{"id":813,"date":"2013-03-27T15:30:07","date_gmt":"2013-03-27T15:30:07","guid":{"rendered":"https:\/\/blogs.bmj.com\/sti\/?p=813"},"modified":"2013-03-25T20:07:25","modified_gmt":"2013-03-25T20:07:25","slug":"disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2","status":"publish","type":"post","link":"https:\/\/blogs.bmj.com\/sti\/2013\/03\/27\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\/","title":{"rendered":"Disappointing tenofovir PrEP trials: maybe \u201cadherence\u201d is not to blame"},"content":{"rendered":"<p>Reports of modest success from <b>two<\/b> trials (2010) of tenofovir as pre-exposure prophylaxis against HIV (PrEP)\u2013 <b>CAPRISA 004<\/b> (1) (topical gel\/women) relative risk reduction (RRR) <b>39%<\/b>; <b>iPrEX<\/b> (2) (oral tablet\/MSM) RRR <b>44%<\/b> \u2013 have inspired recent contributions to STI journal. \u00a0In particular, there have been attempts to model the possible impact on the epidemic of incorporating PrEP in the toolbox of interventions (STI 2011; 87: suppl. 1, see especially: <a href=\"http:\/\/sti.bmj.com\/content\/87\/Suppl_1\/A36.1.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9\">http:\/\/sti.bmj.com\/content\/87\/Suppl_1\/A36.1.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9<\/a>; <a href=\"http:\/\/sti.bmj.com\/content\/87\/Suppl_1\/A350.2.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9\">http:\/\/sti.bmj.com\/content\/87\/Suppl_1\/A350.2.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9<\/a>): also studies evaluating the potential acceptability of PrEP in various settings (see: <a href=\"http:\/\/sti.bmj.com\/content\/early\/2012\/09\/25\/sextrans-2012-050648.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9\">http:\/\/sti.bmj.com\/content\/early\/2012\/09\/25\/sextrans-2012-050648.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9<\/a>; <a href=\"http:\/\/sti.bmj.com\/content\/88\/4\/258.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9\">http:\/\/sti.bmj.com\/content\/88\/4\/258.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9<\/a>).<\/p>\n<p>Further tenofovir PrEP trials have produced results that are puzzlingly varied, and, given the hopes placed in PrEP as a preventative tool, somewhat disappointing:\u00a0 <b>CDC TDF2 <\/b>(3) (oral tablet\/heterosexual partners of men\/women of indeterminate HIV status) RRR <b>62%<\/b>; <b>Partner\u2019s PrEP<\/b> (4) (oral tablet\/heterosexual partners of HIV+ men\/women) RRR <b>75%<\/b>;\u00a0 <b>FEM-PrEP<\/b> (5) (oral tablet\/women) <b>discontinued<\/b> for futility; <b>VOICE<\/b> (topical gel\/women) <b>discontinued<\/b> for futility. This has prompted some reflection on the efficacy of large RCT of the kind, with the discussion focussing on the difficulties around adherence (<a href=\"http:\/\/sti.bmj.com\/content\/87\/Suppl_1\/A196.3.abstract?sid=778e710d-42a6-4de3-a7e3-b9cd3f22a57e\">http:\/\/sti.bmj.com\/content\/87\/Suppl_1\/A196.3.abstract?sid=778e710d-42a6-4de3-a7e3-b9cd3f22a57e<\/a>).\u00a0 Crucially, Hendrix discusses the problem of disentangling the drug-related factors from issues of adherence (<a href=\"http:\/\/sti.bmj.com\/content\/87\/Suppl_1\/A1.4.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9\">http:\/\/sti.bmj.com\/content\/87\/Suppl_1\/A1.4.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9<\/a>).<\/p>\n<p>One complicating factor in assessing tenofovir PrEP trial results is the use of two \u201croutes\u201d \u2013 oral tablet and topical gel \u2013 likely to produce concentrations of the drug at different anatomical sites.\u00a0 This issue has now been taken up in an important recent paper (Hendrix &amp; Bumpus) reporting the results of <i>Microbicide Trials Network<\/i> (MTN) study 001 (<a href=\"http:\/\/www.plosone.org\/article\/info%3Adoi%2F10.1371%2Fjournal.pone.0055013\">http:\/\/www.plosone.org\/article\/info%3Adoi%2F10.1371%2Fjournal.pone.0055013<\/a>).\u00a0 In discussing pharmacokinetic issues, this paper also deals with the role of adherence as an explanatory variable in a way that casts an altogether fresh light on the issues Hendrix tackles in the above-cited paper (<a href=\"http:\/\/sti.bmj.com\/content\/87\/Suppl_1\/A1.4.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9\">http:\/\/sti.bmj.com\/content\/87\/Suppl_1\/A1.4.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9<\/a>).