Safety and Efficacy of Dolutegravir in Treatment-Experienced Subjects With Raltegravir-Resistant HIV Type 1 Infection: 24-Week Results of the VIKING Study
Joseph J. Eron,Bonaventura Clotet,J. Durant,Christine Katlama,Princy Kumar,Adriano Lazzarin,Isabelle Poizot-Martin,Gary Richmond,Vincent Soriano,Mounir Ait-Khaled,Tamio Fujiwara,Jenny Huang,Sherene Min,Cindy Vavro,Jane Yeo +14 more
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TLDR
These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL, and dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen.Abstract:
Integrase inhibitors (INIs) represent a class of drugs for the treatment of human immunodeficiency virus (HIV)–infected individuals, blocking HIV genome integration into the host cell DNA [1]. They have been shown to be highly effective for the treatment of antiretroviral-naive and antiretroviral-experienced subjects, as demonstrated first with raltegravir (RAL) and more recently with elvitegravir (EVG) [2–6]. However, these first-generation INIs share common resistance pathways. In clinical studies of RAL, subjects with virologic failure and reduced RAL susceptibility typically harbored virus with 1 of 3 signature mutational pathways (ie, N155H, Q148H/K/R, or Y143C/H/R) in the integrase gene [7]. Continuing RAL treatment in these circumstances may lead to the addition of secondary mutations or pathway evolution; N155H may evolve to Y143 or Q148 pathways [4]. In addition, EVG does not appear to have activity against RAL-resistant isolates, and RAL does not appear to have activity against EVG-resistant isolates [8–10]. Therefore, there is a need for an INI with a high barrier to resistance and activity in subjects with human immunodeficiency virus type 1 (HIV-1) resistant to EVG and RAL.
Dolutegravir (DTG) is a new HIV-1 INI that has demonstrated good efficacy and safety in treatment-naive, HIV-infected individuals [11]. In vitro studies demonstrate limited cross-resistance between DTG and RAL or EVG, with no or minimal impact on DTG fold-change against Q148 single mutants or against viruses with Y143 or N155 signature mutations regardless of RAL-associated secondary mutations [12, 13]. However, the DTG fold-change increased for Q148H/K/R as secondary RAL resistance–associated mutations increased. On the basis of these in vitro findings, this phase IIb pilot study was conducted to assess and demonstrate the activity of DTG in HIV-1–infected individuals with RAL-resistant viral isolates.read more
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Dolutegravir plus Abacavir–Lamivudine for the Treatment of HIV-1 Infection
Sharon Walmsley,Antonio Antela,Nathan Clumeck,Dan Duiculescu,Andrea Eberhard,Felix Gutieŕrez,Laurent Hocqueloux,Franco Maggiolo,Uriel Sandkovsky,Catherine Granier,Keith A. Pappa,Brian Wynne,Sherene Min,Garrett Nichols +13 more
TL;DR: Dolutegravir plus abacavir-lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz-tenofovir DF-emtricitabine, thus meeting the criterion for superiority.
Journal ArticleDOI
Dolutegravir in Antiretroviral-Experienced Patients With Raltegravir- and/or Elvitegravir-Resistant HIV-1: 24-Week Results of the Phase III VIKING-3 Study
Antonella Castagna,Franco Maggiolo,Giovanni Penco,David Wright,Anthony Mills,Robert M. Grossberg,Jean-Michel Molina,Julie Chas,J. Durant,Santiago Moreno,Manuela Doroana,Mounir Ait-Khaled,Jenny Huang,Sherene Min,Ivy Song,Cindy Vavro,Garrett Nichols,Jane M. Yeo +17 more
TL;DR: DTG 50 mg BID–based therapy was effective in this highly treatment-experienced population with INI-resistant virus, and a strong association between baseline DTG susceptibility and response was demonstrated.
Journal Article
Update of the drug resistance mutations in HIV-1: March 2013.
Victoria A. Johnson,Vincent Calvez,Huldrych F. Günthard,Roger Paredes,Deenan Pillay,Robert W. Shafer,Annemarie M. J. Wensing,Douglas D. Richman +7 more
TL;DR: 2 integrase strand transfer inhibitors (InSTIs), elvitegra-vir and dolutegravir, have become available and were added to the treatment of HIV-1 treat-ment-naive patients.
Journal ArticleDOI
Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir.
