O424

Presented at the 9th International Congress on HIV and Drug Therapy in HIV Infection, Glasgow, UK, 9–13 November 2008.

This poster is available on-line at www.tibotec.com

Supported by Tibotec

Conclusions• These TITAN study findings from the 96-week analysis confirm the results

from the 48-week analysis and showed that:– the VF rate in the DRV/r arm was 50% of the VF rate in the LPV/r arm– DRV/r was better than LPV/r in preventing the development of resistance

upon VF– cross-resistance with other PIs was less frequent with DRV than with LPV

upon VF.

Address correspondence to: Sandra De Meyer, PhD, Tibotec BVBA, Generaal De Wittelaan L11 B3, B2800 Mechelen, Belgium; Fax: +32 15 461 942; E-mail: sdmeyer@its.jnj.com

Resistance development in virological failures with DRV/r or LPV/r: 96-week analysisof the Phase III TITAN trial in treatment-experienced patientsSandra De Meyer,1 Erkki Lathouwers,1 Inge Dierynck,1 Els De Paepe,1 Ben Van Baelen,1 Tony Vangeneugden,1 Frank Tomaka,2 Marie-Pierre de Béthune,1 Gaston Picchio2

1Tibotec BVBA, Mechelen, Belgium; 2Tibotec Inc., Yardley, PA, USA

Acknowledgements• The patients and their families for their participation and support during the study

• TITAN study team and the investigators and co-investigators

Argentina: Pedro Cahn, Arnaldo Casiro, Isabel Cassetti, Daniel David, Marcelo Losso and Sergio Lupo; Australia:David Cooper, Robert Finlayson, Jenny Hoy, Patricia Martinez, Marilyn McMurchie and Cassy Workman; Austria:Armin Rieger and Norbert Vetter; Belgium: Nathan Clumeck, Jean-Christophe Goffard and Lut Lynen; Brazil:Clóvis Arns Da Cunha, Beatriz Grinsztejn, Cláudio Gonsalez, José Valdez-Madruga, Rogério Pedro, José Henrique Pilotto,Mauro Schechter and Artur Timerman; Canada: John Gill, Norbert Gilmore, Donald Kilby, Patrice Junod, Anita Rachlis,Benoit Trottier, Chris Tsoukas and Sharon Walmsley; Chile: Juan Ballesteros, Rebeca Northland and Carlos Pérez;Denmark: Henrik Nielsen; France: Jacques Durant, Pierre-Marie Girard, Christine Katlama, Christian Michelet,Jean-Michel Molina, Gilles Pialoux, Christophe Piketty, Dominique Salmon, Daniel Vittecoq and Patrick Yeni; Germany:Keikawus Arastéh, Gerd Fätkenheuer, Heribert Knechten, Antonius Mutz, Dieter Schuster, Albrecht Stoehr and Andreas Trein; Greece: George Panos; Guatemala: Eduardo Arathoon and Carlos Mejia-Villatoro; Hungary:Denes Banhegyi; Italy: Andrea Antinori, Giampiero Carosi, Roberto Esposito, Adriano Lazzarin, Francesco Mazzotta,Anna Orani, Stefano Rusconi, Laura Sighinolfi and Fredy Suter; Malaysia: Adeeba Kamarulzaman and Christopher Lee;Mexico: Jaime Andrade; The Netherlands: Kees Brinkman, Bart Rijnders and Herman Sprenger; Panama: Nestor Sosa;Portugal: Teresa Branco, António Diniz and Rui Sramento e Castro; Puerto Rico: Javier Morales Ramirez; Russia:Oleg Kozyrev, Grigory Moshkovich, Alexander Pronin, Oleg Romanenko, Elena Vinogradova and Alexey Yakovlev;South Africa: Ezio Baraldi, Francesca Conradie, Gulam Hoosan Latiff, Lerato Mohapi, Catherine Orrell, Osman Ebrahimand David Spencer; Spain: José Ramon Arribas, Daniel Podzamczer and Maria Jesus Perez-Elias; Switzerland:Milos Opravil; Thailand: Ploenchan Chetchotisakd, Kiat Ruxrungtham, Wichai Techasathit and Chaiwat Ungsedhapand(key coordinator); UK: Philippa Easterbrook and Anton Louis Pozniak; USA: Ben Barnett, John Baxter, Paul Benson,Daniel Berger, Jack Bissett, Cynthia Brinson, Alfred Burnside, Thomas Campbell, Amy Colson, Frederick Cruickshank,Edwin DeJesus, Robin Dretler, Robert Eng, Charles Farthing, Jeffrey Fessel, Michael Frank, David Hardy,Dushyantha Jayaweera, Thomas Jefferson, Harold Katner, Clifford Kinder, Harry Lampiris, Marc LaRiviere, Jason Leider,Steven Marlowe, Cynthia Mayer, David McDonough, Jose Montero, Karam Mounzer, Robert Myers, Dorece Norris,Frank Palella, Gerald Pierone, Bruce Rashbaum, Afsoon Roberts, Barry Rodwick, Peter Ruane, Kunthavi Sathasivam,Stefan Schneider, Shannon Schrader, Anita Scribner, Michael Sension, Peter Shalit, William Short, Stephen Smith,Alan Taege, Melanie Thompson, Timothy Wilkin and Bienvenido Yangco.

