Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study
Summary Background Elvitegravir is a once daily inhibitor of HIV-1 integrase boosted by ritonavir. We aimed to compare the efficacy and safety of elvitegravir with raltegravir, another HIV-1 integrase inhibitor, in patients in whom previous antiretroviral treatment failed. Methods We conducted a ran...
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| Veröffentlicht in: | The Lancet infectious diseases 2012, Vol.12 (1), p.27-35 |
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| creator | Molina, Jean-Michel, Dr LaMarca, Anthony, MD Andrade-Villanueva, Jaime, MSc Clotet, Bonaventura, MD Clumeck, Nathan, MD Liu, Ya-Pei, PhD Zhong, Lijie, PhD Margot, Nicolas, MA Cheng, Andrew K, MD Chuck, Steven L, MD |
| description | Summary Background Elvitegravir is a once daily inhibitor of HIV-1 integrase boosted by ritonavir. We aimed to compare the efficacy and safety of elvitegravir with raltegravir, another HIV-1 integrase inhibitor, in patients in whom previous antiretroviral treatment failed. Methods We conducted a randomised, double-blind, double-dummy, phase 3 study at 234 sites in 13 countries. Eligible patients had plasma HIV RNA of 1000 copies per mL or greater, any CD4 cell count, and resistance to or 6 months' experience with at least two classes of antiretroviral drugs. They received an open-label background regimen of a fully active, ritonavir-boosted protease inhibitor and a second agent. We randomly allocated patients (1:1) by computer with a block size of four to receive either elvitegravir 150 mg once daily (n=361; 85 mg dose if given with atazanavir, or lopinavir with ritonavir) or raltegravir 400 mg twice daily (n=363). Placebo tablets were given to mask the difference in daily dosing. The primary endpoint was achievement and maintenance of virological response (HIV RNA |
| doi_str_mv | 10.1016/S1473-3099(11)70249-3 |
| format | Article |
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We aimed to compare the efficacy and safety of elvitegravir with raltegravir, another HIV-1 integrase inhibitor, in patients in whom previous antiretroviral treatment failed. Methods We conducted a randomised, double-blind, double-dummy, phase 3 study at 234 sites in 13 countries. Eligible patients had plasma HIV RNA of 1000 copies per mL or greater, any CD4 cell count, and resistance to or 6 months' experience with at least two classes of antiretroviral drugs. They received an open-label background regimen of a fully active, ritonavir-boosted protease inhibitor and a second agent. We randomly allocated patients (1:1) by computer with a block size of four to receive either elvitegravir 150 mg once daily (n=361; 85 mg dose if given with atazanavir, or lopinavir with ritonavir) or raltegravir 400 mg twice daily (n=363). Placebo tablets were given to mask the difference in daily dosing. The primary endpoint was achievement and maintenance of virological response (HIV RNA <50 copies per mL) through week 48. Non-inferiority was prespecified with a margin of 10%. We did a modified intention-to-treat analysis. This study is registered with ClinicalTrials.gov , number NCT00708162. Findings Ten patients allocated elvitegravir and 12 assigned raltegravir were excluded from the analysis (either for protocol violations or because they did not receive treatment). 207 (59%) of 351 patients allocated elvitegravir achieved virological response compared with 203 (58%) of 351 assigned raltegravir (treatment difference 1·1%, 95% CI −6·0 to 8·2), meeting the criterion for non-inferiority (p=0·001). Three patients allocated elvitegravir had serious adverse events related to study drugs compared with seven assigned raltegravir; two and eight patients died, respectively. More individuals assigned elvitegravir reported diarrhoea up to week 48 (p=0·023), and more patients assigned raltegravir had grade 3 or 4 rises in alanine aminotransferase (p=0·020) or aspartate aminotransferase (p=0·009). Interpretation Elvitegravir used in combination with a ritonavir-boosted protease inhibitor in treatment-experienced patients has similar efficacy and safety to raltegravir. Since elvitegravir can be given once a day compared with twice a day for raltegravir, elvitegravir might improve patients' adherence. Funding Gilead Sciences.