Cross-Resistance Between Integrase Inhibitors
HIV integrase inhibitors represent a new class of antiretroviral drugs that target a crucial post-transcriptional event in the life cycle of HIV. There is considerable excitement about the potential of this new class of antiretroviral agents to revolutionize the management of both treatment-experienced and treatment-naive patients. A key attribute of integrase inhibitors, when used in treatment-experienced patients, is that their novel mechanism of action means that these agents are not cross-resistant with other antiretroviral classes.
Two agents in the integrase inhibitor class are in the advanced stages of clinical development. Raltegravir (RAL, formerly MK-0518) has already been filed for U.S. Food and Drug Administration approval, and elvitegravir (EVT, formerly GS 9137) is entering phase 3 studies.
Both agents have demonstrated potent activity in patients with significant prior antiretroviral experience and resistance to other classes of agents. In addition, raltegravir has shown durable potency and rapid viral suppression in treatment-naive individuals. It is not known if there will be two chances with these agents -- meaning that one can be used after the other in the event of resistance -- or if cross-resistance across the integrase inhibitor class will limit the chance of success to only one agent within the class. Preliminary reports have suggested that there is some overlap in resistance mutations selected by these agents.
A small cohort study evaluated virologic responses in patients who experienced virologic rebound on elvitegravir + ritonavir (RTV, Norvir) and who then replaced this agent with raltegravir.1 More specifically, patients receiving elvitegravir + ritonavir in the GS-183-0105 phase 2 dose-finding study who experienced virologic failure made a single substitution from elvitegravir + ritonavir to raltegravir 400 mg twice daily for one week without any change to their background regimen.
After day eight, the background regimen was optimized based on patient history and prior resistance testing. Baseline safety data, viral load, CD4+ cell count, HIV-1 RNA, phenotypic and genotypic analysis, viral replication capacity, and samples for integrase inhibitor genotyping were obtained at weeks one, two and four and monthly thereafter until week 24.
Only two patients were included in the current study. No significant viral load reductions were observed in these two patients after the first week of raltegravir substitution. The HIV-1 RNA declines observed after one week of raltegravir therapy were only 0.16 to 0.29 log10 copies/mL, suggesting that cross-resistance between elvitegravir and raltegravir may be to blame.
The initial mutation patterns observed in these patients did not follow the mutation patterns originally described in vitro for elvitegravir (i.e., E92Q or T66I). Interestingly, data collected from the larger GS-183-0105 study indicated that approximately one third of patients with virologic rebound did not follow one of these two main mutation pathways. In some cases, in fact, mutation patterns similar to those reported from studies with raltegravir were observed.
The initial results obtained for the two patients who switched from elvitegravir + ritonavir to raltegravir prompted cessation of the study due to concerns about cross-resistance. Attempts to study a switch to elvitegravir after raltegravir failure have not been reported.
Although further research is needed, it appears that virologic failure with one of the current integrase inhibitors is likely to severely limit subsequent treatment options within that class. On the bright side, several companies, including Merck & Co., Inc., and Ambrilia Biopharma Inc., have reported some success with efforts to design integrase inhibitors with activity against virus resistant to the current generation of these agents.
To hear a summary of this study by its lead author, Edwin DeJesus, M.D., click here.
- DeJesus E, Cohen C, Elion R, et al. First report of raltegravir (RAL, MK-0518) use after virologic rebound on elvitegravir (EVT, GS 9137). In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUPEB032.