Julia Rose Palmucci, PhD
Nominated From: University of Minnesota
Research Site: Makerere University
Research Area: HIV, nutrition, cryptococcal meningitis
Primary Mentor: Dr. David Boulware
Research Project
Ketogenic dietary intervention as an adjunctive therapy in the standard treatment of HIV-associated cryptococcal meningitis: sub-study of the PLATFORM-CM clinical trial
Cryptococcal meningitis is a life-threatening HIV-associated opportunistic fungal infection, and is the most common cause of adult meningitis in Africa, with over 99% of cases in Africa co-occurring with HIV. Standard antifungal treatment strategies result in a 10-week mortality of 25%. This project aims to investigate the efficacy of a ketogenic diet as an adjunctive therapy to standard induction treatment for cryptococcal meningitis in persons with HIV. Building upon the clinical evidence that a ketogenic diet can improve cognition in individuals with HIV-associated cognitive impairments and preclinical evidence that suggest a ketogenic diet can enhance antifungal efficacy and modulate the host immune response during infection, we propose a sub-study within the Platform Trial For Cryptococcal Meningitis (PLATFORM-CM). This prospective, open-label, randomized trial will evaluate a 3:1 ketogenic diet (comprising of 75% fats and 5% carbohydrates) or a standard, carbohydrate-intensive nutritional formula in combination with induction therapy consisting of intravenous amphotericin B, flucytosine, and an azole antifungal. We will evaluate the early fungicidal activity of each treatment regimen through quantitative Cryptococcus cerebrospinal fluid cultures over two weeks. Secondary objectives include evaluating the impact of a ketogenic diet on patient immune response including paradoxical immune reconstitution inflammatory syndrome (IRIS) and culture-positive relapse, antifungal pharmacokinetics, and incidence of seizures. We will assess the interaction of ketogenic diet and HIV antiretroviral therapy by evaluating differences in outcomes among those who were not receiving HIV therapy, receiving ineffective HIV therapy with virologic failure, and receiving effective HIV therapy at baseline. This study may provide a foundation for exploring dietary interventions for the management of invasive fungal infections, addressing a critical need for accessible and effective treatment strategies for individuals with HIV in resource-limited healthcare settings.
Research Significance
Cryptococcal meningitis is a global public health issue that causes 19% of AIDS-related deaths globally. In Africa, over 99% of persons with cryptococcal meningitis are living with HIV. The United States has several thousand recognized cases of cryptococcosis each year, and the population at risk of developing opportunistic fungal infections like cryptococcosis is increasing given the expansion of immune-modulating therapies for cancer and autoimmune disorders. This study may present a significant adjunctive therapy for HIV-associated cryptococcal meningitis in resource-limited healthcare settings, and a novel strategy for enhancing antifungal drug efficacy. Mortality in HIV-related cryptococcosis remains around 25% with optimal therapy, and patients may experience significant morbidity due to neurocognitive defects after infection. This study would emphasize the need for future investigation into dietary or nutritional effects in cryptococcal infection outcome. While there are currently several novel antifungal drugs in development, there is a pressing need for highly-accessible strategies for treating invasive fungal infections. Improving antifungal efficacy with a dietary intervention represents a sustainable intervention in resource-limited settings. Additionally, these results may also inform therapeutic strategies for other invasive fungal infections that are treated with azoles.
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