Table 3.
Differential effects of ARV drugs on the gut microbiome: summary of the main findings
| Nowak et al. [29] | Pinto-Cardoso et al., 2017 [30▪▪] | Villanueva-Millán et al. [31▪▪] | |
| Type of cohort | Longitudinal | Cross-sectional | Cross-sectional |
| Sampling | Feces and blood (plasma) | Feces and blood (plasma) | Feces and blood (plasma and serum) |
| Cohort | 28 viremic HIV+ with pVL3 elite controllers9 HIV- controls | 33 HIV+ on ART10 HIV- controls | 45 HIV+ on ART5 untreated HIV+21 HIV- controls |
| Type of ART combinations and number of individuals (number per group) | NNRTIs with NRTIs (n = 8)RTV-protease inhibitors with NRTIs (n = 11) | NNRTIs with NRTIs (n = 18)RTV-protease inhibitors with NRTIs (n = 15) | NNRTIs with NRTIs (n = 22)Protease inhibitors with NRTIs (n = 15)INSTIs with NRTIs (n = 8) |
| Time on ART | 10 months | 5 years | 13 years |
| Effective ART suppression | At 10-month follow-up: pVL < 40 (n = 15)pVL: median 60 (29–224; n = 4) | pVL < 40 for all ART patients | ART for at least 1 year and pVL less than 20 for at least 6 months |
| Markers of microbial translocation | sCD14LPSLBP | sCD14 | sCD14LBP |
| Markers of endothelial damage/turnover/activation | Not included | I-FABP | I-CAMV-CAM |
| Markers of systemic inflammation–immune activation | IL-6D-Dimer | IL-6D-DimerhsCRP% HLADR+ CD38+ CD8+ T cell | IL-6 |
| Effect of ARVs on alpha diversity (number of species) | No differences were observed between NNRTIs and protease inhibitors↓↓↓ Number bacterial taxa in ART patients compared with baseline*** | ↓ Protease inhibitors versus controls*↓ NNRTIs versus controls*≈ Protease inhibitors versus NNRTIs | ↓↓ Protease inhibitors versus controls **↓ NNRTIs versus controls *≈ INSTIs versus controls≈ Protease inhibitors versus NNRTIs versus INSTIs |
| Effects of ARVs on microbial translocation | Not assessedNegative correlation between LPS, LBP, sCD14, sCD163 and CD4+/CD8+ ratio | ↑ sCD14 protease inhibitors versus controls*≈ NNRTIs versus controls≈ Protease inhibitors versus NNRTIs | ↑ sCD14 protease inhibitors versus controls *↑ sCD14 NNRTIs versus controls *≈ sCD14 INSTIs versus controls |
| Effects of ARVs on gut microbiome | ↓↓ In Firmicutes: Lachnospira spp.***, Oribacterium spp.***, Oscillospira spp.**); ↓↓ in proteobacteria (Sutturella spp.**) and ↓↓ in bacteroidetes (Prevotella spp.***) after ART initiation | Differential clustering of gut microbiome with ART regimens (Adonis R2 = 10.37%***)↓↓↓ Ruminococcaceae family (including Faecalibacterium prausnitzii) OTUs in HIV+ on ART versus controls | ↑ Proteobacteria in ART versus controls↓ Firmicutes in protease inhibitors versus controls*↓ Number of bacterial species in protease inhibitors versus controls*13 genera depleted (↓↓↓) in protease inhibitors versus controls, against 7 for NNRTIs and 6 for INSTIsINSTIs cluster inside the control cluster↓↓↓ F. prausnitzii in protease inhibitors versus controls***↑↑↑ Desulfovibrio spp. and Blautia spp. in INSTIs versus controls***↑↑ Pseudomonas spp. in NNRTIs versus controls** |
| Effects of ARVs on systemic inflammation and immune activation | No correlation between IL-6 and D-dimer and observed bacterial species | ≈ Protease inhibitors versus NNRTIs≈ Protease inhibitors versus controls≈ NNRTIs versus controls | ↑ IL-6 protease inhibitors versus controls** |
| Effects of ARVs on endothelial damage/turnover/activation | Not assessed | ↑↑↑ I-FABP protease inhibitors versus controls ***↑↑ I-FABP protease inhibitors versus NNRTIs **≈ NNRTIs versus controls | ↑ I-CAM NNRTIs versus controls*↑ I-CAM INSTIs versus controls*↑↑ I-CAM protease inhibitors versus controls**↑↑ V-CAM protease inhibitors versus controls*** |
| Main findings and conclusions | Bacterial diversity correlated positively with CD4+ T-cell counts and negatively with markers of microbial translocation and monocyte activation | Long-term ART does not restore richness of the gut microbiomeBPB are depleted in treated HIV infectionAbsence of BPB correlates with increased endothelial barrier damage | INSTIs with NRTIs ART combination restores the richness of the gut microbiome to normal levels (control group) |
| Strengths | Longitudinal study | Dietary assessment | Inclusion of INSTIs in ART cohortCo-infection with HCV and HBV |
| Limitations acknowledged by authors | Did not control for dietLack of intestinal biopsies to corroborate findings in fecesControl group not matched for ethnical background | Did not control for sexual practicesAbsence of untreated HIV+ individualsSmall number of HIV- individuals | Did not control for confounding factors (HIV acquisition, diet) |
Symbols to denote a significant increase (↑) or decrease (↓) or no differences (≈) were used. The asterisks (*), (**), (***) are used according to the P-values, P < 0.05, P < 0.01 and P < 0.001, respectively, as reported in the individual manuscripts.
ART, antiretroviral therapy; ARV, antiretroviral; BPB, butyrate-producing bacteria; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HIV+, HIV-infected; HIV-, HIV-uninfected; hsCRP, high-sensitivity C-reactive protein; I-CAM, intercellular adhesion molecule; I-FABP, intestinal-fatty acid-binding protein; IL-6, interleukin 6; INSTIs, integrase strand transfer inhibitors; LBP, LPS-binding protein; LPS, lipopolysaccharide; NNRTIs, nonnucleoside reverse transcriptase inhibitors; NRTIs, nucleoside reverse transcriptase inhibitors; pVL, plasma viral load (copies/ml); RTV, ritonavir; sCD14, soluble CD14; V-CAM, vascular cell adhesion molecule.