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Raltegravir 48-week Naives potent; No Lipids Elevations
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Reported by Jules Levin
9th IAS Conference, July 22-25, 2007, Sydney, Australia
Today's oral session was a major presentation at IAS Sydney. There were a number of important studies presented: the 48-week raltegravir in naives data was presented showing no lipid elevations, good side effects profile, and potent activity (83-88% <50 copies/ml, 90% <400 c/ml); Incyte presented potent activity from 14 days monotherapy with their CCR5 inhibitor (1.8 log reduction); TMC278 in naives showed a favorable lipids profile; the TITAN study compared kaletra and TMC114 in an earlier than salvage patient situation; and we saw 48-week data from the CCR5 drug vicriviroc ACTG study 5211.
Rapid Onset and Durable Antiretroviral Effect of Raltegravir, a Novel HIV-1 Integrase Inhibitor, as Part of Combination ART in Treatment-Naive HIV-1 Infected Patients:
48-Week Results
M. Markowitz1, B.-Y. Nguyen2, E. Gotuzzo3, F. Mendo4, W. Ratanasuwan5, C. Kovacs6, H. Wan2, L. Gilde2, 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
AUTHOR SAFETY/EFFICACY SUMMARY
Overall AE profiles were generally similar across treatment groups
--No dose-related toxicities
--Drug-related clinical AEs less common with raltegravir (48%) than EFV (71%); no drug-related serious AEs
--Neuropsychiatric symptoms* less common with raltegravir than EFV:
8% vs 21% at wk 8
13% vs 29% at wk 48
--Grade 3 / 4 lab abnormalities uncommon
-- Neutral effect of raltegravir on serum lipids
Raltegravir is a promising new HIV integrase inhibitor with rapid and durable antiretroviral effect
In treatment naive patients with HIV RNA ≥ 5000 copies/ml and CD4 ≥ 100/mm3,
raltegravir at all doses studied for 48 weeks:
-- had potent antiretroviral activity
83-88% with HIV RNA < 50 copies/mL
achieved viral suppression faster than EFV
was generally well tolerated
Raltegravir (MK-0518): HIV Integrase Strand-Transfer Inhibitor
--HIV integrase inhibition: a novel mechanism of action
--Raltegravir: potent in vitro activity
--IC95 = 31 nM ± 20 nM in 50% human serum
--Metabolism primarily via glucuronidation (UGT1A1)
--Not a potent inhibitor or inducer of CYP3A4
--Does not require "ritonavir boosting"
In Phase I studies,
--Doses up to 800 mg p.o. BID were generally well tolerated
--At 100 mg BID, mean C12hr > mean IC95
No dose adjustment when used with other ARTs
Protocol 004: Study design
This is a phase II study where 8 patients each were randomized to 5 different dosing schemes for a brief monotherapy in Part I and then 30 patients were given 4 different raltegravir doses + TDF/3TC or efavirenz + TDF/3TC in Part II.
Protocol 004: Part II Design
--Part I patients continued at same dose in Part II (pbo_efv)
--About 150 additional patients randomized for Part II
Key inclusion criteria
--Susceptible to EFV, 3TC , TFV (by genotype)
--No prior ART (<7 days allowed)
-- HIV RNA ≥ 5000 copies/mL
baseline stratification for HIV RNA ² or > 50,000 copies/mL
--CD4 ≥ 100 cells/mm3
Endpoints
HIV-1 RNA and CD4 counts, Adverse experiences
Hypotheses: Raltegravir + TFV/3TC
--will be generally safe and well tolerated
--will have antiretroviral activity similar to EFV + TFV/3TC
Patient Baseline Characteristics
65% were non-white; HIV RNA: mean 43,000-65,000; CD4: 300; % with AIDS: 30%
Patient Status at Week 48
About 200 patients in study
Discontinued by week 48: 5% in 400mg raltergavir arm, 8% in EFV arm. 0 withdrew for lack of efficacy in both arms.
HIV RNA <400 Copies/mL (95% CI) (Primary Endpoint)
[Non-Completer=Failure]
Appears to be 90%+ <400 in raltegravir arm.
HIV RNA <50 Copies/mL (95% CI)
[Non-Completer=Failure]
83-88% <50 c/ml in raltegravir arm.
Virologic Failure
Definitions: 2 measurements of HIV-1 RNA at least 1 week apart
Non-response:
-- >400 copies/mL at week 24 or early discontinuation, or
Virologic relapse:
-- >400 copies/mL after initial response to <400 copies/mL, or
-- >1.0 log10 increase above nadir level.
Resistance testing in all patients with virologic failure; performed at time of failure, compared with baseline
--5 of 160 (3%) in RAL group
--1 of 38 (3%) in EFV group
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