Transcript Session 11

Second Line ART:
Doses & Side Effects
HAIVN
Harvard Medical School AIDS
Initiative in Vietnam
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Learning Objectives
By the end of this session, participants
should be able to:
 Explain the choice of second line
regimens based on first failure
regimens
 Describe common side effects of
second line drugs
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Overview of Second Line
ARVs in Vietnam
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Switching for Treatment Failure
1st Line ARV
TDF + 3TC + NVP/EFV
AZT/d4T + 3TC + NVP/EFV
AZT/d4T + 3TC +TDF/ABC
2nd Line ARV
AZT + 3TC
or ddI + ABC
TDF + 3TC
or ddI + ABC
EFV/NVP + ddI
Vietnam MOH, HIV/AIDS Treatment Guidelines, 2009.
+
LPV/r
Second Line ARVs Available in
Vietnam
Class
Drugs
Lamivudine (3TC)
Tenofovir (TDF)
NRTI
Zidovudine (AZT)
Abacavir (ABC)
Didanosine (DDI)
NNRTI
PI
Lopinavir/ritonavir (LPV/r)
Indinavir*
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Second-Line ARV:
NRTI
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Tenofovir (TDF)
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TDF – Dosing
Adult Dosing
 300mg tab, once daily
 Dose reduction recommended for
Clcr < 50 mL/minute
Preparations Individual drug
Indications
• First-line ARV
• Second-line ARV when AZT used in first
line
Food
restrictions
None
TDF – Side Effects
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Usually very well tolerated
Most common side effects are minor:
nausea, vomiting, flatulence
Most concerning is renal dysfunction
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Usually mild, asymptomatic
Reverses when TDF stopped
Should monitor creatinine every 6 months
Acute renal failure rare: reduce TDF dose
or switch to another NRTI
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TDF Dosing in Renal Failure
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TDF should be dosed by Creatinine
Clearance (CrCl)
CrCl is measured in milliliters/min (ml/min)
Normal values are:
• Male: 97 to 137 ml/min
• Female: 88 to 128 ml/min
Creatinine Clearance (ml/min)
and TDF dose (TDF 300 mg)
> 50ml/min 30 – 49 ml/min 10 – 29 ml/min
Once daily
Every other
day
< 10 ml/min
Every 3- 4 days Contra-indicated
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or twice a week
Lamivudine (3TC)
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3TC – Dosing
Adult Dosing
 150 mg twice daily or 300 mg once
daily
 Dose reduction recommended for
Clcr < 50 mL/minute
Preparations
 Individual component 150mg tablets
 Part of FDC:
• AZT + 3TC, AZT+3TC+NVP
• d4T + 3TC, d4T+3TC+NVP
Indications
Food
restrictions
• First-line ARV
• Second-line ARV
None
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3TC – Side Effects
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Side effects and toxicities:
• Well tolerated
• Headache, dizziness, malaise, fatigue
• Rash/allergy (rare)
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Other effects:
• Active against Hepatitis B
• Cessation may cause Hepatitis B flares
Mandell et al. Principle and practice of infectious diseases
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Zidovudine (AZT)
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AZT - Dosing and
Contraindications
Adult Dosing
300 mg tab twice daily
Preparations
• Individual drug
• Fixed dose combination:
• AZT+3TC
• AZT+3TC+NVP
Food
restrictions
None (food may improve
tolerability)
Contraindications
• Hb < 80g/L
• Should not be given with D4T
(antagonistic)
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AZT – Side Effects
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Headache, nausea, bloating,
dyspepsia
Anemia
Lipoatrophy
Proximal myopathy
Skin hyperpigmentation (face)
Nail discoloration
Lactic acidosis (rare)
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Abacavir (ABC)
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ABC - Dosing and
Contraindications
Adult Dosing
300 mg twice daily
Formulations
300 mg tablet
Food restrictions
None
Indications
• Second line therapy
• Can be used in 1st line if
other NRTIs are not tolerated
Contraindications
Previous ABC hypersensitivity
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Abacavir Hypersensitivity (1)
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ABC hypersensitivity is a multi-organ
systemic illness
Occurs in approximately 5 to 8% of
HIV-infected patients who start ABC
More than 90% of cases occur within
the first 6 weeks
• Median time to onset of symptoms is 8 to
11 days
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Can cause life-threatening
complications if ABC is continued
despite worsening symptoms
Clin Ther. 2001;23:1603-14
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Abacavir Hypersensitivity (2):
Symptoms/Signs
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ABC hypersensitivity reaction presents
with signs or symptoms from at least 2
of the following groups:
• fever
• rash
• gastrointestinal (nausea, vomiting,
diarrhea, abdominal pain)
• constitutional (fatigue, myalgias, malaise)
• respiratory (dyspnea, cough, pharyngitis)
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Abnormal laboratory findings are
nonspecific
Clin Ther. 2001;23:1603-14
