Slide 1
Complicações Metabólicas e
Ósseas da Infecção pelo HIV:
Sugar and Bones
Todd T. Brown, MD, PhD
Associate Professor of Medicine and Epidemiology
Division of Endocrinology, Diabetes, & Metabolism
Johns Hopkins University
Baltimore, Maryland, USA
Slide 2
Disclosures
• Dr Brown has served as a consultant to
Gilead, ViiV Healthcare, Merck, Abbvie,
EMD-Serono, and Theratechnologies.
Slide 3
Endocrine and Metabolic
Conditions are Prevalent Among
HIV-infected Persons
• Osteoporosis
• Diabetes Mellitus
• Dyslipidemia
• Hypogonadism
HIV
Slide 4
Endocrine and Metabolic
Conditions are Prevalent Among
HIV-infected Persons
• Osteoporosis
• Diabetes Mellitus
• Dyslipidemia
• Hypogonadism
Aging
HIV
Slide 5
Endocrine and Metabolic
Conditions are Prevalent Among
HIV-infected Persons
• Osteoporosis
• Diabetes Mellitus
• Dyslipidemia
• Hypogonadism
Aging
HIV Inflammation
Slide 6
Endocrine and Metabolic
Conditions are Prevalent Among
HIV-infected Persons
• Osteoporosis
• Diabetes Mellitus
• Dyslipidemia
• Hypogonadism
Aging
HIV Fracture
CVD
Frailty
Slide 7
Objective
• To know the optimal evaluation and
treatment of endocrine and metabolic
problems in HIV-infected patients,
focusing on osteoporosis and diabetes
mellitus
Slide 8
Bones
Slide 9
Wasnich RD, Osteoporos Int 1997;7 Suppl 3:68-72 Images from the National Osteoporosis Foundation
Fragility Fractures in Women
and Men over 50 years
Slide 10
10
Fracture Prevalence in HIV-infected and
non-HIV-infected Persons in MGH/Partners
Healthcare System: 1996-2008
Women Men
Triant, JCEM, 2008
8,525 HIV-infected
2,208,792 non HIV-infected patients
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
30-39 40-49 50-59 60-69 70-79
Fra
ctu
re P
reva
len
ce
/100
Pe
rson
s
HIV Non-HIV
P=0.002
(overall comparison)
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
20-29 30-39 40-49 50-59 60-69
Fra
ctu
re P
reva
len
ce
/100
Pe
rson
s
P<0.0001
(overall comparison)
HIV Non-HIV
Slide 11
11
Prevalence of Osteoporosis in HIV-
infected Patients vs HIV-uninfected
Controls: A Meta-analysis
Brown, AIDS, 2006
Overall prevalence of osteoporosis in HIV-infected patients 15%
Odds ratio
.01 1 100
Amiel (2004)
Brown (2004)
Bruera (2003)
Dolan (2004)
Huang (2002)
Knobel (2001)
Loiseau-Peres (2002)
Madeddu (2004)
Tebas (2000)
Teichman (2003)
Yin (2005)
Overall (95% CI)
5.03 (1.47,17.27)
4.26 (0.22,82.64)
4.51 (0.26,79.27)
2.11 (0.54,8.28)
3.52 (0.15,81.92)
5.13 (1.80,14.60)
4.28 (0.46,39.81)
29.84 (1.80,494.92)
3.40 (0.19,61.67)
17.41 (0.97,313.73)
2.37 (1.09,5.16)
3.68 (2.31,5.84)
Study
Odds ratio
(95% CI)
Slide 12
12
Pathophysiology and Risk Factors
• HIV Disease Factors • Inflammation and Viral Proteins
–↑bone resorption
– ↓ bone formation
• Medication Factors
– Tenofovir (TDF)
– Certain PIs
– ART initiation (↓ 2-6% over 96 weeks)
Slide 13
13
Pathophysiology and Risk Factors
• Patient-Related Factors
– Low Body Weight
– Smoking
– Alcohol Use
– Opiate Use
– Hepatitis C Co-infection
– Physical Inactivity
– Hypogonadism
– Low Vitamin D
Slide 14
14
To Screen or Not to Screen….
