First-line NNRTI to second-line PI/r

Outcomes of 2 nd line ART First-line NNRTI to second-line PI/r Laura Waters, David Asboe,, Anton Pozniak, Loveleen Bansi, Chloe Orkin, Erasmus Smit, Esther Fearnhill & Andrew Phillips. UK Resistance Database and UK CHIC Study Background A combination of 2 NRTI + 1 NNRTI is the most common first line regimen worldwide Treatment failures continue to occur Second line regimens are usually PI/r based and should include at least 2 active agents 1 Unclear how many active NRTI are necessary with 2nd line PI/r based therapy cross resistance effectiveness PI/r monotherapy 1) 2008 BHIVA Guidelines

Objectives To identify factors associated with failure of 2 nd line, ritonavir boosted PI-based ART To investigate the importance of the number of new OR fully active NRTI started at 2 nd line Cohorts studied UK Collaborative HIV cohort (CHIC) 11 centres submitting routine clinic data since 1996 UK Resistance database cohort database of most genotypic resistance tests performed within UK

Methods 1 Eligibility Patients failing first line NNRTI-ART (VL >200 copies/ml after 4 months) and starting PI/r for the first time Exclusions VL<200 copies/ml at start of 2 nd line <4 months follow up failed new NRTI between first and second-line therapy Methods 2 Virological failure of 2 nd line ART: VL>200 copies/ml despite 4 months continuous use NRTI GSS calculated for 2 nd line regimens using Stanford Statistical Analyses: Kaplan-Meier: time to failing 2 nd line ART Logistic regression: identify factors associated with having a resistance test Cox regression: identify factors associated with failing 2 nd line ART

Patient disposition Patients starting NNRTI -ART 9285 VL>200 copies/ml despite 4 months continuous use of NNRTI Patients starting new drugs after failing first line 1103 Started 2 nd line PI/r 601* VL>200 copies/ml at start of 2 nd line PI/r 501 Excluding those without 4 months follow up 445 Excluding those who failed a new NRTI after failing 1 st 403 line and before starting 2 nd line ART 1692 (18.2%) *Patients not meeting 2 nd line criteria 502 Started single PI 45 Started new NNRTI 138 Started new NRTIs only 318 Started other drugs 1 Patients starting new drugs 2 nd line (n = 1103) Started PI/r Regimen 2 nd line (n = 601) Started non-pi/r regimen 2 nd line (n = 502) Excluded HIV-RNA <200 at 2 nd line 100 <4 months follow-up 56 Failed new NRTI between 1 st and 2 nd line 42 Unboosted PI 45 New NNRTI 138 New NRTI only 318 Other 1 Eligible for Study (n = 403)

Baseline characteristics Patients starting 2 nd line PI/r ART 403 Time to failing 1 st line ART (months) Median (IQR) 9.4 (5.3, 20.0) New PI/r started n (%) LPV 222 (55.1) AZV 92 (22.8) Other 89 (22.1) New NRTI started at 2 nd line 0 69 (17.1) n (%) 1 113 (28.0) >2 221 (54.8) Year of starting 2 nd line n (%) 1999-2001 195 (48.4) 2002-2004 164 (40.7) 2005-2007 44 (10.9) White ethnicity n (%) 161 (40.0) MSM n (%) 154 (38.2) VL<200 after failing 1 st line and before starting 2 nd 63 (15.6) line n (%) CD4 at start of 1 st line (cells/mm 3 ) Median (IQR) 150 (54, 22.0) VL at start of 1 st line (log copies/ml) Median (IQR) 5.1 (4.6, 5.5) CD4 at start of 2 nd line (cells/mm 3 ) Median (IQR) 213 (124, 310) VL at start of 2 nd line (log copies/ml) Median (IQR) 4.4 (3.6, 5.0.) Time to virological failure of 2 nd line ART 222/403 (55.1%) experienced virological failure 1 0.8 0.6 0.4 0.2 0 0 12 24 36 48 60 72 84 96 Months since starting 2nd line HAART

