Download Session 5 - Teaching Slides

Antiretroviral Drugs:
Dosages and Side Effects of
first-line ARV
HAIVN
Harvard Medical School AIDS Initiative
in Vietnam
1
Learning Objectives
At the end of this lecture, each trainee should:
• Know the names and dosages of the first-line ARVs
in Vietnam.
• Be able to recognize, diagnose and manage rash
due to nevirapine.
• Be able to recognize, diagnose and manage ARV
related hepatotoxicity.
• Know the common short-term and long-term
toxicities of NRTI
2
Content
• First-line antiretrovirals recommended
in Vietnam
• First-line ARV regimens and their side
effects
– NRTIs and Mitochondrial Toxicity
– NNRTIs
3
Side Effects, Adverse
reactions and toxicities
• Adverse reactions:
– All effects of drugs other than intended therapeutic effect
– Includes side effects and toxicities
– Some are predictable (occur in most people to a greater or lesser
extent) e.g. nausea
– Some are unpredictable (occur only in some people) e.g.
hypersensitivity
• Side effects:
– E.g. nausea, anemia, dizziness
– Mostly occur early and subside with time
– May be managed without switching drug depending on nature and
severity
– Symptomatic treatment should be offered
• Toxicities:
– Organ or tissue damage or metabolic problems caused medications
– May occur more slowly than side effects and progress continuously
– Often require switching of the drug
4
Importance of recognizing
side effects and toxicities
• Quality of life:
– Cause suffering and ill health
– Can be prevented, managed or controlled
• Adherence:
– Side effects and toxicities cause non-adherence
and loss to follow up
5
Antiretroviral dosages and
side effects for first line ARV
regimens in Vietnam
6
First line ARV Regimens in
Vietnam
NVP
D4T
or
AZT
+
3TC
+
or
EFV
or
ABC
Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.
7
First line ARV Regimens in
Vietnam
First-Line ARV regimens:
AZT/3TC/NVP
AZT/3TC/EFV
D4T/3TC/NVP
D4T/3TC/EFV
AZT/3TC/ABC
D4T/3TC/ABC
Preferred regimen:
AZT/3TC/NVP
Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.
8
Drugs are given on the basis of
weight and need to be adjusted
as the child grows
9
AZT Dosing
• Individual
– Syrup: 10 mg/ml
– Capsules: 100 mg 250
mg
– capsule: 300 mg
• Fixed Dose Combination
– AZT/3TC
– AZT/3TC/NVP
• Baby 60/30/50
• Adult 300/150/200
• Food restrictions: none (food may improve tolerability)
• Contraindications:
– Hb ≤ 8.0 mg/dL
– AZT should not be given with d4T (antagonistic)
10
AZT Side Effects and Toxicities
•
•
•
•
•
•
•
•
•
Common
Anemia
Neutropenia
Headache
Nausea and Vomiting
Altered taste
Fatigue
Anorexia
Insomnia
Myalgia
•
•
•
•
•
•
•
Long-Term Use
Myopathy
Nail pigmentation
Lipoatrophy
Rare
Fever
Rash
Hepatitis
Steatosis/lactic acidosis
11
AZT: Anemia
• Very common side effect of AZT therapy.
– 1%-18% of patients experienced anemia grade 1 or 2
– 0-3% of patients develop moderate/severe anemia
(grade 3 or 4)
• Do not use AZT if baseline Hb < 80g/L
• Requires monitoring:
– Symptoms and signs of anemia
– Checking Hb levels (month 1, 3, 6 after starting AZT, and every 6
months thereafter)
• If severe anemia develops (Hg < 70 g/L), change to d4T
12
AZT: Neutropenia
• Less common than anemia but can occur in
children
• If mild-moderate (ANC 500 – 1000/mm3) and no
concerning signs and symptoms (i.e., no fever or
infection), then can continue AZT with repeat
CBC after 1 month.
• If severe (ANC < 500), then exclude other
causes of neutropenia or bone marrow
suppression and, if no other treatable cause is
identified, change AZT to d4T or ABC
13
Nausea and Vomiting
• Very common at start of therapy
• Improves with time and often resolves within 2-4 weeks
• Management:
– Reassure patient/caregiver
– Recommend taking ARVs with food and small meals
frequently between doses.
– Anti-nausea medication as needed or 30 min prior to ART
• Metoclopramide: < 6 years old: 0.1 mg/kg three times a day if
required
• Metoclopramide: 6-14 years old: 2.5-5 mg taken 30min
before ARV dose if the patient experiences vomiting with
ARV
– Rehydration therapy if persistent vomiting
14
Fatigue, Headache, Myalgias
• Common at start of therapy
• Improves with time
• Paracetamol for headache and myalgias.
