{"id":8419,"date":"2017-07-19T05:46:45","date_gmt":"2017-07-19T09:46:45","guid":{"rendered":"http:\/\/blogs.nejm.org\/hiv-id-observations\/?p=8419"},"modified":"2017-07-24T14:16:06","modified_gmt":"2017-07-24T18:16:06","slug":"mystifying-cochrane-library-review-hcv-therapy-elicits-strong-response-idsa","status":"publish","type":"post","link":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/mystifying-cochrane-library-review-hcv-therapy-elicits-strong-response-idsa\/2017\/07\/19\/","title":{"rendered":"Mystifying Cochrane Library Review on HCV Therapy Elicits Strong Response from IDSA"},"content":{"rendered":"<p><a href=\"http:\/\/blogs.nejm.org\/hiv-id-observations\/wp-content\/uploads\/sites\/2\/2017\/07\/balloons.png\"><img loading=\"lazy\" decoding=\"async\" class=\"alignright wp-image-8420\" src=\"http:\/\/blogs.nejm.org\/hiv-id-observations\/wp-content\/uploads\/sites\/2\/2017\/07\/balloons-300x220.png\" alt=\"\" width=\"243\" height=\"178\" srcset=\"https:\/\/blogs.nejm.org\/hiv-id-observations\/wp-content\/uploads\/sites\/2\/2017\/07\/balloons-300x220.png 300w, https:\/\/blogs.nejm.org\/hiv-id-observations\/wp-content\/uploads\/sites\/2\/2017\/07\/balloons.png 623w\" sizes=\"auto, (max-width: 243px) 100vw, 243px\" \/><\/a>Last month, the Cochrane Review published\u00a0a <a href=\"http:\/\/www.cochrane.org\/CD012143\/LIVER_direct-acting-antivirals-chronic-hepatitis-c\" target=\"_blank\" rel=\"noopener noreferrer\">controversial paper<\/a> on HCV therapy that left many ID doctors and hepatologists perplexed.<\/p>\n<p>After reviewing 138 randomized clinical trials using directly acting, non-interferon based therapies, they came to the following conclusions:<\/p>\n<ul>\n<li>The use of sustained virologic response (&#8220;SVR&#8221;) &#8212; or &#8220;cure&#8221;, if you want to use plain English &#8212; as a valid endpoint for predicting clinical outcomes is questionable.<\/li>\n<li>There is currently insufficient\u00a0evidence that treatment with DAA-based\u00a0regimens\u00a0improves clinical outcome.<\/li>\n<li>The studies reviewed were at high risk of bias, so tended to overestimate benefits and minimize harm.<\/li>\n<li>More randomized clinical trials are needed.<\/li>\n<\/ul>\n<p>Anyone &#8212; clinician, researcher, or patient &#8212; who has experienced the miraculous advances in HCV therapy that started\u00a0in\u00a02014 could easily be scratching their heads at these\u00a0conclusions.<\/p>\n<p>The FDA might be surprised as well, since they have allowed SVR\u00a0as an appropriate &#8220;surrogate&#8221; marker of the effectiveness of HCV therapy for some time.<\/p>\n<p>Fortunately, we now have a focused, persuasive response by the IDSA, <a href=\"https:\/\/academic.oup.com\/cid\/article\/doi\/10.1093\/cid\/cix620\/3965298\/IDSA-AASLD-response-to-Cochrane-Review-on-Direct\" target=\"_blank\" rel=\"noopener noreferrer\">just published in\u00a0<em>Clinical Infectious Diseases.<\/em><\/a><\/p>\n<p>I strongly encourage anyone who doubts the clinical benefits of curing HCV to read the full paper, but in essence the argument goes like this:<\/p>\n<ol>\n<li><strong>The review was overly selective in the papers it included.<\/strong> Remember, many HCV trials could not include a control group since DAA therapies were so rapidly effective and well tolerated it\u00a0would have been unethical. These non-controlled studies were not included in the review.<\/li>\n<li><strong>HCV cure as an appropriate marker for treatment efficacy was\u00a0established during the years of interferon-based therapy.<\/strong>\u00a0Liver inflammation (as measured by biopsy or serial LFTs), fibrosis, portal hypertension, splenomegaly, even cirrhosis improved in those with SVR. And I would add that some surrogate markers are more intuitively obvious than others &#8212; and you can&#8217;t really get more obvious than <em>curing the very infection that&#8217;s causing the disease.