{"id":5489,"date":"2014-10-12T09:44:53","date_gmt":"2014-10-12T13:44:53","guid":{"rendered":"http:\/\/blogs.nejm.org\/?p=5489"},"modified":"2015-05-18T11:11:38","modified_gmt":"2015-05-18T15:11:38","slug":"approval-of-sofosbuvirledipasvir-was-expected-but-still-is-a-huge-advance","status":"publish","type":"post","link":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/approval-of-sofosbuvirledipasvir-was-expected-but-still-is-a-huge-advance\/2014\/10\/12\/","title":{"rendered":"Approval of Sofosbuvir\/Ledipasvir Was Expected, but Still Is a Huge Advance"},"content":{"rendered":"<p>As expected, <a href=\"http:\/\/www.fda.gov\/NewsEvents\/Newsroom\/PressAnnouncements\/ucm418365.htm\" target=\"_blank\">the FDA just approved<\/a> the first single-pill treatment for hepatitis C genotype 1, a tablet containing\u00a0400 mg of sofosbuvir (SOF) and 90 mg of ledipasvir (LDV). For those not following this story closely, sofosbuvir is the pan-genotypic NRTI polymerase inhibitor approved last December to much rejoicing &#8212; and controversy about the price. Ledipasvir is the first HCV NS5A inhibitor, and is\u00a0only available as part of this combination.<\/p>\n<p>The brand name is &#8220;Harvoni&#8221;, which sounds a bit like an exotic offering on a menu that you need to ask your waiter to explain &#8212; &#8220;Ancho chile-rubbed Niman Ranch pork chop\u00a0roasted in soy, ginger, and sesame, served with pan-sauted garlic kale, and garnished with corn and\u00a0pinapple-harvoni salsa.&#8221;<\/p>\n<p>But even though the approval was no surprise, and the brand name will (like all of them) take some getting used to, there&#8217;s no denying this is\u00a0a huge step forward for HCV therapy. Let me list some of the reasons:<\/p>\n<p><!--more--><\/p>\n<ul>\n<li>One pill a day. Can it get simpler than that? Full prescribing information <strong><a href=\"http:\/\/www.gilead.com\/~\/media\/Files\/pdfs\/medicines\/liver-disease\/harvoni\/harvoni_pi.pdf\" target=\"_blank\">here<\/a><\/strong>.<\/li>\n<li>No interferon, no ribavirin. In clinical trials, all the latter added to the SOF\/LDV combination was side effects. Ribavirin offered no\u00a0additional efficacy even in cirrhotics.<\/li>\n<li>For most patients, 12 weeks of therapy will have a 95%+ chance of cure.<\/li>\n<li>For treatment-naive patients without cirrhosis who have a pretreatment HCV RNA level &lt; 6 million copies\/mL, just 8 weeks should\u00a0do the trick.<\/li>\n<li>For treatment-experienced patients who do have cirrhosis, 24 weeks is recommended, as &#8220;only&#8221; around 4 out 5 were cured with 12 weeks.<\/li>\n<li>The rate of treatment discontinuation due to adverse effects in 3 different studies was 1%, 0%, and &lt;1%, respectively. Think about that for a moment.<\/li>\n<\/ul>\n<p>So yahoo. This is instantly a\u00a0treatment of choice &#8212; and for now, <em>the<\/em> treatment of choice &#8212; for genotype 1 patients, and no doubt the HCV treatment guidelines will say as much when they&#8217;re revised. I&#8217;m not on the guidelines panel, just stating the obvious: The amount of supporting clinical trials data for SOF\/LDV combination\u00a0is vastly <a href=\"http:\/\/blogs.nejm.org\/index.php\/simeprevir-sofosbuvir-and-the-limitations-of-the-cosmos\/2014\/07\/31\/\" target=\"_blank\">greater than the simeprevir-sofosbuvir treatment<\/a>, which is <a href=\"http:\/\/www.hcvguidelines.org\/full-report\/initial-treatment-hcv-infection-patients-starting-treatment\" target=\"_blank\">already listed.<\/a><\/p>\n<p>As with any new medical treatment, there are a few issues and questions to address with SOF\/LDV &#8212; so\u00a0let&#8217;s start with the elephant in the exam room, the cost.<\/p>\n<p>The list price of this combination therapy for 12 weeks will be around $95,000, which means the ledipasvir component\u00a0is priced around the same as 12 weeks of interferon\/ribavirin &#8212; and\u00a0substantially\u00a0less than the current price of simeprevir. I&#8217;ve gone over before the various issues on the cost of HCV treatment &#8212; <a href=\"http:\/\/blogs.nejm.org\/index.php\/both-simeprevir-and-sofosbuvir-likely-approved-by-2014-clinicalethicalpharmacoeconomic-dilemmas-loom\/2013\/06\/11\/\" target=\"_blank\"><strong>it totally depends on your perspective.