Independent factors associated with failure of 2 nd line ART (N=403) HR (95% CI) P-value Age at start of 2 nd line (years) Per 10 years older 1.08 (0.86, 1.34) 0.52 Time from failing 1 st line to starting 2 nd line Per 1 month increase 1.01 (1.00, 1.03) 0.07 Number of new NRTI 0 0.83 (0.51, 1.33) 0.44 started at 2 nd line 1 1 1.11 (0.79, 1.56) 0.56 >2 1 - Ethnicity White 1 - Black 0.95 (0.60, 1.51) 0.95 Other 0.52 (0.24, 1.12) 0.52 Sex/Exposure MSM 1 - Hetero male 1.93 (1.17, 3.20) 0.01 Hetero female 2.33 (1.26, 4.02) 0.002 Other 1.59 (0.62, 2.80) 0. 11 Year of starting 2 nd line Per 1 year increase 0.94 (0.86, 1.02) 0.15 VL<200 after failing 1 st line and before starting 2 nd line 0.76 (0.47, 1.24) 0.28 CD4 at 2 nd line (cells/mm 3 ) Per 50 cells higher 0.89 (0.83, 0.94) <0.0001 VL at 2 nd line (copies/ml) Per 1 log increase 1.23 (1.06, 1.42) 0.01 1 HR=1.00 (0.82, 1.21), p=0.99 if fitted as a continuous variable Characteristics of patients, stratified by whether or not they had a resistance test performed after failing 1 st line ART Resistance test performed No Yes P- value N 187 216 Age at failing 1 st line (years) Median (IQR) 35 (31, 39) 36 (32, 40) 0.31 Ethnicity n (%) White 73 (45.3) 88 (54.7) 0.73 Black 99 (48.1) 107 (51.9) Other 15 (41.7) 21 (58.3) Sex/Exposure n (%) MSM 69 (44.8) 85 (55.2) 0.06 Hetero male 59 (56.7) 45 (43.3) Hetero female 47 (42.7) 63 (57.3) Other 12 (34.3) 23 (65.7) Achieved VL<500 before starting 2 nd line n (%) 137 (43.8) 176 (56.2) 0.05 Year of failing 1 st line n (%) 1999-2001 54 (49.1) 56 (50.9) 0.16 2002-2004 90 (49.5) 92 (50.6) 2005-2007 43 (38.7) 68 (61.3) CD4 at failing 1 st line (cells/mm 3 ) Median (IQR) 220 (124,349) 287 0.01 (168,390) VL at failing 1 st line (log copies/ml) Median(IQR) 4.0 (3.1, 4.8) 3.7 (3.0, 4.5) 0.08 None of the above factors were independently associated with having a resistance test

Independent factors associated with failure of 2 nd line ART (N=211) HR (95% CI) P-value NRTI GSS 1 <1 0.73 (0.37, 1.41) 0.34 1.25-1.75 0.70 (0.42, 1.15) 0.16 >2 1 Time from failing 1 st line to starting 2 nd line Per 1 month increase 1.01 (0.99, 1.02) 0.44 Age at start of 2 nd line (years) Per 10 years older 1.29 (0.94, 1.79) 0.12 Ethnicity White 1 - Black 0.61 (0.30, 1.23) 0.17 Other 0.61 (0.23, 1.59) 0.31 Sex/Exposure MSM 1 - Hetero male 2.53 (1.14, 5.63) 0.02 Hetero female 2.79 (1.28, 6.08) 0.01 Other 1.32 (0.60, 2.90) 0.50 Year of starting 2 nd line Per 1 year increase 0.97 (0.86, 1.10) 0.67 VL<200 after failing 1 st line and before starting 2 nd line 0.63 (0.31, 1.27) 0.19 CD4 at 2 nd line (cells/mm 3 ) Per 50 cells higher 0.85 (0.77, 0.95) 0.004 VL at 2 nd line (copies/ml) Per 1 log increase 1.26 (0.99, 1.59) 0.06 1 HR=1.14 (0.76, 1.72), p=0.51 if fitted as a continuous variable Summary Of 403 patients who started 2 nd line PI/r, 216 (54%) patients had a resistance test performed after failing 1 st line ART NRTI GSS was >2 for 50% of patients with resistance tests performed

Conclusions We found little evidence that number of new NRTI started or predicted NRTI activity within the regimen, were associated with risk of virological failure of the 2nd line regimen Conclusions These findings may reflect the effectiveness of PI/r component negative impact of initiating more new agents Overall: high risk of virological failure heterosexuals low CD4 count Further analyses/prospective studies required

