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Key Etravirine Mutations Also Render HIV Resistant to Rilpivirine
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Mark Mascolini
XVIII International Drug Resistance Workshop, June 9-13, 2009, Fort Myers, Florida
Site-directed mutants bearing the mutation K101P, Y181I, or Y181V made virus in-vitro resistant both to etravirine, the most recently licensed nonnucleoside, and to rilpivirine (TMC278), an experimental nonnucleoside in phase 3 trials [1]. (From Jules: in a cross-resistance analysis in vitro, see graph, 25% of samples resistant to TMC278 were sensitive to etravirine and 25% of samples resistant to etravirine were sensitive to TMC278, and 28% of samples were cross-resistant to both TMC278 & etravirine). The IAS-USA lists these three substitutions as etravirine mutations but notes that single mutations generally do not render virus completely resistant to etravirine [2]. The new study suggests that most single mutations--including K103N and Y181C--may not compromise response to rilpivirine: the study authors said the mutant virus was susceptible to TMC278.
Laurence Rimsky and Tibotec colleagues selected resistant mutants in classic in vitro passage studies, then generated site-directed mutants and recombinant clinical isolates to further test susceptibility to rilpivirine, etravirine, efavirenz, and nevirapine. To rate viral susceptibility to these nonnucleosides, the Tibotec researchers used Antivirogram biological cutoffs of 3.3 for efavirenz, 3.2 for etravirine, and 6.0 for nevirapine, and a preliminary cutoff of 3.7 for rilpivirine.
Tested against a standard lab strain of HIV-1, rilpivirine had a 50% effective concentration 2.4-fold lower than that of efavirenz, 3.7-fold lower than that of etravirine, and 46.7-fold lower than that of nevirapine. Although Tibotec is developing rilpivirine primarily as a first-line nonnucleoside [3,4], if its activity against resistant virus differs from that of etravirine, it could prove useful for certain patients in whom an earlier nonnucleoside failed.
Analyzing 4786 recombinant clinical isolates resistant to efavirenz and/or nevirapine, Rimsky found 2984 of them (62.2%) susceptible to rilpivirine and 2977 (62.3%) susceptible to etravirine. Among 1802 of these recombinant isolates resistant to etravirine, 445 (25%) remained susceptible to rilpivirine.
In serial passage studies, HIV did not escape rilpivirine control at concentrations that made virus lose susceptibility to efavirenz and nevirapine. L100I, K101E, V106I, Y181I, Y181C, M230I, and other classic nonnucleoside mutations (excluding K103N) emerged in these experiments.
Among 22 single-mutation site-directed mutants, 19 were susceptible to rilpivirine. The exceptions were K101P, Y181I, and Y181V, which had decreased sensitivity to rilpivirine and etravirine at the following fold-changes in 50% effective concentration:
· K101P: 46.5-fold resistance to rilpivirine, 5.6-fold resistance to etravirine
· Y181I: 14.3-fold resistance to rilpivirine, 11.5-fold resistance to etravirine
· Y181V: 12.6-fold resistance to rilpivirine, 17.4-fold resistance to etravirine
These mutations represented fewer than 2% of nonnucleoside-resistant samples in a Tibotec study of more than 100,000 isolates submitted to Virco [5]. A site-directed mutant carrying only K103N remained susceptible to rilpivirine (0.8-fold change), as did a mutant bearing only Y181C (2.6-fold change).
As with the single K101P mutation, a few double and triple mutation combinations made HIV more resistant to rilpivirine than to etravirine:
· K100I + K103N: 6.0-fold resistance to rilpivirine, 3.8-fold resistance to etravirine
· K103N + Y181C: 95.2-fold resistance to rilpivirine, 16.8-fold resistance to etravirine
· Y181C + Y188L: 30.9-fold resistance to rilpivirine, 6.4-fold resistance to etravirine
· L100I + K103N + V179L: 51-fold resistance to rilpivirine, 14.6-fold resistance to etravirine
· K101P + K103N + V108I: 180.3-fold resistance to rilpivirine, 18.4-fold resistance to etravirine
Another handful of double or triple mutants were more resistant to etravirine than to rilpivirine. Five double mutants remained susceptible to rilpivirine, according to the preliminary cutoff used in this study: K101E + K103N, K103N + F227L, K103N + V108I, K103N + Y181C, and V197I + Y181C.
Antiviral activity and selection rates of rilpivirine-resistant strains did not differ from one HIV-1 subtype to the next.
The Tibotec researchers suggested these results show rilpivirine has a higher in vitro genetic barrier to resistance and "a more robust resistance profile" than efavirenz or nevirapine. In a phase 2b trial of rilpivirine versus efavirenz in previously untreated people, the two nonnucleosides produced equivalent virologic response rates through 96 weeks [4].
References
1. Rimsky LT, Azijn H, Tirry I, et al. In vitro resistance profile of TMC278, a next-generation NNRTI; evidence of a higher genetic barrier and a more robust resistance profile than first generation NNRTIs. XVIII International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 120.
2. Johnson VA, Brun-Vezinet F, Clotet B et al. Update of the drug resistance mutations in HIV-1: spring 2008. Top HIV Med. 2008;16:62-68.
3. Goebel F, Yakovlev A, Pozniak AL, et al. Short-term antiviral activity of TMC278--a novel NNRTI--in treatment-naive HIV-1-infected subjects. AIDS. 2006;20:1721-1726.
4. Santoscoy M, Cahn P, Gonsalez C, et al. TMC278 (rilpivirine), a next-generation NNRTI, demonstrates long-term efficacy and tolerability in ARV-naive patients: 96-week results of study C204. XVII International AIDS Conference. August 3-8, 2008. Mexico City. Abstract TUAB0103.
5. Tambuyzer L, Azijn H, Rimsky LT, et al. Compilation and prevalence of mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors. Antivir Ther. 2009;14:103-109.
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