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Metabolic Complications of HIV Infection and Antiretroviral Therapy (ART)

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Title: Metabolic Complications of HIV Infection and Antiretroviral Therapy (ART)


1
Metabolic Complications of HIV Infection and
Antiretroviral Therapy (ART)
  • Christopher Behrens, MD
  • University of Washington

2
Metabolic Complications of HIV Infection and ART
  • Lactic Acidemia
  • Lipodystrophy
  • Dyslipidemia
  • Insulin Resistance
  • Cardiovascular Disease
  • Bone Mineralization Disorders

3
Lactic Acidemia Lactic AcidosisDefinitions
  • 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 200231257-75
4
Classification of Lactic Acidemia
0
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 200231257-75
5
Proposed Pathophysiology of Lactic Acidemia
  • NRTI-induced mitochondrial toxicity

6
NRTI-induced mitochondrial toxicity Proposed
Pathogenesis
0
CELL
glucose
MITOCHONDRION
pyruvate
lactate
Acetyl CoA
Krebs cycle
Fatty Acids
NADH FADH2
Oxidative phosphorylation
ATP
7
NRTI-induced mitochondrial toxicity Proposed
Pathogenesis
0
CELL
glucose
MITOCHONDRION
pyruvate
lactate
Acetyl CoA
Krebs cycle
Fatty Acids
NADH FADH2
mtDNA
DNA pol ?
Oxidative phosphorylation
ATP
8
0
NRTI-induced mitochondrial toxicity Proposed
Pathogenesis
CELL
glucose
MITOCHONDRION
pyruvate
lactate
Acetyl CoA
Krebs cycle
Fatty Acids
NADH FADH2
NRTIs
mtDNA
DNA pol ?
Oxidative phosphorylation
ATP
9
NRTI-induced mitochondrial toxicity Proposed
Pathogenesis
0
CELL
glucose
MITOCHONDRION
pyruvate
lactate
Acetyl CoA
Krebs cycle
Fatty Acids
NADH FADH2
NRTIs
mtDNA
DNA pol ?
Oxidative phosphorylation
ATP
10
NRTI-induced mitochondrial toxicity Proposed
Pathogenesis
0
CELL
glucose
MITOCHONDRION
pyruvate
lactate
Acetyl CoA
Krebs cycle
Fatty Acids
NADH FADH2
NRTIs
mtDNA
DNA pol ?
Oxidative phosphorylation
ATP
11
NRTI-induced mitochondrial toxicity Proposed
Pathogenesis
0
CELL
glucose
MITOCHONDRION
pyruvate
lactate
Acetyl CoA
Krebs cycle
Fatty Acids
NADH FADH2
NRTIs
mtDNA
DNA pol ?
Oxidative phosphorylation
ATP
12
NRTI-induced mitochondrial toxicity Proposed
Pathogenesis
0
CELL
glucose
MITOCHONDRION
pyruvate
lactate
Acetyl CoA
Krebs cycle
Fatty Acids
NADH FADH2
NRTIs
mtDNA
DNA pol ?
Oxidative phosphorylation
ATP
13
NRTI-induced mitochondrial toxicity Proposed
Pathogenesis
0
CELL
glucose
MITOCHONDRION
lactate
pyruvate
Acetyl CoA
Krebs cycle
Fatty Acids
NADH FADH2
NRTIs
mtDNA
DNA pol ?
Oxidative phosphorylation
ATP
14
NRTIs have different levels of mitochondrial
toxicity
0
  • Rank ddC/ddI/d4T gt 3TC gt ZDV gt 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 Jun22(6)685-708 2.
Johnson AA et al. J Biol Chem 2001 Nov
2276(44)40847-57 3. Schambelan M et al. JAIDS
200231257-75
15
Risk Factors for the Development of Lactic
Acidemia in Persons Taking NRTIs
0
Most cases have involved stavudineEspecially
with the use of stavudine plus didanosine
Source HIV Web Study (www.hivwebstudy.org)
16
Hyperlactatemia Lactic AcidosisMeasuring Serum
Lactate Levels
0
  • 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 200231257-75.
17
Recommendations for the Management of Lactic
Acidemia
0
Source HIV Web Study (www.hivwebstudy.org) Carr
A. Clin Infect Dis 200336 (Suppl 2)S96-100.
18
Case
  • 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?
  • Do not resume ART continue to monitor
  • Resume ART with efavirenz lopinavir/ritonavir
  • Resume ART with TDF 3TC efavirenz
  • Resume prior ART regimen, supplemented with
    L-carnitine
  • I dont know just tell me the answer and get on
    with the talk

