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HIV and HCV Independently Lower BMD through Different Mechanisms

HIV and HCV Independently Lower BMD through Different Mechanisms. N Maalouf, MD; S Zhang, PhD; H Drechsler, MD; J Cutrell, MD, I Farukhi, MD; R Castanon , MD; G Brown, MD; P Tebas, MD; and R Bedimo, MD. Role of HCV in Fracture Risk of HIV Patients.

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HIV and HCV Independently Lower BMD through Different Mechanisms

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  1. HIV and HCV Independently Lower BMD through Different Mechanisms N Maalouf, MD; S Zhang, PhD; H Drechsler, MD; J Cutrell, MD, I Farukhi, MD; R Castanon, MD; G Brown, MD; P Tebas, MD; and R Bedimo, MD

  2. Role of HCV in Fracture Risk of HIV Patients • HIV and HAART initiation increase fracture risk • HCV co-infection is a significant risk factor for osteoporotic fractures in several cohorts of HIV-infected patients: • ANRS CO8 APROCO-COPILOTE cohort: HR: 3.6 (95% CI: 1.6–8.1)1 • WIHS: HR: 1.86 (1.33 - 2.61)2; HOPS: HR: 1.99 (1.01–3.90)3 • However, the mechanisms of this increased risk (impact of HCV on BMD and bone turnover) is not clearly established. • It could be related to HCV-induced liver fibrosis • HCV is associated with higher levels of inflammatory markers (TNF-, IL-8).4 These could in turn enhance osteoclastogenesis leading to excessive bone resorption and osteoporosis3 1Collin et al., AIDS. 2009 May ; 23(8): 1021–1024. 2Yin et al., AIDS 2010; 24:2679–2686; 3Young et al., Clin Infect Dis 2011; 52:1061–1068; 4Guerra. Dig Liver Dis2007,39 Suppl 1:S76-82

  3. Osteoporosis in HIV Disease specific factors HCV HIV The virus The virus (inflammation) Immune reconstitution Severity of liver disease? HAART (TDF) Advancing age, Improved Survival Hypogonadism OSTEOPOROSIS and FRACTURE RISK Tobacco, EtOH, Drugs Glucocorticoids Low BMI, Malnutrition Traditional risk factors Race/Ethnicity, Genetics

  4. Impact of Severity of Liver Disease on Fracture Risk in HIV Patients • US Veterans Cohort: 56,660 HIV patients (98.1% male; 31.2% HCV co-infected; mean age: 45.0 years) 1,2 • HCV co-infection remained a strong independent predictor of osteoporotic fractures after controlling AST-to-platelet ratio (APRI; HR: 1.32; p= 0.001) or the presence of cirrhosis (HR: 1.30; CI: 1.09-1.54; p=0.003). • Johns Hopkins Cohort: 179 HIV/HCV patients 3 • Severity of liver disease (METAVIR score) did not predict low BMD 1Bedimo et al., AIDS 2012; 2Maalouf et al., JBMR 2013; 3 El-Maouche et al. J Hepatol 2011

  5. Goals of the study Q1. What are the mechanisms? Disease specific factors HCV HIV The virus The virus (inflammation) Immune reconstitution Severity of liver disease? HAART (TDF) Advancing age, Improved Survival Hypogonadism OSTEOPOROSIS and FRACTURE RISK Tobacco, EtOH, Drugs Glucocorticoids Low BMI, Malnutrition Traditional risk factors Race/Ethnicity, Genetics

  6. Q2. How much is HIV? How much HCV? Is there an interaction? Goals of the study Disease specific factors HCV HIV The virus The virus (inflammation) Immune reconstitution Severity of liver disease? HAART (TDF) Advancing age, Improved Survival Hypogonadism OSTEOPOROSIS and FRACTURE RISK Tobacco, EtOH, Drugs Glucocorticoids Low BMI, Malnutrition Traditional risk factors Race/Ethnicity, Genetics

