HIV infection is associated with upregulated circulating levels of the inflammaging miR-21-5p.

BACKGROUND: HIV infection produces a chronic inflammation which leads to early aging of people living with HIV. Even though antiretroviral treatments (ART) have significantly increased HIV patient survival, an underlying chronic inflammation persists leading to HIV-related comorbidities. In this context, changes in microRNAs (miRNAs) expression may contribute to this inflammatory response. This study aims to detect differential expression of circulating miRNAs in treatment-naïve HIV-infected individuals compared to uninfected controls and evaluation of altered miRNAs after one year of ART. METHODS: Serum from patients and controls was collected at baseline and after 48-weeks on ART in HIV-treated patients. Circulating miRNAs were analysed using next generation sequencing. RESULTS: A total of 32 HIV patients and 10 controls were recruited. Of HIV+ individuals, 7 were long-term non-progressors (elite controllers), a group of HIV-infected individuals that spontaneously control the infection. Higher circulating levels of miR-21-5p, and lower levels of miR-6503-3p and miR-3135b were detected in HIV+ progressors. After one year of ART, these miRNAs remain altered. Moreover, miR-21-5p and miR-6503-3p were also altered in elite controllers compared to control group. In silico analyses showed that miR-21-5p target pathways are related to inflammation mechanisms and immune system. CONCLUSION: miR-21-5p circulating levels are involved in inflammation and oxidative stress mechanisms in HIV patients even after one year of ART or in elite controllers.

Changes in bone quality after switching from a TDF to a TAF based ART: A pilot randomized study.

Background: The impact of tenofovir disoproxil fumarate (TDF) antiretroviral (ART) regimens on bone health has been characterized mostly by bone mineral density (BMD), but recently also by bone quality (BQ). The aim of this pilot study is to assess the changes in BMD and BQ after switch from TDF to tenofovir alafenamide (TAF) ART. Methods: HIV individuals receiving TDF-based ART were randomized to switch to Bictegravir-TAF-Emtricitabine or to remain in the same regimen. At baseline and 24-weeks after randomization, participants underwent bone mineral density (BMD) by DXA and BQ assessment using bone microindentation, a validated technique that measures bone tissue quality expressed as bone material strength index (BMSi). A panel of plasma bone turnover biomarkers were measured by ELISA at the same time-points. Values are expressed as median [interquartile range] and non-parametric tests were used where appropriate. Results: A total of 24 HIV individuals were included in the study, 19 of which were men (80%). Median age at baseline was 43 years (IQR 38-54). Half of individuals were allocated in the TDF group while the other half changed to TAF treatment. No differences at baseline between both groups were detected in any parameter. Non-significant changes nor in lumbar or femoral BMD at week 24 was found in any regimen. In contrast, there was an increase in BMSi in the TAF arm at 24 weeks, and thus an improvement in BQ[81.6 (79-83) to 86 (80-88) (+5.1%);p=0.041], whereas the TDF arm remained stable from 82 (76-85) at baseline to 82 (73-83);p=0.812. Hence, at week 24 there were significant differences in BQ between arms (p=0.049). A reduction in bone formation markers was found at week 24 in both regimens: N-terminal propeptide of type-1 collagen decreased a 20% (-35 - -0.6); p=0.031 with TAF and -16% (-25 - -5); p=0.032 with TDF. Also a decrease in bone resorption marker C-telopeptide with TAF was detected [-10% (-19 - -5);p=0.028] but not with TDF (p=0.232), suggesting a less metabolically active bone after switching to TAF. Conclusion: A bone quality improvement was found after switching from a TDF to a TAF based ART independently of BMD, suggesting that the bone health benefits of TAF may extend beyond BMD. Future research should be directed to confirm these findings and to identify the underlying mechanisms of ART related bone toxicity.

An Abnormal Inflammatory Pattern Associated with Long-Term Non-Progression of HIV Infection Impacts Negatively on Bone Quality.

Introduction. Long-term non-progressors (LTNPs) are HIV-infected individuals (HIV+) whose viral replication is controlled. However, these individuals experience complications associated with HIV, among them, bone remodeling impairment. This study aims to perform a comprehensive bone health assessment and its association with the inflammatory status of HIV+ LTNPs. A cross-sectional study was conducted comparing bone strength components (bone mineral density and bone tissue quality) between age-, sex-, and comorbidities-matched groups of HIV+ LTNPs, HIV+ progressors, and HIV-negative individuals. A panel of bone turnover and inflammatory biomarkers was measured in fasting plasma using ELISA. Bone tissue quality was assessed by bone microindentation, a technique that directly measures the bone resistance to fracture and yields a dimensionless quantifiable parameter called bone material strength (BMSi). Thirty patients were included: ten LTNPs, ten HIV+ progressors, and ten HIV-negative individuals. LTNPs showed an abnormal pattern of immune activation that was represented by significantly lower levels of anti-inflammatory cytokine IL-10 (p = 0.03), pro-inflammatory cytokine IL-8 (p = 0.01), and TNF-α (p < 0.001) with respect to the other groups. Regarding bone health, LTNPs presented lower BMSi, and thus, worse bone tissue quality than HIV-negative individuals (83 (78−85) vs. 90 (89−93), respectively; p = 0.003), and also lower BMSi than HIV+ progressors (83 (78−85) vs. 86 (85−89), respectively; p = 0.022). A trend was found of lower BMSi in HIV+ progressors with respect to the HIV-negative individuals (86 (85−89) vs. 90 (89−93), respectively; p = 0.083). No differences were detected in bone mineral density between groups. In conclusion, LTNPs showed a different inflammatory profile, along with worse bone tissue quality, when compared to HIV+ progressors and HIV-negative individuals. This may contribute to increasing evidence that HIV infection itself has a deleterious effect on bone tissue, likely through a persistent altered inflammation status.

