ias-usa update: abnormal glucose metabolism and bone disease in hiv-infected patients kimberly y....

IAS-USA Update: Abnormal Glucose Metabolism and Bone Disease in HIV-Infected Patients

IAS-USA Update: Abnormal Glucose Metabolism and Bone Disease in HIV-Infected Patients

Kimberly Y. Smith, MD, MPH

The International AIDS Society–USAKY Smith, MD, MPH.Presented at IAS–USA/RWCA Clinical Conference, June 2005.

KY Smith, MD, MPH. Presented at IAS–USA/RWCA Clinical Conference, June 2005.

Abnormal Glucose Metabolism

Slide #3


Case JB is a 34 yo HIV male (dx 7/01) who has been

clinically stable and virologically suppressed on fd[ZDV+3TC]+ efavirenz for 3+ yrs

PMH: mild HTN FH: DM, HTN, CVA SH: social TOB and ETOH Meds: fd[ZDV+3TC], efavirenz, omeprazole,

HCTZ Physical exam remarkable for mild obesity Weight: 234; Height: 5’7’’ (BMI=36.6)

Slide #4


Case-JB

Labs: CD4: 800-1000, VL: <50 {2002-2004} Tchol: 170-220; LDL 90-110 HDL: 21-27;

Trig: 350-600 Fasting glucose: 110-130 HbA1C: 6.5% (nondiabetic: <6.0%)

Slide #5


Possible Interventions

Increase Exercise and Improve Diet Switch efavirenz to nevirapine Add Insulin sensitizing Agent

Slide #6


Glucose Metabolism:PI-Associated History

Milestones

1997

FDA issues health advisory on PI use and hyperglycemia and diabetes cases1

1998

Insulin resistance and diabetes reported2,3

1999

Long-term NRTI use is not associated with abnormalities4

Significant hyperinsulinemia occurs in women independent of PI use5

2001

Some PIs have a direct effect onimpairing glucose transport6,7

1FDA Talk Paper. June 11, 1997. 2Carr A, et al. AIDS. 1998;12:F51-F58.

3Viraben R, et al. AIDS. 1998;12:F37-F39. 4Saint-Marc T, et al. AIDS. 1999;13:1659-1667.

5Hadigan C, et al. J Clin Endocrinol Metab. 1999;84:1932-1937.6Nolte LA, et al. Diabetes. 2001;50:1397-1401.

7Noor MA, et al. AIDS. 2001:15:F11-F18.

Slide #7


Impaired Glucose Metabolism: Reported Incidence Glucose metabolism (HOPS)1 - 5%-17% Hyperglycemia (SALSA)2 -15% (Men) 6%

(Women) Glucose intolerance (APROCO)3

Impaired Glucose metabolism4 - 16.2%

Insulin resistance5- 23% ; 55% (PIs) 27% (NRTIs)

Diabetes mellitus2,3,6,7 2.4%-4.4%

HOPS, HIV Outpatient Study; SALSA, Self Assessment Lipodystrophy Study

Slide #8


HIV-Infected Men at Increased Riskfor Diabetes Data from MACS: HIV-infected men on ART

develop prediabetes (fasting plasma glucose [FPG] 110mg/dL and <126 mg/dL) and diabetes (FPG 126 mg/dL) at a higher rate than HIV-negative men

Of 627 men evaluated, 71 demonstrated prediabetes and 28 had diabetes

Risk in HIV-positive men on therapy vs HIV-negative men 1.4 x higher for prediabetes 1.8 x higher for diabetesBrown TT, et al. 5th International Workshop on ADR and Lipodystrophy; July 8-11, 2003. Abstract 43.

Slide #9


Prevalence of Diabetes inHIV Infection

Medi-Cal database (July 1994–June 2000) Examined for diabetes

mellitus age-specific incidence rates

Diabetes mellitus diagnosed by ICD-9 codes

7,101,180 person-years 7,219 HIV (61% male) 2,792,971 non-HIV people

(30% male)0

2

4

6

8

10

12

14

Inci

den

ce o

f D

iab

etes

Mel

litu

sIn

cid

ence

of

Dia

bet

es M

ellit

us

(per

100

per

son

-yea

rs)

(per

100

per

son

-yea

rs)

18-24 25-34 35-44 45-54 55-64 65+

Age Group (y)

Currier JS, et al. 9th CROI. Seattle, 2002. Abstract 677-T.

