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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

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 impr... Full description

Journal Title: The Lancet (British edition) 2015, Vol.385 (9987), p.2606-2615
Main Author: Sax, Paul E, Dr Prof
Other Authors: Wohl, David, MD , Yin, Michael T, Prof , Post, Frank, MD , DeJesus, Edwin, MD , Saag, Michael, MD , Pozniak, Anton, MD , Thompson, Melanie, MD , Podzamczer, Daniel, MD , Molina, Jean Michel, Prof , Oka, Shinichi, MD , Koenig, Ellen, MD , Trottier, Benoit, MD , Andrade-Villanueva, Jaime, MD , Crofoot, Gordon, MD , Custodio, Joseph M, PharmD , Plummer, Andrew, MS , Zhong, Lijie, PhD , Cao, Huyen, MD , Martin, Hal, MD , Callebaut, Christian, PhD , Cheng, Andrew K, MD , Fordyce, Marshall W, MD , McCallister, Scott, MD
Format: Electronic Article Electronic Article
Language: English
Subjects:
Acquired immune deficiency syndrome
Adenine - administration & dosage
Adenine - adverse effects
Adenine - analogs & derivatives
Adult
AIDS
Analysis
Anti-HIV Agents - adverse effects
Anti-HIV Agents - therapeutic use
Antiretroviral drugs
Arthralgia - chemically induced
Bone Density - drug effects
Carbamates - administration & dosage
Carbamates - adverse effects
CD4 Lymphocyte Count
Clinical trials
Cobicistat
Cross infection
Deoxycytidine - administration & dosage
Deoxycytidine - adverse effects
Deoxycytidine - analogs & derivatives
Double-Blind Method
Drug Combinations
Drug therapy
Emtricitabine
Female
Headache - chemically induced
Health aspects
HIV
HIV (Viruses)
HIV infection
HIV Infections - drug therapy
HIV Infections - virology
Human immunodeficiency virus
Humans
immune system diseases
Infections
Internal Medicine
Kidney - drug effects
Male
Medical colleges
Nausea
Nosocomial infections
Organophosphonates - administration & dosage
Organophosphonates - adverse effects
Quinolones - administration & dosage
Quinolones - adverse effects
Respiration Disorders - chemically induced
Sleep Initiation and Maintenance Disorders - chemically induced
Tenofovir
Thiazoles - administration & dosage
Thiazoles - adverse effects
Treatment Outcome
Viral Load - drug effects
virus diseases
Quelle: Alma/SFX Local Collection
Publisher: England: Elsevier Ltd
ID: ISSN: 0140-6736
Link: https://www.ncbi.nlm.nih.gov/pubmed/25890673
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title: 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
format: Article
creator:
  • Sax, Paul E, Dr Prof
  • Wohl, David, MD
  • Yin, Michael T, Prof
  • Post, Frank, MD
  • DeJesus, Edwin, MD
  • Saag, Michael, MD
  • Pozniak, Anton, MD
  • Thompson, Melanie, MD
  • Podzamczer, Daniel, MD
  • Molina, Jean Michel, Prof
  • Oka, Shinichi, MD
  • Koenig, Ellen, MD
  • Trottier, Benoit, MD
  • Andrade-Villanueva, Jaime, MD
  • Crofoot, Gordon, MD
  • Custodio, Joseph M, PharmD
  • Plummer, Andrew, MS
  • Zhong, Lijie, PhD
  • Cao, Huyen, MD
  • Martin, Hal, MD
  • Callebaut, Christian, PhD
  • Cheng, Andrew K, MD
  • Fordyce, Marshall W, MD
  • McCallister, Scott, MD
subjects:
  • Acquired immune deficiency syndrome
  • Adenine - administration & dosage
  • Adenine - adverse effects
  • Adenine - analogs & derivatives
  • Adult
  • AIDS
  • Analysis
  • Anti-HIV Agents - adverse effects
  • Anti-HIV Agents - therapeutic use
  • Antiretroviral drugs
  • Arthralgia - chemically induced
  • Bone Density - drug effects
  • Carbamates - administration & dosage
