Rilpivirine

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Marita Stevens - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetic interaction between etravirine or Rilpivirine and telaprevir in healthy volunteers a randomized two way crossover trial
    The Journal of Clinical Pharmacology, 2014
    Co-Authors: Thomas N Kakuda, Steven Nijs, Lorant Leopold, James Witek, Yvon Van Delft, Ann Vandevoorde, Kirk Bertelsen, Marita Stevens, Herta Crauwels, Frank Tomaka
    Abstract:

    Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may require treatment with an HIV non-nucleoside reverse transcriptase inhibitor (NNRTI), for example, Rilpivirine or etravirine, and an HCV direct-acting antiviral drug such as telaprevir. In a two-panel, two-way, crossover study, healthy volunteers were randomized to receive etravirine 200 mg twice daily ± telaprevir 750 mg every 8 hours or Rilpivirine 25 mg once daily ± telaprevir 750 mg every 8 hours. Pharmacokinetic assessments were conducted for each drug at steady-state when given alone and when coadministered; statistical analyses were least-square means with 90% confidence intervals. Telaprevir minimum plasma concentration (Cmin), maximum plasma concentration (Cmax), and area under the concentration–time curve (AUC) decreased 25%, 10%, and 16%, respectively, when coadministered with etravirine and 11%, 3%, and 5%, respectively, when coadministered with Rilpivirine. Telaprevir did not affect etravirine pharmacokinetics, but increased Rilpivirine Cmin, Cmax, and AUC by 93%, 49%, and 78%, respectively. Both combinations were generally well tolerated. The small decrease in telaprevir exposure when coadministered with etravirine is unlikely to be clinically relevant. The interaction between telaprevir and Rilpivirine is not likely to be clinically relevant under most circumstances. No dose adjustments are deemed necessary when they are coadministered.

  • Lack of an effect of Rilpivirine on the pharmacokinetics of ethinylestradiol and norethindrone in healthy volunteers.
    International journal of clinical pharmacology and therapeutics, 2014
    Co-Authors: Herta Crauwels, Marita Stevens, Rolf P. G. Van Heeswijk, Annemie Buelens, Richard M. W. Hoetelmans
    Abstract:

    Rilpivirine is a human immunodeficiency virus Type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor. Objective: Rilpivirine metabolism involves cytochrome P450 3A4 (CYP3A4). This trial (ClinicalTrials. gov number: NCT00739622) evaluated the interaction between Rilpivirine and ethinylestradiol/norethindrone (combination oral contraceptives) which are metabolized by multiple pathways including CYP3A4. Methods: During three consecutive 28-day cycles 18 HIV-negative females received once-daily ethinylestradiol (35 mug)/norethindrone (1 mg) (Days 1 - 21); Days 22 - 28 were pill-free. Only in Cycle 3 was once-daily Rilpivirine (25 mg) co-administered (Days 1 - 15). Minimum and maximum plasma concentrations (Cmin; Cmax) and area under the plasma concentration-time curve over 24 hours (AUC24h) of ethinylestradiol/norethindrone (Day 15 Cycles 2 and 3) and Rilpivirine (Day 15 Cycle 3) were evaluated. Results: Rilpivirine coadministration had no effect on (least square mean ratio 90% confidence interval) ethinylestradiol Cmin (1.09 1.03 - 1.16) or AUC24h (1.14 1.10 - 1.19) but increased Cmax by 17% (1.17 1.06 - 1.30) which is unlikely to affect ethinylestradiol pharmacodynamics. Norethindrone pharmacokinetics were unaffected by Rilpivirine (AUC24h: 0.89 0.84 - 0.94; Cmin: 0.99 0.90 - 1.08; Cmax: 0.94 0.83 - 1.06). Steady-state Rilpivirine pharmacokinetics with ethinylestradiol/norethindrone was comparable with historical data for Rilpivirine alone. Rilpivirine with ethinylestradiol/norethindrone was generally well tolerated. No new safety events were identified. Conclusions: Co-administration of Rilpivirine at the therapeutic dosing regimen with ethinylestradiol/norethindrone does not affect hormone pharmacokinetics and is therefore unlikely to affect the efficacy or safety of this oral hormonal contraceptive. Rilpivirine pharmacokinetics was not affected by ethinylestradiol/norethindrone. Rilpivirine (25 mg once daily) can be co-administered with ethinylestradiol/norethindrone-based contraceptives without dose modification.

  • week 96 analysis of Rilpivirine or efavirenz in hiv 1 infected patients with baseline viral load 100 000 copies ml in the pooled echo and thrive phase 3 randomized double blind trials
    Hiv Medicine, 2014
    Co-Authors: Jeanmichel Molina, Simon Vanveggel, Nathan Clumeck, Chloe Orkin, Lt Rimsky, Marita Stevens
    Abstract:

    Objectives These 96-week, ECHO/THRIVE pooled analyses evaluated data for antiretroviral treatment-naive, HIV-1-infected adults with viral load (VL) ≤ 100 000 HIV-1 RNA copies/mL receiving Rilpivirine or efavirenz. Methods ECHO and THRIVE were phase 3, randomized, double-blind trials. Patients received Rilpivirine 25 mg once daily (qd) or efavirenz 600 mg qd, with a fixed (ECHO) or investigator-chosen (THRIVE) nucleoside/tide reverse transcriptase inhibitor (N[t]RTI) background regimen. Response rate (the percentage of patients with VL < 50 copies/mL, using an intent-to-treat-population, time-to-loss-of-virological-response algorithm), virological failure (VF), resistance development, safety and tolerability were evaluated. Results Baseline characteristics were comparable between the Rilpivirine (n = 368) and efavirenz (n = 329) groups. At week 96, response rates [84% for Rilpivirine vs. 80% for efavirenz; difference 4.0%; 95% confidence interval (CI) –1.7% to 9.7%] and incidences of VF for the resistance analysis (VFres) (8% for Rilpivirine vs. 6% for efavirenz; P = 0.46) were similar in the two groups. Among patients with VFres, a comparable proportion in each group developed nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs). Among those with VFres, more patients in the Rilpivirine group than in the efavirenz group developed N[t]RTI RAMs, mostly M184I/V. The mean (95% CI) CD4 cell count increased from baseline to week 96 by 224 (208–240) cells/μL in the Rilpivirine group and by 206 (188–225) cells/μL in the efavirenz group. Treatment-related grade 2–4 overall adverse events, any rash and dizziness were less frequent for Rilpivirine than for efavirenz (P < 0.0001). Conclusions Rilpivirine demonstrated antiviral efficacy similar to that of efavirenz in antiretroviral treatment-naive adults with baseline VL ≤ 100 000 copies/mL over 96 weeks. Frequencies of VFres and emergent NNRTI RAMs in each group were similar. More patients with VFres in the Rilpivirine group than in the efavirenz group developed N[t]RTI RAMs (mostly M184I/V). Rilpivirine had a more favourable safety/tolerability profile than efavirenz.

