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Efficacy and safety of TMC278 in antiretroviral-naive HIV-1 patients: week 96 results of a phase IIb randomized trial

Pozniak, Anton La; Morales-Ramirez, Javierb; Katabira, Ellyc; Steyn, Dewaldd; Lupo, Sergio He; Santoscoy, Mariof; Grinsztejn, Beatrizg; Ruxrungtham, Kiath; Rimsky, Laurence Ti; Vanveggel, Simoni; Boven, Katiaj; on behalf of the TMC278-C204 study group

doi: 10.1097/QAD.0b013e32833032ed
Clinical Science

Objective: TMC278 is a next-generation nonnucleoside reverse transcriptase inhibitor highly active against wild-type and nonnucleoside reverse transcriptase inhibitor-resistant HIV-1 in vitro. The week 96 analysis of TMC278-C204, a large dose-ranging study of TMC278 in treatment-naive HIV-1-infected patients, is presented.

Design: Phase IIb randomized trial.

Methods: Three hundred sixty-eight patients were randomized and treated with three blinded once-daily TMC278 doses 25, 75 or 150 mg, or an open-label, active control, efavirenz 600 mg once daily, all with two nucleoside reverse transcriptase inhibitors. The primary analysis was at week 48.

Results: No TMC278 dose–response relationship for efficacy and safety was observed. TMC278 demonstrated potent antiviral efficacy comparable with efavirenz over 48 weeks that was sustained to week 96 (76.9–80.0% and 71.4–76.3% of TMC278-treated patients with confirmed viral load <50 copies/ml, respectively; time-to-loss of virological-response algorithm). Median increases from baseline in CD4 cell count with TMC278 at week 96 (138.0–149.0 cells/μl) were higher than at week 48 (108.0–123.0 cells/μl). All TMC278 doses were well tolerated. The incidences of the most commonly reported grade 2–4 adverse events at least possibly related to study medication, including nausea, dizziness, abnormal dreams/nightmare, dyspepsia, asthenia, rash, somnolence and vertigo, were low and lower with TMC278 than with efavirenz. Incidences of serious adverse events, grade 3 or 4 adverse events and discontinuations due to adverse events were similar among groups.

Conclusion: All TMC278 doses demonstrated potent and sustained efficacy comparable with efavirenz in treatment-naive patients over 96 weeks. TMC278 was well tolerated with lower incidences of neurological and psychiatric adverse events, rash and lower lipid elevations than those with efavirenz. TMC278 25 mg once daily was selected for further clinical development.

aChelsea and Westminster NHS Foundation Trust and PKR/SSR, London, UK

bClinical Research Puerto Rico, Inc, San Juan, Puerto Rico

cMakerere University, Kampala, Uganda

dUniversity of the Free State, Bloemfontein, South Africa

eUniversidad Nacional de Rosario, Santa Fe, Argentina

fHospital Carlos Mac Gregor IMSS, Mexico City, Mexico

gInstituto de Pesquisa Clínica Evandro Chagas-Fiocruz, Rio de Janeiro, Brazil

hHIV-NAT, Thai Red Cross AIDS Research Centre and Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

iTibotec BVBA, Mechelen, Belgium

jTibotec Inc., Yardley, Pennsylvania, USA.

Received 30 January, 2009

Revised 25 June, 2009

Accepted 26 June, 2009

Correspondence to Anton Pozniak, MD, FRCP, Chelsea and Westminster NHS Foundation Trust, 369 Fulham Road, London SW10 9NH, UK. Tel: +44 208 746 5620; fax: +44 208 746 5628; e-mail: anton.pozniak@chelwest.nhs.uk

© 2010 Lippincott Williams & Wilkins, Inc.