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One step closer to ultra-long-acting PREP?

Harper, Kirsten Nicole

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doi: 10.1097/QAD.0000000000002118
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Pre-exposure prophylaxis (PrEP) has become an increasingly popular means of preventing HIV transmission, but the only currently approved form requires users to take a daily pill. Long-acting forms of PrEP could offer a simpler regimen, potentially improving adherence and effectiveness. One potential concern, however, is how clinicians could respond to side effects that emerge after a long-acting form of PrEP is delivered; at present, formulations in late-stage development cannot be removed from the body once they are injected. Recently, researchers published findings from a preclinical study of a novel type of ultra-long-acting, removable PrEP in Nature Communications[1].

If validated in future studies, ‘this form of PrEP could provide a viable alternative for the numerous individuals who would prefer long-term protection without the need for daily dosing,’ says Martina Kovarova, PhD, of the University of North Carolina at Chapel Hill, lead author of the article. The implant is delivered via subcutaneous injection of a solution containing the antiviral dolutegravir; after being injected, the solution quickly solidifies into a small biodegradable implant that can be removed if problems arise.

In the study, researchers showed that a single implant delivered sustained levels of dolutegravir for up to 9 months in two mouse models [NSG mice and humanized bone marrow/liver/thymus (BLT) mice] and for up to 5 months in macaques. In addition, plasma collected from mice and macaques with the implant was able to inhibit HIV-1 replication ex vivo, and HIV replication was inhibited in BLT mice with the implant in vivo. Finally, the implant was able to protect BLT mice from multiple high-dose vaginal challenges with HIV.

Raphael J. Landovitz, MD, MSc, of UCLA Health in Los Angeles, says that although this technology is exciting, it is still too early to know how much promise it holds for humans. First, the safety of dolutegravir for women of childbearing potential is currently being evaluated. Second, it will be important to investigate how pharmacokinetics vary in response to factors such as sex at birth and BMI. Finally, he notes that during the component of the study simulating HIV treatment, viral resistance to dolutegravir monotherapy developed quickly. This suggests that, if intended for treatment, a future version of the implant would need to include additional antiviral agents, though this might not be necessary for PrEP.

While agreeing that there is much work left to do before the implant is ready for testing in humans, J. Victor Garcia, PhD, senior author of the article and also from the University of North Carolina at Chapel Hill, is optimistic. Referring to the biodegradable implant that forms after injection, he says, ‘The fact that similar technology has already been used in the clinic for other types of applications, such as palliative treatment for advanced prostate cancer, increases our optimism that this form of PrEP can be used for HIV prevention.’

Reference

1. Kovarova M, Benhabbour SR, Massud I, Spagnuolo RA, Skinner B, Baker CE, et al. Ultra-long-acting removable drug delivery system for HIV treatment and prevention. Nat Commun 2018; 9:4156.
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