{"id":22020,"date":"2013-07-25T11:15:24","date_gmt":"2013-07-25T11:15:24","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=22020"},"modified":"2013-07-25T14:13:15","modified_gmt":"2013-07-25T14:13:15","slug":"sgsk744-and-long-acting-formulation-indicate-broadly-similar-resistance-profile-to-dolutegravir","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/22020","title":{"rendered":"S\/GSK744 and long-acting formulation indicate broadly similar resistance profile to dolutegravir"},"content":{"rendered":"

<\/strong>\"\"<\/strong>Simon Collins, HIV i-Base<\/p>\n

The first resistance data on the follow-on integrase inhibitor to dolutegravir, a Long Acting Parenteral (LAP) formulation of S\/GSK1265744, was included as an oral presentation at the workshop.<\/strong> [1]<\/p>\n

Although GSK744 is being developed in an oral formulation, most attention has been focused on a long acting injection with potential indication for both treatment and prevention with rilpivirine, which also has both oral and long acting formulations.<\/p>\n

Pharmacokinetic results last year reported that plasma concentrations of GSK744-LAP remained above the IC90 for at least three months following a single intramuscular or subcutaneous injection at doses of 200 mg or higher. [2] The potential for use as PrEP was shown by impressive results earlier this year that generated full protection in a macaque study following multiple rectal exposure. [3]<\/p>\n

Previous in vitro studies also supported a resistance profile that retains sensitivity to raltegravir and elvitegravir associated mutations. [4]<\/p>\n

At the workshop new data were presented showing that, as with raltegravir, GSK744 effectively inhibits HIV integration and reduces LTR-circles without impacting levels of viral DNA. No further mutations emerged when GSK744 was passaged for 56 days with raltegravir-associated single site directed mutations E92Q or N155H. However, further mutations developed with the Q148H\/K\/R pathway although the associated reduced fold change (FC) sensitivity (FC 5.6 with Q148R and FC 5.1 with Q148R) could be overcome by higher dosing.<\/p>\n

comment<\/h3>\n

The resistance profile for GSK-744 appears similar to dolutegravir, rather than being a compound that could salvage dolutegravir resistance. This should inform the approach both to future studies and to proposed integrase sequencing.<\/strong><\/p>\n

Current studies with GSK-744 include an ongoing safety study with rilpivirine LA in HIV negative volunteers and an induction\/maintenance study (starting with GSK-744 plus two RTIs and switching to GSK-744 plus rilpivirine maintenance) in treatment naive patients.<\/strong> [5, 6]<\/p>\n

References:<\/p>\n

    \n
  1. Yoshinaga T et al. Advanced mechanistic studies of GSK1265744, a new HIV integrase inhibitor (INI) dosed by oral administration or long-acting parenteral injection. International Workshop on HIV and Hepatitis Virus Drug Resistance and Curative Strategies, 4-8 June 2013, Toronto. Oral abstract O22.
    \nhttp:\/\/www.intmedpress.com\/journals\/avt\/abstract.cfm?id=2658&pid=88<\/a> (abstract book)
    \n    http:\/\/www.informedhorizons.com\/resistance2013\/pdf\/Presentations\/Yoshinaga.pdf<\/a> (PDF slides)<\/li>\n
  2. Spreen W et al. Pharmacokinetics, safety and tolerability of the HIV integrase inibitor SGSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults. 19th International AIDS Conference, 22-27 July 2012, Washington. Abstract TUPE040.
    \n    http:\/\/pag.aids2012.org\/abstracts.aspx?aid=10191<\/a><\/li>\n
  3. Andrews C et al. Long-acting parenteral formulation of GSK1265744 protects macaques against repeated intrarectal challenges with SHIV. 20th CROI, 3-6 March 2013, Atlanta. Oral late breaker abstract 24LB.
    \n    http:\/\/www.retroconference.org\/2013b\/Abstracts\/48044.htm<\/a><\/li>\n
  4. Yoshinaga T et al. Antiviral characteristics of S\/GSK1265744, an HIV integrase inhibitor (INI) dosed by oral or long-acting parenteral Injection. 52nd ICAAC, San Francisco, 9-12 September 2012. Oral abstract H-550.
    \n    http:\/\/www.abstractsonline.com\/Plan\/ViewAbstract.aspx?sKey=e1c18d5b-830f-4b4e-8671-35bcfb20eed5&cKey=3ecd6397-c9eb-4793-94f5-fde7784fe6ab&mKey=%7b6B114A1D-85A4-4054-A83B-04D8B9B8749F%7d<\/a><\/li>\n
  5. ClinicalTrials.gov. A study to investigate the safety, tolerability and pharmacokinetics of repeat dose administration of long-acting GSK1265744 and long-acting TMC278 intramuscular and subcutaneous injections in healthy adult subjects.
    \n    http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01593046<\/a><\/li>\n
  6. ClinicalTrials.gov. Dose ranging study of GSK1265744 plus nucleoside reverse transcriptase inhibitors for induction of HIV-1 virologic suppression followed by virologic suppression maintenance by GSK1265744 plus rilpivirine.
    \n    http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01641809<\/a><\/li>\n<\/ol>\n

    \n<\/strong><\/div>\n","protected":false},"excerpt":{"rendered":"

    Simon Collins, HIV i-Base The first resistance data on the follow-on integrase inhibitor to dolutegravir, a Long Acting Parenteral (LAP) formulation of S\/GSK1265744, was included as an oral presentation at the workshop. [1] Although GSK744 is being developed in an …<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,3,36],"tags":[179],"class_list":["post-22020","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-antiretrovirals","category-drug-resistance","tag-idrw-toronto-2013"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/22020","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=22020"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/22020\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=22020"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=22020"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=22020"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}