</description><identifier>ISSN: 1473-3099</identifier><identifier>EISSN: 1474-4457</identifier><identifier>DOI: 10.1016/S1473-3099(11)70249-3</identifier><identifier>PMID: 22015077</identifier><identifier>CODEN: LANCAO</identifier><language>eng</language><publisher>London: Elsevier Ltd</publisher><subject>Adult ; Alanine Transaminase - blood ; Anti-Retroviral Agents - adverse effects ; Anti-Retroviral Agents - therapeutic use ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiretroviral agents ; Antiviral agents ; Aspartate Aminotransferases - blood ; Atazanavir Sulfate ; Biological and medical sciences ; CD4 Lymphocyte Count ; Diarrhea - chemically induced ; Double-Blind Method ; Drug Therapy, Combination - adverse effects ; Female ; HIV Infections - drug therapy ; HIV Infections - immunology ; HIV Infections - virology ; HIV Integrase Inhibitors - therapeutic use ; HIV Protease Inhibitors - therapeutic use ; HIV-1 - immunology ; Human viral diseases ; Humans ; Immunodeficiencies ; Immunodeficiencies. Immunoglobulinopathies ; Immunopathology ; Infectious Disease ; Infectious diseases ; Lopinavir - therapeutic use ; Male ; Medical sciences ; Middle Aged ; Oligopeptides - therapeutic use ; Pharmacology. Drug treatments ; Proteinase inhibitors ; Pyridines - therapeutic use ; Pyrrolidinones - administration & dosage ; Pyrrolidinones - adverse effects ; Pyrrolidinones - therapeutic use ; Quinolones - administration & dosage ; Quinolones - adverse effects ; Quinolones - therapeutic use ; Raltegravir Potassium ; Ritonavir ; Ritonavir - therapeutic use ; RNA, Viral - blood ; Safety ; Treatment Outcome ; Viral diseases ; Viral diseases of the lymphoid tissue and the blood. Aids ; Viral Load</subject><ispartof>The Lancet infectious diseases, 2012, Vol.12 (1), p.27-35</ispartof><rights>Elsevier Ltd</rights><rights>2012 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier Limited Jan 2012</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c476t-8baf16f446acd392ebd478d3f4eea9c4beb2854482d0162be145832c8817d06e3</citedby><cites>FETCH-LOGICAL-c476t-8baf16f446acd392ebd478d3f4eea9c4beb2854482d0162be145832c8817d06e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1473309911702493$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,4010,27900,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25399908$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22015077$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Molina, Jean-Michel, Dr</creatorcontrib><creatorcontrib>LaMarca, Anthony, MD</creatorcontrib><creatorcontrib>Andrade-Villanueva, Jaime, MSc</creatorcontrib><creatorcontrib>Clotet, Bonaventura, MD</creatorcontrib><creatorcontrib>Clumeck, Nathan, MD</creatorcontrib><creatorcontrib>Liu, Ya-Pei, PhD</creatorcontrib><creatorcontrib>Zhong, Lijie, PhD</creatorcontrib><creatorcontrib>Margot, Nicolas, MA</creatorcontrib><creatorcontrib>Cheng, Andrew K, MD</creatorcontrib><creatorcontrib>Chuck, Steven L, MD</creatorcontrib><creatorcontrib>for the Study 145 Team</creatorcontrib><creatorcontrib>Study 145 Team</creatorcontrib><title>Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study</title><title>The Lancet infectious diseases</title><addtitle>Lancet Infect Dis</addtitle><description>Summary Background Elvitegravir is a once daily inhibitor of HIV-1 integrase boosted by ritonavir. We aimed to compare the efficacy and safety of elvitegravir with raltegravir, another HIV-1 integrase inhibitor, in patients in whom previous antiretroviral treatment failed. Methods We conducted a randomised, double-blind, double-dummy, phase 3 study at 234 sites in 13 countries. Eligible patients had plasma HIV RNA