Transcript Complications of HIV Infection and its Therapies

Metabolic Complications of HIV
Infection and Antiretroviral
Therapy (ART)
Christopher Behrens, MD
University of Washington
Metabolic Complications of HIV
Infection and ART
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Lactic Acidemia
Lipodystrophy
Dyslipidemia
Insulin Resistance
Cardiovascular Disease
Bone Mineralization Disorders
Lactic Acidemia & Lactic Acidosis
Definitions
• Lactic Acidemia: serum lactate level greater than 2.0 mmol/L
in conjunction with a normal serum pH
– Common in HIV-infected patients on ART
– Varying degrees of severity
– Often asymptomatic
• Lactic Acidosis: serum lactate level greater than 2.0 mmol/L in
conjunction with a serum pH less than 7.30
– Reflects most serious form of lactic acidemia
– Rare but potentially fatal
– Common signs & symptoms include lethargy, fatigue, weight loss,
nausea, abdominal pain, and dyspnea
– Concomitant hepatotoxicity common with hepatomegaly, hepatic
steatosis, and even ascites and encephalopathy
Schambelan M et al. JAIDS 2002;31:257-75
Classification of Lactic Acidemia
*Symptoms and signs that suggest lactic acidemia consist of nausea, vomiting, abdominal pain,
weight loss, fatigue, myalgias, abdominal distention, abdominal pain, dyspnea, and cardiac
dysrhythmias.
Source: HIV Web Study (www.hivwebstudy.org); Schambelan M et al. JAIDS 2002;31:257-75
Proposed Pathophysiology of
Lactic Acidemia
NRTI-induced mitochondrial toxicity
NRTI-induced mitochondrial toxicity
Proposed Pathogenesis
CELL
glucose
MITOCHONDRION
lactate
pyruvate
Acetyl CoA
Krebs
cycle
Fatty Acids
NADH
FADH2
ATP
Oxidative
phosphorylation
NRTI-induced mitochondrial toxicity
Proposed Pathogenesis
CELL
glucose
MITOCHONDRION
lactate
pyruvate
Acetyl CoA
Krebs
cycle
Fatty Acids
NADH
FADH2
DNA pol γ
mtDNA
ATP
Oxidative
phosphorylation
NRTI-induced mitochondrial toxicity
Proposed Pathogenesis
CELL
glucose
MITOCHONDRION
lactate
pyruvate
Acetyl CoA
Krebs
cycle
Fatty Acids
NRTIs
NADH
FADH2
DNA pol γ
mtDNA
ATP
Oxidative
phosphorylation
NRTI-induced mitochondrial toxicity
Proposed Pathogenesis
CELL
glucose
MITOCHONDRION
lactate
pyruvate
Acetyl CoA
Krebs
cycle
Fatty Acids
NRTIs
NADH
FADH2
DNA pol γ
mtDNA
ATP
Oxidative
phosphorylation
NRTI-induced mitochondrial toxicity
Proposed Pathogenesis
CELL
glucose
MITOCHONDRION
lactate
pyruvate
Acetyl CoA
Krebs
cycle
Fatty Acids
NRTIs
NADH
FADH2
DNA pol γ
mtDNA
ATP
Oxidative
phosphorylation
NRTI-induced mitochondrial toxicity
Proposed Pathogenesis
CELL
glucose
MITOCHONDRION
lactate
pyruvate
Acetyl CoA
Krebs
cycle
Fatty Acids
NRTIs
NADH
FADH2
DNA pol γ
mtDNA
ATP
Oxidative
phosphorylation
NRTI-induced mitochondrial toxicity
Proposed Pathogenesis
CELL
glucose
MITOCHONDRION
lactate
pyruvate
Acetyl CoA
Krebs
cycle
Fatty Acids
NRTIs
NADH
FADH2
DNA pol γ
mtDNA
ATP
Oxidative
phosphorylation
NRTI-induced mitochondrial toxicity
Proposed Pathogenesis
CELL
glucose
MITOCHONDRION
lactate
pyruvate
Acetyl CoA
Krebs
cycle
Fatty Acids
NRTIs
NADH
FADH2
DNA pol γ
mtDNA
ATP
Oxidative
phosphorylation
NRTIs have different levels of
mitochondrial toxicity
• Rank: ddC/ddI/d4T > 3TC > ZDV > ABC for
effects on mitochondrial DNA polymerase
gamma1
• Tenofovir has low affinity for mitochondrial
polymerase gamma2
• However, cases of severe hyperlactatemia
