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Section 2
Select presentations related to new ART
Defining the Upper and Lower Phenotypic Clinical Cut-offs for Darunavir/Ritonavir by the PhenoSense Assay
Poster# 610, Coakley E
The POWER 1, 2, and 3 trials demonstrated high efficacy of darunavir/ritonavir (DRV/r) in treatment-experienced patients. Four-week RNA outcomes were evaluated to define upper and lower efficacy cutoffs for DRV/r levels using the PhenoSense HIV test by Monogram Biosciences. Patients taking enfuvirtide (T-20, Fuzeon) were eliminated from the dataset. Eighty-seven patients had no active antiretroviral agents in their background therapy and so were on functional monotherapy with DRV/r. The lower clinical cut-off was defined as the fold change where the HIV RNA response was first observed to decline relative to the wild type reference population. The upper clinical cut-off was defined as the fold change above which the HIV RNA change from baseline was less than -0.3 log10 copies/mL. The week 4 HIV RNA reductions from baseline were analyzed to come up with the lower DRV phenotypic clinical cut-off of 10 fold. Additional analyses were performed using 2-week and 8-week data and generated consistent results. A gradual reduction in HIV RNA response was seen as the fold change increased above 10; the upper clinical cut-off for DRV was defined as a fold change of 90.
Efficacy and Safety of Maraviroc plus Optimized Background Therapy in Viremic ART-experienced Patients Infected with CCR5-tropic HIV-1
Oral presentations# 104aLB, Nelson, M, and # 104bLB, Lalezari J
24-Week Results of a Phase 2b/3 Study in (a) Europe, Australia, and USA and (b) in the US and Canada: 24-week results. These abstracts presented results of a planned 24-week interim analysis. Patients with triple-class ARV experience, only R5-tropic virus, and VL over 5000 were randomized to receive placebo or Maraviroc (MVC) 300 mg once or twice daily plus optimized background therapy (OBT) consisting t of 3 to 6 antiretroviral drugs with or without low -dose ritonavir. Dose adjustments were made when optimized background regimens (OBR) included a PI other than tipranavir and/or delavirdine. The primary endpoint was mean reduction in HIV-1 RNA from baseline to week 24. Motivate 1 in the US and Canada included 585 patients who received at least one dose of study drug. Motivate 2 in Europe, Australia, and the US included 464 patients who received at least one dose of study drug. Viral load and CD4 Results for patients taking MVC were significantly better than for those on placebo in both of these studies. The treatment difference compared to placebo exceeded 1 log of VL reduction, with slightly better results in the US and Canada. The % of patients achieving <50 VL exceeded 40% and the mean change in CD4 cells from baseline exceeded 100 across all of the MVC-containing arms. Maraviroc was generally well-tolerated, with no substantial difference in adverse events as compared to the placebo control arm.
Results of BENCHMRK-1 & 2, Phase III Studies Evaluating the Efficacy and Safety of MK-0518, a Novel HIV-1 Integrase Inhibitor, in Patients with Triple-class Resistant Virus
Oral presentations 105aLB Cooper D & 105bLB, Steigbigel R
BENCHMRK 1 was conducted in Europe, Asia, the Pacific, and Peru. BENCHMRK-2 was conducted in North, Central and South America. These results are from a planned 16-week interim analysis of data from a 2:1 randomization of patients to MK-0518 400 mg bid vs placebo. This new compound, now called raltegravir, blocks the integration of the virus into host cell DNA. The Benchmrk 1 and 2 studies respectively enrolled 350 and 349 patients with triple-class drug failure defined as genotypic/phenotypic resistance to 1 or more drugs in each of the 3 classes and HIV RNA viral load of more than 1000 copies/mL. Background therapy was optimized. Combined interim analysis of the 2 studies found that 79% of patients receiving raltegravir plus optimized background therapy (OBT) suppressed the virus below 400 copies/mL at week 16 compared with 43% of those receiving placebo plus OBT. There was no significant difference in CD4+ cell increases between the placebo and treatment arms.
RELATED ARTICLES:
- Fatkenheuer G, Pozniak AL, Johnson MA, et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med 2005; 11: 1170-2. Epub 2005 Oct 5.
- Westby M , Smith-Burchnell C, Mori J, Lewis M, et al Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry.
- Hazuda DJ, Felock P, Witmer M, et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science. 2000;287(5453):646-650.
- Hazuda DJ, Young SD, Guare JP, et al. Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques. Science. 2004;305(5683):528-532.
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