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Abacavir Hypersensitivity (3)
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Clinical suspicion should be high if
symptoms:
• appear within first 6 weeks of abacavir
therapy
• appear together as both constitutional
and organ specific (particularly
gastrointestinal symptoms)
• worsen with each successive dose
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Abacavir Hypersensitivity (4):
Treatment
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Stop ABC immediately if
hypersensitivity is suspected
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Symptoms usually improve within days
Never give ABC again
Note ABC hypersensitivity in patient record
Notify patient of reaction and counsel them
not to take ABC again
For severe reactions or hypotension:
• Admit to hospital or ICU
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Didanosine (DDI)
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DDI – Dosing
Adult Dosing
• <60 kg: 250 mg once daily
• >60 kg: 200 mg twice daily
• Dose reduction recommended for
Clcr <60 mL/minute
Formulations
• DDI: 25mg, 50mg
• DDI EC: 125, 200 and 250mg
Food
restrictions
• Take 30 min before or 2h after a meal
for 25mg tablets
(levels decrease if taken with food)
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DDI – Side Effects
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Pancreatitis
Peripheral Neuropathy
Lipoatrophy
Lactic acidosis
Noncirrhotic portal hypertension
Avoid combination: DDI + D4T due
to increased toxicities
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Second-Line ARVs: PI
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LPV/r – Dosing
Adult Dosing
400/100 mg twice a day
(2 tablets ALUVIA twice
per day)
Formulations
• Aluvia: 200/50 mg
• Kaletra: 133/33 mg
• Oral solution
Increased absorption if
Food restrictions taken with food
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Ritonavir (RTV)
High-dose:
(600mg twice a day)
 Treatment dose for
HIV
 Not used due to
high rate of patient
intolerance (GI
side effects) and
liver toxicity
Low-dose:
(< 400 mg/day)
 No anti-HIV
activity
 Used to “boost” or
increase the level
of other PI drugs
 Nomenclature: /r
(LPV/r, SQV/r)
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Ritonavir Boosting
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Most potent CYP 450 3A4 inhibitor
available
Used to boost other PI:
“boosted PI”
Increases AUC of the other PI
Can use lower dose of other PI
Increases the Cmin (trough concentration)
of other PI, decreasing risk for resistance
• Allows once or twice daily dosing of PI
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Benefits from Using Ritonavir to
Boost Other PIs
High levels increase risk of side effects
Drug Levels
Peak levels
Ritonavir
smoothes out
the peak and
trough levels of
the active PI
Without ritonavir
trough levels are
lower and peak
levels are often
higher
Trough levels
Low levels increase risk of resistance
Time (Hours)
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LPV/r – Side Effects (1)
Short Term Side Effects
 Diarrhea
• Occurs in 15-25% of patients
• Treat with loperamide 2mg
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Nausea and vomiting
• Take with food
• Ginger tea
• If severe, prescribe metoclopramide
10mg
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LPV/r – Side Effects (2)
Long Term Side Effects
Lypodystrophy
• fat redistribution
Hyperlipidemia
• increased cholesterol,
triglycerides
• insulin resistance
• hyperglycemia
• diabetes
Dysglycemia
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Fat Accumulation
“Humpback”
Increase in visceral
adipose tissue
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Lipodystrophy – Treatment
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Difficult to treat or reverse
Low-fat diet
Exercise
Switch PI to NNRTI (if not resistant
to NNRTI already)
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Metabolic Effects
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Insulin resistance, hyperglycemia
• Check fasting glucose every 6-12 months
• Treat for diabetes as in non-HIV patient
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Elevated Cholesterol
• Check lipid panels yearly
• Treatment: same as non-HV patient
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Exercise, low-fat diet
Stop smoking
Lipid lowering drugs
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LPV/r – Drug Interactions
Interaction of
LPV/r with:
Results
Management
Rifampicin
 level of LPV
by 75%
Avoid combination
Methadone
 level of
methadone
Monitor closely for
signs of withdrawal
Lovastatin
Simvastatin
 levels of
these drugs
Contra-indicated.
Use other lipid
lowering agents
Case Scenarios
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Key Points
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The preferred MOH second-line ARV
regimens are TDF+3TC+LPV/r and
AZT+3TC+LPV/r
Patients with ABC hypersensitivity
should never take ABC again
Patients on PI should have glucose
and lipid tests done at least yearly to
screen for metabolic side effects
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Thank you!
Questions?
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