{"id":46525,"date":"2023-12-01T07:31:25","date_gmt":"2023-12-01T07:31:25","guid":{"rendered":"https:\/\/i-base.info\/htb\/?p=46525"},"modified":"2023-12-09T23:59:50","modified_gmt":"2023-12-09T23:59:50","slug":"monthly-injectable-art-potential-nanoformulation-of-tenofovir-3tc-and-dolutegravir","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/46525","title":{"rendered":"Potential for monthly injectable: nanoformulated tenofovir\/3TC\/dolutegravir"},"content":{"rendered":"
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Polly Clayden, HIV i-Base<\/span><\/strong><\/p>\n<\/div>\n

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A novel long-acting injectable formulation of tenofovir, lamivudine and dolutegravir (TLD) sustained effective concentrations over four weeks in a macaque study. These findings were published ahead of print in AIDS, 23 August 2023. [1]<\/span><\/strong><\/p>\n<\/div>\n

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Researchers from the University of Washington TLC-ART (Targeted,\u00a0Long-acting\u00a0and\u00a0Combination\u00a0Anti-Retroviral\u00a0Therapy), are developing a long-acting TLD drug-combination. [2] <\/span><\/p>\n<\/div>\n

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The group have previously successfully formulated water insoluble-and-soluble antiretrovirals with biocompatible lipid-excipient to form drug-combination-nanoparticles (DcNP). <\/span><\/p>\n<\/div>\n

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This pre-clinical pharmacokinetic study looked at whether short-acting TLD can be transformed into a single long-acting formulation.<\/span><\/p>\n<\/div>\n

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The investigators used oral ARVs from generic manufacturers to formulate TLD-in-DcNP. <\/span><\/p>\n<\/div>\n

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Five macaques were dosed 6.2, 5.1 10 mg\/kg TLD-in-DcNP suspension and two (control) were dosed with free-soluble mixture TLD (dissolved in liquid but not using DcNP) \u2013 both by subcutaneous injection. <\/span><\/p>\n<\/div>\n

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Blood samples for the TLD-in-DcNP were collected at 0, 0.25, 0.5, 1, 3, 5, 8, 24, 48, 120, 168, 192, 336, 50, 672 hours (4 weeks) for drug analysis \u2013 the free TLD samples were collected at the same time points up to 120 hours. <\/span><\/p>\n<\/div>\n

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In four animals dosed with TLD-in-DcNP, peripheral blood mononuclear cells (PBMC) were isolated, in the 48\u2013 and 168\u2013hour blood samples, and also analysed for drug content.<\/span><\/p>\n<\/div>\n

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Tenofovir, 3TC and dolutegravir were detectable in plasma throughout a four-week period. By contrast, plasma drug levels in the animals receiving TLD-free dosage fell below detectable levels within three days.<\/span><\/p>\n<\/div>\n

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TLD-in-DcNP AUC were 7.0\u2013, 2.1\u2013, and 20\u2013fold higher, for tenofovir, 3TC, and dolutegravir, respectively. The effects of DcNP on TLD half-life extension were 10\u2013, 8.3\u2013, and 5.9\u2013fold over the free-soluble combination. <\/span><\/p>\n<\/div>\n

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All drug concentrations were above the estimated IC90 for the four-week study: 0.3, 0.2, and 0.25 ng\/mL for tenofovir, 3TC and dolutegravir, respectively. <\/span><\/p>\n<\/div>\n

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The intracellular tenofovir concentration in PBMCs was 2.2\u2013 and 3.1\u2013fold higher than plasma, at 48 and 168 hours, respectively; 3TC in PBMC was 3\u2013 and 15\u2013fold higher than in plasma; and dolutegravir in PBMC was 29\u2013 and 4.1\u2013fold higher than in plasma.<\/span><\/p>\n<\/div>\n

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The investigators concluded that these data show water-soluble tenofovir, 3TC, and water-insoluble dolutegravir combined into the single TLD-in-DcNP injectable provided four weeks plasma exposure in monkeys above detectable, measurable, and IC90-predicted levels.<\/span><\/p>\n<\/div>\n

