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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

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
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

osteoporosis in hiv
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

impact of severity of liver disease on fracture risk in hiv patients
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

goals of the study
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

goals of the study1

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

study design
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
results patient characteristics
Results: Patient Characteristics

*Data shown as mean (standard deviation)

impact of hiv and hcv on t scores
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

impact of hiv and hcv on bone markers
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

correlations of bone turnover markers and bone mineral density
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)

bone turnover coupling the rank rankl opg system
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

impact of hiv and hcv on bone markers and turnover regulation
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

conclusions
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
osteoporosis in hiv1
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

increased bone turnover in hiv potential mechanisms
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)
potential mechanisms for increased bone turnover in hiv haart impact tdf ftc drv r vs ral drv r
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

acknowledgements
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