have been reported in association with all
NRTIs3
1. Kakuda TN. Clin Ther 2000 Jun;22(6):685-708
2. Johnson AA et al. J Biol Chem 2001 Nov 2;276(44):40847-57
3. Schambelan M et al. JAIDS 2002;31:257-75
Risk Factors for the Development of Lactic
Acidemia in Persons Taking NRTIs
*Most cases have involved stavudine
**Especially with the use of stavudine plus didanosine
Source: HIV Web Study (www.hivwebstudy.org)
Hyperlactatemia & Lactic Acidosis
Measuring Serum Lactate Levels
 No vigorous exercise for 24 hours prior
 Draw without tourniquet and fist clenching
 Use pre-chilled gray top (fluoride-oxalate) tube
 Place on ice and promptly send to lab; process within 4
hours
 If increased, confirm with repeat measurement
 Arterial pH measurement if frank acidosis suspected
Schambelan M et al. JAIDS 2002;31:257-75.
Recommendations for the Management
of Lactic Acidemia
Source: HIV Web Study (www.hivwebstudy.org); Carr A. Clin Infect Dis 2003;36 (Suppl 2):S96-100.
Case
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44 year old male with C3 AIDS, well-controlled on ART
regimen of d4T/3TC/efavirenz
Develops severe lactic acidosis and is admitted to the ICU
Recovers with discontinuation of ART and supportive care,
but CD4 count now 290 cells/mm³, HIV viral load 66,000
copies/mL
What are your recommendations regarding antiretroviral
therapy?
1. Do not resume ART – continue to monitor
2. Resume ART with efavirenz + lopinavir/ritonavir
3. Resume ART with TDF + 3TC + efavirenz
4. Resume prior ART regimen, supplemented with Lcarnitine
5. I don’t know; just tell me the answer and get on with the
talk
Resumption of Antiretroviral Therapy
after Lactic Acidosis
• NRTI-sparing regimen?
– Promising early results from trials of efavirenz +
lopinavir/ritonavir1
• Addition of mitochondrial-supporting compounds as
prophylaxis against recurrent lactic acidosis?
– Limited evidence of benefit in hastening recovery of
patients with lactic acidosis, but efficacy in preventing the
condition has not been established2-4
• Re-initiation of therapy using ‘mitochondria-sparing’
NRTIs (tenofovir, abacavir, 3TC, AZT)?
– Reasonably safe in two studies5,6
1. Allavena C et al. JAIDS 2005;39(3):300-306.
2. Fouty B et al. Lancet. 1998;352:291-2.
3. Lenzo NP et al. AIDS. 1997;11:1294-6.
4. Schramm C et al. Eur J Anaesthesiol. 1999;16:733-5.
5. Lonergan JT et al. AIDS. 2003;17:2495-9.
6. ESS40010 Study Team. JAIDS. 2004;36:935-42.
Case
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44 year old male with C3 AIDS, well-controlled on ART
regimen of d4T/3TC/efavirenz
Develops severe lactic acidosis and is admitted to the ICU
Recovers with discontinuation of ART and supportive care,
but CD4 count now 290 cells/mm³, HIV viral load 66,000
copies/mL
What are your recommendations regarding antiretroviral
therapy?
1. Do not resume ART – continue to monitor
2. Resume ART with efavirenz + lopinavir/ritonavir
3. Resume ART with TDF + 3TC + efavirenz
4. Resume prior ART regimen, supplemented with Lcarnitine
5. I don’t know; just tell me the answer and get on with the
talk
Lipodystrophy
Case 1
• 41 year old HIV-infected man on PI-based ART
presents for routine follow-up
• Complains of recent weight gain, especially in
the abdomen
• “It’s the protease paunch!”
