Transcript Session 11 - Teaching Slides

Dosages and Side Effects
of First-line ART
HAIVN
Harvard Medical School AIDS
Initiative in Vietnam
1
Learning Objectives
By the end of this session, participants
should be able to:
 Describe the importance of recognizing
side effects and toxicities
 Describe the side effects caused by
NRTIs and NNRTIs
 Explain dosing for NRTIs and NNRTIs
 Explain how to change or stop NNRTIs
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Why is it Important to Recognize
Side Effects and Toxicities?
Quality of life:
 Cause suffering
and ill health
 Can be prevented,
managed, and
controlled
Adherence:
 Side effects and
toxicities cause
non-adherence and
loss to follow up
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Help Patients Manage Side
Effects: Warn Them in Advance

To help patients deal with side
effects, counsel them about:
• Which side effects to expect
• How to contact ARV clinic if side effects
occur
• When to return to clinic or to hospital
• The fact that most side effects are mild
and will resolve with continued use of
the medications
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Overview of First-line ARVs in
Vietnam
NRTI
NNRTI
•d4T
•AZT
•3TC
•TDF
•NVP
•EFV
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NRTIs
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Overview of NRTI Toxicity



All NRTIs cause some amount of side
effect or toxicity
Majority of NRTI toxicities are related to
drug’s effect on mitochondrial cells
These toxicities include:
•
•
•
•
•
Peripheral neuropathy
Pancreatitis
Lipoatrophy/dystrophy
Lactic acidosis
Hepatic steatosis
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NRTIs and Mitochondrial Toxicity (1)

NRTIs are nucleoside analogues and inhibit:
• HIV reverse transcriptase enzyme
• polymerase gamma in human mitochondria


Mitochondria produce energy in human cells
Inhibition of polymerase gamma leads to:
• gradual damage to cell mitochondria
• impairment of aerobic metabolism
• cell dysfunction
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NRTIs and Mitochondrial Toxicity (2)


Different NRTIs affect different cells,
tissues and organs
Symptoms of mitochondrial toxicity
vary according to tissues affected
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NRTIs and Mitochondrial Toxicity (3) Spectrum of Disease
Organs
Nerve
tissue
Bone
Marrow
Body fat
Pancreas
Liver
Muscle
NRTIs
Diseases
•
Peripheral neuropathy
d4T, ddI
AZT
d4T
ddI
d4T, ddI
AZT
• Anemia
• Leukopenia
• Lipoatrophy
• Pancreatitis
• Hyperlactatemia
• Lactic acidosis
• Hepatic Steatosis
• Myopathy
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Dosing and Side Effects
of Specific NRTIs
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d4T – Dosing
Adult Dosing • 30 mg twice daily
• Dose reduction recommended
for Clcr< 50 mL/minute
Preparations • Individual 30 mg pills
• FDC
Food
restriction
• None
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d4T – Contraindications

AZT + d4T are antagonistic:
• Do not use together

D4T + ddI = increased toxicity:
• Avoid combination

Pregnancy:
• AZT preferred over d4T
• Increased toxicity of d4T in pregnancy,
but can use if necessary

Peripheral neuropathy
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d4T – Adverse Reactions
Short term
 Few or no short term
side effects
 Very well tolerated in
the short term
Long term
Common and severe:
 Peripheral neuropathy
 Lipodystrophy
 Lactic acidosis
 Hypertriglyceridemia
 Pancreatitis
Switch to AZT or TDF after 1 year treatment or
earlier if symptoms or side effects appear
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d4T – Side Effects:
Peripheral Neuropathy

Clinical presentations:
• 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

Management: switch to AZT or TDF
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d4T – Side Effects:
Lipoatrophy (1)



Lipoatrophy, or fat atrophy, involves
the loss of subcutaneous fat in the
face, arms, legs, and buttocks
Related to NRTI-induced
mitochondrial toxicity
d4T is the NRTI most closely
associated with lipoatrophy
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d4T – Side Effects:
Lipoatrophy (2)
Management: switch to AZT or TDF
d4T – Side Effects:
Lactic Acidosis (1)
Hyperlactatemia and lactic acidosis are
caused by mitochondrial dysfunction in
tissues
 Hyperlactatemia refers to elevated
blood levels of lactate
 Lactic acidosis, the severe form,
occurs in the setting of liver
dysfunction, typically hepatic
steatosis
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d4T – Side Effects:
Lactic Acidosis (2)

Risk factors:
• NRTIs, particularly ddI combined with d4T
• Female, pregnancy, obesity

Symptoms include:
• Abdominal discomfort, loss of appetite, nausea,
vomiting, diarrhea, fatigue, weight loss, dyspnea
• Can progress to multi-organ failure, coma, death