TL;DR: Dolutegravir is the first of the second-generation INSTIs and exhibits a predictable pharmacokinetic profile and a well-defined exposure–response relationship and is poised to become a commonly used component of antiretroviral regimens.
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HIV-1 drug resistance and resistance testing
TL;DR: Understanding the scientific basis and clinical implications of HIVDR is useful in all regions in order to shape appropriate surveillance, inform treatment algorithms, and manage difficult cases.
References
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Raltegravir with Optimized Background Therapy for Resistant HIV-1 Infection
Roy T. Steigbigel,David A. Cooper,Princy Kumar,Joseph E. Eron,Mauro Schechter,Martin Markowitz,Mona R. Loutfy,Jeffrey L. Lennox,Jose M. Gatell,Jürgen K. Rockstroh,Christine Katlama,Patrick Yeni,Adriano Lazzarin,Bonaventura Clotet,Jing Zhao,Joshua Chen,Desmond Ryan,Rand R. Rhodes,John A. Killar,Lucinda R. Gilde,Kim M. Strohmaier,Anne R. Meibohm,Michael D. Miller,Daria J. Hazuda,Michael L. Nessly,Mark J. DiNubile,Robin Isaacs,Bach-Yen Nguyen,Hedy Teppler +28 more
TL;DR: In HIV-infected patients with limited treatment options, raltegravir plus optimization background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks.
Journal ArticleDOI
Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection.
David A. Cooper,Roy T. Steigbigel,Jose M. Gatell,Jürgen K. Rockstroh,Christine Katlama,Patrick Yeni,Adriano Lazzarin,Bonaventura Clotet,Princy Kumar,Joseph E. Eron,Mauro Schechter,Martin Markowitz,Mona R. Loutfy,Jeffrey L. Lennox,Jing Zhao,Joshua Chen,Desmond Ryan,Rand R. Rhodes,John A. Killar,Lucinda R. Gilde,Kim M. Strohmaier,Anne R. Meibohm,Michael D. Miller,Daria J. Hazuda,Michael L. Nessly,Mark J. DiNubile,Robin Isaacs,Hedy Teppler,Bach-Yen Nguyen +28 more
TL;DR: When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score.
Journal ArticleDOI
Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study.
Martin Markowitz,Bach-Yen Nguyen,Eduardo Gotuzzo,Fernando Mendo,Winai Ratanasuwan,Colin Kovacs,Guillermo Prada,Javier O Morales-Ramirez,Clyde S. Crumpacker,Robin Isaacs,Lucinda R. Gilde,Hong Wan,Michael D. Miller,Larissa Wenning,Hedy Teppler +14 more
TL;DR: Raltegravir exhibited potent and durable antiretroviral activity similar to that of efavirenz at 24 and 48 weeks but achieved HIV-1 RNA levels below detection at a more rapid rate.
Journal ArticleDOI
In Vitro Antiretroviral Properties of S/GSK1349572, a Next-Generation HIV Integrase Inhibitor
Masanori Kobayashi,Tomokazu Yoshinaga,Takahiro Seki,Chiaki Wakasa-Morimoto,Kevin W. Brown,Robert G. Ferris,Scott A. Foster,Richard J. Hazen,Shigeru Miki,Akemi Suyama-Kagitani,Shinobu Kawauchi-Miki,Teruhiko Taishi,Takashi Kawasuji,Brian A. Johns,Mark R. Underwood,Edward P. Garvey,Akihiko Sato,Tamio Fujiwara +17 more
TL;DR: Findings demonstrate that S/GSK1349572 would be classified as a next-generation drug in the integrase inhibitor class, with a resistance profile markedly different from that of first-generation integrase inhibitors.
Journal ArticleDOI
Antiviral Activity, Pharmacokinetics, and Dose Response of the HIV-1 Integrase Inhibitor GS-9137 (JTK-303) in Treatment-Naive and Treatment-Experienced Patients
Edwin DeJesus,Daniel S Berger,Martin Markowitz,Calvin J. Cohen,Trevor Hawkins,Peter Ruane,Richard Elion,Charles Farthing,Lijie Zhong,Andrew K. Cheng,Damian J McColl,Brian P. Kearney +11 more
TL;DR: GS-9137 demonstrated substantial short-term antiviral activity and was well tolerated as monotherapy, thus warranting further study.
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