NATAP/CROI: Probiotics Did Not Succeed in ACTG Study/does not alter inflammation/activation markers

Jules Levin

Probiotic does not alter inflammation/activation markers in group on stable ART    

"Assessing the probiotic effect in treated HIV: results of ACTG A5350"

Conference on Retroviruses and Opportunistic Infections (CROI), March 4-7, 2019, Seattle

Mark Mascolini

Visbiome, a commercially available probiotic, did not affect markers of systemic inflammation or T-cell activation in a randomized AIDS Clinical Trials Group (ACTG) study of people on stable antiretroviral therapy (ART) [1]. The agent had a modest impact on gut microbiome populations.

Containing 8 strains of live bacteria, Visbiome is intended for "dietary management of dysbiosis associated with irritable bowel syndrome, ulcerative colitis, pouchitis, and hepatic encephalopathy." [2] Previous studies of probiotics in people with HIV found drops in CD4 and CD8 cells expressing the cell-activation markers CD38 and HLA-DR, increased Th17 in blood and gut-associated lymphoid tissue (GALT), and increased Th1 subsets in GALT [3-5].

ACTG trial A5350 enrolled 93 adults on stable ART with a viral load below 200 copies and a CD4 count above 200. In a blinded design, researchers randomized 47 participants to add Visbiome ES (extra strength) to ART for 24 weeks and 46 participants to add placebo. The researchers hypothesized that Visbiome would lower systemic levels of sCD14, the T-cell activation marker, along with other inflammation or coagulation markers such as IL-6, IP-10, and D-dimer.

The Visbiome and placebo groups were similar in age (median 51 and 52 years), proportion of women (15% and 13%), proportions of whites (53% and 57%) and blacks (47% and 37%), body mass index (median 27 and 26 kg/m2), CD4 count (702 and 715), and proportion with a viral load below 40 copies (100% and 98%).

Forty-three participants (91%) randomized to Visbiome and 31 (72%) randomized to placebo completed treatment. Two people stopped Visbiome because of adverse events, while 1 stopped placebo for that reason. One person in each study arm had a grade 3 or 4 gastrointestinal disorder. Seventeen taking Visbiome and 8 taking placebo (36% and 19%, P = 0.098) had any adverse event.

In a per protocol analysis change in systemic sCD14 levels did differ significantly between the Visbiome group (+41 through week 25/26, -188 over weeks 25/26-38) and the placebo group (+92 through week 25/26, -232 over weeks 25/26-38) (average differences at those two points -51, P = 0.60, and +44, P = 0.79).

No other biomarker level changed significantly from baseline to week 26 in either study arm, though there was a trend toward higher levels of D-dimer, the coagulation marker, in the Visbiome arm (fold-change through 26 weeks 1.20 versus 0.94 with placebo, mean difference 28%, P = 0.09). Lipid changes through 26 weeks did not differ significantly between study groups. Participants taking Visbiome had a significant drop in HOMA-IR-measured insulin resistance (-1.0 versus +12.4 with placebo, P = 0.045).

CD4 count and CD4/CD8 ratio did not change significantly in either group or differ between groups. Nor did the groups differ in changes in levels of activated (CD38+/HLA-DR+) CD4 or CD8 cells. Gut microbiome changes measured by the Shannon diversity index and the Chao1 richness index did not differ significantly between groups, but fold-change in Gammaproteobacteria significantly favored the Visbiome arm (-77% difference from placebo, P = 0.04).

The ACTG investigators concluded that Visbiome is safe and well tolerated but failed to change markers of systemic inflammation or T-cell activation. They suggested 5 reasons for failure to see a probiotic effect in this trial: (1) Wrong target (dysbiosis may be a consequence of HIV-related disease rather than a cause, or endpoints may not be directly altered by the microbiome), (2) the study population was too healthy, (3) lack of engraftment, (4) inadequate dosing or adherence, or (5) other confounders, such as diet or obesity.

1. Overton ET, Yeh E, Presti R, et al. Assessing the probiotic effect in treated HIV: results of ACTG A5350. Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2019. Seattle. Abstract 35.
2. Visbiome high potency probiotic.
3. Scheri GC, Fard SN, Schietroma I, et al. Modulation of tryptophan/serotonin pathway by probiotic supplementation in human immunodeficiency virus-positive patients: preliminary results of a new study approach. Int J Tryptophan Res. 2017;10:1178646917710668. doi: 10.1177/1178646917710668.
4. d'Ettorre G, Rossi G, Scagnolari C, et al. Probiotic supplementation promotes a reduction in T-cell activation, an increase in Th17 frequencies, and a recovery of intestinal epithelium integrity and mitochondrial morphology in ART-treated HIV-1-positive patients. Immun Inflamm Dis. 2017;5:244-260.
5. d'Ettorre G, Ceccarelli G, Giustini N, et al. Probiotics reduce inflammation in antiretroviral treated, HIV-infected individuals: results of the "probio-HIV" clinical trial. PLoS One. 2015;10:e0137200.

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