HIV and HCV Independently Lower BMD through Different Mechanisms
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Transcript of 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
• 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 Dis 2007,39 Suppl 1:S76-82
Osteoporosis in HIV
OSTEOPOROSIS and
FRACTURE RISK
Advancing age, Improved SurvivalHypogonadism
Glucocorticoids
Low BMI, Malnutrition
Tobacco, EtOH, Drugs
Race/Ethnicity, Genetics
HIV
HAART (TDF)
HCV
The virus
Immune reconstitution
The virus (inflammation)
Severity of liver disease?
Traditional risk factors
Disease specific factors
Impact of Severity of Liver Disease on Fracture Risk in HIV
Patients
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Frac
ture
Rat
e(p
er 1
,000
pat
ient
-yea
rs)
HIV/HCV
HIV
< 0.5 ≥ 1.50.5-1.5APRI
<1.45 > 3.251.45-3.25FIB-4
•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
OSTEOPOROSIS and
FRACTURE RISK
Advancing age, Improved SurvivalHypogonadism
Glucocorticoids
Low BMI, Malnutrition
Tobacco, EtOH, Drugs
Race/Ethnicity, Genetics
HIV
HAART (TDF)
HCV
The virus
Immune reconstitution
The virus (inflammation)
Severity of liver disease?
Traditional risk factors
Disease specific factors
Q1. What are the mechanisms?
Goals of the study
OSTEOPOROSIS and
FRACTURE RISK
Advancing age, Improved SurvivalHypogonadism
Glucocorticoids
Low BMI, Malnutrition
Tobacco, EtOH, Drugs
Race/Ethnicity, Genetics
HIV
HAART (TDF)
HCV
The virus
Immune reconstitution
The virus (inflammation)
Severity of liver disease?
Traditional risk factors
Disease specific factors
Q2. How much is HIV?How much HCV?Is there an interaction?
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
Variable HIV/HCV (N=28)
HIV (N=62)
HCV (N=45)
Controls (N=33)
P-Value (Unadjusted)
Age* (years) 55 (6) 57 (8) 55 (5) 53 (8) 0.048
Race / Ethnicity (% AA/C/H) 71/25/4 32/55/13 67/27/7 88/12/0 <0.0001
BMI* (Kg/m2) 27.5 (6.0) 27.5 (4.5) 28.6 (5.3) 29.9 (5.8) 0.18
Smokers (%) 32 32 47 64 0.015
Glucocorticoid Use (%) 7 6 2 9 0.087
Alcohol Use (%) 0 8 2 3 0.30
Tenofovir Use (%) 71 76 - -
Protease Inhibitors Use (%) 60 52 - -
*Data shown as mean (standard deviation)
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
*Controlling for Age, BMI and Race
Data shown as mean (standard deviation)
BMD T-scoreMean (SD)
HIV/HCV (N=28)
HIV (N=62)
HCV (N=45)
Controls (N=33)
P-value Adj*
HIV vs. non-HIV Adj*
HCV vs. non-HCV Adj*
HIV-HCV inter-action
Fem Neck -1.6 (0.8) -1.4 (1.0) -1.2 (0.8) -0.6 (1.0) 0.02 0.01 0.02 0.55
Total Hip -1.2 (0.7) -0.9 (0.9) -0.7 (0.7) -0.4 (0.8) 0.05 <0.01 0.12 0.87
L-Spine -1.4 (1.4) -0.8 (1.7) -0.5 (1.5) -0.7 (1.6) 0.32 0.13 0.6 0.26
Impact of HIV and HCV on T-Scores
T-Score
-4 -3 -2 -1 0
L-spine
Total hip
Femoral neck
Control HCV HIV HIV/HCV
Impact of HIV and HCV on T-Scores
Percent Osteoporosis at F Neck
HIV/HCVHIV
HCVControl
0
10
20
30
40
50
60
70
% Osteoporosis
% Osteopenia
% Osteopenia or Osteoporosis8 13
5
0
58
5057
37
6663
62
37
HIV/HCV (N=28)
HIV
(N=62)
HCV
(N=45)
Controls
(N=33)
P-value Adj*
HIV vs.
