HIV and damage to the CNS: Difficult to define

There is continuing controversy about the clinical effect of HIV in the brain. This session sought to examine the effects of cART, started early or not, on both the physical health of the brain and mental health of the patients. 

Dr Serena Spudich - HIV-1 persists in CSF cells in half of people on ART

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Background: HIV DNA has been found in the postmortem brain with symptomatic CSF HIV escape from the immune system described in the literature. The frequency at which HIV-1 persists in the CSF is not known.

The nature of CNS HIV persistence is poorly understood, and does it related to neurocognitive disorder?

Key point: It is difficult to assess HIV persistence in CNS - presence in the CSF isn’t enough as it is often not present as HIV-1 RNA. It is obviously difficult to get brain tissue, however the CSF is a window to the CNS at large.

It is possible to check CSF for viral copies, for inflammatory mechanisms as a marker of ongoing HIV-1 presence, and for cells in the CSF for viral infection (HIV DNA - not RNA). Another small study found 62.5% people had HIV DNA detected in cells of CSF.

Objective: To look at frequency of HIV detection in CSF supernatant and cells during suppression with combined antiretroviral therapy (cART). Cross-sectional samples of both peripheral venous blood and CSF were assessed.

Patients were long-term on cART, with high CD8 and low peripheral RNA levels.

Results: IN CSF: Positive for RNA - 4% of samples, Cell-associated RNA - 9%, Cell-associated DNA - 48% (median copies was 2.1 copies / 10^3 which is quite small).

Did not find higher levels of the above in peripheral blood samples.

CSF inflammatory biomarkers were elevated despite long-term cART and suppression through traditional means of monitoring (CD4 + VL in peripheral blood).

Discussion: Just under half of HIV-1 infected people on long term ART have HIV infected cells in CSF but this was independent of peripheral blood sample findings.

Clinical Application: Adding to what we already know about HIV-1 infection and reservoirs, cART is not enough to clear the presence of the virus and associated inflammation in the CNS and other methods of reservoir clearance need to be described. 

Robertson et al, Abstract CROI2018 - shows neurocognitive decline in CSF persistence.

 


Dr Ryan Sanford - Brain volume and cortical thickness in initial infection

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Background: HIV penetrates the CNS soon after initial infection through inflammation and immune activation. Structural changes in the CNS are not well known.

Objective: To map the trajectory of brain volumes and cortical thickness and correlate this with standard biomarkers in the blood (CD4/CD8, VL).

Methods: T1 MRI and lab markers performed at enrolment, 6 weeks and every 6 months after.

Results: MRI - median follow-up was 5 months.

Duration of HIV infection was 3-4 months reinforcing study was performed during early infection.

Longer duration of untreated infection correlates to thinning in the cerebral cortex and volume loss in areas like cerebellum and thalamus.

Brain changes after ART - no longer see brain volume loss or cortical thinning, however frontal and temporal lobe cortex thickness tended to remain stable.

Regarding biomarker influence, the thalamus loses volume with increased CSF RNA, higher CD4/8 trended to less volume loss but all of this was small effect.

Discussion: This research reinforces the assumption that cortical thinning and subcortical volume loss occurs in the untreated HIV-1 infection and continues without cART. Early treatment is important as this data reflects early establishment of CNS structural changes. Neuroimaging may have applications in early HIV infection and disease monitoring, but the clinical significance of this volume loss needs to be better described.

 


Dr Lucette Cysique - HIV and brain atrophic signature in asymptomatic neurocognitive impairment

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Background: MRI based research tells us that HIV related brain damage persists despite viral suppression. Most studies had limitations so the magnitude of atrophy is uncertain and particularly in those with HIV-associated neurocognitive disorders (HAND). One component of HAND is asymptomatic neurocognitive impairment (ANI), whose existence still remains controversial. Some studies assert that ANI - in which there is neurocognitive impairment without impact on daily functioning - is represented in 20% of people with HIV infection.

Objective: To determine the presence and magnitude of brain atrophy in patients with clinically-determined ANI and virally suppressed HIV-1 infection. Demographically comparable HIV negative controls were used.  

Methods: Participants were screened for alcohol and drug abuse and excluded if present. Median duration of HIV infection was 20 years.

T1 MRI used to determine brain volumes, neuropsychiatric testing for cognitive impairment occurred and standard HIV biomarkers were tested.

Results: Those with HIV infection showed subcortical grey and white matter loss but spared cortical thickness compared with the HIV negative controls.

Those with ANI showed territorial volume loss in the white matter compared with controls. 

Discussion: There appears to be a neurobiological basis to ANI with reduced white matter particularly in the frontal territories of the brain, and this was correlated with longer duration of disease. These results raise questions such as whether ANI progresses to clinically significant neurocognitive impairment in HIV-1 infected people and what that burden of disease could look like.

 


Phillip Chan - Longitudinal Cognitive Outcomes After Treatment in Acute HIV Infection

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Background: ART reduced incidence of severe cognitive impairment (CI) but milder forms still persist. Most studies come from chronically infected groups, and it is unknown if cART during acute HIV infection results in reduced cognitive impairment.

Objective: Determine long term cognitive outcomes associated with cART initiated during acute HIV infection. In this study, participants must be commenced on regular cART within 30 days of infection with HIV-1.

Method: Neurocognitive assessments performed to evaluate psychomotor speed, executive function, and fine motor function. Mood level was tested with HADS - hospital anxiety and depression scale.

Biomarkers CD4/CD8 and VL were also tested. >90% of participants were men with a medial age of 26 years.

Results: 26% of participants had CI at baseline, which decreased to 10% at 2 years from diagnosis and 15% at 6 years, which was significant (p=<0.001). Mood scores also improved when compared with controls

Discussion: Early initiation of ART may improve cognitive function and mood, however improvements in mood have been shown to improve cognitive function, though this study reports that the data was adjusted for ‘practice effect’. This, however, does not account for mental state and cognitive impairment related to recent diagnosis (diagnosis was within 1 month at enrolment) and other social factors. However, there is evidence to suggest that earlier detection and effective treatment of HIV-1 has favourable outcomes on mental health and neurocognitive function.

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