Introduction: People living with HIV (PLWH) on antiretroviral therapy (ART) do not progress to AIDS. However, they still suffer from an increased risk of inflammation-associated complications. HIV persists in long-lived CD4+ T cells, which form the major viral reservoir. The persistence of this reservoir despite long-term ART is the major hurdle to curing HIV. Importantly, the size of the HIV reservoir is larger in individuals who start ART late in the course of infection and have a low CD4+/CD8+ ratio. HIV reservoir size is also linked to the levels of persistent inflammation on ART. Thus, novel strategies to reduce immune inflammation and improve the host response to control the HIV reservoir would be a valuable addition to current ART. Among the different strategies under investigation is metformin, a widely used antidiabetic drug that was recently shown to modulate T-cell activation and inflammation. Treatment of non-diabetic individuals with metformin controls inflammation by improving glucose metabolism and by regulating intracellular immunometabolic checkpoints such as the adenosin 5 monophosphate activated protein kinase and mammalian target of rapamycin, in association with microbiota modification.
Methods and analysis: 22 PLWH on ART for more than 3 years, at high risk of inflammation or the development of non-AIDS events (low CD4+/CD8+ ratio) will be recruited in a clinical single-arm pilot study. We will test whether supplementing ART with metformin in non-diabetic HIV-infected individuals can reduce the size of the HIV reservoir as determined by various virological assays. The expected outcome of this study is a reduction in both the size of the HIV reservoir and inflammation following the addition of metformin to ART, thus paving the way towards HIV eradication.
Ethics and dissemination: Ethical approval: McGill university Health Centre committee number MP-37-2016-2456. Canadian Canadian Institutes of Health Research/Canadian HIV Trials Network (CTN) protocol CTNPT027. Results will be made available through publication in peer-reviewed journals and through the CTN website.
Trial registration number: NCT02659306.
Keywords: HIV reservoir; immune activation; metformin; pilot study.
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