{"id":34919,"date":"2018-09-19T09:18:41","date_gmt":"2018-09-19T09:18:41","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=34919"},"modified":"2018-11-28T23:37:49","modified_gmt":"2018-11-28T23:37:49","slug":"fda-approves-doravirine-pifeltro-and-new-fdc-with-tdf3tc-delstrigo-in-the-us","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/34919","title":{"rendered":"FDA approves doravirine (Pifeltro)\u00a0and new FDC with TDF\/3TC (Delstrigo)\u00a0in the US"},"content":{"rendered":"<p class=\"HTBsubhead3authorcredit\"><strong><span lang=\"EN-US\">Simon Collins, HIV i-Base<\/span><\/strong><\/p>\n<p class=\"HTBBODYtext\"><b><span lang=\"EN-US\">On 30 August 2018, the US FDA approved doravirine as a separate formulation for use with ART and in a fixed dose combination (FDC) with generic tenofovir DF and lamivudine (3TC). [1]<\/span><\/b><\/p>\n<p class=\"HTBBODYtext\"><span lang=\"EN-US\">Doravirine is a once daily NNRTI that was initially developed as <\/span>MK-1439<span lang=\"EN-US\">. The standard adult dose is 100 mg once-daily, with or without food.<\/span><\/p>\n<p class=\"HTBBODYtext\"><span lang=\"EN-US\">Approval is for adults (18 years and older) based on results from two large international randomised phase 3 studies in treatment-naive participants with control arms <\/span>using darunavir (in DRIVE-FORWARD) and efavirenz (in DRIVE-AHEAD).<\/p>\n<p class=\"HTBBODYtext\">Each study reported primary endpoint results of viral suppression &lt;50 copies\/mL at 48 weeks in 84% vs approximately 81% (doravirine vs control respectively), with 95% confidence intervals that confirmed non-inferiority.<\/p>\n<p class=\"HTBBODYtext\">Although discontinuation rates were low in all study arms, tolerability advantages favoured doravirine from fewer darunavir\/ritonavir-associated or efavirenz-associated side effects.<\/p>\n<p class=\"HTBBODYtext\"><span lang=\"EN-US\">Doravirine is contraindicated with drugs that are strong cytochrome P450 CYP3A enzyme inducers, because of the potential to reduce doravirine levels.<\/span><\/p>\n<p class=\"HTBBODYtext\"><span lang=\"EN-US\">These drugs include, but are not limited to, the following:<\/span><\/p>\n<ul>\n<li class=\"HTBBODYindent\"><span lang=\"EN-US\">Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin.<\/span><\/li>\n<li class=\"HTBBODYindent\"><span lang=\"EN-US\">Androgen receptor inhibitor: enzalutamide.<\/span><\/li>\n<li class=\"HTBBODYindent\"><span lang=\"EN-US\">Antimycobacterials: rifampin, rifapentine.<\/span><\/li>\n<li class=\"HTBBODYindent\"><span lang=\"EN-US\">Mitotane.<\/span><\/li>\n<li class=\"HTBBODYindent\"><span lang=\"EN-US\">St. John\u2019s wort (<i>Hypericum perforatum).<\/i><\/span><\/li>\n<\/ul>\n<p class=\"HTBBODYtext\"><span lang=\"EN-US\">Doravirine is marketed in the US with the trade name Pifeltro and the doravirine\/TDF\/3TC FDC is marketed as Delstrigo. Both formulations were developed by Merck (MSD). <\/span><\/p>\n<h3 class=\"HTBcommenttitle\"><span lang=\"EN-US\">comment<\/span><\/h3>\n<p><b>The submission for EU approval is already underway, with the CHMP opinion due by 20 September and final decision expected late November.<\/b><\/p>\n<p><b>Although most treatment guidelines now recommend integrase inhibitor-based first line treatment, drug-pricing is also increasingly important.<\/b><\/p>\n<p><b>Doravirine has a better tolerability profile compared to efavirenz (which is still widely used despite the guidelines).<span class=\"Apple-converted-space\">\u00a0<\/span><\/b><\/p>\n<p><b>The FDA indication is only for people who are treatment naive. However, in vitro, doravirine retains sensitivity to common NNRTI resistance mutations (K103N, Y181C, G190A, E101K, E138K, and K103N\/Y181C), with a profile that suggests limited cross-resistance to rilpivirine and etravirine. In vivo, doravirine selects for distinct mutations (V106A and F227L) that remain sensitive to rilpivirine and efavirenz (with possible increased sensitivity to the NRTI MK-8591).<\/b><\/p>\n<p class=\"HTBcommenttext\"><strong><span lang=\"EN-US\">Several studies in treatment-experienced participants are ongoing, but only as switch options in people with current viral suppression.<\/span><\/strong><\/p>\n<p class=\"HTBcommenttext\"><strong><span lang=\"EN-US\">Doravirine is also included in an FDC with 3TC plus the investigational NRTI EFdA (MK-8591), with phase 2 results expected in mid-2019. [2]<\/span><\/strong><\/p>\n<p><strong>The DRIVE-AHEAD study is now published as an open-access paper in CID. [3]<\/strong><\/p>\n<p class=\"HTBreferences\">References<\/p>\n<ol>\n<li class=\"HTBreferences\"><span lang=\"EN-US\">Merck (MSD) press release. FDA approves Merck\u2019s Delstrigo (doravirine\/lamivudine\/tenofovir disoproxil fumarate), a once-daily fixed-dose combination tablet as a complete regimen and Pifeltrotm (doravirine), an NNRTI, both for the treatment of HIV-1 in appropriate patients<\/span>. (30 August 2018).<br \/>\n<span lang=\"EN-US\"><a href=\"https:\/\/www.mrknewsroom.com\/news-release\/research-and-development-news\/fda-approves-mercks-delstrigo-doravirine-lamivudine-tenof\">https:\/\/www.mrknewsroom.com<\/a><\/span><\/li>\n<li class=\"HTBreferences\">ClinicalTrials.gov. MK-8591\u00a0with doravirine and lamivudine in participants infected with HIV type 1 (MK-8591-011) (DRIVE2Simplify). NCT03272347.<br \/>\n<a href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03272347\">https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03272347\u00a0<\/a><\/li>\n<li class=\"HTBreferences\">Orkin C et al. Doravirine\/lamivudine\/tenofovir disoproxil fumarate is non-inferior to efavirenz\/emtricitabine\/tenofovir disoproxil fumarate in treatment-naive adults with HIV\u20131 infection: week 48 results of the DRIVE-AHEAD trial. <span lang=\"EN-US\">Clinical Infectious Diseases<\/span><span lang=\"EN-US\">, ciy540. (August 2018).<\/span><br \/>\n<a href=\"https:\/\/doi.org\/10.1093\/cid\/ciy540\">https:\/\/doi.org\/10.1093\/cid\/ciy540<\/a><\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"<p>Simon Collins, HIV i-Base On 30 August 2018, the US FDA approved doravirine as a separate formulation for use with ART and in a fixed dose combination (FDC) with generic tenofovir DF and lamivudine (3TC). [1] Doravirine is a once &hellip;<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3],"tags":[],"class_list":["post-34919","post","type-post","status-publish","format-standard","hentry","category-antiretrovirals"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/34919","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\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=34919"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/34919\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=34919"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=34919"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=34919"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}