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E Dejesus - One of the best experts on this subject based on the ideXlab platform.

  • emtricitabine and Tenofovir alafenamide vs emtricitabine and Tenofovir disoproxil fumarate for hiv pre exposure prophylaxis discover primary results from a randomised double blind multicentre active controlled phase 3 non inferiority trial
    The Lancet, 2020
    Co-Authors: E Dejesus, Jean Michel Molina, Melanie A Thompson, Peter L Anderson, Kenneth H Mayer, Karam Mounzer, Joss J De Wet, Heiko Jessen, Robert M Grant
    Abstract:

    Summary Background Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with Tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and Tenofovir alafenamide versus emtricitabine and Tenofovir disoproxil fumarate for HIV prevention. Methods This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and Tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and Tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and Tenofovir alafenamide group), or emtricitabine (200 mg) and Tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and Tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and Tenofovir alafenamide to emtricitabine and Tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov , NCT02842086 , and is no longer recruiting. Findings Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and Tenofovir alafenamide (n=2694) or emtricitabine and Tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and Tenofovir alafenamide was non-inferior to emtricitabine and Tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19–1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and Tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06–0·33]), and 15 participants in the emtricitabine and Tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19–0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and Tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and Tenofovir disoproxil fumarate group). Emtricitabine and Tenofovir alafenamide was superior to emtricitabine and Tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints. Interpretation Daily emtricitabine and Tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and Tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and Tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and Tenofovir disoproxil fumarate. Funding Gilead Sciences.

  • fixed dose combination bictegravir emtricitabine and Tenofovir alafenamide versus dolutegravir containing regimens for initial treatment of hiv 1 infection week 144 results from two randomised double blind multicentre phase 3 non inferiority trials
    The Lancet HIV, 2020
    Co-Authors: Chloe Orkin, Hj Stellbrink, Franco Maggiolo, E Dejesus, Carlos Martorell, David A Wohl, Jeffrey L Stephens, Samir K. Gupta, Jose R. Arribas, Melanie A Thompson
    Abstract:

    Summary Background In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and Tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies. Methods We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and Tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and Tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and Tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov , NCT02607930 and NCT02607956 . Findings 629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and Tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and Tenofovir alafenamide, 325 to dolutegravir, emtricitabine, Tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and Tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and Tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference −2·6%, 95% CI −8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and Tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and Tenofovir alafenamide group (difference −1·9%, −7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and Tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and Tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and Tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (−0·1 vs −0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study. Interpretation These long-term data support the use of bictegravir, emtricitabine, and Tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance. Funding Gilead Sciences.

  • Tenofovir alafenamide versus Tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials
    2020
    Co-Authors: Paul E Sax, Daniel Podzamczer, E Dejesus, Anton Pozniak, Melanie Thompson, David Wohl, Michael T Yin, Frank Post, Michael Saag, Jean Michel Molina
    Abstract:

    Summary Background Tenofovir disoproxil fumarate can cause renal and bone toxic eff ects related to high plasma Tenofovir concentrations. Tenofovir alafenamide is a novel Tenofovir prodrug with a 90% reduction in plasma Tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with Tenofovir disoproxil fumarate-containing regimens

  • Tenofovir alafenamide plus emtricitabine versus abacavir plus lamivudine for treatment of virologically suppressed hiv 1 infected adults a randomised double blind active controlled non inferiority phase 3 trial
    The Lancet HIV, 2018
    Co-Authors: Alan Winston, Frank A Post, Daniel Podzamczer, Vicente Estrada, Paula Peyrani, Francois Raffi, Peter Ruane, Giovanni Di Perri, E Dejesus, Gordon Crofoot
    Abstract:

    Summary Background Abacavir and Tenofovir alafenamide offer reduced bone toxicity compared with Tenofovir disoproxil fumarate. We aimed to compare safety and efficacy of Tenofovir alafenamide plus emtricitabine with that of abacavir plus lamivudine. Methods In this randomised, double-blind, active-controlled, non-inferiority phase 3 trial, HIV-1-positive adults (≥18 years) were screened at 79 sites in 11 countries in North America and Europe. Eligible participants were virologically suppressed (HIV-1 RNA vs other drug) at screening. Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary endpoint was the proportion of participants with virological suppression (HIV-1 RNA Findings Study enrolment began on June 29, 2015, and the cutoff enrolment date for the week 48 primary endpoint analysis was May 23, 2016. 501 participants were randomly assigned and treated. At week 48, virological suppression was maintained in 227 (90%) of 253 participants receiving Tenofovir alafenamide plus emtricitabine compared with 230 (93%) of 248 receiving abacavir plus lamivudine (difference −3·0%, 95% CI −8·2 to 2·0), showing non-inferiority. Few participants discontinued treatment because of adverse events: 12 (4%) of 280 participants in the Tenofovir alafenimide plus emtricitabine group and nine (3%) of 276 in the abacavir plus lamivudine group. Three participants had serious, treatment-related adverse events: one each with renal colic and neutropenia in the Tenofovir alafenamide plus emtricitabine group, and one myocardial infarction in the abacavir plus lamivudine group. There were no treatment-related deaths. Interpretation Tenofovir alafenamide, in combination with emtricitabine and various third drugs, maintained high efficacy with a renal and bone safety profile similar to that of abacavir. In virologically suppressed patients, a regimen containing Tenofovir alafenamide could be an alternative to those containing abacavir, without concern for new onset of renal or bone toxicities or hyperlipidaemia. Funding Gilead Sciences Inc.

