START Neurology substudy
Purpose:The purpose of the study is to determine whether immediate initiation of ART in ART-naïve persons with a CD4+ count > 500 cells/mm3 is superior with respect to neurocognitive function to deferring ART initiation until CD4+ counts decline to below 350 cells/mm3.
Study Hypothesis:We hypothesize that early ART results in improved neurocognitive function compared to deferred ART.
Study Design:This is a substudy of START. It is planned to co-enroll a total of 600 participants over 3 years at selected, geographically diverse sites. Randomization (1:1 ratio) to the early or deferred treatment groups will be determined by the START study. Participants will be followed to the common closing date of START. This is estimated to be 6 years after the beginning of enrollment (3 years of enrollment and a minimum of 3 years follow-up for each participant). Before enrollment ends, sample size of the main START study will be re-assessed and sample size recalculated. At the same time, sample size for the Neurology substudy will be re-calculated.
START Neurology Substudy Schematic
HIV-infected, ART-naïve individuals with CD4+ > 500 cells/mm3
co-enrolled in START N=600
Early ART Group N=300
Initiate ART immediately following randomization
Deferred ART Group N=300
Defer ART until the CD4+ count declines to < 350 cells/mm3 or AIDS develops
Data collection:To be collected at baseline (within 60 days prior to randomization), months 4, 8, and 12, and annually thereafter:
a. The quantitative neurocognitive performance (QNPZ-8) score, derived from a test battery consisting of:
- Grooved Pegboard test
- Color Trails 1 test
- Color Trails 2 test
- WAIS-III Digit Symbol test
- Finger Tapping test
- Hopkins Verbal Learning test – revised (HVLT-R), Learning and Delayed Recall
- Semantic Verbal Fluency test (category fluency)
b. Center for Epidemiologic Studies Depression Scale (CES-D), a tool to screen for depression.
Additionally, to be collected at baseline: Extended demographics, including years of education, occupation, employment status, income, and area of residence (urban or rural)
Primary Objective:To compare the early group with the deferred group for changes in neurocognitive function, as measured by the QNPZ-8 score.
Major Secondary Objectives:
a. To compare the early and deferred ART groups for:
- Changes in QNPZ-8 scores through the first year
- Changes in neurocognitive function, as measured by each of the neuropsychological tests in the QNPZ-8 test battery, through the first year and overall
- Proportions of participants with neurocognitive impairment
- Changes in neurocognitive deficits as measured by the average deficit score (ADS)
- Proportions of participants with depression as measured by the CES-D, and for changes in CES-D scores
b. To compare the early and deferred ART groups for changes in neurocognitive function in subgroups of participants defined by demographics (age, gender, education), geographic location, CD4+ cell count, HIV RNA level, estimated level of CNS penetration of the planned baseline ART regimen, drug classes in the planned baseline ART regimen, level of neurocognitive function at baseline, and other baseline characteristics, and to assess homogeneity of the treatment difference with respect to these baseline characteristics.
c. To determine the association of changes in neurocognitive function with baseline characteristics, including demographics (age, gender, education, occupation, employment status, income, urban or rural area of residence), geographic location, CD4+ cell count, HIV RNA level, perceived general health, estimated level of CNS penetration of the planned baseline ART regimen, drug classes in the planned baseline ART regimen, level of neurocognitive function at baseline, dominant versus non-dominant hand, and others.
d. To determine whether changes in neurocognitive function are associated with CD4+ and HIV RNA levels through follow-up, perceived general health, duration of exposure to certain drug classes, estimated level of CNS penetration of the ART regimen, and other time-varying factors.
e. To study the association of factors measured at baseline with neurocognitive function at baseline. These factors include demographics, geographic location, CD4+ cell count, HIV RNA level, health history, perceived general health, and others.
f. To describe associations between the neuropsychological tests at baseline, and associations between the tests when measuring change in neurocognitive functioning through follow-up.
Study Endpoints and Outcome Measures Neuropsychological Test Battery:The neuropsychological quantitative performance test battery to be used is comprised of eight neuropsychological tests that assess neurocognitive functioning across a range of cognitive abilities, shown in Table 1. Tests are described in more detail below.
Table 1. Neuropsychological Tests
|Attention/speed of information processing
Speed of information processing
|Color Trails 1
WAIS-III Digit Symbol