Abstract
T-1249 is a peptide HIV fusion inhibitor (FI) previously under development for use in FI-naive and experienced patients. Here we present prospectively planned longitudinal analyses of FI resistance during 48 weeks of T-1249 dosing in patients with extensive prior FI exposure. T1249-105 was a single-arm rollover study in patients with prior resistance to enfuvirtide (ENF) and 10 days of T-1249 functional monotherapy exposure. The phenotype and genotype of plasma virus envelopes were analyzed at baseline and at study weeks 8, 16, and 48. At study entry, viruses had a geometric mean decrease in susceptibility to ENF of 51.8-fold but to T-1249 of 1.8-fold; extensive genotypic resistance to ENF was observed. A median viral load response of - 1.5 log(10) copies/ml was observed at week 2 that was partially sustained (- 0.5 log(10) copies/ml) through 48 weeks. Resistance to T-1249 gradually increased to a geometric mean 92.7-fold decrease from FI-naive baseline; this occurred concomitant with further evolution of gp41 amino acids 36-45, most commonly the G36D (n = 6, 16%) or N43K (n = 9, 24%) substitutions. A novel substitution, A50V (n = 12, 32%), was also common, as were the N126K and S138A substitutions in heptad-repeat 2 (HR-2). Th...Continue Reading
References
Jan 28, 1998·Journal of Virology·L T RimskyT J Matthews
Jun 18, 1998·Cell·D C Chan, P S Kim
Dec 23, 1998·Proceedings of the National Academy of Sciences of the United States of America·D C ChanP S Kim
May 23, 2002·Antimicrobial Agents and Chemotherapy·Xiping WeiJohn C Kappes
Mar 5, 2004·The Journal of Infectious Diseases·Joseph J EronG Diego Miralles
Apr 14, 2004·Journal of Virology·Jing LuDaniel R Kuritzkes
Jul 20, 2004·Journal of Medical Virology·Eva PovedaVincent Soriano
Aug 19, 2004·AIDS·Prakash R SistaMichael L Greenberg
Aug 31, 2004·Reviews in Medical Virology·Michael GreenbergLynn Smiley
Jan 14, 2005·Current Opinion in Infectious Diseases·Eoin CoakleyJeannette M Whitcomb
Feb 25, 2005·Antimicrobial Agents and Chemotherapy·L XuD Pillay
Mar 5, 2005·The Journal of Infectious Diseases·Jacob P LalezariUNKNOWN T1249-102 Study Group
Mar 30, 2005·Journal of Virology·Jacqueline D ReevesRobert W Doms
Sep 15, 2005·Journal of Virology·M MinkM L Greenberg
May 19, 2006·AIDS Research and Human Retroviruses·T MelbyM L Greenberg
Citations
Feb 14, 2013·Antiviral Research·Luis Menéndez-Arias
Jul 21, 2009·The Journal of Biological Chemistry·Dirk EgginkRogier W Sanders
Oct 13, 2010·The Journal of Biological Chemistry·Kazuya ShimuraEiichi N Kodama
May 22, 2013·Antimicrobial Agents and Chemotherapy·Kazuki ShimaneEiichi N Kodama
Jun 6, 2009·Journal of Virology·Chungen PanShibo Jiang
Apr 25, 2008·Journal of Virology·Dirk EgginkBen Berkhout
Mar 13, 2009·Journal of Virology·Felix G HermannDorothee von Laer
Jan 23, 2009·Journal of Virology·Stéphane HuéUNKNOWN UK Collaborative Group on HIV Drug Resistance
Aug 13, 2011·Journal of Virology·Dirk EgginkRogier W Sanders
Mar 4, 2009·Annual Review of Biochemistry·Peter M Colman
Jul 16, 2011·PloS One·Franky BaatzDanielle Perez Bercoff
Jan 25, 2013·Viruses·Christopher J De Feo, Carol D Weiss
Jun 9, 2014·The Journal of Antimicrobial Chemotherapy·Huihui ChongYuxian He
Mar 9, 2010·Journal of the Formosan Medical Association = Taiwan Yi Zhi·Chungen PanShibo Jiang
Mar 24, 2012·Current Opinion in Virology·Ben BerkhoutRogier W Sanders
Mar 17, 2010·Antiviral Research·Kris CovensKristel Van Laethem
Jul 21, 2009·Antiviral Research·Luis Menéndez-Arias
Apr 26, 2011·Antiviral Research·Ben Berkhout, Rogier W Sanders
Dec 21, 2011·Antiviral Chemistry & Chemotherapy·Fusako Miyamoto, Eiichi N Kodama
Jun 22, 2011·The Journal of Biological Chemistry·Chungen PanShibo Jiang
Oct 24, 2019·Retrovirology·Amanda R SmithMichael S Kay