1. EuroCoord-CHAIN joint project Impact of transmitted drug resistance on virological and immunological response to intial combination antiretroviral therapy L Wittkop on behalf of the EuroCoord-CHAIN joint project team  EuroCoord (CASCADE, COHERE, EuroSIDA and PENTA) and CHAIN (a pan-European project on HIV Drug resistance)  largest database on this topic so far Geneviève Chêne (Project lead), Hannah Castro (née Green), Marie-Laure Chaix, Bonaventura Clotet, Dominique Costagliola, Alessandro Cozzi-Lepri, David Dunn, Huldrych Günthard, Ali Judd, Claudia Kücherer, Andrea de Luca, Jens D Lundgren, Bernard Masquelier, Roger Paredes, Deenan Pillay, Andrew Phillips, Anton Pozniak, Rodolphe Thiébaut, Frank de Wolf, Viktor von Wyl

2. 2 Background Prevalence of transmitted drug resistance – between 10 and 15% in Europe – up to 25% in North America Genotypic testing is recommended for naïve patients in recent treatment guidelines (EACS, BHIVA) Impact of transmitted drug resistance remains controversial especially in patients who are prescribed a fully active regimen

3. 3 Objective To assess the impact of transmitted drug resistance mutations on virological and immunological response up to 16 months after starting a combination antiretroviral therapy (cART) Specific analyses: –Transmitted drug resistance and fully active treatment –2NRTI + 1NNRTI or 2NRTI + 1boosted PI regimen HIV infected patients regardless of age Start of cART after 1.1.1998 ≥1 sample taken before antiretroviral treatment for genotypic testing Study population

4. 4 Methods WHO – list 2009 1 Group 0 Patients with no detected mutation (used as a reference group) Patients having at least one mutation Group 1 show no drug resistance to their prescribed drug (classified as ‘susceptible’ or as ‘potential low level resistance’) Group 2 resistant to at least one of their prescribed drugs (classified as ‘Low-level resistance‘, ‘Intermediate' or as ‘High level resistance‘) Stanford 2 version 6.0.5 Virologic endpoint: –time to first of two consecutive viral load>500 copies/mL after six months of therapy Definition TDR (two steps): 1 Bennett PlosOne 2009, 2 Liu CID 2006

5. 5 Characteristics at the time of starting cART 10 458 patients from 25 cohorts 76% male Median age 38 years 56% of European origin 62% harboured a subtype B virus Pre-treatment viral load and CD4 counts were 5 log 10 cp/mL and 217 cells/mm 3 Transmission risk groups: 50% homosexual, 33% heterosexual, 8% IDUs and 2.1% perinatal 9.1% (n=953) patients harboured a virus with ≥1 mutation 4.5% (n=476) received a fully active treatment 4.6% (n=477) had virus predicted to have at least low level resistance for ≥1 prescribed drug

6. 6 Virological failure according to TDR 6.0% 6.3% 16.2% In adjusted analysis*:  Patients with resistance to ≥1 drug: - significant higher risk of VF compared to patients without mutations - HR: 2.6 [2.0; 3.4], P<10 -4  patients receiving a fully active cART and patients with no mutation: - risk of VF was not significantly different - HR: 1.2 [0.8; 1.8], P=0.34 % VF months *All models stratified by cohort ; multivariable models ajusted for: Gender, age, pre-treatment viral load and CD4 count, year of treatment start, previous AIDS diagnosis, subtype, HIV transmission risk group, origin

7. 7 Impact of TDR according to treatment strata HR* All 2NRTIs+1NNRTI 2NRTIs+1PI/rtv N: 9505 4703 2881 476 477 160 175237 132 1 1122 2 %VF at M12: 6.06.316.2 3.76.412.1 4.33.7 11.7 Global interaction P=0.08 *All models stratified by cohort ; multivariable models ajusted for: Gender, age, pre-treatment viral load and CD4 count, year of treatment start, previous AIDS diagnosis, subtype, HIV transmission risk group, origin

8. 8 Summary and conclusion Transmitted drug resistance was associated with a poorer virological response if the treatment was not adapted to the patients genotype In the presence of TDR and when an active regimen was used: potential higher risk of virological failure if a combination of NNRTI + 2 NRTIs was used, though not if boosted PI + 2 NRTIs were prescribed  Our results underscore that genotypic testing in treatment naive patients in regions with medium to high prevalence TDR is important to select a fully active regimen for treatment initiation  In regions where genotypic testing is not routinely available but high prevalence of TDR is suspected, first line regimens containing boosted PI should be discussed

9. 9 Acknowledgments EuroCoord-CHAIN project team: EuroCoord-CHAIN Project Leader: Geneviève Chêne (Linda Wittkop, project coordinator and statistician/epidemiologist) Statisticians/Epidemiologists: Hannah Castro (née Green), Dominique Costagliola, Alessandro Cozzi-Lepri, David Dunn, Ali Judd, Andrew Phillips, Rodolphe Thiébaut, Viktor von Wyl Virologists: Marie-Laure Chaix, Claudia Kücherer, Bernard Masquelier, Deenan Pillay, Frank de Wolf Clinicians: Bonaventura Clotet/Roger Paredes, Huldrych Günthard, Andrea de Luca, Jens D Lundgren, Anton Pozniak Contributing cohorts: Giota Touloumi (AMACS), François Dabis (ANRS CO3 AQUITAINE), Catherine Leport (ANRS CO8 COPILOTE), Frank de Wolf (ATHENA), Peter Reiss (ATHENA), Kholoud Porter (CASCADE), Maria Prins (CASCADE), Caroline Sabin (CHIC), Julia Del Amo (Co-RIS), Niels Obel (Danish HIV Cohort), Amanda Mocroft (EuroSIDA), Ole Kirk (EuroSIDA), Christoph Stephan (Frankfurt), Andrea Antinori (ICC), Antonella d’Arminio Monforte (ICONA), Patrick Francioli (SHCS), Jordi Casabona (PISCIS), Jose M. Miró (PISCIS), Antonella Castagna (San Raffaele), Stephane de Wit (St. Pierre Cohort), Carlo Torti (Italian Master Cohort), Ramon Teira (VACH),Myriam Garrido (VACH), Ali Judd (PENTA- EPPICC/CHIPS, UK and Ireland), Jose T Ramos (PENTA-EPPICC/Madrid cohort, Spain), Dan Duiculescu (PENTA-EPPICC/Dr Victor Babes Hospital cohort, Romania), Carlo Giaquinto (PENTA-EPPICC/PENTA, Europe), Magda Marczynska (PENTA-EPPICC/Warsaw cohort, Poland), Tessa Goetghebuer (PENTA-EPPICC/St Pierre, Belgium), Pat Tookey (PENTA-EPPICC/ National Study of HIV in Pregnancy and Childhood, UK and Ireland), B Brichard (PENTA- EPPICC/ Hospital UCL St Luc, Belgium), Niels Valerius (PENTA-EPPICC/Danish Paediatric HIV Cohort Study), Josiane Warszawski (PENTA-EPPICC/EPF, France), Christoph Rudin (PENTA-EPPICC/MOCHIV, Switzerland), Antoni Noguera (PENTA-EPPICC/ CoRISPE-cat, Spain), Marc Lallemant (PENTA- EPPICC/PHPT, Thailand) Datamanagers: Céline Colin (COHERE, Bordeaux RCC), Jesper Kjaer (COHERE, Copenhagen RCC, EuroSIDA), Charlotte Duff (PENTA-EPPICC), Keith Fairbrother (CASCADE) To all patients