Presentation by Ruth Hennessy showed a study in a Sydney based HIV clinic.  This demonstrated a higher level of mental health issues, depression, anxiety, suicide, alcohol and IV drug use, social isolation in people who are HIV positive.

It was also found that these client has issues compliance to treatment in general thereby mitigated against optimal care

 Considering this complex association between HIV and mental health illnesses it is suggested that;

-          A multidisciplinary intensive specialist care should be adopted in caring for people with HIV

-          Establishing guidelines for identifying patients who will require extra supports and appropriate referrals will ensure adequate care for people living with HIV

I tried something a little different this afternoon. The conference venue set up a simulcast of all concurrent sessions in a theatre-like venue with six screens displaying the slides from each session. Audio was provided by personal channel-selected headphones, much like the system used in some gymnasiums broadcasting TV audio to users. It was a great way to flick between sessions rather than having to run between rooms. Despite this great technology, the human limitation still applies, and you can only pay attention to one presentation at a time!

The themed discussion afternoon consisted of 4 or 5 short presentations, following by robust discussion with the audience. The session on CNS treatment strategies addressed the issue about HIV and the CNS, in particular the issue of the potential for neurocognitive deficits to persist despite apparent complete viral suppression on ART. This effect is likely due to reservoir seeding to a sequestered site, resulting in ongoing immunogenitic and inflammatory effects of HIV, as discussed at other points at the conference.

The CNS is an early target for HIV. HIV-associated Neurocognitive Disorder (HAND) encompasses the spectrum of disorders related to HIV infection and AIDS, and includes disorders of varying severities. What is known is that early identification and treatment improves HAND, and ART improves established HAND.

A study into whether delays in ART initiation would impair neurocognitive function compared initiation immediately after infection with a 24 week delay. Interestingly, early initiation led to a greater improvement in neurocognitive function over time. The observation has important implications to clinical practice and in discussions with patients about when to start treatment. Early ART initiation may prove to be an important treatment strategy to decrease the severity of HAND or lead to better improvement in HAND.  [TD-380]

The next presentation looked at the cognitive trajectories over 4 years of HIV positive women with optimal viral suppression. There was a lower baseline cognitive function in several neurocognitive domains (attention, learning, memory and global functioning) in the HIV infected group compared with demongraphically similar uninfected women. The difference observered was at least one standard deviation worse across these domains and persisted over time. In the domain of motor skills, where there was no difference at baseline, a decline was observed over the 4 year period.

In comparing women who were virally suppressed with those that were not, in some domains (eg. global function) there was no difference in the measured decline over time. Interestingly, in some domains (eg. attention and fluency) virally suppressed women actually performed worse than non-virally suppressed women.

The difference at baseline may be attributed to co-morbidities such a susbtance use, trauma and psychological risk factors. These, combined with a low cognitive reserve, are hypothesised to be contributing to accelerated CNS ageing.

The vulnerabilities in various neuropsychological domains provides a framework for further study into the pathophysiology of the CNS damage observed. Clinically it is important to understand how co-morbidities in HIV infected individuals may be contributing to the HIV specific effects.  [TD-350]

CCR5 blockade using Maraviroc intensification has been shown to improve cognitive performance in HIV infected adults on ART. CCR5 binds multiple chemokines and is a co-receptor for HIV.

Cenicriviroc (CVC) is an new oral dual CCR2 and CCR5 antagonist. CCR2 is a chemokine receptor for the monocyte chemoattractant MCP-1. Monocytes have been implicated with contributing to HIV-associated Neurocognitive Impairment (HIV NCI). In ART naive HIV infected adults, CVC has been shown to decrease viraemia and soluble CD14 levels (CD14 is a marker for monocyte activation). Additionally, in animal models CVC has been shown to have anti-inflammatory and anti-fibrotic activity.

The pilot study hypothesised that CVC will improve cognitive function in HIV NCI by reducing monocyte activation. The sample cohort was older (average age 55), ART experienced (average 16 years on ART) and had low cognitive performance at baseline. Depression was an exclusion criterion. Neuropsychological testing was conducted at entry and at 24 weeks, along with plasma markers of monocyte activation (neopterin, soluble CD14 and sCD163).

The study observed that CVC intensification improved global cognitive performance, along with specific improvements in the neurospsychological subdomains of working memory and attention. There was a positive trend seen in the domains of psychomotor speed and visuospatial. Monocyte activation was significantly decreased with all three markers measured, with a trend seen between neopterin and working memory scores.

Although only a small study (17 participants) the results are certainly promising. Even in virally suppressed, ART experienced individuals, the measured improvements in cognitive function at 24 weeks suggests that HIV NCI may be treatable. Additionally, neopterin may be a predictor of improvement in working memory. A larger randomised control trial in HIV infected people with cognitive abnormalities is required to explore these effects further.  [TD-381]

Serena Spudich presented information about HIV infection causing ongoing active injury to the central nervous system (CNS) - comprising the brain, meninges and cerebrospinal fluid (CSF) - despite antiretroviral therapy (ART). Abstract #66

CNS injury can be measured by:

- Neurocognitive testing: persistent milder forms of HIV associated neurocognitive disorder (HAND) can be demonstrated in 18-50% of individuals on ART.

