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Hints on Integrase Inhibitor Cross-Resistance From Two Case Studies
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4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention
July 22-25, 2007
Sydney, Australia
Mark Mascolini
Clinical trial results presented at the 2007 Resistance Workshop suggested physicians can expect cross-resistance between at least the first two integrase inhibitors--Merck's raltegravir (MK-0518) and Gilead's elvitegravir (GS 9137) [1,2]. Two case reports spotlighted at the 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention supported this likelihood [3].
This pilot study involved 2 people with virologic failure while taking elvitegravir [3]. Both had triple-class resistance and a detectable viral load but reached a load below 50 copies 2 weeks after starting elvitegravir/ritonavir with tenofovir/emtricitabine (as Truvada). One patient also took the fusion inhibitor enfuvirtide.
After institutional review board approval and informed consent from the patients, clinicians swapped elvitegravir for raltegravir for 1 week, while continuing the same other drugs in the regimen. The object was to see whether raltegravir could control virus that had probably become resistant to elvitegravir. At week 2 the investigators optimized the background regimen--in each case by adding darunavir/ritonavir.
In both people simply substituting raltegravir for elvitegravir failed to damp down viral replication (Table). After the switch to raltegravir, viral load fell by only 0.29 log copies in the first person and by 0.16 log copies in the second. Adding darunavir pushed the viral load back below 50 copies in one person but not in the other (Table).
The elvitegravir-related mutation N155H evolved upon failure of that integrase inhibitor in the first patient. The same mutation has emerged when raltegravir failed [1]. After elvitegravir failure the second patient had an array of integrase mutations that may confer resistance to both elvitegravir and raltegravir--E138E/K, G140G/C, S147S/G, and Q148R. The Q148R mutation persisted in this person after he switched to raltegravir.
At this point the investigators halted the pilot study because of "lack of significant virologic activity" after substituting raltegravir for elvitegravir. They were not able to measure levels of the antiretrovirals given to test for possible drug-drug interactions. Still, they concluded that their findings "support the possibility that at least some cross-resistance occurs between elvitegravir and raltegravir."
References
1. Miller DJ, Miller MD, Nguyen BY, Zhao J. Resistance to the HIV-integrase inhibitor raltegravir: analysis of protocol 005, a phase II study in patients with triple-class resistant HIV-1 infection. Antiviral Therapy. 2007;12:S10. Abstract 8.
2. McColl DJ, Fransen S, Gupta S, et al. Resistance and cross-resistance to first generation integrase inhibitors: insights from a phase II study of elvitegravir (GS-9137). Antiviral Therapy. 2007;12:S11. Abstract 9.
3. DeJesus E, Cohen C, Elion R, et al. First report of raltegravir (RAL, MK-0518) use after virologic rebound on elvitegravir (EVT, GS 9137). 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract TUPEB032.
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