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-inferiority study

DeJesus, Edwin; Ramgopal, Moti; Crofoot, Gordon; Ruane, Peter; LaMarca, Anthony; Mills, Anthony; Martorell, Claudia; Wet, Joseph de; Stellbrink, Hans‐Jürgen; Molina, Jean‐Michel; Post, Frank A.; Pérez‐Valero, Ignacio; Porter, Danielle; Liu, Ya-Pei; Cheng, Andrew; Quirk, Erin; SenGupta, Devi; Cao, Huyen

doi:10.1016/s2352-3018(17)30032-2

Cited by 46 publications

(49 citation statements)

References 19 publications

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“…The number of AEs leading to study drug discontinuation deemed related to study drugs was similar (DeJesus et al, 2016(DeJesus et al, , 2017Post et al, 2017;Raffi et al, 2017;Mills et al, 2016;Orkin et al, 2017Orkin et al, , 2018Gallant et al, 2016): sixty-six (1.49%) in the TAFcontaining regimens and fifty (1.68%) in the TDF-containing regimens. The combined prevalence rate of discontinuations had no significant difference in both treatment groups between week 48 and week 96 (RR, 0.98; 95CI, 0.57-1.68; p > 0.05) (Figure 4, B).…”

Section: Discontinuation Due To Adverse Eventssupporting

confidence: 56%

“…After 48 and 96 weeks of therapy, 709 (18.82%) of 3767 participants in the TAF-containing regimens versus 452 (18.76%) of 2410 participants in the TDF-containing regimens had grade 3 or 4 laboratory abnormalities (DeJesus et al, 2016(DeJesus et al, , 2017Mills et al, 2016;Orkin et al, 2017Orkin et al, , 2018Gallant et al, 2016), which was similar between the two groups. The combined grade 3 or 4 AEs prevalence rate of ART-experienced patients with the use of TAFcontaining regimens was not statistically different from those of TDF-containing regimens (RR, 0.92; 95CI, 0.80-1.06; p > 0.05) (Figure 4, C).…”

Section: Grade 3 or 4 Adverse Eventsmentioning

confidence: 90%

“…Fractures were uncommon in both treatment groups (thirtytwo [0.72%] of 4434 patients in the TAF-containing regimens vs. twenty-two [0.72%] of 3073 patients in the TDF-containing regimens), which had no significant difference between the two groups (Post et al, 2017;Raffi et al, 2017;Mills et al, 2016;Orkin et al, 2017Orkin et al, , 2018Gallant et al, 2016;DeJesus et al, 2017; World Health Organization, 2016) (RR, 1.08; 95CI, 0.60-1.93; p > 0.05) (Figure 4, D). Therefore, we regarded all fractures as related to trauma and not to study drug, and none led to discontinuation of study drug.…”

Section: Fracturesmentioning

confidence: 97%

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Virologically suppressed HIV-infected patients on TDF-containing regimens significantly benefit from switching to TAF-containing regimens: A meta-analysis of randomized controlled trials

Tao

Zhou

et al. 2019

International Journal of Infectious Diseases

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Background: To investigate whether TDF-containing regimens significantly benefited efficacy, safety, and tolerability in TAF-containing regimens in virologically suppressed HIV-infected patients. Methods: PubMed, Embase, Web of Science, and the Cochrane Trial Registry were systematically searched for eligible studies. We extracted and evaluated the pooled data from available randomized controlled trials (RCTs). Results: Eight eligible RCTs were included. In the intention-to-treat (ITT) analysis, patients who switched to TAF-containing regimens had significantly better viral suppression than those continuing TDF-containing regimens at weeks 48 and 96 (RR, 1.02; 95CI, 1.00-1.03; p < 0.05), but no significant difference in the per-protocol (PP) analysis (RR, 1.00; 95CI, 0.99-1.01; p > 0.05). Compared with those receiving the TDF-containing regimens, virologically suppressed HIV-infected patients on the TAF-containing regimens had significant increases in CD4 cell counts (SMD, 0.12; 95CI, 0.08 to 0.17; p < 0.05), renal and bone parameters at the hip (RR, 2.86; 95CI, 2.24-3.64; p < 0.05) and the spine (RR, 2.43; 95 CI, 2.03-2.90; p < 0.05) between weeks 48 and 96. Conclusions: Virologically suppressed HIV-infected patients on TDF-containing regimens significantly benefit from switching to TAF-containing regimens, resulting in better viral suppression, better immune reconstruction, and less bone and renal problems.

