Strategy trial of personalized immunomodulatory therapy for HIV-related cryptococcal meningitis

The National Institute of Allergy and Infectious Diseases awarded a cooperative agreement of $331,353 to the Regents of the University of Minnesota on September 2, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855).

The award funds a phase II/III platform trial investigating the efficacy and safety of immunomodulatory therapy for HIV-related cryptococcal meningitis. The research addresses the damage-response immune framework underlying the disease, moving beyond antifungal monotherapy toward personalized treatment strategies that account for individual immune status. Current first-line therapy combining liposomal amphotericin B, flucytosine, and fluconazole yields approximately 15 percent early mortality within 90 days and 25 percent mortality by one year in high-income countries, with substantially worse outcomes globally. The trial hypothesizes that assessing each patient's position on the damage-response immune parabola and addressing their host immune status will improve outcomes beyond what additional antifungal therapy alone can achieve.

Work is performed in Minneapolis, Minnesota. The period of performance runs through August 31, 2031.

Abstract

Fungal infections are a common cause of opportunistic infections (OIS) in immunocompromised individuals. Among the most severe HIV-related OIS is fungal meningitis, with cryptococcal meningitis being the most common cause of adult meningitis in africa, accounting for approximately 19% of HIV-related deaths globally. Incidence in the united states is ~1.1 per 100,000 population with hospitalizations being long and expensive. Current treatment guidelines in both the united states and internationally recommend intravenous (IV) liposomal amphotericin B with oral flucytosine (5FC) and fluconazole. However, even with this first-line therapy, mortality by 10 weeks is ~25% in low- and middle-income settings. Outcomes in high-income countries are similarly suboptimal, with ~15% early mortality within 90 days and ~25% mortality by 1 year. Historically, treatment has focused solely on antifungal therapy, largely ignoring the host immune response due to its complexity and heterogeneity. Emerging human data suggest that the damage-response immune framework underlies HIV-associated cryptococcal meningitis. Today, individuals with HIV and cryptococcosis are more immunologically complex, as half present while receiving antiretroviral therapy, which may or may not be effective for that person. Additional antifungal therapy is unlikely to further improve outcomes, as we have demonstrated that individuals with enhanced CSF early fungicidal activity (i.e., more rapid fungal killing, >0.60 LOG10CFU/ML/day) do not have better survival outcomes than those with more modest CSF clearance rates (e.g. 0.20-0.30 LOG10 CFU/ML/day). To further improve outcomes, we hypothesize that IT is necessary to assess where individuals reside on the damage-response immune parabola and address their host immune status. We propose a phase II/III platform trial to investigate the efficacy and safety of individually customized immunotherapy in HIV-related cryptococcal meningitis. We will conduct a phase II trial (N=40) followed by a phase III trial (N=200 in total in the experimental arm). Treatment effect will be compared against 200 concurrently randomized controls receiving standard of care antifungal therapy alone. Adjunctive immunotherapy will be customized based on pathogen burden and host immune status, addressing type 1 T helper cell (TH1) deficits, TH1 excessive responses, or inappropriate type 2 T helper cell (TH2) responses. Specific aim 1. Validate the damage-response immune framework for HIV-associated cryptococcal meningitis to identify the subgroups with an immunologic contribution to disease. Specific aim 2. Determine if personalized adjunctive immunomodulatory therapy improves clinical outcomes in HIV-associated cryptococcal meningitis in a randomized controlled trial. Impact: we seek to innovate infectious disease clinical medicine by testing personalized immunotherapy tailored to an individual's immune response and pathogen burden in cryptococcal meningitis.