Transcript Powerpoint

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
Disease specific
factors
HCV
HIV
The virus
The virus (inflammation)
Severity of liver disease?
Immune reconstitution
HAART (TDF)
Hypogonadism
OSTEOPOROSIS and
FRACTURE RISK
Tobacco, EtOH, Drugs
Glucocorticoids
Traditional
risk factors
Advancing age,
Improved Survival
Low BMI,
Malnutrition
Race/Ethnicity,
Genetics
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-toplatelet ratio (APRI; HR: 1.32; p=
0.001) or the presence of cirrhosis
(HR: 1.30; CI: 1.09-1.54; p=0.003).
4.5
HIV/HCV
Fracture Rate
(per 1,000 patient-years)
4
HIV
3.5
3
2.5
2
1.5
1
0.5
0
< 0.5
0.5-1.5
APRI
1Bedimo
≥ 1.5
•Johns Hopkins Cohort: 179 HIV/HCV
patients 3
of liver disease (METAVIR
<1.45 •Severity
1.45-3.25 > 3.25
score)
did not predict low BMD
FIB-4
et al., AIDS 2012; 2Maalouf et al., JBMR 2013;
3 El-Maouche et al. J Hepatol 2011
Goals of the study
Disease specific
factors
HCV
Q1. What
are the
mechanisms?
HIV
The virus
The virus (inflammation)
Severity of liver disease?
Immune reconstitution
HAART (TDF)
Hypogonadism
OSTEOPOROSIS and
FRACTURE RISK
Tobacco, EtOH, Drugs
Glucocorticoids
Traditional
risk factors
Advancing age,
Improved Survival
Low BMI,
Malnutrition
Race/Ethnicity,
Genetics
Goals of the study
Disease specific
factors
HCV
HIV
The virus
The virus (inflammation)
Severity of liver disease?
Q2. How much is
HIV?
How much HCV?
Is there an
interaction?
Immune reconstitution
HAART (TDF)
Hypogonadism
OSTEOPOROSIS and
FRACTURE RISK
Tobacco, EtOH, Drugs
Glucocorticoids
Traditional
risk factors
Advancing age,
Improved Survival
Low BMI,
Malnutrition
Race/Ethnicity,
Genetics
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
Age* (years)
Race / Ethnicity (% AA/C/H)
BMI* (Kg/m2)
HIV/HCV
(N=28)
HIV
(N=62)
HCV
(N=45)
Controls
P-Value
(N=33) (Unadjusted)
55 (6)
57 (8)
55 (5)
53 (8)
0.048
71/25/4
32/55/13
67/27/7
88/12/0
<0.0001
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 vs. HCV vs. HIVnonnonHCV
HIV
HCV
interAdj*
Adj*
action
HIV/HCV
(N=28)
HIV
(N=62)
HCV
(N=45)
PControls
value
(N=33)
Adj*
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
BMD T-score
Mean (SD)
• 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 T-Scores
Control
HCV
HIV
HIV/HCV
Femoral neck
Total hip
L-spine
-4
-3
-2
T-Score
-1
0
Impact of HIV and HCV on T-Scores
Percent Osteoporosis at F Neck
66
63
70
62
58
57
60
50
50
37
37
40
30
20
10
8
13
% Osteopenia or Osteoporosis
5
0
HIV/HCV
% Osteopenia
0
HIV
% Osteoporosis
HCV
Control
Impact of HIV and HCV on Bone Markers
HIV
HCV vs. HIVPvs.
HIV/HCV HIV
HCV Controls
nonHCV
value non(N=28) (N=62) (N=45) (N=33)
HCV
interAdj* HIV
Adj* action
Adj*
Osteocalcin
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)
0.62 (0.24) 0.58 (0.29) 0.45 (0.23) 0.41 (0.15) 0.01
<0.01
0.44
0.93
ng/mL
ng/mL
18.5 (6.3)
C-telopeptide
ng/ml
Bone Sp Alk Phos
U/L
0.0
0
10
20
30
40
50
0.4
0.6
0.8
HIV groups had higher bone resorption
and formation
No increased resorption in HCV groups
Control
HCV
HIV
HIV/HCV
Osteocalcin
ng/ml
0.2
60
Data shown as mean (standard deviation)
*Controlling for Age, BMI and Race
1.0
Correlations of Bone Turnover Markers and
Bone Mineral Density
Total Hip BMD (g/cm2)
r= -0.21, p<0.001
Serum C-Telopeptide (ng/ml)
Total Hip BMD (g/cm2)
r= -0.28, p<0.001
Serum Osteocalcin (ng/ml)
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
HIV
HCV vs. HIVPvs.
HIV/HCV HIV
HCV Controls
nonHCV
value non(N=28) (N=62) (N=45) (N=33)
HCV
interAdj* HIV
Adj* action
Adj*
Osteocalcin
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
0.23
0.89
0.08
0.29
ng/mL
Osteoprotegerin
pmol/L
(OPG)
RANKL/OPG
ratio
18.5 (6.3)
236 (306)
131 (168) 190 (201) 179 (118)
4.9 (2.5)
4.3 (1.5)
4.9 (2.2)
3.6 (1.2)
<0.01
0.24
<0.01
0.48
49 (53)
34 (40)
40 (31)
52 (34)
0.37
0.5
0.88
0.11
RANK: receptor activator of NFκB; RANKL: receptor activator of NFκB ligand
Data shown as mean (standard deviation)
*Controlling for Age, BMI and Race
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
Fibrosis
Cirrhosis
HCV
HIV
?
?
NoTurnover; OPG?
Hypogonadism
HAART
(TDF)
High Bone Turnover
OSTEOPOROSIS and
FRACTURE RISK
Advancing age,
Improved Survival
Tobacco, EtOH, Drugs
Glucocorticoids
Low BMI,
Malnutrition
Race/Ethnicity,
Genetics
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 Impact
TDF/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 CX00041801A1
• 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