HIV HIV Non-HIVNon-HIV

Slide #10


Obesity and HIV study 1678 patients in the U of Penn Center for AIDS Research Clinical

Core Cohort Registry were enrolled in this retrospective cross-sectional study. Definitions: overweight (BMI 25 -29.9 kg/m2); obese (>30 kg/m2);

wasting BMI<20 kg/m2. Results

Data were available for 1654 (98.6%) subjects. 78% men, 60% AA, 46% smokers, 18% with prior IDU, 67% with income

<25,000. Median CD4: 377 cells/µL; 52% had a viral load <400 copies/mL; 9%

treatment naïve. Overweight 31%, Obesity14%, and Wasting 9%

Women vs. Men; Overweight (30% vs 31%, p = 0.655), Obese (29% vs 11%, p <0.001).

AA vs. Non-AA: overweight or obese (49% vs 42%, p = 0.012). Current CD4 >200 (RR 2.0, 1.5 to 2.6) associated with being overweight or

obese. Current smoking was protective (RR 0.6, 0.5 to 0.7).

V Amorosa et AL. A Tale of 2 Epidemics: The Intersection between Obesity and HIV Infection in the Urban United States. Abstract 879 (poster). 11th CROI. Feb 8-11, 2004. San Francisco, CA.

Slide #11


Obesity and HIV study

In a logistic regression model, female sex (RR 2.0, 1.5-2.7), AA race (RR 1.3, 1.0-1.6), smoking (RR 0.6; 0.5-0.8), and CD4 (for each 100 cells/µL increment, RR 1.11, 1.06-1.16) were independent predictors of obesity.

Age, income, employment, education, past or current IDU, being on HIV treatment and viral load were not associated with obesity.

Conclusions Obesity is a much more common problem than wasting in the

current therapeutic era. The combined 45% prevalence of overweight and obesity is less than the overall 60% population prevalence for the state of Pennsylvania, it is nonetheless of epidemic proportion.

V Amorosa et AL. A Tale of 2 Epidemics: The Intersection between Obesity and HIV Infection in the Urban United States. Abstract 879 (poster). 11th CROI. Feb 8-11, 2004. San Francisco, CA.

Slide #12


American Diabetic Association Definitions

Slide #13


Metabolic Syndrome The Metabolic Syndrome was defined by NCEP

(ATP-III) criteria, which requires individuals to have at least three at the following; abdominal obesity (defined by waist

circumference measurement), triglycerides >150mg/dl, blood pressure (>130mmHg systolic or >85

diastolic), fasting glucose >110mg/dl, low HDL-cholesterol (<40mg/dl in men, <50mg/dl

in women).

Slide #14


Diabetes Mellitus:Screening Recommendation Fasting plasma glucose

Before starting antiretroviral therapy 3-6 months after starting antiretroviral therapy Annually thereafter

Schambelan M, et al. J Acquir Immune Defic Syndr. 2002;31:257-275.

Slide #15


Diabetes Risk Factors

M. Dube- Insulin Resistance and HIV-Infected Patients…. clinicaloptions.com

Slide #16


Indinavir vs. Amprenavir

Dube MP et al. JAIDS 2001 27:130-34; Dube MP CID 2002: 35; 475-81

Slide #17


Atazanavir/r vs. Lopinavir/r

New cases of metabolic syndrome Atazanavir/r – 9 Lopinavir/r- 16

Regression in individuals with the metabolic syndrome at baseline 14 of 31 cases in the atazanavir

group 10 of 31 cases in the lopinavir/r

group. A logistic regression model

adjusted for baseline metabolic syndrome status suggested a lower risk for metabolic syndrome in atazanavir/r treated subjects (OR=0.52, 95%CI 0.27-1.01)

U Iloeje, Y Wu, P Cislo, T Kelleher, L Odeshoo, M Giordano Risk of metabolic syndrome (metsyn) among highly-treatment

experienced HIV-infected patients - 48 week results from BMS study AI 424045 WePeB5957

Slide #18


Management Strategiesfor Diabetes

Prevention in HIV/AIDS Same as in HIV-negative population

Diet, reduced alcohol use, exercise, weight reduction

Treatment Same treatment as for HIV-negative patients

Optimal management of impaired glucose tolerance is not known (2-hour glucose >140 mg/dL and <200 mg/dL)

Insulin sensitizing agents: Rosiglitazone

Metformin1,2

Possible role for switching antiretroviral agents

1Saint-Marc T, et al. 6th CROI. Chicago, 1999. Abstract 672.2Fonseca V, et al. JAMA. 2000;283:1695-1702.