  7. Study design • Prospective, cross-sectional study: 168 males with HIV, HCV, HIV/HCV co-infection and uninfected. • Included if age ≥ 40; eGFR ≥ 60; no known osteoporosis • All HIV patients were virologically suppressed on HAART; • All HCV patients were HCV treatment-naive • Study measurements: • bone mineral density (BMD) by DXA scan • Bone turnover markers: serum C-telopeptide (CTX), bone-specific alkaline phosphatase (BSAP) and osteocalcin (OC) • Regulatory cytokines: receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG). • Statistics: • Groups means compared by ANOVA and by ANCOVA adjusting for age, race and BMI

  8. Results: Patient Characteristics *Data shown as mean (standard deviation)

  9. Impact of HIV and HCV on T-Scores • HIV and HCV independently lower T scores (smaller contribution for HCV). • Effect most pronounced in femoral neck and total hip. • No interaction between the two infections Data shown as mean (standard deviation) *Controlling for Age, BMI and Race

  10. Impact of HIV and HCV on T-Scores

  11. Impact of HIV and HCV on T-ScoresPercent Osteoporosis at F Neck

  12. Impact of HIV and HCV on Bone Markers HIV groups had higher bone resorption and formation No increased resorption in HCV groups Data shown as mean (standard deviation) *Controlling for Age, BMI and Race

  13. Correlations of Bone Turnover Markers and Bone Mineral Density Total Hip BMD (g/cm2) Total Hip BMD (g/cm2) r= -0.21, p<0.001 r= -0.28, p<0.001 Serum C-Telopeptide (ng/ml) Serum Osteocalcin (ng/ml)

  14. Bone Turnover Coupling: The RANK/RANKL/OPG System • RANK, RANKL, and OPG are members of TNF and TNF receptors superfamily. • RANK and RANKL involved in formation and activation of osteoclast • OPG is decoy receptor competing with RANK-RANKL RANK: receptor activator of NFκB; RANKL: receptor activator of NFκB ligand OPG: osteoprotegerin cf. Ott, Endo Reviews, 2007

  15. Impact of HIV and HCV on Bone Markers and Turnover Regulation RANK: receptor activator of NFκB; RANKL: receptor activator of NFκB ligand Data shown as mean (standard deviation) *Controlling for Age, BMI and Race

  16. Conclusions • HIV and HCV independently lower BMD and T-scores (smaller contribution for HCV). • Effect most pronounced in femoral neck and total hip. • No interaction between the two infections. • HIV impact on BMD could be explained by increased turnover (resorption and formation markers). • See Cotter et al. 7th IAS, MOPE077 • Turnover doesn’t appear to be driven by RANK/RANKL/OPG system • HCV is not associated with increased bone resorption • Increased OPG and trends toward increased RANKL

  17. Osteoporosis in HIV HCV HIV Fibrosis Cirrhosis ? ? HAART (TDF) NoTurnover; OPG? High Bone Turnover Advancing age, Improved Survival Hypogonadism OSTEOPOROSIS and FRACTURE RISK Tobacco, EtOH, Drugs Glucocorticoids Low BMI, Malnutrition Race/Ethnicity, Genetics

  18. Increased Bone Turnover in HIV: Potential Mechanisms • HIV Infection Itself: • Dysregulation of Bone Metabolism: • No changes in the RANKL and OPG • Gonadal Hormones; PTH and Vitamin D • Increased Inflammation: TNF-alfa; IL-1, IL-6 • HAART: • Immune reconstitution? • VL control associated with lower BMD (El-Maouche. J Hepatol2011) • Tenofovir: • Renal insufficiency with secondary hyperparathyroidism • Proximal tubular dysfunction? (Hamza, 7th IAS; MOPE076)

  19. Potential Mechanisms for Increased Bone Turnover in HIV: HAART ImpactTDF/FTC/DRV/rvsRAL/DRV/r Significant increases in bone formation (P1NP) and resorption (CTx) following initiation of TDF/FTC + DRV/r vs. RAL + DRV/r. No difference in changes in inflammatory markers from baseline Bedimo et al., IAS 2013; Poster WEPE512

  20. Acknowledgements • Study funded by VA MERIT grant I01 CX000418-01A1 • Thanks to Holly Wise and Joyce Ghormley, our study coordinators • Thanks to IAS for giving us the opportunity to share our work • Special thanks to all the study volunteers

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