  • switching from Tenofovir disoproxil fumarate to Tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with hiv 1 infection a randomised double blind multicentre phase 3b non inferiority study
    The Lancet HIV, 2017
    Co-Authors: Chloe Orkin, Gordon Crofoot, Peter Ruane, E Dejesus, Anthony Mills, Moti Ramgopal, Anthony Lamarca, Bernard Vandercam, Joseph De Wet, Jurgen K Rockstroh
    Abstract:

    Summary Background Tenofovir alafenamide, a Tenofovir prodrug, results in 90% lower Tenofovir plasma concentrations than does Tenofovir disproxil fumarate, thereby minimising bone and renal risks. We investigated the efficacy, safety, and tolerability of switching to a single-tablet regimen containing rilpivirine, emtricitabine, and Tenofovir alafenamide compared with remaining on rilpivirine, emtricitabine, and Tenofovir disoproxil fumarate. Methods In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-1-infected adults were screened and enrolled at 119 hospitals in 11 countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA Findings Between Jan 26, 2015, and Aug 25, 2015, 630 participants were randomised (316 to the Tenofovir alafenamide group and 314 to the Tenofovir disoproxil fumarate group). At week 48, 296 (94%) of 316 participants on Tenofovir alafenamide and 294 (94%) of 313 on Tenofovir disoproxil fumarate had maintained less than 50 copies per mL HIV-1 RNA (difference −0·3%, 95·001% CI −4·2 to 3·7), showing non-inferiority of Tenofovir alafenamide to Tenofovir disoproxil fumarate. Numbers of adverse events were similar between groups. 20 (6%) of 316 participants had study-drug related adverse events in the Tenofovir alafenamide group compared with 37 (12%) of 314 in the Tenofovir disoproxil fumarate group; none of these were serious. Interpretation Switching to rilpivirine, emtricitabine, and Tenofovir alafenamide was non-inferior to continuing rilpivirine, emtricitabine, Tenofovir disoproxil fumarate in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending Tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection. Funding Gilead Sciences.

Peter Ruane - One of the best experts on this subject based on the ideXlab platform.

  • Tenofovir alafenamide plus emtricitabine versus abacavir plus lamivudine for treatment of virologically suppressed hiv 1 infected adults a randomised double blind active controlled non inferiority phase 3 trial
    The Lancet HIV, 2018
    Co-Authors: Alan Winston, Frank A Post, Daniel Podzamczer, Vicente Estrada, Paula Peyrani, Francois Raffi, Peter Ruane, Giovanni Di Perri, E Dejesus, Gordon Crofoot
    Abstract:

    Summary Background Abacavir and Tenofovir alafenamide offer reduced bone toxicity compared with Tenofovir disoproxil fumarate. We aimed to compare safety and efficacy of Tenofovir alafenamide plus emtricitabine with that of abacavir plus lamivudine. Methods In this randomised, double-blind, active-controlled, non-inferiority phase 3 trial, HIV-1-positive adults (≥18 years) were screened at 79 sites in 11 countries in North America and Europe. Eligible participants were virologically suppressed (HIV-1 RNA vs other drug) at screening. Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary endpoint was the proportion of participants with virological suppression (HIV-1 RNA Findings Study enrolment began on June 29, 2015, and the cutoff enrolment date for the week 48 primary endpoint analysis was May 23, 2016. 501 participants were randomly assigned and treated. At week 48, virological suppression was maintained in 227 (90%) of 253 participants receiving Tenofovir alafenamide plus emtricitabine compared with 230 (93%) of 248 receiving abacavir plus lamivudine (difference −3·0%, 95% CI −8·2 to 2·0), showing non-inferiority. Few participants discontinued treatment because of adverse events: 12 (4%) of 280 participants in the Tenofovir alafenimide plus emtricitabine group and nine (3%) of 276 in the abacavir plus lamivudine group. Three participants had serious, treatment-related adverse events: one each with renal colic and neutropenia in the Tenofovir alafenamide plus emtricitabine group, and one myocardial infarction in the abacavir plus lamivudine group. There were no treatment-related deaths. Interpretation Tenofovir alafenamide, in combination with emtricitabine and various third drugs, maintained high efficacy with a renal and bone safety profile similar to that of abacavir. In virologically suppressed patients, a regimen containing Tenofovir alafenamide could be an alternative to those containing abacavir, without concern for new onset of renal or bone toxicities or hyperlipidaemia. Funding Gilead Sciences Inc.

