Bones of Contention – HIV and Bone Disease Dr Paddy Mallon MB BCh BAO FRACP FRCPI PhD

Bones of Contention – HIV and Bone Disease

Dr Paddy MallonMB BCh BAO FRACP FRCPI PhD

School of Medicine and Medical SciencesMater Misericordiae University Hospital

University College DublinIreland

[email protected]

UCD School of Medicine & Medical Science

Scoil an Leighis agus Eolaíocht An Leighis UCD

What are the ‘bones of contention’?

• Is low BMD more common in HIV?

• Are fractures more common in HIV?

• What’s the best measure – the ‘T’ score or the ‘Z’ score?

• Is it ARV, BMI or vitamin D?

• Which patients should I screen?







Publication Number of patients

% BMD

HIV+ HIV– HIV+ HIV–

Amiel et al 2004 148 81 82.5 35.8Brown et al 2004 51 22 63 32Bruera et al 2003 111 31 64.8 13Dolan et al 2004 84 63 63 35Huang et al 2002 15 9 66.6 11Knobel et al 2001 80 100 87.5 30Loiseau-Peres et al 2002

47 47 68 34

Madeddu et al 2004 172 64 59.3 7.8Tebas et al 2000 95 17 40 29Teichman et al 2003 50 50 76 4Yin et al 2005 31 186 77.4 56

Adapted from Brown TT & Qaqish RB. AIDS 2006; 20:2165-2174

Low BMD is common in HIV+ patients

Cazanave C et al. 17th CROI 2010. Abstract 747. Bonjoch A et al. 18 th IAC 2010. Abstract THPDB104.

Progression of BMD is common

Spain. N=391.49% osteopenic, 22% osteoporosis.Progression after 2.5 years:

- 12.5% to osteopenia- 15.6% to osteoporosis

Aquitaine cohort. N=255. 68% men. Age 44 yrs. All on ART.72% osteopenic (osteoporosis excluded)Progression after 2.3 years:

- 7.8% to osteopenia- 11.4% to osteoporosis







Frac

ture

pre

vale

nce

in w

omen

/100

per

sons

Healthcare Registry study8,525 HIV-infected patients2,208,792 non HIV-infected patientsFracture rates in women demonstrated

Overall comparison p=0.002

HIV+

HIV-

30-39 40-49 50-59 60-69 70-79

Years

Triant VA et al, JCEM 2008;93:3499-3504

7

6

5

4

3

2

1

0

Fractures are more common in HIV+ patients







Osteoporosis / osteopenia

T score = standard deviation (SD) difference from BMD of white women at peak bone density (aged 30 years)1,2

Z score = SD difference from BMD of individuals of the same age, race and gender 2

Disorder T scoreNormalOsteopeniaOsteoporosis

> –1.0–2.5 to –1.0

< –2.5Disorder Z scoreOsteoporosis < –2.0

1. World Health Organ Tech Rep Ser 1994; 843:1–1292. NIH consensus development panel on osteoporosis prevention, diagnosis and therapy. JAMA 2001; 285:785–795

<50 yrs – Z score>50 yrs – T score







#

#

*

Lumbar spine Z score

month0 3 12 24

-0.9

-0.8

-0.7

-0.6

-0.5

-0.3

-0.2

ZDV/3TC/LPV/rNVP/LPV/r

von Voderen M. et al. AIDS 2009; 23(11): 1367-1376

Within group and between-group differences all

P<0.05

• Changes in BMD accompanied by increases in markers of bone turnover

Greater loss in BMD with ART containing NRTI

ART initiation is associated with bone loss

-0.4

ABC/3TC: -1.90%TDF/FTC: -3.55%D = -1.68 ; 95% CI (-2.26, -1.09)

ABC/3TC: -1.59%TDF/FTC: -2.41%D = -0.84 ; 95% CI (-1.61, -0.06)

0

-1

- 2

- 3

- 4

0 24 48

Hip

0

-1

- 2

- 3

- 4

0 24

P<0.001

Lumbar Spine

48

P=0.036

week week

% c

hang

e in

BM

D

% c

hang

e in

BM

D

SubjectsABC/3TC: 176 134 117 182 141 125TDF/FTC: 180 156 138 183 165 143

ART and bone Loss -ABC/3TC vs TDF/FTC

Stellbrink HJ et al., EACS 2009

Lumbar Spine

McComsey GA et al. CROI 2010

Hip

ART and bone loss - ABC/3TC vs TDF/FTCACTG A5224s

PI/NNRTI

NNRTI/NRTI

PI/NRTI

-4.4

-5.81

-1.48

-7

-6

-5

-4

-3

-2

-1

0

Lumbar Spine

-2.35

-3.86

-2.73

-7

-6

-5

-4

-3

-2

-1

0

PI/NNRTI

NNRTI/NRTI

PI/NRTI

Hip

Duvivier, et al., AIDS 2009; 27:817-24

PI: LPV/r (40-74%) NNRTI: EFV (55-60%) NRTIs: AZT/3TC (85%) IDV/r (25-47%) NVP (37-45%)

