As mentioned earlier in this issue of TreatmentUpdate, research strongly suggests that in HIV-positive people fungi and/or fungal products leak across the intestine into the blood. Scientists call this transfer of fungi and/or fungal products from the gut to the blood “fungal translocation.” Once in the blood, these fungi and/or their products, such as beta-D-glucan (BDG), circulate throughout the body and may contribute to the issue of HIV-related excess immune activation and inflammation. This problem is not reduced by taking ART.

Back to the future

Scientists in the U.S. have tested the antifungal drug fluconazole (Diflucan, Diflucan One) in a small placebo-controlled study with HIV-positive people. These people all had problems with memory and thinking clearly (collectively called neurocognitive impairment). Fluconazole did not improve their condition.

However, fluconazole only has a limited spectrum of activity against the fungi that normally live in the gut. Physician-scientist and fungus expert Martin Hoenigl, MD, from the University of California at San Diego suggests that different antifungal agents be tested for their potential to reduce excess HIV-related immune activation and inflammation. In an editorial in the journal Clinical Infectious Diseases, Dr. Hoenigl states that such antifungal drugs should have the following properties:

• “be well tolerated”
• “have a broad spectrum of activity (ideally covering the whole spectrum of BDG-producing fungi [that live] in the human gut, including [species of Aspergillus, Penicillium and Fusarium])”
• “be easy to use in terms of frequency and application”

Although broad-spectrum antifungals such as posaconazole (Posanol, Noxafil) may be considered for future studies of fungal translocation, Dr. Hoenigl noted that emerging antifungal drugs are likely “better tolerated and/or allow for once weekly [dosing].” Such antifungal drugs are currently in phase II or phase III clinical trials and include the following:

• ibrexfungerp
• rezafungin

Fungal translocation is an emerging idea in HIV research and it may take some time before more scientists accept it. The exact cause of the excess immune activation and inflammation seen in HIV-positive people is not clear. Nevertheless, if regulatory authorities in high-income countries eventually license drugs such as ibrexfungerp and rezafungin, it is likely that at least pilot studies on fungal translocation will be done in the future. Although the evidence for fungal translocation is growing, scientists working on interfering with bacterial translocation need to continue their efforts.

Resource

TreatmentUpdate 223

—Sean R. Hosein

REFERENCES:

1. Mehraj V, Ramendra R, Isnard S, et al. Circulating (1→3)-β-D-Glucan is associated with immune activation during HIV infection. Clinical Infectious Diseases. 2019; in press.
2. Hoenigl M. Fungal translocation: A driving force behind the occurrence of non-AIDS events? Clinical Infectious Diseases. 2019; in press.
3. Hoenigl M, Moser C, Funderburg N, et al. Soluble urokinase plasminogen activator receptor (suPAR) is predictive of non-AIDS events during antiretroviral therapy-mediated viral suppression. Clinical Infectious Diseases. 2019; in press.
4. Ramendra R, Isnard S, Mehraj V, et al. Circulating LPS and (1→3)-β-D-Glucan: A folie à deux contributing to HIV-associated immune activation. Frontiers in Immunology. 2019 Mar 18;10:465.
5. Weiner LD, Retuerto M, Hager CL, et al. Fungal translocation is associated with immune activation and systemic inflammation in treated HIV. AIDS Research and Human Retroviruses. 2019 May;35(5):461-472.
6. Sofjan AK, Mitchell A, Shah DN, et al. Rezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapy. Journal of Global Antimicrobial Resistance. 2018 Sep;14:58-64.
7. Larkin EL, Long L, Isham N, et al. A Novel 1,3-Beta-d-Glucan Inhibitor, Ibrexafungerp (formerly SCY-078), shows potent activity in the lower pH Environment of vulvovaginitis. Antimicrobial Agents and Chemotherapy. 2019 Apr 25;63(5).