<\/p>\n<p>MTN-001 is a crossover study in which all participants were assigned to a randomized sequence of daily tenofovir orally vaginally, or both orally and vaginally in three 6-week periods.\u00a0 The key finding is that the concentration of the drug in its active form tenofovir disphosphate in <i>vaginal mucosa<\/i> achieved by the <b>gel<\/b> is <b>130-173 times greater<\/b> than that achieved by the tablet; whereas the concentration in the <i>serum and peripheral blood mononuclear cells (PMBC)<\/i> achieved by the <b>gel<\/b> is respectively <b>58 and 56 times less<\/b>.<\/p>\n<p>It has generally been assumed that it is vaginal tissue concentration of the drug which gives protection.\u00a0 One possible conclusion we might draw from these findings is that vaginal tissue is not, in fact, the critical site of ARV action.\u00a0 The problem is that CAPRISA 004 (1) demonstrates that vaginal gel is having <i>some<\/i> effect through the vaginal compartment; yet that effect \u2013 given that it exists \u2013 is not at the level that might have been anticipated given 1. the increased HIV protection, and, especially, 2. increased toleration of missed doses, that we would expect from such a concentration. The second point is particularly important given the weight attached in this discussion to adherence as an explanatory variable.\u00a0 With the half-life of elimination of tenofir diphosphate an estimated 90 hours, women having dosed once with gel could stop all dosing for more than 2 weeks before their vaginal tissue concentration fell to the vaginal concentrations achieved in oral dosing!\u00a0 Hence, non-adherence appears <i>not<\/i> to be a plausible as a sole explanatory variable. \u00a0Something else must be going on.\u00a0 But what?\u00a0 The authors suggest, first, the possibility of tissue toxicity either from the tenofovir or the gel vehicle; second, some other factor that we are as yet unable to determine.<\/p>\n<p>The authors conclude, naturally, that identification of the unknown variable is essential to improving future PrEP development&#8230;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Reports of modest success from two trials (2010) of tenofovir as pre-exposure prophylaxis against HIV (PrEP)\u2013 CAPRISA 004 (1) (topical gel\/women) relative risk reduction (RRR) 39%; iPrEX (2) (oral tablet\/MSM) RRR 44% \u2013 have inspired recent contributions to STI journal. \u00a0In particular, there have been attempts to model the possible impact on the epidemic of [&#8230;]<\/p>\n<p><a class=\"btn btn-secondary understrap-read-more-link\" href=\"https:\/\/blogs.bmj.com\/sti\/2013\/03\/27\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\/\">Read More&#8230;<\/a><\/p>\n","protected":false},"author":152,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[2380],"tags":[],"class_list":["post-813","post","type-post","status-publish","format-standard","hentry","category-pre-exposure-prophylaxis"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.4 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Disappointing tenofovir PrEP trials: maybe \u201cadherence\u201d is not to blame - Sexually Transmitted Infections<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/blogs.bmj.com\/sti\/2013\/03\/27\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Disappointing tenofovir PrEP trials: maybe \u201cadherence\u201d is not to blame - Sexually Transmitted Infections\" \/>\n<meta property=\"og:description\" content=\"Reports of modest success from two trials (2010) of tenofovir as pre-exposure prophylaxis against HIV (PrEP)\u2013 CAPRISA 004 (1) (topical gel\/women) relative risk reduction (RRR) 39%; iPrEX (2) (oral tablet\/MSM) RRR 44% \u2013 have inspired recent contributions to STI journal. \u00a0In particular, there have been attempts to model the possible impact on the epidemic of [...]Read More...