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Potent Antiretroviral Effect of MK-0518,
a Novel HIV-1 Integrase Inhibitor, in Patients with Triple-class Resistant Virus: 24 Week Data
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Reported by Jules Levin
ICAAC
San Francisco, Sept 27-30, 2006
1Grinsztejn, B.; 2Nguyen, B-Y.; 3Katlama, C.; 4Gatell, J.; 5Lazzarin, A.; 6Vittecoq, D.; 7Gonzalez, C.; 2Chen, J.; 2Harvey, C.; 2Isaacs, R.; Protocol 005 Team
1Evandro Chagas Clinical Research Institute/ Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; 2Merck Research Laboratories, P.A., USA; 3Hosp. Pitie Salpetriere, Paris, France; 4 Univ. of Barcelona, Spain; 5 San Raffaele Sci. Inst., Milan, Italy; 6Hosp. Paul Brousse, Villejuif, France; 7New York Univ. School of Medicine, New York, New York
There were 178 patients in this study randomized to placebo or 1 of 3 MK-0518 dose groups. All patients were highly HIV drug experienced and received optimized treatment background therapy (OBT). Patients had on average 9 years of prior ART experience and resistance in all 3 HIV drug classes. Average baseline CD4 count was 220. When looking at the graphs below you'll notice by 2 weeks there was a deep viral load reduction of a potent 2 logs, which was maintained through 24 weeks. Patients who were naïve to Fuzeon had a significant benefit from Fuzeon use, as you can see in the table below. The safety and side effect profile looked good.
-- 77-80% of the study patients achieved >1 log reduction in viral load
-- 70-73% achieved <400 copies/ml viral load
-- 57-67% achieved <50 copies/ml viral load
-- for the 50 patients with no active ART in OBT the percent achieving <50 copies/ml viral load at week 24 was 54% in the 200mg dose group (n=13), 69% in the 400mg dose group (n=13), and 62% in the 600 mg dose group (n=13), and 0 in the OBT without MK-0518 group (n=11).
BACKGROUND
MK-0518:
A Novel HIV-1 Integrase Inhibitor
A new mechanism of action
-- Potent in vitro activity
-- IC95 = 33 nM ± 23 nM in 50% human serum
Active against:
-- multi-drug resistant HIV-1
-- CCR5 and CXCR4 HIV-1
-- HIV resistant to MK-0518 remain sensitive to other ARTs
-- Synergistic in vitro with all ARTs
-- Potent activity in combination therapy
in ART-naive patients at Week 24 (Markowitz et al, IAC 2006, Abst THLB0214)
85 - 95% with HIV RNA < 50 copies/mL
In patients failing therapy with triple class resistant virus at Week 16 (Grinsztejn et al, CROI 2006, Abst 159LB) 56 - 72% with HIV RNA < 50 copies/mL
STUDY DESIGN
Randomized, double-blind:
-- 200, or 400, or 600 mg MK-0518 b.i.d. p.o. vs Placebo
-- All in combination with optimized background therapy (OBT)
Baseline stratification
-- Use of enfuvirtide (T-20) in OBT
-- Resistant to 1 PI or > 1 PI at entry
To evaluate potential atazanavir (UGT1A1 inhibitor) effect
-- Sub-study A (non-ATV containing OBT) (hypothesis testing)
-- Sub-study B (ATV containing OBT)
-- Similar treatment effect observed across Sub-Study A and B, Data presented are combined from 2 sub-studies
Key Inclusion Criteria
-- Documented genotypic/phenotypic resistance to ≥ 1 drug in each of 3 classes (NNRTI + NRTI + PI)
--HIV RNA > 5000 copies/mL and CD4 > 50 cells/mm3
Endpoints at Week 24
-- HIV RNA and CD4 counts
-- Adverse experiences
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