  • switching from Tenofovir disoproxil fumarate to Tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with hiv 1 infection a randomised double blind multicentre phase 3b non inferiority study
    The Lancet HIV, 2017
    Co-Authors: Chloe Orkin, Gordon Crofoot, Peter Ruane, E Dejesus, Anthony Mills, Moti Ramgopal, Anthony Lamarca, Bernard Vandercam, Joseph De Wet, Jurgen K Rockstroh
    Abstract:

    Summary Background Tenofovir alafenamide, a Tenofovir prodrug, results in 90% lower Tenofovir plasma concentrations than does Tenofovir disproxil fumarate, thereby minimising bone and renal risks. We investigated the efficacy, safety, and tolerability of switching to a single-tablet regimen containing rilpivirine, emtricitabine, and Tenofovir alafenamide compared with remaining on rilpivirine, emtricitabine, and Tenofovir disoproxil fumarate. Methods In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-1-infected adults were screened and enrolled at 119 hospitals in 11 countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA Findings Between Jan 26, 2015, and Aug 25, 2015, 630 participants were randomised (316 to the Tenofovir alafenamide group and 314 to the Tenofovir disoproxil fumarate group). At week 48, 296 (94%) of 316 participants on Tenofovir alafenamide and 294 (94%) of 313 on Tenofovir disoproxil fumarate had maintained less than 50 copies per mL HIV-1 RNA (difference −0·3%, 95·001% CI −4·2 to 3·7), showing non-inferiority of Tenofovir alafenamide to Tenofovir disoproxil fumarate. Numbers of adverse events were similar between groups. 20 (6%) of 316 participants had study-drug related adverse events in the Tenofovir alafenamide group compared with 37 (12%) of 314 in the Tenofovir disoproxil fumarate group; none of these were serious. Interpretation Switching to rilpivirine, emtricitabine, and Tenofovir alafenamide was non-inferior to continuing rilpivirine, emtricitabine, Tenofovir disoproxil fumarate in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending Tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection. Funding Gilead Sciences.

  • switching from efavirenz emtricitabine and Tenofovir disoproxil fumarate to Tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with hiv 1 infection a randomised double blind multicentre phase 3b non inf
    The Lancet HIV, 2017
    Co-Authors: E Dejesus, Hj Stellbrink, Gordon Crofoot, Peter Ruane, Carlos Martorell, Anthony Mills, Moti Ramgopal, Anthony Lamarca, Joseph De Wet, Jean Michel Molina
    Abstract:

    Summary Background Tenofovir alafenamide is a prodrug that reduces Tenofovir plasma concentrations by 90% compared with Tenofovir disoproxil fumarate, thereby decreasing bone and renal risks. The coformulation of rilpivirine, emtricitabine, and Tenofovir alafenamide has recently been approved, and we aimed to investigate the efficacy, safety, and tolerability of switching to this regimen compared with remaining on coformulated efavirenz, emtricitabine, and Tenofovir disoproxil fumarate. Methods In this randomised, double-blind, placebo-controlled, non-inferiority trial, HIV-1-infected adults were enrolled at 120 hospitals and outpatient clinics in eight countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA Findings Between Jan 26, 2015, and Aug 27, 2015, 875 participants were randomly assigned and treated (438 with rilpivirine, emtricitabine, and Tenofovir alafenamide and 437 with efavirenz, emtricitabine, Tenofovir disoproxil fumarate). Viral suppression at week 48 was maintained in 394 (90%) of 438 participants assigned to the Tenofovir alafenamide regimen and 402 (92%) of 437 assigned to the Tenofovir disoproxil fumarate regimen (difference −2·0%, 95·001% CI −5·9 to 1·8), demonstrating non-inferiority. 56 (13%) of 438 in participants in the rilpivirine, emtricitabine, and Tenofovir alafenamide group experienced treatment-related adverse events compared with 45 (10%) of 437 in the efavirenz, emtricitabine, and Tenofovir disoproxil fumarate group. Interpretation Switching to rilpivirine, emtricitabine, and Tenofovir alafenamide from efavirenz, emtricitabine, and Tenofovir disoproxil fumarate was non-inferior in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending Tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection. Funding Gilead Sciences.

  • efficacy and safety of Tenofovir alafenamide versus Tenofovir disoproxil fumarate given as fixed dose combinations containing emtricitabine as backbones for treatment of hiv 1 infection in virologically suppressed adults a randomised double blind act
    The Lancet HIV, 2016
    Co-Authors: Joel E Gallant, Francois Raffi, Peter Ruane, E Dejesus, Cynthia Brinson, Margaret Johnson, Eric S. Daar, Nathan Clumeck, O Osiyemi, Doug Ward
    Abstract:

    Summary Background Emtricitabine with Tenofovir disoproxil fumarate is a standard-of-care nucleoside reverse transcriptase inhibitor (NRTI) backbone. However, Tenofovir disoproxil fumarate is associated with renal and bone toxic effects; the novel prodrug Tenofovir alafenamide achieves 90% lower plasma Tenofovir concentrations. We aimed to further assess safety and efficacy of fixed-dose combination emtricitabine with Tenofovir alafenamide in patients switched from emtricitabine with Tenofovir disoproxil fumarate. Methods In this controlled, double-blind, multicentre phase 3 study, we recruited virologically suppressed (HIV RNA vs other agent). Investigators, patients, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary outcome was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the US Food and Drug Administration snapshot algorithm with a prespecified non-inferiority margin of 10%. The primary efficacy endpoint was analysed with the per-protocol analysis set, whereas the safety analysis included all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02121795. Findings We recruited patients between May 6, 2011, and Sept 11, 2014; 780 were screened and 668 were randomly assigned to receive either Tenofovir alafenamide (n=333) or Tenofovir disoproxil fumarate (n=330). Through week 48, virological success (HIV-1 RNA Interpretation In patients switching from emtricitabine with Tenofovir disoproxil fumarate to emtricitabine with Tenofovir alafenamide, high rates of virological suppression were maintained. With its safety advantages, fixed-dose emtricitabine with Tenofovir alafenamide has the potential to become an important NRTI backbone. Funding Gilead Sciences.

  • phase i ii study of the pharmacokinetics safety and antiretroviral activity of Tenofovir alafenamide a new prodrug of the hiv reverse transcriptase inhibitor Tenofovir in hiv infected adults
    Journal of Antimicrobial Chemotherapy, 2014
    Co-Authors: Martin Markowitz, Brian P Kearney, Peter Ruane, Andrew R Zolopa, Kathleen Squires, Dion F Coakley, Lijie Zhong, Michael Wulfsohn, Michael D Miller, William A Lee
    Abstract:

    Background Tenofovir alafenamide (formerly GS-7340) is a new oral prodrug of Tenofovir, a nucleotide analogue that inhibits HIV-1 reverse transcription. Unlike the currently marketed Tenofovir prodrug, Tenofovir disoproxil fumarate, Tenofovir alafenamide is stable in plasma and then rapidly converted into Tenofovir once inside cells. Methods The pharmacokinetics, safety and antiviral activity of 40 or 120 mg of Tenofovir alafenamide compared with 300 mg of Tenofovir disoproxil fumarate when administered as monotherapy once daily for 14 days in HIV-1-infected, treatment-naive subjects was studied. Results Administration of 40 mg of Tenofovir alafenamide for 14 days resulted in lower Tenofovir Cmax (13 versus 207 ng/mL) and lower systemic exposures (AUC0-t, 383 versus 1810 ng · h/mL) compared with subjects who received Tenofovir disoproxil fumarate. There were higher intracellular Tenofovir concentrations within peripheral blood mononuclear cells with both 40 mg of Tenofovir alafenamide (8.2 μM) and 120 mg of Tenofovir alafenamide (16.9 μM) compared with 300 mg of Tenofovir disoproxil fumarate (0.9 μM). The most commonly observed adverse events were headache, nausea and flatulence, which occurred similarly across the three groups. After 14 days, the mean changes in HIV-1 RNA were -0.94 log₁₀copies/mL for the Tenofovir disoproxil fumarate group, -1.57 log₁₀ copies/mL for the 40 mg of Tenofovir alafenamide group and -1.71 log₁₀ copies/mL for the 120 mg of Tenofovir alafenamide group. The mean first-phase HIV-1 RNA decay slopes were -0.36, -0.63 and -0.64 for the Tenofovir disoproxil fumarate group, the 40 mg of Tenofovir alafenamide group and the 120 mg of Tenofovir alafenamide group, respectively. No resistance mutations to either Tenofovir alafenamide or Tenofovir disoproxil fumarate were detected. Conclusions Tenofovir alafenamide, a new once-daily oral prodrug of Tenofovir, showed more potent anti-HIV-1 activity and higher intracellular Tenofovir levels compared with Tenofovir disoproxil fumarate, while maintaining lower plasma Tenofovir exposure at 40 mg with good tolerability over 14 days of monotherapy.

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

  • emtricitabine and Tenofovir alafenamide vs emtricitabine and Tenofovir disoproxil fumarate for hiv pre exposure prophylaxis discover primary results from a randomised double blind multicentre active controlled phase 3 non inferiority trial
    The Lancet, 2020
    Co-Authors: E Dejesus, Jean Michel Molina, Melanie A Thompson, Peter L Anderson, Kenneth H Mayer, Karam Mounzer, Joss J De Wet, Heiko Jessen, Robert M Grant
    Abstract:

    Summary Background Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with Tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and Tenofovir alafenamide versus emtricitabine and Tenofovir disoproxil fumarate for HIV prevention. Methods This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and Tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and Tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and Tenofovir alafenamide group), or emtricitabine (200 mg) and Tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and Tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and Tenofovir alafenamide to emtricitabine and Tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov , NCT02842086 , and is no longer recruiting. Findings Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and Tenofovir alafenamide (n=2694) or emtricitabine and Tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and Tenofovir alafenamide was non-inferior to emtricitabine and Tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19–1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and Tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06–0·33]), and 15 participants in the emtricitabine and Tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19–0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and Tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and Tenofovir disoproxil fumarate group). Emtricitabine and Tenofovir alafenamide was superior to emtricitabine and Tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints. Interpretation Daily emtricitabine and Tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and Tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and Tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and Tenofovir disoproxil fumarate. Funding Gilead Sciences.