<\/strong><\/a> It&#8217;s either incredible value for what your getting (a virtual guarantee of HCV cure, with no side effects!), or\u00a0horribly too much ($95,000! That&#8217;s over $1100\/pill!).<\/p>\n<p>Regardless,\u00a0SOF\/LDV is already one-third cheaper <em>and<\/em> more effective than HCV treatment was last week with SIM\/SOF, and will cost even less if the patient qualifies for 8 weeks of treatment. We&#8217;ll see how this all shakes out when the next interferon-free drug regimen gets approved later this year. I&#8217;m referring, of course, to the parataprevir\/ritonavir\/ombitasvir plus dasabuvir regimen, which is now so close to approval that all the drugs have real names. The guidelines committee will need to consider this one too when it&#8217;s\u00a0approved.<\/p>\n<p>A few more items of note:<\/p>\n<ul>\n<li>There are remarkably few serious drug-drug interactions. Don&#8217;t use rifampin or the tricky\u00a0anticonvulsants (phenytoin, carbamazepine, phenobarbital). And rosuvastatin levels go way up, avoid that statin. Further details in the package insert, linked above.<\/li>\n<li>For patients\u00a0with HIV co-infection, ledipasvir will increase\u00a0tenofovir levels by around 30%, the same magnitude as ritonavir-boosted PIs and TDF\/FTC\/EVG\/COBI. If you&#8217;re patient is on the former, the prescribing info\u00a0advises to monitor closely; if on the latter, to switch. I&#8217;d recommend switching both, if possible, to a raltegravir, dolutegravir, or rilpivirine-based regimen until there are more safety data. A phase III study of SOF\/LDV in HIV-coinfected subjects is fully enrolled.<\/li>\n<li>No dosage change is required for those with mild-moderate renal impairment; for severe renal impairment or ESRD, no\u00a0dose recommendation can be made.<\/li>\n<\/ul>\n<p>Finally, did the FDA consider cost when they recommended 24 weeks of treatment for treatment-experienced patients with cirrhosis? Probably not, since an 80% cure would leave just 20% who would need\u00a0a longer course. In support of the 24 week up front course of SOF\/LDV, however, is that we don&#8217;t really have a proven approach to treatment failures yet (24 weeks of the same treatment with RBV? 24 weeks of SIM-SOF? Other?) Additionally,\u00a0this is the group of patients who need HCV treatment most urgently.<\/p>\n<p>Enjoy this video, I sure did.<\/p>\n<p><center><iframe loading=\"lazy\" src=\"\/\/www.youtube.com\/embed\/WAlWrT5P2VI\" width=\"420\" height=\"315\" frameborder=\"0\" allowfullscreen=\"allowfullscreen\"><\/iframe><\/center><\/p>\n","protected":false},"excerpt":{"rendered":"<p>As expected, the FDA just approved the first single-pill treatment for hepatitis C genotype 1, a tablet containing\u00a0400 mg of sofosbuvir (SOF) and 90 mg of ledipasvir (LDV). For those not following this story closely, sofosbuvir is the pan-genotypic NRTI polymerase inhibitor approved last December to much rejoicing &#8212; and controversy about the price. Ledipasvir [&hellip;]<\/p>\n","protected":false},"author":6,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3,4,5,8,9],"tags":[408,558,861],"class_list":["post-5489","post","type-post","status-publish","format-standard","hentry","category-health-care","category-hiv","category-infectious-diseases","category-patient-care","category-policy","tag-hcv","tag-ledipasvir","tag-sofosbuvir"],"post_mailing_queue_ids":[],"_links":{"self":[{"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/posts\/5489","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/users\/6"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/comments?post=5489"}],"version-history":[{"count":0,"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/posts\/5489\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/media?parent=5489"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/categories?post=5489"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/tags?post=5489"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}