{"id":5961,"date":"2015-04-08T18:15:12","date_gmt":"2015-04-08T22:15:12","guid":{"rendered":"http:\/\/blogs.nejm.org\/hiv-id-observations\/?p=5961"},"modified":"2015-04-08T18:15:12","modified_gmt":"2015-04-08T22:15:12","slug":"new-hiv-treatment-guidelines-and-the-end-of-an-era","status":"publish","type":"post","link":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/new-hiv-treatment-guidelines-and-the-end-of-an-era\/2015\/04\/08\/","title":{"rendered":"New HIV Treatment Guidelines, and the End of an Era"},"content":{"rendered":"<p><a href=\"http:\/\/blogs.nejm.org\/hiv-id-observations\/wp-content\/uploads\/sites\/2\/2015\/04\/babe-ruth-bows-out2-jpg.jpeg\"><img loading=\"lazy\" decoding=\"async\" class=\"alignright size-medium wp-image-5965\" src=\"http:\/\/blogs.nejm.org\/hiv-id-observations\/wp-content\/uploads\/sites\/2\/2015\/04\/babe-ruth-bows-out2-jpg-300x235.jpeg\" alt=\"babe-ruth-bows-out2-jpg\" width=\"300\" height=\"235\" \/><\/a>The new Department of Health and Human Services (DHHS) HIV treatment guidelines are out, and thanks to skillful direction by Alice Pau, it&#8217;s as usual a must-read document &#8212; all 288 pages, of course!<\/p>\n<p>There are several major\u00a0changes, so a good place to start is the all-important <a href=\"http:\/\/aidsinfo.nih.gov\/guidelines\/html\/1\/adult-and-adolescent-arv-guidelines\/0\" target=\"_blank\">&#8220;What&#8217;s New in the Guidelines&#8221; summary page.<\/a>\u00a0Some of the biggest modifications come in the\u00a0<a href=\"http:\/\/aidsinfo.nih.gov\/guidelines\/html\/1\/adult-and-adolescent-arv-guidelines\/11\/what-to-start\" target=\"_blank\">&#8220;What to Start&#8221;<\/a> section:<\/p>\n<ul>\n<li><strong>There&#8217;s now a more focused list of &#8220;Recommended regimens&#8221;<\/strong> &#8212; it&#8217;s down to just 5. Specifically,\u00a0TDF\/FTC plus DTG <em>or<\/em> EVG\/c <em>or<\/em> RAL (that&#8217;s 3), ABC\/3TC\/DTG (4), and TDF\/FTC plus\u00a0DRV\/r (5).<\/li>\n<li><strong>The regimens that are limited to patients with low HIV RNA\u00a0<\/strong>are now classified either as &#8220;Alternative&#8221; &#8212; TDF\/FTC\/RPV &#8212; or &#8220;Other&#8221; (ABC\/3TC plus EFV, ABC\/3TC plus ATV\/r).<\/li>\n<li><strong>TDF\/FTC plus ATV\/r is now an &#8220;Alternative&#8221; regimen<\/strong>, largely due to the results of <a href=\"http:\/\/annals.org\/article.aspx?articleid=1911116\" target=\"_blank\">ACTG 5257.<\/a><\/li>\n<li><strong>TDF\/FTC\/EFV is now an &#8220;Alternative&#8221; regimen<\/strong>, largely due to issues of tolerability.<\/li>\n<\/ul>\n<p>With the caveat that as a member of the Guidelines panel, I can only give you my personal perspective (not that of the committee), here are a few comments on this last one &#8212; the demotion of efavirenz from &#8220;Recommended&#8221; to &#8220;Alternative&#8221; &#8212; which seems to me a pretty big deal.<\/p>\n<p>First the good stuff about EFV, which was approved by the FDA way back in 1998:<\/p>\n<ol>\n<li><strong>In clinical trials, efavirenz has been\u00a0better or as good virologically than all its comparators for years and years.<\/strong> I still remember the shock when we learned that <strong><a href=\"http:\/\/www.nejm.org\/doi\/full\/10.1056\/NEJM199912163412501\" target=\"_blank\">EFV\u00a0creamed indinavir<\/a><\/strong> &#8212; a potent protease inhibitor, who would have predicted that? &#8212; and subsequently it won or tied in numerous head-to-head studies.\u00a0That\u00a0success continued until the drug was compared to integrase inhibitors (in particular dolutegravir), but note that rates of\u00a0<em>virologic failure<\/em>\u00a0were still just as low with EFV even in this comparison. And is\u00a0there any agent that so consistently does well\u00a0in patients with high baseline HIV RNA and\/or low CD4?