Kinetics of microbial translocation markers in patients on efavirenz or lopinavir/r based antiretroviral therapy

Abstract

Objectives: We investigated whether there are differences in the effects on microbial translocation (MT) and enterocyte damage by different antiretroviral therapy (ART) regimens after 1.5 years and whether antibiotic use has impact on MT. In a randomized clinical trial (NCT01445223) on first line ART, patients started either lopinavir/r (LPV/r) (n = 34) or efavirenz (EFV) containing ART (n = 37). Lipopolysaccharide (LPS), sCD14, anti-flagellin antibodies and intestinal fatty acid binding protein (I-FABP) levels were determined in plasma at baseline (BL) and week 72 (w72).

Results: The levels of LPS and sCD14 were reduced from BL to w72 (157.5 pg/ml vs. 140.0 pg/ml, p = 0.0003; 3.13 ug/ml vs. 2.85 ug/ml, p = 0.005, respectively). The levels of anti-flagellin antibodies had decreased at w72 (0.35 vs 0.31 [OD]; p<0.0004), although significantly only in the LPV/r arm. I-FABP levels increased at w72 (2.26 ng/ml vs 3.13 ng/ml; p<0.0001), although significantly in EFV treated patients only. Patients given antibiotics at BL had lower sCD14 levels at w72 as revealed by ANCOVA compared to those who did not receive (Δ = -0.47 µg/ml; p = 0.015).

Conclusions: Markers of MT and enterocyte damage are elevated in untreated HIV-1 infected patients. Long-term ART reduces the levels, except for I-FABP which role as a marker of MT is questionable in ART-experienced patients. Why the enterocyte damage seems to persist remains to be established. Also antibiotic usage may influence the kinetics of the markers of MT.

Trial registration: ClinicalTrials.gov NCT01445223.

Conflict of interest statement

Competing Interests: The authors do not have a commercial or other association that might pose a conflict of interest with the exception of Dr HF is employed by DS Pharma Biomedical Co., Ltd, the company that developed a kit for I-FABP. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Trial profile and reasons for discontinuations in each group.

Figure 2. Levels of LPS.

Levels of LPS were significantly reduced after 72 weeks of antiretroviral therapy in the whole cohort, with a unified pattern in both treatment arms. Data are shown as individual values with corresponding baseline LPS levels at X-axis and week 72 levels at Y-axis, respectively. Individuals treated with lopinavir (LPV/r) are indicated with shaded and efavirenz (EFV) with black circles. Dotted lines refer to median values at the corresponding time-point.

Figure 3. Levels of sCD14.

Levels of sCD14 were significantly reduced after 72 weeks of antiretroviral therapy in the whole group, with a unified pattern in both treatment arms. Data are shown as individual values with corresponding baseline sCD14 levels at X-axis and week 72 levels at Y-axis, respectively. Individuals treated with lopinavir (LPV/r) are indicated with shaded and efavirenz (EFV) with black circles. Dotted lines refer to median values at the corresponding time-point.

Figure 4. Correlations between sCD14, CD4+ T-cells and HIV-1 RNA.

At baseline, significant correlations were found between sCD14 and CD4-T cell counts (A) or HIV-1 RNA viral load (B), respectively. Rho and p-value refer to Spearman’s rank test.

Figure 5. Levels of Intestinal Fatty Acid Binding Protein (I-FABP).

Plasma levels of I-FABP were significantly elevated after 72 weeks of antiretroviral treatment as compared to baseline in the whole cohort. Stratified to treatment arms, efavirenz (EFV) treated patients had significantly increased levels, but not the patients on lopinavir/r (LPV/r) therapy. Data are shown as individual values with corresponding baseline I-FABP levels at X-axis and week 72 levels at Y-axis, respectively. Individuals treated with lopinavir (LPV/r) are indicated with shaded and efavirenz (EFV) with black circles. Dotted lines refer to median values at the corresponding time-point.

Figure 6. Plasma levels of anti-flagellin antibodies.

A significant reduction of anti-flagellin IgG levels was seen after 72 weeks of antiretroviral treatment compared to baseline in the whole cohort. Plasma levels of anti-flagellin IgG decreased significantly in lopinavir/r (LPV/r) treated patients, but not during efavirenz (EFV) therapy. Data are shown as individual values with corresponding baseline anti-flagellin IgG levels at X-axis and week 72 levels at Y-axis, respectively. Individuals treated with lopinavir (LPV/r) are indicated with shaded and efavirenz (EFV) with black circles. Dotted lines refer to median values at the corresponding time-point.

Figure 7. Change (Δ) in sCD14 levels in relation to antibiotics.

Change (Δ) in sCD14 levels between baseline (BL) and 72 weeks of treatment (w72). Patients treated with antibiotics at BL had a larger reduction in sCD14 levels at w72 than those who did not receive antibiotics at BL. P-value refers to Mann-Whitney test.