  • Tenofovir alafenamide versus Tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials
    2020
    Co-Authors: Paul E Sax, Daniel Podzamczer, E Dejesus, Anton Pozniak, Melanie Thompson, David Wohl, Michael T Yin, Frank Post, Michael Saag, Jean Michel Molina
    Abstract:

    Summary Background Tenofovir disoproxil fumarate can cause renal and bone toxic eff ects related to high plasma Tenofovir concentrations. Tenofovir alafenamide is a novel Tenofovir prodrug with a 90% reduction in plasma Tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with Tenofovir disoproxil fumarate-containing regimens

  • bone mineral density in virologically suppressed people aged 60 years or older with hiv 1 switching from a regimen containing Tenofovir disoproxil fumarate to an elvitegravir cobicistat emtricitabine and Tenofovir alafenamide single tablet regimen a
    The Lancet HIV, 2019
    Co-Authors: Franco Maggiolo, David Piontkowsky, Maria Gracia Mateogarcia, Yongwu Shao, Ian Mcnicholl, Federico Pulido, Francois Raffi, Giuliano Rizzardini, Jean Michel Molina, Richard Haubrich
    Abstract:

    Summary Background Tenofovir alafenamide is associated with less renal and bone toxicity than Tenofovir disoproxil fumarate and might improve the long-term safety of antiretroviral therapy. We aimed to investigate the effect on bone mineral density of switching from a regimen containing Tenofovir disoproxil fumarate to one containing Tenofovir alafenamide in participants aged 60 years and older. Methods We did a prospective, open-label, multicentre, randomised trial in 36 European centres. Participants were virologically suppressed (HIV-1 RNA ClinicalTrials.gov , NCT02616783 . Findings Between Dec 22, 2015, and March 21, 2018, 167 participants were randomly assigned to elvitegravir, cobicistat, emtricitabine, and Tenofovir alafenamide (n=111 [66%]) or Tenofovir disoproxil fumarate (n=56 [34%]). One participant in the elvitegravir, cobicistat, emtricitabine, and Tenofovir alafenamide group did not receive treatment and was excluded from all analyses. At week 48, the mean percentage change in spine bone mineral density was 2·24% (SD 3·27) in the elvitegravir, cobicistat, emtricitabine, and Tenofovir alafenamide group and −0·10% (3·39) in the Tenofovir disoproxil fumarate group (between-group difference 2·43% [95% CI 1·34–3·52]; p Interpretation The significantly improved bone mineral density, overall safety, and efficacy data show the feasibility of switching from a regimen containing Tenofovir disoproxil fumarate to elvitegravir, cobicistat, emtricitabine, and Tenofovir alafenamide in virologically suppressed people living with HIV aged 60 years or older. Funding Gilead Sciences.

  • switching from efavirenz emtricitabine and Tenofovir disoproxil fumarate to Tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with hiv 1 infection a randomised double blind multicentre phase 3b non inf
    The Lancet HIV, 2017
    Co-Authors: E Dejesus, Hj Stellbrink, Gordon Crofoot, Peter Ruane, Carlos Martorell, Anthony Mills, Moti Ramgopal, Anthony Lamarca, Joseph De Wet, Jean Michel Molina
    Abstract:

    Summary Background Tenofovir alafenamide is a prodrug that reduces Tenofovir plasma concentrations by 90% compared with Tenofovir disoproxil fumarate, thereby decreasing bone and renal risks. The coformulation of rilpivirine, emtricitabine, and Tenofovir alafenamide has recently been approved, and we aimed to investigate the efficacy, safety, and tolerability of switching to this regimen compared with remaining on coformulated efavirenz, emtricitabine, and Tenofovir disoproxil fumarate. Methods In this randomised, double-blind, placebo-controlled, non-inferiority trial, HIV-1-infected adults were enrolled at 120 hospitals and outpatient clinics in eight countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA Findings Between Jan 26, 2015, and Aug 27, 2015, 875 participants were randomly assigned and treated (438 with rilpivirine, emtricitabine, and Tenofovir alafenamide and 437 with efavirenz, emtricitabine, Tenofovir disoproxil fumarate). Viral suppression at week 48 was maintained in 394 (90%) of 438 participants assigned to the Tenofovir alafenamide regimen and 402 (92%) of 437 assigned to the Tenofovir disoproxil fumarate regimen (difference −2·0%, 95·001% CI −5·9 to 1·8), demonstrating non-inferiority. 56 (13%) of 438 in participants in the rilpivirine, emtricitabine, and Tenofovir alafenamide group experienced treatment-related adverse events compared with 45 (10%) of 437 in the efavirenz, emtricitabine, and Tenofovir disoproxil fumarate group. Interpretation Switching to rilpivirine, emtricitabine, and Tenofovir alafenamide from efavirenz, emtricitabine, and Tenofovir disoproxil fumarate was non-inferior in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending Tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection. Funding Gilead Sciences.