Case 1 continued
• PMH:
– HIV infection x 5 years
• Well-controlled on ART
• CD4 nadir = 140 cells/mm³, most recent = 360
• No OIs, though radiology studies have suggested HIV
encephalopathy
– Hypertension
• Medications:
– d4T + 3TC + lopinavir/ritonavir (Kaletra) x 2 years
– Enalapril 10mg qd
Case 1 continued
• PE: obese abdomen, otherwise unremarkable
What intervention would you
recommend?
A. Ask his wife to padlock the fridge and get
him a treadmill
B. Discontinue lopinavir/ritonavir, substitute an
NNRTI such as efavirenz or nevirapine
C. Start metformin 500mg bid
D. Liposuction
E. None of the above have been demonstrated
to improve HIV-associated visceral fat
accumulation
HIV/ART Toxicities:
Lipodystrophy
• Constellation of body habitus changes
– Fat accumulation (lipohypertrophy): central (esp. visceral)
fat, dorso-cervical fat pad (buffalo hump), breasts,
lipomata, within muscle & liver
– Fat wasting (lipoatrophy): face, extremities, buttocks, and
trunk
• Lack of clear case definition has hampered clinical
research: wide variation in reported prevalence
• Increasing evidence that lipoatrophy and
lipohypertrophy are distinct entities, though can occur
simultaneously
• Hyperlipidemia and insulin resistance also variably
present
Facial lipoatrophy
Breast enlargement
Central adiposity
Peripheral lipoatrophy
Dorsocervical Fat Pad
FRAM Study: Defining
Lipodystrophy
Study Outline
• Aim: compare randomly selected HIV-infected
subjects and healthy controls to identify statistically
significant differences and any linkages between
lipodystrophic body changes
• Three types of evaluation:
– Self-report re: body habitus changes
– Clinical evaluation of presence/degree of visible
lipoatrophy
– Body composition measures including whole-body MRI
and DEXA scanning
Grunfeld C. XIV International AIDS Conference, 2002, Abstract TuOr158.
FRAM: Defining Lipodystrophy
• N = 565 men 33-45 years old
Results for concordant self-report & exam
– 412 HIV+ w/o OIs in past month
– 153 HIV-negative controls from
CARDIA study
HV positive
50
% of patients
• Examined fat loss/deposition in
peripheral sites (cheeks, face,
arms, legs, buttocks) and central
sites (waist, abdomen, neck, chest,
upper back)
• Peripheral and central lipoatrophy
more common in HIV+ subjects
• Central lipohypertrophy more
common in HIV-negative subjects
• Lack of concordance between
lipoatrophy and lipohypertrophy
60
HIV negative
40
30
p < 0.05 for all
20
10
0
peripheral
central
lipoatrophy lipoatrophy
Gripshover B et al. 10th CROI, Boston, 2003, Abstract 732.
central fat
deposition
Lipodystrophy in Women: WIHS
• Women’s Interagency HIV Study (WIHS): prospective,
multi-site study of progression of HIV infection in women
• 1,057 HIV-infected and HIV-uninfected women evaluated
every 4 months over an 18-month period beginning in 1999
• Over 18 months, mean weight and total body fat increased
slightly in HIV-negative women but remained stable in HIVpositive women
• Incidence of peripheral and central lipoatrophy in HIVpositive women was double that of HIV-negative women
• Incidence of central lipohypertrophy was similar in HIVpositive vs HIV-negative women
Tien PC et al. 10th CROI, Boston, 2003. Abstract 736.
Lipohypertrophy
Risk Factors
Pathophysiology
Interventions
Lipohypertrophy: Risk Factors
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Duration of antiretroviral therapy
Use of protease inhibitors
Markers of disease severity
Age
Female gender
Lichtenstein KA. JAIDS 2005;39:395-400.
