Reply to Haddow et al

Extract

To the Editor—Haddow and colleagues [1] have expressed 2 concerns regarding interpretation of the longitudinal CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study of neurocognitive (NC) outcomes in 436 human immunodeficiency virus (HIV)-infected patients—namely, that “NC change is common in HIV infection and appears to be driven by a complex set of risk factors involving HIV disease, its treatment, and comorbid conditions” [2].

Haddow et al are correct that the probability of a person experiencing NC decline at any point across multiple visits is somewhat greater than the 5% defined by the published norms for NC change [3] at a single follow-up. However, these authors' use of standard binomial probability estimates to arrive at an overall chance-based “decliner” rate of 20.4% over 6 follow-up visits is inaccurate (excessive), because of the acknowledged assumption that all visits for any individual patient are independent. In fact, in the survival analysis used in our article, “decline” was an absorbing state. Visits were not independent: Once a patient was first classified as a “decliner,” the endpoint of interest in our study, that person had no opportunities to (or chance-based risk for) decline at any future visit. Also, of the 99 decliners in our study, 62.3% had declined by their second follow-up visit, and 85% had declined by their third. In the published study that provided norms for NC change in controls [3], the overall prevalence of “decliner” status for participants with ≥4 visits (required for the CHARTER study) was 12.3%. The 22.7% rate of decliners in CHARTER is almost double that in the normative study, a consequential difference that is not easily attributable to chance.