Abstract Body

Long-acting and extended-release (LA/ER) formulations of antiretroviral drugs have the potential to revolutionize treatment and prevention. Formulations in current development run the gamut from oral products capable of delivering effective systemic anti-HIV drug concentrations for 7-14 days after a single dose, to implants capable of providing effective treatment for as long as 6, and possibly 12 or more months. These approaches are ideal for patients having difficulty with adherence, suffering from pill fatigue, or living in areas where the stigma of taking daily HIV pills is a concern. Other important applications include use in patients who cannot or will not take daily oral medication, including infants, children, and adolescents. Recent survey research suggests widespread popularity of switching to parenteral LA/ER treatment amongst those already taking daily oral combination ART. Two injectable LA formulations — of rilpivirine and cabotegravir — are in Phase 3 clinical testing, and several others have entered clinical development. Other candidates for LA/ER delivery include biologics and broadly neutralizing monoclonal antibodies. New approaches to developing a broader array of possible LA/ER products include prodrug approaches to modify existing ARV’s in order to make them more amenable to nanoformulation. Physiologically-based pharmacokinetic (PBPK) modeling can be used to prioritize candidate formulations for further preclinical and clinical development, based on a better understanding of the fundamental principles governing drug release from an intramuscular depot or subcutaneous implant. Class-wide problems associated with LA/ER approaches include concerns about drug resistance, missed doses, coverage of the long tail of drug concentrations when treatment is stopped or switched, and what to do about drug interactions, pregnancy, and irreversible or long-lived side effects. Although the many drawbacks of LA/ER formulations will need to be addressed during clinical development, there is little doubt that these approaches to drug delivery are going to have a meaningful impact on the treatment and prevention of HIV and other infectious diseases.