DXA
DXA
Slide 15
15
Case Presentation: AD
• 62 year old white male referred to LD clinic for
body fat changes
• HIV diagosed in 1987, nadir CD4 22, from 1997
to 2002 on d4T/3Tc/IDV, currently
TDF/FTC/EFV
• Hypogonadism on transdermal testosterone
• COPD (60 pack-year tobacco history), multiple
steroid courses
• No history of fracture, no height loss
Slide 16
16
US National Osteoporosis Foundation (NOF)
Guidelines for DXA Screening
• Those with a fragility fracture after age 50
• Women ≥ 65 yrs, Men ≥ 70 yrs
• Younger postmenopausal women and men
50-69 years with clinical risk factors for
fracture
• Adults with a condition (e.g., rheumatoid
arthritis) or taking a medication (e.g.,
glucocorticoids in a daily dose ≥ 5 mg
prednisone or equivalent for ≥ three months)
associated with low bone mass or bone loss
Slide 17
Recommendations for DXA
Screening in Brazil
Slide 18
Slide 19
19 http://www.shef.ac.uk/FRAX/
Slide 20
20
Case Presentation: AD
Dual X-ray Absorptiometry
T-score
L1-L4 -2.2
Femoral Neck -2.2
Total Hip -2.3
Slide 21
21
Definitions
Functional Definition (DXA)- WHO Definition
• Osteoporosis: T-score < -2.5
• Osteopenia: T-score= -1.0 to -2.5
• Normal: T-score > -1.0
↑ Risk of fracture by 1.5-3.0 x for each SD decrease
Caveats:
• Z-score ( <-2.0) used in men < 50 years and premenopausal women
• BMD explains only about 50% of fracture risk
Slide 22
Secondary Causes of Low BMD
• Vitamin D deficiency 25 OH Vit D
• Hyperparathyroidism PTH, Ca++
• Subclinical Hyperthyroidism TSH
• Hypogonadism Males: Free Testosterone
• Phosphate wasting Fractional Excretion of
Phosphate
• Idiopathic Hypercalciuria 24 hr Urinary Calcium
• Celiac Sprue Tissue Transglutaminase
• Multiple Myeloma Serum Protein Electrophoresis
• Mastocytosis Serum Tryptase
• Cushing’s Syndrome 24 hr Urinary Free Cortisol
Slide 23
23
Secondary Causes of Low BMD
• Vitamin D deficiency 25 OH Vit D
• Phosphate wasting Fractional Excretion of
Phosphate
Slide 24
24
Osteomalacia • Impaired bone mineralization
• Accompanied by weakness, fracture,
pain, anorexia, and weight loss
• Treated with Vitamin D, Ca++, +/-
phosphate, not bisphosphonates
• Most important differential diagnosis for
low BMD
Slide 25
25
US NOF Guidelines: Who to
Treat*
• Those with hip or vertebral fractures
• Those with BMD T-scores ≤ -2.5 at the
femoral neck, total hip, or spine by DXA
• Those with T-score b/t -1 and -2.5
(osteopenia) at above sites AND 10-
year hip fracture probability ≥ 3% or 10-
year all major osteoporosis-related
fracture ≥ 20% based on FRAX model
*applies to post-menopausal women and men ≥ 50 years
Slide 26
26 http://www.shef.ac.uk/FRAX/
Slide 27
27
Slide 28
Management Options
• General recommendations
– Calcium/vitamin D supplementation
– Smoking cessation, Alcohol reduction
– Weight-bearing exercise
– Assess fall risk (Are you worried about falling?)
• Strength/Balance Training
• Rx options – Bisphosphonates
– Selective estrogen receptor modulator
– Estrogen
– PTH analogue
Slide 29
29
Considerations When Choosing
Between Bisphosphonates Alendronate Risedronate Ibandronate Zoledronate
Efficacy +++ ++ + +++
Cost (1 year) $350 $350 $1200 $1100
Compliance - - - (oral)/ + (IV) +
GI Side Effects Yes (20%) Yes (20%) Yes
(oral)/No(IV)
No
Osteonecrosis of
the Jaw
Yes Yes Yes Yes
Acute Phase
Reaction
No No No
(oral)/Yes(IV)
Yes (~10%)
Atrial Fibrillation ? ? ? ?
