Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells.

Despite the success of combination antiretroviral therapy (cART), HIV persists in long lived latently infected cells in the blood and tissue, and treatment is required lifelong. Recent clinical studies have trialed latency-reversing agents (LRA) as a method to eliminate latently infected cells; however, the effects of LRA on the central nervous system (CNS), a well-known site of virus persistence on cART, are unknown. In this study, we evaluated the toxicity and potency of a panel of commonly used and well-known LRA (panobinostat, romidepsin, vorinostat, chaetocin, disulfiram, hexamethylene bisacetamide [HMBA], and JQ-1) in primary fetal astrocytes (PFA) as well as monocyte-derived macrophages as a cellular model for brain perivascular macrophages. We show that most LRA are non-toxic in these cells at therapeutic concentrations. Additionally, romidepsin, JQ-1, and panobinostat were the most potent at inducing viral transcription, with greater magnitude observed in PFA. In contrast, vorinostat, chaetocin, disulfiram, and HMBA all demonstrated little or no induction of viral transcription. Together, these data suggest that some LRA could potentially activate transcription in latently infected cells in the CNS. We recommend that future trials of LRA also examine the effects of these agents on the CNS via examination of cerebrospinal fluid.

Fluid and electrolyte pathophysiology in common febrile illness in children and the implications for clinical management.

Achieving fluid homeostasis and the management of fluid and electrolyte complications are constants in the treatment of seriously ill children worldwide. Consensus on the most appropriate fluid strategy for unwell children has been difficult to achieve and has evolved over the last two decades, most notably in high-income countries where adverse events relating to poor fluid management were identified more readily, and official robust inquiries were possible. However, this has not been the situation in many low-income settings where fluids that are prohibited from use in high-income countries may be all that are available, local guidelines and processes to recognise adverse events are not developed, and there has been limited training on safe fluid management for front-line healthcare workers. This narrative review outlines the fluid and electrolyte pathophysiology of common febrile illnesses in children, describes the evolution of this field and concludes with implications and principles of a fluid management strategy for seriously ill children. This review was prepared as a physiological background paper to support evidence presented to the WHO Guideline Development Group for Fluid Guidelines in Children, Geneva, March 2024.