JAC Advance Access originally published online on June 10, 2009
Journal of Antimicrobial Chemotherapy 2009 64(2):398-410; doi:10.1093/jac/dkp198
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Original research |
Fosamprenavir/ritonavir in advanced HIV disease (TRIAD): a randomized study of high-dose, dual-boosted or standard dose fosamprenavir/ritonavir in HIV-1-infected patients with antiretroviral resistance
1 Service des Maladies Infectieuses et Tropicales, Hôpital Saint-Louis and University of Paris Diderot, Paris 7, 1 Avenue Claude-Vellefaux, 75475 Paris Cedex 10, France 2 GlaxoSmithKline, Greenford Road, Greenford, Middlesex UB6 0HE, UK 3 Divisione di Malattie Infettive e Tropicali, Via Nicolò Giustiniani 1, Azienda Ospedaliera di Padova, 35128 Padova, Italy 4 E. O. Ospedali Galliera, Via A. Volta 8, 16128 Genova, Italy 5 Clinique Médicale du Quartier Latin, 905 boul René-Lévesque est, Montréal, Quebec, H2L 5B1, Canada 6 Istituto di Clinica delle Malattie Infettive, Università Cattolica S. Cuore, Largo Francesco Vito 1, 00168 Roma, Italy 7 Department of Infectious Diseases, Hospital Carlos III, Calle Silesio Delgado 10, 28090 Madrid, Spain 8 Hôpital Tenon, Service des Maladies Infectieuses, 4 Rue de la Chine, 75970 Paris Cedex 20, France 9 GlaxoSmithKline, Research Triangle Park, NC, USA 10 International Clinical Virology, Gunnel's Wood Road, GlaxoSmithKline, Stevenage SG1 2NY, UK
Received 25 February 2009; returned 27 March 2009; revised 6 May 2009; accepted 10 May 2009
* Corresponding author. Tel: +33 1 42 49 90 64; Fax: +33 1 42 49 48 20; E-mail: jean-michel.molina{at}sls.aphp.fr
Background: APV102002 was an open-label study comparing a dual-boosted HIV-1 protease inhibitor (PI) [fosamprenavir/lopinavir/ritonavir (FPV/LPV/RTV; 1400 mg/533 mg/133 mg twice daily)] and a high dose of FPV/RTV 1400 mg/100 mg twice daily (HD-FPV/RTV) versus the standard FPV/RTV 700 mg/100 mg twice-daily (STD-FPV/RTV) regimen for 24 weeks.
Methods: Adult patients with prior failure to two or more PI-based regimens and on a failing PI regimen were randomized to STD-FPV/RTV (n = 24), HD-FPV/RTV (n = 25) or FPV/LPV/RTV (n = 25). The primary aim was to test week 24 superiority of HD-FPV/RTV and FPV/LPV/RTV over STD-FPV/RTV as measured by plasma HIV-1 RNA average area under the curve minus baseline (AAUCMB).
Results: There was no difference in the week 24 AAUCMB between the regimens. The proportion of patients with <50 copies/mL of plasma HIV RNA was 21%, 24% and 20%, respectively, by time to loss of virological response (TLOVR) analysis. High baseline drug resistance provided some explanation for the low efficacy. A lower baseline background drug resistance and higher fosamprenavir genotypic inhibitory quotient led to better antiviral responses. The plasma amprenavir trough concentartion (C
) was 49% higher in the HD-FPV/RTV arm than in the STD-FPV/RTV arm and similar in the FPV/LPV/RTV and STD-FPV/RTV arms. The plasma lopinavir C was similar to historical data with standard LPV/RTV 400 mg/100 mg twice daily. All regimens were relatively well tolerated, although diarrhoea was more frequent in the HD-FPV/RTV and FPV/LPV/RTV arms, and hypertriglyceridaemia and increased total cholesterol were more common in the FPV/LPV/RTV arm.
Conclusions: While the strategies of higher dose FPV/RTV and dual FPV/LPV/RTV were relevant at the time of study initiation, new therapies for antiretroviral-experienced patients make such strategies of limited interest. In addition, this study failed to demonstrate antiviral superiority of the HD-FPV/RTV or FPV/LPV/RTV regimen over the STD-FPV/RTV twice-daily regimen in highly treatment-experienced patients.
Keywords: LPV/RTV , protease inhibitors (PI) , multi PI-experienced , high-dose FPV/RTV , dual-boosted PIs
Members of the TRIAD Study Group are listed in the Acknowledgements.