\" \/>\n<meta property=\"og:url\" content=\"https:\/\/blogs.bmj.com\/sti\/2013\/03\/27\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\/\" \/>\n<meta property=\"og:site_name\" content=\"Sexually Transmitted Infections\" \/>\n<meta property=\"article:published_time\" content=\"2013-03-27T15:30:07+00:00\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"4 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/2013\\\/03\\\/27\\\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\\\/#article\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/2013\\\/03\\\/27\\\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\\\/\"},\"author\":{\"name\":\"\",\"@id\":\"\"},\"headline\":\"Disappointing tenofovir PrEP trials: maybe \u201cadherence\u201d is not to blame\",\"datePublished\":\"2013-03-27T15:30:07+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/2013\\\/03\\\/27\\\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\\\/\"},\"wordCount\":720,\"publisher\":{\"@id\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/#organization\"},\"articleSection\":[\"pre-exposure prophylaxis\"],\"inLanguage\":\"en-US\"},{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/2013\\\/03\\\/27\\\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\\\/\",\"url\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/2013\\\/03\\\/27\\\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\\\/\",\"name\":\"Disappointing tenofovir PrEP trials: maybe \u201cadherence\u201d is not to blame - Sexually Transmitted Infections\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/#website\"},\"datePublished\":\"2013-03-27T15:30:07+00:00\",\"breadcrumb\":{\"@id\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/2013\\\/03\\\/27\\\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\\\/#breadcrumb\"},\"inLanguage\":\"en-US\",\"potentialAction\":[{\"@type\":\"ReadAction\",\"target\":[\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/2013\\\/03\\\/27\\\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\\\/\"]}]},{\"@type\":\"BreadcrumbList\",\"@id\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/2013\\\/03\\\/27\\\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\\\/#breadcrumb\",\"itemListElement\":[{\"@type\":\"ListItem\",\"position\":1,\"name\":\"Home\",\"item\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/\"},{\"@type\":\"ListItem\",\"position\":2,\"name\":\"Disappointing tenofovir PrEP trials: maybe \u201cadherence\u201d is not to blame\"}]},{\"@type\":\"WebSite\",\"@id\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/#website\",\"url\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/\",\"name\":\"Sexually Transmitted Infections\",\"description\":\"Discussion and suggestion space for readers of STIs\",\"publisher\":{\"@id\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/#organization\"},\"potentialAction\":[{\"@type\":\"SearchAction\",\"target\":{\"@type\":\"EntryPoint\",\"urlTemplate\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/?s={search_term_string}\"},\"query-input\":{\"@type\":\"PropertyValueSpecification\",\"valueRequired\":true,\"valueName\":\"search_term_string\"}}],\"inLanguage\":\"en-US\"},{\"@type\":\"Organization\",\"@id\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/#organization\",\"name\":\"Sexually Transmitted Infections\",\"url\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/\",\"logo\":{\"@type\":\"ImageObject\",\"inLanguage\":\"en-US\",\"@id\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/#\\\/schema\\\/logo\\\/image\\\/\",\"url\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/files\\\/2017\\\/10\\\/blog-logo-sti.png\",\"contentUrl\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/files\\\/2017\\\/10\\\/blog-logo-sti.png\",\"width\":378,\"height\":34,\"caption\":\"Sexually Transmitted Infections\"},\"image\":{\"@id\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/#\\\/schema\\\/logo\\\/image\\\/\"}},{\"@type\":\"Person\",\"@id\":\"\",\"url\":\"https:\\\/\\\/blogs.bmj.com\\\/sti\\\/author\\\/\"}]}<\/script>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"Disappointing tenofovir PrEP trials: maybe \u201cadherence\u201d is not to blame - Sexually Transmitted Infections","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/blogs.bmj.com\/sti\/2013\/03\/27\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\/","og_locale":"en_US","og_type":"article","og_title":"Disappointing tenofovir PrEP trials: maybe \u201cadherence\u201d is not to blame - Sexually Transmitted Infections","og_description":"Reports of modest success from two trials (2010) of tenofovir as pre-exposure prophylaxis against HIV (PrEP)\u2013 CAPRISA 004 (1) (topical gel\/women) relative risk reduction (RRR) 39%; iPrEX (2) (oral tablet\/MSM) RRR 44% \u2013 have inspired recent contributions to STI journal. \u00a0In particular, there have been attempts to model the possible impact on the epidemic of [...]Read More...","og_url":"https:\/\/blogs.bmj.com\/sti\/2013\/03\/27\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\/","og_site_name":"Sexually Transmitted Infections","article_published_time":"2013-03-27T15:30:07+00:00","twitter_card":"summary_large_image","twitter_misc":{"Written by":"","Est. reading time":"4 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"Article","@id":"https:\/\/blogs.bmj.com\/sti\/2013\/03\/27\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\/#article","isPartOf":{"@id":"https:\/\/blogs.bmj.com\/sti\/2013\/03\/27\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\/"},"author":{"name":"","@id":""},"headline":"Disappointing tenofovir PrEP trials: maybe \u201cadherence\u201d is not to blame","datePublished":"2013-03-27T15:30:07+00:00","mainEntityOfPage":{"@id":"https:\/\/blogs.bmj.com\/sti\/2013\/03\/27\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\/"},"wordCount":720,"publisher":{"@id":"https:\/\/blogs.bmj.com\/sti\/#organization"},"articleSection":["pre-exposure prophylaxis"],"inLanguage":"en-US"},{"@type":"WebPage","@id":"https:\/\/blogs.bmj.com\/sti\/2013\/03\/27\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\/","url":"https:\/\/blogs.bmj.com\/sti\/2013\/03\/27\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\/","name":"Disappointing tenofovir PrEP trials: maybe \u201cadherence\u201d is not to blame - Sexually Transmitted Infections","isPartOf":{"@id":"https:\/\/blogs.bmj.com\/sti\/#website"},"datePublished":"2013-03-27T15:30:07+00:00","breadcrumb":{"@id":"https:\/\/blogs.bmj.com\/sti\/2013\/03\/27\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\/#breadcrumb"},"inLanguage":"en-US","potentialAction":[{"@type":"ReadAction","target":["https:\/\/blogs.bmj.com\/sti\/2013\/03\/27\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\/"]}]},{"@type":"BreadcrumbList","@id":"https:\/\/blogs.bmj.com\/sti\/2013\/03\/27\/disappointing-tenofovir-prep-trials-maybe-adherence-is-not-to-blame-2\/#breadcrumb","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https:\/\/blogs.bmj.com\/sti\/"},{"@type":"ListItem","position":2,"name":"Disappointing tenofovir PrEP trials: maybe \u201cadherence\u201d is not to blame"}]},{"@type":"WebSite","@id":"https:\/\/blogs.bmj.com\/sti\/#website","url":"https:\/\/blogs.bmj.com\/sti\/","name":"Sexually Transmitted Infections","description":"Discussion and suggestion space for readers of STIs","publisher":{"@id":"https:\/\/blogs.bmj.com\/sti\/#organization"},"potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/blogs.bmj.com\/sti\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"en-US"},{"@type":"Organization","@id":"https:\/\/blogs.bmj.com\/sti\/#organization","name":"Sexually Transmitted Infections","url":"https:\/\/blogs.bmj.com\/sti\/","logo":{"@type":"ImageObject","inLanguage":"en-US","@id":"https:\/\/blogs.bmj.com\/sti\/#\/schema\/logo\/image\/","url":"https:\/\/blogs.bmj.com\/sti\/files\/2017\/10\/blog-logo-sti.png","contentUrl":"https:\/\/blogs.bmj.com\/sti\/files\/2017\/10\/blog-logo-sti.png","width":378,"height":34,"caption":"Sexually Transmitted Infections"},"image":{"@id":"https:\/\/blogs.bmj.com\/sti\/#\/schema\/logo\/image\/"}},{"@type":"Person","@id":"","url":"https:\/\/blogs.bmj.com\/sti\/author\/"}]}},"_links":{"self":[{"href":"https:\/\/blogs.bmj.com\/sti\/wp-json\/wp\/v2\/posts\/813","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.bmj.com\/sti\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.bmj.com\/sti\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.bmj.com\/sti\/wp-json\/wp\/v2\/users\/152"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.bmj.com\/sti\/wp-json\/wp\/v2\/comments?post=813"}],"version-history":[{"count":0,"href":"https:\/\/blogs.bmj.com\/sti\/wp-json\/wp\/v2\/posts\/813\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.bmj.com\/sti\/wp-json\/wp\/v2\/media?parent=813"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.bmj.com\/sti\/wp-json\/wp\/v2\/categories?post=813"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.bmj.com\/sti\/wp-json\/wp\/v2\/tags?post=813"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}