of 1000 copies per mL or greater, any CD4 cell count, and resistance to or 6 months' experience with at least two classes of antiretroviral drugs. They received an open-label background regimen of a fully active, ritonavir-boosted protease inhibitor and a second agent. We randomly allocated patients (1:1) by computer with a block size of four to receive either elvitegravir 150 mg once daily (n=361; 85 mg dose if given with atazanavir, or lopinavir with ritonavir) or raltegravir 400 mg twice daily (n=363). Placebo tablets were given to mask the difference in daily dosing. The primary endpoint was achievement and maintenance of virological response (HIV RNA <50 copies per mL) through week 48. Non-inferiority was prespecified with a margin of 10%. We did a modified intention-to-treat analysis. This study is registered with ClinicalTrials.gov , number NCT00708162. Findings Ten patients allocated elvitegravir and 12 assigned raltegravir were excluded from the analysis (either for protocol violations or because they did not receive treatment). 207 (59%) of 351 patients allocated elvitegravir achieved virological response compared with 203 (58%) of 351 assigned raltegravir (treatment difference 1·1%, 95% CI −6·0 to 8·2), meeting the criterion for non-inferiority (p=0·001). Three patients allocated elvitegravir had serious adverse events related to study drugs compared with seven assigned raltegravir; two and eight patients died, respectively. More individuals assigned elvitegravir reported diarrhoea up to week 48 (p=0·023), and more patients assigned raltegravir had grade 3 or 4 rises in alanine aminotransferase (p=0·020) or aspartate aminotransferase (p=0·009). Interpretation Elvitegravir used in combination with a ritonavir-boosted protease inhibitor in treatment-experienced patients has similar efficacy and safety to raltegravir. Since elvitegravir can be given once a day compared with twice a day for raltegravir, elvitegravir might improve patients' adherence. Funding Gilead Sciences.</description><subject>Adult</subject><subject>Alanine Transaminase - blood</subject><subject>Anti-Retroviral Agents - adverse effects</subject><subject>Anti-Retroviral Agents - therapeutic use</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiretroviral agents</subject><subject>Antiviral agents</subject><subject>Aspartate Aminotransferases - blood</subject><subject>Atazanavir Sulfate</subject><subject>Biological and medical sciences</subject><subject>CD4 Lymphocyte Count</subject><subject>Diarrhea - chemically induced</subject><subject>Double-Blind Method</subject><subject>Drug Therapy, Combination - adverse effects</subject><subject>Female</subject><subject>HIV Infections - drug therapy</subject><subject>HIV Infections - immunology</subject><subject>HIV Infections - virology</subject><subject>HIV Integrase Inhibitors - therapeutic use</subject><subject>HIV Protease Inhibitors - therapeutic use</subject><subject>HIV-1 - immunology</subject><subject>Human viral diseases</subject><subject>Humans</subject><subject>Immunodeficiencies</subject><subject>Immunodeficiencies. Immunoglobulinopathies</subject><subject>Immunopathology</subject><subject>Infectious Disease</subject><subject>Infectious diseases</subject><subject>Lopinavir - therapeutic use</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Oligopeptides - therapeutic use</subject><subject>Pharmacology. Drug treatments</subject><subject>Proteinase inhibitors</subject><subject>Pyridines - therapeutic use</subject><subject>Pyrrolidinones - administration & dosage</subject><subject>Pyrrolidinones - adverse effects</subject><subject>Pyrrolidinones - therapeutic use</subject><subject>Quinolones - administration & dosage</subject><subject>Quinolones - adverse effects</subject><subject>Quinolones - therapeutic use</subject><subject>Raltegravir Potassium</subject><subject>Ritonavir</subject><subject>Ritonavir - therapeutic use</subject><subject>RNA, Viral - blood</subject><subject>Safety</subject><subject>Treatment Outcome</subject><subject>Viral diseases</subject><subject>Viral diseases of the lymphoid tissue and the blood. 