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Large Sample Analysis Confirms Impact of Known Rilpivirine Mutations
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51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-20, 2011, Chicago
Mark Mascolini
Matched genotyping and phenotyping of more than 8500 patient viral samples in the Monogram commercial database confirmed that most mutations identified earlier as rilpivirine resistance mutations do, individually, reduce viral susceptibility to this newest nonnucleoside [1]. The K103N mutation, which confers resistance to efavirenz and nevirapine but not to etravirine, did not appear to make HIV resistant to rilpivirine.
The FDA licensed rilpivirine (TMC278, Edurant) for once-daily treatment of antiretroviral-naive adults and approved a fixed-dose formulation that combines 25 mg of rilpivirine with tenofovir and emtricitabine (300/200 mg) [2]. Clinical trial data noted by the FDA indicate that rilpivirine (1) does not control HIV as well in people beginning treatment with a viral load above 100,000 copies as in those starting with a lower viral load and (2) appears to have a lower barrier to resistance than efavirenz [2].
Workers from Monogram Biosciences and Tibotec, rilpivirine's maker, planned this study of more than 8500 clinical specimens that got both genotyped and phenotyped and had no mutations associated with resistance to protease inhibitors or nucleosides. Researchers looked for four sets of rilpivirine-related mutations (K101E/P, E138G/K/Q/R, Y181C/I/V, and H221Y), as well as for K103N. They weighed the impact of individual mutations, excluding viral samples that carried two or more mutations.
The Monogram-Tibotec team measured viral susceptibility to rilpivirine as fold change (FC) in 50% inhibitory concentration over or under the biological cutoff (BCO) for rilpivirine, which has been set at 2.0. A virus with a FC below the 2.0 cutoff is considered susceptible to rilpivirine, and a virus above the cutoff is considered resistant. The investigators calculated odds ratios (ORs) as the ratio of the percent FC at or above the BCO with a certain mutation to the percent FC below the BCO with that mutation.
Median FC, OR, and percent with a FC at or above the BCO for mutations at positions E138, K101, H221, and Y181 indicated that all of these mutations except H221Y have a high probability of conferring resistance to rilpivirine:
-- E138G: FC 2.25, OR 50, 33.5% at or above BCO
-- E138K: FC 1.65, OR 22.38, 40% at or above BCO
-- E138Q: FC 3.04, OR 100.78, 75% at or above BCO
-- K101E: FC 1.68, OR 22.34, 40% at or above BCO
-- K101P: FC 25.5, percent 100% at or above BCO
-- H221Y: FC 1.05, OR 5.17, 13% FC at or above BCO
-- Y181C/I/V: FC 3.82, OR 114.25, 77% FC at or above BCO
There were only 3 patient viral samples carrying Y181I or Y181V, and the researchers calculated that FC for all those samples was above 10. The investigators did not have enough samples to analyze the impact of the four mutations considered possible rilpivirine resistance mutations: E138R, V179L, F227C, and M230I.
Fold-change resistance with K103N was 0.96, and only 7.5% of these samples had a FC at or above the BCO.
Attendees noted that these findings must be interpreted cautiously because the investigators evaluated the impact of mutations one at a time. In clinical practice, however, one resistance mutation may often arise with another and together they may confer a higher level of resistance.
IAS-USA resistance experts list K101P as a major resistance mutation for all three of the other nonnucleosides and K101E as a major etravirine mutation [3]. They list Y181C/I as major mutations for the three other nonnucleosides and Y181V as a major etravirine mutation. Mutations at E138 and H221 are not major mutations for the other nonnucleosides, although E138 substitutions do reduce susceptibility to etravirine, according to IAS-USA.
The Monogram and Tibotec researchers concluded that all established rilpivirine mutations except H221Y are strongly associated with decreased susceptibility to rilpivirine at odds ratios above 20 and with at least 40% of samples associated with a fold change in susceptibility above the biologic cutoff for rilpivirine.
References
1. Napolitano LA, Paquet AC, Petropoulos C, et al. Impact of genotypic mutations on phenotypic susceptibility to rilpivirine. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract H1-371.
2. aidinfo.nih.gov. Rilpivirine. http://www.aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=426.
3. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: December 2010. Top HIV Med. 2010;18:156-163. http://www.iasusa.org/pub/topics/2010/issue5/156.pdf.
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