Slide #19


Studies of Rosiglitazone for Insulin Resistance and Fat Redistribution in HIV-Infected Subjects

M. Dube- Insulin Resistance and HIV-Infected Patients…. clinicaloptions.com

Slide #21


Case Follow-up

Had prolonged and repeated discussions with patient informing him that he was in early stages of diabetes, offered diet recommendations

6 months later, 25lb weight loss due to exercise and diet

9 months later: Fasting glucose: 85; trig: 205; Tchol: 150; LDL: 78; HDL: 32

Slide #22


Bone Disorders

Osteopenia and osteoporosis have been described as adverse events associated with HIV disease

Data on the effects of HAART on bone abnormalities are conflicting

Little data are available on the prevalence of bone abnormalities in HIV-infected men and women

Guaraldi G, et al. AIDS. 2001;15:137-138.Amiel C, et al. 9th CROI. Seattle, 2002. Abstract 715-T. Arnsten JH, et al. 9th CROI. Seattle, 2002. Abstract 717-T.Peabody et al. XIV IAC. Barcelona, 2002. Abstract ThPeB7330.

Slide #23


Basic definitions t- score: # of Std deviations between the obtained result and the

value expected in a young person (20-35 years). z- score: # of Std deviations between the obtained value and an

age and sex-matched value for healthy individuals

Osteopenia: Diffuse decrease in bone mineral density (BMD). T-score b/w 1 and 2.5 std deviations below average found in young

persons (-1 to -2.5)- 2x fracture risk Osteoporosis: Decrease in mass PLUS disruption of normal

bone architecture. T-score lower than 2.5 std deviations below average found in young

persons (< -2.5)- 4-5x fracture risk Osteonecrosis/ avascular necrosis: Death of bone tissue due

to compromised blood flow.

Slide #24


Risk factors for osteopeniaNon-HIV related

Older age

Female sex/menopause

Ethnicity (Asian, Hispanic)

Family history

Smoking

Alcohol use

Estrogen/testosterone

Weight loss/low BMI

Physical inactivity

Pancreatitis

SLE/vasculitides

Medications (steroids,benzodiazepine,

anticonvulsants, heparin, vitamin A)

HIV relatedHIV infection

Steroid use (PCP rx)

Wasting

Nadir CD4 count

HAART use?

Protease inhibitor use?

Nucleoside analogues?

Tenofovir?

Lipid lowering agents?

Slide #25


Why are HIV+ patients at risk for osteopenia?

Direct virus effect on osteogenic cells HIV+ pts have increased osteocalcin levels Increased T cell activation (TNF-a, IL-6) Decreased formation and increased resorption

markers Hypogonadism Mitochondrial abnormalities/lactic acidemia Alterations in Vitamin D metabolism

Aukrust P, et al. Aukrust P, et al. J Clin Endocrinol Metabol. J Clin Endocrinol Metabol. 1999;84:145-150.1999;84:145-150.

Slide #26


Cross sectional study—HIV+ on PI (n=60), vs HIV+ no PI (n=35) vs HIV- (n=17). HIV+PI+ 50% rate of osteopenia/porosis (OR

2.19) (p=0.02).1

Longitudinal study—93 HIV+pt followed prospectively for 72 wks.2 Classic risk factors (low BMI, wt loss, steroid use,

smoking) associated with osteopenia. Weak association b/w low BMD and PI use.

Osteopenia in HIV+ patients

1Tebas, et al. AIDS 2000,14:F63-F67; 2Mondy et al, CID 2003;36:482-90

Slide #27


WIHS study—84 HIV+ women, 63HIV-.1 Hip and L-spine BMD decreased in HIV vs controls. Osteopenia (54% vs 30%) (OR 2.5), Osteoporosis (10% vs 5%)(n=ns). No difference in BMD by PI/NNRTI or NRTI use. ()

55 HIV+ on HAART, 35% osteopenia, 10% osteoporosis. HIV+ pts had increased osteocalcin,osteoprotegrin and

cholesterol. Negative correlation b/w chol and BMD (p=0.01).