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Section: Discontinuation Due To Adverse Eventssupporting

confidence: 56%

Section: Grade 3 or 4 Adverse Eventsmentioning

confidence: 90%

Section: Fracturesmentioning

confidence: 97%

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Virologically suppressed HIV-infected patients on TDF-containing regimens significantly benefit from switching to TAF-containing regimens: A meta-analysis of randomized controlled trials

Tao

Zhou

et al. 2019

International Journal of Infectious Diseases

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“…Other studies investigating F/TAF containing STR regimens showed similar results. Two Phase III studies investigating virologically suppressed participants who switched to rilpivirine/emtricitabine/tenofovir alafenamide reported zero and two M184V RAMs postbaseline out of 438 19 and 316 20 participants, respectively. Of 959 virologically suppressed participants assigned to the elvitegravir/cobicistat/emtricitabine/ tenofovir (E/C/F/TAF) alafenamide arm, one had HIV-1 that developed M184M/I.…”

Section: Discussionmentioning

confidence: 99%

Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

Lathouwers

Wong

Brown

et al. 2020

AIDS Research and Human Retroviruses

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Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatmentexperienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) ‡400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL <50 copies/mL) in EMERALD. Through week 48 across both studies, no darunavir, primary PI, or tenofovir resistance-associated mutations (RAMs) were observed in HIV-1 viruses of 1,125 participants receiving D/C/F/TAF or 629 receiving boosted darunavir plus emtricitabine/ tenofovir-disoproxil-fumarate. In AMBER, the nucleos(t)ide analog reverse transcriptase inhibitor (N(t)RTI) RAM M184I/V was identified in HIV-1 of one participant during D/C/F/TAF treatment. M184V was detected pretreatment as a minority variant (9%). In EMERALD, in participants with prior VF and genoarchive data (N = 140; 98 D/C/F/TAF and 42 control), 4% had viruses with darunavir RAMs, 38% with emtricitabine RAMs, mainly at position 184 (41% not fully susceptible to emtricitabine), 4% with tenofovir RAMs, and 21% ‡ 3 thymidine analogassociated mutations (24% not fully susceptible to tenofovir) detected at screening. All achieved VL <50 copies/mL at week 48 or prior discontinuation. D/C/F/TAF has a high genetic barrier to resistance; no darunavir, primary PI, or tenofovir RAMs were observed through 48 weeks in AMBER and EMERALD. Only one postbaseline M184I/V RAM was observed in HIV-1 of an AMBER participant. In EMERALD, baseline archived RAMs to darunavir, emtricitabine, and tenofovir in participants with prior VF did not preclude virologic response.

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“…The primary 48‐week endpoints were previously reported 5, 8. Herein, we present efficacy, safety and tolerability outcomes up to week 96.…”

Section: Introductionmentioning

confidence: 94%

Switching to coformulated rilpivirine (RPV), emtricitabine (FTC) and tenofovir alafenamide from either RPV, FTC and tenofovir disoproxil fumarate (TDF) or efavirenz, FTC and TDF: 96‐week results from two randomized clinical trials

Hagins

Orkin

et al. 2018

HIV Medicine

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ObjectivesThe single‐tablet regimen rilpivirine, emtricitabine and tenofovir alafenamide (RPV/FTC/TAF) for treatment of HIV‐1‐infected adults was approved based on bioequivalence. We assessed the clinical efficacy, safety and tolerability of switching to RPV/FTC/TAF from either RPV/FTC/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF.MethodsWe conducted two distinct randomized, double‐blind, active‐controlled, noninferiority trials in participants taking RPV/FTC/TDF (Study 1216) and EFV/FTC/TDF (Study 1160). Each study randomized virologically suppressed (HIV‐1 RNA < 50 copies/mL) adults (1:1) to switch to RPV/FTC/TAF or continue their current regimen for 96 weeks. We evaluated efficacy as the proportion with HIV‐1 RNA < 50 copies/mL using the Food and Drug Administration snapshot algorithm and prespecified bone and renal endpoints at week 96.ResultsWe randomized and treated 630 participants in Study 1216 (RPV/FTC/TAF, n = 316; RPV/FTC/TDF, n = 314) and 875 in Study 1160 (RPV/FTC/TAF, n = 438; EFV/FTC/TDF, n = 437). In both studies, the efficacy of switching to RPV/FTC/TAF was noninferior to that of continuing baseline therapy at week 96, with respective percentages of patients with HIV RNA < 50 copies/mL being 89.2% versus 88.5% in Study 1216 [difference 0.7%; 95% confidence interval (CI) −4.3 to +5.8%] and 85.2% versus 85.1% in Study 1160 (difference 0%; 95% CI −4.8 to +4.8%). No participant on RPV/FTC/TAF developed treatment‐emergent resistance versus two on EFV/FTC/TDF and one on RPV/FTC/TDF. Compared with continuing baseline therapy, significant improvements in bone mineral density and renal tubular markers were observed in the RPV/FTC/TAF groups (P < 0.001).ConclusionsSwitching to RPV/FTC/TAF from RPV/FTC/TDF or EFV/FTC/TDF was safe and effective and improved bone mineral density and renal biomarkers up to 96 weeks with no cases of treatment‐emergent resistance.

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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-inferiority study

Cited by 46 publications

References 19 publications

Virologically suppressed HIV-infected patients on TDF-containing regimens significantly benefit from switching to TAF-containing regimens: A meta-analysis of randomized controlled trials

Virologically suppressed HIV-infected patients on TDF-containing regimens significantly benefit from switching to TAF-containing regimens: A meta-analysis of randomized controlled trials

Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

Switching to coformulated rilpivirine (RPV), emtricitabine (FTC) and tenofovir alafenamide from either RPV, FTC and tenofovir disoproxil fumarate (TDF) or efavirenz, FTC and TDF: 96‐week results from two randomized clinical trials

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