  • Tenofovir alafenamide versus Tenofovir disoproxil fumarate coformulated with elvitegravir cobicistat and emtricitabine for initial treatment of hiv 1 infection two randomised double blind phase 3 non inferiority trials
    The Lancet, 2015
    Co-Authors: David A Wohl, Frank A Post, Daniel Podzamczer, E Dejesus, Jean Michel Molina, Anton Pozniak, Ellen Koenig, Michael S Saag, Melanie Thompson, Benoit Trottier
    Abstract:

    Summary Background Tenofovir disoproxil fumarate can cause renal and bone toxic effects related to high plasma Tenofovir concentrations. Tenofovir alafenamide is a novel Tenofovir prodrug with a 90% reduction in plasma Tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with Tenofovir disoproxil fumarate-containing regimens. Methods In these two controlled, double-blind phase 3 studies, we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries. Patients were randomly assigned (1:1) to receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg Tenofovir alafenamide (E/C/F/Tenofovir alafenamide) or 300 mg Tenofovir disoproxil fumarate (E/C/F/Tenofovir disoproxil fumarate) with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size 4) and was stratified by HIV-1 RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary intention-to-treat efficacy and safety analyses. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the the US Food and Drug Adminstration (FDA) snapshot algorithm (pre-specified non-inferiority margin of 12%) and pre-specified renal and bone endpoints at 48 weeks. These studies are registered with ClinicalTrials.gov, numbers NCT01780506 and NCT01797445. Findings We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2175 screened and 1744 randomly assigned), and gave treatment to 1733 patients (866 given E/C/F/Tenofovir alafenamide and 867 given E/C/F/Tenofovir disoproxil fumarate). E/C/F/Tenofovir alafenamide was non-inferior to E/C/F/Tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the Tenofovir alafenamide group and 784 (90%) of 867 patients in the Tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2·0%, 95% CI −0·7 to 4·7). Patients given E/C/F/Tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/Tenofovir disoproxil fumarate (0·08 vs 0·12 mg/dL; p vs 20; p vs –2·86; p vs –2·95; p Interpretation Through 48 weeks, more than 90% of patients given E/C/F/Tenofovir alafenamide or E/C/F/Tenofovir disoproxil fumarate had virological success. Renal and bone effects were significantly reduced in patients given E/C/F/Tenofovir alafenamide. Although these studies do not have the power to assess clinical safety events such as renal failure and fractures, our data suggest that E/C/F/Tenofovir alafenamide will have a favourable long-term renal and bone safety profile. Funding Gilead Sciences.

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  • fixed dose combination bictegravir emtricitabine and Tenofovir alafenamide versus dolutegravir containing regimens for initial treatment of hiv 1 infection week 144 results from two randomised double blind multicentre phase 3 non inferiority trials
    The Lancet HIV, 2020
    Co-Authors: Chloe Orkin, Hj Stellbrink, Franco Maggiolo, E Dejesus, Carlos Martorell, David A Wohl, Jeffrey L Stephens, Samir K. Gupta, Jose R. Arribas, Melanie A Thompson
    Abstract:

    Summary Background In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and Tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies. Methods We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and Tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and Tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and Tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov , NCT02607930 and NCT02607956 . Findings 629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and Tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and Tenofovir alafenamide, 325 to dolutegravir, emtricitabine, Tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and Tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and Tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference −2·6%, 95% CI −8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and Tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and Tenofovir alafenamide group (difference −1·9%, −7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and Tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and Tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and Tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (−0·1 vs −0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study. Interpretation These long-term data support the use of bictegravir, emtricitabine, and Tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance. Funding Gilead Sciences.

  • switching from Tenofovir disoproxil fumarate to Tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with hiv 1 infection a randomised double blind multicentre phase 3b non inferiority study
    The Lancet HIV, 2017
    Co-Authors: Chloe Orkin, Gordon Crofoot, Peter Ruane, E Dejesus, Anthony Mills, Moti Ramgopal, Anthony Lamarca, Bernard Vandercam, Joseph De Wet, Jurgen K Rockstroh
    Abstract:

