No benefit on HIV-associated neurocognitive impairment from CNS-penetrating ART

Kirk Taylor, HIV i-Base

A randomised-controlled trial (ACTG5324) of ART intensification for people with HIV-associated neurocognitive impairment (NCI) was published in Clinical Infectious Diseases. 

Dolutegravir (DTG) or maraviroc (MVC) were added to existing ART regimens because they achieve therapeutic levels in cerebrospinal fluid.

Adding DTG+MVC to ART did not lead to global improvement of NCI overall although verbal learning and memory tests showed some benefit.

People living with HIV (n=191) were recruited into the double-blind placebo-controlled study across 24 sites, including the USA, Brazil and South Africa. Participants were randomised 1:1:1 to either dual placebo, DTG + placebo or DTG+MVC and followed over two years. The primary outcome was the change from baseline to week 48 based on the mean of the individual NC test z-scores.

Participant demographics included 21% women, 51% Black, 22% Hispanic and mean age was 54 (SD ±8) years. Baseline viral load was ≤50 copies/mL, mean CD4 count was 703 (±300) cells/mm3 and 30% had a CD4 nadir <100 cell/mm3. Gender identity was not collected. Exclusion criteria included a wide range of factors that could contribute to NCI, including previous depression and current substance use.

Multiple comorbidities included an average of ≥4 conditions (e.g. 39% hypertension, 12% asthma or 12% arthritis). All participants had NCI at baseline and two thirds met the criteria for HIV-associated dementia (HAND).

NCI was assessed at six-month intervals using a battery of neurocognitive tests across six domains and classified according to Frascati criteria. Tests were translated for non-English speaking regions and regular training was given to those administering the tests.

In all arms, total z-score, depressive symptoms, and daily functioning improved over time, with no significant differences between them at week 48 or later in adjusted analyses. This disproved the study hypothesis that NCI was linked to residual HIV replication.

The DTG+MVC arm showed greatest improvement relative to placebo (p=0.01) for verbal learning (z-score 0.53, 95% CI: 0.26 to 0.79) and memory domains (z-score 0.64, 95% CI: 0.24 to 1.04). For all other test domains, changes were similar across all arms and sub-analyses by HAND diagnosis or CD4 nadir were not significant.

CD4 and CD8 cell counts increased in the DTG+MVC arm compared to dual placebo. Over two years mean BMI increased by 0.32 kg/m2 (95% CI: 0.11 to 0.74 kgm2) across all study arms and was not due to DTG use.

Adverse events (n=15) were between grades 1 to 3 and included reduced creatine clearance (n=6) and gastrointestinal disorders (n=5). Virologic failures were reported for participants on the dual placebo (n=4) and DTG+MVC (n=1) arms.


The lack of benefit from adding HIV drugs that cross the blood-brain barrier to ART for people diagnosed with HIV-associated neurocognitive impairment is an unexpected finding that challenges current HIV treatment guidelines.

Even though this is the largest RCT on this issue, the discussion in the paper includes that the study was likely underpowered for some of the results that it reported, including the impact on people with higher scores of NCI impairment.

This study was sponsored by the US NIH.


Letendre SL et al. Antiretroviral therapy intensification for neurocognitive impairment in HIV. 2023 Clinical infectious diseases, ciad265, DOI 10.1093/cid/ciad265. (15 May 2023).

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