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High prevalence of bevirimat resistance mutations in non-B subtypes and in PI-resistant HIV isolates
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J Verheyen1, C Verhofstede2, E Knops1,
L Vandekerckhove2, A Fun3, D Brunen3, K Dauwe2,
A Wensing3, H Pfister1, R Kaiser1 and M Nijhuis3
1Institute of Virology, University of Cologne, Cologne, Germany
2Aids Reference Laboratory, Ghent University, Ghent, Belgium
3Department of Medical Microbiology, University Medical Center
Utrecht, Utrecht, the Netherlands
BACKGROUND: Bevirimat is the first drug in the new class of maturation inhibitors that hampers the processing of gag CA/p2 precursor protein. Mutations in the bevirimat target region conferring phenotypic resistance have been identified after in vitro selection experiments (aa 358/363/364/366). Furthermore, mutations in the QVTmotif (aa 369-371), associated with reduced bevirimat activity, have been observed as baseline polymorphism in several clinical isolates. The objective of this study was to assess the prevalence of bevirimat resistance mutations in isolates from treatment-naive and PI-experienced patients.
METHODS: Of 644 HIV isolates collected at three different sites in Europe, the bevirimat target region comprising gag aa 357-382 was sequenced. Isolates from treatment-naive (B: n=270; non-B: n=167) and PI-experienced patients harbouring resistance mutations in the viral protease (B: n=166; non-B: n=41), were selected.
RESULTS: In the 208 non-B isolates, no association between the prevalence of bevirimat resistance mutations and PI treatment-experience was observed. Still 60% harboured at least one mutation associated with bevirimat resistance. This was largely explained by the presence of V370A, which is a consensus amino acid on this codon in many non-B subtypes. Of the 270 treatment-naive patients infected with HIV-1 subtype B, approximately 30% harboured HIV with at least one mutation associated with a reduced susceptibility to bevirimat (H358Y, L363M, Q369H, V370A/M/del and T371del). In the 166 isolates with genotypic PI-resistance from pre-treated individuals, bevirimat associated mutations were significantly more prevalent (45%). Accumulation of mutations at four specific positions, S368C, Q369H, V370A and S373P, were observed. Furthermore, a significant association between the number of resistance mutations in the viral protease and the presence of bevirimat mutations was observed.
CONCLUSIONS: Mutations conferring resistance to bevirimat were observed in approximately one third of treatment-naive subtype-B HIV isolates and in 60% of treatment-naive non-B isolates. Interestingly, an accumulation of bevirimat resistance mutations was observed in subtype B isolates with resistance mutations in the viral protease. These data emphasize the importance of screening for gag mutations before administration of bevirimat. Reduced activity of the drug may be expected in patients infected with non-B isolates and in patients who have been exposed to protease inhibitors.
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