HIV infection in the brain: a long-term limitation of HAART?
Simon Collins, HIV i-Base
The recent focus on the impact of unsuppressed viral replication in the SMART and other studies, has lead to emerging concerns that overlap the issues of aging, cardiovascular health, bone disease and higher rates of some cancers. For the last three years at CROI, neurological function has expanded from the previous single lectures to full plenary sessions. This year provided perhaps the most compelling and concerning results yet from many different research approaches.
While many discussions on HIV in the brain focus on viral replication, cell activation was highlighted in pre-meeting lectures as more important than viral replication in terms of disease. Current understanding of the pathogenesis of HIV infection in the brain starts with infected monocytes (CD16+/CD14+ indicating a degree of activation) that cross the blood-brain barrier and are more prone to infecting endogenous tissues in the brain such as microglia etc. It is the process of activation of either infected cells or bystander cells that leads to the production of viral proteins, excitatory amino acids, cytokines and free radicals which lead to the death of neurons. The degree of inflammation appears out of proportion to the amount of virus in the brain. 
However, cerebrospinal fluid (CSF) viral load and drug penetration are also clearly an important factor in most studies looking at neurological function and HIV disease.
High plasma levels of LPS (another key area of recent research arising from early and rapid depletion of CD4 cells in the gut mucosa, see further HTB CROI reports) and soluble CD14 have also been associated with higher rates of HIV-associated dementia, linking ongoing immune activation to neurological complications. 
An oral session on Monday, available as a webcast, included an important and diverse collection of studies on HIV and cognitive function. 
Igor Grant presented an update from the Charter study, aspects of which have been presented at earlier CROI meetings. This is a cohort study of 1555 patients at six sites initiated in 2002 by the US NIH to look at neurological complications and biomarkers relating to neuropathy and neurocognitive impairment (NCI) that are still prevalent despite HAART. 
The group broadly represents the US HIV demographics. About one-fifth of the group are women, half are African-American and 40% non-Hispanic White. A quarter of the patients were infected through drug use and 60% are gay men. Mean age at enrolment was 43 (+/-8) and median CD4 count and nadir were 420 (IQR 256-603 cells/mm3) and 174 (49-300 cells/mm3) respectively. Most patients had other health issues that could contribute to impairment, but these were minimal for around half the patients and severe in only 15%. Prior AIDS was diagnosed in around 60% and 26% were coinfected with HCV.
Approximately 70% of patients were on HAART, with 15% treatment-naive, another 15% having interrupted treatment.
Viral load was suppressed to <50 copies/mL, in 60% plasma samples and 34% of CSF. Although 5% of the patients had greater CSF levels than plasma, less than 1% of patients with undetectable virus in blood had detectable viral load in CSF (mean 235 copies/mL). Notably, approximately 40% of 300 patients with an undetectable viral load using the <50 test, had detectable CSF viral load using a more sensitive (<2 copy/mL) test. Detectable CSF viral load was associated with both assumed CNS penetration of the HAART regimen used and a greater likelihood of cognitive impairment in terms of lower CPE scores (d=0.25; p<0.03).
Based on a panel of tests, NCI was found in just under half the group and the rates were higher when other factors were present. For example, the highest rate of NCI (80%) was in the 15% patients with severe cofactors. Rates were higher in patients with more severe HIV-infection and whose CD4 counts had dropped the lowest before treatment.
Compared to pre-HAART cohort data, HAART has not reduced patterns of impairment. These cross-sectional baseline results are important, but interpretation is limited because viral load results were not categorised by treatment use, because of the high rate of co-morbidity, and the lack of a matched HIV-negative control group. When looking at the 843 patients in the group not confounded by co-morbidity factors, CD4 nadir <200 cells/mm3 and unsuppressed viraemia were associated with significantly higher rates of NCI. Imaging on a sub group of these patients found a 30% incidence of abnormal changes (either reductions in white matter or cortical grey matter or an increase presence of abnormal white matter), and that these had at least a modest relationship with cognitive function.
Even though exact prevalence of NCI may be debated, there seems consensus that rates are higher than they should be and this was supported by other groups.
Fabrice Bonnet presented results from the ANRS Aquitaine cohort, suggesting that 25% adults with well-controlled HIV-infection had a mild cognitive disorder, and that this compared to a rate of 6% in an elder French general population (age 65 years or older). 
Matteo Vassallo, presenting data from the prospective French Nueradapt study, found only 30% of patients to have normal function scores, again, only explained by co-morbidity factors in a perhaps half of these patients (mainly relating the HCV coinfection and use of antidepressants). 