  • The effect of Rilpivirine on the pharmacokinetics of methadone in HIV-negative volunteers.
    Journal of clinical pharmacology, 2013
    Co-Authors: Herta Crauwels, Ann Vandevoorde, Marita Stevens, Rolf P. G. Van Heeswijk, Annemie Buelens, Richard M. W. Hoetelmans
    Abstract:

    Antiretrovirals may influence methadone exposure in HIV-1-infected patients receiving methadone for opiate addiction. Rilpivirine is a non-nucleoside reverse transcriptase inhibitor for treating HIV-1 infection. In this open-label trial (NCT00744770), 13 HIV-negative volunteers continued on their regular stable methadone therapy (60 to 100 mg once daily; Days -14 to 12), with Rilpivirine coadministration (Days 1 to 11). Methadone and Rilpivirine pharmacokinetics and opiate withdrawal symptoms (Short Opiate Withdrawal Scale, Desires for Drugs Questionnaire, pupillometry) were evaluated. Rilpivirine decreased methadone minimum and maximum plasma concentrations (Cmin ; Cmax ) and area under the plasma concentration-time curve versus methadone alone (least-square mean ratio; 90% confidence interval) by 22% (0.78; 0.67, 0.91), 14% (0.86; 0.78, 0.95), and 16% (0.84; 0.74, 0.95), respectively (R-methadone), and 21% (0.79; 0.67, 0.92), 13% (0.87; 0.78, 0.97), and 16% (0.84; 0.74, 0.96), respectively (S-methadone). Rilpivirine pharmacokinetics with methadone were consistent with historic data. No clinically relevant opiate withdrawal symptoms were reported. Methadone and Rilpivirine coadministration was generally well tolerated. No grade 3/4 adverse events (AEs), serious AEs, or discontinuations due to AEs were seen. No methadone dose adjustment is prompted by Rilpivirine coadministration. Clinical monitoring for opiate withdrawal is recommended, as some patients may require adjustment of methadone maintenance therapy.

  • neurological and psychiatric tolerability of Rilpivirine tmc278 vs efavirenz in treatment naive hiv 1 infected patients at 48 weeks
    Hiv Medicine, 2013
    Co-Authors: Anthony Mills, Marita Stevens, Simon Vanveggel, Bonaventura Clotet, Jan Fourie, Andrea Antinori, G Herrera, Charles B Hicks, Jose Valdez Madruga, Katia Boven
    Abstract:

    Objectives The aim of the study was to compare the neuropsychiatric safety and tolerability of Rilpivirine (TMC278) vs. efavirenz in a preplanned pooled analysis of data from the ECHO and THRIVE studies which compared the safety and efficacy of the two drugs in HIV-1 infected treatment naive adults. Methods ECHO and THRIVE were randomized, double-blind, double-dummy, 96-week, international, phase 3 trials comparing the efficacy, safety and tolerability of Rilpivirine 25 mg vs. efavirenz 600 mg once daily in combination with two background nucleoside/tide reverse transcriptase inhibitors. Safety and tolerability analyses were conducted when all patients had received at least 48 weeks of treatment or discontinued earlier. Differences between treatments in the incidence of neurological and psychiatric adverse events (AEs) of interest were assessed in preplanned statistical analyses using Fisher's exact test. Results At the time of the week 48 analysis, the cumulative incidences in the Rilpivirine vs. efavirenz groups of any grade 2–4 treatment-related AEs and of discontinuation because of AEs were 16% vs. 31% (P < 0.0001) and 3% vs. 8% (P = 0.0005), respectively. The incidence of treatment-related neuropsychiatric AEs was 27% vs. 48%, respectively (P < 0.0001). The incidence of treatment-related neurological AEs of interest was 17% vs. 38% (P < 0.0001), and that of treatment-related psychiatric AEs of interest was 15% vs. 23% (P = 0.0002). Dizziness and abnormal dreams/nightmares occurred significantly less frequently with Rilpivirine vs. efavirenz (P < 0.01). In both groups, patients with prior neuropsychiatric history tended to report more neuropsychiatric AEs but rates remained lower for Rilpivirine than for efavirenz. Conclusions Rilpivirine was associated with fewer neurological and psychiatric AEs of interest than efavirenz over 48 weeks in treatment-naive, HIV-1-infected adults.

Simon Vanveggel - One of the best experts on this subject based on the ideXlab platform.

  • week 96 analysis of Rilpivirine or efavirenz in hiv 1 infected patients with baseline viral load 100 000 copies ml in the pooled echo and thrive phase 3 randomized double blind trials
    Hiv Medicine, 2014
    Co-Authors: Jeanmichel Molina, Simon Vanveggel, Nathan Clumeck, Chloe Orkin, Lt Rimsky, Marita Stevens
    Abstract:

    Objectives These 96-week, ECHO/THRIVE pooled analyses evaluated data for antiretroviral treatment-naive, HIV-1-infected adults with viral load (VL) ≤ 100 000 HIV-1 RNA copies/mL receiving Rilpivirine or efavirenz. Methods ECHO and THRIVE were phase 3, randomized, double-blind trials. Patients received Rilpivirine 25 mg once daily (qd) or efavirenz 600 mg qd, with a fixed (ECHO) or investigator-chosen (THRIVE) nucleoside/tide reverse transcriptase inhibitor (N[t]RTI) background regimen. Response rate (the percentage of patients with VL < 50 copies/mL, using an intent-to-treat-population, time-to-loss-of-virological-response algorithm), virological failure (VF), resistance development, safety and tolerability were evaluated. Results Baseline characteristics were comparable between the Rilpivirine (n = 368) and efavirenz (n = 329) groups. At week 96, response rates [84% for Rilpivirine vs. 80% for efavirenz; difference 4.0%; 95% confidence interval (CI) –1.7% to 9.7%] and incidences of VF for the resistance analysis (VFres) (8% for Rilpivirine vs. 6% for efavirenz; P = 0.46) were similar in the two groups. Among patients with VFres, a comparable proportion in each group developed nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs). Among those with VFres, more patients in the Rilpivirine group than in the efavirenz group developed N[t]RTI RAMs, mostly M184I/V. The mean (95% CI) CD4 cell count increased from baseline to week 96 by 224 (208–240) cells/μL in the Rilpivirine group and by 206 (188–225) cells/μL in the efavirenz group. Treatment-related grade 2–4 overall adverse events, any rash and dizziness were less frequent for Rilpivirine than for efavirenz (P < 0.0001). Conclusions Rilpivirine demonstrated antiviral efficacy similar to that of efavirenz in antiretroviral treatment-naive adults with baseline VL ≤ 100 000 copies/mL over 96 weeks. Frequencies of VFres and emergent NNRTI RAMs in each group were similar. More patients with VFres in the Rilpivirine group than in the efavirenz group developed N[t]RTI RAMs (mostly M184I/V). Rilpivirine had a more favourable safety/tolerability profile than efavirenz.