15
Myopathy
• Most commonly presents within 6-12 months of
initiating AZT
• Can have an insidious onset
• Typically involves proximal muscle weakness
and exercise-induced myalgias
• Serum creatine kinase (CK) levels are often
elevated
• Stopping AZT generally results in a gradual
resolution of symptoms over 6 to 8 weeks
16
Nail pigmentation
17
Rahav et al. (1992) Scandinavian Journal of Infectious Diseases,24:5,557
AZT Adverse Effects: Other
• Lactic acidosis, Lipoatrophy,
Hepatotoxicity
– All can occur with AZT therapy
– Less frequent than with d4T
– If present, stop AZT and change to ABC
18
D4T/Stavudine
• Individual
– Syrup: 1 mg/ml
– Capsules: 15, 20, 30 mg
• Fixed Dose Combination
– D4T/3TC/NVP
• Baby 6/30/50
• Junior 12/60/100
• Adult 30/150/200
• Food restrictions: none
• Contraindications:
– Peripheral neuropathy
– D4T should not be given with AZT (antagonistic) or ddI
(increased toxicity)
– Pregnancy: AZT is preferred
19
d4T – Adverse reactions
• Short term side effects:
– Few or no short term side effects
– Very well tolerated in the short term
• Long term toxicities:
– Common and severe
• Peripheral neuropathy
• Lipodystrophy
• Lactic acidosis
• To avoid d4T long term toxicities:
– AZT preferred
– Substitute AZT after one year of D4T use or change
earlier if signs of toxicity appear.
20
Peripheral Neuropathy
• Appears to occur less frequently in
children compared to adults.
• Onset typically occurs after many months
of d4T use
• Symptoms include numbness, tingling,
and/or burning
• Symptoms begin distally (toes and/or
fingers) and move proximally over time
• D4T-related peripheral neuropathy may
resolve if therapy is withdrawn promptly.
• However, severe and permanent disability
can occur.
21
Lipoatrophy
• Lipoatrophy is the loss of subcutaneous body
fat; most commonly in the extremities, face,
and buttocks
• It is closely associated with d4T use in both
adults and children.
• Studies of children on d4T-based ART
estimate the prevalence of body fat changes
from 18 to 33%.
• The presence of lipoatrophy can be
stigmatizing, can reduce quality of life, and
can adversely affect adherence to ART.
22
Lipoatrophy (Peripheral Fat
Wasting)
Prominence of
blood vessels
Sunken
Cheeks
23
Lactic Acidosis
• Lactic acidosis is caused by NRTI-induced
mitochondrial dysfunction in tissues
• Mild asymptomatic hyperlactatemia is common
in children (17-32%), but symptomatic severe
hyperlactatemia (> 5.0 mmol/L) is less common
than in adults.
• Symptoms include fatigue, weight loss, nausea,
vomiting, abdominal pain, shortness of breath
• Can lead to multi-organ failure, coma, and death
24
NRTIs and Mitochondrial
Toxicity
• NRTI’s are nucleoside analogues:
– inhibit of HIV reverse transcriptase enzyme
– Inhibit of 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 and cell dysfunction
• Different NRTIs effect different cells, tissues and
organs
• Symptoms of mitochondrial toxicity vary according
to the tissues affected
25
The NRTI and Mitochondrial
Toxicity Hypothesis
NRTIs
Polymerase γ
mtDNA
mtDNA
mtDNA encoded protein
function
dysfunction
mitochondrion
mtDNA encoded proteins
nDNA encoded proteins
26
Adapted slide from Dr. Cecilia Shikuma
NRTIs and Mitochondrial
Toxicity: Spectrum of Disease
• Nerve tissue: d4T, ddI
– Peripheral Neuropathy
• Bone Marrow: AZT
– Anemia
– Neutropenia
• Liver: d4T, ddI
– Hyperlactatemia
– Lactic acidosis
– Hepatic Steatosis
• Muscle: AZT
– Myopathy
• Body fat: d4T
– Lipoatrophy
• Pancreas: ddI
– pancreatitis
27
Hyperlactatemia and Lactic
Acidosis
• Aerobic metabolism (mitochondria dependent)
– uses oxygen and glucose and releases carbon dioxide
• Anaerobic metabolism
– Releases lactic acid or lactate into the blood stream
– Lactic acid is processed by the liver.
