Recent data suggests that proliferation of latently infected memory CD4+ T cells is essential to the maintenance of the HIV reservoir in individuals who are taking suppressive antiretroviral therapy (ART). Mathematical model projections suggest that curtailing lymphocyte proliferation may accelerate the rate of reservoir clearance. We conducted a clinical trial to test this hypothesis.
We performed a small (n=4), open-label, non-randomized Phase II clinical trial (NCT03262441) to assess the safety and tolerability of 22 months of low-dose mycophenolate mofetil (MMF) in chronically HIV-infected men on suppressive ART. The in vivo anti-proliferative effect of MMF was assessed using a “total antiproliferation test” (TAPT) assay, in which anti-CD3/CD28-stimulated participant T cells are exposed to serum from participants after MMF dosing. The TAPT is reported as percent reduction in proliferation compared to serum/cells taken before the start of the trial. We escalated the MMF dose in those individuals with <80% anti-proliferative effect at peak drug levels (one-hour after dosing). We measured the effect of MMF on levels of total (“total”) and potentially intact (“intact”) HIV proviral DNA at 3-month intervals. HIV proviral DNA was measured with a multiplexed digital droplet PCR assay simultaneously targeting HIV-1gag, env and pol genes.
All participants maintained stable CD4 T cell counts and subset composition, remained suppressed on ART and tolerated MMF. One participant required dose escalation from MMF 500 to 750 mg twice daily to achieve >80% anti-proliferative effect at drug peak. Proliferation inhibition at drug trough pre-dosing was highly variable. No participant met the pre-specified criteria for study continuation at 12 months (0.25 log reduction in total HIV DNA) and MMF was therefore stopped for all participants. Intact HIV DNA levels were undetectable in one participant and remained stable in the remaining participants over one year of MMF (Table).
One year of low-dose MMF was safe and well-tolerated in ART suppressed men but did not lower total or intact HIV proviral DNA levels. The anti-proliferative effect waned during the dosing interval, suggesting that higher doses, or more frequent or extended-release dosing may be necessary to lower the HIV reservoir.