  • change in vitamin d levels and risk of severe vitamin d deficiency over 48 weeks among hiv 1 infected treatment naive adults receiving Rilpivirine or efavirenz in a phase iii trial echo
    Antiviral Therapy, 2014
    Co-Authors: David A Wohl, Simon Vanveggel, Chloe Orkin, Manuela Doroana, Jose Henrique Pilotto, Somnuek Sungkanuparph, Patrick Yeni, Henri Deckx, Katia Boven
    Abstract:

    BACKGROUND: This analysis assessed changes in serum 25-hydroxyvitamin D (25[OH]D; the precursor form of active vitamin D) in antiretroviral-naive adults receiving Rilpivirine or efavirenz over 48 weeks in a randomized, double-blind, Phase III trial (ECHO). METHODS: ECHO included 690 patients randomized 1:1 to receive Rilpivirine 25 mg once daily (n=346) or efavirenz 600 mg once daily (n=344), plus tenofovir disoproxil fumarate/emtricitabine. 25(OH)D was measured in stored serum samples collected at baseline, and weeks 24 and 48. Proportions of patients with optimal/sufficient (≥30 ng/ml), insufficient (21-29 ng/ml), deficient (10-20 ng/ml) and severely deficient (<10 ng/ml) 25(OH)D levels were determined. Data are presented for patients with paired baseline and week 48 25(OH)D data (Rilpivirine, n=292; efavirenz, n=290). RESULTS: After 48 weeks, mean 25(OH)D levels remained largely unchanged from baseline with Rilpivirine (-0.2 ng/ml; P=0.57 versus no change), but were significantly reduced with efavirenz (-2.5 ng/ml; P<0.0001 versus no change). When adjusting for season of randomization and the combined variable of race (Black/African American, White/Caucasian, Asian, other race) and ethnicity (Hispanic or Latino and not Hispanic or not Latino), the conclusion about the treatment difference between the Rilpivirine and efavirenz treatment groups remained valid. At baseline the proportion of patients with severe 25(OH)D deficiency was similar in both groups (5%) but was significantly lower with Rilpivirine than efavirenz at week 48 (5% versus 9%, respectively; P=0.032). Furthermore, of the patients with 25(OH)D insufficiency/deficiency at baseline, the proportion who developed severe 25(OH)D deficiency at week 48 was significantly lower with Rilpivirine than efavirenz (2% versus 8%, respectively; P=0.0079). CONCLUSIONS: Rilpivirine had little effect on 25(OH)D, whereas efavirenz resulted in a significant reduction in 25(OH)D levels and an increase in the risk of severe 25(OH)D deficiency.

  • neurological and psychiatric tolerability of Rilpivirine tmc278 vs efavirenz in treatment naive hiv 1 infected patients at 48 weeks
    Hiv Medicine, 2013
    Co-Authors: Anthony Mills, Marita Stevens, Simon Vanveggel, Bonaventura Clotet, Jan Fourie, Andrea Antinori, G Herrera, Charles B Hicks, Jose Valdez Madruga, Katia Boven
    Abstract:

    Objectives The aim of the study was to compare the neuropsychiatric safety and tolerability of Rilpivirine (TMC278) vs. efavirenz in a preplanned pooled analysis of data from the ECHO and THRIVE studies which compared the safety and efficacy of the two drugs in HIV-1 infected treatment naive adults. Methods ECHO and THRIVE were randomized, double-blind, double-dummy, 96-week, international, phase 3 trials comparing the efficacy, safety and tolerability of Rilpivirine 25 mg vs. efavirenz 600 mg once daily in combination with two background nucleoside/tide reverse transcriptase inhibitors. Safety and tolerability analyses were conducted when all patients had received at least 48 weeks of treatment or discontinued earlier. Differences between treatments in the incidence of neurological and psychiatric adverse events (AEs) of interest were assessed in preplanned statistical analyses using Fisher's exact test. Results At the time of the week 48 analysis, the cumulative incidences in the Rilpivirine vs. efavirenz groups of any grade 2–4 treatment-related AEs and of discontinuation because of AEs were 16% vs. 31% (P < 0.0001) and 3% vs. 8% (P = 0.0005), respectively. The incidence of treatment-related neuropsychiatric AEs was 27% vs. 48%, respectively (P < 0.0001). The incidence of treatment-related neurological AEs of interest was 17% vs. 38% (P < 0.0001), and that of treatment-related psychiatric AEs of interest was 15% vs. 23% (P = 0.0002). Dizziness and abnormal dreams/nightmares occurred significantly less frequently with Rilpivirine vs. efavirenz (P < 0.01). In both groups, patients with prior neuropsychiatric history tended to report more neuropsychiatric AEs but rates remained lower for Rilpivirine than for efavirenz. Conclusions Rilpivirine was associated with fewer neurological and psychiatric AEs of interest than efavirenz over 48 weeks in treatment-naive, HIV-1-infected adults.

  • Rilpivirine vs efavirenz in hiv 1 patients with baseline viral load 100 000 copies ml or less week 48 phase iii analysis
    AIDS, 2013
    Co-Authors: Jeanmichel Molina, Laurence T. Rimsky, Simon Vanveggel, Nathan Clumeck, Karla Redant, Marita Stevens
    Abstract:

    OBJECTIVES To compare efficacy, resistance development, and safety between Rilpivirine and efavirenz in treatment-naive, HIV-1-infected adults with baseline viral load 100,000 copies/ml or less in the pooled 48-week dataset of the ECHO (Efficacy Comparison in treatment-naive HIV-infected subjects Of TMC278 and EFV) and THRIVE (TMC278 against HIV, in a once-daily RegImen Vs. Efavirenz) trials. DESIGN Phase III, double-blind, double-dummy, randomized trials. METHODS Patients received Rilpivirine 25 mg once daily (q.d.) or efavirenz 600 mg q.d. with two nucleoside/tide reverse transcriptase inhibitors [N(t)RTIs]. This analysis considers the subpopulation of 368 Rilpivirine and 330 efavirenz patients with baseline viral load 100,000 copies/ml or less. RESULTS Significantly higher 48-week response rates (viral load <50 copies/ml, intent-to-treat-time-to-loss-of-virological response) were observed with Rilpivirine vs. efavirenz [90 vs. 84%, respectively; difference 6.6% (95% confidence interval 1.6-11.5%)]. The proportion of patients experiencing virological failure (VF(res)) was 5% in each treatment group. A comparable proportion of VF(res) patients in each group developed nonnucleoside reverse transcriptase inhibitor resistance-associated mutations (RAMs) [Rilpivirine: 6/16 (38%) vs. efavirenz: 5/12 (42%)]. A numerically higher proportion of Rilpivirine VF(res) patients developed N(t)RTI RAMs [7/16 (44%)] vs. efavirenz [2/12 (17%)]; P = 0.2232. A significantly lower incidence for Rilpivirine vs. efavirenz was observed for the following events: treatment-related grade 2-4 overall adverse events (17 vs. 30%; P <0.0001), rash (any type; 2 vs. 12%; P <0.0001), and neurological adverse events (19 vs. 40%; P <0.0001), including dizziness (10 vs. 29%; P <0.0001). There was no significant difference between groups in the total cholesterol/high-density lipoprotein cholesterol ratio. CONCLUSION In treatment-naive patients with baseline viral load 100,000 copies/ml or less, Rilpivirine along with two N(t)RTIs achieved a high response, with a comparable frequency of VF(res) and more favorable tolerability than efavirenz.

