Chronic inflammation may contribute to HIV persistence on antiretroviral therapy (ART) through proliferation of infected CD4+ T cells and/or exhaustion of an effective immune response against HIV. Vitamin D3 has been shown to inhibit T cell proliferation and exhaustion in vivo. We sought to determine whether vitamin D3 could inhibit HIV persistence and immune cell activation, differentiation and exhaustion on ART.
In this pilot randomized double-blind placebo-controlled trial, we enrolled participants aged over 18 years living with HIV-1 on ART with plasma HIV RNA < 40 copies/ml for at least 3 years. Participants were randomized to take 10,000 international units vitamin D3 or placebo orally daily for 24 weeks and were followed for a further 12 weeks. The primary outcome was the difference between arms in the mean change in frequency of total HIV DNA within CD4+ T cells from baseline to week 24. Virology was evaluated with mixed effects negative binomial regression models while immunology and 25-hydroxyvitamin D levels were evaluated using mixed effects linear models.
Thirty participants (all cisgender male) were enrolled with 15 assigned to each intervention. There was a 1.15 (95% confidence interval (CI) 0.94 – 1.40) fold difference in the vitamin D3 arm compared to the placebo arm in change in frequency of total HIV DNA from week 0 to week 24 (p = 0.19). However, there was a 1.24 (95% CI 1.01 – 1.51) fold increase (p = 0.039) from week 0 to week 12 and a 0.76 (95% CI 0.62 – 0.94) fold decrease (p = 0.009) from week 0 to week 36 in frequency of total HIV DNA relative to placebo. Decreases in frequencies of effector memory and terminally differentiated CD4+ T cells and increases in frequencies of activated and exhausted CD8+ T cells and activated NK cells were also seen compared to placebo. 25-hydroxyvitamin D levels remained elevated at week 36 relative to placebo.
Frequency of total HIV DNA was not affected by vitamin D3 at week 24 but decreased at week 36 relative to placebo. This could relate to antiproliferative effects of vitamin D3 over time, reducing frequency of more differentiated CD4+ T cell subsets enriched for HIV DNA, and/or to unexpected increases in CD8+ T cell and NK cell activation. Persistently elevated 25-hydroxyvitamin D levels at week 36 likely reflect its long half-life. Larger studies are now required potentially including ART interruption to determine whether vitamin D3 can exert a clinically significant impact on the HIV reservoir.