UK CHIC Steering Committee: Jonathan Ainsworth, Jane Anderson, Abdel Babiker, David Dunn, Philippa Easterbrook, Martin Fisher, Brian Gazzard (Chair), Richard Gilson, Mark Gompels, Teresa Hill, Margaret Johnson, Clifford Leen, Chloe Orkin, Andrew Phillips, Deenan Pillay, Kholoud Porter, Caroline Sabin, Tariq Sadiq, Achim Schwenk, Nicky Mackie, Alan Winston, Valerie Delpech. Central Co-ordination: Medical Research Council Clinical Trials Unit (MRC CTU), London (David Dunn, Kholoud Porter, Stephen Sheehan); Royal Free NHS Trust and RFUCMS, London (Loveleen Bansi, Teresa Hill, Andrew Phillips, Caroline Sabin). Participating Centres: Barts and The London NHS Trust, London (Chloe Orkin, Kevin Jones, Rachel Thomas); Brighton and Sussex University Hospitals NHS Trust (Martin Fisher, Nicky Perry, Anthony Pullin, Duncan Churchill,Wendy Harris); Chelsea and Westminster NHS Trust, London (Brian Gazzard, Steve Bulbeck, Sundhiya Mandalia, Jemima Clarke); Health Protection Agency Centre for Infections London (HPA) (Valerie Delpech); Homerton University Hospital NHS Trust, London (Jane Anderson, Selina Gann); King s College Hospital, London (Philippa Easterbrook, Yasar Khan, Fatimah Karim, Eghosa Bazuaye, Stephen Duffell); Medical Research Council Clinical Trials Unit (MRC CTU), London (Abdel Babiker, David Dunn, Kholoud Porter, Stephen Sheehan); Mortimer Market Centre, Royal Free and University College Medical School (RFUCMS), London (Richard Gilson, Julie Dodds, Shuk-Li Man, Ian Williams); North Middlesex University Hospital NHS Trust, London (Achim Schwenk); Royal Free NHS Trust and RFUCMS, London (Margaret Johnson, Mike Youle, Fiona Lampe, Colette Smith, Helen Grabowska, Clinton Chaloner, Dewi Ismajani Puradiredja, Loveleen Bansi, Teresa Hill, Andrew Phillips, Caroline Sabin); St. Mary s Hospital, London (John Walsh, Jonathan Weber, Christian Kemble, Mark Carder); The Lothian University Hospitals NHS Trust, Edinburgh (Clifford Leen, Alan Wilson). UK Collaborative Group on HIV Drug Resistance Steering Committee Jane Anderson, Homerton University Hospital; David Asboe, Anton Pozniak, Chelsea & Westminster Hospital, London; Sheila Burns, Royal Infirmary of Edinburgh; Sheila Cameron, Gartnavel General Hospital, Glasgow; Patricia Cane, Health Protection Agency, Porton Down; Ian Chrystie, Guy s and St. Thomas NHS Foundation Trust, London; Duncan Churchill, Brighton and Sussex University Hospitals NHS Trust; Duncan Clark, St Bartholemews and The London NHS Trust; Valerie Delpech, Deenan Pillay, Health Protection Agency-Centre for Infections London; David Dunn, Esther Fearnhill, Hannah Green, Kholoud Porter, MRC Clinical Trials Unit, London; Philippa Easterbrook, Mark Zuckerman, King s College Hospital, London; Anna Maria Geretti, Royal Free NHS Trust, London; Paul Kellam, Deenan Pillay, Andrew Phillips, Caroline Sabin, Royal Free and University College Medical School, London; David Goldberg, Health Protection Scotland, Glasgow; Mark Gompels, Southmead Hospital, Bristol; Antony Hale, Leeds Teaching Hospitals NHS Trust; Steve Kaye, St. Mary s Hospital, London; Svilen Konov, Community Advisory Board; Linda Lazarus, Department of Health; Andrew Leigh-Brown, University of Edinburgh; Nicola Mackie, St. Mary s Hospital, London; Chloe Orkin, St. Bartholemews Hospital, London; Erasmus Smit, Health Protection Agency, Birmingham Heartlands Hospital; Peter Tilston, Manchester Royal Infirmary; Ian Williams, Mortimer Market Centre, London; Hongyi Zhang, Addenbrooke s Hospital, Cambridge. Central Co-ordination: Medical Research Council Clinical Trials Unit (MRC CTU), London (David Dunn, Esther Fearnhill, Hannah Green, Kholoud Porter); Funding The UK HIV Drug Resistance Database is partly funded by the Department of Health; the views expressed in the publication are those of the authors and not necessarily those of the Department of Health. Additional financial support is provided by Boehringer Ingelheim; Bristol-Myers Squibb; Gilead; Tibotec, a division of Janssen-Cilag Ltd; and Roche.