    Summary Background Tenofovir alafenamide, a Tenofovir prodrug, results in 90% lower Tenofovir plasma concentrations than does Tenofovir disproxil fumarate, thereby minimising bone and renal risks. We investigated the efficacy, safety, and tolerability of switching to a single-tablet regimen containing rilpivirine, emtricitabine, and Tenofovir alafenamide compared with remaining on rilpivirine, emtricitabine, and Tenofovir disoproxil fumarate. Methods In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-1-infected adults were screened and enrolled at 119 hospitals in 11 countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA Findings Between Jan 26, 2015, and Aug 25, 2015, 630 participants were randomised (316 to the Tenofovir alafenamide group and 314 to the Tenofovir disoproxil fumarate group). At week 48, 296 (94%) of 316 participants on Tenofovir alafenamide and 294 (94%) of 313 on Tenofovir disoproxil fumarate had maintained less than 50 copies per mL HIV-1 RNA (difference −0·3%, 95·001% CI −4·2 to 3·7), showing non-inferiority of Tenofovir alafenamide to Tenofovir disoproxil fumarate. Numbers of adverse events were similar between groups. 20 (6%) of 316 participants had study-drug related adverse events in the Tenofovir alafenamide group compared with 37 (12%) of 314 in the Tenofovir disoproxil fumarate group; none of these were serious. Interpretation Switching to rilpivirine, emtricitabine, and Tenofovir alafenamide was non-inferior to continuing rilpivirine, emtricitabine, Tenofovir disoproxil fumarate in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending Tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection. Funding Gilead Sciences.

  • comparison of changes in bone density and turnover with abacavir lamivudine versus Tenofovir emtricitabine in hiv infected adults 48 week results from the assert study
    Clinical Infectious Diseases, 2010
    Co-Authors: Hj Stellbrink, Hans-georg Sprenger, Jan Gerstoft, Eric Van Wijngaerden, Juliet E. Compston, Chloe Orkin, Giuliano Rizzardini, Adriano Lazzarin, Jaime Rodriguez Arribas, John D C Lambert
    Abstract:

    Background. Abacavir-lamivudine and Tenofovir DF-emtricitabine fixed-dose combinations are commonly used as first-line antiretroviral therapies. However, few studies have comprehensively compared their relative safety profiles. Methods. In this European, multicenter, open-label, 96-week study, antiretroviral-naive adult subjects with human immunodeficiency virus (HIV) infection were randomized to receive either abacavir-lamivudine or Tenofovir- emtricitabine with efavirenz. Primary analyses were conducted after 48 weeks of treatment. Bone mineral density (BMD), a powered secondary end point, was assessed by dual energy x-ray absorptiometry. Bone turnover markers (osteocalcin, procollagen 1 N-terminal propeptide, bone specific alkaline phosphatase, and type 1 collagen cross-linked C telopeptide [CTx]) were assessed in an exploratory analysis. Results. A total of 385 subjects were enrolled in the study. BMD loss was observed in both treatment groups, with a significant difference in the change from baseline in both total hip (abacavir-lamivudine group, -1.9%; Tenofovir-emtricitabine group, -3.6%; P= 6% was more common in the Tenofovir-emtricitabine group (13% of the Tenofovir-emtricitabine group vs 3% of the abacavir-lamivudine group had a loss of >= 6% in the hip; 15% vs 5% had a loss of >= 6% in the spine). Bone turnover markers increased in both treatment groups over the first 24 weeks, stabilizing or decreasing thereafter. Increases in all markers were significantly greater in the Tenofovir-emtricitabine treatment group than in the abacavir-lamivudine group at week 24. All but CTx remained significantly different at week 48 (eg, osteocalcin: abacavir-lamivudine group, +8.07 mg/L; Tenofovir-emtricitabine group, +11.92 mg/L; P Conclusions. This study demonstrated the impact of first-line treatment regimens on bone. Greater increases in bone turnover and decreases in BMD were observed in subjects treated with Tenofovir-emtricitabine than were observed in subjects treated with abacavir-lamivudine.

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  • Tenofovir alafenamide plus emtricitabine versus abacavir plus lamivudine for treatment of virologically suppressed hiv 1 infected adults a randomised double blind active controlled non inferiority phase 3 trial
    The Lancet HIV, 2018
    Co-Authors: Alan Winston, Frank A Post, Daniel Podzamczer, Vicente Estrada, Paula Peyrani, Francois Raffi, Peter Ruane, Giovanni Di Perri, E Dejesus, Gordon Crofoot
    Abstract:

    Summary Background Abacavir and Tenofovir alafenamide offer reduced bone toxicity compared with Tenofovir disoproxil fumarate. We aimed to compare safety and efficacy of Tenofovir alafenamide plus emtricitabine with that of abacavir plus lamivudine. Methods In this randomised, double-blind, active-controlled, non-inferiority phase 3 trial, HIV-1-positive adults (≥18 years) were screened at 79 sites in 11 countries in North America and Europe. Eligible participants were virologically suppressed (HIV-1 RNA vs other drug) at screening. Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary endpoint was the proportion of participants with virological suppression (HIV-1 RNA Findings Study enrolment began on June 29, 2015, and the cutoff enrolment date for the week 48 primary endpoint analysis was May 23, 2016. 501 participants were randomly assigned and treated. At week 48, virological suppression was maintained in 227 (90%) of 253 participants receiving Tenofovir alafenamide plus emtricitabine compared with 230 (93%) of 248 receiving abacavir plus lamivudine (difference −3·0%, 95% CI −8·2 to 2·0), showing non-inferiority. Few participants discontinued treatment because of adverse events: 12 (4%) of 280 participants in the Tenofovir alafenimide plus emtricitabine group and nine (3%) of 276 in the abacavir plus lamivudine group. Three participants had serious, treatment-related adverse events: one each with renal colic and neutropenia in the Tenofovir alafenamide plus emtricitabine group, and one myocardial infarction in the abacavir plus lamivudine group. There were no treatment-related deaths. Interpretation Tenofovir alafenamide, in combination with emtricitabine and various third drugs, maintained high efficacy with a renal and bone safety profile similar to that of abacavir. In virologically suppressed patients, a regimen containing Tenofovir alafenamide could be an alternative to those containing abacavir, without concern for new onset of renal or bone toxicities or hyperlipidaemia. Funding Gilead Sciences Inc.

