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Jean Michel Molina - One of the best experts on this subject based on the ideXlab platform.

  • doravirine versus ritonavir boosted Darunavir in antiretroviral naive adults with hiv 1 drive forward 96 week results of a randomised double blind non inferiority phase 3 trial
    The Lancet HIV, 2020
    Co-Authors: Jean Michel Molina, E Dejesus, Kathleen Squires, P Cahn, Johan Lombaard, Anthony Rodgers, Paul E Sax, Mingtain Lai, Lisa Lupinacci
    Abstract:

    Summary Background Doravirine is a novel, non-nucleoside reverse transcriptase inhibitor that has shown non-inferior efficacy to ritonavir-boosted Darunavir, with a superior lipid profile, in adults with HIV who were treatment naive at week 48 in the phase 3 DRIVE-FORWARD trial. Here we present the 96-week data for the study. Methods This randomised, controlled, double-blind, multicentre, non-inferiority, phase 3 study was undertaken at 125 clinical centres in 15 countries. Eligible participants were adults (aged ≥18 years) infected with HIV-1 who were naive to antiretroviral therapy, with a plasma HIV-1 RNA concentration of 1000 copies per mL or higher at screening, and no known resistance to any of the study drugs. Participants were randomly assigned (1:1) using an interactive voice and web response system, stratified by baseline HIV-1 RNA concentration and background nucleoside reverse transcriptase inhibitor therapy, to doravirine (100 mg per day) or ritonavir-boosted Darunavir (100 mg ritonavir and 800 mg Darunavir per day), both with investigator-selected nucleoside reverse transcriptase inhibitors: emtricitabine and tenofovir disoproxil fumarate or abacavir and lamivudine. Participants and investigators were masked to treatment assignment until week 96. The primary efficacy endpoint was the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at week 48, which has been reported previously. Here we report the key secondary efficacy endpoint of the proportion of participants who achieved this concentration by week 96, assessed in all participants who received at least one dose of any study drug, regardless of whether it was their randomly assigned treatment. We used a US Food and Drug Administration snapshot approach and a margin of 10 percentage points to define the non-inferiority of doravirine to ritonavir-boosted Darunavir at 96 weeks. Key safety endpoints were change in fasting serum lipid concentrations, the incidence of adverse events, and time to discontinuation due to an adverse event, assessed in all participants who received at least one dose of any study medication. This study is registered with ClinicalTrials.gov , NCT02275780 , and is closed to accrual. Findings Between Dec 1, 2014, and Oct 20, 2015, 1027 individuals were screened, of whom 769 participants were randomly assigned to doravirine (n=385) or ritonavir-boosted Darunavir (n=384), and 383 in both groups were given at least one dose of their allocated treatment. Most participants were male (645 [84%] of 766) and white (560 [73%]), with a mean age of 35·2 years (SD 10·6). 292 participants in the doravirine group and 273 in the Darunavir group completed 96 weeks of treatment. At week 96, a higher proportion of the doravirine group (277 [73%] of 383) achieved an HIV-1 RNA concentration of less than 50 copies per mL than did of the Darunavir group (248 [66%] of 383; difference 7·1%, 95% CI 0·5–13·7). Responses were similar regardless of baseline characteristics. Treatment-emergent resistance to any study drug occurred in two (1%) of 383 participants in the doravirine group and one ( Interpretation These results through 96 weeks support the efficacy and safety results reported previously for doravirine at 48 weeks, supporting the use of doravirine for the long-term treatment of adults with previously untreated HIV-1 infection. Funding Merck.

  • a week 48 randomized phase 3 trial of Darunavir cobicistat emtricitabine tenofovir alafenamide in treatment naive hiv 1 patients
    AIDS, 2018
    Co-Authors: Joseph J. Eron, Erika Van Landuyt, Joel E Gallant, Jacques Reynes, Andrea Antinori, Chloe Orkin, Eugenia Negredo, Jean Michel Molina, Anthony Mills, Erkki Lathouwers
    Abstract:

    Objectives:To investigate efficacy and safety of a single-tablet regimen of Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg vs. Darunavir/cobicistat plus emtricitabine/tenofovir disoproxyl fumarate (TDF) (control) in antiretroviral-treatment-naive, HIV-1-infect

  • A week-48 randomized phase-3 trial of Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients
    AIDS, 2018
    Co-Authors: Joseph J. Eron, Jacques Reynes, Andrea Antinori, Chloe Orkin, Eugenia Negredo, Jean Michel Molina, Anthony Mills, Joel Gallant, Erika Van Landuyt, Erkki Lathouwers
    Abstract:

    OBJECTIVES: To investigate efficacy and safety of a single-tablet regimen of Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg vs. Darunavir/cobicistat plus emtricitabine/tenofovir disoproxyl fumarate (TDF) (control) in antiretroviral-treatment-naive, HIV-1-infected adults. DESIGN: Phase-3, randomized, active-controlled, double-blind, international, multicenter, noninferiority study (NCT02431247). METHODS: Seven hundred and twenty-five participants were randomized (1 : 1) to D/C/F/TAF (362) or control (363). The primary objective was to demonstrate noninferiority of D/C/F/TAF vs. control for percentage viral load less than 50 copies/ml (FDA-snapshot analysis) at 48 weeks (10% margin). RESULTS: At week 48, D/C/F/TAF was noninferior to control (91.4 vs. 88.4% achieved viral load

  • doravirine versus ritonavir boosted Darunavir in antiretroviral naive adults with hiv 1 drive forward 48 week results of a randomised double blind phase 3 non inferiority trial
    The Lancet HIV, 2018
    Co-Authors: Jean Michel Molina, E Dejesus, Kathleen Squires, P Cahn, Johan Lombaard, Xia Xu, Anthony Rodgers, Lisa Lupinacci, Sushma Kumar, Peter Sklar
    Abstract:

    Summary Background Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with a pharmacokinetic profile supporting once-daily dosing, and potent in-vitro activity against the most common NNRTI-resistant HIV-1 variants. We compared doravirine with ritonavir-boosted Darunavir, when both were given with two nucleoside reverse transcriptase inhibitors (NRTIs), in adults with previously untreated HIV-1 infection. Methods In this randomised, controlled, double-blind, multicentre, non-inferiority trial, adults with HIV-1 infection were screened and enrolled at 125 clinical centres in 15 countries. Eligible participants (aged ≥18 years) were naive to antiretroviral therapy with plasma HIV-1 RNA of at least 1000 copies per mL at screening. Participants who had previously been treated for a viral infection other than HIV-1, those taking immunosuppressive drugs, and individuals with active acute hepatitis were excluded. Participants were randomly assigned (1:1) via an interactive voice and web response system to receive oral doravirine 100 mg or Darunavir 800 mg plus ritonavir 100 mg once daily, with two investigator-selected NRTIs (tenofovir and emtricitabine or abacavir and lamivudine) for up to 96 weeks. Randomisation was stratified by HIV-1 RNA measurements at screening (≤100 000 vs >100 000 copies per mL) and the NRTI pair. Study participants, funding institution staff, investigators, and study site personnel were masked to treatment group assignment. The primary efficacy endpoint was the proportion of participants achieving HIV-1 RNA of less than 50 copies per mL at week 48 defined by the US Food and Drug Administration snapshot algorithm, with non-inferiority established if the lower bound of the two-sided 95% CI for the treatment difference (doravirine minus Darunavir) was greater than −10 percentage points. All participants who received at least one dose of study drug were included in the primary efficacy and safety analyses. This trial is active, but not recruiting, and is registered with ClinicalTrials.gov, number NCT02275780. Findings Between Dec 1, 2014, and Oct 20, 2015, 1027 participants were screened for eligibility, of whom 769 participants were randomly assigned to treatment (385 with doravirine and 384 with ritonavir-boosted Darunavir). 56 participants discontinued treatment in the doravirine group compared with 71 in the Darunavir group, mostly due to loss to follow-up. 383 participants who received doravirine and 383 who received Darunavir were included in the primary efficacy analyses. At week 48, 321 (84%) participants in the doravirine group and 306 (80%) in the Darunavir group achieved plasma HIV-1 RNA of less than 50 copies per mL (difference 3·9%, 95% CI −1·6 to 9·4), indicating non-inferiority of the doravirine regimen. The most common study drug-related adverse events were diarrhoea (21 [5%] of 383 participants in the doravirine group and 49 [13%] of 383 participants in the Darunavir group), nausea (25 [7%] vs 29 [8%]), and headache (23 [6%] vs ten [3%]). 18 participants (six [2%] of 383 participants in the doravirine group vs 12 [3%] of 383 participants in the Darunavir group) discontinued treatment due to adverse events, which were considered drug-related in four (1%) participants in the doravirine group and 8 (2%) participants in the Darunavir group. Serious adverse events occurred in 19 (5%) of 383 participants in the doravirine group and 23 (6%) of 383 in the Darunavir roup, and were considered study-drug related in one ( Interpretation In treatment-naive adults with HIV-1 infection, doravirine combined with two NRTIs might offer a valuable treatment option for adults with previously untreated HIV-1 infection. Funding Merck & Co.