Incidence & Size of Buffalo Humps
N = 421 HIV(+) men vs 151 matched HIV(-) controls (FRAM cohort)
% of patients
25
20
HIV-infected
80
HIV-negative
70
HIV-infected
HIV-negative
60
15
p = NS
p <0.001
50
40
10
30
20
5
10
0
incidence of buffalo hump (%)
0
buffalo hump size (cm2)
Zolopa A et al. 10th CROI, Boston 2003, Abstract 734.
Lipohypertrophy: Pathophysiology
Lipohypertrophy:
Treatment Options
• Diet/exercise1-4
1. Jones SP et al. AIDS 2001 Oct 19;15(15):2049-51
2. Roubenoff R et al. Clin Infect Dis 2002 Feb 1;34(3):390-3
3. Roubenoff R et al. AIDS. 1999;13:1373-1375.
4. Thoni GJ et al. Diabetes Metab. 2002;28:397-404.
Lipohypertrophy:
Treatment Options
• Diet/exercise
• Switching protease inhibitors out of
ART regimen: inconsistent results
Drechsler H, Powderly WG. Clin Infect Dis. 2002;35:1219-1230.
Lipohypertrophy:
Treatment Options
• Diet/exercise
• Switching protease inhibitors out of
ART regimen: inconsistent results
• Diabetes agents?
– Patients with lipodystrophy often
demonstrate insulin resistance as well
• N = 26 patients on
ART with insulin
resistance and fat
redistribution
• Randomized to
metformin or
placebo for 12 weeks
Mean change in visceral abdominal fat, mm3
Metformin Therapy for
Lipohypertrophy?
1500
1191
Placebo
Metformin
1000
500
0
-500
p = 0.08
-1000
-1115
-1500
Hadigan C et al. JAMA 2000;284:472-7.
Lipohypertrophy:
Treatment Options
• Diet/exercise
• Switching protease inhibitors out of
ART regimen: inconsistent results
• Diabetes agents?
• Plastic surgery?
Surgical Correction of
Buffalo Hump?
• Liposuction or surgical
excision a reasonable option,
esp. if pain or functional
limitations
• Only small studies to date
• Generally well-tolerated with
favorable initial results
• Conflicting data regarding
recurrence: one study found
a recurrence rate of just 5%
(1/18 patients)1 while
another study reported a
recurrence rate of 50% (5/10
patients)2
1. Gervasoni C et al. 10th CROI, Boston, 2003. Abstract 723.
2. Piliero PJ et al. 10th CROI, Boston, 2003. Abstract 724.
What intervention would you
recommend?
A. Ask his wife to padlock the fridge and get
him a treadmill
B. Discontinue lopinavir/ritonavir, substitute an
NNRTI such as efavirenz or nevirapine
C. Start metformin 500mg bid
D. Liposuction
E. None of the above have been demonstrated
to improve HIV-associated visceral fat
accumulation
Case 2: Lipoatrophy
• 43 year old woman with history of PCP now
doing well on ART: d4T/3TC/lopinavir/
ritonavir
• She complains that her cheeks appear sunken
and the veins in her arms and legs are more
prominent
What intervention would you
recommend for her condition?
A. Discontinue lopinavir/ritonavir, substitute
atazanavir or an NNRTI
B. Discontinue d4T, substitute abacavir or
tenofovir
C. Initiate rosiglitazone therapy
D. Plastic surgery: facial injections
E. None of these interventions is likely to help
Lipoatrophy: Risk Factors
• Antiretroviral therapy
– ART, esp. 2 NRTIs plus PI
– d4T, esp. when used with ddI
– Hierarchy: d4T/ddI/ddC > AZT > TDF/ABC/3TC
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Prior AIDS diagnosis
Lower CD4 nadir
Lower body weight before ART
Caucasian race
Male gender
Older age
Grinspoon S et al. N Engl J Med 2005;352:48-62.
Lichtenstein KA et al. JAIDS 2003;32:48-56.
Podzamczer D et al. 11th CROI, 2004, Abstract 716.
Joly V et al. AIDS 2002;16:2447-2454.
Dube M et al. 4th Int’l Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, 2002, abstract 27.