  • Clinical perspective on drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor Rilpivirine.
    AIDS reviews, 2013
    Co-Authors: Herta Crauwels, Marita Stevens, Rolf P. G. Van Heeswijk, Annemie Buelens, Simon Vanveggel, Katia Boven, Richard M. W. Hoetelmans
    Abstract:

    Rilpivirine (TMC278) is a non-nucleoside reverse transcriptase inhibitor approved in combination with other antiretrovirals for the treatment of HIV-1 infection in treatment-naive adults (Edurant(®) 25 mg once daily; Complera(®) [USA]/Eviplera(®) [EU] once daily single-tablet regimen). Rilpivirine should be administered with a meal to optimize bioavailability. Its solubility is pH dependent. Rilpivirine is primarily excreted via the feces with negligible renal elimination. Rilpivirine is predominantly metabolized by cytochrome P450 3A4. There is no clinically relevant effect of age, gender, bodyweight, race, estimated glomerular filtration rate, or hepatitis B/C coinfection status on Rilpivirine pharmacokinetics in adults. Drug-drug interactions were investigated with cytochrome P450 3A substrates, inducers and inhibitors, drugs altering intragastric pH, antiretrovirals, and other often coadministered drugs. Rilpivirine 25 mg once daily does not have a clinically relevant effect on exposure of coadministered drugs. Coadministration with cytochrome P450 3A inhibitors (ketoconazole, ritonavir-boosted protease inhibitors, telaprevir) results in increased Rilpivirine plasma concentrations, but these are not considered clinically relevant; no dose adjustments are required. Coadministration of Rilpivirine with cytochrome P450 3A inducers (e.g. rifampin, rifabutin) or compounds increasing gastric pH (e.g. omeprazole, famotidine) results in decreased Rilpivirine plasma concentrations, which may increase the risk of virologic failure and resistance development. Therefore, strong cytochrome P450 3A inducers and proton-pump inhibitors are contraindicated. Histamine-2 receptor antagonists and antacids can be coadministered with Rilpivirine, provided doses are temporally separated. No dose adjustments are required when Rilpivirine is coadministered with: acetaminophen, phosphodiesterase type 5 inhibitors (sildenafil, etc.), atorvastatin (and other statins), oral contraceptives (ethinyl estradiol, norethindrone), chlorzoxazone (cytochrome P450 2E1 substrate), methadone, digoxin, tenofovir disoproxil fumarate, didanosine and other nuceos(t)ide reverse transcriptase inhibitors, and HIV integrase inhibitors (raltegravir, dolutegravir, GSK1265744).

Laurence T. Rimsky - One of the best experts on this subject based on the ideXlab platform.

  • Prevalence in the USA of Rilpivirine resistance-associated mutations in clinical samples and effects on phenotypic susceptibility to Rilpivirine and etravirine.
    Antiviral therapy, 2014
    Co-Authors: Gaston Picchio, Laurence T. Rimsky, Veerle Van Eygen, Mojgan Haddad, Laura A Napolitano, Johan Vingerhoets
    Abstract:

    BACKGROUND The prevalence of Rilpivirine resistance-associated mutations (RAMs) in the USA, and their effect on phenotypic susceptibility to Rilpivirine and etravirine, was evaluated in clinical samples from HIV-1-infected patients. METHODS In total, 15,991 samples submitted to Monogram Biosciences (South San Francisco, CA, USA) for routine resistance testing between January 2010 and June 2011 were assessed for the presence of known Rilpivirine RAMs K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C and M230I/L; non-nucleoside reverse transcriptase inhibitor (NNRTI) RAMs K103N, L100I and L100I+K103N; and the nucleoside reverse transcriptase inhibitor (NRTI) RAMs M184I/V and their combinations with Rilpivirine RAMs. Phenotypic susceptibility (PhenoSenseGT(®) assay; Monogram Biosciences) was evaluated, with reduced susceptibility defined as fold change (FC) in 50% inhibitory concentration (IC50)>2.0 for Rilpivirine and FC>2.9 for etravirine. RESULTS Of the 15,991 samples, 17% harboured ≥1 Rilpivirine RAMs. The prevalence of most Rilpivirine RAMs and combinations of NNRTI RAMs of interest was low (≤3%), except for Y181C (7%). Rilpivirine RAMs were often associated with reduced Rilpivirine phenotypic susceptibility. Median FC values >2.0 were observed for clinical isolates with Rilpivirine RAMs K101P, E138Q/R, Y181C/I/V, Y188L or M230L, and for the combination of E138K with M184I/V, and K101E with M184I. Most Rilpivirine FC values >2.0 were associated with etravirine FC values >2.9 for individual Rilpivirine RAMs and those combined with M184I/V. There was no relationship between the presence of K103N and Rilpivirine FC. However, the L100I+K103N combination (without Rilpivirine RAMs), at 2.0. CONCLUSIONS Based on 15,991 US clinical samples from HIV-1-infected patients, the frequency of most known Rilpivirine RAMs apart from Y181C was low.

  • week 96 efficacy and safety of Rilpivirine in treatment naive hiv 1 patients in two phase iii randomized trials
    AIDS, 2013
    Co-Authors: Calvin J Cohen, Herta Crauwels, Jeanmichel Molina, Chloe Orkin, Isabel Cassetti, Ploenchan Chetchotisakd, Adriano Lazzarin, Frank S Rhame, Hans Jurgen Stellbrink, Laurence T. Rimsky
    Abstract:

    BACKGROUND In the week 48 primary analysis of ECHO and THRIVE, Rilpivirine demonstrated noninferior efficacy and more favourable tolerability versus efavirenz in treatment-naive, HIV-1-infected adults. Pooled 96-week results are presented. METHODS Patients (N = 1368) received Rilpivirine 25 mg once-daily (q.d.) or efavirenz 600 mg q.d., with two background nucleoside/nucleotide reverse transcriptase inhibitors, in two randomized, double-blind, double-dummy Phase III trials. RESULTS At week 96, response rate (% confirmed viral load <50 copies/ml; intent-to-treat, time-to-loss-of-virologic response) was 78% in both groups. Responses were similar for both treatments by background regimen, sex, race, and in patients with more than 95% adherence (M-MASRI) or baseline viral load 100,000 copies/ml or less. Responses were lower and virologic failure higher for Rilpivirine versus efavirenz in patients with 95% or less adherence or baseline viral load more than 100,000 copies/ml. Beyond week 48, the incidence of virologic failure was comparable (3 versus 2%) between treatment groups, Rilpivirine resistance-associated mutations were consistent with those observed in year 1, there were few adverse events in both groups and no new safety concerns. Over 96 weeks, discontinuations due to adverse events (4 versus 9%), treatment-related grade 2-4 adverse events (17 versus 33%), rash (4 versus 15%), dizziness (8 versus 27%) and abnormal dreams/nightmares (8 versus 13%), and grade 2-4 lipid abnormalities were lower with Rilpivirine than efavirenz. Only 2 and 4% of patients in the Rilpivirine and efavirenz treatment groups, respectively, reported at least possibly treatment-related grade 2-4 adverse events during the second year of treatment. CONCLUSIONS Rilpivirine 25 mg q.d. and efavirenz 600 mg q.d. had comparable responses at week 96. Rilpivirine had more virologic failures but improved tolerability versus efavirenz. The majority of virologic failures occurred in the first 48 weeks.

