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Cross-Resistance Between Integrase Inhibitors Looks Likely
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XVI International HIV Drug Resistance Workshop
June 12-16, 2007
Barbados
Mark Mascolini
Independent work by developers of the two leading integrase inhibitors offered evidence that resistance to one drug may well mean resistance to the other. Though neither Merck nor Gilead seemed keen to declare cross-resistance between their promising agents at this early resistance research stage, Gilead's Damian McColl ended his talk at the Resistance Workshop by conceding that "data we have already gives us some pause" in thinking that one of these drugs may be used after the other fails.
Merck's Michael Miller reported that two key mutations make HIV more than 10-fold resistant to raltegravir (MK-0518) in a phase 2 trial he analyzed [1]. When add-on mutations join these two primary mutations, they render HIV highly resistant to raltegravir. And virus with high-level resistance to this drug can also escape other stand-transfer integrase inhibitors, including Gilead's elvitegravir.
Raltegravir got high marks in twin phase 3 trials comparing two doses of the drug with placebo--each with an optimized regimen of other antiretrovirals--in people with virus already resistant to nucleosides, nonnucleosides, and protease inhibitors (PIs) [2,3]. After 16 weeks of follow-up, a noncompleter-equals-failure analysis figured that 79% in the raltegravir arms of the two studies had a viral load under 400 copies, compared with 41% and 43% in the two placebo arms. An even higher proportion, 90%, reached a sub-400 load at week 16 if they combined raltegravir with either darunavir or enfuvirtide (naïve to T20).
At week 24 of a phase 2 study comparing 200, 400, or 600 mg of raltegravir with placebo in treatment-experienced people, Miller reported virologic failure in 38 of 133 people (28.6%) taking raltegravir. Merck researchers managed to sequence virus from 35 of those 38 people and identified two pathways to resistance--one starting with an N155H mutation in 14 people and the other with Q148H/R/K in 20 people. The first lowered viral susceptibility to raltegravir 10-fold and the second 25-fold.
The most common resistance pathway coupled G148H with G140S, and that pairing also yielded the most resistant virus with more than a 100-fold loss of susceptibility to raltegravir. Miller speculated that patterns stemming from G148 mutations may prove more dominant than those branching from N155 because G148 patterns were more common than N155 patterns so far, and because further work showed that G148 mutations can replace N155 mutations as the virus continued to evolve.
Appearance of mutations at these two integrase sites proved less likely among people who started the trial with a viral load below 100,000 copies, people who used enfuvirtide with raltegravir, and people whose virus had a phenotypic sensitivity score above 0 when the study began (meaning they had at least one other active drug to combine with raltegravir).
When L74M, E92Q, and G163R evolved in the wake of N155H, high-level resistance resulted. The same thing happened after E138K and G140S/A evolved with Q148 mutations. Some of these additional mutations improved the replication capacity of the N155 or Q148 mutants, and all of the additional mutations made resistance worse.
Two resistance patterns rendered virus highly resistant to both raltegravir and Gilead's integrase inhibitor, elvitegravir--G140S plus Q148H, and G140S plus Q148R. Other mutation sets also decreased susceptibility to both drugs, but to a lesser degree. Miller suggested these findings do not establish broad cross-resistance between all integrase inhibitors. Just as certain PIs remain active against virus resistant to other PIs, he proposed, structurally diverse integrase inhibitors may differ in their activity against virus with different integrase mutations.
A few clinicians and virologists attending the workshop worried that Merck may have settled too quickly on the 400-mg dose of raltegravir for further development. In trials so far 400 mg worked as well as 600 mg. But attendees wondered whether more study might show that 600 mg get levels of the drug high enough to ward off emergence of some resistant virus. (note from Jules: But I don't think the added 200 mg will make a difference).
Gilead's Damian McColl drew corroborating evidence of integrase inhibitor cross-resistance from a phase 2 trial of ritonavir-boosted elvitegravir (GS-9137) versus boosted PIs in people with heavy treatment experience [4]. Investigators randomized 278 people with one or more PI mutations to a boosted PI plus nucleosides or to one of three elvitegravir doses--20, 50, or 125 mg once daily--plus 100 mg of ritonavir daily and two nucleosides [5]. These people had a median of three thymidine nucleoside analog mutations and 10 PI mutations when the study began.
After 16 weeks time-weighted change from baseline viral load averaged -1.2 log in the PI control arm, -1.5 log in the 50-mg elvitegravir arm (P = 0.09 versus control), and -1.7 log in the 125-mg arm (P = 0.01). A safety panel shut down the 20-mg arm because responses in that group lagged those in others. People who combined 125 mg of elvitegravir with at least one other active drug averaged more than a 100-fold drop in viral load at week 24. Those who had no active drugs to combine with elvitegravir usually endured rebounds.
The Gilead group compared prestudy and on-treatment genotypes of virus from 28 of 30 people who had a virologic failure while taking 125 mg of elvitegravir. E92Q, E138K, Q148R/K/H, or N155H (the last two both key raltegravir mutations) cropped up in 11 of 28 failure samples (39%). Q148R appeared with E138K and S147G in 6 of 28 failure samples (21%) and Q148R/H/K with G140C/S in 3 of 28 samples (11%).
Average susceptibility to elvitegravir fell more than 151-fold (range 1.02- to 301-fold) in virologic failure samples, while average susceptibility to raltegravir dropped more than 28-fold (range 0.78- to more than 256-fold) in those samples. These results suggest that most virus resistant to elvitegravir will have at least moderate resistance to 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. Cooper D, Gatell J, Rockstrok J, et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles. Abstract 105aLB.
3. Steigbigel R, Kumar P, Eron J, et al. Results of BENCHMRK-2, a phase III study
evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles. Abstract 105bLB.
4. 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.
5. Zolopa A, Mullen M, Berger D, et al. The HIV integrase inhibitor GS-9137 demonstrates potent ARV activity in treatment-experienced patients. 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles. Abstract 143LB.
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