<\/li>\n<li><strong>Efavirenz\u00a0has such\u00a0a long half life that regimens with the drug are\u00a0remarkably forgiving,<\/strong> even if people forget to take it every day. It&#8217;s so forgiving, in fact, that studies suggest you can do fine\u00a0taking\u00a0it <strong><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/17434845\" target=\"_blank\">only 5 days a week<\/a><\/strong>, or at a <strong><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24522178\" target=\"_blank\">reduced\u00a0daily dose<\/a>.<\/strong> Not that we recommend these strategies, but still &#8212; we all have patients on EFV-based regimens who admit that they skip it periodically (usually because of side effects, but that&#8217;s a different story), yet they maintain virologic control.<\/li>\n<li>Although no HIV treatment is cheap, <a href=\"http:\/\/aidsinfo.nih.gov\/guidelines\/html\/1\/adult-and-adolescent-arv-guidelines\/459\/cost-considerations-and-antiretroviral-therapy\" target=\"_blank\"><strong>TDF\/FTC\/EFV is less expensive than most of the other initial regimens we use today.<\/strong><\/a><\/li>\n<li><a href=\"http:\/\/www.who.int\/hiv\/pub\/guidelines\/arv2013\/intro\/rag\/en\/index4.html\" target=\"_blank\"><strong>Efavirenz (with TDF\/FTC or TDF\/3TC) is the default initial treatment\u00a0globally<\/strong><\/a>, where it is widely available as a single pill taken once a day. That counts for a lot &#8212; obviously the vast majority of people with HIV in the world don&#8217;t live here.<\/li>\n<\/ol>\n<p>So what&#8217;s the issue? Why then is it now an &#8220;Alternative&#8221; rather than a &#8220;Recommended&#8221; option? In my opinion, it comes down to progress we&#8217;ve made in <em>improving side effects.\u00a0<\/em>Many choices are available now that are\u00a0simply easier for patients &#8212; and clinicians, who can skip\u00a0the time on pre-treatment education and management of tricky side effects. Specifically:<\/p>\n<ol>\n<li><strong>All\u00a0the clinical trials comparing EFV with integrase-based options demonstrate significantly lower rates of central nervous system (CNS) side effects with the latter.<\/strong> As already noted, in the <strong><a href=\"http:\/\/www.nejm.org\/doi\/full\/10.1056\/NEJMoa1215541\" target=\"_blank\">head-to-head study against\u00a0dolutegravir<\/a><\/strong>, drug discontinuations due to adverse events led to a superior result for DTG. The same thing happened when <strong><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24508782\" target=\"_blank\">EFV was compared to RPV<\/a><\/strong> &#8212;\u00a0in the low viral load stratum, RPV was superior\u00a0because it was better tolerated.<\/li>\n<li><strong>Virtually everyone who starts EFV gets some sort of CNS side effect of varying severity in the first week or two.<\/strong> Not a good idea to\u00a0start the day (or even a week) before a big presentation, or travel, or some other major life event.\u00a0In\u00a0most patients, these CNS side effects diminish rapidly over\u00a0the first few weeks of therapy. However, a minority still have some residual weirdness going on long term &#8212; dizziness, abnormal dreams, morning grogginess. Some learn to live with it\u00a0and are fine, but others don&#8217;t realize how off they&#8217;ve been feeling until they stop the drug. (Brief aside &#8212; what&#8217;s up with the small fraction of\u00a0patients who choose to take EFV during the day? That always perplexed me.)<\/li>\n<li><strong>More serious CNS side effects can rarely occur, in particular depression.<\/strong> In this retrospective analysis of four randomized clinical trials, patients randomized to EFV-based regimens had a more than<strong> <a href=\"http:\/\/annals.org\/article.aspx?articleid=1884528\" target=\"_blank\">two-fold increased risk of suicide or suicidal ideation compared with those not receiving EFV.<\/a><\/strong> And while the absolute risk was overall low, this is a severe enough adverse\u00a0effect that one should be very cautious about using the drug in anyone with a history of depression. Although observational cohort and claims data have not shown this association, remember that this is a tricky thing to find in such data, and that in clinical practice we avoid prescribing EFV to patients with psychiatric disease.