Factors in AIDS Dementia Complex Trial Design: Results and Lessons from the Abacavir Trial

Abstract

Objectives:To determine the efficacy of adding abacavir (Ziagen, ABC) to optimal stable background antiretroviral therapy (SBG) to AIDS dementia complex (ADC) patients and address trial design.Design:Phase III randomized, double-blind placebo-controlled trial.Setting:Tertiary outpatient clinics.Participants:ADC patients on SBG for ≥8 wk.Interventions:Participants were randomized to ABC or matched placebo for 12 wk.Outcome Measures:The primary outcome measure was the change in the summary neuropsychological Z score (NPZ). Secondary measures were HIV RNA and the immune activation markers β-2 microglobulin, soluble tumor necrosis factor (TNF) receptor 2, and quinolinic acid.Results:105 participants were enrolled. The median change in NPZ at week 12 was +0.76 for the ABC + SBG and +0.63 for the SBG groups (p = 0.735). The lack of efficacy was unlikely related to possible limited antiviral efficacy of ABC: at week 12 more ABC than placebo participants had plasma HIV RNA ≤400 copies/mL (p = 0.002). There were, however, other factors. Two thirds of patients were subsequently found to have had baseline resistance to ABC. Second, there was an unanticipated beneficial effect of SBG that extended beyond 8 wk to 5 mo, thereby rendering some of the patients at baseline unstable. Third, there was an unexpectedly large variability in neuropsychological performance that underpowered the study. Fourth, there was a relative lack of activity of ADC: 56% of all patients had baseline cerebrospinal fluid (CSF) HIV-1 RNA <100 copies/mL and 83% had CSF β-2 microglobulin <3 nmol/L at baseline.Conclusions:The addition of ABC to SBG for ADC patients was not efficacious, possibly because of the inefficacy of ABC per se, baseline drug resistance, prolonged benefit from existing therapy, difficulties with sample size calculations, and lack of disease activity. Assessment of these trial design factors is critical in the design of future ADC trials.

Cognitive function in treated HIV patients

“…A Phase III randomized, double-blinded, placebo-controlled trial of adding abacavir to optimal stable background therapy failed to find any differences in cognitive performance between the placebo and the abacavir group at week 12. 44 This was in contrast with placebo-controlled trials performed in the monotherapy era.…”

Pharmacokinetics and Pharmacodynamics of Antiretrovirals in the Central Nervous System

“…[145,146] Abacavir was tested as an adjunctive therapy in patients with HAD: neurocognitive performance and CSF HIV RNA showed no significant change. [86] Protease inhibitors monotherapies have been tested given the need for reducing long-term toxicities and drug expenditure: this strategy is less effective than triple therapy but it is efficacious in the majority of patients. Concerns have been raised on the compartmental activity of low penetrating drugs such as PIs: several data on neurocognitive tests and a review of available data were reassuring on the effect of such strategies.…”

Neuropsychological Functioning and Antiretroviral Treatment in HIV/AIDS: A Review

“…Indeed, Brew et al (2007) found that among the causes for abacavir's lack of efficacy in reversing cognitive disturbance in a large group of patients with HAND, was the high frequency of baseline resistance to the drug (to which the patients were naïve) and which had been acquired most likely through cross resistant drug mutations within the same class of ART agents. In fact, another study from the HNRC group (Strain et al 2005) with 18 individuals having advanced HIV infection, showed that nine of 13 participants with drug resistance had discordant resistance patterns between the CSF and plasma compartments, supporting other findings (Cunningham et al 2000).…”