  • doravirine versus ritonavir boosted Darunavir in antiretroviral naive adults with hiv 1 drive forward 48 week results of a randomised double blind phase 3 non inferiority trial
    The Lancet HIV, 2018
    Co-Authors: Jean Michel Molina, E Dejesus, Kathleen Squires, P Cahn, Johan Lombaard, Anthony Rodgers, Lisa Lupinacci, Paul E Sax, Mingtain Lai, Sushma Kumar
    Abstract:

    Summary Background Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with a pharmacokinetic profile supporting once-daily dosing, and potent in-vitro activity against the most common NNRTI-resistant HIV-1 variants. We compared doravirine with ritonavir-boosted Darunavir, when both were given with two nucleoside reverse transcriptase inhibitors (NRTIs), in adults with previously untreated HIV-1 infection. Methods In this randomised, controlled, double-blind, multicentre, non-inferiority trial, adults with HIV-1 infection were screened and enrolled at 125 clinical centres in 15 countries. Eligible participants (aged ≥18 years) were naive to antiretroviral therapy with plasma HIV-1 RNA of at least 1000 copies per mL at screening. Participants who had previously been treated for a viral infection other than HIV-1, those taking immunosuppressive drugs, and individuals with active acute hepatitis were excluded. Participants were randomly assigned (1:1) via an interactive voice and web response system to receive oral doravirine 100 mg or Darunavir 800 mg plus ritonavir 100 mg once daily, with two investigator-selected NRTIs (tenofovir and emtricitabine or abacavir and lamivudine) for up to 96 weeks. Randomisation was stratified by HIV-1 RNA measurements at screening (≤100 000 vs >100 000 copies per mL) and the NRTI pair. Study participants, funding institution staff, investigators, and study site personnel were masked to treatment group assignment. The primary efficacy endpoint was the proportion of participants achieving HIV-1 RNA of less than 50 copies per mL at week 48 defined by the US Food and Drug Administration snapshot algorithm, with non-inferiority established if the lower bound of the two-sided 95% CI for the treatment difference (doravirine minus Darunavir) was greater than −10 percentage points. All participants who received at least one dose of study drug were included in the primary efficacy and safety analyses. This trial is active, but not recruiting, and is registered with ClinicalTrials.gov, number NCT02275780. Findings Between Dec 1, 2014, and Oct 20, 2015, 1027 participants were screened for eligibility, of whom 769 participants were randomly assigned to treatment (385 with doravirine and 384 with ritonavir-boosted Darunavir). 56 participants discontinued treatment in the doravirine group compared with 71 in the Darunavir group, mostly due to loss to follow-up. 383 participants who received doravirine and 383 who received Darunavir were included in the primary efficacy analyses. At week 48, 321 (84%) participants in the doravirine group and 306 (80%) in the Darunavir group achieved plasma HIV-1 RNA of less than 50 copies per mL (difference 3·9%, 95% CI −1·6 to 9·4), indicating non-inferiority of the doravirine regimen. The most common study drug-related adverse events were diarrhoea (21 [5%] of 383 participants in the doravirine group and 49 [13%] of 383 participants in the Darunavir group), nausea (25 [7%] vs 29 [8%]), and headache (23 [6%] vs ten [3%]). 18 participants (six [2%] of 383 participants in the doravirine group vs 12 [3%] of 383 participants in the Darunavir group) discontinued treatment due to adverse events, which were considered drug-related in four (1%) participants in the doravirine group and 8 (2%) participants in the Darunavir group. Serious adverse events occurred in 19 (5%) of 383 participants in the doravirine group and 23 (6%) of 383 in the Darunavir roup, and were considered study-drug related in one ( Interpretation In treatment-naive adults with HIV-1 infection, doravirine combined with two NRTIs might offer a valuable treatment option for adults with previously untreated HIV-1 infection. Funding Merck & Co.

Gilles Peytavin - One of the best experts on this subject based on the ideXlab platform.

  • placental transfer of Darunavir in an ex vivo human cotyledon perfusion model
    Antimicrobial Agents and Chemotherapy, 2014
    Co-Authors: Laurent Mandelbrot, Dominique Duro, Emilie Belissa, Gilles Peytavin
    Abstract:

    Placental transfer of the HIV protease inhibitor Darunavir was investigated in 5 term human cotyledons perfused with Darunavir (1,000 ng/ml) in the maternal to fetal direction. The mean (± the standard deviation [SD]) fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 30 to 90 min) was 15.0% ± 2.1%, and the mean (±SD) clearance index (Darunavir FTR/antipyrine FTR) was 40.3% ± 5.8%. This shows that Darunavir crosses the placenta at a relatively low rate, resulting in fetal exposure.

  • efficacy of Darunavir ritonavir maintenance monotherapy in patients with hiv 1 viral suppression a randomized open label noninferiority trial monoi anrs 136
    AIDS, 2010
    Co-Authors: Christine Katlama, Jean Michel Molina, Pierremarie Girard, Marc Antoine Valantin, Michele Algartegenin, Claudine Duvivier, Sidonie Lambertniclot, B Hoen, Sophie Pakianather, Gilles Peytavin
    Abstract:

    Background: Darunavir/ritonavir (Darunavir/r) maintenance strategy, in patients with suppressed HIV RNA viremia, is a potential long-term strategy to avoid nucleoside analogue toxicities and to reduce costs. Methods: MONOtherapy Inhibitor protease is a prospective, open-label, noninferiority, 96-week safety and efficacy trial in virologically suppressed patients on triple therapy who were randomized to a Darunavir/r triple drug regimen or Darunavir/r monotherapy. The primary endpoint was the proportion of patients with HIV RNA less than 400 copies/ml at week 48; treatment failure was defined as two consecutive HIV RNA more than 400copies/ml (time to loss of virologic response) or any change in treatment. The trial had 80% power to show noninferiority for the monotherapy arm (δ=―10%, 90% confidence interval). Results: A total of 242 patients were screened, 225 of whom were randomized. In the per protocol efficacy analysis, treatment success was 99% on Darunavir/r triple drug versus 94% on Darunavir/r monotherapy (δ=―4.9%, 90% confidence interval, from ―9.1 to ―0.8). Similar results were found in intent-to-treat population (92 versus 87.5%, δ=―4.5%, 90% confidence interval from ―11.2 to 2.1). Three patients experienced virologic failure on Darunavir/monotherapy and none on Darunavir/r triple drug. No resistance to protease inhibitor emerged in patients with plasma viral load above 50copies/ml. The two groups did not differ in the number of serious adverse events. Conclusion: Darunavir/r monotherapy exhibited efficacy rate over 85% with concordant results in the magnitude of difference with Darunavir/r triple drug regimen in both intent-to-treat and per protocol analyses, but discordant conclusions with respect to the noninferiority margin. Patients failing on Darunavir/r monotherapy had no emergence of new Darunavir resistance mutations preserving future treatment options.

  • efficacy of Darunavir ritonavir maintenance monotherapy in patients with hiv 1 viral suppression a randomized open label noninferiority trial monoi anrs 136
    AIDS, 2010
    Co-Authors: Christine Katlama, Jean Michel Molina, Pierremarie Girard, Marc Antoine Valantin, Michele Algartegenin, Claudine Duvivier, Sidonie Lambertniclot, B Hoen, Sophie Pakianather, Gilles Peytavin
    Abstract:

    BACKGROUND Darunavir/ritonavir (Darunavir/r) maintenance strategy, in patients with suppressed HIV RNA viremia, is a potential long-term strategy to avoid nucleoside analogue toxicities and to reduce costs. METHODS MONOtherapy Inhibitor protease is a prospective, open-label, noninferiority, 96-week safety and efficacy trial in virologically suppressed patients on triple therapy who were randomized to a Darunavir/r triple drug regimen or Darunavir/r monotherapy. The primary endpoint was the proportion of patients with HIV RNA less than 400 copies/ml at week 48; treatment failure was defined as two consecutive HIV RNA more than 400 copies/ml (time to loss of virologic response) or any change in treatment. The trial had 80% power to show noninferiority for the monotherapy arm (delta =-10%, 90% confidence interval). RESULTS A total of 242 patients were screened, 225 of whom were randomized. In the per protocol efficacy analysis, treatment success was 99% on Darunavir/r triple drug versus 94% on Darunavir/r monotherapy (delta = -4.9%, 90% confidence interval, from -9.1 to -0.8). Similar results were found in intent-to-treat population (92 versus 87.5%, delta = -4.5%, 90% confidence interval from -11.2 to 2.1). Three patients experienced virologic failure on Darunavir/monotherapy and none on Darunavir/r triple drug. No resistance to protease inhibitor emerged in patients with plasma viral load above 50 copies/ml. The two groups did not differ in the number of serious adverse events. CONCLUSION Darunavir/r monotherapy exhibited efficacy rate over 85% with concordant results in the magnitude of difference with Darunavir/r triple drug regimen in both intent-to-treat and per protocol analyses, but discordant conclusions with respect to the noninferiority margin. Patients failing on Darunavir/r monotherapy had no emergence of new Darunavir resistance mutations preserving future treatment options.

Bonaventura Clotet - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics of Darunavir cobicistat and etravirine alone and co administered in hiv infected patients
    Journal of Antimicrobial Chemotherapy, 2018
    Co-Authors: José Moltó, Elizabeth Challenger, Adrian Curran, J. Santos, Cristina Miranda, Marta Valle, Esteban Ribera, Saye Khoo, Bonaventura Clotet
    Abstract:

    Objectives To determine the effect of etravirine on the pharmacokinetics of Darunavir/cobicistat and vice versa. Safety and tolerability of this combination were also evaluated. Methods Open-label, fixed-sequence trial in two cohorts of HIV-infected patients on therapy with Darunavir/cobicistat 800/150 mg once daily (DRV cohort; n = 15) or etravirine 400 mg once daily (ETR cohort; n = 15). Etravirine or Darunavir/cobicistat were added on days 1-14 and 1-7 in participants in the DRV or ETR cohort, respectively. Full pharmacokinetic profiles were obtained on days 0 and 14 in the DRV cohort, and on days 0 and 7 in the ETR cohort. Darunavir, cobicistat and etravirine pharmacokinetic parameters [AUC0-24, Cmax and trough concentrations in plasma (C24)] were calculated for each individual by non-compartmental analysis and were compared using linear mixed-effects models. Adverse events and HIV-1 RNA in plasma were monitored. Results Etravirine co-administration decreased cobicistat AUC0-24, Cmax and C24 by 30%, 14% and 66%, respectively. Although Darunavir AUC0-24 and Cmax were unchanged by etravirine, Darunavir C24 was 56% lower for Darunavir/cobicistat co-administered with etravirine relative to Darunavir/cobicistat alone. Etravirine pharmacokinetics were unchanged by Darunavir/cobicistat. Treatments were well tolerated, and HIV-1 RNA remained undetectable in all participants. Conclusions Although etravirine pharmacokinetics was unchanged by Darunavir/cobicistat, there was a significant decrease in cobicistat exposure and in Darunavir C24 when Darunavir/cobicistat was co-administered with etravirine. Boosting Darunavir with ritonavir instead of with cobicistat may be preferred if Darunavir is to be combined with etravirine in clinical practice.