  • switching from Tenofovir disoproxil fumarate to Tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with hiv 1 infection a randomised double blind multicentre phase 3b non inferiority study
    The Lancet HIV, 2017
    Co-Authors: Chloe Orkin, Gordon Crofoot, Peter Ruane, E Dejesus, Anthony Mills, Moti Ramgopal, Anthony Lamarca, Bernard Vandercam, Joseph De Wet, Jurgen K Rockstroh
    Abstract:

    Summary Background Tenofovir alafenamide, a Tenofovir prodrug, results in 90% lower Tenofovir plasma concentrations than does Tenofovir disproxil fumarate, thereby minimising bone and renal risks. We investigated the efficacy, safety, and tolerability of switching to a single-tablet regimen containing rilpivirine, emtricitabine, and Tenofovir alafenamide compared with remaining on rilpivirine, emtricitabine, and Tenofovir disoproxil fumarate. Methods In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-1-infected adults were screened and enrolled at 119 hospitals in 11 countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA Findings Between Jan 26, 2015, and Aug 25, 2015, 630 participants were randomised (316 to the Tenofovir alafenamide group and 314 to the Tenofovir disoproxil fumarate group). At week 48, 296 (94%) of 316 participants on Tenofovir alafenamide and 294 (94%) of 313 on Tenofovir disoproxil fumarate had maintained less than 50 copies per mL HIV-1 RNA (difference −0·3%, 95·001% CI −4·2 to 3·7), showing non-inferiority of Tenofovir alafenamide to Tenofovir disoproxil fumarate. Numbers of adverse events were similar between groups. 20 (6%) of 316 participants had study-drug related adverse events in the Tenofovir alafenamide group compared with 37 (12%) of 314 in the Tenofovir disoproxil fumarate group; none of these were serious. Interpretation Switching to rilpivirine, emtricitabine, and Tenofovir alafenamide was non-inferior to continuing rilpivirine, emtricitabine, Tenofovir disoproxil fumarate in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending Tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection. Funding Gilead Sciences.

  • switching from efavirenz emtricitabine and Tenofovir disoproxil fumarate to Tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with hiv 1 infection a randomised double blind multicentre phase 3b non inf
    The Lancet HIV, 2017
    Co-Authors: E Dejesus, Hj Stellbrink, Gordon Crofoot, Peter Ruane, Carlos Martorell, Anthony Mills, Moti Ramgopal, Anthony Lamarca, Joseph De Wet, Jean Michel Molina
    Abstract:

    Summary Background Tenofovir alafenamide is a prodrug that reduces Tenofovir plasma concentrations by 90% compared with Tenofovir disoproxil fumarate, thereby decreasing bone and renal risks. The coformulation of rilpivirine, emtricitabine, and Tenofovir alafenamide has recently been approved, and we aimed to investigate the efficacy, safety, and tolerability of switching to this regimen compared with remaining on coformulated efavirenz, emtricitabine, and Tenofovir disoproxil fumarate. Methods In this randomised, double-blind, placebo-controlled, non-inferiority trial, HIV-1-infected adults were enrolled at 120 hospitals and outpatient clinics in eight countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA Findings Between Jan 26, 2015, and Aug 27, 2015, 875 participants were randomly assigned and treated (438 with rilpivirine, emtricitabine, and Tenofovir alafenamide and 437 with efavirenz, emtricitabine, Tenofovir disoproxil fumarate). Viral suppression at week 48 was maintained in 394 (90%) of 438 participants assigned to the Tenofovir alafenamide regimen and 402 (92%) of 437 assigned to the Tenofovir disoproxil fumarate regimen (difference −2·0%, 95·001% CI −5·9 to 1·8), demonstrating non-inferiority. 56 (13%) of 438 in participants in the rilpivirine, emtricitabine, and Tenofovir alafenamide group experienced treatment-related adverse events compared with 45 (10%) of 437 in the efavirenz, emtricitabine, and Tenofovir disoproxil fumarate group. Interpretation Switching to rilpivirine, emtricitabine, and Tenofovir alafenamide from efavirenz, emtricitabine, and Tenofovir disoproxil fumarate was non-inferior in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending Tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection. Funding Gilead Sciences.