Esophageal
Cancer
? ? ? No
Atypical Femoral
Fracture
Yes Yes Yes Yes
Slide 30
Would you switch him off of
TDF? 1. Yes
2. No
Slide 31
ART Management
Slide 32
Switch from TDF to ABC in Osteopenia/Osteoporosis
Changes in Spine and Hip BMD at Week 48
OsteoTDF Study
Negredo E, et al. J of Antimicrob Chemother. E-published August 13, 2014. doi:10.1093/jac/dku300.
Two-centered, randomized pilot study in virologically suppressed subjects receiving TDF with
osteopenia/osteoporosis. Twenty six subjects switched to ABC and 28 continued TDF.
In this small cohort,
switching from TDF to ABC
resulted in increases in hip
and decreases in spine BMD
at week 48.
Slide 33
Open-label, non-randomized study comparing BMD changes at week 48 in patients
with osteopenia/osteoporosis at baseline on TDF, switching to RAL with boosted PI
(N=37).
Switch from TDF to ABC in Osteopenia/Osteoporosis
Changes in Spine and Hip BMD at Week 48
TROP Study (Switch): TDF to RAL M
ea
n %
Ch
an
ge
fro
m B
L
at
We
ek
48
Changes in Spine and Hip BMD at Week 48
3.0% 2.5%
P <0.001 P <0.001
* Left total hip
In this small switch cohort, there are increases in spine
and hip BMD at week 48.
Bloch M, et al. HIV Medicine 2014;15:373-380.
Change in Spine and Hip Bone Mineral Density
Median percentage changes (Q1, Q3) in hip and spine BMD from baseline to Week 48
were 0.9% (-0.3, 2.7) and 1.9% (-0.3, 4.3), respectively
34 *Two-sided Wilcoxon signed-rank test.
12 24 36 48
0
2
4
6
Weeks
-2 0
Spine
Me
dia
n %
Cha
nge
(Q
1,Q
3)
Fro
m B
ase
line
236 226 214
BMD Changes From Baseline to W e ek 48
12 24 36 48
0
2
4
6
Weeks
-2
0
236 225 216
0.9%
p <0.001*
1.9%
p <0.001*
Hip
E/C/F/TAF
E/C/F/TAF n=
Posniak, CROI, 2015
Slide 35
Diabetes
Slide 36
Why Care about Diabetes?
• Very common with rapidly increasing
prevalence
• One of leading causes of cardiovascular
disease, blindness, ESRD, amputations,
hospitalizations
• Common in HIV-infected Populations
• Diabetes can be controlled, but
management is complicated and requires
individualization
Slide 37
Diabetes Prevalence in Brazil
Almeida-Pititto, Diabetes, Met Syn, Obesity, 2015
Slide 38
Pathogenesis of Diabetes in
HIV-infected Patients • Antiretroviral Medication Factors
– Thymidine analogues, older PIs
• HIV Factors
– Residual immune activation/inflammation
• Host Factors
– Adiposity
– HCV
– Genetic Factors: Family History, Race
– Concomitant Medications: Corticosteroids/Aytpical
Antipsychotics
Slide 39
Case
• 53 year-old African American Male, HIV+ for 20 years, on ART since 2000
• HIV RNA< 50 FTC/TDF/ EFV
• Mild/moderate lipoatrophy of face/buttocks/thighs
• Mild HTN, Normal lipids, no smoking
• Strong family history of DM
• BMI 27 kg/m2
Slide 40
Diabetes Screening
• Who?
IDSA: Prior to ART, within 4-6 weeks after ART
initiation, every 6-12 months thereafter
Slide 41
Caveats for the use of HgbA1c
for diagnosis
“For conditions with abnormal red cell
turnover….., the diagnosis of diabetes
must employ glucose criteria
exclusively”
ADA Clinical Practice Recommendations, 2016
Slide 42
HbA1c Underestimates Glycemia
in HIV-infected Persons
0
50
100
150
200
250
300
350
400
450
4 5 6 7 8 9 10 11 12 13 14
HBA1C (%)
Glu
cose
(m
g/d
L)
HIV (n=100)
- - - Control (n=200)
Glu
cose
(m
g/d
L)
Kim, Diabetes Care, 2009
8.3 mmol/L
Slide 43
Diabetes Screening in HIV-
infected Persons • How?
