Download Long Term Side Effects of ART

Long Term Side Effects
of ARVs
HAIVN
Harvard Medical School AIDS
Initiative in Vietnam
1
Learning Objectives
By the end of this session, participants
should be able to:
 Describe the symptoms and explain
how to diagnose and manage the
following side effects:
•
•
•
•
•
•
Lipodystrophy syndrome
Peripheral neuropathy
Diabetes
Dyslipidemia
Gynecomastia
Bone disorders
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Lipodystrophy
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Overview of Lipodystrophy (1)

Lipodystrophy is a syndrome of body
shape abnormalities characterized by:
• central fat accumulation
• peripheral fat loss


Some patients have only fat loss,
others have fat gain, and others have a
mixed picture of both
There can also be associated disorders
in glucose and lipid metabolism
4
Overview of Lipodystrophy (2)
Lipoatrophy:
 Loss of
subcutaneous body
fat:
• Extremities
• Face
• Buttocks
Lipohypertrophy:
 Increased fat
accumulation in
the center of the
body:
• Abdomen
• Breasts
• Dorso-cervix
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Prevalence of Lipodystrophy
6
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Lipodystrophy: Prevalence in
Asian Cohorts

Cambodian cohort:
• D4T-associated lipodystrophy in 20% of
patients after 24 months of follow-up

Singapore cohort:
• Lipoatrophy 46%
• Fat accumulation 32%
• Mixed 8%
Sources: Ferradini AIDS 2007; Nicholas CID 2002
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Lipoatrophy: Risk Factors
Risk factors for lipoatrophy include:
NRTIs
 D4T is strongest
risk factor
 AZT to a lesser
extent
 3TC, TDF, ABC
much less common
Other non-drug
factors
 Older age
 Lower body weight
 AIDS diagnosis
 Lower pretreatment
CD4 cell count
8
Lipohypertrophy: Risk Factors
Risk factors for lipohypertrophy
include:
 Older age
 Female sex
 Amount of body fat
 Longer duration of ART
 Exposure to protease inhibitors
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Manifestations of Lipoatrophy
Face
Extremities:
Prominent vein
Buttocks
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Manifestations of Lipohypertrophy
Dorsocervical
Area
Breasts
Abdomen
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Treatment of Lipodystrophy
Lipoatrophy:
 Change d4T to
AZT, ABC or TDF
 Cosmetic surgery
or injections
Lipohypertrophy:
 Change PI’s to
NNRTI
 Exercise
 Liposuction
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Metabolic Disorders




Insulin resistance and diabetes
Dyslipidemia
Lactic acidosis/hyperlactatemia
Cardiovascular risk
13
Insulin Resistance and Diabetes (1)

Incidence of 3-5 % among ARV
patients
• After months or years

Risk factors
• Use of PI-containing ARV regimen
• Previous hyperglycemia
• Family history of diabetes

Laboratory diagnosis: the same as
for non-HIV patients
14
Insulin Resistance and Diabetes (2)

Screening:
• Fasting glucose before starting ARV,
then every 6-12 months

Treatment:
• Treat diabetes as in non-HIV patients
• Consider switch PI to another PI (such
as ATV if available) or NNRTI (if not
already resistant to 1st line ARV)
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Dyslipidemia
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Dyslipidemia – Terms
Parameter
Total
Cholesterol
Low Density
Lipoprotein
High Density
Lipoprotein
Triglycerides
Acronym
Comment
TC
Total cholesterol found in the
serum
LDL
 LDL: increased risk for
cardiovascular disease
HDL
•HDL levels (>1.6mmol/l):
protective of cardiovascular
disease
•HDL levels (< 1.03mmol/l):
risks for cardiovascular disease
TG
levels: associated with
cardiovascular disease,
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pancreatitis
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ART – Induced Lipid
Abnormalities
18
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Dyslipidemia - ARV Specific
Effects
Drug
PIs (except
Atazanavir)
Ritonavir
D4T
EFV or NVP
Effect
  LDL, TC & TG
  HDL
 TG,  LDL and TC
 TG, occasional  LDL and TC
  TG, especially EFV
  HDL
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PI – Induced Lipid Effects
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Dyslipidemia: Screening


Dyslipidemia occurs is up to 75% of
patients on PIs
Screening should be performed for
all patients on ART and especially for
those on PIs:
• Baseline fasting lipid level
• Yearly lipid screening
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Management of Dyslipidemia




Screen for other cardiovascular risk
factors to assess likelihood of future
cardiovascular events
Encourage positive behavior change
Consider lipid lowering drugs
Consider changing PI to another
agent that does not cause lipid
elevations (NNRTI or ATV)
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Drug Management of
Dyslipidemia (1)
HMG-coA reductase inhibitors “Statins”
 Start for elevated TC and/or LDL
 Very effective at  LDL ( 20-60%)
 Beware of drug interactions
• Atorvastatin & Pravastatin: safe to use
with PI
• Lovastatin & Simvastatin:  levels
when used with PI  Do Not Use
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Drug Management of
Dyslipidemia (2)
Fibrates (Fenofibrate, Gemfibrozil )
 Indication usually if TG > 500 mg/dL
 Best for isolated  TG:
•  TG 30-50%
•  LDL 10-20%;  HDL 5-15 %


No significant drug interactions with
ARV
Less expensive than statins
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Cardiovascular Risk
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What are the Traditional Cardiac
Risk Factors?





