Predicting NNRTI Resistance – do polymorphisms matter?

1. Predicting NNRTI Resistance – do polymorphisms matter? • Nicola E Mackie1, Lucy Garvey1, Anna Maria Geretti2, Linda Harrison3, Peter Tilston4, Andrew Phillips2, Caroline Sabin2, David Dunn1 • 1Department of HIV Medicine, Imperial College Healthcare NHS Trust, St. Mary’s Hospital, London W2 1NY, UK; 2Royal Free and University College Medical School, London, UK; • 3MRC Clinical Trials Unit, London, UK; 4Manchester Royal Infirmary, Manchester, UK CROI 2011 Abstract #: M-109, Poster Board #: 595 Correspondence to Nicola Mackie nicola.mackie@imperial.nhs.uk Inclusion criteria • ARV-naïve patients starting nevirapine (NVP) or efavirenz (EFV) with at least 2 nucleoside reverse transciptase inhibitors (NRTIs) between 1997-2008 • Pre-therapy GT available • Wild-type (WT) or polymorphisms only on baseline GT • Viral load measurement available at week 4 (range 2-6 weeks) Exclusion criteria • Major NNRTI mutation on baseline GT • Undetectable plasma HIV RNA at baseline • Less than 0.5 log10 copies/mL fall in plasma HIV RNA by week 4 Introduction Results - % of samples with VL<200 at weeks 24 and 48 Results: Prevalence of polymorphisms • Polymorphisms occur at reverse transcriptase (RT) codons within regions 90-108, 135-138, 179-190 and 225-348 in antiretroviral (ARV)-naive individuals • Although in isolation some confer low-level resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in vitro, their impact on virological response in vivo remains unclear • Avoiding NNRTIs in first-line therapy for patients with such polymorphisms may have implications for pill burden, adherence and cost • 829/2058 (40%) of subjects had at least one NNRTI polymorphism on baseline GT • 301/2058 (15%) had multiple polymorphisms • Polymorphisms most frequently observed at codons 135 (40%), 179 (10%), 98 (8%) • 9 codons were selected for further analysis (where ≥ 10 subjects had a polymorphism): 90, 98, 101, 103, 106, 135, 138, 179, 238 Results: Change in VL at week 4 Results: Patient demographics Aims • To determine the prevalence of NNRTI polymorphisms in ARV-naive subjects at the following RT codons: 90, 98, 100, 101, 103, 106, 108, 135, 138, 179, 181, 188, 190, 225, 227, 230, 234, 236, 238, 318, 348 • To assess their impact on virological response to first-line NNRTI-based therapy • Conclusions: • RT polymorphisms involving codons potentially implicated in NNRTI resistance are observed frequently in ARV-naïve individuals • No effect of single or multiple polymorphisms upon early virological response (week 4) • Polymorphisms at codon 101 (R, Q, I) were associated with a lower virological response at week 48, however this was not observed at weeks 4 or 24 or sustained to week 72 and 96 • Use of NNRTI-containing (EFV or NVP) first-line therapy should note be avoided in ARV-naïve subjects with RT polymorphisms at codons 90, 98, 101, 103, 106, 135, 138, 179, 238 • The impact of these mutations on second generation NNRTIs remains to be determined Methods • Data collection: • Results of baseline genotype (GT) from the UK HIV Drug Resistance Database and linked clinical data from UK CHIC Study • Data analysis: • Prevalence of NNRTI-polymorphisms in ARV-naïve subjects calculated • Polymorphisms defined using IAS-USA and Stanford database mutation lists (2009) • Codons were selected for further analysis where ≥ 10 subjects had a polymorphism at that position • Virological response compared between subjects with ≥1 polymorphism and those with wild-type (WT) virus • Logistic regression analysis performed to assess impact of polymorphisms upon virological response adjusting for timing of test, baseline HIV RNA and CD4+ count and specific NNRTI or NRTI backbone (STATA 11.0) • Endpoints: • Change from baseline HIV RNA level (log10 copies/mL) at week 4 • Proportion of subjects <200 copies/mLat weeks 24, 48, 72 and 96 Results: Change in VL according to number of polymorphisms Acknowledgements