  • Rilpivirine vs efavirenz in hiv 1 patients with baseline viral load 100 000 copies ml or less week 48 phase iii analysis
    AIDS, 2013
    Co-Authors: Jeanmichel Molina, Laurence T. Rimsky, Simon Vanveggel, Nathan Clumeck, Karla Redant, Marita Stevens
    Abstract:

    OBJECTIVES To compare efficacy, resistance development, and safety between Rilpivirine and efavirenz in treatment-naive, HIV-1-infected adults with baseline viral load 100,000 copies/ml or less in the pooled 48-week dataset of the ECHO (Efficacy Comparison in treatment-naive HIV-infected subjects Of TMC278 and EFV) and THRIVE (TMC278 against HIV, in a once-daily RegImen Vs. Efavirenz) trials. DESIGN Phase III, double-blind, double-dummy, randomized trials. METHODS Patients received Rilpivirine 25 mg once daily (q.d.) or efavirenz 600 mg q.d. with two nucleoside/tide reverse transcriptase inhibitors [N(t)RTIs]. This analysis considers the subpopulation of 368 Rilpivirine and 330 efavirenz patients with baseline viral load 100,000 copies/ml or less. RESULTS Significantly higher 48-week response rates (viral load <50 copies/ml, intent-to-treat-time-to-loss-of-virological response) were observed with Rilpivirine vs. efavirenz [90 vs. 84%, respectively; difference 6.6% (95% confidence interval 1.6-11.5%)]. The proportion of patients experiencing virological failure (VF(res)) was 5% in each treatment group. A comparable proportion of VF(res) patients in each group developed nonnucleoside reverse transcriptase inhibitor resistance-associated mutations (RAMs) [Rilpivirine: 6/16 (38%) vs. efavirenz: 5/12 (42%)]. A numerically higher proportion of Rilpivirine VF(res) patients developed N(t)RTI RAMs [7/16 (44%)] vs. efavirenz [2/12 (17%)]; P = 0.2232. A significantly lower incidence for Rilpivirine vs. efavirenz was observed for the following events: treatment-related grade 2-4 overall adverse events (17 vs. 30%; P <0.0001), rash (any type; 2 vs. 12%; P <0.0001), and neurological adverse events (19 vs. 40%; P <0.0001), including dizziness (10 vs. 29%; P <0.0001). There was no significant difference between groups in the total cholesterol/high-density lipoprotein cholesterol ratio. CONCLUSION In treatment-naive patients with baseline viral load 100,000 copies/ml or less, Rilpivirine along with two N(t)RTIs achieved a high response, with a comparable frequency of VF(res) and more favorable tolerability than efavirenz.

  • genotypic and phenotypic characterization of hiv 1 isolates obtained from patients on Rilpivirine therapy experiencing virologic failure in the phase 3 echo and thrive studies 48 week analysis
    Journal of Acquired Immune Deficiency Syndromes, 2012
    Co-Authors: Laurence T. Rimsky, Veerle Van Eygen, Johan Vingerhoets, Katia Boven, Joseph J Eron, Bonaventura Clotet, Annemie Hoogstoel, Gaston Picchio
    Abstract:

    Genotypic and phenotypic characterization was performed of HIV-1 isolates from treatment-naive HIV-1-infected patients experiencing virologic failure (VF) during treatment with the nonnucleoside reverse transcriptase inhibitor (NNRTIs) Rilpivirine or efavirenz in the pooled phase 3 studies ECHO and THRIVE. Among 686 patients receiving Rilpivirine, 72 (10%) experienced VF versus 39 of 682 (6%) receiving efavirenz. In patients with low baseline viral load (VL) ≤100,000 copies per milliliter, the proportions of Rilpivirine VFs (19 of 368) and efavirenz VFs (16 of 330) were the same (5%). In patients with high baseline VL >100,000 copies per milliliter, the proportion of VFs was higher with Rilpivirine (53 of 318; 17%) than efavirenz (23 of 352; 7%). The rate of Rilpivirine VF was comparable between HIV-1 subtype B-infected (11%) and nonsubtype B-infected (8%) patients. The absolute number of VFs with treatment-emergent NNRTI resistance-associated mutations (RAMs) was higher for Rilpivirine (most commonly E138K or K101E) than efavirenz (most commonly K103N), but relative proportions were similar [63% (39 of 62) vs. 54% (15 of 28), respectively]. More Rilpivirine VFs had treatment-emergent nucleoside/nucleotide reverse transcriptase inhibitor RAMs than efavirenz VFs [68% (42 of 62) versus 32% (9 of 28), respectively], most commonly M184I and M184V. The proportion of Rilpivirine VFs with RAMs in patients with low baseline VL was lower than in those with high baseline VL [38% (6 of 16) versus 72% (33 of 46) for NNRTI RAMs and 44% (7 of 16) versus 76% (35 of 46) for nucleoside/nucleotide reverse transcriptase inhibitor RAMs, respectively]. In summary, VF and treatment-emergent reverse transcriptase RAMs were similar at low baseline VL but more frequent at high baseline VL in Rilpivirine-treated than in efavirenz-treated patients. The frequent emergence of E138K, especially in combination with M184I, in Rilpivirine VFs is a unique finding of these trials.

  • genotypic and phenotypic characterization of hiv 1 isolates obtained from patients on Rilpivirine therapy experiencing virologic failure in the phase 3 echo and thrive studies 48 week analysis
    Journal of Acquired Immune Deficiency Syndromes, 2012
    Co-Authors: Laurence T. Rimsky, Johan Vingerhoets, Katia Boven, Joseph J Eron, Bonaventura Clotet, Annemie Hoogstoel, Veerle Van Eygen, G Picchio
    Abstract:

    : Genotypic and phenotypic characterization was performed of HIV-1 isolates from treatment-naive HIV-1-infected patients experiencing virologic failure (VF) during treatment with the nonnucleoside reverse transcriptase inhibitor (NNRTIs) Rilpivirine or efavirenz in the pooled phase 3 studies ECHO and THRIVE. Among 686 patients receiving Rilpivirine, 72 (10%) experienced VF versus 39 of 682 (6%) receiving efavirenz. In patients with low baseline viral load (VL) ≤100,000 copies per milliliter, the proportions of Rilpivirine VFs (19 of 368) and efavirenz VFs (16 of 330) were the same (5%). In patients with high baseline VL >100,000 copies per milliliter, the proportion of VFs was higher with Rilpivirine (53 of 318; 17%) than efavirenz (23 of 352; 7%). The rate of Rilpivirine VF was comparable between HIV-1 subtype B-infected (11%) and nonsubtype B-infected (8%) patients. The absolute number of VFs with treatment-emergent NNRTI resistance-associated mutations (RAMs) was higher for Rilpivirine (most commonly E138K or K101E) than efavirenz (most commonly K103N), but relative proportions were similar [63% (39 of 62) vs. 54% (15 of 28), respectively]. More Rilpivirine VFs had treatment-emergent nucleoside/nucleotide reverse transcriptase inhibitor RAMs than efavirenz VFs [68% (42 of 62) versus 32% (9 of 28), respectively], most commonly M184I and M184V. The proportion of Rilpivirine VFs with RAMs in patients with low baseline VL was lower than in those with high baseline VL [38% (6 of 16) versus 72% (33 of 46) for NNRTI RAMs and 44% (7 of 16) versus 76% (35 of 46) for nucleoside/nucleotide reverse transcriptase inhibitor RAMs, respectively]. In summary, VF and treatment-emergent reverse transcriptase RAMs were similar at low baseline VL but more frequent at high baseline VL in Rilpivirine-treated than in efavirenz-treated patients. The frequent emergence of E138K, especially in combination with M184I, in Rilpivirine VFs is a unique finding of these trials.

Katia Boven - One of the best experts on this subject based on the ideXlab platform.

