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
- HIV reservoir
- immune activation
- pilot study
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Contributors J-PR, VM, MO, NC, PA and JBA designed the study. J-PR, SI and VM wrote the manuscript. RP, DP, FPD and SI will participate in data collection and analysis. All authors critically reviewed the manuscript and approved the final version.
Funding This study was funded by the Canadian Institutes of Health Research (CIHR) Canadian HIV trials Network (CTN) (CTN PT027 grant to JPR), CIHR (IBC-154053 grant to PA) and by the Canadian HIV Cure Enterprise (CanCURE) (Team Grant HIG-133050 to JPR), awarded by the CIHR in partnership with the Canadian Foundation for AIDS Research (CANFAR) and with the International AIDS Society (IAS). Authors who are CTN and/or CanCURE members were involved in the study design and in the writing of the manuscript, and will also be involved in data collection, analysis and interpretation.
Competing interests J-PR has performed contract research and/or served on Advisory Boards for Gilead Sciences Canada, Merck Canada, Abbvie, ViiV Healthcare, Bristol Myers Squibb, Janssen, Argos Pharmaceuticals from InnaVirVax and has served on the Advisory Board of Theravectys. JBA has performed contract research and/or served on Advisory Boards for Gilead Sciences Canada, Merck Canada, Abbvie, ViiV Healthcare, Bristol Myers Squibb, Janssen and Argos Pharmaceuticals. MO has performed contract research and/or served on Advisory Boards for Gilead Sciences Canada, Merck Canada, Abbvie, ViiV Healthcare, Bristol Myers Squibb and Janssen. NC has received research funding from Merck & Co. and from InnaVirVax and has served on the Advisory Board of Theravectys.
Ethics approval This study was approved by the Research Ethics Boards of the Research Institute of the McGill University Health Centre (MUHC) number MP-37-2016-2456 and by the Health Canada Therapeutic Products Directorate, and will be conducted in accordance with the Declaration of Helsinki of 1975, as revised in 2000.
Provenance and peer review Not commissioned; externally peer reviewed.
Collaborators Group Authorship/Collaborating Author Names: J-PR, SI, VM, MO, NC, PA, RP, DP, FPD and JBA for the Lilac Study Group.
Patient consent for publication Not required.
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