Shlay J et al. XV International AIDS Conference, 2004, Abstract ThOrB1360.
? Etiology of Lipoatrophy: Evidence of
Mitochondrial Toxicity in Adipocytes
These are your mitochondria
These are your mitochondria on ARVs
J Acquir Immune Defic Syndr 2002 February 1;29(2):117-121
Lipoatrophy: Treatment Options
• Switching d4T out of
regimen: evidence for
slow reversal of
lipoatrophy
Abacavir substitution for patients with
subcutaneous lipoatrophy (LA): MITOX
• 111 patients with subjective
LA on stable AZT- or d4Tcontaining ART randomized
to substitute abacavir or
continue current regimen1
• Limb fat mass measured by
DEXA and by subjective
physician assessment
• Statistically significant
increase in limb fat mass by
DEXA at 104 weeks of
follow-up2
• Similar findings from other
studies3,4,5
Mean change in limb fat mass (intention-to-treat analysis)
1. JAMA 2002;288(2): 207-15.
2. AIDS 2004;18:1029-36.
3. CID 2004;38:263-270.
4. JAIDS 2003;33:22-8.
5. JAIDS 2003;33:29-33.
Lipoatrophy: Treatment Options
• Switching d4T out of
regimen: evidence for
slow reversal of
lipoatrophy
• Diabetes agents?
- Rosiglitazone increases subcutaneous fat in
type 2 diabetic patients and reverses the
block of adipocyte differentiation induced
by ART in vitro
Rosiglitazone for Lipoatrophy?
Discouraging results to date
• N=108 HIV-1-infected
adults with LA on ART
randomized to
rosiglitazone 4 mg twice
daily (n=53) or matching
placebo (n=55) for 48
weeks1
• Limb fat increased by
0.14 kg in the
rosiglitazone group and
0.18 kg in the placebo
group (p=NS)
• Two other similar studies:
– One showed no
improvement2
– One showed modest
benefit3
Change in limb fat by DEXA
www.clinicaloptions.com
1. Carr A et al. Lancet. 2004;363:429-438.
2. Sutinen J et al. Antivir Ther 2003;8:199-207.
3. Hadigan C et al. Ann Intern Med 2004;140:786-794.
Lipoatrophy: Treatment Options
• Switching d4T out of
regimen: evidence for
slow reversal of
lipoatrophy
• Diabetes agents?
• Facial injections?
– Intradermal injections of
polylactic acid
Valantin MA et al. AIDS 2003, 17:2471–2477
VEGA: 96 week results
Valantin MA et al. AIDS 2003, 17:2471–2477
What intervention would you
recommend for her condition?
A. Discontinue lopinavir/ritonavir, substitute
atazanavir or an NNRTI
B. Discontinue d4T, substitute abacavir or
tenofovir
C. Rosiglitazone
D. Plastic surgery: facial injections
E. None of these interventions are likely to help
Dyslipidemia
Dyslipidemia: Case continued
• He returns for followup 3 months later and
reports some improvement with increased
physical activity
• You check a fasting lipid panel
Case continued
• Fasting lipid panel
• Total cholesterol = 320 mg/dL
• Triglycerides= 870 mg/dL
• HDL cholesterol = 32 mg/dL
• LDL cholesterol: could not be calculated
What intervention(s) would you
recommend to improve his lipid profile?
A. Discontinue lopinavir/ritonavir,
substitute atazanavir
B. Discontinue d4T, substitute tenofovir
C. Ask his employer to replace the donuts
in the vending machine with granola
D. Start simvastatin
E. Start gemfibrozil
F. Nothing needs to be done; dyslipidemia
associated with HIV/ART is not
associated with an increase in CAD
HIV/ART Toxicities:
Dyslipidemia
• Decreased levels of HDL & LDL (especially HDL) and elevated
triglycerides seen in HIV-infected patients prior to introduction of
ART
• Most protease inhibitors have been associated with marked
elevations in triglycerides and LDL but little effect on HDL levels
• NNRTIs and stavudine also associated with dyslipidemic effects
• HIV infection and PI-based ART each associated with proatherogenic profile dyslipidemia
• Substantial evidence that PI-based ART increases risk of coronary
artery disease (CAD)2-4
1. Schambelan M et al. JAIDS 2002; 31(3):257-75.
2. 11th CROI, 2004, Abstract 739.
