Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection

An ultra-long-acting injectable, removable, self-administered (e.g. subcutaneous administration) formulation that sustain protective plasma levels of antiretrovirals through extended dosing intervals such as every six months or longer may facilitate large-scale implementation to HIV PrEP.
Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection
Like

In situ forming implants (ISFIs) may provide desirable properties for an ultra-long-acting cabotegravir (CAB) formulation including long dosing intervals, small injection volumes, and retrievability. 

Herein, we developed and characterized a CAB ISFI formulation with high drug loading and that is amenable for subcutaneous administration in small volumes. We defined stability, microstructure, injectability, and release kinetics in vitro and in vivo. We show that this formulation is safe in mice and non-human primates and can release CAB for 6-11 months at levels that are above established benchmarks for PrEP protection in macaques and humans (664 ng/mL or 4x PA-IC90). We associate the extended release of CAB from the ISFI with long-lasting protection against SHIV infection in a macaque model of PrEP that predicted clinical efficacy of CAB LA and other approved oral PrEP regimens. Our study identifies a promising platform for the extended release of CAB at levels that are known to be associated with PrEP protection in humans.

To investigate if CAB delivered from ISFIs could confer rectal protection, we performed a series of SHIV challenge experiments at different times after implantation. We first evaluated short-term protection in two macaques (RH-1093 and RH-1097) challenged twice-weekly between weeks 4 and 8 (total of 8 challenges per animal) (Fig. 5a). Both animals were protected against SHIV infection as opposed to an untreated real time control (RH-1092) that was infected after a single SHIV exposure. Long-term protection was evaluated in two additional macaques (RH-1048 and RH-1080) that were exposed twice per week to SHIV between weeks 14 and 18 (8 challenges per animal) (Fig 5b).  One animal (RH-1048) that maintained plasma CAB levels above 4x PA-IC90 received an additional 6 SHIV challenges between weeks 25 and 28. The two CAB treated animals were protected from infection while an untreated real time control (RH-1084) was infected after a single SHIV exposure (Fig 5b). Overall, a single ISFI treatment completely protected 4 macaques during a cumulative of 38 rectal SHIV exposures that spanned a period of 27 weeks.

Our results showing 100% protection in macaques over several months also represent to our knowledge the longest documented PrEP activity seen with a single CAB administration. 

Please sign in or register for FREE

If you are a registered user on Research Communities by Springer Nature, please sign in

Go to the profile of Rahima Benhabbour
about 1 year ago

It has been an exciting journey to see our ultra-long-acting injectable formulation make it through several years of development and learnings along the way to finally bring it to a place where we demonstrated the ability to achieve critical milestones including: 1) the ability to develop a stable and safe injectable formulation of cabotegravir (CAB); 2) sustain plasma CAB levels in macaques above the benchmark for HIV pre-exposure prophylaxis (PrEP; 4x PA-IC90) for more than 6 months; 3) demonstrate the ability to safely remove the implant and reduce CAB plasma levels by up to 100-fold within 1 week; and 4) demonstrate 100% protection in macaques over several months which represents to our knowledge the longest documented PrEP activity seen with a single CAB administration. 

I am excited to continue to move forward this technology and pave the way towards clinical translation to ultimately make an impact to curb the HIV epidemic. 

Subscribe to the Topic

Biotechnology
Life Sciences > Biological Sciences > Biotechnology

Related Collections

With collections, you can get published faster and increase your visibility.

Pre-clinical drug discovery

We welcome studies reporting advances in the discovery, characterization and application of compounds active on biologically or industrially relevant targets. Examples include emerging screening technologies, the development of small bioactive compounds/peptides/proteins, and the elucidation of compound structure-activity relationships, target interactions and mechanism-of-action.

Publishing Model: Open Access

Deadline: Mar 31, 2024

Biomedical applications for nanotechnologies

Overall, there are still several challenges on the path to the clinical translation of nanomedicines, and we aim to bridge this gap by inviting submissions of articles that demonstrate the translational potential of nanomedicines with promising pre-clinical data.

Publishing Model: Open Access

Deadline: Dec 31, 2023