title: Regulatory challenges in developing long-acting antiretrovirals for treatment and prevention of HIV infection.
abstract: OBJECTIVE
  To outline some of the regulatory challenges inherent to the development of long-acting antiretrovirals (ARVs) for the treatment or prevention of HIV infection.
  
  
  RESULTS
  Despite advances in drug development that have reduced ARV dosing to once daily, suboptimal drug adherence remains an obstacle to successful HIV treatment. Further, large randomized trials of once daily oral ARVs for preexposure prophylaxis (PrEP) have shown that drug adherence correlates strongly with prophylactic effect and study outcomes. Thus, the prospect of developing long-acting ARVs, which may mitigate drug adherence issues, has attracted considerable attention lately.
  
  
  CONCLUSIONS
  Because of their pharmacokinetic properties, the development of long-acting ARVs can present novel regulatory challenges. Chief among them is determining the appropriate dosing regimen, the need for an oral lead-in, and whether existing data with an approved oral agent, if available, can be leveraged for a treatment or prevention indication. For PrEP, because validated biomarkers are lacking, additional nonclinical studies and evaluation of tissue concentrations in multiple compartments may be necessary to identify optimal dosages. Study design and choice of controls for registrational trials of new long-acting PrEP agents might also prove challenging following the availability of an oral PrEP drug.
authors.affiliation: aDivision of Clinical Pharmacology 4, Office of Clinical Pharmacology, Office of Translational Sciences bDivision of Antiviral Products, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Arya
authors.forename: Stanley
authors.initials: S
authors.lastname: Au
authors.forename: Yodit
authors.initials: Y
authors.lastname: Belew
authors.forename: Peter
authors.initials: P
authors.lastname: Miele
authors.forename: Kimberly
authors.initials: K
authors.lastname: Struble
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage*; D003692:Delayed-Action Preparations; D055808:Drug Discovery; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control / Q000628:therapy*; D006801:Humans; D007880:Legislation, Drug; D014481:United States
chemical_list: D019380:Anti-HIV Agents; D003692:Delayed-Action Preparations