19
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-spari
    ng NRTIs (tenofovir, abacavir, 3TC, AZT)?
  • Reasonably safe in two studies5,6

1. Allavena C et al. JAIDS 200539(3)300-306.
2. Fouty B et al. Lancet. 1998352291-2. 3.
Lenzo NP et al. AIDS. 1997111294-6.
4. Schramm C et al. Eur J Anaesthesiol.
199916733-5. 5. Lonergan JT et al. AIDS.
2003172495-9. 6. ESS40010 Study Team. JAIDS.
200436935-42.
20
Case
  • 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?
  • Do not resume ART continue to monitor
  • Resume ART with efavirenz lopinavir/ritonavir
  • Resume ART with TDF 3TC efavirenz
  • Resume prior ART regimen, supplemented with
    L-carnitine
  • I dont know just tell me the answer and get on
    with the talk

21
Lipodystrophy
22
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
  • Its the protease paunch!

23
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

24
Case 1 continued
  • PE obese abdomen, otherwise unremarkable

25
What intervention would you recommend?
  • Ask his wife to padlock the fridge and get him a
    treadmill
  • Discontinue lopinavir/ritonavir, substitute an
    NNRTI such as efavirenz or nevirapine
  • Start metformin 500mg bid
  • Liposuction
  • None of the above have been demonstrated to
    improve HIV-associated visceral fat accumulation

26
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

27
Facial lipoatrophy
Breast enlargement
Central adiposity
Peripheral lipoatrophy
28
Dorsocervical Fat Pad
29
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.
30
FRAM Defining Lipodystrophy
  • N 565 men 33-45 years old
  • 412 HIV w/o OIs in past month
  • 153 HIV-negative controls from CARDIA study
  • 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

Results for concordant self-report exam
of patients
p lt 0.05 for all
Gripshover B et al. 10th CROI, Boston, 2003,
Abstract 732.
31
Lipodystrophy in Women WIHS
  • Womens 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 HIV-positive women
  • Incidence of peripheral and central lipoatrophy
    in HIV-positive women was double that of
    HIV-negative women
  • Incidence of central lipohypertrophy was similar
    in HIV-positive vs HIV-negative women

Tien PC et al. 10th CROI, Boston, 2003. Abstract
736.
32
Lipohypertrophy
  • Risk Factors
  • Pathophysiology
  • Interventions

33
Lipohypertrophy Risk Factors
0
  • Duration of antiretroviral therapy
  • Use of protease inhibitors
  • Markers of disease severity
  • Age
  • Female gender

Lichtenstein KA. JAIDS 200539395-400.
34
Incidence Size of Buffalo Humps
N 421 HIV() men vs 151 matched HIV(-) controls
(FRAM cohort)
p NS
p lt0.001
of patients
Zolopa A et al. 10th CROI, Boston 2003, Abstract
734.
35
Lipohypertrophy Pathophysiology
0
36
Lipohypertrophy Treatment Options
0
  • Diet/exercise1-4

1. Jones SP et al. AIDS 2001 Oct
1915(15)2049-51 2. Roubenoff R et al. Clin
Infect Dis 2002 Feb 134(3)390-3 3. Roubenoff R
et al. AIDS. 1999131373-1375. 4. Thoni GJ et
al. Diabetes Metab. 200228397-404.
37
Lipohypertrophy Treatment Options
0
  • Diet/exercise
  • Switching protease inhibitors out of ART regimen
    inconsistent results

Drechsler H, Powderly WG. Clin Infect Dis.
2002351219-1230.
38
Lipohypertrophy Treatment Options
0
  • Diet/exercise
  • Switching protease inhibitors out of ART regimen
    inconsistent results
  • Diabetes agents?
  • Patients with lipodystrophy often demonstrate
    insulin resistance as well

39
Metformin Therapy for Lipohypertrophy?
0
  • 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
p 0.08
Hadigan C et al. JAMA 2000284472-7.
40
Lipohypertrophy Treatment Options
0
  • Diet/exercise
  • Switching protease inhibitors out of ART regimen
    inconsistent results
  • Diabetes agents?
  • Plastic surgery?

