Browsing by Author "Mills, Andrew"

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    Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial
    (2007) Madruga, Jose Valdez; Cahn, Pedro; Grinsztejn, Beatriz; Haubrich, Richard; Lalezari, Jacob; Mills, Andrew; Pialoux, Gilles; Wilkin, Timothy; Peeters, Monika; Vingerhoets, Johan; de Smedt, Goedele; Leopold, Ludovic; Trefiglio, Ronald; Woodfall, Brian; DUET-1 study group
    Background: Antiretroviral agents active against drug-resistant HIV-1 are needed for treatment-experienced patients. The aim of this trial was to assess the efficacy, safety, and tolerability of TMC125 (etravirine), a non-nucleoside reverse transcriptase inhibitor (NNRTI). Methods: DUET-1 is a continuing, multinational randomised, double-blind, placebo-controlled, phase III trial. Treatment-experienced adult patients with virological failure on stable antiretroviral therapy, documented genotypic evidence of NNRTI resistance, viral load over 5000 copies per mL, and three or more primary protease inhibitor mutations were randomly assigned to receive 200 mg TMC125 or placebo twice daily. All patients also received darunavir with low-dose ritonavir and investigator-selected nucleoside reverse transcriptase inhibitors. Enfuvirtide use was optional. The primary endpoint was a confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, with the number NCT00254046. Findings: 612 patients were randomised and treated (304 in the TMC125 group, 308 in the placebo group). By week 24, 42 (14%) patients in the TMC125 group and 56 (18%) in the placebo group had discontinued, mainly due to virological failure. At week 24, 170 (56%) patients in the TMC125 group and 119 (39%) patients in the placebo group achieved a confirmed viral load of less than 50 copies per mL (difference in response rates 17%; 95% CI 9-25; p=0.005). Most adverse events were mild or moderate in severity. The type and incidence of adverse events, including neuropsychiatric events, seen with TMC125 were generally comparable with placebo, with the exception of rash (61 [20%] patients on TMC125 vs 30 [10%] on placebo) and diarrhoea (36 [12%] patients on TMC125 vs 63 [20%] on placebo). Interpretation: In treatment-experienced patients with NNRTI resistance, treatment with TMC125 achieved better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.
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    Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): A phase 3 randomised double-blind active-controlled trial
    (2011) Molina, Jean-Michel; Cahn, Pedro; Grinsztejn, Beatriz; Lazzarin, Adriano; Mills, Andrew; Saag, Michael; Supparatpinyo, Khuanchai; Walmsley, Sharon L.; Crauwels, Herta; Rimsky, Laurence T.; Vanveggel, Simon; Boven, Kristof
    Background: Efavirenz with tenofovir-disoproxil-fumarate and emtricitabine is a preferred antiretroviral regimen for treatment-naive patients infected with HIV-1. Rilpivirine, a new non-nucleoside reverse transcriptase inhibitor, has shown similar antiviral efficacy to efavirenz in a phase 2b trial with two nucleoside/nucleotide reverse transcriptase inhibitors. We aimed to assess the efficacy, safety, and tolerability of rilpivirine versus efavirenz, each combined with tenofovir-disoproxil-fumarate and emtricitabine. Methods: We did a phase 3, randomised, double-blind, double-dummy, active-controlled trial, in patients infected with HIV-1 who were treatment-naive. The patients were aged 18 years or older with a plasma viral load at screening of 5000 copies per mL or greater, and viral sensitivity to all study drugs. Our trial was done at 112 sites across 21 countries. Patients were randomly assigned by a computer-generated interactive web response system to receive either once-daily 25 mg rilpivirine or once-daily 600 mg efavirenz, each with tenofovir-disoproxil-fumarate and emtricitabine. Our primary objective was to show non-inferiority (12% margin) of rilpivirine to efavirenz in terms of the percentage of patients with confirmed response (viral load <50 copies per mL intention-to-treat time-to-loss-of-virological-response [ITT-TLOVR] algorithm) at week 48. Our primary analysis was by intention-to-treat. We also used logistic regression to adjust for baseline viral load. This trial is registered with ClinicalTrials.gov, number NCT00540449. Findings: 346 patients were randomly assigned to receive rilpivirine and 344 to receive efavirenz and received at least one dose of study drug, with 287 (83%) and 285 (83%) in the respective groups having a confirmed response at week 48. The point estimate from a logistic regression model for the percentage difference in response was -0.4 (95% CI -5.9 to 5.2), confirming non-inferiority with a 12% margin (primary endpoint). The incidence of virological failures was 13% (rilpivirine) versus 6% (efavirenz; 11%vs 4% by ITT-TLOVR). Grade 2-4 adverse events (55 [16%] on rilpivirine vs 108 [31%] on efavirenz, p<0.0001), discontinuations due to adverse events (eight [2%] on rilpivirine vs 27 [8%] on efavirenz), rash, dizziness, and abnormal dreams or nightmares were more common with efavirenz. Increases in plasma lipids were significantly lower with rilpivirine. Interpretation: Rilpivirine showed non-inferior efficacy compared with efavirenz, with a higher virological-failure rate, but a more favourable safety and tolerability profile. Funding: Tibotec.