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  49th ICAAC
San Francisco, CA
September 12-15, 2009
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Lab Study Suggests High Barrier to Resistance With New Integrase Inhibitor
  49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy), September 12-15, 2009, San Francisco
Mark Mascolini
S/GSK1349572, an integrase inhibitor being developed by Shinogi and GlaxoSmithKline, did not allow resistant virus to evolve from wild-type (nonmutant) virus in standard serial passage studies [1]. Raltegravir, the only licensed integrase inhibitor, did select resistant virus under the same study conditions. When the experiments began with virus bearing a single integrase mutation, raltegravir often (but not always) selected more mutations than S/GSK1349572, and resistance was always greater with mutations selected by raltegravir.
In an early 10-day monotherapy study of unboosted S/GSK1349572 in integrase inhibitor-naive people with HIV, 7 of 10 study participants taking the highest dose, 50 mg once daily, reached an undetectable viral load [2]. Viral load dropped an average 2.46 log in the 50-mg group.
The resistance study tested S/GSK1349572 and raltegravir against a wild-type laboratory strain of HIV and against viral clones bearing a single mutation involved in resistance to raltegravir. Starting concentrations of the inhibitors were 6.4, 32, and 160 nM. If viral replication could be observed by light microscopy, further passaging was performed at 1-fold and 5-fold higher concentrations of S/GSK1349572 or raltegravir.
At an initial concentration of 32 nM, S/GSK1349572 prevented all viral replication. Replication did occur and resistance mutations emerged at an initial S/GSK1349572 concentration of 6.4 nM, but those mutants could not replicate at a concentration of 160 nM. In contrast, an initial 32-nM concentration of raltegravir allowed viral replication, and mutations conferring 9.2-fold resistance to more than 510-fold resistance arose at higher concentrations.
After 56 days of serial passage at increasing concentrations of S/GSK1349572 and raltegravir, mutations that emerged with S/GSK1349572 conferred substantially less resistance than mutations that emerged with raltegravir:
Wild-type starting virus:
· S/GSK1349572: E92Q, 3.1-fold resistance; G193E, 3.2-fold resistance
· Raltegravir: Q148R, 300-fold resistance; N155H, 14- to 22-fold resistance; F121Y/D232N, 9.2-fold resistance; N155S/D232N, fold change not determined
Q148K mutant starting virus:
· S/GSK1349572: E138K/Q148K, 47- to 190-fold resistance
· Raltegravir: E138K/Q148K, more than 510-fold resistance; more than 510-fold resistance with Q148K alone
Q148R starting virus:
· S/GSK1349572: G140S/Q148R, 16-fold resistance; E138K/G140S/Q148R, 13-fold resistance; G140S/Q148R/V201I, 39-fold resistance
· Raltegravir: G140S/Q148R, more than 510-fold resistance; L74M/G140S/Q148R, fold change not determined; G140S/Q148R/V259I, fold change not determined; 84- to 370-fold resistance with Q148R alone
Q148H starting virus:
· S/GSK1349572: G140S/Q148H, 4.8- to 8.0-fold resistance; T97A/G140S/Q148H, 44-fold resistance; V75I/E138K/G140S/Q148H/M154I, 46-fold resistance
· Raltegravir: G140S/Q148H, more than 150-fold resistance N155H starting virus:
· S/GSK1349572: No additional mutations selected; 2- to 3.9-fold resistance with N155H alone
· Raltegravir: G70R/N155H, fold change not calculated; S119R/N155H, 88- to 180-fold resistance; N155H/G163R/D232N, 38- to 54-fold resistance; P124T/N155H/G163R, 270-fold resistance; 22- to 250-fold resistance with N155H alone
E92Q starting virus:
· S/GSK1349572: No additional mutations selected; 2.9- to 4.1-fold resistance with E92Q alone
· Raltegravir: L74M/E92Q, 21- to 120-fold resistance; 4.8- to 14-fold resistance with E92Q alone
The investigators also determined fold change in susceptibility to four secondary mutations evaluated as site-directed mutants: G140S (added to Q148H), E138K (added to Q148R), G140S (added to Q148R), and E138K (added to Q148K). All four increased resistance to both raltegravir and S/GSK1349572, though fold change in susceptibility to S/GSK1349572 never exceeded 19.
1. Sato A, Seki T, Kobayashi M, et al. In vitro passage of drug resistant HIV-1 against a next generation integrase inhibitor, S/GSK1349572. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract H-932.
2. Lalezari J, Sloan L, Dejesus E, et al. Potent antiviral activity of S/GSK1349572, a next generation integrase inhibitor (INI), in INI-naive HIV-1-infected patients. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract TUAB105.