Neurological, visual and neurocognitive performance in perinatally HIV-1- infected patients as compared to healthy controls.*
NOVICE II Follow up study

Since HIV-infected children are being treated with cART, the incidence of
HIV-encephalopathy has decreased while in the meantime neuro-imaging
abnormalities shown by these conventional neuroimaging techniques have improved
(Patel, 2007). Children can present with other neurologic disorders such as
seizures, headaches and neurocognitive impairments (e.g. learning-,
behavioural-, and motor deficits) (Chiriboga, 2005). The etiology of this
neurocognitive impairment is complex and, most likely, not purely biologically
determined. Environmental factors, such as home environment and socioeconomic
status (SES), may play a confounding role in cognitive development. In our
patient group, the SES is generally lower than in the average population.

As we have recently shown in the NOVICE case-control cohort in 2013,
manifestations of HIV in the pediatric central nervous system (CNS) include
reduced neurocognitive functioning (Cohen, CID, 2015), brain volume reduction
and white matter lesions, as well as widespread microstructural changes, such
as poorer white matter integrity (Cohen, Neurology, 2016) and alterations in
cerebral metabolites (Blokhuis, Medicine 2016). Evidence implies significant
roles for ongoing neuroinflammation, vascular dysfunction and
hypercoagulability. Investigations combining neuropsychological assessment,
multimodal neuroimaging and laboratory evaluation of inflammatory and
neurodegenerative markers could greatly increase our understanding and improve
treatment strategies. Longitudinal research will be crucial to observe and
understand mechanisms underlying these long-term consequences of CNS exposure
to HIV and cART as PHIV-infected survive into adulthood. In this study we will
evaluate neurological and cognitive outcomes in the NOVICE case-control cohort
which consists of PHIV infected children and sex, ethnicity and socioeconomic
status matched healthy controls at an interval period of four years. We will
investigate potential mechanisms and factors (such as inflammatory and neuronal
biomarkers) that may influence these longitudinal CNS functions. There is an
unmet need to longitudinally evaluate neurological, neuroimaging results with
neuropsychological performances in the perinatally hiv infected (pediatric) hiv
population as compared to matched healthy controls and to our knowledge this
NOVICE follow up study is the first study that will address these issues.
With this study, we will compare for the first time neurological,
neurocognitive outcomes with neuroradiological alterations and cART levels in
CSF and blood while monitoring immune responses (i.e inflammatory, coagulation,
endothelial cell activation and neural damage markers) in CSF and blood in
perinatally HIV- infected children in a longitudinal setting after an interval
of 4 years.
With this study we will be able to demonstrate alterations in the severity and
nature of cerebral injury of perinatally HIV-infected children and alterations
in underlying mechanisms. The results of this study may have direct
implications on the pediatric hiv patient care. Guidelines advice on when to
start with cART during childhood and what cART should be used based on
international data of clinical data and systemic virological and immunological
markers. The results of this proposed study may imply that we may need to start
treating asymptomatic hiv-infected children at an earlier time point in life
using those drug regimens that are most optimal for neurological and
neurocognitive outcomes of perinatally HIV-infected children.
Additionally we may find that we need to investigate other compartments in the
body (than blood alone) of the perinatally HIV- infected children in order to
monitor optimal treatment of these children.

To increase insight in cerebral injury of perinatally HIV-infected children by
comparing neurological, ophtalmological and neurocognitive outcomes to those of
matched controls (with respect to age, sex, ethnic background, home environment
and socio-economic status) in a longitudinal setting after an interval period
of four years and to increase insight in underlying mechanisms associated with
these cerebral insults.

An longitudinal observational case-control study in which all participants will
undergo neuropsychological tests (NPA), advanced MRI techniques (MRS, DTI,
ASL), and ophthalmological investigation (optical coherence tomography; OCT).
In addition, several clinical and laboratory factors will be measured. This is
a second assessment of the same battery of tests the same NOVICE case-control
cohort will undergo after an interval of four years. The existing NOVICE case
control cohort will be enlarged with new cases and controls that have reached
the age of eight years.

This study is classified as an observational study in subjects that are
competent (older than 18 years of age) and incompetent (younger than 18 years
of age) to give informed consent. HIV positive study participants undergo NPA,
MRI, LP and venous blood sampling as part of their normal treatment plan. For
this study, HIV positive study participants will undergo one additional NPA,
MRI and LP, and one ophthalmological examination. Any venous blood sampling
will as much as possible be combined with standard blood sampling.
All patients are given extensive information on all tests and will be included
on voluntary basis.
During all procedures we will guarantee guidance from research staff for all
participants. Parents/guardians can join their child at all times except the
NPA, which will be taken by an experienced pediatric neuropsychologist will
guide the participant.
Our research question is group related. To understand the pathophysiology of
neurocognitive deficits still found in HIV positive children (in the era of
cART) we need to evaluate patients at an age as early as possible, without the
confounding factors of general aging. We need the control group to minimize
confounding effects of sex, age, ethnic background, home environment and
socioeconomic status.
By accomplishing this study, we may be able to diagnose neurological and
neurocognitive disorders at an early stage in HIV positive patients. The
patients may benefit from close monitoring, and in the future early
intervention could improve their general development. Former case-controlled
pediatric neuro-imaging studies have obtained medical ethical approval and have
produced satisfying results (Aukema, Int J Rad Onc 2009; Cohen, CID, 2015;
Demirkaya , IOVS 2015; Cohen, AIDS Care. 2015; Cohen Neurology, 2016; van
Dalen, Medicine, 2016; Blokhuis, IOVS 2016).
This NOVICE II follow up study is granted by the AIDSfonds, further indicating
the importance of this study and the need for longitudinal observations of
perinatally HIV-infected children that grow (or have grown) into adulthood. The
Dutch patient participation group HIV Vereniging Nederland fully supports this
study.