• Hyperlactatemia:
– High blood levels of lactate
– Caused by mitochondrial dysfunction in tissues
– Causes symptoms of shortness of breath, nausea, malaise,
fatigue, abdominal pain. (8-21% of NRTI treated patients)
• Lactic acidosis
– With hepatic steatosis
– Multiorgan failure, coma, and death (1-2 % in prospective
analyses)
28
Lamivudine (3TC)
• Individual
– Syrup: 10 mg/ml
– Tablet: 150 mg
• Fixed Dose Combination
– AZT/3TC, d4T/3TC
– AZT/3TC/NVP
• Baby 60/30/50
• Adult 300/150/200
– D4T/3TC/NVP
• Baby 6/30/50
• Junior 12/60/100
• Adult 30/150/200
• Food restrictions: none
29
3TC/lamivudine
Side effects and toxicites
• Few/rare
Other effects:
• Active against Hep B
• Cessation may cause Hep B flares
• Patients with chronic HBV taking 3TC may
have false-negative HBsAg test results
30
Nevirapine (NVP)
• Individual
– Syrup: 10 mg/ml
– Tablet: 200 mg
• Fixed Dose Combination
– AZT/3TC/NVP
– D4T/3TC/NVP
• Dose escalation instructions:
• Dose by weight once per day for the first 2 weeks
• Then, Increase to twice per day or change to FDC
(twice daily)
• If rash occurs at lower dose, delay dose
escalation for up to one week
• Food restrictions: none
31
Example of NVP Dosing
32
Nevirapine – Side Effects
• Rash
– Incidence:
•
•
•
•
20-25% 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
• High CD4 count (> 250 for females or > 400 for males)
– Clinical presentation:
• Gradual onset
• Begins on trunk later extending to whole body (if severe)
• Commence around 10 days commonest but any time in first 1-6
weeks
• May worsen after dose escalation
33
Grading the rash
Grade 1: Mild
– Erythema, with or without pruritis
Grade 2: Moderate
– Diffuse maculopapular rash or
– Dry desquamation or
– Target lesions without blistering, vesicles,
or ulceration and
– No systemic symptoms (fever, muscle
pain, joint pain)
34
Grade 1-2 NVP Rash
35
Grading the Rash
Grade 3: Severe
–
–
–
–
Vesiculation
Moist desquamation
Ulceration
Systemic symptoms
• Fever
• Blistering
• Muscle and/or joint pain,
edema
• Elevated transaminases
36
Grading the Rash
Grade 4: Potentially life-threatening
– Mucous membrane involvement
• Ulceration in the mouth, eyes, genitals
– Suspected Stevens-Johnson syndrome
– Erythema multiform
– Exfoliative dermatitis
37
Stage IV NVP Rash
38
Stage IV NVP Rash
39
Nevirapine – Rash
Practice points:
– Warn patient to return immediately if rash develops and
then review frequently
– If mild or moderate (Grade 1 – 2)
•
•
•
•
Continue nevirapine
Delay dose escalation up to 1 week
Antihistamines
Steroids not proven to be helpful
– If Grade III or persistent grade I-II:
• Replace NVP with EFV (if age > 3 and weight > 10 kg):
90% will tolerate EFV without allergy
– If grade IV
• Admit to hospital, cease all drugs
40
Nevirapine Rash: Treatment Protocol
•Assess rash
•Check for systemic symptoms and signs and systemic
•Check LFTs
Grade 1-2
Grade 3
Grade 4
•Reassess Frequently
•Delay dose escalation for up to one
week
Resolves
•Dose escalate and
continue regimen
Continues
•Stop NVP
•Continue NRTIs
•Start EFV* after 3-7
days
•Admit to hospital
•Stop all drugs
•Start different
combination later
41
* If age > 3 and weight > 10 kg
Nevirapine – Hepatotoxicity
• Hepatotoxicity
– Risk factors:
• LFTs > 2.5x ULN before treatment
• Higher CD4 counts
• HBV and/or HCV co-infection
– Clinical presentation
• Fever, malaise
• With or without rash
• High LFTs
42
Grading Hepatotoxicity
GRADE
 LFT > normal
mild
severe
1
1.25 – 2.50
2
2.60 - 5
3
5 - 10
4
> 10
43
Nevirapine – Hepatotoxicity
• 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 nevirapine
• Monitor LFTs and clinical symptoms frequently
– LFTs > 5x ULN (Grade 3-4)
• Switch to EFV if appropriate
Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.
