1 / 12

Protocol 004: Part II Design

Raltegravir in antiretroviraler Kombinationstherapie bei therapienaiven HIV-1 infizierten Patienten: 96-Wochen-Daten.

honorato-berger
Download Presentation

Protocol 004: Part II Design

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Raltegravir in antiretroviraler Kombinationstherapie bei therapienaiven HIV-1 infizierten Patienten: 96-Wochen-Daten M. Markowitz1, B.-Y. Nguyen2, E. Gotuzzo3, F. Mendo4, W. Ratanasuwan5, C. Kovacs6, H. Wan2, H. Campbell2, M. Miller2, R. Isaacs2, H. Teppler2, and the Protocol 004 Part II Study Team 1Aaron Diamond AIDS Research Center, New York, NY; 2Merck Research Labs, West Point, PA; 3Hospital Nacionale Cayetano Heredia, Lima, Peru; 4Hospital Nacionale Edgardo Rebagliati, Lima, Peru; 6Maple Leaf Medical Center, Toronto, Canada; 5Siriraj Hospital, Bangkok, Thailand

  2. Protocol 004: Part II Design • Key inclusion criteria • Susceptible to EFV, TDF, 3TC • No prior ART • HIV RNA ≥ 5000 copies/mL; CD4 ≥ 100 cells/mm3 • Hypotheses: Raltegravir (RAL) + TDF/3TC • will be generally well tolerated, with similar antiretroviral activity vs efavirenz + TDF/3TC • Endpoints • HIV RNA, CD4 counts, Adverse experiences • Exploratory: CNS and lipids • Timepoints: 24 wk primary, 48 and 96 wk secondary • 48 week data presented AIDS 2007 • Current presentation is 96 week update • 0-48 wks RAL given at doses of 100, 200, 400 or 600 mg b.i.d. • doses could not be differentiated at 48 wk • After 48 wk, all RAL groups received 400 mg bid • Therefore all RAL data post 48 wk shown as single RAL group (n=160)

  3. Baseline Charakteristika / Patientenstatus ± Defined as history of clinical diagnosis of AIDS at baseline, * With TDF/3TC, **geometric mean † RAL / EFV (# of patients); Lack of efficacy (3/1), AE (3/1), withdrew consent (7/4), Loss-to-follow up (3/0), Other reasons (6/0)

  4. 1 0 0 84% 84% 8 0 6 0 HIV RNA <400 copies/mL Percent of Patients with Using Observed Failure approach: RAL 94% and EFV 91% 4 0 2 0 0 0 4 8 1 6 2 4 3 2 4 0 4 8 6 0 7 2 8 4 9 6 W e e k N u m e r o f C o n t r i b u t i n g P a t i e n t s Protocol 004 – 96 Wochen Prozent Patienten (95% CI) mit HIV-RNA <400 Kopien/ml [Non-Completer=Failure] * b Raltegravir 100 mg b.i.d. 39 39 39 Raltegravir 200 mg b.i.d. 40 40 40 Raltegravir 400 mg b.i.d. 41 41 41 160 160 159 160 Raltegravir 600 mg b.i.d. 40 40 40 Efavirenz 600 mg q.d. 38 37 38 38 38 38 38 m 5 1 8 p 4 r 4 0 0 7 M a n u _ J u l y 1 7 , 2 0 0 8 *After Week 48 patients in all RAL groups continued at 400 mg b.i.d. All patients received TDF/3TC

  5. 83% 84% Protocol 004 – 96 Wochen Prozent Patienten (95% CI) mit HIV-RNA <50 Kopien/ml [Non-Completer=Failure] 1 0 0 * 8 0 6 0 HIV RNA <50 copies/mL Percent of Patients with Using Observed Failure approach: RAL 92% and EFV 91% 4 0 2 0 0 0 4 8 1 6 2 4 3 2 4 0 4 8 6 0 7 2 8 4 9 6 W e e k N u m b e r o f C o n t r i b u t i n g P a t i e n t s Raltegravir 100 mg b.i.d. 39 39 39 Raltegravir 200 mg b.i.d. 40 40 40 Raltegravir 400 mg b.i.d. 41 41 41 160 160 159 160 Raltegravir 600 mg b.i.d. 40 40 40 Efavirenz 600 mg q.d. 38 37 38 38 38 38 38 m 5 1 8 p 4 r 5 0 7 M a n u _ J u l y 1 7 , 2 0 0 8 *Nach Woche 48 erhielten Patienten in allen RAL-Gruppen Raltegravir 400 mg b.i.d. Alle Patienten erhielten TDF/3TC