Labs:
• Increased lactate level
• Other labs: CPK, LDH, AST/ALT, low albumin,
low pH or bicarbonate
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Lactic Acidosis: Treatment
Symptoms
Action
• Lactic acid
Change NRTI (change d4T, AZT, ddI
to ABC or TDF)
level<5mM
• No or mild
symptoms
Lactic acid level
Switch NRTI as above
between 5-10mM
• Hospitalize and supportively treat
• Lactic acid
• Treat with riboflavin 50mg/day
level>10mM
• All ARV should be stopped
• When stable, restart ARV using ABC
• Or severe
or TDF plus 3TC, or use NRTIsymptoms
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sparing regimens
d4T – Side Effect Management
Toxicity
• Neuropathy
• Pancreatitis
Lipodystrophy
Action
Switch to AZT or TDF
Switch to AZT or TDF
• Switch to TDF
•
Use
AZT
or
ABC
if
TDF
not
Lactic acidosis
available or
contraindicated
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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 never 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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AZT – Side Effects
Nausea and
Fatigue, headache,
vomiting:
tiredness
 Common at start of
 Common at start of
therapy
therapy
 Improve with time
 Improves with time
 Management:
 Management:
• Take with food
• Anti-nausea
medication
• Ginger tea
• Paracetamol for
headache
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AZT – Side Effects (1)
Anemia


Anemia is the most common side effect of
AZT (due to bone marrow suppression)
Two patterns:
• Acute drop of Hgb after a few months of
therapy, sometimes necessitating transfusion
• Slowly declining of Hgb, 0.5-1.0 gm, over
several months

Management:
• CBC monitoring required
• Change AZT to d4T/TDF if severe
• Avoid AZT if Hb < 80g/L
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AZT – Side Effects (2)
Finger Nail Discoloration
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AZT – Side Effects (3)
Myopathy

Progressive proximal muscle weakness
• Proximal muscle weakness and atrophy
(legs > arms)
• Muscle tenderness and myalgias
• No sensory findings, reflexes intact
• ↑ creatinine kinase levels

Management:
• Stop AZT
• Responds to prednisone
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AZT - Side Effect Management
Toxicity
Action
• Persistent GI
intolerance
• Severe
hematological
toxicity
• Switch to TDF or d4T
• Lipoatrophy
• Lactic acidosis
• Switch to TDF
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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, AZT+3TC+NVP
Food
restrictions
None
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3TC – Side Effects

Side effects and toxicities:
• Well tolerated
• Headache, dizziness, malaise, fatigue
• Rash/allergy (rare)

Other effects:
• Active against Hepatitis B
• Cessation may cause Hepatitis B flares
• Patients with chronic HBV taking 3TC may
have false-negative HBsAg test results
Mandell et al. Principle and practice of infectious diseases
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TDF – Dosing
Adult Dosing
Preparations
Indications
Food
restrictions
• 300mg tab, once daily
• Dose reduction recommended for
Clcr < 50 mL/minute
Individual drug
• First-line ARV
• Second-line ARV if AZT used in first
line
None
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TDF – Side Effects
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
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Usually very well tolerated
Most common side effects are minor:
nausea, vomiting, flatulence
Most concerning is renal dysfunction
• Usually mild, asymptomatic
• Reverses when TDF stopped
• Creatinine should be monitored every 6
months
• Acute renal failure is rare: reduce TDF dose
when renal failure 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
NRTI Case Studies
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NNRTIs
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NVP – Dosing
Adult
dose
Dose escalation:
• 200mg per day for the first 2
weeks
• 200mg two times per day after
that
If rash occurs at lower dose,
delay dose escalation on 1 week
Food
None
restriction
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NVP – Side Effects


Rash
Hepatotoxicity
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NVP – Rash (1)
Incidence:
 25-37% of patients
have mild rash
 1-5% must stop NVP
due to rash
 1% rash with
hepatotoxicity or
systemic symptoms
 <1% Stevens
Johnson Syndrome
Risk factors for
rash:
 Female
 Early weeks of
treatment
 CD4 counts > 250
for females, > 400
for males
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NVP – Rash (2)

Clinical presentation:
• Gradual onset
• Begins on trunk; extends to whole body
(if severe)
• Most commonly starts after 10 days but
commonly occurs any time in first 4-6
weeks
• May worsen after dose escalation
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Grading Rash
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Four Grades of Rash (1)
Grade 1: •
Mild
Grade 2: •
Moderate •
•
•
Erythema, with or without pruritis
Diffuse maculopapule rash or
Dry desquamation or
Target lesions without blistering, vesicles,
or ulceration and
No systemic symptoms (fever, muscle
pain, joint pain)
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Four Grades of Rash (2)
Grade 3:
Severe
•
•
•
•
Vesiculation
Moist desquamation
Ulceration
Systemic symptoms
• Fever
• Blistering
• Muscle and/or
joint pain, edema
• Elevated
transaminases
Four Grades of Rash (3)
Grade 4:
Potentially
life-threatening
• Mucous membrane involvement:
• Ulceration in mouth, eyes,
genitals
• Suspected Stevens-Johnson
syndrome
• Erythema multiform
• Exfoliative dermatitis
NVP Rash - Management
Mild or
• Continue NVP
moderate
• Delay dose escalation up to 1 week
(Grade 1 – 2) • Antihistamines
• Steroids not proven to be helpful
Grade III or
persistent
grade I-II
Grade IV
• Replace NVP with EFV: 90% will
tolerate EFV without allergy
• Admit to hospital, cease all drugs
Practice points: Warn patient to return
immediately if rash develops and then
review frequently
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NVP – Hepatotoxicity (1)

