Impact of HIV and antiretroviral initiation on skeletal biology

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ABSTRACT Osteoporosis and fractures are known complications of HIV and antiretroviral therapy (ART). Bone mineral density (BMD) decreases 2-4% within the first year after ART initiation and is worse with exposure to specific ART such as tenofovir disoproxil fumarate (TDF). The mechanisms of HIV and ART associated bone loss are still uncertain because tissue-level data are lacking. Through a collaboration between investigators at Columbia University and University of São Paulo with complementary expertise in HIV and bone research, we were able to perform the first comprehensive longitudinal bone biopsy study in ART-naïve young men before and 12 months after initiation of TDF/lamivudine/efavirenz. We found evidence of bone formation and mineralization abnormalities before ART. After ART, there was an increase in bone cellularity, but a persistence in bone mineralization defects. Our goal is to enroll adult ART-naïve men and women with HIV (n=30) who are initiating abacavir/lamivudine/dolutegravir an ART regimen that is not associated with bone loss, in a comprehensive longitudinal study to compare the skeletal effects of the two ART regimens. We will evaluate bone density and strength using dual energy Xray absorptiometry (DXA) and High Resolution peripheral Quantitative CT (HRpQCT) with finite element analysis (Aim 1), obtain paired iliac-crest bone biopsies to evaluate histomorphometry and tissue-level mechanical properties using nanoindentation/ramen spectroscopy (Aim 2), and perform bone cell transcriptomics to explore underpinning molecular pathways. These studies are critical for development of safer ART options for long-term use in children with HIV to attain peak bone mass and in older adults with HIV to prevent fracture. This proposal leverages state-of-the art bone research techniques in a multidisciplinary collaboration of HIV and bone researchers from the U.S. and Brazil and provide opportunities for training to augment the bone research capacity at the University of São Paulo.