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Antiinfectious agents. Antiparasitic agents</topic><topic>Antiretroviral agents</topic><topic>Antiviral agents</topic><topic>Aspartate Aminotransferases - blood</topic><topic>Atazanavir Sulfate</topic><topic>Biological and medical sciences</topic><topic>CD4 Lymphocyte Count</topic><topic>Diarrhea - chemically induced</topic><topic>Double-Blind Method</topic><topic>Drug Therapy, Combination - adverse effects</topic><topic>Female</topic><topic>HIV Infections - drug therapy</topic><topic>HIV Infections - immunology</topic><topic>HIV Infections - virology</topic><topic>HIV Integrase Inhibitors - therapeutic use</topic><topic>HIV Protease Inhibitors - therapeutic use</topic><topic>HIV-1 - immunology</topic><topic>Human viral diseases</topic><topic>Humans</topic><topic>Immunodeficiencies</topic><topic>Immunodeficiencies. Immunoglobulinopathies</topic><topic>Immunopathology</topic><topic>Infectious Disease</topic><topic>Infectious diseases</topic><topic>Lopinavir - therapeutic use</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Oligopeptides - therapeutic use</topic><topic>Pharmacology. Drug treatments</topic><topic>Proteinase inhibitors</topic><topic>Pyridines - therapeutic use</topic><topic>Pyrrolidinones - administration & dosage</topic><topic>Pyrrolidinones - adverse effects</topic><topic>Pyrrolidinones - therapeutic use</topic><topic>Quinolones - administration & dosage</topic><topic>Quinolones - adverse effects</topic><topic>Quinolones - therapeutic use</topic><topic>Raltegravir Potassium</topic><topic>Ritonavir</topic><topic>Ritonavir - therapeutic use</topic><topic>RNA, Viral - blood</topic><topic>Safety</topic><topic>Treatment Outcome</topic><topic>Viral diseases</topic><topic>Viral diseases of the lymphoid tissue and the blood. Aids</topic><topic>Viral Load</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Molina, Jean-Michel, Dr</creatorcontrib><creatorcontrib>LaMarca, Anthony, MD</creatorcontrib><creatorcontrib>Andrade-Villanueva, Jaime, MSc</creatorcontrib><creatorcontrib>Clotet, Bonaventura, MD</creatorcontrib><creatorcontrib>Clumeck, Nathan, MD</creatorcontrib><creatorcontrib>Liu, Ya-Pei, PhD</creatorcontrib><creatorcontrib>Zhong, Lijie, PhD</creatorcontrib><creatorcontrib>Margot, Nicolas, MA</creatorcontrib><creatorcontrib>Cheng, Andrew K, MD</creatorcontrib><creatorcontrib>Chuck, Steven L, MD</creatorcontrib><creatorcontrib>for the Study 145 Team</creatorcontrib><creatorcontrib>Study 145 Team</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Pharma and Biotech Premium PRO</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nursing & Allied Health Database</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Lancet Titles</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><jtitle>The Lancet infectious diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Molina, Jean-Michel, Dr</au><au>LaMarca, Anthony, MD</au><au>Andrade-Villanueva, Jaime, MSc</au><au>Clotet, Bonaventura, MD</au><au>Clumeck, Nathan, MD</au><au>Liu, Ya-Pei, PhD</au><au>Zhong, Lijie, PhD</au><au>Margot, Nicolas, MA</au><au>Cheng, Andrew K, MD</au><au>Chuck, Steven L, MD</au><aucorp>for the Study 145 Team</aucorp><aucorp>Study 145 Team</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study</atitle><jtitle>The Lancet infectious diseases</jtitle><addtitle>Lancet Infect Dis</addtitle><date>2012</date><risdate>2012</risdate><volume>12</volume><issue>1</issue><spage>27</spage><epage>35</epage><pages>27-35</pages><issn>1473-3099</issn><eissn>1474-4457</eissn><coden>LANCAO</coden><abstract>Summary Background Elvitegravir is a once daily inhibitor of HIV-1 integrase boosted by ritonavir. We aimed to compare the efficacy and safety of elvitegravir with raltegravir, another HIV-1 integrase inhibitor, in patients in whom previous antiretroviral treatment