  • change in vitamin d levels and risk of severe vitamin d deficiency over 48 weeks among hiv 1 infected treatment naive adults receiving Rilpivirine or efavirenz in a phase iii trial echo
    Antiviral Therapy, 2014
    Co-Authors: David A Wohl, Simon Vanveggel, Chloe Orkin, Manuela Doroana, Jose Henrique Pilotto, Somnuek Sungkanuparph, Patrick Yeni, Henri Deckx, Katia Boven
    Abstract:

    BACKGROUND: This analysis assessed changes in serum 25-hydroxyvitamin D (25[OH]D; the precursor form of active vitamin D) in antiretroviral-naive adults receiving Rilpivirine or efavirenz over 48 weeks in a randomized, double-blind, Phase III trial (ECHO). METHODS: ECHO included 690 patients randomized 1:1 to receive Rilpivirine 25 mg once daily (n=346) or efavirenz 600 mg once daily (n=344), plus tenofovir disoproxil fumarate/emtricitabine. 25(OH)D was measured in stored serum samples collected at baseline, and weeks 24 and 48. Proportions of patients with optimal/sufficient (≥30 ng/ml), insufficient (21-29 ng/ml), deficient (10-20 ng/ml) and severely deficient (<10 ng/ml) 25(OH)D levels were determined. Data are presented for patients with paired baseline and week 48 25(OH)D data (Rilpivirine, n=292; efavirenz, n=290). RESULTS: After 48 weeks, mean 25(OH)D levels remained largely unchanged from baseline with Rilpivirine (-0.2 ng/ml; P=0.57 versus no change), but were significantly reduced with efavirenz (-2.5 ng/ml; P<0.0001 versus no change). When adjusting for season of randomization and the combined variable of race (Black/African American, White/Caucasian, Asian, other race) and ethnicity (Hispanic or Latino and not Hispanic or not Latino), the conclusion about the treatment difference between the Rilpivirine and efavirenz treatment groups remained valid. At baseline the proportion of patients with severe 25(OH)D deficiency was similar in both groups (5%) but was significantly lower with Rilpivirine than efavirenz at week 48 (5% versus 9%, respectively; P=0.032). Furthermore, of the patients with 25(OH)D insufficiency/deficiency at baseline, the proportion who developed severe 25(OH)D deficiency at week 48 was significantly lower with Rilpivirine than efavirenz (2% versus 8%, respectively; P=0.0079). CONCLUSIONS: Rilpivirine had little effect on 25(OH)D, whereas efavirenz resulted in a significant reduction in 25(OH)D levels and an increase in the risk of severe 25(OH)D deficiency.

  • neurological and psychiatric tolerability of Rilpivirine tmc278 vs efavirenz in treatment naive hiv 1 infected patients at 48 weeks
    Hiv Medicine, 2013
    Co-Authors: Anthony Mills, Marita Stevens, Simon Vanveggel, Bonaventura Clotet, Jan Fourie, Andrea Antinori, G Herrera, Charles B Hicks, Jose Valdez Madruga, Katia Boven
    Abstract:

    Objectives The aim of the study was to compare the neuropsychiatric safety and tolerability of Rilpivirine (TMC278) vs. efavirenz in a preplanned pooled analysis of data from the ECHO and THRIVE studies which compared the safety and efficacy of the two drugs in HIV-1 infected treatment naive adults. Methods ECHO and THRIVE were randomized, double-blind, double-dummy, 96-week, international, phase 3 trials comparing the efficacy, safety and tolerability of Rilpivirine 25 mg vs. efavirenz 600 mg once daily in combination with two background nucleoside/tide reverse transcriptase inhibitors. Safety and tolerability analyses were conducted when all patients had received at least 48 weeks of treatment or discontinued earlier. Differences between treatments in the incidence of neurological and psychiatric adverse events (AEs) of interest were assessed in preplanned statistical analyses using Fisher's exact test. Results At the time of the week 48 analysis, the cumulative incidences in the Rilpivirine vs. efavirenz groups of any grade 2–4 treatment-related AEs and of discontinuation because of AEs were 16% vs. 31% (P < 0.0001) and 3% vs. 8% (P = 0.0005), respectively. The incidence of treatment-related neuropsychiatric AEs was 27% vs. 48%, respectively (P < 0.0001). The incidence of treatment-related neurological AEs of interest was 17% vs. 38% (P < 0.0001), and that of treatment-related psychiatric AEs of interest was 15% vs. 23% (P = 0.0002). Dizziness and abnormal dreams/nightmares occurred significantly less frequently with Rilpivirine vs. efavirenz (P < 0.01). In both groups, patients with prior neuropsychiatric history tended to report more neuropsychiatric AEs but rates remained lower for Rilpivirine than for efavirenz. Conclusions Rilpivirine was associated with fewer neurological and psychiatric AEs of interest than efavirenz over 48 weeks in treatment-naive, HIV-1-infected adults.

  • Impact of food and different meal types on the pharmacokinetics of Rilpivirine.
    Journal of clinical pharmacology, 2013
    Co-Authors: Herta Crauwels, Marita Stevens, Annemie Buelens, Katia Boven, Rolf Van Heeswijk, Richard M. W. Hoetelmans
    Abstract:

    The objective of the study was to determine the impact of food and different meal types on the pharmacokinetics of Rilpivirine, a nonnucleoside reverse transcriptase inhibitor. In this open-label, randomized, crossover study, healthy volunteers received a single, oral 75 mg dose of Rilpivirine either with a normal-fat breakfast (reference), under fasting conditions, with a high-fat breakfast, or with a protein-rich nutritional drink. Pharmacokinetic parameters were determined by non-compartmental methods and analyzed using a linear mixed-effects model. Safety was assessed throughout. The least-squares mean ratio for area under the plasma concentration-time curve to last timepoint was 0.57 (90% confidence interval [CI]: 0.46-0.72) under fasting conditions compared to dosing with a normal-fat breakfast. With a high-fat breakfast or only a protein-rich nutritional drink, the corresponding values were 0.92 (90% CI: 0.80-1.07) and 0.50 (90% CI: 0.41-0.61), respectively, compared to dosing with a normal-fat breakfast. Under all conditions, Rilpivirine was generally safe and well tolerated. Administration of Rilpivirine under fasting conditions or with only a protein-rich nutritional drink substantially lowered the oral bioavailability when compared to administration with a normal-fat breakfast. Rilpivirine bioavailability was similar when administered with a high-fat or normal-fat breakfast. Rilpivirine should always be taken with a meal to ensure adequate bioavailability.