  • Carbamates - adverse effects
  • CD4 Lymphocyte Count
  • Clinical trials
  • Cobicistat
  • Cross infection
  • Deoxycytidine - administration & dosage
  • Deoxycytidine - adverse effects
  • Deoxycytidine - analogs & derivatives
  • Double-Blind Method
  • Drug Combinations
  • Drug therapy
  • Emtricitabine
  • Female
  • Headache - chemically induced
  • Health aspects
  • HIV
  • HIV (Viruses)
  • HIV infection
  • HIV Infections - drug therapy
  • HIV Infections - virology
  • Human immunodeficiency virus
  • Humans
  • immune system diseases
  • Infections
  • Internal Medicine
  • Kidney - drug effects
  • Male
  • Medical colleges
  • Nausea
  • Nosocomial infections
  • Organophosphonates - administration & dosage
  • Organophosphonates - adverse effects
  • Quinolones - administration & dosage
  • Quinolones - adverse effects
  • Respiration Disorders - chemically induced
  • Sleep Initiation and Maintenance Disorders - chemically induced
  • Tenofovir
  • Thiazoles - administration & dosage
  • Thiazoles - adverse effects
  • Treatment Outcome
  • Viral Load - drug effects
  • virus diseases
ispartof: The Lancet (British edition), 2015, Vol.385 (9987), p.2606-2615
description: 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
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0140-6736
fulltext: fulltext
issn:
  • 0140-6736
  • 1474-547X
url: Link


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titleTenofovir 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
sourceAlma/SFX Local Collection
creatorSax, Paul E, Dr Prof ; Wohl, David, MD ; Yin, Michael T, Prof ; Post, Frank, MD ; DeJesus, Edwin, MD ; Saag, Michael, MD ; Pozniak, Anton, MD ; Thompson, Melanie, MD ; Podzamczer, Daniel, MD ; Molina, Jean Michel, Prof ; Oka, Shinichi, MD ; Koenig, Ellen, MD ; Trottier, Benoit, MD ; Andrade-Villanueva, Jaime, MD ; Crofoot, Gordon, MD ; Custodio, Joseph M, PharmD ; Plummer, Andrew, MS ; Zhong, Lijie, PhD ; Cao, Huyen, MD ; Martin, Hal, MD ; Callebaut, Christian, PhD ; Cheng, Andrew K, MD ; Fordyce, Marshall W, MD ; McCallister, Scott, MD
creatorcontribSax, Paul E, Dr Prof ; Wohl, David, MD ; Yin, Michael T, Prof ; Post, Frank, MD ; DeJesus, Edwin, MD ; Saag, Michael, MD ; Pozniak, Anton, MD ; Thompson, Melanie, MD ; Podzamczer, Daniel, MD ; Molina, Jean Michel, Prof ; Oka, Shinichi, MD ; Koenig, Ellen, MD ; Trottier, Benoit, MD ; Andrade-Villanueva, Jaime, MD ; Crofoot, Gordon, MD ; Custodio, Joseph M, PharmD ; Plummer, Andrew, MS ; Zhong, Lijie, PhD ; Cao, Huyen, MD ; Martin, Hal, MD ; Callebaut, Christian, PhD ; Cheng, Andrew K, MD ; Fordyce, Marshall W, MD ; McCallister, Scott, MD ; GS-US-292-0104/0111 Study Team
descriptionSummary 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<0·0001), significantly less proteinuria (median % change −3 vs 20; p<0·0001), and a significantly smaller decrease in bone mineral density at spine (mean % change −1·30 vs –2·86; p<0·0001) and hip (−0·66 vs –2·95; p<0·0001) at 48 weeks. 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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3PMID: 25890673
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languageeng
publisherEngland: Elsevier Ltd
subject
ispartofThe Lancet (British edition), 2015, Vol.385 (9987), p.2606-2615
rights
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2Copyright © 2015 Elsevier Ltd. All rights reserved.
3COPYRIGHT 2015 Elsevier B.V.
