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?

1. Ask his wife to padlock the fridge and get him a
   treadmill
2. Discontinue lopinavir/ritonavir, substitute an
   NNRTI such as efavirenz or nevirapine
3. Start metformin 500mg bid
4. Liposuction
5. 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

1. Ask his wife to padlock the fridge and get him a
   treadmill
2. Discontinue lopinavir/ritonavir, substitute an
   NNRTI such as efavirenz or nevirapine
3. Start metformin 500mg bid
4. Liposuction
5. 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

1. Discontinue lopinavir/ritonavir, substitute
   atazanavir or an NNRTI
2. Discontinue d4T, substitute abacavir or tenofovir
3. Initiate rosiglitazone therapy
4. Plastic surgery facial injections
5. 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?

1. Discontinue lopinavir/ritonavir, substitute
   atazanavir or an NNRTI
2. Discontinue d4T, substitute abacavir or tenofovir
3. Rosiglitazone
4. Plastic surgery facial injections
5. 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?

1. Discontinue lopinavir/ritonavir, substitute
   atazanavir
2. Discontinue d4T, substitute tenofovir
3. Ask his employer to replace the donuts in the
   vending machine with granola
4. Start simvastatin
5. Start gemfibrozil
6. 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
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
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
Pre-diabetes Pre-diabetes Diabetes mellitus
Impaired fasting glucose Impaired glucose tolerance Diabetes mellitus
Fasting glucose 100-125 mg/dL 2-hour post-load glucose 140-199 mg/dL during OGTT Fasting glucose 126 mg/dL or 2 hr post-load glucose 200mg/dL during OGTT, or symptoms of diabetes with random glucose 200mg/dL
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
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 gt1 year protective
combined prevalence of osteopenia and
osteoporosis
Adapted from Arnsten JH et al, 10th CROI, Boston
2003, Abstract 103
82
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

87
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

88
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