Neurological, cardiovascular, visual and neurocognitive performance in pediatric HIV-1- infected patients as compared to healthy controls NOVICE - III a follow up study

The introduction of combination antiretroviral therapy (cART) against human
immunodeficiency virus (HIV) improved the survival rates of effectively treated
children and adolescents living with perinatally acquired HIV (PHIV).
Simultaneously the incidence of severe HIV-associated complications, such as
HIV-related encephalopathy decreased. Despite adequate viral suppression with
cART, literature suggests structural neurologic and developmental cognitive
impairment in PHIV children and adolescents. Longitudinal studies with
long-term follow-up are scarce, but available studies report cerebral structure
abnormalities such white matter hyperintensities (WMH) and lower white matter
(WM) and gray matter (GM) volume on Magnetic Resonance Imaging (MRI) sequences
and cognitive impairment in multiple cognitive domains and school performance.
Longitudinal studies on cognitive impairment imply persistently lower
intelligence quotient (IQ) and impaired executive functioning. In addition, the
earlier NOVICE I and II studies (METC 2012_093 en METC 2016_173) looked at
cardiovascular risk in children and young adults. In adults with HIV, HIV is an
independent risk factor for the development of cardiovascular disease (CVD) and
is associated with a metabolic risk. Studies in children with PHIV may suggest
a possible cardiovascular risk with cardiac abnormalities, endothelial
dysfunction, subclinical vascular disease, increased carotid intima-media
thickness, increased metabolic risk and insulin resistance despite adequate
treatment.
The pathogenesis of comorbidities despite adequate viral suppression is not
fully understood and several MRI, cerebrospinal fluid (CSF) and plasma
biomarkers for immune activation, neuronal injury, endothelial activation and
vascular inflammation have been studied in PHIV children. Hypotheses for
HIV-associated neurological morbidities are HIV induced low-grade ongoing
immune activation and inflammation, early neurological damage prior to
treatment initiation, ongoing viral replication, possible toxic effects of
early cART, endothelial systemic damage related to metabolic syndrome and
possible confounding factors such as socio-economic factors. Hypotheses of
increased CVD risk include vascular inflammation and some cART regimes are
suggested as possible contributors to increased CVD or metabolic risk.
Additionally, HIV related immunological activation and damage of the
gastro-intestinal mucosa is hypothesized to result in an adverse change of the
gut microbiome which could lead to systemic leukocyte activation, increased
inflammatory proteins, ongoing inflammation and immune activation.

This study is a follow-up study of the NOVICE I & NOVICE II (METC 2012_093
and METC 2016_173). The objective of the study is to both cross-sectionally and
longitudinally, after an interval of 10 years, gain more insight into the
presence, severity and development of cerebral damage, cognitive impairment and
cardiovascular risks in children with perinatally acquired HIV (PHIV) with
adequate treatment compared to HIV-negative controls (matched for age, sex,
ethnicity and socio-economic status). In addition, the study aims to measure
neurological, cognitive and cardiovascular outcomes and investigate
associations using advanced MRI techniques, neurocognitive examination, faecal
microbiome and plasma biomarkers in in children and adolescents with PHIV and
HIV-negative controls. In order to identify HIV-associated comorbidities, in
children and adolescents growing up with PHIV with adequate treatment, and to
improve future monitoring or treatment directions and to further understand the
underlying pathophysiological mechanisms.

The NOVICE III is a longitudinal observational cohort study and in accordance
with previous cohorts of NOVICE I and II (METC 2012_093 en METC 2016_173), all
participants will undergo neuropsychological assessment (NPA), advanced MRI
techniques (MRI, MRS, DTI, ASL) and various clinical and laboratory factors are
measured. In addition, a faecal sample will be obtained. This follow-up study
repeats virtually the same battery of tests as the NOVICE studies cohort I and
II to compare longitudinal data with additional improvement or supplementations
of NPO and MRI, laboratory studies, physical examination and analysis of the
microbiome based on new insights and results of NOVICE I and II studies. CSF
collection or ophthalmic examination will not be performed in this follow-up
study. The current NOVICE case-control cohort will be expanded with new cases
and controls aged 8 - 18 years, as carried out in accordance with the NOVICE I
and II studies.

This study is a follow-up study and observational study in competent
inidividuals both younger than 18 years and older than 18 years, who have been
asked for permission to participate. Like previous NOVICE studies (METC
2012_093 en METC 2016_173), all study participants will undergo a
neurocognitive assessment (NPA), MRI, and venipuncture. In addition, all study
participants will collect fecal swab sample. The test battery consists of
negligible or minimal risk. For the HIV-positive participants, an NPA, MRI and
venipuncture are part of their normal treatment plan. HIV participants will
undergo an additional NPO, MRI and venipuncture. Each blood sample is combined
with regular blood collection as much as possible.
All patients will receive comprehensive information on all tests and will be
enrolled on a voluntary basis. The burden mainly includes time consumption by
children, adolescents and parents, and will be limited where possible by
scheduling combination appointments with outpatient visits for cases. In
addition, the examinations that take place per study participant will be
scheduled for 1 day, in order to limit the load. There will be guidance for
participants through each procedure, by an experienced nurse, researcher
physician, pediatrician and pediatric neuropsychologist. Parents, guardians and
friends or family are allowed to accompany participants at all times, with the
exception of the NPA which is supervised by an experienced pediatric
neuropsychologist. Some of the study participants, who have previously
participated in one of the NOVICE studies, also have experience with the
examinations. In addition, it was decided not to perform ophthalmic examination
or lumbar puncture in this follow-up study (NOVICE III), with duration and risk
being (further) limited.