ART and bone loss - PI vs NNRTI

ART and bone loss - PI vs NNRTI

Lumbar Spine

McComsey GA et al. CROI 2010

HipACTG A5224s

• Consistently associated with low BMD in HIV1-7

• In one meta-analysis, low BMI explained much of the difference in BMD between HIV+ and HIV- 8

• Association between weight loss and BMD loss observed in HIV- male populations9

• Usually associated with negative health implications• Lower BMI in HIV+ patients associated with greater loss of

BMD in prospective studies10

• Low BMI does not explain loss of BMD with ARV initiation

1. Mondy K, et al. CID 2003; 36:482–490 2. Fausto A et al. Bone 2006;38:893-7 3. Carr A et al. AIDS 2001;15:703-9 4. Nolan D et al. AIDS 2001;15:1275-80 5. Arnsten JH et al. AIDS 2007;21:617-23 6. Arnsten

JH et al. CID 2006;42:1014-20 7. Dolan SE et al. JCEM 2006;91:2938-45 8. Bolland MJ et al. JCEM 2007;92:4522-8. 9. Shen Y et al. J Bone Mineral Res 2009;24:1290-1298. 10. Bonjoch A et al. 18th IAC

2010. Abstract THPDB104.

Body Mass Index and BMD….

Vitamin D…..

• High prevalence of low vitamin D in HIV+ patients1-3

• High prevalence of low vitamin D in general population4

• Associations with EFV exposure and low 25-OH vitamin D (but not 1,25-OH vitamin D)2,5

• N=33. PHI. 45% osteopenia, 6% osteoporosis but none had vitamin D deficiency (25-OH and 1,25-OH)6

• Seasonal variation important4

• EFV use not associated with accelerated bone loss7

• High bone turnover state in HIV+ patients8

1. Jacobson D, et al. JAIDS 2008; 49:298–308, 2. Dao, CN et al, CROI 2010 #750. 3. 2. Fux et al. CROI 2010t #749. 4. Stephensen CB, et al. Am J Clin Nutr 2006; 83:1135–41. 5. Muller N. et al. CROI 2010 #752. 6. Grijsen ML et al. AIDS 2010;24

7. McComsey GA et al. CROI 2010. 8. Stellbrink HJ et al., EACS 2009

In a multivariate analysis, differences between arms were statistically significant for P1NP, Osteocalcin and BSAP

N= 114 134 112 130 114 134 113 134

81%

44%

72%

44%

92%

75%

97%

80%

0

20

40

60

80

100

P1NP Osteocalcin BSAP CTX

Una

djus

ted

% c

hang

e fr

om b

asel

ine

ABC/3TCTDF/FTC

Biomarkers and ART initiation…

Stellbrink HJ et al., EACS 2009







Who should be screened?EVERYBODY!

>40 years old use FRAX (www.shef.ac.uk/FRAX)

History of low-impact fracturesHigh falls risk

Post-menopausal womenMen >50 yrs

HypogonadismSteroid Exposure

http://www.europeanaidsclinicalsociety.org/guidelines.asp

Or

Consider DXA if ≥ 1 of following:

BMD and the ‘Double Edged Sword’

‘Main Entry: double–edged swordFunction: noun Date: 15th century: something that has or can have both favorable and unfavorable consequences’

Patient age in Brighton cohort: 1996-2009

Personal communication, M. Fisher

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

<50 >50

HIV+ patients are getting older

0

100

200

300

400

500

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

>50

>60

>70

Personal communication, M. Fisher

Most of the age increase is in the 50-60 age groupPatient age in Brighton cohort: 1996-2009

HIV+ patients are getting older

The increase in the over 50s is greater than the overall cohort

Acknowledgements

Grants / research support: Science Foundation Ireland, Molecular Medicine Ireland, European Union (NEAT), Irish Lung Foundation, Mater College, GlaxoSmithKline, PfizerSpeaker Bureau / Honoraria: GlaxoSmithKline, ViiV Healthcare, Merck, Gilead, Abbott, Tibotec, BMS

Documents

Bones of Contention – HIV and Bone Disease Dr Paddy Mallon MB BCh BAO FRACP FRCPI PhD