Treatment Strategies for CNS Complications in People with HIV

Presenter

Vasudev R. Rao, M.B.B.S. [M.D.], M.S. 
Division of AIDS Research

Goal

The purpose of this concept is to identify modifiable targets and mechanisms to alleviate clinically relevant central nervous system (CNS) complications and to develop comprehensive validated treatment strategies to improve outcomes in people with HIV. The key goal of the concept is to improve quality of life, reduce symptom severity, and maximize functional capacity in individuals with HIV experiencing adverse CNS outcomes.

Rationale

A significant proportion of individuals living with HIV experience clinically relevant symptomatic CNS complications, which impact their quality of life and functional capacity. Despite extensive research efforts, existing clinical trials that have primarily focused on reducing inflammation and intensifying antiretroviral therapy (ART) have not achieved the anticipated improvements in CNS outcomes. Multifactorial pathogenesis of CNS complications results in significant outcome heterogeneity, making it challenging to identify broadly applicable treatment strategies. This highlights a critical gap and underscores the urgent need for identifying modifiable therapeutic targets and mechanisms in people with HIV experiencing adverse CNS complications. The identification of such targets and mechanisms is essential for the design of novel, effective treatment strategies. By leveraging clinical data-based decision trees, it is feasible to identify patient groups with modifiable targets (treatable traits) that can be precisely engaged through proven targeted interventions. This approach not only ensures a more personalized treatment strategy but also increases the likelihood of achieving meaningful clinical outcomes.

Furthermore, this concept encourages adopting milestone-based go/no-go approaches in treatment strategy design, coupled with iterative testing to validate target engagement and its correlation with observable changes in clinical outcomes ensuring that only promising interventions are advanced through the trial phases. This concept extends NIMH’s experimental therapeutics paradigm to foster development of personalized treatment strategies involving identifying and targeting specific, modifiable factors (treatable traits) contributing to CNS pathogenesis in people with HIV, ultimately improving the brain health outcomes in people with HIV. In conclusion, addressing the multifactorial nature of CNS complications in people with HIV requires a paradigm shift towards identifying patient groups with specific modifiable factors using clinical data-driven methodologies and structured milestone-based trial design.