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comment <\/span><\/h3>\n<\/div>\n
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Oral TLD is a currently recommended by WHO and national guidelines as first-line (and increasingly subsequent) HIV treatment. <\/span><\/strong><\/p>\n<\/div>\n

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Through its competitive tenders, the Global Fund, with its partners and generic manufacturers, recently announced further price reductions for eligible countries, making this one-pill-once-a-day available for less than US $45 a year. [3]<\/span><\/strong><\/p>\n<\/div>\n

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The TLC-ART group suggest that a long-acting TLD may overcome daily pill fatigue \u2013 for people who find this a problem (and if it can be manufactured for an acceptable price). <\/span><\/strong><\/p>\n<\/div>\n

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They also note that as the TLD-in-DcNP can be given by subcutaneous injection it may mean people can self-administrate this formulation, unlike intramuscular injection needed for long-acting cabotegravir and rilpivirine, that requires a health worker (and cold chain for RPV-LA).<\/span><\/strong><\/p>\n<\/div>\n

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Another advantage could be that an oral lead-in may not be necessary due this LA formulation\u2019s short time to peak. <\/span><\/strong><\/p>\n<\/div>\n

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And because the combination includes tenofovir it provides coverage for people with HIV and HBV (unlike cabotegravir and rilpivirine). <\/span><\/strong><\/p>\n<\/div>\n

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Most importantly, if this formulation becomes available, there is already a wealth of experience with oral TLD \u2013 including in populations where data can be scarce for new drugs and strategies notably pregnant women.<\/span><\/strong><\/p>\n<\/div>\n

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On the downside, monthly administration is less desirable than longer dosing intervals.<\/span><\/strong><\/p>\n<\/div>\n

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A monthly injectable formulation could be very useful for paediatric populations \u2013 where there is still a huge need for effective ART. This would need to include abacavir instead of tenofovir. But the monthly dosing interval might be more acceptable in infants and children as dosing is weight-based and this changes as they grow.<\/span><\/strong><\/p>\n<\/div>\n

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Phase 1 human data will be presented in early 2024.<\/span><\/strong><\/p>\n<\/div>\n

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References<\/span><\/p>\n<\/div>\n

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  1. Perazzolo S et al. A novel formulation enabled transformation of 3 HIV drugs tenofovir-lamivudine-dolutegravir (TLD) from short-Acting to long-acting all-in-one injectable.\u00a0AIDS ():10.1097\/QAD.0000000000003706, August 25, 2023. | DOI: 10.1097\/QAD.0000000000003706.
    \n<\/span>https:\/\/journals.lww.com\/aidsonline\/abstract\/9900\/a_novel_formulation_enabled_transformation_of_3.333.aspx<\/a><\/li>\n
  2. University of Washington. TLC-ART
    \n    https:\/\/depts.washington.edu\/tlcart\/<\/a><\/li>\n
  3. Global Fund press release. Global Fund agreements substantially reduce the price of first-line HIV treatment to below US$45 a year. 30 August 2023.
    \n    https:\/\/www.theglobalfund.org\/en\/news\/2023\/2023-08-30-global-fund-agreements-substantially-reduce-price-first-line-hiv-treatment-below-usd45-a-year<\/a><\/li>\n<\/ol>\n

    First published online 11 October 2023.<\/em><\/p>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

    Polly Clayden, HIV i-Base A novel long-acting injectable formulation of tenofovir, lamivudine and dolutegravir (TLD) sustained effective concentrations over four weeks in a macaque study. These findings were published ahead of print in AIDS, 23 August 2023. [1] Researchers from …<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3],"tags":[],"class_list":["post-46525","post","type-post","status-publish","format-standard","hentry","category-antiretrovirals"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/46525","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=46525"}],"version-history":[{"count":5,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/46525\/revisions"}],"predecessor-version":[{"id":46840,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/46525\/revisions\/46840"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=46525"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=46525"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=46525"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}