Bone density, microarchitecture and tissue quality after 1 year of treatment with dolutegravir/abacavir/lamivudine.

BACKGROUND: Bone mineral density (BMD) decreases with ART initiation with a tenofovir disoproxil fumarate-containing regimen, although bone tissue quality increases. The impact of dolutegravir (DTG)/abacavir (ABC)/lamivudine (3TC)-based ART initiation on bone health parameters is not clear. OBJECTIVES: To study the impact of DTG/ABC/3TC-based therapy on bone health parameters in ART-naive individuals with HIV after 48 weeks of treatment. METHODS: An observational, prospective and analytical study of treatment-naive patients with HIV undergoing a DTG/ABC/3TC-based regimen at 48 week follow-up. Changes in bone strength parameters (BMD, bone microarchitecture and bone tissue quality) were assessed with non-parametric methods. RESULTS: Sixteen HIV-infected ART-naive patients starting DTG/ABC/3TC were included. BMD in the lumbar spine showed a significant decrease of -2.25% (P = 0.007) and -4.1% in the femoral neck (P = 0.007). Bone microarchitecture, as measured by trabecular bone score, also decreased significantly by -2.5% (P = 0.03). In contrast, bone quality [bone material strength index (BMi)], as measured by microindentation, significantly increased with respect to baseline after 48 weeks of treatment, showing better bone properties of +6.53% (P < 0.001). No significant changes were found in bone turnover markers. In addition, a positive significant correlation between the CD4/CD8 cell count ratio at baseline and changes in BMSi after 48 weeks of treatment was observed (Spearman's rho = 0.4974; P = 0.04). CONCLUSIONS: After a 48 week treatment with DTG/ABC/3TC-based ART, BMD and trabecular bone score decreased while bone tissue quality, as measured by microindentation, improved significantly. The state of the immune system at ART initiation is related to bone quality recovery. An overarching approach to assess bone toxicity in ART-treated patients is needed.

Inflammation status in HIV-positive individuals correlates with changes in bone tissue quality after initiation of ART.

BACKGROUND: The mechanisms behind ART-induced bone changes in HIV-infected patients are poorly known. We aimed to analyse changes in inflammatory and bone markers in HIV after tenofovir disoproxil fumarate initiation, and the associations with changes in the bone strength parameters. METHODS: HIV-positive participants starting tenofovir disoproxil fumarate-based ART underwent dual-energy X-ray absorptiometry (QDR 4500 SL®, Hologic, Waltham, MA, USA) for bone mineral density (BMD), a microindentation test (OsteoProbe®, Active Life Scientific, Santa Barbara, CA, USA) for bone quality [bone material strength index (BMSi)] and phlebotomy at baseline and 48 weeks after ART. A panel of inflammatory biomarkers and bone turnover markers were measured by ELISA. HIV-negative controls underwent identical procedures once. Values are expressed as medians and IQRs, and non-parametric tests were used to perform the analysis. RESULTS: Twenty HIV-infected individuals and 20 HIV-negative control individuals were matched in terms of age and gender. HIV individuals showed higher levels of inflammatory markers. We found no differences in bone turnover markers. HIV-positive individuals presented lower BMSi values at baseline compared with controls [86 (83-90) versus 89 (88-93), respectively; P = 0.034]. We found no difference in BMD (at either of the sites evaluated). BMSi tended to increase with treatment. IL-1ß at baseline was positively correlated with changes in BMSi after ART (rho = 0.564, P = 0.014). Baseline levels of sclerostin tended to be negatively correlated with changes in BMSi (rho = -0.402, P = 0.097). We found a negative correlation between time since HIV diagnosis and changes in BMSi (rho = -0.466, P = 0.04). CONCLUSIONS: We observed a correlation between changes in bone quality and the inflammatory environment in HIV-positive individuals. Moreover, among the underlying mechanisms we highlight the Wnt pathway as having a potentially significant role in ART bone quality recovery.

Bone density, microarchitecture, and tissue quality after 1 year of treatment with tenofovir disoproxil fumarate.

OBJECIVE: Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is used to assess bone health in HIV patients. DXA measures the amount of mineral, but not other key aspects of bone strength such as bone microarchitecture or bone quality. Trabecular bone score (TBS) and in-vivo microindentation directly measure trabecular microarchitecture and bone tissue quality, respectively. The aim of this study is to measure bone strength properties using these techniques. RESULTS: Forty naive HIV patients who were going to start antiretroviral therapy (ART), a single pill treatment with elvitegravir/cobicistat, tenofovir disoproxil fumarate (TDF), emtricitavine (FTC) were included. A significant reduction in BMD at spine (-3.25%, P < 0.001) and in femoral neck (-3.82%, P = 0.016) between baseline and 48 weeks of treatment were found. Bone microarchitecture score at the spine, as measured by TBS, also significantly decreased from 1.357 (0.09) to 1.322 (0.09) (-2.5%, P = 0.011) between baseline to 48 weeks of treatment. Microindentation (BMSi) values were significantly higher than at baseline [89.04 (4.2) versus 86.07 (6.1); 3.49%, P < 0.001] after 48 weeks of TDF-based ART treatment, indicating improved bone material properties CONCLUSION:: A significant decrease in BMD and TBS were observed after 1 year of TDF therapy. However, tissue quality significantly improved after 1 year of treatment, suggesting a recovery of bone material properties following the control of the infection despite the significant reduction of BMD. These techniques provide additional and necessary information to DXA about bone health in treated HIV patients, and because of its convenience and feasibility they could be routinely apply to assess bone in clinical practice.