  • use of a physiologically based pharmacokinetic model to simulate drug drug interactions between antineoplastic and antiretroviral drugs
    Journal of Antimicrobial Chemotherapy, 2016
    Co-Authors: José Moltó, Andrew Owen, Cristina Miranda, Bonaventura Clotet, Marta Valle, Rajith K R Rajoli, D J Back, Marco Siccardi
    Abstract:

    Background Co-administration of antineoplastics with ART is challenging due to potential drug-drug interactions (DDIs). However, trials specifically assessing such DDIs are lacking. Our objective was to simulate DDIs between the antineoplastics erlotinib and gefitinib with key antiretroviral drugs and to predict dose adjustments using a physiologically based pharmacokinetic (PBPK) model. Methods In vitro data describing chemical properties and pharmacokinetic processes of each drug and their effect on cytochrome P450 isoforms were obtained from the literature. Plasma drug-concentration profiles were simulated in a virtual population of 50 individuals receiving erlotinib or gefitinib alone or with Darunavir/ritonavir, efavirenz or etravirine. Simulated pharmacokinetic parameters and the magnitude of DDIs with probe drugs (midazolam, maraviroc) were compared with literature values. Erlotinib and gefitinib pharmacokinetics with and without antiretrovirals were compared and dose-adjustment strategies were evaluated. Results Simulated parameters of each drug and the magnitude of DDIs with probe drugs were in agreement with reference values. Darunavir/ritonavir increased erlotinib and gefitinib exposure, while efavirenz and etravirine decreased erlotinib and gefitinib concentrations. Based on our predictions, dose-adjustment strategies may consist of once-daily dosing erlotinib at 25 mg and gefitinib at 125 mg with Darunavir/ritonavir; or erlotinib at 200 mg and gefitinib at 375 mg with etravirine. The interaction with efavirenz was not overcome even after doubling erlotinib or gefitinib doses. Conclusions PBPK models predicted the in vivo pharmacokinetics of erlotinib, gefitinib and the antiretrovirals Darunavir/ritonavir, efavirenz and etravirine, and the DDIs between them. The simulated dose-adjustments may represent valuable strategies to optimize antineoplastic therapy in HIV-infected patients.

  • once daily dolutegravir versus Darunavir plus ritonavir for treatment naive adults with hiv 1 infection flamingo 96 week results from a randomised open label phase 3b study
    The Lancet HIV, 2015
    Co-Authors: Jean Michel Molina, Keith Henry, Jan Van Lunzen, Bonaventura Clotet, Valeriv Kulagin, Naomi Givens, Carlos Fernando De Oliveira, Adriano Lazzarin, Matthias Cavassini, Clare Brennan
    Abstract:

    Summary Background The primary analysis of the FLAMINGO study at 48 weeks showed that patients taking dolutegravir once daily had a significantly higher virological response rate than did those taking ritonavir-boosted Darunavir once daily, with similar tolerability. We present secondary efficacy and safety results analysed at 96 weeks. Methods FLAMINGO was a multicentre, open-label, phase 3b, non-inferiority study of HIV-1-infected treatment-naive adults. Patients were randomly assigned (1:1) to dolutegravir 50 mg or Darunavir 800 mg plus ritonavir 100 mg, with investigator-selected combination tenofovir and emtricitabine or combination abacavir and lamivudine background treatment. The main endpoints were plasma HIV-1 RNA less than 50 copies per mL and safety. The non-inferiority margin was –12%. If the lower end of the 95% CI was greater than 0%, then we concluded that dolutegravir was superior to ritonavir-boosted Darunavir. This trial is registered with ClinicalTrials.gov, number NCT01449929. Findings Of 595 patients screened, 488 were randomly assigned and 484 included in the analysis (242 assigned to receive dolutegravir and 242 assigned to receive ritonavir-boosted Darunavir). At 96 weeks, 194 (80%) of 242 patients in the dolutegravir group and 164 (68%) of 242 in the ritonavir-boosted Darunavir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 12·4, 95% CI 4·7–20·2; p=0·002), with the greatest difference in patients with high viral load at baseline (50/61 [82%] vs 32/61 [52%], homogeneity test p=0·014). Six participants (three since 48 weeks) in the dolutegravir group and 13 (four) in the Darunavir plus ritonavir group discontinued because of adverse events. The most common drug-related adverse events were diarrhoea (23/242 [10%] in the dolutegravir group vs 57/242 [24%] in the Darunavir plus ritonavir group), nausea (31/242 [13%] vs 34/242 [14%]), and headache (17/242 [7%] vs 12/242 [5%]). Interpretation Once-daily dolutegravir is associated with a higher virological response rate than is once-daily ritonavir-boosted Darunavir. Dolutegravir compares favourably in efficacy and safety to a boosted Darunavir regimen with nucleoside reverse transcriptase inhibitor background treatment for HIV-1-infected treatment-naive patients. Funding ViiV Healthcare and Shionogi & Co.