<\/em>\u00a0HCV RNA is not an obscure, indirect tumor\u00a0marker (oncology), or a change in lipids (cardiology). It&#8217;s analogous to HIV RNA in HIV therapy, only better. And is there any plausible biologic reason why HCV cure with DAAs might be less effective in improving clinical outcomes than using interferon?<\/li>\n<li><strong>The time horizon to see the full clinical benefit for HCV cure will take many years.<\/strong> We&#8217;ve only had these therapies widely available since 2015 &#8212; hardly enough time to see reductions in the incidence of long-term complications such as cirrhosis or hepatocellular carcinoma. Note that we&#8217;ve already seen <a href=\"http:\/\/www.croiconference.org\/sessions\/substantial-decline-acute-hcv-infections-among-dutch-hivmsm-after-daa-roll-out\" target=\"_blank\" rel=\"noopener noreferrer\">benefits in HCV transmission<\/a>\u00a0from treatment in a clinical cohort of MSM from Europe.<\/li>\n<li><strong>Despite this short time period of DAA availability, clinical benefits have <em>already<\/em> been observed with HCV cure.<\/strong> These include resolution of vasculitis, spontaneous remission of non-Hodgkin lymphoma, and &#8212; perhaps most remarkably &#8212; stabilization or improvement in those with the most advanced forms of HCV liver disease.<\/li>\n<\/ol>\n<p>I will note that this isn&#8217;t the first time a &#8220;systematic review&#8221; of an Infectious Disease treatment under\u00a0the Cochrane name ended up with\u00a0a surprising conclusion.<\/p>\n<p>Remember <a href=\"http:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/a-truly-bizarre-systematic-review\/2012\/02\/26\/\" target=\"_blank\" rel=\"noopener noreferrer\">this one on HIV treatment with TDF\/FTC\/efavirenz?<\/a> The one which stated\u00a0there was insufficient evidence to support its\u00a0use, despite numerous randomized clinical trials documenting its efficacy? And its widespread adoption in clinical\u00a0guidelines?<\/p>\n<p>It may be hard to find today, <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/22592718\" target=\"_blank\" rel=\"noopener noreferrer\">since it was later withdrawn.<\/a><\/p>\n<p>&nbsp;<\/p>\n<p><a href=\"https:\/\/secure.jwatch.org\/registerm?cpc=JWATCH&amp;promo=OJFOBLOG&amp;step=1\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-925\" src=\"https:\/\/blogs.nejm.org\/hiv-id-observations\/wp-content\/uploads\/sites\/2\/2017\/03\/hivJWAd540x250.jpg\" alt=\"Register Now for more NEJM Journal Watch Content\" width=\"540\" height=\"250\" \/><\/a><\/p>\n<p><span style=\"text-indent: 20px;width: auto;padding: 0px 4px 0px 0px;text-align: center;font: bold 11px\/20px 'Helvetica Neue',Helvetica,sans-serif;color: #ffffff;background: #bd081c no-repeat scroll 3px 50% \/ 14px 14px;cursor: pointer\">Save<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Last month, the Cochrane Review published\u00a0a controversial paper on HCV therapy that left many ID doctors and hepatologists perplexed. After reviewing 138 randomized clinical trials using directly acting, non-interferon based therapies, they came to the following conclusions: The use of sustained virologic response (&#8220;SVR&#8221;) &#8212; or &#8220;cure&#8221;, if you want to use plain English &#8212; [&hellip;]<\/p>\n","protected":false},"author":6,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3,5,8,9],"tags":[408,417],"class_list":["post-8419","post","type-post","status-publish","format-standard","hentry","category-health-care","category-infectious-diseases","category-patient-care","category-policy","tag-hcv","tag-hepatitis-c"],"post_mailing_queue_ids":[],"_links":{"self":[{"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/posts\/8419","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=8419"}],"version-history":[{"count":0,"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/posts\/8419\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/media?parent=8419"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/categories?post=8419"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/tags?post=8419"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}