More recently, long-acting ART (LA-ART) has further revolutionized anti-HIV therapy. In 2021, the first combination long-acting injectable ART (LAI-ART), cabotegravir and rilpivirine, was approved by the FDA . Cabotegravir is an INSTI with a high barrier to resistance and a high antiviral potency , while rilpivirine is a potent NNRTI that is active against NNRTI-resistant HIV . It’s an effective combination: together, the drugs are highly potent and last a long time due to their strong antiretroviral activity and long half-life . When formulated into a suspension, pure nanosized drug crystals are produced, which is suitable for intramuscular depot injection [13 – 15].
LAI-ART like cabotegravir and rilpivirine is convenient in that the daily pill burden of traditional ART is decreased to only six or twelve intramuscular injections per year . Furthermore, these drugs are administered under direct medical supervision, thereby overcoming treatment adherence problems associated with traditional ART. In addition to convenience, LAI-ART also reduces the social stigma associated with the daily oral intake of anti-HIV treatments, which can provide tremendous emotional benefits to people living with HIV.
Researchers are also developing long-lasting implants as therapy as well as antibody-based strategies. Islatravir is a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI) that is intended to be formulated as an implant with a dosing interval of one year or greater . NRTTIs act as a reverse transcriptase chain terminator and prevent DNA translocation. The drug lenacaptavir is also currently being evaluated in combination with islatravir and is a first-in-class capsid inhibitor which interferes with multiple capsid-dependent functions required for viral replication . Notable antibody-based strategies for LAI-ART include ibalizumab and leronlimab, which are humanized IgG4 antibodies directed towards CD4 and CCR5, respectively . Ibalizumab is injected every two weeks intravenously, while leronlimab is injected subcutaneously every week, both of which follow a more frequent dosing regimen compared to other LAI-ARTs .
LA-ART is not without its limitations, however. Currently available LA-ARTs are administered at fixed standard doses which do not take into account a patient’s weight or host factors that influence their systemic disposition . Although patients receiving LAI-ART appreciate its convenience, many patients report immense pain and discomfort at the injection site . Current and future formulation efforts are intended to alleviate injection-induced pain by extending injection intervals or by using microneedle patches.