– Fasting Glucose
– If 5.7-6.9 mmol/L (100-125 mg/dL), consider
75 g OGTT
– Avoid A1c for screening (particularly in those
on ABC, low CD4, PIs, high MCV)
Slide 44
Case • 53 year-old African American Male, HIV+
for 20 years, on ART since 2000
• VL< 50 FTC/TDF/ EFV
• Mild/moderate lipoatrophy of face/buttocks/thighs
• Mild HTN, Normal lipids, no smoking
• Strong family history of DM
• BMI 27 kg/m2
• Fasting Glucose 8.05 mmol/L (145 mg/dL)
(confirmed)
• A1c 6.8%
Slide 45
After DM is diagnosed, what
should be the next steps?
– Lifestyle Modification
– First-line Drug
– Combination Therapy
Slide 46
Lifestyle Modifications for
Prediabetes Diabetes Prevention
Program:
• 150 minutes/week of
exercise and caloric
restriction
• goal: 7% weight loss
• ↓ 58% diabetes
incidence
Knowler WC, et al. N Engl J Med. 2002;346:393-403.
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 0
10
20
30
40
Cum
ula
tive I
ncid
ence
of D
iabete
s (
%)
Year
4.5
Lifestyle
Placebo
Slide 47
Effect of Cutting 500 cal/day
over 8 weeks in Obese Persons
Effect on Weight Effect on Inflammation
Hermana, Endocrine, 2009
Slide 48
After DM is diagnosed, what
should be the next steps?
– Lifestyle Modification
– First-line Drug
– Combination Therapy
Slide 49
Metformin: THE First Line Drug
Slide 50
Metformin: Pros and Cons Pros
• ↓ A1c ~1%
• Long Track Record
• No Hypoglycemia
• No Weight Gain
• ? CVD benefit
Cons
• GI side effects
• Lactic Acidosis (rare)
• Contraindications: – CKD (Scr>1.4 in women, 1.5 men)
– Hypoxia
– Decompensated Liver Disease
– Severe CHF
– Alcohol Abuse
– Past H/O Lactic Acidosis
• ? Worsening Lipoatrophy
Slide 51
After DM is diagnosed, what
should be the next steps?
– Lifestyle Modification
– First-line Drug
– Combination Therapy
Slide 52
What drug to add next?
• Sulfonylureas
• Glitazones (Pioglitazone)
• Insulin
• GLP-1 Analogues
• DPP-IV Inhibitors
• SGLT-2 Inhibitors
Incretins
Slide 53
Sulfonylureas: Pros and Cons
Pros
• ↓ A1c ~1%
• Long Track Record
• ↓ Microvascular
Events
• Cost* ($7/month)
Cons
• Weight Gain
• Hypoglycemia
• High Failure Rate
*lowest price for average dose 30 day fill at goodrx.com
Slide 54
Pioglitazone: Pros and Cons
Pros
• ↓ A1c ~1%
• No Hypoglycemia
• ? CVD benefit
• ↑ HDL, ↓ TGs
• ↓ Liver Fat
• ? ↓ Inflammation
• Low Failure Rate
• Modest effect on
lipoatrophy
(~200-500 g)
Cons
• Weight Gain
• Fluid Retention/CHF
• Macular Edema
• Osteoporosis/Fracture
• Bladder Cancer
Slide 55
Insulin: Pros and Cons
Pros
• ↓ A1c: Unlimited
• ↓ Microvascular
events
Cons
• Hypoglycemia
• Weight Gain
• ? Mitogenic effects
• Injectable
Slide 56
Starting Insulin in Type 2 DM
• Start with bedtime glargine, detemir, or NPH (10-
15 units, increase by 2-3 units q 3 days until
fasting is < 6.6 mmol/L (120 mg/dl))
• Add prandial insulin if not at goal.
• Recommended as first line if A1c >9%, severe
liver disease/kidney disease,
hypertriglyceridemia
Slide 57
GLP-1 Effects in Humans: Understanding
the Glucoregulatory Role of Incretins
Promotes satiety and
reduces appetite
Beta cells:
Enhances glucose-
dependent insulin
secretion
Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.