  • Clinical perspective on drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor Rilpivirine.
    AIDS reviews, 2013
    Co-Authors: Herta Crauwels, Marita Stevens, Rolf P. G. Van Heeswijk, Annemie Buelens, Simon Vanveggel, Katia Boven, Richard M. W. Hoetelmans
    Abstract:

    Rilpivirine (TMC278) is a non-nucleoside reverse transcriptase inhibitor approved in combination with other antiretrovirals for the treatment of HIV-1 infection in treatment-naive adults (Edurant(®) 25 mg once daily; Complera(®) [USA]/Eviplera(®) [EU] once daily single-tablet regimen). Rilpivirine should be administered with a meal to optimize bioavailability. Its solubility is pH dependent. Rilpivirine is primarily excreted via the feces with negligible renal elimination. Rilpivirine is predominantly metabolized by cytochrome P450 3A4. There is no clinically relevant effect of age, gender, bodyweight, race, estimated glomerular filtration rate, or hepatitis B/C coinfection status on Rilpivirine pharmacokinetics in adults. Drug-drug interactions were investigated with cytochrome P450 3A substrates, inducers and inhibitors, drugs altering intragastric pH, antiretrovirals, and other often coadministered drugs. Rilpivirine 25 mg once daily does not have a clinically relevant effect on exposure of coadministered drugs. Coadministration with cytochrome P450 3A inhibitors (ketoconazole, ritonavir-boosted protease inhibitors, telaprevir) results in increased Rilpivirine plasma concentrations, but these are not considered clinically relevant; no dose adjustments are required. Coadministration of Rilpivirine with cytochrome P450 3A inducers (e.g. rifampin, rifabutin) or compounds increasing gastric pH (e.g. omeprazole, famotidine) results in decreased Rilpivirine plasma concentrations, which may increase the risk of virologic failure and resistance development. Therefore, strong cytochrome P450 3A inducers and proton-pump inhibitors are contraindicated. Histamine-2 receptor antagonists and antacids can be coadministered with Rilpivirine, provided doses are temporally separated. No dose adjustments are required when Rilpivirine is coadministered with: acetaminophen, phosphodiesterase type 5 inhibitors (sildenafil, etc.), atorvastatin (and other statins), oral contraceptives (ethinyl estradiol, norethindrone), chlorzoxazone (cytochrome P450 2E1 substrate), methadone, digoxin, tenofovir disoproxil fumarate, didanosine and other nuceos(t)ide reverse transcriptase inhibitors, and HIV integrase inhibitors (raltegravir, dolutegravir, GSK1265744).

  • genotypic and phenotypic characterization of hiv 1 isolates obtained from patients on Rilpivirine therapy experiencing virologic failure in the phase 3 echo and thrive studies 48 week analysis
    Journal of Acquired Immune Deficiency Syndromes, 2012
    Co-Authors: Laurence T. Rimsky, Veerle Van Eygen, Johan Vingerhoets, Katia Boven, Joseph J Eron, Bonaventura Clotet, Annemie Hoogstoel, Gaston Picchio
    Abstract:

    Genotypic and phenotypic characterization was performed of HIV-1 isolates from treatment-naive HIV-1-infected patients experiencing virologic failure (VF) during treatment with the nonnucleoside reverse transcriptase inhibitor (NNRTIs) Rilpivirine or efavirenz in the pooled phase 3 studies ECHO and THRIVE. Among 686 patients receiving Rilpivirine, 72 (10%) experienced VF versus 39 of 682 (6%) receiving efavirenz. In patients with low baseline viral load (VL) ≤100,000 copies per milliliter, the proportions of Rilpivirine VFs (19 of 368) and efavirenz VFs (16 of 330) were the same (5%). In patients with high baseline VL >100,000 copies per milliliter, the proportion of VFs was higher with Rilpivirine (53 of 318; 17%) than efavirenz (23 of 352; 7%). The rate of Rilpivirine VF was comparable between HIV-1 subtype B-infected (11%) and nonsubtype B-infected (8%) patients. The absolute number of VFs with treatment-emergent NNRTI resistance-associated mutations (RAMs) was higher for Rilpivirine (most commonly E138K or K101E) than efavirenz (most commonly K103N), but relative proportions were similar [63% (39 of 62) vs. 54% (15 of 28), respectively]. More Rilpivirine VFs had treatment-emergent nucleoside/nucleotide reverse transcriptase inhibitor RAMs than efavirenz VFs [68% (42 of 62) versus 32% (9 of 28), respectively], most commonly M184I and M184V. The proportion of Rilpivirine VFs with RAMs in patients with low baseline VL was lower than in those with high baseline VL [38% (6 of 16) versus 72% (33 of 46) for NNRTI RAMs and 44% (7 of 16) versus 76% (35 of 46) for nucleoside/nucleotide reverse transcriptase inhibitor RAMs, respectively]. In summary, VF and treatment-emergent reverse transcriptase RAMs were similar at low baseline VL but more frequent at high baseline VL in Rilpivirine-treated than in efavirenz-treated patients. The frequent emergence of E138K, especially in combination with M184I, in Rilpivirine VFs is a unique finding of these trials.

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

  • week 96 analysis of Rilpivirine or efavirenz in hiv 1 infected patients with baseline viral load 100 000 copies ml in the pooled echo and thrive phase 3 randomized double blind trials
    Hiv Medicine, 2014
    Co-Authors: Jeanmichel Molina, Simon Vanveggel, Nathan Clumeck, Chloe Orkin, Lt Rimsky, Marita Stevens
    Abstract:

    Objectives These 96-week, ECHO/THRIVE pooled analyses evaluated data for antiretroviral treatment-naive, HIV-1-infected adults with viral load (VL) ≤ 100 000 HIV-1 RNA copies/mL receiving Rilpivirine or efavirenz. Methods ECHO and THRIVE were phase 3, randomized, double-blind trials. Patients received Rilpivirine 25 mg once daily (qd) or efavirenz 600 mg qd, with a fixed (ECHO) or investigator-chosen (THRIVE) nucleoside/tide reverse transcriptase inhibitor (N[t]RTI) background regimen. Response rate (the percentage of patients with VL < 50 copies/mL, using an intent-to-treat-population, time-to-loss-of-virological-response algorithm), virological failure (VF), resistance development, safety and tolerability were evaluated. Results Baseline characteristics were comparable between the Rilpivirine (n = 368) and efavirenz (n = 329) groups. At week 96, response rates [84% for Rilpivirine vs. 80% for efavirenz; difference 4.0%; 95% confidence interval (CI) –1.7% to 9.7%] and incidences of VF for the resistance analysis (VFres) (8% for Rilpivirine vs. 6% for efavirenz; P = 0.46) were similar in the two groups. Among patients with VFres, a comparable proportion in each group developed nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs). Among those with VFres, more patients in the Rilpivirine group than in the efavirenz group developed N[t]RTI RAMs, mostly M184I/V. The mean (95% CI) CD4 cell count increased from baseline to week 96 by 224 (208–240) cells/μL in the Rilpivirine group and by 206 (188–225) cells/μL in the efavirenz group. Treatment-related grade 2–4 overall adverse events, any rash and dizziness were less frequent for Rilpivirine than for efavirenz (P < 0.0001). Conclusions Rilpivirine demonstrated antiviral efficacy similar to that of efavirenz in antiretroviral treatment-naive adults with baseline VL ≤ 100 000 copies/mL over 96 weeks. Frequencies of VFres and emergent NNRTI RAMs in each group were similar. More patients with VFres in the Rilpivirine group than in the efavirenz group developed N[t]RTI RAMs (mostly M184I/V). Rilpivirine had a more favourable safety/tolerability profile than efavirenz.

