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  10th International Congress on Drug Therapy in HIV Infection
November 7-11, 2010
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New Nonnucleoside Retains Activity Against Some Virus Resistant to Etravirine
  Tenth International Congress on Drug Therapy in HIV Infection, November 7-11, 2010, Glasgow
Mark Mascolini
10th Congress Drug Therapy HIV: Lersivirine: a new NNRTI active across HIV-1 subtypes with a unique resistance profile (activity vs etravirine resistance) - (11/17/10)
ICAAC 2010: GSK New NNRTI Selects No Resistance Mutations in 7 Days of Monotherapy - Written by Mark Mascolini - (09/15/10)
ICAAC 2010: GSK2248761, an NNRTI with Activity Against Common NNRTI Resistance Mutants, Did Not Select for NNRTI Resistance Mutations in Two 7-Day Monotherapy Studies - (09/15/10)
Lersivirine (UK-453,061), an experimental nonnucleoside (NNRTI), remained active against more than half of tested patient isolates with reduced susceptibility to etravirine in a phenotyping study [1]. The new NNRTI showed activity against a wide array of HIV-1 subtypes and circulating recombinant forms (CRFs).
Earlier work determined the lersivirine binds to reverse transcriptase in a manner distinct from other NNRTIs. Other experiments calculated a 50% inhibitory concentration (IC50) of 5.83 nM against wild-type (nonresistant) virus and a resistance pathway featuring the V108I mutation and requiring three or more mutations to confer high-level resistance [2]. A 7-day monotherapy trial found an average 1.6-log reduction in viral load at a dose of 500 mg twice daily and an average 1.8-log drop with 750 mg once daily [3]. Doses of 500 and 750 mg once daily have been selected for phase 2b studies.
The investigators used the PhenoSense assay to assess antiviral activity of lersivirine against three groups of patient-derived isolates from (1) 80 people infected with subtypes A, A1, B, BF, C, C/H, D, F, F1, G, and H and CRFs CR01_AE and CRF02_AG, (2) 19 people with virus showing reduced susceptibility to etravirine, and (3) the first 76 candidates for enrollment in a phase 2b trial of antiretroviral-experienced people.
The subtype study analyzed viral isolates from Africa, Europe, North and South America, and Australia. Seventy-eight of 80 isolates proved fully susceptible to lersivirine with less than a 2-fold change in IC50, while 2 isolates with minor polymorphisms had an IC50 fold change between 2 and 10. Overall median fold change in IC50 was 0.92. The investigators detected no NNRTI resistance-associated mutations in any of these viral isolates.
Against the panel of 19 viral isolates with reduced susceptibility (greater than 2.9-fold change in IC50) to etravirine, the investigators found that lersivirine retained activity against 11 isolates, defined as less than a 10-fold change in susceptibility. Three isolates had greater than 100-fold resistance to etravirine. One harboring the mutations V108I, V179I, and Y181I remained susceptible to lersivirine at a fold change of 5.5. The second carried the K103N, V179I, and Y181C mutations and had 12-fold resistance to lersivirine. The third harbored the K103N and Y181C mutations and had 51-fold resistance to lersivirine.
Two viral isolates had more than 100-fold resistance to lersivirine, one bearing V106I, V179I, and Y188L, and one bearing K103N and Y188L. Four other isolates had more than 10-fold resistance to lersivirine with these mutation sets: (1) A98S, K103N, V179I, Y181C (18-fold resistance), (2) K101E, Y181C, G190A (35-fold resistance), (3) K103N, P225H (12-fold resistance), and (4) K101I, G190A (11-fold resistance). These findings suggest that key NNRTI mutations--including K103N, Y181C, and G190A--play some role in resistance to this experimental NNRTI and that resistance pathways are complex.
Overall, though, Pfizer investigators detected no clear relationship between lersivirine and etravirine susceptibility in these experiments, which they proposed "is consistent with different genotypic profiles." This lack of resistance relationship held true in the screening samples from the phase 2b trial.
1. Mori J, Westby M, Tawadrous M, van der Ryst E, Craig C. Lersivirine: a new NNRTI active across HIV-1 subtypes with a unique resistance profile. Tenth International Congress on Drug Therapy in HIV Infection. November 7-11, 2010. Glasgow. Slides online at http://www.natap.org/2010/interHIV/InterHIV_38.htm.
2. Corbau R, Mori J, Phillips C, et al. Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2010;54:4451-4463.
3. Fatkenheuer G, Staszewski S, Plettenburg A, et al. Activity, pharmacokinetics and safety of lersivirine (UK-453,061), a next-generation nonnucleoside reverse transcriptase inhibitor, during 7-day monotherapy in HIV-1-infected patients. AIDS. 2009;23:2115-2122. 4.