4Copyright Elsevier Limited Jun 27, 2015
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0Sax, Paul E, Dr Prof
1Wohl, David, MD
2Yin, Michael T, Prof
3Post, Frank, MD
4DeJesus, Edwin, MD
5Saag, Michael, MD
6Pozniak, Anton, MD
7Thompson, Melanie, MD
8Podzamczer, Daniel, MD
9Molina, Jean Michel, Prof
10Oka, Shinichi, MD
11Koenig, Ellen, MD
12Trottier, Benoit, MD
13Andrade-Villanueva, Jaime, MD
14Crofoot, Gordon, MD
15Custodio, Joseph M, PharmD
16Plummer, Andrew, MS
17Zhong, Lijie, PhD
18Cao, Huyen, MD
19Martin, Hal, MD
20Callebaut, Christian, PhD
21Cheng, Andrew K, MD
22Fordyce, Marshall W, MD
23McCallister, Scott, MD
24GS-US-292-0104/0111 Study Team
title
0Tenofovir 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
1The Lancet (British edition)
addtitleLancet
descriptionSummary 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<0·0001), significantly less proteinuria (median % change −3 vs 20; p<0·0001), and a significantly smaller decrease in bone mineral density at spine (mean % change −1·30 vs –2·86; p<0·0001) and hip (−0·66 vs –2·95; p<0·0001) at 48 weeks. 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.
subject
0Acquired immune deficiency syndrome
1Adenine - administration & dosage
2Adenine - adverse effects
3Adenine - analogs & derivatives
4Adult
5AIDS
6Analysis
7Anti-HIV Agents - adverse effects
8Anti-HIV Agents - therapeutic use
9Antiretroviral drugs
10Arthralgia - chemically induced
11Bone Density - drug effects
12Carbamates - administration & dosage
13Carbamates - adverse effects
14CD4 Lymphocyte Count
15Clinical trials
16Cobicistat
17Cross infection
18Deoxycytidine - administration & dosage
19Deoxycytidine - adverse effects
20Deoxycytidine - analogs & derivatives
21Double-Blind Method
22Drug Combinations
23Drug therapy
24Emtricitabine
25Female
26Headache - chemically induced
27Health aspects
28HIV
29HIV (Viruses)
30HIV infection
31HIV Infections - drug therapy
32HIV Infections - virology
33Human immunodeficiency virus
34Humans
35immune system diseases
36Infections
37Internal Medicine
38Kidney - drug effects
39Male
40Medical colleges
41Nausea
42Nosocomial infections
43Organophosphonates - administration & dosage
44Organophosphonates - adverse effects
45Quinolones - administration & dosage
46Quinolones - adverse effects
47Respiration Disorders - chemically induced
48Sleep Initiation and Maintenance Disorders - chemically induced
49Tenofovir
50Thiazoles - administration & dosage
51Thiazoles - adverse effects
52Treatment Outcome
53Viral Load - drug effects
54virus diseases
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2Yin, Michael T, Prof
3Post, Frank, MD
4DeJesus, Edwin, MD
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6Pozniak, Anton, MD
7Thompson, Melanie, MD
8Podzamczer, Daniel, MD
9Molina, Jean Michel, Prof
10Oka, Shinichi, MD
11Koenig, Ellen, MD
12Trottier, Benoit, MD
13Andrade-Villanueva, Jaime, MD
14Crofoot, Gordon, MD
15Custodio, Joseph M, PharmD
16Plummer, Andrew, MS
17Zhong, Lijie, PhD
18Cao, Huyen, MD
19Martin, Hal, MD
20Callebaut, Christian, PhD
21Cheng, Andrew K, MD
22Fordyce, Marshall W, MD
23McCallister, Scott, MD
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titleTenofovir 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
authorSax, Paul E, Dr Prof ; Wohl, David, MD ; Yin, Michael T, Prof ; Post, Frank, MD ; DeJesus, Edwin, MD ; Saag, Michael, MD ; Pozniak, Anton, MD ; Thompson, Melanie, MD ; Podzamczer, Daniel, MD ; Molina, Jean Michel, Prof ; Oka, Shinichi, MD ; Koenig, Ellen, MD ; Trottier, Benoit, MD ; Andrade-Villanueva, Jaime, MD ; Crofoot, Gordon, MD ; Custodio, Joseph M, PharmD ; Plummer, Andrew, MS ; Zhong, Lijie, PhD ; Cao, Huyen, MD ; Martin, Hal, MD ; Callebaut, Christian, PhD ; Cheng, Andrew K, MD ; Fordyce, Marshall W, MD ; McCallister, Scott, MD