<\/li>\n<li><strong>Every ID\/HIV doctor has had patients who just can&#8217;t take this drug, and it&#8217;s not from depression.<\/strong>\u00a0OK, anecdote time &#8212; here are a few of mine: \u00a0The guy who drives for a living who knew immediately he wasn&#8217;t as alert on the road taking EFV. The person whose dreams were so vivid that they were essentially indistinguishable from hallucinations (and not pleasant ones). The high-functioning scientist\u00a0who simply couldn&#8217;t concentrate at work. The person (actually a few)\u00a0with severe rash and fevers. Of course some of the vivid dream stories were pretty funny &#8212; my favorite was someone\u00a0who dreamt that her kitchen had been extensively renovated, including specific selections of cabinets and appliances. Imagine her\u00a0disappointment when she came downstairs to find\u00a0the scruffy old kitchen unchanged!<\/li>\n<\/ol>\n<p>Yes, I still have patients on EFV-based treatment who are doing great, and they don&#8217;t want to switch &#8212; that&#8217;s fine, no reason to do so. But the bottom line is that I haven&#8217;t prescribed TDF\/FTC\/EFV to a patient starting HIV therapy in nearly three\u00a0years. Too many other good options out there now.<\/p>\n<p>Hey, progress is a good thing!<\/p>\n<p>I did <a href=\"http:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/single-study-underscores-waning-of-the-efavirenz-era-but-probably-just-in-the-usa\/2013\/11\/06\/\" target=\"_blank\">this poll before<\/a> &#8212; now let&#8217;s try it again, a year and a half later:<\/p>\n<div id=\"polls-26\" class=\"wp-polls\">\n\t<form id=\"polls_form_26\" class=\"wp-polls-form\" action=\"\/index.php\" method=\"post\">\n\t\t<p style=\"display: none;\"><input type=\"hidden\" id=\"poll_26_nonce\" name=\"wp-polls-nonce\" value=\"8172a558df\" \/><\/p>\n\t\t<p style=\"display: none;\"><input type=\"hidden\" name=\"poll_id\" value=\"26\" \/><\/p>\n\t\t<p style=\"text-align: center;\"><strong>I still frequently use efavirenz-based regimens as initial therapy.<\/strong><\/p><div id=\"polls-26-ans\" class=\"wp-polls-ans\"><ul class=\"wp-polls-ul\">\n\t\t<li><input type=\"radio\" id=\"poll-answer-84\" name=\"poll_26\" value=\"84\" \/> <label for=\"poll-answer-84\">True \u2014 still the gold standard.<\/label><\/li>\n\t\t<li><input type=\"radio\" id=\"poll-answer-85\" name=\"poll_26\" value=\"85\" \/> <label for=\"poll-answer-85\">False \u2014 plenty of better options out there now.<\/label><\/li>\n\t\t<\/ul><p style=\"text-align: center;\"><input type=\"button\" name=\"vote\" value=\"   Vote   \" class=\"Buttons\" onclick=\"poll_vote(26);\" \/><\/p><p style=\"text-align: center;\"><a href=\"#ViewPollResults\" onclick=\"poll_result(26); return false;\" title=\"View Results Of This Poll\">View Results<\/a><\/p><\/div>\n\t<\/form>\n<\/div>\n\n","protected":false},"excerpt":{"rendered":"<p>The new Department of Health and Human Services (DHHS) HIV treatment guidelines are out, and thanks to skillful direction by Alice Pau, it&#8217;s as usual a must-read document &#8212; all 288 pages, of course! There are several major\u00a0changes, so a good place to start is the all-important &#8220;What&#8217;s New in the Guidelines&#8221; summary page.\u00a0Some of [&hellip;]<\/p>\n","protected":false},"author":6,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3,4,8,9],"tags":[],"class_list":["post-5961","post","type-post","status-publish","format-standard","hentry","category-health-care","category-hiv","category-patient-care","category-policy"],"post_mailing_queue_ids":[],"_links":{"self":[{"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/posts\/5961","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=5961"}],"version-history":[{"count":0,"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/posts\/5961\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/media?parent=5961"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/categories?post=5961"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/wp-json\/wp\/v2\/tags?post=5961"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}