44
Nevirapine Hepatotoxicity: Treatment Protocol
•Assess rash
•Check for systemic symptoms and signs and systemic
•Check LFTs
Grade 3
or with
fever/rash
Grade 1-2 and
No systemic symptoms and
Grade 4 or with
fever, rash
No rash
•Continue NVP
•Check LFTs every 1-2 weeks
•Dose escalate and
continue regimen
•Stop NVP
•Continue NRTIs
•Start EFV* after 3-7
days
•Admit to hospital
•Stop all drugs
•Start different
combination later
45
* If age > 3 and weight > 10 kg
Stopping drugs with different half lives
Last Dose
Day 1
Day 2
Drug concentration
NNRTI
MONOTHERAPY
IC
Zone of potential replication
IC
0
12
24
36
90
50
48
Time (hours)
Taylor S, et al. 11th CROI, San Francisco, 2004, #131
46
Efavirenz (EFV)
• Individual
– Capsule: 50, 200, 600 mg
• Food restriction:
• Take on empty stomach or with light snack.
• High-fat meal will quicken drug absorption and
increase side effects.
• Contraindications:
• Children < 3 years old or weight < 10 kg
• Pregnant adolescent in 1st trimester
47
Efavirenz – Side Effects
• Central Nervous System:
– Sleep disturbance, vivid dreams,
dizziness, drowsiness.
– Unsteady walking: particularly at night
– Timing
• Onset 1 - 2 days
• Peak 4 - 7 days
• Resolution over 2 - 4 weeks
48
Efavirenz – Side Effects
• Rash:
– Commonly reported in children (30–40%)
– Most often a maculopapular eruption
– Typically mild; the rash usually resolves with
continued treatment.
– Antihistamines and/or corticosteroids may
improve the tolerability and hasten the
resolution of the rash.
49
Efavirenz – Side Effects
• Hepatotoxicity:
– Much less than NVP
– Safe in patients with raised LFTs, HBV and/or HCV.
• Teratogenic in first trimester
– Avoid in women of childbearing age if other options
available.
– Consider pregnancy test before starting.
– Contraception mandatory for women of child bearing
age
– Never give to pregnant women in 1st 12 weeks of
pregnancy
50
Hepatotoxicity: Differential
Diagnosis
ARV toxicity
• Hepatotoxicity, hypersensitivity:
– NNRTI (NVP, EFV)
– Abacavir (hypersensitivity)
– Indinavir (rare)
• Lactic acidosis with hepatic
steatosis
– nRTIs (d4T, ddI, AZT, ABC)
•
•
•
•
Non-ARV drugs
TB drugs – PZA, RIF, INH
Antifungal drugs
– Ketoconazole, fluconazole,
itraconazole
Others– Paracetamol
Alcohol
Infectious diseases
• Viral: CMV, HAV, HBV, HCV, HDV, HEV, dengue
• Bacterial: TB, MAC, sepsis
• Fungal: Penicillium, candida
• Parasitic: Amoebiasis
Other causes
•
•
•
•
IRS (HBV)
Steatosis (fatty liver)
Tumor: lymphoma
Autoimmune hepatitis
51
Additive Side Effects – Not Just
ARVs
• Rash: Cotrimoxazole, TB drugs and
NVP
• Liver toxicity: INH, RIF, PZA and
NNRTI’s or PI’s
• Bone marrow suppression: AZT and
Cotrimoxazole
• Peripheral Neuropathy: Isoniazid and
D4T
52
Key Points
• Counseling patient/caregiver on early side effects is critical for
good adherence.
–
–
–
–
What side effects to expect
How to contact ARV clinic if side effects occur.
When to return to clinic or to hospital
Most side effects are mild and will resolve with continued use of the
medications
• The most common side effects in first line treatment are rash and
hepatotoxicity from NNRTI
–
–
–
–
–
Side effects more common with NVP than EFV
Delay dose escalation of NVP if rash occurs.
Severe hepatotoxicity occurs in 2-4% of patients on NVP.
The risk higher in Hepatitis B and/or Hepatitis C.
EFV preferred when LFTs > 2.5 x ULN (AST,ALT > 100)
53
Key Points
• Side effects of NRTI:
– Short term toxicities:
• AZT: nausea, vomiting, anemia
• d4T: usually well tolerated in the short term
– Long term toxicities
• More common with d4T
• Related to inhibition of mitochondrial polymerase gamma
– Lactic acidosis
– Lipodystrophy
– Peripheral neuropathy
54
Thank you
Questions?
55