AbstractIn the randomised, controlled, Phase III TITAN trial, at Week 96, significantly morepatients on darunavir (DRV) co-administered with low-dose ritonavir (DRV/r) than onlopinavir/r (LPV/r) achieved HIV-1 RNA <400 copies/mL (67.5% vs 59.5%; difference8%, 95% confidence intervals [CI]: 0.1–15.8), confirming non-inferiority (p<0.001) andsuperiority of DRV/r over LPV/r (p=0.034). A detailed resistance characterisation ofvirological failures (VFs) was performed.Treatment-experienced, LPV-naïve patients with HIV-1 RNA >1,000 copies/mL wererandomised to DRV/r 600/100mg bid (n=298) or LPV/r 400/100mg bid (n=297)combined with an optimised background regimen (OBR; NRTIs ± NNRTI). VFs weredefined as patients who lost or never achieved HIV-1 RNA <400 copies/mL after Week16. Genotyping and phenotyping (Antivirogram®) were performed by Virco.The VF rate in the LPV/r arm (25.6%, n=76) was higher than in the DRV/r arm (13.8%, n=41). Among VFs with an available genotype at baseline and endpoint (72 for LPV/r and 39 for DRV/r), more patients developed primary protease inhibitor (PI)mutations at endpoint as compared to baseline in the LPV/r arm (n=25) than in theDRV/r arm (n=7). Primary PI mutations developing in DRV/r VFs were V32I in threepatients, I47V and L76V in two patients and M46I, I54L, I54M and L90M in one patient(L90M was already present at screening). All but the M46I and L90M mutations were2007 DRV resistance-associated mutations (RAMs). In addition, more VFs developedNRTI RAMs in the LPV/r arm (n=20) than in the DRV/r arm (n=4). Phenotypically, moreLPV/r VFs than DRV/r VFs lost susceptibility to the study PI (17/55 vs 3/36) or any PI(25/69 vs 7/37). Among the DRV/r VFs, the majority retained susceptibility toamprenavir (APV; 31/31), atazanavir (ATV; 29/30), indinavir (IDV; 31/32), LPV (33/33),nelfinavir (24/26), saquinavir (SQV; 31/31) and tipranavir (TPV; 34/35). Furthermore,more LPV/r VFs than DRV/r VFs lost susceptibility to the NRTI(s) used in the OBR (20/55vs 4/35) or any NRTI (27/66 vs 7/38). Similar results were obtained when patients withLPV fold-change (FC) >10 or patients who previously used ≥2 PIs were excluded fromthe analysis.In this treatment-experienced, LPV-naïve patient population, the overall VF rate withDRV/r was half compared to LPV/r. Furthermore, the majority of DRV/r VFs did notdevelop primary PI mutations or NRTI RAMs and preserved susceptibility to PIs andNRTIs.