TDF and quantitative ultrasound bone quality in African patients on second line ART, ANRS 12169 2LADY sub-study.

BACKGROUND: Bone demineralization, which leads to osteoporosis and increased fracture risk, is a common metabolic disorder in HIV-infected individuals. In this study, we aimed to assess the change in bone quality using quantitative ultrasound (QUS) over 96 weeks of follow-up after initiation of second-line treatment, and to identify factors associated with change in bone quality. METHODS AND FINDINGS: In a randomized trial (ANRS 12169), TDF and PI-naïve participants failing standard first-line treatment, from Burkina Faso, Cameroon, and Senegal were randomized to receive either TDF/FTC/LPVr, ABC/ddI/LPVr or TDF/FTC/DRVr. Their bone quality was assessed using calcaneal QUS at baseline and every 24 weeks until week 96. Stiffness index (SI) was used to measure bone quality. Out of 228 participants, 168 (74%) were women. At baseline, median age was 37 years (IQR: 33-46 years) and median T-CD4 count was 199 cells/µl (IQR: 113-319 cells/µl). The median duration of first-line antiretroviral treatment (ART) was 52 months (IQR: 36-72 months) and the median baseline SI was 101 (IQR: 87-116). In multivariable analysis, factors associated with baseline SI were sex (ß = -10.8 [-18.1,-3.5] for women), age (ß = -8.7 [-12.4,-5.1] per 10 years), body mass index (BMI) (ß = +0.8 [0.1,1.5] per unit of BMI), and study site (ß = +12.8 [6.5,19.1] for Cameroon). After 96 weeks of second-line therapy, a reduction of 7.1% in mean SI was observed, as compared with baseline. Factors associated with SI during the follow-up were similar to those found at baseline. Exposure to TDF was not associated with a greater loss of bone quality over time. CONCLUSION: Bone quality decreased after second-line ART initiation in African patients independently of TDF exposure. Factors associated with bone quality include age, sex, baseline BMI, study site, and duration of follow-up.

Comparison of peripheral forearm DXA and clinical risk factor screening using FRAX® to assess the risk of HIV-associated low bone mass: a cross-sectional study.

UNLABELLED: There is growing awareness that HIV infection is associated with low bone mass and fracture. DXA is a relatively scarce resource. Therefore, we evaluated two tools: peripheral DXA (pDXA) at the forearm and Fracture Risk Assessment Tool (FRAX®) to see which performed best at identifying men who should undergo DXA. In this setting, neither pDXA nor FRAX® showed good sensitivity and specificity for DXA. PURPOSE: Infection with human immunodeficiency virus (HIV) is associated with an increased risk of low bone mineral density (BMD) and fractures. European guidance advocates screening using the FRAX® tool at diagnosis, on initiation of antiretroviral therapy and biannually thereafter in order to decide the need for DXA scanning. This cross-sectional study evaluates the performance of FRAX® and compares its sensitivity and specificity with that of another screening tool, peripheral forearm DXA (pDXA). METHODS: HIV-infected men with varying exposure to antiretroviral therapies were recruited. FRAX® scores were calculated for all participants and everybody underwent pDXA scanning. Femoral neck and lumbar spine BMD was acquired on a Hologic QDR machine by an assessor blinded to the results of the FRAX® and pDXA. RESULTS: One hundred and sixty-eight men (median age 45 years) were recruited with a median duration since HIV diagnosis of 74 months. In total, 21 % of subjects had either osteoporosis (aged ≥50 years) or BMD lower than expected for age (aged <50 years), according to axial DXA. Using a pDXA screening threshold of T ≤ -0.9, sensitivity was high (91 %) in defining those with the worst BMD on axial DXA but with poorer specificity (33 %). Alternately, using a threshold of T ≤ -2.7 reduced sensitivity (34 %) with an increase in specificity (91 %). FRAX® with HIV included as a secondary risk factor had poor sensitivity (31 %) and specificity (74 %) for detecting those with the poorest BMD on axial DXA. CONCLUSION: In this setting, neither pDXA scanning nor FRAX® was sensitive and specific for low bone mass on DXA and neither was performance much improved by using both screening tools. Prospective studies with fracture as an outcome are required in HIV.

WNT/beta-catenin signaling is involved in regulation of osteoclast differentiation by human immunodeficiency virus protease inhibitor ritonavir: relationship to human immunodeficiency virus-linked bone mineral loss.

Untreated human immunodeficiency virus (HIV) infection is accompanied by reduced bone mineral density, which appears to be exacerbated by certain HIV protease inhibitors (PIs). The mechanisms leading to this apparent paradox, however, remain unclear. We have previously shown that, the HIV envelope glycoprotein gp120 used at levels similar those in plasmas of untreated HIV(+) patients, induced expression of the osteoclast (OC) differentiation factor RANKL in CD4+ T cells. In addition, the HIV PI ritonavir abrogated the interferon-gamma-mediated degradation of the RANKL nuclear adapter protein TRAF6, a physiological block to RANKL activity. Here, using oligonucleotide microarrays and quantitative polymerase chain reaction, we explored potential upstream mechanisms for these effects. Ritonavir, but not the HIV PIs indinavir or nelfinavir, up-regulated the production of transcripts for OC growth factors and the non-canonical Wnt Proteins 5B and 7B as well as activated promoters of nuclear factor-kappaB signaling, but suppressed genes involved in canonical Wnt signaling. Similarly, ritonavir blocked the cytoplasmic to nuclear translocation of beta-catenin, the molecular node of the Wnt signaling pathway, in association with enhanced beta-catenin ubiquitination. Exposure of OC precursors to LiCl, an inhibitor of the canonical Wnt antagonist GSK-3beta, suppressed OC differentiation, as did adenovirus-mediated overexpression of beta-catenin. These data identify, for the first time, a biologically relevant role for Wnt signaling via beta-catenin in isolated OC precursors and the modulation of Wnt signaling by ritonavir. The reversal of these ritonavir-mediated changes by interferon-gamma provides a model for possible intervention in this metabolic complication of HIV therapy.