- Inflammatory biomarkers: examination of CSF shows elevated levels of neurofilament light chain (NFL) which is a marker for axonal injury marker

- Neuroimaging: structural or functional imaging shows persistent abnormalities of HIV positive individuals on treatment.

The mechanism of CNS injury is unknown, but is likely multifactorial:

- CNS injury prior to treatment. HIV is brought into the brain by infected lymphocytes (and perhaps infected monocytes) in the setting of immune activation. The viral load of CNS HIV is reflective of the plasma HIV levels in primary infection. Infection of brain cells occurs, with immune activation of microglia and macrophages, leading to breakdown of the blood brain barrier and release of cytokines. This results in axonal death and further HIV infection and mutation in the CNS of susceptible cells.

- Persistent compartmentalised infection. Despite suppressed plasma viral load, researchers can still demonstrate detectable virus in the CSF ("CSF escape"). Active CNS replication of HIV occurs despite apparent peripheral control. HIV in the CNS undergoes distinct evolution, with analysis of CSF showing that CSF HIV is distinct from plasma HIV during suppressive ART.

- Ongoing immune activation. Elevation of inflammatory biomarkers such as neopterin (a derived product of activated monocytes and macrophages in the brain) demonstrate ongoing immune activation.

- Contribution of vascular disease. Vascular immune activation and/or co-morbid risk factors contribute to vascular disease in HIV positive individuals on ART. Higher stroke rates are seen in HIV positive women and younger patients, compared to their HIV negative counterparts.

- Acceleration of normal brain ageing. Normal brain ageing may be accelerated in the setting of HIV and ART, with increased macrophage activation and increased permeability of the blood brain barrier.

- Effect of co-morbidities. Higher rate of cognitive impairment are seen in HIV positive individuals with concurrent depression and substance abuse.

- CNS penetration of antiretrovirals. Antiretroviral medications with higher CNS penetration show lower CSF viral loads, but this may not reduce the risk of CNS disease. 

Additionally, the use of mono/dual therapy may increase risk of CSF escape. Potential neurotoxicity is only seen with particular antiretrovirals such as efavirenz.

Apart from the persistent smouldering immune activation in the CNS compartment, viral latency and integration may be important. HIV-1 DNA can be found in microglial cells, macrophages and astrocytes. Animal models show that by day 4 of primary infection with treatment, SIV RNA is no longer found in CSF, but SIV DNA can be demonstrated.

In the future there may be the ability to block HIV entry into CNS during primary infection. While the exact reasons for CNS perturbations is unknown, and likely multifactorial, there is plenty of opportunity for further research.

It's official: there has been an HIV Neurology spring uprising in Seattle. This conference saw over 60 posters, two themed discussions, an oral abstract session and a presentation on HIV neurology in the closing clinical session- all devoted to HIV neurology. Early CNS infection, screening for HAND, Aging and neurocognitive impairment, identifying biomarkers in plasma and CSF for HAND diagnosis, neuroimaging studies and HAND in longterm virologically suppressed populations were the key themes. The two leading topics in HIV neurology at the moment are (1) whether high CNS penetrating regimens are superior to low penetrating regimens for patients with HAND and (2) whether asymptomatic neurocognitive impairment (ANI) leads to more severe symptomatic HAND. The latter was in a presentation from the CHARTER group (Poster 77) wherein patients with ANI and the symptomatic minor neurocognitive disorder (MND) were likelier to have neurocognitive decline over 36 months than neurocognitively normal controls. Not all patients with ANI/MND were virologically suppressed. Given that ANI is the commonest form of HAND in our populations, if it is shown to lead to MND or HIV dementia this will be a finding of import at a patient and population health level. Abstracts came from a number of groups including Alan Winston's group at Imperial College London, Johns Hopkins, (Justin McArthur) the CHARTER group, the Belgian group led by Bernard Du Pasquier, Serena Spudich's group at Yale, Richard Price from UCSF, Magnus Gisslen from Gothenberg, Beau Ance's group from Washington University, Lucette Cysique and Bruce Brew from Sydney, UNSW, Victor Valcour (UCSF) and Brad Navia from Tufts. It was an enjoyable meeting but, as always, too much to take in at once- hence jump onto the CROI website and watch some of the presentations and search for the abstracts also. Signing off for now.

Today was a good day for HIV Neurology with a themed discussion on advances in diagnosis and management of cryptococcal meningitis (Session 15). This included a review by Rolfes et al of the concordance between a new point-of-care assay for plasma- the lateral flow assay- and serum /CSF cryptococcal antigen and CSF culture. Overall the concordance was high - hence important early findings for a test that should prove promising in resource limited settings (Abstract 953).

Another presentation by Chang et al revealed that achieving CSF sterility prior to commencement of cART was significantly associated with decreased risk of neurological deterioration and decreased risk of mycological persistence or relapse at 24 weeks of cART therapy (Abstract 955). These data are important because cryptococcal meningitis remains a common AIDS illness in resource poor settings and because cryptococcal IRIS is a relatively common sequelae when cART is introduced. Lots of excellent posters today also with an emphasis on findings in early HIV infection.

Tomorrow we see sessions on ageing and neurocognitive impairment and on the natural history, markers and treatment of HIV neurological disease. Goodnight!