Phase II study to evaluate the efficacy and safety of baricitinib for reduction of HIV-1 in the central nervous system

HIV-1 infection is controllable with antiretroviral therapy (ART); however, HIV-1 cure remains elusive. Despite ART, people with HIV-1 (PWH) face increased morbidity and mortality, requiring long-term treatment. A growing body of evidence demonstrates the central nervous system (CNS) is an HIV-1 reservoir representing a barrier to HIV-1 eradication. HIV-1 DNA is found in brain tissue from PWH on suppressive ART, with multiple reports of CNS virologic escape. Despite suppressive ART, HIV-1 RNA and anti-HIV-1 antibodies have been detected in cerebrospinal fluid (CSF). We have performed extensive preclinical and clinical work on the Janus kinase (Jak) 1/2 inhibitor drug class to target HIV-1, including baricitinib, an FDA-approved treatment for acute COVID-19, rheumatoid arthritis, and alopecia areata. Our studies with Jak 1/2 inhibitors demonstrate inhibition of (1) HIV-1 replication, (2) HIV-1-induced activation and infection in the CNS, and (3) reservoir lifespan, size, and reactivation. Peripheral administration of baricitinib decreased CNS HIV-1 burden, markers of HIV-1 persistence, and reversed behavioral abnormalities associated with HIV-1-induced inflammation in a murine model of CNS HIV-1 infection. Here, we describe our phase IIa trial of baricitinib to decrease the HIV-1 CNS reservoir in PWH exhibiting durable virologic suppression on ART. This is a phase IIa randomized, double-blind, placebo-controlled trial in individuals aged 18–64 years with well-controlled HIV-1 receiving ART. The study will randomize 64 participants to receive oral baricitinib 2 mg/day or placebo for 10 weeks. The primary outcome is change in HIV-1 CNS reservoir. Secondary outcomes include inflammatory quantifications (neuroimaging, blood, and CSF) and neuropsychological performance. Our primary hypothesis is that individuals receiving baricitinib will be more likely to achieve a change in CSF integrated proviral DNA (IPDA). Secondary hypotheses include baricitinib treatment will be associated with a significant decrease in other markers of HIV-1 CNS persistence (CSF cell-associated viral DNA, CSF viral RNA, CSF HIV-1 Tat, CSF and blood markers of inflammation, and magnetic resonance imaging markers). Additionally, we hypothesize baricitinib treatment will improve neurocognitive performance, depressive symptoms, and neuronal damage markers. We expect this study will provide strong rationale for inclusion of baricitinib in future trials targeting eradication of HIV-1. The trial was registered at ClinicalTrials.gov NCT05452564 on 06 July 2022 at URL https://clinicaltrials.gov/study/NCT05452564 .