BioProject

Background: Some HIV-1 infected patients are unable to completely recover normal T-CD4+ counts after achieving HIV-1 suppression with combined Antiretroviral Therapy (cART), hence being classified as immunodiscordant. The human microbiome plays a crucial role in maintaining immune homeostasis and is a potential target towards immune reconstitution. Setting: RECOVER (NCT03542786) was a double-blind placebo-controlled clinical trial designed to evaluate if probiotic i3.1 (AB-Biotics, Sant Cugat del Vallès, Spain) consisting on two strains of L.plantarum and one of P.acidilactici, given with (synbiotic) or without a fiber-based prebiotic, was able to improve immune reconstitution in HIV-1 infected immunodiscordant patients with stable cART and CD4+ counts <500 cells/mm3. Methods: 71 patients were randomized 2:2:1 to probiotic, synbiotic or placebo and were followed over 6 months + 3-month washout period, in which we evaluated changes on systemic immune status and gut microbiome. Primary endpoints were safety and tolerability. Secondary endpoints were changes on CD4+ and CD8+ counts, inflammation markers and microbiome structure, defined by alpha diversity (Gene Richness), beta diversity (Bray-Curtis) and functional profile.Comparisons across/within groups were performed using standard/paired Wilcoxon test, respectively. Results: Adverse event (AE) incidence was similar between groups (55%, 33%, and 53% in the synbiotic, probiotic and placebo arms, respectively, the most common being grade 1 digestive AEs: flatulence, bloating and diarrhoea. 2 grade 3 AEs were reported, all in the synbiotic: abdominal distension (possibly related) and cancer (unrelated), and 1 grade 4 AE in the placebo: cancer (unrelated). Synbiotic exposure was associated with a higher increase in CD4/CD8 ratio at 6 months vs baseline (0.77 ± 0.51 vs 0.72 ± 0. 45, median change= 0.04 ± 0.19, p = 0.03). At month 9, the synbiotic group had a higher increase in CD4/CD8 ratio (0.827 ± 0.55 vs 0.825 ± 0.53, median change = 0.04 ± 0.15, p= 0.03), higher CD4 counts (447±157 vs 342±73.2 counts/ml, p = 0.03), and lower sCD14 values (2.16±0.67 vs 3.2±0.8 p = 0.007) relative to placebo. No effect in immune parameters was observed in the probiotic arm. None of the two interventions modified microbial gene richness (alpha diversity). However, intervention as categorical variable was associated with slight but significant effect on Bray-Curtis distance variance (Adonis R2=0.02, p = 0.005). At month 6, probiotic detection in feces was associated with higher decreases in CRP vs baseline (11.1 ± 22 vs 19.2 ± 66, median change= -2.7 ± 13.2 ug/ml ± 13,2 ug/ml, p = 0.03) and lower IL-6 values (0.58±1.13 vs 1.17±1.59 ug/ml, p = 0.03) than non-detection. After washout, probiotic non-detection, conversely, was associated with a higher increase in CD4 (457 ± 153 vs 416 ± 142, median change = 45 ± 75, counts/ml, p = 0.005) and CD4/CD8 ratio (0.67 ± 0.5 vs 0.59 ± 0.49, median change = 0.04 ± 0.18, p = 0.02). Conclusion: A synbiotic intervention with L.plantarum and P.acidilactici was safe and led to small increases in CD4/CD8 ratio and minor reductions in sCD14 of uncertain clinical significance. A probiotic with the same composition was also safe but did not achieve any impact on immune parameters or gut microbiome composition.