The Charter study has taken five years to enrol and the results presented this year were from a single time-point when patients joined the study. The group will now follow patients to track brain function and changes over time.
Three other presentations from Charter were also present at CROI.
In abstract 702, Best and colleagues reported that both efavirenz and FTC concentrations consistently exceed wild-type IC50 in CSF.  This has implications for earlier studies looking at CSF penetration scores, including from the Charter group who previously evaluated both drugs as having only intermediate penetration based on IC50 concentrations.  More importantly, it has implications for how CSF penetration is interpreted for the current first-line regimens. Roland Ellis and colleagues reported that despite HAART, and reduced use of d-drugs, HIV Distal Sensory Peripheral Neuropathy (DSPN) was present in almost 60% of the Charter cohort.
Finally, also controversially, Desiree Byrd and colleagues reported in abstract 478 that current or historical substance use (IDU, cocaine, methamphetamine) was not associated with compromised neuropsychological function at baseline when important co-factors were considered, suggesting that historic substance use and acute stimulant use do not require special consideration in cross-sectional analyses of neuropsychological function in neuro-AIDS research. 
The oral symposium, included several other studies looking at brain function, contributing to a compelling focus on overlapping issues of aging. A study from Ian Everall, from the US National NeuroAIDS tissue Consortium, looked at autopsy results from almost 600 people who had died since 1999, many of whom were known to have neurological problems. 
Although only around 100 patients (~18%) had evidence of brain disease that would directly affect brain function (5% with cerebral lymphoma), only 25% of the remaining 500 patients were described as having normal brains. Lowest-ever CD4, not being on treatment, and detectable viral load at death were all associated with higher of this evidence of brain impairment.
Brad Navia and colleagues, from Tufts University and the HIV Neuroimaging Consortium, used Proton Magnetic Resonance Spectroscopy (MRS) to prospectively track changes brain function in 300 asymptomatic patients whose CD4 nadir was less than 200 cells/mm3 and who had been on treatment for at least a year. Importantly, this study excluded patients with neurological, psychiatric or medical health issues or active drug use. 
Most patients had been HIV-positive for over 12 years with a CD4 nadir of <50 cells/mm3. Median age 47 (30% aged 50-50), 25% non-white, and 50% with an education level <12 years.
When looking at three brain regions, the group found patterns of inflammation (Cho/Cr and MI/Cr metabolite ratios) that were independent of cognitive function suggesting brain injury at all stages of HIV infection and linking decreases in neuronal biomarkers (NAA/Cr metabolite ratio) to patients with reduced cognitive function that are associated with evidence of neuronal damage. Age, lowest ever CD4 count, and detectable CSF viral load suggested a strong effect on the risk for brain injury in the HAART era.
Beau Ances and colleagues from Washington University School of Medicine looked at the relationship between HIV and aging with findings that were particularly sobering for the long-term implications of this area of research. 
HIV infection (for four year or less) in a range of studies has been linked to premature aging by ten years. This group looked at changes in blood flow in the brain (in 26 HIV-positive patients aged 20-62, 58% of who were on HAART and 25 HIV-negative controls) and the response to a panel of tasks that showed an equivalent CNS aging linked to HIV of an additional 15-20 years.
Patients not on HAART had larger functional changes in blood flow and lower baseline blood flow, but no significant differences were found by age (when comparing patients <50 to > 50 years old.
In a graphic used to illustrate these data (as sensitive as the ubiquitous HIV progression train travelling to the site of an impending ravine), both age and HIV were shown to strain a bridge which broke completely when HIV, aging and co-morbidity were combined.
Ances summarised the importance of a multi-disciplinary approach to future research on HIV, aging and brain function, including neuropsychological performance testing, CSF biomarkers (of astrocyte and endothelial dysfunction), and both structural and functional MRI imaging.
Finally, Dulioust and colleagues, confirmed significant NCI in a cross-sectional study group of 37 patients older than 60 in the Neurosigma substudy. 
In this study, people with active neurologic or psychiatric diseases and low educational level were excluded. Patients underwent a brief neuropsychological exam (assessing psychomotor speed, attention, cognitive sequencing, and shifting cognitive sets) in addition to the Mini-Mental State Examination (MMSE), the Geriatric Depression Scale (GDS), and the Instrumental Activity of Daily Living (IADL).