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rsrctypearticles
prefilterarticles
languageeng
creationdate2015
topic
0Acquired immune deficiency syndrome
1Adenine - administration & dosage
2Adenine - adverse effects
3Adenine - analogs & derivatives
4Adult
5AIDS
6Analysis
7Anti-HIV Agents - adverse effects
8Anti-HIV Agents - therapeutic use
9Antiretroviral drugs
10Arthralgia - chemically induced
11Bone Density - drug effects
12Carbamates - administration & dosage
13Carbamates - adverse effects
14CD4 Lymphocyte Count
15Clinical trials
16Cobicistat
17Cross infection
18Deoxycytidine - administration & dosage
19Deoxycytidine - adverse effects
20Deoxycytidine - analogs & derivatives
21Double-Blind Method
22Drug Combinations
23Drug therapy
24Emtricitabine
25Female
26Headache - chemically induced
27Health aspects
28HIV
29HIV (Viruses)
30HIV infection
31HIV Infections - drug therapy
32HIV Infections - virology
33Human immunodeficiency virus
34Humans
35immune system diseases
36Infections
37Internal Medicine
38Kidney - drug effects
39Male
40Medical colleges
41Nausea
42Nosocomial infections
43Organophosphonates - administration & dosage
44Organophosphonates - adverse effects
45Quinolones - administration & dosage
46Quinolones - adverse effects
47Respiration Disorders - chemically induced
48Sleep Initiation and Maintenance Disorders - chemically induced
49Tenofovir
50Thiazoles - administration & dosage
51Thiazoles - adverse effects
52Treatment Outcome
53Viral Load - drug effects
54virus diseases
toplevel
0peer_reviewed
1online_resources
creatorcontrib
0Sax, Paul E, Dr Prof
1Wohl, David, MD
2Yin, Michael T, Prof
3Post, Frank, MD
4DeJesus, Edwin, MD
5Saag, Michael, MD
6Pozniak, Anton, MD
7Thompson, Melanie, MD
8Podzamczer, Daniel, MD
9Molina, Jean Michel, Prof
10Oka, Shinichi, MD
11Koenig, Ellen, MD
12Trottier, Benoit, MD
13Andrade-Villanueva, Jaime, MD
14Crofoot, Gordon, MD
15Custodio, Joseph M, PharmD
16Plummer, Andrew, MS
17Zhong, Lijie, PhD
18Cao, Huyen, MD
19Martin, Hal, MD
20Callebaut, Christian, PhD
21Cheng, Andrew K, MD
22Fordyce, Marshall W, MD
23McCallister, Scott, MD
24GS-US-292-0104/0111 Study Team
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jtitleThe Lancet (British edition)
delivery
delcategoryRemote Search Resource
fulltextfulltext
addata
au
0Sax, Paul E, Dr Prof
1Wohl, David, MD
2Yin, Michael T, Prof
3Post, Frank, MD
4DeJesus, Edwin, MD
5Saag, Michael, MD
6Pozniak, Anton, MD
7Thompson, Melanie, MD
8Podzamczer, Daniel, MD
9Molina, Jean Michel, Prof
10Oka, Shinichi, MD
11Koenig, Ellen, MD
12Trottier, Benoit, MD
13Andrade-Villanueva, Jaime, MD
14Crofoot, Gordon, MD
15Custodio, Joseph M, PharmD
16Plummer, Andrew, MS
17Zhong, Lijie, PhD
18Cao, Huyen, MD
19Martin, Hal, MD
20Callebaut, Christian, PhD
21Cheng, Andrew K, MD
22Fordyce, Marshall W, MD
23McCallister, Scott, MD
aucorpGS-US-292-0104/0111 Study Team
formatjournal
genrearticle
ristypeJOUR
atitleTenofovir 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
jtitleThe Lancet (British edition)
addtitleLancet
date2015
risdate2015
volume385
issue9987
spage2606
epage2615
pages2606-2615
issn0140-6736
eissn1474-547X
codenLANCAO
abstractSummary 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<0·0001), significantly less proteinuria (median % change −3 vs 20; p<0·0001), and a significantly smaller decrease in bone mineral density at spine (mean % change −1·30 vs –2·86; p<0·0001) and hip (−0·66 vs –2·95; p<0·0001) at 48 weeks. 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.
copEngland
pubElsevier Ltd
pmid25890673
doi10.1016/S0140-6736(15)60616-X