Andrea Antinori1, Jose Arribas2, Jan Fehr3, Pierre-Marie Girard4, Andrzej Horban5, Andrew Hill9, Yvon van Delft7, Christiane Moecklinghoff8, Andrew Hill9. 1. Infectious Diseases, National Institute of Infectious Diseases, Rome, Italy. 2. IdiPAZ, Hospital la Paz, Madrid, Spain. 3. Infectious Diseases, University Hospital Zurich, Zurich, Switzerland. 4. Maladies Infectiueses et Tropicales, Hôpital Saint-Antoine, Paris, France. 5. Infectious Diseases, Warsaw Medical University, Warsaw, Poland. 6. Janssen, R&D, High Wycombe, UK. 7. Janssen, EMEA, Tilburg, Netherlands. 8. Janssen, EMEA, Neuss, Germany. 9. Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
Abstract
INTRODUCTION: In previous studies, protease inhibitor (PI) monotherapy has shown trends for higher low-level elevations in HIV-1 RNA compared to triple therapy, but no increase in the risk of drug resistance. METHODS: A total of 273 patients with HIV-1 RNA <50 copies/mL for over 24 weeks on current antiretrovirals switched to DRV/r (darunavir/ritonavir) 800/100 mg once-daily, either as monotherapy (n=137) or with 2NRTIs (nucleoside reverse-transcriptase inhibitors) (n=136), after a 4 week run-in phase with DRV/r + 2NRTI. Treatment failure was defined as HIV-1 RNA levels above 50 copies/mL (FDA Snapshot method) by Week 48, or switches off study treatment. Patients with elevations in HIV-1 RNA on DRV/r monotherapy could be re-intensified with NRTIs. The trial had 80% power to show non-inferiority for the monotherapy arm (delta = - 12%). RESULTS: Patients were 83% male and 87% Caucasian, with mean age 42 years; 10% were HCV antibody positive. In the DRV/r monotherapy arm, there were more patients with nadir CD4 count below 200 cells/µL (30% versus 22%). In the primary efficacy analysis, HIV-1 RNA <50 copies/mL by Week 48 (intent-to-treat (ITT)) was 118/137 (86.1%) in the DRV/r monotherapy arm versus 129/136 (94.9%) in the triple therapy arm; DRV/r monotherapy did not show non-inferiority versus triple therapy in the primary analysis (difference=- 8.7%, 95% CI -15.5 to -1.8%). In the multivariate analysis, the main predictor of treatment failure was nadir CD4 count. For patients with nadir CD4 counts <200 cells/µL, HIV-1 RNA suppression rates at Week 48 were 27/41 (66%) in the DRV/r monotherapy arm and 29/30 (97%) in the triple therapy arm; for patients with CD4 nadir at least 200 cells/µL, HIV-1 RNA suppression rates were 91/96 (95%) in the DRV/r monotherapy arm and 100/106 (94%) in the triple therapy arm. In the overall population, by a switch included analysis, efficacy was 92.0% versus 96.3%, showing non-inferiority (difference=- 4.3%, 95% CI=-9.7 to +1.2%). No treatment-emergent primary PI mutations were detected in three patients with sustained elevations in HIV-1 RNA at least 400 copies/mL (two on PI monotherapy, one on triple therapy). CD4 counts remained stable during the trial in both arms. CONCLUSIONS: In this study for patients with HIV-1 RNA < 50 copies/mL at baseline, switching to DRV/r monotherapy showed lower efficacy versus triple antiretroviral therapy at Week 48 in the primary switch equals failure analysis (86% versus 95%). However, this lower efficacy was seen mainly in patients with CD4 nadir levels below 200 cells/µL. There was no development of PI resistance.
INTRODUCTION: In previous studies, protease inhibitor (PI) monotherapy has shown trends for higher low-level elevations in HIV-1 RNA compared to triple therapy, but no increase in the risk of drug resistance. METHODS: A total of 273 patients with HIV-1 RNA <50 copies/mL for over 24 weeks on current antiretrovirals switched to DRV/r (darunavir/ritonavir) 800/100 mg once-daily, either as monotherapy (n=137) or with 2NRTIs (nucleoside reverse-transcriptase inhibitors) (n=136), after a 4 week run-in phase with DRV/r + 2NRTI. Treatment failure was defined as HIV-1 RNA levels above 50 copies/mL (FDA Snapshot method) by Week 48, or switches off study treatment. Patients with elevations in HIV-1 RNA on DRV/r monotherapy could be re-intensified with NRTIs. The trial had 80% power to show non-inferiority for the monotherapy arm (delta = - 12%). RESULTS:Patients were 83% male and 87% Caucasian, with mean age 42 years; 10% were HCV antibody positive. In the DRV/r monotherapy arm, there were more patients with nadirCD4 count below 200 cells/µL (30% versus 22%). In the primary efficacy analysis, HIV-1 RNA <50 copies/mL by Week 48 (intent-to-treat (ITT)) was 118/137 (86.1%) in the DRV/r monotherapy arm versus 129/136 (94.9%) in the triple therapy arm; DRV/r monotherapy did not show non-inferiority versus triple therapy in the primary analysis (difference=- 8.7%, 95% CI -15.5 to -1.8%). In the multivariate analysis, the main predictor of treatment failure was nadirCD4 count. For patients with nadirCD4 counts <200 cells/µL, HIV-1 RNA suppression rates at Week 48 were 27/41 (66%) in the DRV/r monotherapy arm and 29/30 (97%) in the triple therapy arm; for patients with CD4nadir at least 200 cells/µL, HIV-1 RNA suppression rates were 91/96 (95%) in the DRV/r monotherapy arm and 100/106 (94%) in the triple therapy arm. In the overall population, by a switch included analysis, efficacy was 92.0% versus 96.3%, showing non-inferiority (difference=- 4.3%, 95% CI=-9.7 to +1.2%). No treatment-emergent primary PI mutations were detected in three patients with sustained elevations in HIV-1 RNA at least 400 copies/mL (two on PI monotherapy, one on triple therapy). CD4 counts remained stable during the trial in both arms. CONCLUSIONS: In this study for patients with HIV-1 RNA < 50 copies/mL at baseline, switching to DRV/r monotherapy showed lower efficacy versus triple antiretroviral therapy at Week 48 in the primary switch equals failure analysis (86% versus 95%). However, this lower efficacy was seen mainly in patients with CD4nadir levels below 200 cells/µL. There was no development of PI resistance.
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