{"id":910,"date":"2010-05-02T17:43:20","date_gmt":"2010-05-02T21:43:20","guid":{"rendered":"http:\/\/blogs.nejm.org\/?p=910"},"modified":"2015-06-04T15:25:20","modified_gmt":"2015-06-04T19:25:20","slug":"learning-from-clinical-trials-with-limited-generalizability","status":"publish","type":"post","link":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/learning-from-clinical-trials-with-limited-generalizability\/2010\/05\/02\/","title":{"rendered":"Learning from Clinical Trials with Limited &#8220;Generalizability&#8221;"},"content":{"rendered":"<p><img loading=\"lazy\" decoding=\"async\" class=\"alignright size-full wp-image-913\" title=\"crypto\" src=\"http:\/\/blogs.nejm.org\/hiv-id-observations\/wp-content\/uploads\/sites\/2\/2010\/05\/crypto1.jpg\" alt=\"crypto\" width=\"199\" height=\"157\" \/>In the ongoing debate about when to start antiretroviral therapy in our <em>sickest <\/em>patients &#8212; those with acute opportunistic infections &#8212; comes <a href=\"http:\/\/www.journals.uchicago.edu\/doi\/full\/10.1086\/652652\" target=\"_blank\">this study<\/a> from Zimbabwe of early vs. deferred ART in patients with cryptococcal meningitis:<\/p>\n<blockquote><p>The median durations of survival were 28 days and 637 days in the early and delayed ART groups, respectively (<em>P<\/em><img decoding=\"async\" src=\"http:\/\/blogs.nejm.org\/hiv-id-observations\/wp-content\/uploads\/sites\/2\/2010\/05\/2009.gif\" alt=\"\" align=\"bottom\" \/>=<img decoding=\"async\" src=\"http:\/\/blogs.nejm.org\/hiv-id-observations\/wp-content\/uploads\/sites\/2\/2010\/05\/2009.gif\" alt=\"\" align=\"bottom\" \/>.031, by log\u2010rank test). The risk of mortality was almost 3 times as great in the early ART group versus the delayed ART group (adjusted hazard ratio, 2.85; 95% confidence interval, 1.1\u20137.23). The study was terminated early by the data safety monitoring committee.<\/p><\/blockquote>\n<p>In sum, early ART made a terrible situation even worse: 3-year survival for the early ART group was <em>only 22%<\/em>, vs 46% in the deferred therapy group.<\/p>\n<p>The challenges of applying this study to clinical practice here are numerous, including use of non-amphotericin therapy for cryptococcal CNS disease, lack of protocol-directed management of suspected raised intracranial pressure or immune reconstitution inflammatory syndrome (IRIS), and the highly unstable social and political situation in the country at that time.<\/p>\n<p>Still &#8212; sometimes a study&#8217;s findings are so overwhelming that that there is something to be learned, issues of limited generalizabilty notwithstanding.<\/p>\n<p>I suspect here it&#8217;s that ART should be deferred for at least a couple of weeks in patients with crytpotoccal meningitis, giving the amphotericin\/5FC time to bring down the organism burden.\u00a0 Importantly, this slight delay would still be consistent with the <a href=\"http:\/\/www.plosone.org\/article\/info:doi%2F10.1371%2Fjournal.pone.0005575\" target=\"_blank\">&#8220;early&#8221; ART strategy of A5164<\/a>, where the median time to start therapy was 12 days after OI treatment.<\/p>\n<p>At least that&#8217;s what I&#8217;ll be doing until the results of <a href=\"http:\/\/clinicaltrials.gov\/ct2\/show\/NCT00976040?term=cryptococcal+meningitis+hiv&amp;rank=2\" target=\"_blank\">this study<\/a> are available.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>In the ongoing debate about when to start antiretroviral therapy in our sickest patients &#8212; those with acute opportunistic infections &#8212; comes this study from Zimbabwe of early vs. deferred ART in patients with cryptococcal meningitis: The median durations of survival were 28 days and 637 days in the early and delayed ART groups, respectively [&hellip;]<\/p>\n","protected":false},"author":6,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,5,8],"tags":[77,83,255,423],"class_list":["post-910","post","type-post","status-publish","format-standard","hentry","category-hiv","category-infectious-diseases","category-patient-care","tag-antiretroviral-therapy","tag-art","tag-cryptococcal-meningitis","tag-hiv"],"post_mailing_queue_ids":[],"_links":{"self":[{"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/posts\/910","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=910"}],"version-history":[{"count":0,"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/posts\/910\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/media?parent=910"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/categories?post=910"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/tags?post=910"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}