Male gender
Older age
Hypertension
Diabetes mellitus
Tobacco use



Hyperlipidemia
Family history of
premature
coronary artery
disease (CAD)
Personal history of
CAD
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HIV and ARVs As Risk Factors
for Cardiovascular Disease

Use of ART has been associated with an
increased risk of cardiovascular events:
• May be seen from a few months to years after
the start of ARV
• Can occur in patients without any other cardiac
risk factor


PIs have highest risk
Presence of the lipodystrophy syndrome
has been shown to add further risk of
cardiovascular events in some studies
27
Management of Cardiovascular
Complications of ARV


Early diagnosis and treatment of
traditional cardiac risk factors
Behavioral changes
• Diet
• Regular physical exercise
• Smoking cessation

Diminish further risks from ARV by:
• Use NNRTI instead of PI
• Use NRTIs, but avoid d4T
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Peripheral Neuropathy
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Peripheral Neuropathy

NRTIs and other drugs may cause
peripheral neuropathy:
• D4T and DDI have the highest risk
• Increased risk when D4T combined with
DDI or Ribavirin
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Risk Factors

The risk of NRTI-induced neuropathy is
higher in the following circumstances:
•
•
•
•
•
•
•
Preexisting neuropathy
Concurrent diabetes
Lower pretreatment CD4+ cell count
Higher viral load
Alcoholism
Poor nutrition
Older age
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Symptoms




Onset after many weeks or months
“Stocking and glove” distribution:
starts at fingertips/toes and spreads
inward
Symptoms: numbness, tingling, pain
Progressive and irreversible if left
untreated
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Treatment

Eliminate other causes or contributing
factors:
• Stop alcohol use
• Screen for and treat other diseases:
diabetes, thyroid dysfunction, syphilis
• Stop use of other neurotoxic agents (INH)


Switch from D4T to AZT, ABC or TDF
Neuropathic pain can be treated with
Amitriptyline
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Lactic Acidosis
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Lactic Acidosis


Incidence 0.5% - 1.5% per year
Risk of lactic acidosis:
• D4T+DDI > D4T > DDI > AZT
• Very Low risk: 3TC, TDF, ABC

Symptoms: can develop slowly
• Mild: fatigue, body aches, nausea,
vomiting, diarrhea, weight loss
• Severe: wasting, dyspnea, abdominal
pain, coma
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Lactic Acidosis: Diagnosis

Elevated lactic acid levels
Normal
Mild elevation
Moderate elevation
Severe elevation

< 2 mmol/L
2 – 5 mmol/L
5-10 mmol/L
> 10 mmol/L
If lactic acid testing is not available:
• Increased anion gap [Na-(Cl+HCO3)] >
16
• LFT, CPK, LDH, pH, HCO3
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Lactic Acidosis: Treatment
No or mild symptoms
Lactic acid level ≤10
Change NRTI:
d4T
AZT
ddI
ABC or
TDF
Severe symptoms
Lactic acid level >10
 Hospitalize
 Provide supportive care
 Stop all ARVs
 When stable, restart ARV:
•use ABC or TDF plus 3TC
•or use NRTI-sparing
regimens
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Bone Disorders
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Osteonecrosis (1)


Ischemic death of the cellular
components of the bone, normally at
the epiphyseal or subarticular
regions
85% of cases are at one or both
femoral heads but, may affect any
bone
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Symptoms and Diagnosis


Presentation often insidious onset
with subtle symptoms
The most common presenting
symptom is pain
• Groin pain is most common location
• Pain on movement or weight bearing

Diagnosis is made clinically in a
symptomatic patient with typically
radiologic findings
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Risk Factors







Diabetes
Prior history of prolonged steroid use
Older age
Excessive use of alcohol
Hyperlipidemia
HIV infection
Use of protease inhibitors
Glesby M, Clin Inf Dis.2003;37:S91-S95
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Treatment



Eliminate contributing factors:
alcohol, steroids
Treat the pain with NSAIDS and/or
opiate drugs
Severe pain in the hip may be an
indication for hip replacement
surgery
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Gynecomastia
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Gynecomastia (1)


Enlargement of
one or both breasts
as a result of
increased glandular
tissue
Most common with
EFV, D4T is less
common
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Gynecomastia (2)


Symptoms: may be painful
Differential diagnosis
• Other medications (INH, ketoconazole,
cimetidine, metronidazole)
• Pseudo-gynecomastia (fatty deposit
such as in lipodystrophy)
• Hypogonadism (testicular tumors)
• Breast cancer
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Treatment of EFV-Induced
Gynecomastia


NSAIDS for pain
Treatment options:
Continue EFV:
Complete
regression after 2
months when no
change in
treatment was
done
(One author noted)
Stop EFV:
Complete
regression seen
after 5 months
when EFV changed
to NVP
(in a cohort of patients
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in Haiti)
Key Points



Patients on ARVs may develop one or
more long term side effects
Screening and early recognition of
these potential side effects is
important
Cardiovascular disease is an
increasingly recognized complication
of long-term HIV infection and ARV
use
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Thank you
Questions?
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