV) Toxicity in ACTG A5095
  Reported by Jules Levin
ICAAC/IDSA Oct 28 2008 Wash DC
Jeffrey Schouten1, Amy Krambrink2, Heather Ribaudo2, Anne Kmack3, Nancy Webb3, Cecilia Shikuma4, Karen Klingman5, Daniel Kuritzkes6, Roy Gulick7, for the A5095 Team.1Univ of WA, Seattle, WA, US; 2Harvard Sch of Pub Hlth, Boston, MA, US; 3Frontier Sci & Technology Res Fndn Inc, Amherst, NY, US; 4Univ of HI, Honolulu, HI, US; 5DAIDS, NIAID/NIH, Bethesda, MD, US, 6Harvard Med Sch, Boston, MA, US; and 7Weill Med Coll, New York, NY, US
70/765 subjects substituted NVP for EFV due to AEs.
8/70 subjects subsequently discontinued NVP due to AEs.
Prior history of psychiatric disorders increased the probability of EFV discontinuation due to CNS symptoms.
Most CNS symptoms resolved with NVP substitution.
Rates of grade 3/4 hepatotoxicitywere higher in subjects substituting NVP vs. subjects continuing EFV (14% vs. 6%).
Most skin symptoms resolved with NVP substitution although some subjects ultimately discontinued NVP.
Virologic suppression 24 weeks post NVP-substitution was 67% (ITT) and 76% (AT).
African-American subjects were underrepresented in the substitution cohort.
Substituting NVP for EFV was generally safe and efficacious in subjects who experienced toxicity attributed to EFV.
Background: The safety and efficacy of substituting NVP for EFV-related adverse events (AEs) is uncertain.
Methods: In ACTG A5095, 765 therapy-na´ve subjects were randomized to receive EFV. Subjects who experienced treatment-limiting AE to EFV could substitute NVP and were followed prospectively.
Results: Overall, 70 subjects (20 female) with median pre-therapy CD4 246 cells/mm3 substituted NVP for EFV due to CNS symptoms (47), rash (18), fatigue (3), elevated hepatic transaminase (1), or hypertriglyceridemia (1). Women who switched due to pregnancy (5) were analyzed separately. Of the substitutions, 78% occurred within 24 weeks of starting therapy. Median CD4 count and HIV RNA at substitution were 323 cells/mm3 and 279 copies/ml (c/ml).
After NVP substitution, 40 of 47 subjects resolved CNS symptoms, 2 had recurrent depression and 3 reported different CNS symptoms. Rash resolved in 15 of 18 subjects; 6 had a recurrence of rash while taking NVP. Fatigue resolved in all 3 subjects. The rate of grade 3/4 HEP was 14% in subjects who switched to NVP, vs. 6% in matched non-switching cohorts. Rates of overall grade 2-4 AEs after substitution were similar by HIV RNA level at the time of substitution (<200 or >200c/ml).
At 24 weeks after the switch, 45 (67%) of 67 subjects with available HIV RNA levels had <50 c/ml. Ultimately 15 subjects discontinued NVP: 8 for AE; 3 for virologic failure; and 4 subject choice.
Conclusions: Substituting NVP for EFV was generally safe and efficacious in subjects who experienced toxicity attributed to EFV.
Study population
-HIV-1-infected subjects with no prior antiretroviral therapy
-HIV-1 RNA >400 copies/ml; any CD4 cell count
-Stratified by pre-therapy HIV-1 RNA: < or >100,000 cp/ml
A5095 was a double-blind, randomized, placebo-controlled study:
-ZDV/3TC/ABC (3-nucleosides) (Arm A)
-ZDV/3TC + EFV (control arm) (Arm B)
-ZDV/3TC/ABC + EFV (4-drug regimen) (Arm C)
Substitution of study drugs permitted for treatment-limiting toxicity (in the opinion of the site investigator):
-d4T for ZDV; ddI for ABC; NVP for EFV
Cox proportional hazards models were used to evaluate the relationship between baseline characteristics and substituting NVP for EFV.
Cause-specific cumulative incidence functions were plotted to show associations between baseline characteristics and specific reasons for substituting , in the presence of other reasons for substituting.
Descriptive analyses were used to examine the resolution and recurrence of targeted events before and after the substitution.
Among subjects who substituted NVP for EFV, virologicefficacy was evaluated at 24 weeks post-NVP substitution.
Bootstrapped case-control analysis -compared rates of hepatotoxicity* among subjects who substituted vscohort of matched randomly selected non-substituting subjects:
-Each of the 70 substitutersrandomly matched to 3 remaining A5095 non-substituters-Matched on baseline CD4, race, gender
-Prevalence and incidence rates of hepatotoxicitywere calculated for subjects who substituted NVP for EFV and for those who did not
-Analysis repeated 1000 times
*AST, ALT, total bilirubin, direct bilirubin, alkaline phosphatase, and/or GGT.
From Jules: I will make note of 2 items in this table: patients who switched due to CNS/neuropsych symptoms had higher percent of HCV+ and higher percent o patients with a history of psychiatric disorder.


* Fatigue (3), elevated hepatic transaminase(1), and hypertriglyceridemia(1). --
-- HepatitisBandCserologieswereonlyrequiredatstudyentryunderVersion2.0; subjectsenteringunderVersion1.0,