  • week 96 efficacy and safety of Rilpivirine in treatment naive hiv 1 patients in two phase iii randomized trials
    AIDS, 2013
    Co-Authors: Calvin J Cohen, Herta Crauwels, Jeanmichel Molina, Chloe Orkin, Isabel Cassetti, Ploenchan Chetchotisakd, Adriano Lazzarin, Frank S Rhame, Hans Jurgen Stellbrink, Laurence T. Rimsky
    Abstract:

    BACKGROUND In the week 48 primary analysis of ECHO and THRIVE, Rilpivirine demonstrated noninferior efficacy and more favourable tolerability versus efavirenz in treatment-naive, HIV-1-infected adults. Pooled 96-week results are presented. METHODS Patients (N = 1368) received Rilpivirine 25 mg once-daily (q.d.) or efavirenz 600 mg q.d., with two background nucleoside/nucleotide reverse transcriptase inhibitors, in two randomized, double-blind, double-dummy Phase III trials. RESULTS At week 96, response rate (% confirmed viral load <50 copies/ml; intent-to-treat, time-to-loss-of-virologic response) was 78% in both groups. Responses were similar for both treatments by background regimen, sex, race, and in patients with more than 95% adherence (M-MASRI) or baseline viral load 100,000 copies/ml or less. Responses were lower and virologic failure higher for Rilpivirine versus efavirenz in patients with 95% or less adherence or baseline viral load more than 100,000 copies/ml. Beyond week 48, the incidence of virologic failure was comparable (3 versus 2%) between treatment groups, Rilpivirine resistance-associated mutations were consistent with those observed in year 1, there were few adverse events in both groups and no new safety concerns. Over 96 weeks, discontinuations due to adverse events (4 versus 9%), treatment-related grade 2-4 adverse events (17 versus 33%), rash (4 versus 15%), dizziness (8 versus 27%) and abnormal dreams/nightmares (8 versus 13%), and grade 2-4 lipid abnormalities were lower with Rilpivirine than efavirenz. Only 2 and 4% of patients in the Rilpivirine and efavirenz treatment groups, respectively, reported at least possibly treatment-related grade 2-4 adverse events during the second year of treatment. CONCLUSIONS Rilpivirine 25 mg q.d. and efavirenz 600 mg q.d. had comparable responses at week 96. Rilpivirine had more virologic failures but improved tolerability versus efavirenz. The majority of virologic failures occurred in the first 48 weeks.

  • Rilpivirine vs efavirenz in hiv 1 patients with baseline viral load 100 000 copies ml or less week 48 phase iii analysis
    AIDS, 2013
    Co-Authors: Jeanmichel Molina, Laurence T. Rimsky, Simon Vanveggel, Nathan Clumeck, Karla Redant, Marita Stevens
    Abstract:

    OBJECTIVES To compare efficacy, resistance development, and safety between Rilpivirine and efavirenz in treatment-naive, HIV-1-infected adults with baseline viral load 100,000 copies/ml or less in the pooled 48-week dataset of the ECHO (Efficacy Comparison in treatment-naive HIV-infected subjects Of TMC278 and EFV) and THRIVE (TMC278 against HIV, in a once-daily RegImen Vs. Efavirenz) trials. DESIGN Phase III, double-blind, double-dummy, randomized trials. METHODS Patients received Rilpivirine 25 mg once daily (q.d.) or efavirenz 600 mg q.d. with two nucleoside/tide reverse transcriptase inhibitors [N(t)RTIs]. This analysis considers the subpopulation of 368 Rilpivirine and 330 efavirenz patients with baseline viral load 100,000 copies/ml or less. RESULTS Significantly higher 48-week response rates (viral load <50 copies/ml, intent-to-treat-time-to-loss-of-virological response) were observed with Rilpivirine vs. efavirenz [90 vs. 84%, respectively; difference 6.6% (95% confidence interval 1.6-11.5%)]. The proportion of patients experiencing virological failure (VF(res)) was 5% in each treatment group. A comparable proportion of VF(res) patients in each group developed nonnucleoside reverse transcriptase inhibitor resistance-associated mutations (RAMs) [Rilpivirine: 6/16 (38%) vs. efavirenz: 5/12 (42%)]. A numerically higher proportion of Rilpivirine VF(res) patients developed N(t)RTI RAMs [7/16 (44%)] vs. efavirenz [2/12 (17%)]; P = 0.2232. A significantly lower incidence for Rilpivirine vs. efavirenz was observed for the following events: treatment-related grade 2-4 overall adverse events (17 vs. 30%; P <0.0001), rash (any type; 2 vs. 12%; P <0.0001), and neurological adverse events (19 vs. 40%; P <0.0001), including dizziness (10 vs. 29%; P <0.0001). There was no significant difference between groups in the total cholesterol/high-density lipoprotein cholesterol ratio. CONCLUSION In treatment-naive patients with baseline viral load 100,000 copies/ml or less, Rilpivirine along with two N(t)RTIs achieved a high response, with a comparable frequency of VF(res) and more favorable tolerability than efavirenz.

  • efficacy and safety of Rilpivirine tmc278 versus efavirenz at 48 weeks in treatment naive hiv 1 infected patients pooled results from the phase 3 double blind randomized echo and thrive trials
    Journal of Acquired Immune Deficiency Syndromes, 2012
    Co-Authors: Calvin J Cohen, Jeanmichel Molina, Bonaventura Clotet, Pedro Cahn, Jan Fourie, Beatriz Grinsztejn, Hao Wu, M A Johnson, Michael S Saag, Khuanchai Supparatpinyo
    Abstract:

    BACKGROUND: Pooled analysis of phase 3, double-blind, double-dummy ECHO and THRIVE trials comparing Rilpivirine (TMC278) and efavirenz. METHODS: Treatment-naive HIV-1-infected adults were randomized 1:1 to Rilpivirine 25 mg once daily or efavirenz 600 mg once daily, with background tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) (ECHO) or TDF/FTC, zidovudine/lamivudine, or abacavir/lamivudine (THRIVE). The primary endpoint was confirmed response [viral load <50 copies per milliliter; intent-to-treat time-to-loss-of-virologic-response (ITT-TLOVR) algorithm] at week 48. The pooled data set enabled analyses of subgroups and predictors of response/virologic failure. RESULTS: Confirmed responses were 84% (Rilpivirine) and 82% (efavirenz). The difference in response rates (95% confidence interval) was 2.0% (-2.0% to 6.0%). The incidence of virologic failure was 9% (Rilpivirine) versus 5% (efavirenz). Responses in ITT-TLOVR and ITT-snapshot analyses were consistent. Responses were similar for Rilpivirine and efavirenz by background regimen, gender, race and clade. Suboptimal adherence and higher baseline viral load resulted in lower responses, higher virologic failure, and development of resistance in both groups; the effects on virologic failure were more apparent with Rilpivirine. CD4 cell count increased over time in both groups. Rilpivirine compared with efavirenz gave smaller incidences of adverse events leading to discontinuation (3% vs. 8%, respectively), treatment-related grade 2-4 adverse events (16% vs. 31%), rash (3% vs. 14%), dizziness (8% vs. 26%), abnormal dreams/nightmares (8% vs. 13%), and grade 2-4 lipid abnormalities. CONCLUSIONS: At week 48, Rilpivirine 25 mg once daily and efavirenz 600 mg once daily had comparable response rates. Rilpivirine had more virologic failures and improved tolerability versus efavirenz.

  • 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
    The Lancet, 2011
    Co-Authors: Jeanmichel Molina, Herta Crauwels, Pedro Cahn, Beatriz Grinsztejn, Michael S Saag, Khuanchai Supparatpinyo, Anthony Mills, Adriano Lazzarin, Sharon Walmsley, Laurence T. Rimsky
    Abstract:

    Summary 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 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 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.

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