 |
|
|
| |
Raltegravir Resistance Pattern Critical in Early Response to S/GSK1349572
|
| |
| |
XVIII International AIDS Conference, July 18-23, 2010, Vienna
Mark Mascolini
Most people with raltegravir-related resistance mutations responded to the investigational integrase inhibitor S/GSK1349572 (572), with no other new antiretrovirals, during the first 11 days of the phase 2b VIKING study [1]; with 3 of 9 patients with virus carrying a Q148 mutation plus one or more other integrase mutations responded to 572 in the trial's first 11 days.
VIKING researchers enrolled 27 antiretroviral-experienced adults with a viral load above 999 copies and with mutations that confer resistance to raltegravir and two or more other antiretroviral classes. Mutation patterns included Q148H/K/R, N155H, and/or Y143H with or without additional mutations. No one enrolled turned out to have a Q148 mutation with no other mutations. Study participants began 572 at a dose of 50 mg once daily without changing other drugs in their regimen, except raltegravir. After 11 days, patients switched the other drugs in their regimen to create an optimized background regimen. This presentation focused on the primary endpoint--virologic response after 11 days of functional 572 monotherapy.
Earlier, VIKING investigators reported that they screened 53 patients and enrolled 27 in the trial [2]. Forty-three of the 53 screened people (81%) had raltegravir-related mutations, including 7 people with N155H, 13 with changes at Y143, 18 with changes at Q148, 2 with a mixture of Q148H and Y143H pathways, and 3 with rarely seen substitutions: T97A, V151I, and E138D plus V151I plus E157Q. Compared with published results of the RAL P005 and BENCHMRK trials, in this screening population proportions of N155H were lower while proportions of Y143C/H/R or Q148H/K/R with two or more other mutations were higher.
In the new report [1], median (and range) fold change in susceptibility to raltegravir on day 0 were 161-fold (0.6 to >166-fold), while fold change in susceptibility to 572 was 1.5-fold (0.5 to 35-fold). Investigator Joseph Eron explained that the study was designed to enroll patients with a range of susceptibilities to 572.
The study group had a median age of 48 years (range 19 to 61), 25 were men, and 2 were women. Median CD4 count was low at 110 (interquartile range 40 to 230), and median viral load stood at 4.47 log (about 30,000 copies). Raltegravir was failing in 21 patients when they enrolled in VIKING, and 6 had a record of raltegravir failure. Antiretroviral duration stood at a median of 14 years (range 4 to 21), and high percentages of participants had tried etravirine (70%), enfuvirtide (81%), darunavir (85%), and maraviroc (37%).
By day 11 of VIKING, 21 of 27 people (78%) had a viral load below 400 copies or at least a 0.7-log (5-fold) decline in viral load in response to 572 monotherapy (the primary endpoint). Only 3 of 9 people who came into the study with a Q148 mutations plus 1 or more other mutations (at L74, E138, or G140) met that primary virologic endpoint. Their viral load dropped by an average 0.72 log. In contrast, all 18 people with other mutation patterns met the primary virologic response endpoint, and their viral load dropped by an average 1.82 log.
In 18 paired isolates collected on study days 1 and 11, no signature raltegravir mutations emerged during functional monotherapy with 572. In 17 of the 18 paired isolates, fold-change in susceptibility to 572 lay below 2-fold. Fold-change in susceptibility stood at about 6-fold in the other isolate. Lower fold-change in susceptibility to 572 at study entry correlated with a greater viral load change from baseline by day 11: r = 0.79, P < 0.001.
Diarrhea and insomnia, each affecting 3 people, were the most frequently reported side effects in VIKING. Three people had grade 3 or 4 clinical adverse events, and 4 people had grade 1 or 2 side effects considered related to study drug (diarrhea and nausea in 1, diarrhea alone in 1, anemia in 1, and fatigue and insomnia in 1). Grade 3 lab toxicities affected 6 people (increases in amylase, total cholesterol, or lipase and a decrease in phosphorus). Two people had serious adverse events (neurosyphilis and brain mass) not considered related to 572.
References
1. Eron J, Durant J, Poizot-Martin I, et al. Activity of a next generation integrase inhibitor (INI), S/GSK1349572, in subjects with HIV exhibiting raltegravir resistance: initial results of VIKING study (ING112961). XVIII International AIDS Conference. July 18-23, 2010. Vienna. Abstract MOAB0105.
2. Clotet B, Katlama C, Lalezari J, et al. HIV integrase resistance profiles and S/ GSK1349572 baseline phenotypic susceptibility for individuals experiencing virological failure on raltegravir and enrolling in the VIKING phase IIb pilot study (ING112961). HIV and Hepatitis Drug Resistance Workshop. June 8-12, 2010. Dubrovnik, Croatia. Abstract 50.
|
| |
|
|
|
|
|