41
Surgical Correction ofBuffalo Hump?
0
  • 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.
42
What intervention would you recommend?
0
  • Ask his wife to padlock the fridge and get him a
    treadmill
  • Discontinue lopinavir/ritonavir, substitute an
    NNRTI such as efavirenz or nevirapine
  • Start metformin 500mg bid
  • Liposuction
  • None of the above have been demonstrated to
    improve HIV-associated visceral fat accumulation

43
Case 2 Lipoatrophy
0
  • 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

44
0
45
0
46
What intervention would you recommend for her
condition?
0
  • Discontinue lopinavir/ritonavir, substitute
    atazanavir or an NNRTI
  • Discontinue d4T, substitute abacavir or tenofovir
  • Initiate rosiglitazone therapy
  • Plastic surgery facial injections
  • None of these interventions is likely to help

47
Lipoatrophy Risk Factors
0
  • Antiretroviral therapy
  • ART, esp. 2 NRTIs plus PI
  • d4T, esp. when used with ddI
  • Hierarchy d4T/ddI/ddC gt AZT gt TDF/ABC/3TC
  • 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
200535248-62. Podzamczer D et al. 11th CROI,
2004, Abstract 716.
Lichtenstein KA et al. JAIDS 20033248-56. Joly
V et al. AIDS 2002162447-2454.
Dube M et al. 4th Intl Workshop on Adverse Drug
Reactions and Lipodystrophy in HIV, 2002,
abstract 27. Shlay J et al. XV International AIDS
Conference, 2004, Abstract ThOrB1360.
48
0
? Etiology of Lipoatrophy Evidence of
Mitochondrial Toxicity in Adipocytes
These are your mitochondria on ARVs
These are your mitochondria
J Acquir Immune Defic Syndr 2002 February
129(2)117-121
49
Lipoatrophy Treatment Options
0
  • Switching d4T out of regimen evidence for slow
    reversal of lipoatrophy

50
Abacavir substitution for patients with
subcutaneous lipoatrophy (LA) MITOX
0
  • 111 patients with subjective LA on stable AZT- or
    d4T- containing 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)
4. JAIDS 20033322-8. 5. JAIDS 20033329-33.
1. JAMA 2002288(2) 207-15. 2. AIDS
2004181029-36. 3. CID 200438263-270.
51
Lipoatrophy Treatment Options
0
  • 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
52
Rosiglitazone for Lipoatrophy?Discouraging
results to date
0
  • N108 HIV-1-infected adults with LA on ART
    randomized to rosiglitazone 4 mg twice daily
    (n53) or matching placebo (n55) for 48 weeks1
  • Limb fat increased by 0.14 kg in the
    rosiglitazone group and 0.18 kg in the placebo
    group (pNS)
  • 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. 2004363429-438. 2.
Sutinen J et al. Antivir Ther 20038199-207. 3.
Hadigan C et al. Ann Intern Med 2004140786-794.
53
Lipoatrophy Treatment Options
  • Switching d4T out of regimen evidence for slow
    reversal of lipoatrophy
  • Diabetes agents?
  • Facial injections?
  • Intradermal injections of polylactic acid

54
Valantin MA et al. AIDS 2003, 1724712477
55
VEGA 96 week results
0
Valantin MA et al. AIDS 2003, 1724712477
56
What intervention would you recommend for her
condition?
  • Discontinue lopinavir/ritonavir, substitute
    atazanavir or an NNRTI
  • Discontinue d4T, substitute abacavir or tenofovir
  • Rosiglitazone
  • Plastic surgery facial injections
  • None of these interventions are likely to help

57
Dyslipidemia
58
Dyslipidemia Case continued
  • He returns for followup 3 months later and
    reports some improvement with increased physical
    activity
  • You check a fasting lipid panel

59
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

60
What intervention(s) would you recommend to
improve his lipid profile?
  • Discontinue lopinavir/ritonavir, substitute
    atazanavir
  • Discontinue d4T, substitute tenofovir
  • Ask his employer to replace the donuts in the
    vending machine with granola
  • Start simvastatin
  • Start gemfibrozil
  • Nothing needs to be done dyslipidemia associated
    with HIV/ART is not associated with an increase
    in CAD

61
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 pro-atherogenic profile dyslipidemia
  • Substantial evidence that PI-based ART increases
    risk of coronary artery disease (CAD)2-4