  • once daily dolutegravir versus Darunavir plus ritonavir in antiretroviral naive adults with hiv 1 infection flamingo 48 week results from the randomised open label phase 3b study
    The Lancet, 2014
    Co-Authors: Bonaventura Clotet, Jan Van Lunzen, Judith Feinberg, Marie Aude Khuongjosses, Irina Dumitru, Vadim Pokrovskiy, Roberto Ortiz, Jan Fehr, Michael S. Saag
    Abstract:

    Summary Background Dolutegravir has been shown to be non-inferior to an integrase inhibitor and superior to a non-nucleoside reverse transcriptase inhibitor (NNRTI). In FLAMINGO, we compared dolutegravir with Darunavir plus ritonavir in individuals naive for antiretroviral therapy. Methods In this multicentre, open-label, phase 3b, non-inferiority study, HIV-1-infected antiretroviral therapy-naive adults with HIV-1 RNA concentration of 1000 copies per mL or more and no resistance at screening were randomly assigned (1:1) to receive either dolutegravir 50 mg once daily or Darunavir 800 mg plus ritonavir 100 mg once daily, with investigator-selected tenofovir–emtricitabine or abacavir–lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤100 000 or >100 000 copies per mL) and nucleoside reverse transcriptase inhibitor (NRTI) selection. The primary endpoint was the proportion of patients with HIV-1 RNA concentration lower than 50 copies per mL (Food and Drug Administration [FDA] snapshot algorithm) at week 48 with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, NCT01449929. Findings Recruitment began on Oct 31, 2011, and was completed on May 24, 2012, in 64 research centres in nine countries worldwide. Of 595 patients screened, 484 patients were included in the analysis (242 in each group). At week 48, 217 (90%) patients receiving dolutegravir and 200 (83%) patients receiving Darunavir plus ritonavir had HIV-1 RNA of less than 50 copies per mL (adjusted difference 7·1%, 95% CI 0·9–13·2), non-inferiority and on pre-specified secondary analysis dolutegravir was superior (p=0·025). Confirmed virological failure occurred in two ( vs Darunavir plus ritonavir 70 [29%] patients), nausea (39 [16%] vs 43 [18%]), and headache (37 [15%] vs 24 [10%]). Patients receiving dolutegravir had significantly fewer low-density lipoprotein values of grade 2 or higher (11 [2%] vs 36 [7%]; p=0·0001). Interpretation Once-daily dolutegravir was superior to once-daily Darunavir plus ritonavir. Once-daily dolutegravir in combination with fixed-dose NRTIs represents an effective new treatment option for HIV-1-infected, treatment-naive patients. Funding ViiV Healthcare and Shionogi & Co.

  • herb drug interaction between echinacea purpurea and Darunavir ritonavir in hiv infected patients
    Antimicrobial Agents and Chemotherapy, 2011
    Co-Authors: José Moltó, Samandhy Cedeño, Cristina Miranda, Eugenia Negredo, Marta Valle, Manuel J Barbanoj, Bonaventura Clotet
    Abstract:

    The aim of this open-label, fixed-sequence study was to investigate the potential of Echinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor Darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including Darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included. E. purpurea root extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of Darunavir-ritonavir on days 0 (Darunavir-ritonavir) and 14 (Darunavir-ritonavir plus echinacea). Individual Darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m2. Echinacea was well tolerated, and all participants completed the study. The GMR for Darunavir coadministered with echinacea relative to that for Darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration of E. purpurea with Darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in Darunavir concentrations, although this did not affect the overall Darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring Darunavir concentrations on an individual basis may give reassurance in this setting.

Thomas N Kakuda - One of the best experts on this subject based on the ideXlab platform.