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Risk factors:
•
•
•
•
LFTs > 2.5x ULN before treatment
Women with CD4 > 250
Man with CD4 > 400
HBV and/or HCV co-infection
•
•
•
•
Fever, malaise
With or without rash
High LFTs
Severe hepatotoxicity occurs in 2-4% of
patients on NVP
Clinical presentation:
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NVP – Hepatotoxicity (2)

Need to check LFTs:
• After one month in all patients
• In all patients with rash
• In all patients with fever or illness

Management:
LFTs < 5x ULN
(Grade 1 - 2)
• Continue NVP
• Monitor LFTs and clinical
symptoms frequently
LFTs > 5x ULN
• Switch to EFV if available
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(Grade 3-4)
Guidelines for Diagnosis
and Treatment of to
HIV/AIDS,
Ministry of Health,
Vietnam. August,
• Refer
higher
level
if not
2009.
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EFV – Dosing
Adult
dose
600mg daily before sleep
• Take on empty stomach or with
light snack
Food
• High-fat meal will quicken drug
restriction absorption and increase side
effects
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EFV - Side Effects (1)
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Psychologic disturbances:
depression, psychosis, mania
Sleep disturbances
Headache, lightheadedness,
dizziness
Rash, usually mild, self-limited
Increase in lipids
Teratogenic in first trimester
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Efavirenz – Side Effects (2)

Central Nervous System:
• Sleep disturbance, vivid dreams,
insomnia, dizziness, drowsiness (> 50%
of pts)
• Unsteady walking: Particularly at night
• Progression:



Onset 1 - 2 days
Peak 4 - 7 days
Resolution over 2 - 4 weeks
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Efavirenz – Side Effects (3)

Rash:
• Usually mild
• SJS << 1%

Hepatotoxicity:
• Much less than NVP
• Safe in patients with raised LFTs, HBV
and/or HCV
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Efavirenz – Side Effects (4)

Risk of teratogenic in first trimester:
• Avoid in women of childbearing age if
other options available
• Pregnancy test before starting
• Contraception necessary for women of
child bearing age
• Do not give to pregnant women in first
12 weeks of pregnancy
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Toxicity Management - NNRTI
Toxicity
Action
mild to
•Continue NVP;
moderate
•Switch to EFV if
(grade 1-2) persistent/progressive
NVP: rash,
Severe
hepatotoxicity (grade 3)
life
threatening
(grade 4)
EFV: severe or persistent
CNS symptoms
Switch to EFV
Switch to EFV, PI, or
TDF
Switch to NVP, PI or
TDF
Stopping or Changing
NNRTIs
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Half Lives of ARVs
Problem: NNRTIs (NVP, EFV) have much
longer half lives than NRTIs
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Stopping NNRTIs


For patients a standard regimen (2
NRTI + 1 NNRTI), stopping all 3
drugs at the same time can lead to
development of resistance to NNRTI
If you need to stop the NNRTI due to
toxicity or intolerance, how should
you do it?
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How to Stop an NNRTI? (1)

If changing NNRTI due to:
• Mild side effects (grade 1-2)
• Drug interactions (RIF, TB treatment)
• Pregnancy

Then can stop one NNRTI and start
the other the next day (single drug
substitution)
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How to Stop an NNRTI? (2)


If stopping NNRTI due to major
toxicity or severe allergy
Then stop the NNRTI and continue
the 2 NRTIs medications for 7 days
• If improving  substitute another
NNRTI or PI
• Not improving stop the 2 NRTIs and
continue to monitor. Restart ARV when
the patient is clinically stable.
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Additive Side Effects –
Not Just ARVs
Side Effect
Rash
Liver toxicity
Bone marrow
suppression
Peripheral
Neuropathy
Medications
Cotrimoxazole, TB
drugs and NVP
INH, RIF, PZA and
NNRTIs or PIs
AZT and
Cotrimoxazole
Isoniazid and d4T
NNRTI Case Studies
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Key Points



Counseling patients on side effects is
critical for good adherence
Recognizing side effects is crucial for
treatment
Common side effects of NRTI include:
• Lactic acidosis
• Lipodystrophy
• Peripheral neuropathy

Most common side effects of NNRTI are
rash and hepatotoxicity
60
Thank you!
Questions?
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