predicting nnrti resistance – do polymorphisms matter? nicola e mackie 1, lucy garvey 1, anna...

Predicting NNRTI Resistance – do polymorphisms matter?

Nicola E Mackie1, Lucy Garvey1, Anna Maria Geretti2, Linda Harrison3, Peter Tilston4, Andrew Phillips2, Caroline Sabin2, David Dunn1

11Department of HIV Medicine, Imperial College Healthcare NHS Trust, St. Mary’s Hospital, London W2 1NY, UKDepartment of HIV Medicine, Imperial College Healthcare NHS Trust, St. Mary’s Hospital, London W2 1NY, UK; ; 22Royal Free and University College Royal Free and University College Medical School, London, UK; Medical School, London, UK;

33MRC Clinical Trials Unit, London, UK; MRC Clinical Trials Unit, London, UK; 44Manchester Royal Infirmary, Manchester, UKManchester Royal Infirmary, Manchester, UKIntroduction

CROI 2011Abstract #: 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 Mackienicola.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 (log10 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 log10 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

Codon Prevalence 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) 0.86101 35 (1.7) R (21), Q (13), I(1) 0.01 (-0.17,0.20) 0.87103 33 (1.6) R(31), Q(1), T(1) -0.07 (-0.26,0.12) 0.50106 48 (2.3) I(48) 0.03 (-0.12, 0.19) 0.68135 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) 0.62179 196 (9.5) I(156), D(22), T(8), E(6), A(2), S(1), X(1) -0.07 (-0.15,0.01) 0.07238 29(1.7) R(28), Q(1) 0.05 (-0.16,0.26) 0.63

Total number of subjects eligible and included in analysis 2058

HIV-acquisition risk group MSM 1340 (65)

Female heterosexual 303 (15)

Male heterosexual 248 (12)

Other / missing 167 (8)

Ethnicity White 1324 (64)

Black 508 (25)

Other / missing 226 (11)

HIV-1 subtype B 1421 (69)

C 284 (14)

Other / not classified 353 (17)

Baseline CD4+ count (cells/uL), mean (SD) 201 (138)

Baseline plasma HIV RNA level (log10 copies/mL), mean (SD) 4.94 (0.7)

First-line ARV regimen NNRTI EFV 1704 (83)

NVP 354 (17)

NRTI TDF + FTC / 3TC 721 (35)

AZT + FTC / 3TC 523 (25)

ABC + FTC / 3TC 502 (24)

Other 312 (15)

Codon

Number (%) samples with VL <200 copies/ml

Week 24 Week 48

WT polymorphism OR (95% CI) p-value WT polymorphism OR (95% CI) p-value

90 1408/1519 (93) 41/43 (95) 1.7 (0.4,7.3) 0.51 1123/1223 (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

101 1425/1537 (93) 24/25 (96) 2.2 (0.3, 16.9) 0.45 1141/1240 (92) 15/19 (79) 0.3 (0.1, 0.8) 0.02

103 1420/1533 (93) 29/29 (100) - (0.6, ∞) 0.26 1132/1234 (92) 24/25 (96) 2.0 (0.3, 15.2) 0.51

106 1414/1524 (93) 35/38 (92) 0.8 (0.2, 2.6) 0.69 1126/1227 (92) 30/32 (94) 1.0 (0.2, 4.5) 0.97

135 886/961 (92) 564/602 (94) 1.3 (0.9, 2.0) 0.20 713/779 (92) 443/480 (93) 1.1 (0.7, 1.7) 0.60

138 1400/1509 (93) 50/54 (93) 0.8 (0.3, 2.3) 0.65 1110/1210 (92) 46/49 (94) 1.5 (0.4, 5.3) 0.51

179 1320/1421 (93) 128/140 (91) 0.87 (0.5, 1.6) 0.67 1049/1145 (92) 106/113 (94) 1.5 (0.7, 3.4) 0.33

238 1175/1282 (92) 22/23 (96) 1.3 (0.2, 10.4) 0.78 944/1034 (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

1 829 -0.03 (-0.08, 0.02) 0.21

2 262 -0.03 (-0.10, 0.05) 0.46

3 33 0.02 (-0.17, 0.21) 0.87

4 6 -0.20 (-0.63, 0.22) 0.35