  • Darunavir cobicistat once daily for the treatment of hiv
    Expert Review of Anti-infective Therapy, 2015
    Co-Authors: Thomas N Kakuda, Tom Van De Casteele, Koen Iterbeke, Magda Opsomer, Simon Vanveggel, Frank Tomaka, Herta Crauwels, Goedele De Smedt
    Abstract:

    A current focus in HIV management is improving adherence by minimizing pill burden with convenient formulations, including fixed-dose combinations (FDCs). Darunavir, a HIV protease inhibitor, co-administered with low-dose ritonavir (800/100 mg once daily), is recommended in guidelines in combination with other antiretrovirals for HIV patients with no Darunavir resistance-associated mutations. Cobicistat is an alternative agent to ritonavir for boosting plasma drug levels of Darunavir among other antiretrovirals. Cobicistat is a more specific cytochrome P450 3A inhibitor than ritonavir without enzyme-inducing properties. This review describes the differing effects of cobicistat and ritonavir on metabolic enzymes, which explains their differing drug–drug interactions, and summarizes some of the studied drug–drug interactions for cobicistat. It also outlines the clinical development and data for a once-daily Darunavir/cobicistat FDC. This FDC thus allows for a once-daily treatment regimen (including backgrou...

  • safety and efficacy of Darunavir ritonavir in treatment experienced pediatric patients week 48 results of the ariel trial
    Pediatric Infectious Disease Journal, 2015
    Co-Authors: Avy Violari, Erkki Lathouwers, Thomas N Kakuda, Magda Opsomer, Rosa Bologna, Nagalingeswaran Kumarasamy, Jose Henrique Pilotto, Annemie Hendrickx, Tom Van De Casteele, Frank Tomaka
    Abstract:

    BACKGROUND ARIEL (Darunavir in treatment-experienced pediatric population) was a phase II, open-label study assessing safety and antiviral activity of Darunavir/ritonavir twice daily with an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected pediatric patients (3 to <6 years, weighing 10 to <20 kg). METHODS The study consisted of an initial 4-week screening period, 48 weeks of treatment and a 4-week follow-up period. Patients initially received Darunavir/ritonavir 20/3 mg/kg twice-daily for 2 weeks. Following review of pharmacokinetic, safety and antiviral data, the doses of Darunavir/ritonavir were adjusted to 25/3 mg/kg twice-daily for patients <15 kg, and 375/50 mg twice-daily for patients 15 to <20 kg. RESULTS Of the 34 patients screened, 21 were treated (median treatment duration 48.6 weeks). Darunavir plus an OBR was well tolerated over 48 weeks, with no new safety concerns, and a comparable safety profile to that seen in older children and adults. All treatment-emergent lipid-related and glucose-related laboratory abnormalities were grade 1 or 2. At week 48, 17 of 21 patients (81.0%) had a confirmed virologic response (intent-to-treat, time-to-loss of virologic response). Improvements in height and weight were seen during the study. CONCLUSIONS No new safety concerns were observed over a 48 week period. These results led to lowering the age to 3 years at which Darunavir/ritonavir is indicated for use in treatment-experienced pediatric patients. This study also established doses of Darunavir to use in treatment-experienced, HIV-1-infected patients aged 3 to <6 years. A high virologic response was observed with this dose. No development of resistance was observed in patients who experienced virologic failure.

  • cobicistat boosted Darunavir in hiv 1 infected adults week 48 results of a phase iiib open label single arm trial
    Aids Research and Therapy, 2014
    Co-Authors: Karen T. Tashima, Tom Van De Casteele, Nicolas Margot, Thomas N Kakuda, Magda Opsomer, Anne Brochot, Frank Tomaka, Gordon Crofoot, William Garner, Joseph Custodio
    Abstract:

    Background: Cobicistat is an alternative pharmacoenhancer to ritonavir. In healthy volunteers, Darunavir exposure was comparable when Darunavir 800 mg once daily was co-administered with cobicistat 150 mg once daily (as single agents or a fixed-dose combination) vs. with ritonavir 100 mg once daily. Methods: This 48-week, Phase IIIb, single-arm, US multicenter study (NCT01440569) evaluated safety, efficacy and pharmacokinetics of Darunavir/cobicistat 800/150 mg once daily (as single agents) plus two investigator-selected nucleoside/tide reverse transcriptase inhibitors (N[t]RTIs) in HIV-1-infected adults. Patients had no Darunavir resistance-associated mutations (RAMs), plasma viral load (VL) ≥1000 HIV-1 RNA copies/ml, eGFR ≥80 ml/min and genotypic sensitivity to the two N[t]RTIs. The primary endpoint was any treatment-emergent grade 3 or 4 adverse events (AEs) through Week 24. Results: The majority of the 313 intent-to-treat patients were treatment-naive (295/313; 94%), male (89%), White (60%) and received a tenofovir-based regimen (99%). Median baseline VL and CD4 + count overall were 4.8 log10 HIV-1 RNA copies/ml and 361 cells/mm 3 , respectively. Overall, 86% of patients (268/313) completed the study. The majority of discontinuations were for AEs (15/313; 5%). The incidence of treatment-emergent grade 3 or 4 AEs regardless of causality was 6% through Week 24 and 8% through Week 48. Most common AEs through Week 48 were diarrhea (27%) and nausea (23%), which were grade 1 or 2 in severity. Week 48 virologic response rates (% with VL <50 HIV-1 RNA copies/ml; Snapshot analysis) were 81% overall and 83% in treatment-naive patients; median increases in CD4 + count at 48 weeks were 167 and 169 cells/mm 3 , respectively. Of 15/313 patients who met the criteria for resistance analysis, one developed a Darunavir RAM as a mixture with wild-type (I84I/V), without phenotypic resistance to Darunavir. The mean population pharmacokinetic-derived Darunavir areas under the plasma concentration–time curve were 102,000 overall and 100,620 ngh/ml in treatment-naive patients. No clinically relevant relationships were seen between Darunavir exposure and virologic response, AEs or laboratory parameters. Conclusion: Darunavir/cobicistat 800/150 mg once daily was generally well tolerated through Week 48, with no new safety concerns. Pharmacokinetics, virologic and immunologic responses for Darunavir/cobicistat were similar to previous data for Darunavir/ritonavir 800/100 mg once daily.