failed. Methods We conducted a randomised, double-blind, double-dummy, phase 3 study at 234 sites in 13 countries. Eligible patients had plasma HIV RNA of 1000 copies per mL or greater, any CD4 cell count, and resistance to or 6 months' experience with at least two classes of antiretroviral drugs. They received an open-label background regimen of a fully active, ritonavir-boosted protease inhibitor and a second agent. We randomly allocated patients (1:1) by computer with a block size of four to receive either elvitegravir 150 mg once daily (n=361; 85 mg dose if given with atazanavir, or lopinavir with ritonavir) or raltegravir 400 mg twice daily (n=363). Placebo tablets were given to mask the difference in daily dosing. The primary endpoint was achievement and maintenance of virological response (HIV RNA <50 copies per mL) through week 48. Non-inferiority was prespecified with a margin of 10%. We did a modified intention-to-treat analysis. This study is registered with ClinicalTrials.gov , number NCT00708162. Findings Ten patients allocated elvitegravir and 12 assigned raltegravir were excluded from the analysis (either for protocol violations or because they did not receive treatment). 207 (59%) of 351 patients allocated elvitegravir achieved virological response compared with 203 (58%) of 351 assigned raltegravir (treatment difference 1·1%, 95% CI −6·0 to 8·2), meeting the criterion for non-inferiority (p=0·001). Three patients allocated elvitegravir had serious adverse events related to study drugs compared with seven assigned raltegravir; two and eight patients died, respectively. More individuals assigned elvitegravir reported diarrhoea up to week 48 (p=0·023), and more patients assigned raltegravir had grade 3 or 4 rises in alanine aminotransferase (p=0·020) or aspartate aminotransferase (p=0·009). Interpretation Elvitegravir used in combination with a ritonavir-boosted protease inhibitor in treatment-experienced patients has similar efficacy and safety to raltegravir. Since elvitegravir can be given once a day compared with twice a day for raltegravir, elvitegravir might improve patients' adherence. Funding Gilead Sciences.</abstract><cop>London</cop><pub>Elsevier Ltd</pub><pmid>22015077</pmid><doi>10.1016/S1473-3099(11)70249-3</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1473-3099 |
| ispartof | The Lancet infectious diseases, 2012, Vol.12 (1), p.27-35 |
| issn | 1473-3099 1474-4457 |
| language | eng |
| recordid | cdi_proquest_journals_913120396 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Adult Alanine Transaminase - blood Anti-Retroviral Agents - adverse effects Anti-Retroviral Agents - therapeutic use Antibiotics. Antiinfectious agents. Antiparasitic agents Antiretroviral agents Antiviral agents Aspartate Aminotransferases - blood Atazanavir Sulfate Biological and medical sciences CD4 Lymphocyte Count Diarrhea - chemically induced Double-Blind Method Drug Therapy, Combination - adverse effects Female HIV Infections - drug therapy HIV Infections - immunology HIV Infections - virology HIV Integrase Inhibitors - therapeutic use HIV Protease Inhibitors - therapeutic use HIV-1 - immunology Human viral diseases Humans Immunodeficiencies Immunodeficiencies. Immunoglobulinopathies Immunopathology Infectious Disease Infectious diseases Lopinavir - therapeutic use Male Medical sciences Middle Aged Oligopeptides - therapeutic use Pharmacology. Drug treatments Proteinase inhibitors Pyridines - therapeutic use Pyrrolidinones - administration & dosage Pyrrolidinones - adverse effects Pyrrolidinones - therapeutic use Quinolones - administration & dosage Quinolones - adverse effects Quinolones - therapeutic use Raltegravir Potassium Ritonavir Ritonavir - therapeutic use RNA, Viral - blood Safety Treatment Outcome Viral diseases Viral diseases of the lymphoid tissue and the blood. Aids Viral Load |
| title | Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study |
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