Discussion
neuronal damage, HAND and neurodegenerative dementias, Tau, inflammation, fibrosis, tau-mediated neurodegeneration, traumatic, neurotoxicity, HAND, neurocognitive impairment, axonal damage, neurotoxic, Thomas, depressive disorders
INFLAMMATION, DISEASE, FIBROSIS, DYSFUNCTION, HEPATIC FIBROSIS, NEUROLOGICAL DISORDERS
We observed that six months after switching to a less neurotoxic regimen, participants in the intervention arm had higher CSF levels of neopterin and NFL, no changes in IMT and lipid profile, and a modest improvement in liver function tests and fibrosis scores (in comparison to participants remaining on previous regimen). Our hypothesis was that switching towards drugs that had a lower in vitro neurotoxicity would be associated with better cognitive function in patients with HAND as well as an improvement in biomarkers of neuronal damage. Yet robust evidence of an in vivo neuronal protection is lacking as well as the effect on lipid profile, cardiovascular risk and liver function tests given the use of boosted darunavir, maraviroc and emtricitabine (a triple combination seldom used in clinical practice as well as in medical literature). While the results of the primary objective (neurocognition) have been submitted for publication the other endpoints were mostly exploratory and the sample size was, unfortunately, very small.HAND is a complex phenotype and the path towards effective treatments relies on the identification of pathogenetic mechanisms and reliable biomarkers. We included IMT, lipid, liver scores, and CSF markers in order to understand the potential underlying mechanisms (and response to treatment change) of vascular, hepatic and neurological factors in the neurocognitive impairment observed in PLWH (Msoka et al. CSF biomarkers that reflect processes within the brain constitute an important complementary approach to evaluate ongoing CNS disease. In our study, considering the similar cognitive profiles between HAND and neurodegenerative dementias, Tau, pTau, s100b, beta40, beta42, NFL and neopterin were evaluated, as well as CSF proteins, glucose and cells.From the literature, we know that neopterin is an early marker of intrathecal immune response, whose CSF levels are elevated in most HIV subjects compared to uninfected individuals: recent studies showed an elevated neopterin levels in patients with HAND (Edén et al. NFL is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. One of its main roles is to maintain axonal caliber and facilitate effective nerve conduction; its level increase in CSF and plasma proportionally to the degree of axonal damage in many neurological disorders, including inflammatory, neurodegenerative, traumatic and cerebrovascular (Mielke et al. Tau protein is abundant in the central nervous system and involved in microtubule assembly and stabilization. It is predominantly associated with axonal microtubules and present at lower level in dendrites where it is engaged in signaling functions. Tau it is generally phosphorylated (ptau) during its physiological functioning. Generally speaking, increased phosphorylation results in decreased binding to microtubules which is important in tau-mediated neurodegeneration. Tau protein is also involved in blood–brain barrier dysfunction that was described in numerous neurological conditions and possibly play such role in infectious pathologies of the CNS (Mietelska-Porowska et al. Besides cellular damage and pathway alterations we explored vascular and liver involvement and changes with treatment modifications. When it comes to peripheral markers and non-invasive tool, we observed that IMT did not vary significantly over time. This may be of no surprise, as typically IMT variation may take more time and present alterations later than the 24 weeks study period herein considered. Yet the use of maraviroc was potentially beneficial. It had been associated with significant reduction in IMT, pulse wave velocity and triglycerides, and to have additional cardiovascular and neuroprotective characteristics that may have played a role in this study but were not readily measurable (Piconi et al. Finally we explored whether changes in treatment regimen could be beneficial for liver involvement as measured by non-invasive biomarker of liver function. The hypothesis was a link between liver and brain function, involving the gut-brain axis and macrophage functions in systemic inflammation. (Thomas and Apovain Notably, the chemokine CCL5/RANTES, which acts as the ligand for CCR5, plays a crucial role in hepatic inflammation and fibrosis. CCR5 facilitates interactions among intrahepatic immune cells, promoting activation and migration of Kupffer cells and hepatic stellate cells, which, in turn, trigger inflammation and hepatic fibrosis. Consequently, inhibiting this pathway could potentially reduce the progression of fibrosis (Bradshaw et al. Putting these observations together, we should highlight the importance of following-up patients comprehensively with easy-to-use, informative and reproducible non-invasive tools that may provide important information on the patient’s status.Several limitations should be recognized. It should be emphasised that the number of patients in both intervention and control arm is small, hence more data may be required from bigger study population observed over longer time to detect additional differences. Population was also heterogenous, as many of the enrolled subjects had comorbidities, in particular some suffered from depressive disorders (Hammond et al. However, this study also has strengths: our cohort had demographic characteristics similar to other modern study groups and our results could therefore be extended to minimally confounded PLWH diagnosed with HAND. It is the first real life project on HAND coupling a non-invasive and invasive tools for the evaluation of neurocognitive field, with other classical non-invasive tool such as IMT and Fibroscan that have been largely validated across cohorts (Msoka et al. 