  • pharmacokinetics of Darunavir in fixed dose combination with cobicistat compared with coadministration of Darunavir and ritonavir as single agents in healthy volunteers
    The Journal of Clinical Pharmacology, 2014
    Co-Authors: Thomas N Kakuda, Romana Petrovic, Tom Van De Casteele, Koen Iterbeke, Magda Opsomer, Vera Hillewaert, Maarten Timmers, Richard M. W. Hoetelmans
    Abstract:

    This study compared the bioavailability of two candidate fixed-dose combinations (FDCs: G003 and G004) of Darunavir/cobicistat 800/150 mg with that of Darunavir 800 mg and ritonavir 100 mg coadministered as single agents. Short-term safety and tolerability of the FDC formulations were also assessed. This open-label trial included 36 healthy volunteers and assessed steady-state pharmacokinetics of Darunavir over 3 randomized, 10-day treatment sequences, under fed conditions. Blood samples for determination of plasma concentrations of Darunavir and cobicistat or ritonavir were taken over 24 hours on day 10 and analyzed by liquid-chromatography tandem mass-spectroscopy. Darunavir AUC24h following administration of the FDCs (G003: 74,780 ng ∙ h/mL and G004: 76,490 ng ∙ h/mL) was comparable to that following Darunavir/ritonavir (78,410 ng ∙ h/mL), as was Cmax (6,666 and 6,917 ng/mL versus 6,973 ng/mL, respectively). Modestly lower C0h (1,504 and 1,478 ng/mL versus 2,015 ng/mL) and Cmin (1,167 and 1,224 ng/mL versus 1,540 ng/mL) values were seen with the FDCs. Short-term tolerability of the FDCs was comparable to that of Darunavir/ritonavir when administered as single agents. The most common adverse events reported were headache, gastrointestinal upset, or rash. Cobicistat is an effective pharmacoenhancer of Darunavir when administered as an FDC. Short-term administration of Darunavir/ritonavir or Darunavir/cobicistat was generally well tolerated.

  • bioequivalence of a Darunavir cobicistat fixed dose combination tablet versus single agents and food effect in healthy volunteers
    Antiviral Therapy, 2014
    Co-Authors: Thomas N Kakuda, Van De Casteele T, Romana Petrovic, M Neujens, Hafiz Salih, Magda Opsomer, Richard M. W. Hoetelmans
    Abstract:

    Background: Darunavir requires pharmacokinetic enhancement to increase its bioavailability. Cobicistat is potentially an alternative pharmacokinetic booster to ritonavir. Bioequivalence of a Darunavir/cobicistat fixed-dose combination (FDC) versus Darunavir and cobicistat co-administered as single agents and the effect of a high-fat meal on the pharmacokinetics of the FDC were evaluated. Methods: In this Phase I, open-label, randomized, three-panel, crossover study (NCT01619527), healthy volunteers received a single dose of Darunavir (800 mg) with cobicistat (150 mg) as either an FDC or as single agents co-administered under fasted (panel 1, n=74) or fed (breakfast, panel 2, n=40) conditions, or as the FDC under fasted versus fed (high-fat breakfast) conditions (panel 3, n=19), with a ≥7 day washout period between treatments. Pharmacokinetic profiles, safety and tolerability were assessed. Results: 90% confidence intervals of the least square mean ratios for Darunavir and cobicistat maximum plasma concentration and area under the plasma concentration– time curve (AUC) were all within 80.00% and 125.00% in panels 1 and 2. Administration of the FDC with a highfat breakfast significantly increased Darunavir maximum plasma concentration 2.27-fold and AUC 1.63–1.70-fold, whereas cobicistat pharmacokinetics were unaffected. No volunteers discontinued due to adverse events (AEs). All AEs were grade 1 or 2. Overall, 27 (20%) and 26 (20%) volunteers had ≥1 AE at least possibly related to Darunavir and cobicistat, respectively. Conclusions: Bioequivalence of the Darunavir/cobicistat 800/150-mg FDC was demonstrated versus Darunavir and cobicistat co-administered as single agents under fasted or fed conditions. Food increased Darunavir exposure, therefore, Darunavir/cobicistat should be administered with food.

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