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Early Hints on Potency and Cross-Resistance With New NNRTI
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XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
IDX899, an investigational nonnucleoside (NNRTI) from Idenix, controlled HIV in antiretroviral-naive people in a 7-day single-center monotherapy trial [1]. Lab studies showed emergence of a few familiar NNRTI resistance mutations with the new drug, but perhaps a favorable cross-resistance profile compared with other drugs in this class [2].
Argentine and US clinicians recruited 28 antiretroviral-naive people with a viral load of at least 5000 copies and at least 200 CD4 cells, then randomized them to take 800, 400, or 200 mg of IDX899 daily or placebo and no other antiretrovirals. CD4 counts averaged 654 in the placebo group and from 437 to 490 in the three IDX899 groups. Despite randomization, all 8 people in the 800-mg group had subtype B HIV-1 and all 8 in the 400-mg group had B/F recombinant strains. Quirks like these suggest the limitations of small single-site studies.
After 7 days viral loads fell about 1.8 log in all three IDX899 groups while remaining static with placebo. CD4 changes were highly variable in every group but rose an average 60 cells in all three IDX899 arms while falling a remarkable 80 cells on average over 1 week in the placebo group. Higher doses did not correlate with better virologic responses in this study [Rob Murphy, the presenter said, this was "likely due to drug trough levels being well above the EC90 of IDX89 against wild-type viruses"]. Idenix plans to test 100 mg daily next.
Side effect rates did not differ between people taking IDX899 and those downing placebo. No central nervous system toxicities arose in this brief trial, and no rash. No one quit the study because of side effects, and no one had dose-limiting toxicities or grade 3 or 4 lab abnormalities.
The same investigators performed serial passage studies with IDX899 and cross-resistance comparisons with efavirenz, etravirine (TMC125), and rilpivirine (TMC278, being studied for first-line therapy) [2]. IDX899 required more passages than efavirenz before resistance mutations arose, a finding suggesting a higher barrier to resistance with IDX899.
IDX899 evoke eight mutations: V90I, E138K, Y181C/I, S134I, I135R, G190E, and M230L. Cross-resistance between IDX899-resistant virus and other NNRTIs was more limited than cross-resistance between efavirenz- or etravirine-resistant virus and other NNRTIs, the researchers reported in a meeting abstract, [see the entire data reported in the 2 posters and oral slide presentation on the NATAP website, links provided in this email]. According to the much-thumped IAS-USA bible of antiretroviral-related mutations, some of the IDX899-evoked mutations make HIV resistant to nevirapine, efavirenz, or etravirine [3], and Tibotec serial passage study found one overlapping mutation for rilpivirine [4]:
· Nevirapine: Y181C/I
· Efavirenz: Y181C/I
· Etravirine: V90I, Y181C/I
· Rilpivirine: Y181C
The first three of these NNRTIs may evoke the G190S or G190A mutations; G190E appears to be unique to IDX899. Of course resistance patterns in humans may vary from those that pop up in serial passage studies.
References
1. Murphy R, Zala C, Zhou XJ, et al. Antiviral activity, safety and pharmacokinetics of IDX899, a novel HIV-1 non-nucleoside reverse transcriptase inhibitor with high barrier to resistance, in treatment-naive HIV-1-infected patients. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 25.
2. Murphy R, Zala C, Jakubik JJ, et al. In vitro cross-resistance profile, antiviral activity, safety and pharmacokinetics in HIV-1 infected patients of IDX899, a novel HIV-1 NNRTI with high barrier to resistance. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 5.
3. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1. 2007. Topics HIV Med. 2007;15:119-125.
4. de Bethune MP, Andries K, Azijn H, et al. TMC278, a new potent NNRTI, with an increased barrier to resistance and favourable pharmacokinetic profile. 12th Conference on Retroviruses and Opportunistic Infections. February 22-25, 2005. Boston. Poster 556.
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