Background: By reducing tenofovir plasma levels, tenofovir alafenamide (TAF) preserves bone mineral density (BMD). Changes in bone composition appear to be multifactorial and can be affected by HIV reservoir, probably through the effects of immune dysregulation associated with a persistent lowgrade inflammatory state. The impact of switch to TAFcontaining regimens on osteo-immunity, inflammation and HIV-DNA has been poorly investigated. Thus, we investigated changes in bone turnover, inflammatory markers and HIV-DNA in patients (pts) switching from tenofovir disoproxil fumarate (TDF) to TAF. Methods: We enrolled ART-treated HIV+ pts within Icona (HIV-RNA<50 cp/ml) switching from TDF to TAF regimens. Samples were available pre-switch (T0) and 12 months post-switch (T1). Lab analyses: (a) sCD14, C-reactive protein (CRP), IL-6 and vascular cell adhesion molecule 1 (VCAM-1) (Luminex), (b) C-terminal telopeptide-1 (CTX-1), procollagen type I N-terminal propeptide (P1NP) (Elisa), (c) osteoclast precursors (OCP:CD14+CD16+CD51/61+), osteoblast precursors (OBP:CD15-OC+AP+), CD8+CD38+HLA-DR+ (Cytometry), (d) HIV-DNA (LTR5’ ddPCR assay, normalized by cps/106 CD4+). Pearson correlation and univariable and linear regression models using the markers variation over T0-T1 as outcome were used. Variable selection for inclusion in multivariable models was performed using a best subset approach with manual addition of known confounders. Results: We enrolled 146 pts: median (IQR) CD4 and age at switch were 672/mm3 (475-879), 48 years (40-55). All pts maintained virologic suppression through 12 months. In the unadjusted model, at T1 we observed a reduction in activation (-1.8 p<0.01), inflammatory markers (sCD14: -0.5 p<0.01, IL-6:-0.8 p<0.01),VCAM-1: -0.1 p<.01, with no changes in HIVDNA (+12.5, p=0.85). Among bone markers, only CTX-1 showed a non-significant decreasing trend (-4.9 p=0.06), with no differences in OBP, OCP, P1NP (Fig 1a). Having shown a trend for reduced resorption marker CTX-1, we performed a multivariable model to identify the factors associated with change in osteoclastogenesis. While this model showed no association between bone resorption and inflammation, we found a positive association between OCP change and T0 CD8 +, independent of potential confounders, including CD38+ (0.10 increase in OCP per 100 CD8+/mm3 higher p=.004, Fig 1b) Conclusions: In virologically suppressed HIV+ pts switching from TDF to TAF regimens, we describe an early decrease in pro-inflammatory markers and free osteoclast-derived collagen (CTX-1) suggesting a containment in bone resorption. This finding, together with the independent association between reduced post-switch osteoclast progenitors and high pre-switch CD8+, known osteoclastogenesis inhibitor in murines, might indicate a mechanistic pathway behind the greater bone safety of TAF This study is supported by a grant from Gilead International.
Reduced Bone catabolism and inflammation in patients switching to TAF-containing cART
D. SegalaMembro del Collaboration Group
2020
Abstract
Background: By reducing tenofovir plasma levels, tenofovir alafenamide (TAF) preserves bone mineral density (BMD). Changes in bone composition appear to be multifactorial and can be affected by HIV reservoir, probably through the effects of immune dysregulation associated with a persistent lowgrade inflammatory state. The impact of switch to TAFcontaining regimens on osteo-immunity, inflammation and HIV-DNA has been poorly investigated. Thus, we investigated changes in bone turnover, inflammatory markers and HIV-DNA in patients (pts) switching from tenofovir disoproxil fumarate (TDF) to TAF. Methods: We enrolled ART-treated HIV+ pts within Icona (HIV-RNA<50 cp/ml) switching from TDF to TAF regimens. Samples were available pre-switch (T0) and 12 months post-switch (T1). Lab analyses: (a) sCD14, C-reactive protein (CRP), IL-6 and vascular cell adhesion molecule 1 (VCAM-1) (Luminex), (b) C-terminal telopeptide-1 (CTX-1), procollagen type I N-terminal propeptide (P1NP) (Elisa), (c) osteoclast precursors (OCP:CD14+CD16+CD51/61+), osteoblast precursors (OBP:CD15-OC+AP+), CD8+CD38+HLA-DR+ (Cytometry), (d) HIV-DNA (LTR5’ ddPCR assay, normalized by cps/106 CD4+). Pearson correlation and univariable and linear regression models using the markers variation over T0-T1 as outcome were used. Variable selection for inclusion in multivariable models was performed using a best subset approach with manual addition of known confounders. Results: We enrolled 146 pts: median (IQR) CD4 and age at switch were 672/mm3 (475-879), 48 years (40-55). All pts maintained virologic suppression through 12 months. In the unadjusted model, at T1 we observed a reduction in activation (-1.8 p<0.01), inflammatory markers (sCD14: -0.5 p<0.01, IL-6:-0.8 p<0.01),VCAM-1: -0.1 p<.01, with no changes in HIVDNA (+12.5, p=0.85). Among bone markers, only CTX-1 showed a non-significant decreasing trend (-4.9 p=0.06), with no differences in OBP, OCP, P1NP (Fig 1a). Having shown a trend for reduced resorption marker CTX-1, we performed a multivariable model to identify the factors associated with change in osteoclastogenesis. While this model showed no association between bone resorption and inflammation, we found a positive association between OCP change and T0 CD8 +, independent of potential confounders, including CD38+ (0.10 increase in OCP per 100 CD8+/mm3 higher p=.004, Fig 1b) Conclusions: In virologically suppressed HIV+ pts switching from TDF to TAF regimens, we describe an early decrease in pro-inflammatory markers and free osteoclast-derived collagen (CTX-1) suggesting a containment in bone resorption. This finding, together with the independent association between reduced post-switch osteoclast progenitors and high pre-switch CD8+, known osteoclastogenesis inhibitor in murines, might indicate a mechanistic pathway behind the greater bone safety of TAF This study is supported by a grant from Gilead International.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
