HIV and HCV Independently Lower BMD through Different Mechanisms N Maalouf, MD; S Zhang, PhD; H...

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

Fra

ctu

re R

ate

(per

1,0

00 p

atie

nt-

year

s)

HIV/HCV

HIV

< 0.5 ≥ 1.50.5-1.5

APRI

<1.45 > 3.251.45-3.25

FIB-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


Glucocorticoids




HIV

HAART (TDF)

HCV

The virus






Q1. What are the mechanisms?

Goals of the study

OSTEOPOROSIS and

FRACTURE RISK


Glucocorticoids




HIV

HAART (TDF)

HCV

The virus






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


T-Score

-4 -3 -2 -1 0

L-spine

Total hip

Femoral neck

Control HCV HIV HIV/HCV


Percent Osteoporosis at F Neck

HIV/HCVHIV

HCVControl

0

10

20

30

40

50

60

70

% Osteoporosis

% Osteopenia

% Osteopenia or Osteoporosis

813

5

0

58

50

57

37

66

6362

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 0.29

Osteoprotegerin (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 0.48

RANKL/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


Glucocorticoids




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

HIV and HCV Independently Lower BMD through Different Mechanisms N Maalouf, MD; S Zhang, PhD; H...

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