3. 11th CROI, 2004, Abstract 736. 4. 11th CROI,
2004, Abstract 737.
1. Schambelan M et al. JAIDS 2002
31(3)257-75. 2. 11th CROI, 2004, Abstract 739.
62
Incidence of Myocardial Infarction According to
the Duration of Exposure to Combination
Antiretroviral Therapy
The DAD Study Group, N Engl J Med
20033491993-2003
63
Risk Factors for MI in patients on ART DAD
Risk Factor
Relative Risk of MI
Multivariate analysis
revised to 1.17 on further follow-up
The DAD Study Group, N Engl J Med
20033491993-2003
64
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

65
Switch ART regimen or initiate lipid-lowering
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.
66
Switch ART regimen or initiate lipid-lowering
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.
67
Lipid-Lowering Agents and ARV TherapyPotentially
Dangerous Drug Interactions
Agent
Recommendation
  • Pravastatin
  • Atorvastatin
  • Lovastatin
  • Simvastatin
  • Gemfibrozil
  • Fenofibrate
  • Niacin
  • Bile sequestrants

No dose adjustment Dose titration Avoid Avoid No
dose adjustment No dose adjustment Associated
with insulin resistance Avoid


Dube MP et al. Clin Infect Dis 2000311216-24.
68
What intervention(s) would you recommend to
improve his lipids?
  • Discontinue lopinavir/ritonavir, substitute
    atazanavir
  • Discontinue d4T, substitute tenofovir
  • Ask his employer to replace the donuts in the
    vending machine with granola
  • Start simvastatin
  • Start gemfibrozil
  • Nothing needs to be done, as studies have failed
    to document an increase in CAD in patients on ART

69
Insulin Resistance
70
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 Rifkins Diabetes
Mellitus (1997)513-52.
71
American Diabetic Association Prediabetes
Diabetes
Adapted from http//clinicaloptions.com/2004lipo
72
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 200027130-4. 2. Noor
MA et al. AIDS 2001154. 3. Dube MP et al.
Antivir Ther 20016(4)11. Abst 14. 4. Mehta et
al, 9th CROI, 2002, Abstract 679.
5. Brown TT et al. AIDS 2005, 1913751383 6.
Murata H et al. J Biol Chem 2000275251-4. 7.
Caron M et al. Diabetes 200150137888 8.
Miserez AR et al. AIDS 200216158794.
73
HIV/ART Toxicities Insulin Resistance
  • Indirect mechanism via changes in body fat
    composition (lipohypertrophy, lipoatrophy) 1-4

www.clinicaloptions.com
1. Hadigan C et al. Clin Infect Dis
2001321309. 2. Mynarcik DC et al. J Acquir
Immune Defic Syndr 20002531221. 3. Kosmiski LA
et al. AIDS 20011519932000. 4. Meininger G et
al. Am J Clin Nutr 2002764605.
74
Currier et al, 9th CROI, February 2002, abstract
677-T
75
Insulin resistance is associated with increased
risk of CAD in non-HIV infected patients
www.clinicaloptions.com
Despres JP et al. N Engl J Med. 1996334952-957.
76
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 19991380510. 2.
Martinez E et al. Clin Infect Dis
200031126673. 3. Walli RK et al. Eur J Med Res
2001641321.
77
Bone Mineralization Disorders associated with HIV
and/or ART
  • Osteonecrosis
  • Osteopenia

78
Avascular Necrosis of the Femoral Head
79
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 (plt0.05)
  • 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
2137(1)17-25.
80
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
    HIV-infected patients with shoulder, groin, or
    hip pain

1. Scribner AN et al. JAIDS 20002519-25. 2.
Glesby MJ et al. JID 2001184519-23.
81
Studies on Osteopenia in HIV
0
combined prevalence of osteopenia and
osteoporosis
Adapted from Arnsten JH et al, 10th CROI, Boston
2003, Abstract 103
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Alendronate for HIV-associated osteopenia 48
week results
  • N31 HIV-infected subjects on ART with lumbar
    spine BMD t-scores 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 lt400
    copies/mL
  • Randomized to alendronate 70 mg weekly (n15) or
    placebo (n16)
  • All patients received calcium 1g daily and vit D
    400 IU daily
  • No serious adverse events

p 0.005
change from baseline in BMD
p NS
Mondy K et al. 10th CROI, Boston, 2003.
Abstract 134.
83
Metabolic Complications of HIV and ART
  • Summary Conclusions

84
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

85
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
    HIV-infected 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 - ?

86
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

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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

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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

89
The End
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