1AIDS 2004;18:475-83, CROI 2005 #824

Slide #28


Nutrition For Healthy Living (NFHL) cohort.1 HIV+ pts had lower BMD. Predictors of low BMD were smoking, menopause, bilirubin>2,

longer DDI,Tenofovir use.

Gilead 903 study2. High prevalence of osteopenia at BL (23% TDF, 28% D4T) with

no significant change at wk 144 (28% TDF, 27% D4T). Both arms had decreases in BMD.

Similar at the hip (mean chg -2.8 vs -2.4)(p=0.064), greater at the spine for TDF (-2.2 vs -1.0) (p=0.001).

17 fractures in both arms (16 traumatic). No fractures in the patients with osteoporosis at BL or wk 144 (~3-5%).


1CROI 2005 (#825), 2CROI 2005 (#823)

Slide #29


Influence of HAART on Bone Remodeling After 24 months of HAART

Marked rise in serum osteocalcin levels

Profound fall in TNF components and viral load

Significant correlation between osteocalcin and C-telopeptide

Aukrust P, et al. Aukrust P, et al. J Clin Endocrinol Metabol. J Clin Endocrinol Metabol. 1999;84:145-150.1999;84:145-150.

Slide #30


Antiretroviral agents affect bone in different ways. IDV alters activity of osteoblastic alk(p) in vitro RTV, NFV, IDV—have effects on osteocyte

differentiation and vitamin D metabolism No link between PI or rx duration (Carr) Tenofovir caused osteomalacia in monkeys

(reversible) and reduced BMD in rats and dogs. Mechanism(s) of bone toxicity unknown. ?RTA,? Calcium mobilization from bone.

NRTI’s may cause hyperlactatemia, chronic acid loading which leads to mobilization of bone alkali.

Slide #31


Osteopenia [clinical features] Osteopenia/osteoporosis usually

asymptomatic until patient develops a fracture

Suspect in the presence of non-traumatic fracture.

Patients with low BMI, females and prior steroid use are at higher risk

Slide #32


Osteoporosis:Diagnosis and Treatment

X-rays Bone densitometry DEXA scanning Quantitative CT scan Neutron activation

analysis

DiagnosisDiagnosis TreatmentTreatment

National Osteoporosis Foundation 2002.National Osteoporosis Foundation 2002.Hoy J, et al. 7th CROI. San Francisco, 2000. Abstract 208.Hoy J, et al. 7th CROI. San Francisco, 2000. Abstract 208.

Tebas P, et al. 7th CROI. San Francisco, 2000. Abstract 207.Tebas P, et al. 7th CROI. San Francisco, 2000. Abstract 207.

Oral calcium Vitamin D Estrogens Androgen therapy Bisphosphonates Thiazide diuretics Sodium fluoride

Slide #33


Markers of bone turnover

Deoxypridoline (DPD) Increased urinary levels correlate with increased rates of osteoporosis and fractures

Osteocalcin (marker of bone formation) Osteoprotegerin C-telopeptides Urinary N-telopeptides of type 1 collagen (NTx)

• These markers can be measured in urine + serum and have been used as surrogates in studies of bone metabolism/disease.*

• Have been shown to predict fracture risk independently of BMD in some populations (high bone turnover predicts risk in post menopausal women) though remain controversial.

Marked circadian rhythm, with most markers increased at night (peak between 2-8 am)

Slide #34


Management options(mostly adapted from HIV negative populations)

Lifestyle changes Calcium/ Vitamin D

supplementation Bisphosphonates Hormone

replacement therapy (estrogens, progestins)

SERM (raloxifene) Calcitonin Teriparatide Tibolone (synthetic

steroid) Strontium ?Statins Switching therapy?

Slide #35


Management options

Lifestyle changes: Stop smoking, alcohol use, avoid marked weight loss/wasting, exercise.