3. 11th CROI, 2004, Abstract 736.
4. 11th CROI, 2004, Abstract 737.
Incidence of Myocardial Infarction According to the Duration of
Exposure to Combination Antiretroviral Therapy
The DAD Study Group, N Engl J Med 2003;349:1993-2003
Risk Factors for MI in patients on
ART: DAD
Risk Factor
Relative Risk of MI*
Use of ART (per additional year)
1.26**
Age (per additional 5 yrs)
1.38
Male Sex
1.99
Current or former smoker
2.17
Prior history of CAD
5.84
* Multivariate analysis
** revised to 1.17 on further follow-up
The DAD Study Group, N Engl J Med 2003;349:1993-2003
ART- associated Dyslipidemia:
Treatment
• Often improves with removal of offending
agents from regimen
• Treatment with fibrates and/or statins often
indicated
• Beware of drug interactions, risk of myositis
Switch ART regimen or initiate lipidlowering pharmacotherapy?
Trend of mean plasma triglyceride levels of 130 evaluable patients switched from
protease inhibitor to nevirapine (arm A) or efavirenz (B), or treated with
pravastatin (C) or bezafibrate (D), at baseline and after 3, 6, 9 and 12 months of
follow-up.
Calza L et al. AIDS 2005: 19(10), 1051-8.
Switch ART regimen or initiate lipidlowering pharmacotherapy?
Trend of mean plasma total cholesterol levels of 130 evaluable patients switched from
protease inhibitor to nevirapine (arm A) or efavirenz (B), or treated with pravastatin
(C) or bezafibrate (D), at baseline and after 3, 6, 9, and 12 months of follow-up.
Calza L et al. AIDS 2005: 19(10), 1051-8.
Lipid-Lowering Agents and ARV Therapy:
Potentially Dangerous Drug Interactions
Agent
Recommendation
Pravastatin
No dose adjustment
Atorvastatin
Dose titration
Lovastatin
Avoid
Simvastatin
Avoid
Gemfibrozil
No dose adjustment
Fenofibrate
No dose adjustment
Niacin
Associated with insulin resistance
Bile sequestrants
Avoid
Dube MP et al. Clin Infect Dis 2000;31:1216-24.
What intervention(s) would you
recommend to improve his lipids?
A. Discontinue lopinavir/ritonavir,
substitute atazanavir
B. Discontinue d4T, substitute tenofovir
C. Ask his employer to replace the donuts
in the vending machine with granola
D. Start simvastatin
E. Start gemfibrozil
F. Nothing needs to be done, as studies
have failed to document an increase in
CAD in patients on ART
Insulin Resistance
Insulin Resistance (IR)
• Defined as condition in which increased levels
of insulin are required to exert normal biologic
response1
• Typically associated with increased fasting
insulin levels, but clinically relevant thresholds
of insulin levels have not been defined
• IR should be suspected in setting of elevated
fasting blood glucose levels or impaired
glucose tolerance
1. Olefsky JM. Ellenberg & Rifkin’s Diabetes Mellitus (1997):513-52.
American Diabetic Association:
Prediabetes & Diabetes
Pre-diabetes
Diabetes mellitus
Impaired fasting
glucose
Impaired glucose
tolerance
Fasting glucose 100- 2-hour post-load
Fasting glucose ≥126
125 mg/dL
glucose 140-199
mg/dL or 2 hr postmg/dL during OGTT load glucose
≥200mg/dL during
OGTT, or symptoms
of diabetes with
random glucose
≥200mg/dL
Adapted from: http://clinicaloptions.com/2004lipo
HIV/ART Toxicities:
Insulin Resistance
• Direct mechanism: medication-induced
– PIs can have a direct effect on glucose metabolism1
– Indinavir leads to decreased insulin sensitivity in both HIV-infected and
uninfected subjects2
– Amprenavir may not share this class effect3
– Efavirenz, but not nevirapine, implicated as well4
– NRTIs also recently identified as risk factor5
– Mechanism:
• inhibition of an insulin-regulated glucose transporter GLUT4 ? 6
• Inhibition of peroxisome proliferator-activated receptor gamma? 7,8
1. Dube MP et al. JAIDS 2000;27:130-4.
2. Noor MA et al. AIDS 2001;15:4.
3. Dube MP et al. Antivir Ther 2001;6(4):11. Abst 14.
4. Mehta et al, 9th CROI, 2002, Abstract 679.
5. Brown TT et al. AIDS 2005, 19:1375–1383
6. Murata H et al. J Biol Chem 2000;275:251-4.
7. Caron M et al. Diabetes 2001;50:1378–88
8. Miserez AR et al. AIDS 2002;16:1587–94.
HIV/ART Toxicities:
Insulin Resistance
• Indirect mechanism: via changes in body fat
composition (lipohypertrophy, lipoatrophy) 1-4
1. Hadigan C et al. Clin Infect Dis 2001;32:130–9.
2. Mynarcik DC et al. J Acquir Immune Defic Syndr 2000;25:312–21.
3. Kosmiski LA et al. AIDS 2001;15:1993–2000.
4. Meininger G et al. Am J Clin Nutr 2002;76:460–5.
www.clinicaloptions.com
Currier et al, 9th CROI, February 2002, abstract 677-T
Insulin resistance is associated with increased
risk of CAD in non-HIV infected patients
www.clinicaloptions.com
Insulin Resistance: Treatment
• Consider avoiding implicated PIs for patients
with pre-existing diabetes or significant risk
factors
• Substitution of PI with NNRTIs1,2 or abacavir3,
if regimen potency can be maintained
• Treatment of diabetes mellitus: similar to that
for HIV-uninfected individuals
• Screen for and treat insulin resistance?
1. Martinez E et al. AIDS 1999;13:805–10.
2. Martinez E et al. Clin Infect Dis 2000;31:1266–73.
3. Walli RK et al. Eur J Med Res 2001;6:413–21.
Bone Mineralization Disorders
associated with HIV and/or ART
Osteonecrosis
Osteopenia
Avascular Necrosis of the
Femoral Head
Higher Prevalence of Osteonecrosis
in HIV-Infected Adults
• Screening MRIs performed on 339 asymptomatic
HIV-infected adults and 118 age- and sex-matched
HIV-negative controls
• Osteonecrosis of the femoral head identified in 15
of 339 (4.4%) HIV-infected patients compared to
0/118 controls (p<0.05)
• Comparison of HIV-infected patients with or
without osteonecrosis showed no difference by
age, sex, race, risk factor, CD4 cell count, viral
load, antiretroviral therapy, blood lipids or CBC.
• The risk was increased for those who had received
corticosteroids, lipid-lowering agents or
testosterone.
Miller KD et al. Ann Intern Med 2002 Jul 2;137(1):17-25.
Higher Prevalence of Osteonecrosis
in HIV-Infected Adults
• Other studies of HIV-infected patients have
found similar associations with steroid use and
hyperlipidemia but not with the use of specific
antiretroviral agents1,2
• Implication: consider this diagnosis in HIVinfected patients with shoulder, groin, or hip
