No difference in neuropsychological test results between early and delayed ART in START substudy

15th EACS graphicMark Mascolini,

Through 3.3 years of follow-up, people randomised to immediate antiretroviral therapy (ART) in the international START trial had neuropsychological (NP) test results similar to people in the delayed-ART arm. [1]

Everyone in this young study group entered the trial with a CD4 count above 500 cells/mm3, and the percentage of time on ART was 93% in the early arm versus 34% in the delayed arm.

START randomised more than 4600 asymptomatic antiretroviral-naive people with a CD4 count above 500 cells/mm3 to either immediate ART or to defer treatment until the CD4 count fell to 350 cells/mm3 or clinical AIDS developed [2].

After three years of follow-up, researchers unblinded the trial when significantly more people in the deferred arm met the composite primary endpoint of any serious AIDS or non-AIDS disease or death from any cause.

A neurology substudy aimed to compare NP test results in the immediate and deferred arms over the course of the study. START investigators proposed that early ART may have a neurocognitive impact because HIV enters the central nervous system (CNS) early in the course of infection, overt CNS disease has been reported during primary HIV infection, and cognitive impairment reaches a high prevalence during chronic infection. On the other hand, ART may be neurotoxic.

Neurology substudy participants completed eight NP tests when entering the study then after 4, 8, and 12 months and annually after that. Researchers standardised test scores to Z scores and figured the average of eight Z scores, or QNPZ-8. The analysis involved 291 people in the early ART arm and 301 in the deferred arm with follow-up data.

The neurology substudy group had a young median age of 34 years (IQR: 27 to 42), and 11% were women. While 47% were white, 16% were Asian, 16% Hispanic, and 15% black. The highest proportion of participants came from Brazil (28%), followed by European countries (17%), Thailand (15%), the United States (15%), Argentina or Chile (14%), and the UK or Australia (11%).

More than half (55%) had at least some college education, and three quarters had a job. The two treatment arms did not differ significantly by any of these measures. Nor did they differ by known duration of HIV infection (median 0.9 year), CD4 count (629), or viral load (about 16,000 copies). Fewer than 1% of participants injected drugs. While 8.3% had a psychiatric diagnosis, 5.2% reported alcohol or substance dependence.

The early ART group spent 93% of follow-up time on treatment, compared with 34% in the deferred arm. Half of deferred arm participants started ART by follow-up year three. Three years after randomisation, the average CD4 count rose by about 200 cells/mm3 in the early ART arm while remaining unchanged in the deferred arm.

Through an average 3.3 years of follow-up, QNPZ-8 rose to similar degrees in the two study arms. Estimated difference between the immediate and deferred arms at the end of follow-up was negligible (–0.01, 95%CI: –0.06 to 0.03, p = 0.63). Statistical adjustment for age, race, sex, education, geographic region, viral load, CD4 count, and CD4/CD8 ratio had little impact on this outcome.

The START team concluded that there is “no overall neurocognitive advantage (or disadvantage) for immediate ART initiation in asymptomatic treatment-naive individuals with high CD4 counts.”

The researchers believe their results suggest low prevalence of early neurocognitive impairment that ART can reverse and low incidence of neurocognitive decline that ART can prevent. At the same time, the young age, good health, and high educational attainment of the study group may explain why early ART had no neurocognitive advantage.


Based on the hypothesis that reducing inflammation associated with untreated HIV might have other clinical benefits, many people expected to seee neurological benefits from earlier use of ART. 

This highlights the importance of prospective randomised data including from START sub-studies for other critical questions relating to HIV management.



  1. Wright E, Grund B, Robertson K, et al. No difference between the effects of immediate versus deferred ART on neuropsychological test performance in HIV-positive adults with CD4+ cell counts above 500 cells/µl: the Strategic Timing of Anti Retroviral Treatment (START) Neurology Substudy. 15th European AIDS Conference, October 21-24, 2015, Barcelona. Abstract PS10/6.
  2. The INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795-807.

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