17th International HIV Drug Resistance Workshop 10-14 June 2008, Sitges, Spain

INCREASED PHENOTYPIC SUSCEPTIBILITY TO ETRAVIRINE IN HIV-1 WITH NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR RESISTANCE

Antivir Ther. 2008; 13(Suppl. 3):A24 (abstract no. 22)

J Benhamida, E Coakley, NT Parkin and C Chappey
Monogram Biosciences, South San Francisco, CA, USA

BACKGROUND: Increased susceptibility to the non- nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz, nevirapine and delavirdine associated with mutations selected by nucleoside reverse transcriptase inhibitors (NRTIs) has been previously reported and has been shown to have clinical benefit in some cases. The effects of NRTI resistance-associated mutations (NAMs) on susceptibility to etravirine, the most recently approved NNRTI, are unknown.

METHODS: The median fold change (MFC) in etravirine IC₅₀ of groups of viruses containing various NAMs was determined using data derived from 2,056 samples submitted for routine resistance testing. NAMs were defined as M41L, K65R, D67N, T69X, K70E/R, L74I/V, V75A/M/S/T, Y115F, Q151M, M184I/V, L210W, T215F/Y and K219X (X=any non-wild-type amino acid). NNRTI mutations were defined as A98G, L100I, K101E/P, K103N/S, V106A/M, Y181X, Y188X, G190X, P225H, F227L, M230L and P236L.

RESULTS: Groups of viruses lacking NNRTI mutations containing various NAMs (often in combination with others) demonstrated varying degrees of increased etravirine susceptibility, with MFC ranging from 0.19 (K219N, n=9) to 0.67 (T69N, n=15). When present as the only NAM, T215Y, M41L, M184V and T69N were associated with MFC of 0.36 (n=6), 0.67 (n=17), 0.69 (n=118) and 0.85 (n=5), respectively. In combination with no more than two other NAMs, L74V, M184I, L210W and T215F/Y were associated with MFC<0.4. Increasing numbers of NAMs was associated with decreasing MFC, whether or not NNRTI mutations were present. For example, in the absence of NNRTI mutations, etravirine MFC was 0.89, 0.69, 0.60 and 0.35 with 0, 1, 2 or >2 NAMs; with one NNRTI mutation, MFC was 0.98, 1.0, 1.2, and 0.69, and with two NNRTI mutations it was 6.4, 4.1, 2.6 and 2.1.

CONCLUSIONS: Resistance to NRTIs is associated with increased etravirine susceptibility, causing hypersusceptibility when NNRTI resistance mutations are absent or few and reducing the level of resistance in combination with multiple NNRTI mutations. The clinical relevance of this phenomenon is unknown but deserves further study and may affect the derivation of genotype algorithms for prediction of reduced etravirine susceptibility.

2008-06-10
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