Liver:
↓ Glucagon reduces
hepatic glucose output
Alpha cells:
↓ Postprandial
glucagon secretion
Stomach:
Helps regulate
gastric emptying
GLP-1 secreted upon
the ingestion food
Slide 58
Incretins GLP-1 Analogues
• exenetide (Byetta)
• liraglutide (Victoza)
• Exenetide LAR
(Bydureon)
• dulagltide (Trulicity)
• albiglutide
(Tanzeum)
• Lixisenatide
(Lyxumia)
DPP-IV Inhibitors
• sitagliptin (Januvia)
• saxagliptin (Onglyza)
• vildagliptin (Galvus)
• linagliptin (Trajenta)
• alogliptin
Slide 59
GLP-1 Analogues: Pros and
Cons Pros
• ↓ A1c ~1%
• No Hypoglycemia
• Weight Loss
• ? ↓ Inflammation
• ? CVD benefit
Cons
• GI Side Effects
• ? ↑ Pancreatitis/
Pancreatic Cancer Risk
Slide 60
DPP-IV Inhibitors: Pros and
Cons Pros
• No hypoglycemia
• Weight Neutral
• ? ↓ Inflammation
Cons
• ↓ A1c ~0.5%
• GI Side Effects
• ? ↑ Pancreatitis/
Pancreatic Cancer Risk
• Hypersensitivity reaction
• No CVD benefit
• Heart Failure
Slide 61
Sodium Glucose Co-transporter
2 Inhibition: The “gliflozins” • Insulin-independent reduction
in glucose
– dapaglifozin
– canagliflozin
– empagliflozin
• 0.5-1% A1c reductions
• Weight loss (~2kg)
• Lowers BP
• No hypoglycemia
• ↑ urinary tract
infections/candidiasis
• Polyuria/dehydration
• ↑ DKA risk
• ? CVD benefit (empagliflozin,
NEJM, 2015)
Pancreatic Cancer Risk
Slide 62
What drug to add next?
• Sulfonylureas
• Glitazones (Pioglitazone)
• Insulin
• GLP-1 Analogues
• DPP-IV Inhibitors
• SGLT-2 Inhibitors
Incretins
Slide 63
Questions • How should I diagnose diabetes in the HIV-
infected patient?
• After the diagnosis is made, what should be the
next steps?
• What should be the glycemic target?
• What else should I be doing to prevent
complications?
Slide 64
What should be the glycemic
target?
< 7%
Slide 65 UKPDS: MI and Microvascular
Endpoints Associated With Increasing
HbA1c
Slide 66
Meta-Analysis of Glycemic
Control and CVD in Diabetes
10% Risk Reduction for CVD No Benefit on CVD Mortality
Kelly, Annals of Int Med, 2009
2-fold Increase Risk of Severe
Hypoglycemia with Intensive
Control
Slide 67
Previous Tight DM Control and
CVD: The Legacy Effect 10 Year Follow-Up: UKPDS Study
Holman, NEJM, 2008
Blood Sugar Control in Follow-up Risk of MI over 10 years of Follow-up
Slide 68
A1c Goal
< 7% Individualization is Key:
•Tighter Control (A1c 6.0-6.5%): Younger, Healthier
•Looser Control (A1c 7.5-8.0%+): Older,
Hypoglycemia Prone, Co-morbidities
Slide 69 What else should I be doing to prevent
complications?: Microvascular
• Retinopathy: Yearly ophthalmologic exams
• Nephropathy:
– BP Control
– Spot Urine Microalbumin every 6-12 months
– ACE-I/ARB with microalbuminuria or HTN
– Lipid Control
• Neuropathy:
– Foot exams every 6-12 months
– Instruction in foot care
– Podiatry if evidence of neuropathy
Slide 70 What else should I be doing to prevent
complications?: Macrovascular
• Attention to all CV risk factors
A: Anti-platelet therapy
B: Blood pressure
C: Cholesterol
D: Diabetes/Glucose Management
S: Smoking Cessation
Steno-2 Trial (Gaede, NEJM, 2003):
CV Events ↓ by 50% with intensive control
of all CV Risk Factors
Slide 71
Conclusions
Osteoporosis • DXA screening in HIV-
infected patients in men > 50 yrs and post-menopausal women
• Treatment guidelines should follow those established for the general population
• Remember secondary causes
• Consider switches of TDF in those at higher risk
Diabetes
• Regular DM screening
• Avoid A1c for diagnosis
• Lifestyle changes are
critical
• Metformin first
• Individualize 2nd and 3rd
line-drugs
• Goal < 7% in most, but
should be individualized
• Multiprong approach to
prevent complications
