State of the ART (antiretroviral therapy): Long-acting HIV-1 therapeutics

Abstract

Human immunodeficiency virus (HIV) impacts millions of individuals worldwide, and well over 2/3 of those living with HIV are accessing antiviral therapies that are successfully repressing viral replication. Most often, HIV treatments and prevention are administered in the form of daily pills as combinations of multiple drugs. An emergent and effective strategy for suppressing viral replication is the application of long-acting antiretroviral therapy (LAART), or antivirals that require less-frequent, non-daily doses. Thus far, the repertoire of LAARTs includes the widely used antiviral classes of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (INSTIs) and has recently expanded to include a capsid-targeting antiviral. Possible future additions are nucleoside reverse transcriptase inhibitors (NRTIs) and nucleoside reverse transcriptase translocation inhibitors (NRTTIs). Here, we discuss the different strategies of using long-acting compounds to treat or prevent HIV-1 infection by targeting reverse transcriptase, integrase, and capsid.

Keywords: acquired immunodeficiency syndrome (AIDS); antiretroviral therapy (ART); human immunodeficiency virus (HIV); long-acting formulations; pre-exposure prophylaxis (PrEP).

Figure 1.

Global statistics of HIV-1 infections, treatment, and access in 2023. Regional-specific data below, showing the total estimated infections (in millions, blue) and percent of untreated individuals (red). Data from the UNAIDS 2023 report, "The urgency of now: AIDS at a crossroads" ().

Figure 2.

Timeline of some important discoveries, approvals, and advancements leading to long-acting HIV-1 therapeutics. Compounds are categorized as first-in-class (blue), newer-generation (green), and long-acting therapeutics (red) for treating and preventing infection. Chemical structure and delivery method(s) included for each antiviral on the right. Represented inhibitor classes are nucleoside reverse transcriptase inhibitor (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs), and capsid-targeting antivirals. Pill and syringe icons designed by Freepik.