{"id":47854,"date":"2024-06-05T13:06:22","date_gmt":"2024-06-05T13:06:22","guid":{"rendered":"https:\/\/i-base.info\/htb\/?p=47854"},"modified":"2024-06-19T20:05:02","modified_gmt":"2024-06-19T20:05:02","slug":"challenges-with-annual-taf-implant","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/47854","title":{"rendered":"Challenges with annual TAF implant"},"content":{"rendered":"

Polly Clayden, HIV i-Base<\/strong><\/p>\n

\"\"In the first-in-human tenofovir alafenamide (TAF) implant trial, there was lower than planned drug release in most participants and tolerability was suboptimal \u2013 according to data presented at CROI 2024. [1]<\/strong><\/p>\n

There is an urgent need for a long-acting \u2013 ideally annual or longer \u2013 HIV prevention technology to overcome oral PrEP adherence challenges.<\/p>\n

The CAPRISA 018 phase 1 trial looked at an annual TAF implant in low-risk adult South African cisgender women without HIV.<\/p>\n

The silicone implant, developed by the Oakcrest Institute, has the same dimensions as a contraceptive implant (40 mm length and 2.5 mm OD), except with two delivery channels. It is loaded with 110 mg TAF free-base micro-tablets. Target release 0.25 mg\/day.<\/p>\n

To assess initial safety, six participants aged 18 to 40 years received a single TAF implant (bicep insertion), 28 days in situ) (Group 1).<\/p>\n

After this, 30 were randomised 1:1 to either one or two TAF implants and assigned blinded in a 4:1 active (n=24) to placebo (n=6) ratio, for 48 weeks (Group 2).<\/p>\n

Among the 36 participants, median age was 26 years (IQR: 22 to 30) and weight 72 kg (61\u201380). Five participants had used a contraceptive implant in the past or were using one during the study period. Overall retention was 97%.<\/p>\n

Systemic AEs and ISRs were mostly mild: Grade 1, 55.3% and 90.9% respectively. Two of 36 participants (Group 2) had Grade 3 ISRs \u2013 both implant site abscesses. These were resolved with early removal.<\/p>\n

Overall, 31% (11\/36) were removed early (before 48 weeks) at a median of 19 weeks (range: 2 to 27); of these 55% were participant-initiated and the remainder clinician-initiated. These were mostly associated with ISRs.<\/p>\n

One third (10\/30) of TAF implants and 17% (1\/6) of placebo implants were removed early. As were 22% (4\/18) of single and 50% (6\/12) of double implants.<\/p>\n

ISR incidence per person month: 2.1 (95% CI: 1.8 to 2.6) vs 0.8 (95% CI: 0.6 to 0.9) in early vs scheduled removals, respectively.<\/p>\n

Mean removal time was 40 minutes early vs 19 minutes scheduled for one implant and 81 minutes early vs 33 minutes scheduled for two implants.<\/p>\n

Plasma TAF was detectable in 77% of samples from Group 2 participants in the active arm, with 100% and 50% detection 0.5 and 6 hours post insertion.<\/p>\n

But median TFV-DP concentrations were 3.9 (IQR 1.7 to13.3) and 14.8 (IQR 6.0 to 29.1) fmol\/million cells in participants with 1 and 2 active implants respectively, with only 15% of samples achieving or exceeding the target concentration of 36 fmol\/million cells.<\/p>\n

comment<\/strong><\/h3>\n

The investigators noted that there was no dose dumping, drug released over one year but residual TAF was high at removal.<\/strong><\/p>\n

There was lower than planned drug release \u2013 the implant needs to release more TAF: two implants had a median TFV-DP of 14.8 fmol\/million cells which is well below the target of 36 fmol\/million cells.<\/strong><\/p>\n

Tolerability was poor and early removals were more difficult and took considerable time. <\/strong><\/p>\n

The challenge will be to increase drug release and lower ISRs. If tolerability can be improved, increasing the release from two implants could achieve target TFV-DP levels for a year.<\/strong><\/p>\n

As Charlie Flexner remarked, in his excellent plenary, this is a prototype system and an important study to inform future implants.<\/strong><\/p>\n

If the challenges described in this initial investigation can be overcome, such an implant could meet an urgent HIV prevention need. <\/strong><\/p>\n

References<\/p>\n

    \n
  1. Gengiah TN et al. Phase I safety, tolerability and pharmacokinetics of tenofovir alafenamide implants in African women. CROI 2024. Denver, Colorado. 3\u20136 March 2024. Oral abstract 123.
    \nhttps:\/\/www.croiconference.org\/abstract\/phase-i-safety-tolerability-and-pharmacokinetics-of-tenofovir-alafenamide-implants-in-african-women\/<\/a> (abstract)
    \n<\/span>    https:\/\/www.croiwebcasts.org\/p\/2024croi\/croi\/123<\/a> (webcast)<\/span><\/li>\n
  2. Flexner CW. The end of oral? How long-acting formulations are changing the management of infectious diseases. CROI 2024. Denver, Colorado. 3\u20136 March 2024. Oral abstract 39.
    \n    https:\/\/www.croiwebcasts.org\/console\/player\/52288<\/a><\/li>\n<\/ol>\n

    \n<\/p>","protected":false},"excerpt":{"rendered":"

    Polly Clayden, HIV i-Base In the first-in-human tenofovir alafenamide (TAF) implant trial, there was lower than planned drug release in most participants and tolerability was suboptimal \u2013 according to data presented at CROI 2024. [1] There is an urgent need …<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,3],"tags":[332],"class_list":["post-47854","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-antiretrovirals","tag-croi-2024-denver"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/47854","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=47854"}],"version-history":[{"count":6,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/47854\/revisions"}],"predecessor-version":[{"id":47976,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/47854\/revisions\/47976"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=47854"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=47854"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=47854"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}