All patients (except one) were on HAART, suppressed to <50 copies/mL: 73% were men; median age was 67 (range 60 to 84 years). Median duration of HIV infection and of ART were respectively 11 (IQR 5 to 17) and 10 (IQR 3 to 14) years. Median nadir and current CD4 count was 113 cells/mm3 (IQR 80 to 239) and 522 cells/mm3 (IQR 443 to 675) respectively.
One or more CVR factors was present in 27 patients (diabetes 27%, hypertension 49%, dyslipidaemia 43%). Neurocognitive impairment was detected in 19 patients (51%). Severe impairment was observed in 11 patients (30%), including 4 with abnormal daily activity. Geriatric depression score was abnormal in 7 patients (19%).
The study again highlighted that these rates were significantly more frequent than in the general aging population, and are also under-diagnosed.
The optimism that durable viral suppression could normalise life expectancy may need to be tempered by emerging data from several fields suggesting increased age-related complications.
In 2009, we are at the time where a potential 20-year impact on advanced aging would expect to show clinical symptoms, as this impact on biological age will have greater significance as people reach their 50s and 60s. Cognitive differences between a 20 and 40 year old, or even a 40 and 60 year old may have little impact on daily activity but is likely to present greater difficulties if a 60 year old patient has brain function of an 80 year old.
The focus on possible earlier physical and mental aging may be something to highlight in prevention messages.
This importance of additional well-funded research is clearly important in both adults and children. Neurological sub-studies are planned in the START and NEAT trials that are both due to start shortly. [15, 16]
This also raises the improtance of a simple NCI assement tool, perhap using motor function, to identify those patients most in need of more detailled follow-up.
Nature also carried an interesting editorial commentary on the use of cognitive-enhancing drugs by the healthy population. 
Unless stated otherwise, all references are to the Programme and Abstracts of the 16th Conference on Retroviruses and Opportunistic Infections. 8-11 February 2009, Montreal. All oral abstracts are available as webcasts. http://www.retroconference.org/2009/data/files/webcast.htm
- Michael Malim. Host restriction factors and viral escape mechanisms . Program Committee Workshop for New Investigators and Trainees (Part 1). Web cast Feb 8, 2009 8:30 AM
- Ancuta P, Kamat A, Kunstman KJ, Kim E-Y, Gabuda D, et al. 2008 Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS ONE 3(6): e2516. doi:10.1371/journal.pone.0002516
- Emerging patterns of neuropathogenesis on current ART. Web cast session Feb 11, 2009 10:00 AM
- Igor Grant. HIV-associated neurocognitive impairment remains prevalent in the era of combination ART: the CHARTER study. Oral abstract 154
- Bonnet F et al. High Prevalence of mild neurocognitive disorders in HIV-infected patients, ANRS CO3 Aquitaine Cohort. Abstract 474.
- Vassallo M et al. Neuradapt: a prospective study concerning HIV-related neurocognitve impairment. Abstract 464.
- Best B et al. Efavirenz and emtricitabine concentrations consistently exceed wild-type IC50 in cerebrospinal fluid: CHARTER findings. Abstract 702.
- Letendre S et al. Better antiretroviral penetration into the central nervous system is associated with lower CSF viral load. 13th CROI, 8 February 2006, Denver. Abstract 74.
- Ellis R et al. Persisting high prevalence of HIV distal sensory peripheral neuropathy in the era of combination ART: correlates in the CHARTER study. Abstract 461.
- Byrd D et al. Substance use and HIV infection: neurocognitive effect, the CHARTER cohort. Abstract 478.
- Everall I et al. The neuro-epidemiology of HIV in the US in the era of ART, from the National NeuroAIDS Tissue Consortium . Oral abstract 155.
- Bradford Navia. Persistence of HIV-related brain injury in the HAART era: a multicenter proton magnetic resonance spectroscopy study . Oral abstract 156.
Cohen R et al. Cortical and subcortical volumes on Magnetic Resonance Imaging associated with HIV history and current disease status. Abstract 480.
- Beau Ances. Additive effects of aging and HIV serostatus on cerebral blood flow. Oral abstract 157.
- Dulioust A et al. High frequency of neurocognitive disorders in older HIV-infected patients despite a sustained virological and immunological response on cART: the Sigma study. Abstract 459.
- INSIGHT Trial Network
- Network on European AIDS Treatment (NEAT)
- Greely H et al. Towardsresponsibleuseofcognitive-enhancing drugs by the healthy. Editorial commentary.Nature456,702-705(11DecemberTowards responsible use of cognitive-enhancing drugs by the healthy. Editorial commentary. Nature 456, 702-705 (11 December 2008) | doi:10.1038/456702a; Published online 10 December 2008