title: Measuring the potential role of frailty in apparent declining efficacy of HIV interventions.
abstract: OBJECTIVE
  In recent HIV intervention trials, intervention efficacies appear to decline over time. Researchers have attributed this to "waning," or a loss of intervention efficacy. Another possible reason is heterogeneity in infection risk or "frailty." We propose an approach to assessing the impact of frailty and waning on measures of intervention efficacy and statistical power in randomized-controlled trials.
  
  
  METHODS
  Using multiplicative risk reduction, we developed a mathematical formulation for computing disease incidence and the incidence rate ratio (IRR) as a function of frailty and waning. We designed study scenarios, which held study-related factors constant, varied waning and frailty parameters and measured the change in disease incidence, IRR, and statistical power.
  
  
  RESULTS
  We found that frailty alone can impact disease incidence over time. However, frailty has minimal impact on the IRR. The factor that has the greatest influence on the IRR is intervention efficacy and the degree to which it is projected to wane. We also found that even moderate waning can cause an unacceptable decrease in statistical power while the impact of frailty on statistical power is minimal.
  
  
  CONCLUSIONS
  We conclude that frailty has minimal impact on trial results relative to intervention efficacy. Study resources would, therefore, be better spent on efforts to keep the intervention efficacy constant throughout the trial (e.g., enhancing the vaccine schedule or promoting treatment adherence).
authors.affiliation: Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention , Atlanta, GA, USA.
authors.forename: Felicia P
authors.initials: FP
authors.lastname: Hardnett
authors.forename: Charles E
authors.initials: CE
authors.lastname: Rose
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D015658:HIV Infections / Q000150:complications* / Q000628:therapy*; D006801:Humans; D008954:Models, Biological; D013997:Time Factors
chemical_list: D019380:Anti-HIV Agents
keywords: Frailty; HIV; HIV intervention trial; HIV prevention; HIV vaccine