  6. * 3 0 0 221 2 5 0 232 2 0 0 Change from Baseline in CD4 Cell Count 1 5 0 1 0 0 5 0 0 Copies/mL) - 1 10 Change from Baseline - 2 -2.30 -2.28 in HIV RNA (Log - 3 0 4 8 1 6 2 4 3 2 4 0 4 8 6 0 7 2 8 4 9 6 R a l t e g r a v i r 1 0 0 m g b . i . d . ( n = 3 9 ) R a l t e g r a v i r 4 0 0 m g b . i . d . ( n = 4 1 ) E f a v i r e n z 6 0 0 m g q . d . ( n = 3 8 ) R a l t e g r a v i r 2 0 0 m g b . i . d . ( n = 4 0 ) R a l t e g r a v i r 6 0 0 m g b . i . d . ( n = 4 0 ) m 5 1 8 p 4 C D 4 R N A 3 M a n u J u n e 1 7 , 2 0 0 8 Protocol 004 – 96 WochenVeränderung von Baseline: CD4 und HIV-RNA[Observed Failure Approach] W e e k *After Woche 48 erhielten Patienten in allen RAL-Gruppen Raltegravir 400 mg b.i.d. Alle Patienten erhielten TDF/3TC

  7. Therapie-assoziierte Mutationen Protocol definition of virologic failure: (1) non-response: >400 copies/ml at week 24 or early discontinuation, (2) virologic relapse; >400 copies/ml after initial response of < 400 copies/ml, or >1.0 log10 increase above nadir level. (Percentage of virologic failures in RAL: 6/160 (3.8%), and in EFV: 2/38 (5.3%). *Failure occurred after Week 48, (--- indicates no mutations), †Mutation developed after patient was a virologic failure ‡S230S/N is a common polymorphism that does not affect raltegravir sensitivity in phenotypic assays. All other mutations listed were associated with reduced drug sensitivity. ║All four patients with Non-Response achieved >1.0 log10 decrease in HIV RNA at the nadir.

  8. Protocol 004 – Sicherheit: 96 Wochen • Overall adverse experience (AE) profiles generally similar between RAL and EFV • Drug-related clinical AEs: RAL (51%) vs EFV (74%) • Neuropsychiatric symptoms*: • Most occurred by 48 wks • 13% (RAL) vs 29% (EFV) at wk 48 • 16% (RAL) vs 32% (EFV) at wk 96 • Malignancies†: 1.9% (3/160 pts) for RAL vs. 2.6% (1/38 pts) in EFV • Grade 3 / 4 lab abnormalities uncommon • Neutral effect of RAL on serum lipids †Cases included: 2 pts with Kaposi’s sarcoma, 1 pt with both basal cell carcinoma and squamous cell carcinoma (SC), 1 pt with both gastrointestinal carcinoma and SC #Per investigator *Depression, nightmare, confusional state, suicidal ideation, nervous system disorder, psychotic disorder, abnormal dreams, suicide attempt, acute psychosis, delirium, depressed level of consciousness, hallucination, auditory hallucination, completed suicide, major depression

  9. Häufigste* Arzneimittel-assoziierte Nebenwirkungen (96 Wochen ) RAL taken twice daily; EFV taken once daily; both with TDF/3TC. * Incidence at least 10% in any treatment group; all severity levels included.

  10. Prozent Patienten mit Grade 3 / 4† Laborabweichungen

  11. Effekt auf Lipide (96 weeks) • Total cholesterol, LDL-cholesterol, triglycerides not increased by raltegravir Mean change from baseline (mg/dL) at week 96

  12. P004 Zusammenfassung • Zu Woche 96 hatte RAL einen anhaltenden antiretroviralen Effekt ähnlich wie zu Woche 48 und ähnlich wie EFV (beides mit TDF/3TC) • 83% vs 84% (RAL vs EFV) mit HIV-RNA <50 Kopien/ml • Es wurden keine neuen RAL-Mutationen zu Woche 48 identifiziert • RAL wurde im allgemeinen zu Woche 96 gut vertragen: • Arzneimittel-assoziierte AEs schienen unter RAL vs. EFV geringer zu sein • RAL ist lipidneutral im Hinblick auf Gesamtcholesterin, LDL-Cholesterin und Triglyceride.

More Related