Calcium/Vitamin D supplementation (combination tablets available)

Clinical trials have shown reduction in fractures with calcium/Vit D. At risk patients should have a daily dietary intake of 1000mg elemental calcium (up to 1500mg/day if strong family history or osteoporosis)

Vitamin D intake 400-1000IU/day

Slide #36


Management optionsBisphosphonates Slow down or stop bone

resorption Approved for established

osteoporosis or high risk osteoporosis

Etidronate, Palmidronate, alendronate,* risendronate

Teriparatide 1st in a new class of

meds Recombinant human

PTH Stimulate new bone

formation by increasing the # and/or activity of osteoblasts

Approved in 2001 for the rx of osteoporosis in post menopausal women

SC injection only*Most widely used with improved efficacy over the older bisphosphonates. Well conducted large clinical trials in HIV negative patients support its use. 80% taken up by bone, excreted unchanged in the urine. GI side effects are the main concern.

Slide #37


Alendronate use in HIV+ patients Case report—51 y/o HIV+ osteoporotic fracture

(-score=-3.85) and after alendronate for 6 months (+Calcium and Vit D) (-score=-2.35 (+20% increase)).

52 week study (t-score <-1).—18 pts randomized to Alendronate vs 23 controls (all received Calcium, vit D). Alendronate caused decrease in N-Telopeptides (0.005),improved lumbar BMD (0.004) and minimized femoral BMD decrease (0.05).

Guaraldi et al, CID 2001;33:414Guaraldi et al, HIV Clin Trials 2004;5(5) 269-77

Slide #40


Avascular Necrosis (Osteonecrosis) Etiology

Death of cellular elements of bone, often secondary to impairment in blood supply

Risk factors Corticosteroid treatment, connective tissue disease,

embolization, alcohol use

Common sites Femoral and humoral heads, femoral condyles, proximal

tibia

Hip disease is bilateral in 50% of cases

Glesby MJ, et al. Glesby MJ, et al. J Infect Dis. J Infect Dis. 2001;184:519-523.2001;184:519-523.Miller KD, et al. Miller KD, et al. Ann Intern MedAnn Intern Med. 2002;137:17-25.. 2002;137:17-25.

Slide #41


Avascular Necrosis:Diagnosis and Treatment

Clinical presentation Abrupt onset of articular pain Hip is the most common>femur (knee)>humeral head

(shoulder)>>>small joints of hands and feet. Often bilateral (40-60%) Most often progressive with joint destruction in 3-5 years if untreated.

Imaging X-rays- low sensitivity Bone Scan- Doughnut sign (increased uptake around a cold area). MRI- most sensitive (~91%) and specific modality. Picks up abnormalities

at the earliest stage. Treatment

Surgical, with possible joint replacement

Slide #42


Osteonecrosis

This image demonstrates a classic segmental area of osteonecrosis with a dark line denoting the border between dead bone and living bone.

MRI showing osteonecrosis of right hip, normal left hip.

M. Levine. Ostoenecrosis of the hip- emedicine.com

Slide #43


Avascular necrosis in HIV Reported prior to the HAART era but seems to be increasing

with HAART use. A review of 35 cases in the literature – mean age 35 yrs, 64%

male, 33% had HIV as only risk factor. Other risk factors included steroid use (21%), h/o IDU (21%), hyperlipidemia (12%), alcohol use (12%). 55% were on HAART.

Hopkins cohort (1995-2000) increased rates of AVN 4.8/1000 person years >> general population. (associated with low CD4, increased duration of HIV, elevated lipids and steroid use)

From Spain frequency of AVN 1.6/1000 (93-96) to 14/1000 (97-2000). (80% advanced disease, 90% 1 other risk factor, 70% on HAART)

Monier et al, CID 2000;31:1488-92, Moore et al, AIDS 2003

Slide #44


Management of AVN Prevention-

Risk reduction; judicious steroid use, discontinue alcohol, tobacco use, treat co-morbidities.

Calcium and Vitamin D supplementation Manage hyperlipidemia Screening not recommended

Medical/conservative Avoid weight bearing on affected joint Physical therapy Analgesics, anti-inflammatory agents Early referral to orthopedic surgeon

Surgical

Slide #45


Summary Osteopenia, osteoporosis, and avascular necrosis are

being reported in patients with HIV infection Effect of HAART is controversial Various risk factors may contribute to their

development Clinicians need to be aware of this potential

complication and treat early Further study is needed

ias-usa update: abnormal glucose metabolism and bone disease in hiv-infected patients kimberly y....

Documents