non-HIV Adj*
HCV vs.
non-HCV Adj*
HIV-HCV
inter-action
Osteocalcin ng/mL 18.5 (6.3) 21.7 (8.9) 15.7 (6.5) 15.8 (5.1) <0.01 <0.01 0.17 0.58
Bone Sp Alk Phos U/L 37.1 (12.1) 34.7
(11.4)33.6 (10.1) 26.1 (8.7) <0.01 <0.01 <0.01 0.50
C-telopeptide (CTX) ng/mL 0.62 (0.24) 0.58
(0.29)0.45 (0.23)
0.41 (0.15) 0.01 <0.01 0.44 0.93
Impact of HIV and HCV on Bone Markers
*Controlling for Age, BMI and RaceData shown as mean (standard deviation)
0.0 0.2 0.4 0.6 0.8 1.0
C-telopeptideng/ml
0 10 20 30 40 50 60
Osteocalcin
Bone Sp Alk Phos
Control HCV HIV HIV/HCV
U/L
ng/ml
HIV groups had higher bone resorption and formationNo increased resorption in HCV groups
Correlations of Bone Turnover Markers and Bone Mineral Density
Total Hip BMD (g/cm2)
Serum Osteocalcin (ng/ml)
r= -0.28, p<0.001r= -0.21, p<0.001
Serum C-Telopeptide (ng/ml)
Total Hip BMD (g/cm2)
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
cf. Ott, Endo Reviews, 2007
RANK: receptor activator of NFκB; RANKL: receptor activator of NFκB ligandOPG: osteoprotegerin
HIV/HCV (N=28)
HIV
(N=62)
HCV
(N=45)
Controls
(N=33)
P-value Adj*
HIV vs.
non-HIV Adj*
HCV vs.
non-HCV Adj*
HIV-HCV
inter-action
Osteocalcin ng/mL 18.5 (6.3) 21.7 (8.9) 15.7 (6.5) 15.8 (5.1) <0.01 <0.01 0.17 0.58
Bone Sp Alk Phos U/L 37.1 (12.1) 34.7
(11.4)33.6 (10.1) 26.1 (8.7) <0.01 <0.01 <0.01 0.50
C-telopeptide (CTX) ng/mL 0.62 (0.24) 0.58
(0.29)0.45 (0.23)
0.41 (0.15) 0.01 <0.01 0.44 0.93
RANKL pmol/L 236 (306) 131 (168) 190 (201) 179 (118) 0.23 0.89 0.08 0.29Osteoprotegerin (OPG) pmol/L 4.9 (2.5) 4.3 (1.5) 4.9 (2.2) 3.6 (1.2) <0.01 0.24 <0.01 0.48RANKL/OPG ratio 49 (53) 34 (40) 40 (31) 52 (34) 0.37 0.5 0.88 0.11
Impact of HIV and HCV on Bone Markers and Turnover Regulation
*Controlling for Age, BMI and Race
Data shown as mean (standard deviation)
RANK: receptor activator of NFκB; RANKL: receptor activator of NFκB ligand
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 HIV
OSTEOPOROSIS and
FRACTURE RISK
Advancing age, Improved SurvivalHypogonadism
Glucocorticoids
Low BMI, Malnutrition
Tobacco, EtOH, Drugs
Race/Ethnicity, Genetics
HIV
HAART (TDF)
HCV
FibrosisCirrhosis
High Bone Turnover
?
NoTurnover; OPG?
?
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
Hepatol 2011)– Tenofovir:
• Renal insufficiency with secondary hyperparathyroidism • Proximal tubular dysfunction? (Hamza, 7th IAS; MOPE076)
Potential Mechanisms for Increased Bone Turnover in HIV: HAART ImpactTDF/FTC/DRV/r vs RAL/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• 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