pain
1. Scribner AN et al. JAIDS 2000;25:19-25.
2. Glesby MJ et al. JID 2001;184:519-23.
Studies on Osteopenia in HIV
Study
Sample
Prevalence*
Risk Factors
Carr, 2001
Australia
221 HIV+ men,
Wt. 70-75 kg
25%
Lactate level
low weight
Huang, 2001
Boston, MA
41 HIV+ men, BMI 25
18 HIV- men, BMI 25
BMD reduced in
HIV+ men w/
high visceral fat
Historical low weight;
high visceral fat
McDermott, 2001
New England
203 HIV+ men, BMI 24
62 HIV+ women, BMI 25
BMC reduced in
men on ART
ART use and duration
Knobel 2001
Spain
58 HIV+ men, 22 HIV+
women, BMI 23 overall
100 HIV- controls, BMI 23
89% in HIV+
30% in HIV-
Weight, BMI
Nolan, 2001
Australia
183 HIV+ men
BMI 23-24
56% in PI-treated;
49% in PI-naïve
Low pre-ART BMI;
Indinavir protective
Gold, 2002
Australia
110 HIV+ men
lean mass 57 kg
55%
Age, lean body mass,
duration of NRTI use
Mondy, 2003
St. Louis, MO
108 HIV+ men, 17 HIV+
women; BMI 25
46%
BMI, smoking, wt loss,
steroids
Arnsten, 2003
New York, NY
200 HIV+ women: BMI 28
205 HIV- women: BMI 32
30% in HIV+
24% in HIV-
Age, race, BMI;
PI use >1 year protective
* combined prevalence of osteopenia and osteoporosis
Adapted from Arnsten JH et al, 10th CROI, Boston 2003, Abstract 103
Alendronate for HIV-associated
osteopenia: 48 week results
6
% change from baseline in BMD
• N=31 HIV-infected subjects on
ART with lumbar spine BMD tscores less than -1.0
• 87% male, 80% Caucasian, 29%
smokers, mean age 44 yo; mean
BMI 25kg/m2
• Median CD4 count 561
cells/mm³; 84% had VL <400
copies/mL
• Randomized to alendronate 70 mg
weekly (n=15) or placebo (n=16)
• All patients received calcium 1g
daily and vit D 400 IU daily
• No serious adverse events
p = 0.005
placebo
alendronate
5
4
3
p = NS
2
1
0
Spine
Mondy K et al. 10th CROI, Boston, 2003. Abstract 134.
Hip
Metabolic Complications of
HIV and ART
Summary & Conclusions
Hyperlactatemia/Lactic Acidosis
• Potentially fatal syndrome linked to prolonged
NRTI use, especially ddI, d4T
• Signs and symptoms often subtle, nonspecific
• Venous lactate level useful in diagnosis
• Discontinuation of ART indicated for
symptomatic hyperlactatemia/lactic acidosis
• Resumption of ART that includes NRTIs is
controversial
Lipodystrophy
• Lipoatrophy more common in HIV-infected individuals
and has been linked to markers of HIV disease severity
and to d4T
• Switching out the offending agent appears to improve
lipoatrophy, but very slowly
• Buffalo humps may be no more common in HIVinfected patients, but may be larger when they do occur
• Central fat deposition less common in HIV-infected
individuals
• Diet, exercise are the most effective treatments for
central fat accumulation
• Plastic surgery: short-term benefit; long term - ?
Dyslipidemia & ART
• Many antiretrovirals, especially protease inhibitors,
associated with dyslipidemia
• ART-induced dyslipidemia may contribute to risk of
coronary artery disease, though short-term absolute risk
appears to be small
• Discontinuation of dyslipidemia-inducing agents will
generally improve lipid profile
• ART-induced dyslipidemia can be treated with fibrates
and/or statins, but response is often sub-optimal and
potential drug interactions need to be considered
carefully
Insulin Resistance
• Linked to many protease inhibitors, efavirenz,
and possibly some NRTIs
• Also linked to presence of lipodystrophy
• Progression to frank diabetes mellitus possible
• Monitor with fasting glucose values
• Improvement may or may not be seen with
switching out of the offending agents
HIV & Bone Disease
• Patients with HIV infection, especially Caucasian men, appear to
be at increased risk of osteopenia
• Etiology not known at this time
• Role of ART overall and of individual ARV agents is unclear
• Routine screening not recommended
• Intervention warranted for modifiable risk factors such as
smoking, alcohol, steroid use, hyperlipidemia, wasting, sedentary
lifestyle, low calcium intake
• HIV-infected patients also at increased risk of osteonecrosis
• Consider diagnosis of osteonecrosis in patients with unexplained
shoulder/hip/groin pain
The End