1. Predicting NNRTI Resistance – do polymorphisms matter? Nicola E Mackie 1, Lucy Garvey 1, Anna Maria Geretti 2, Linda Harrison 3, Peter Tilston 4, Andrew Phillips 2, Caroline Sabin 2, David Dunn 1 1 Department of HIV Medicine, Imperial College Healthcare NHS Trust, St. Mary’s Hospital, London W2 1NY, UK; 2 Royal Free and University College Medical School, London, UK; 3 MRC Clinical Trials Unit, London, UK; 4 Manchester Royal Infirmary, Manchester, UK Introduction CROI 2011 Abstract #: M-109, Poster Board #: 595 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 Correspondence to Nicola Mackie nicola.mackie@imperial.nhs.uk 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 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 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 (log 10 copies/mL) at week 4 Proportion of subjects <200 copies/mL at weeks 24, 48, 72 and 96 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 log 10 copies/mL fall in plasma HIV RNA by week 4 Aims Methods Results: Patient demographics Results: Prevalence of polymorphisms 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 CodonPrevalence of polymorphism, n (%) Polymorphisms observed (n) * Effect of polymorphism on VL reduction (95% CI) ** p- value 90 70 (3.4)I(69), X(1)-0.05 (-0.18,0.08)0.47 98 165 (8.0)S(162), G(2), X(1)-0.01 (-0.09,0.08)0.86 101 35 (1.7)R (21), Q (13), I(1)0.01 (-0.17,0.20)0.87 103 33 (1.6)R(31), Q(1), T(1) -0.07 (-0.26,0.12) 0.50 106 48 (2.3) I(48) 0.03 (-0.12, 0.19) 0.68 135 815 (39.6)T(512), V(166), R(48), X(31), M(28), L(26),K(3), A(1) -0.01 (-0.06,0.03)0.58 138 72 (3.5)A(64), G(5), D(1), K(1), X(1)0.03 (-0.10,0.16)0.62 179 196 (9.5)I(156), D(22), T(8), E(6), A(2), S(1), X(1)-0.07 (-0.15,0.01)0.07 238 29(1.7)R(28), Q(1)0.05 (-0.16,0.26)0.63 Total number of subjects eligible and included in analysis2058 HIV-acquisition risk groupMSM1340 (65) Female heterosexual303 (15) Male heterosexual248 (12) Other / missing167 (8) EthnicityWhite1324 (64) Black508 (25) Other / missing226 (11) HIV-1 subtypeB1421 (69) C284 (14) Other / not classified353 (17) Baseline CD4+ count (cells/uL), mean (SD)201 (138) Baseline plasma HIV RNA level (log 10 copies/mL), mean (SD)4.94 (0.7) First-line ARV regimenNNRTIEFV1704 (83) NVP354 (17) NRTITDF + FTC / 3TC721 (35) AZT + FTC / 3TC523 (25) ABC + FTC / 3TC502 (24) Other312 (15) Codon Number (%) samples with VL <200 copies/ml Week 24Week 48 WTpolymorphismOR (95% CI)p-valueWTpolymorphismOR (95% CI)p-value 901408/1519 (93)41/43 (95)1.7 (0.4,7.3)0.511123/1223 (92)33/36 (92)1.1 (0.3,3.6)0.93 98 1329/1433 (93) 120/129 (93) 1.1 (0.5, 2.2) 0.88 993/1160 (86) 88/99 (89) 0.7 (0.3, 1.4) 0.29 1011425/1537 (93)24/25 (96)2.2 (0.3, 16.9)0.451141/1240 (92)15/19 (79)0.3 (0.1, 0.8)0.02 1031420/1533 (93)29/29 (100)- (0.6, ∞)0.261132/1234 (92)24/25 (96)2.0 (0.3, 15.2)0.51 1061414/1524 (93)35/38 (92)0.8 (0.2, 2.6)0.691126/1227 (92)30/32 (94)1.0 (0.2, 4.5)0.97 135886/961 (92)564/602 (94)1.3 (0.9, 2.0)0.20713/779 (92)443/480 (93)1.1 (0.7, 1.7)0.60 1381400/1509 (93)50/54 (93)0.8 (0.3, 2.3)0.651110/1210 (92)46/49 (94)1.5 (0.4, 5.3)0.51 1791320/1421 (93)128/140 (91)0.87 (0.5, 1.6)0.671049/1145 (92)106/113 (94)1.5 (0.7, 3.4)0.33 2381175/1282 (92)22/23 (96)1.3 (0.2, 10.4)0.78944/1034 (91)14/14 (100)- (0.3, ∞)0.62 Results: Change in VL at week 4 Results - % of samples with VL<200 at weeks 24 and 48 Results: Change in VL according to number of polymorphisms Acknowledgements Number of polymorphisms (any codon) Number of samples Effect on VL reduction at week 4 (95% CI)* P-value 1829-0.03 (-0.08, 0.02)0.21 2262-0.03 (-0.10, 0.05)0.46 3330.02 (-0.17, 0.21)0.87 46-0.20 (-0.63, 0.22)0.35