1 dosages and side effects of first-line art haivn harvard medical school aids initiative in vietnam
TRANSCRIPT
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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 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
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Organs NRTIs Diseases
Nerve tissue
• Peripheral neuropathy
Bone Marrow
• Anemia• Leukopenia
Body fat • Lipoatrophy
Pancreas • Pancreatitis
Liver • Hyperlactatemia• Lactic acidosis• Hepatic Steatosis
Muscle • Myopathy
d4T, ddI
AZT
d4T
ddI
d4T, ddI
AZT
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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
Switch to AZT or TDF after 1 year treatment or earlier if symptoms or side effects appear
Short term Long termFew or no short term side effects
Very well tolerated in the short term
Common and severe: Peripheral neuropathy Lipodystrophy Lactic acidosis Hypertriglyceridemia Pancreatitis
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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:Lactic Acidosis (1)
Hyperlactatemia and lactic acidosis are caused by mitochondrial dysfunction in tissuesHyperlactatemia refers to elevated blood levels of lactateLactic 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
level<5mM• No or mild
symptoms
Change NRTI (change d4T, AZT, ddI to ABC or TDF)
Lactic acid levelbetween 5-10mM
Switch NRTI as above
• Lactic acid level>10mM • Or severe
symptoms
• Hospitalize and supportively treat• Treat with riboflavin 50mg/day• All ARV should be stopped• When stable, restart ARV using ABC
or TDF plus 3TC, or use NRTI-sparing regimens
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d4T – Side Effect Management
Toxicity Action•Neuropathy• Pancreatitis
Switch to AZT or TDF
Lipodystrophy Switch to AZT or TDF
Lactic acidosis
• Switch to TDF•Use AZT or ABC if TDF not 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)
Contra-indications
• Hb < 80g/L• Should never be given with D4T (antagonistic)
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AZT – Side Effects
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 vomiting:
Common at start of therapy
Improve with time Management:
• Take with food• Anti-nausea
medication• Ginger tea
Fatigue, headache, tiredness
Common at start of therapy
Improves with time Management:
• 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 (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 TDF28
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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 resultsMandell et al. Principle and practice of infectious diseases
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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 if AZT used in first line
Food restrictions
None
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TDF – Side Effects
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
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
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Creatinine Clearance (ml/min) and TDF dose (TDF 300 mg)
>50ml/min 30 – 49 ml/min 10 – 29 ml/min <10 ml/min
Once daily Every other day
Every 3- 4 days or twice a week
Contra-indicated
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NVP – Dosing
Adult dose
Dose escalation:• 200mg per day for the first 2
weeks• 200mg two times per day after
thatIf rash occurs at lower dose,
delay dose escalation on 1 week
Food restriction
None
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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
Four Grades of Rash (1)Grade 1: Mild
•Erythema, with or without pruritis
Grade 2: Moderate
• 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: Potentiallylife-threatening
• Mucous membrane involvement:• Ulceration in mouth, eyes,
genitals• Suspected Stevens-Johnson
syndrome• Erythema multiform• Exfoliative dermatitis
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NVP Rash - ManagementMild or moderate (Grade 1 – 2)
• Continue NVP• Delay dose escalation up to 1 week• Antihistamines• Steroids not proven to be helpful
Grade III orpersistent grade I-II
• Replace NVP with EFV: 90% will tolerate EFV without allergy
Grade IV • 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)
Risk factors:• LFTs > 2.5x ULN before treatment• Women with CD4 > 250• Man with CD4 > 400• HBV and/or HCV co-infection
Clinical presentation:• Fever, malaise• With or without rash• High LFTs• Severe hepatotoxicity occurs in 2-4% of
patients on NVP
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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:
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Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.
LFTs < 5x ULN(Grade 1 - 2)
• Continue NVP• Monitor LFTs and clinical
symptoms frequently
LFTs > 5x ULN (Grade 3-4)
• Switch to EFV if available• Refer to higher level if not
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EFV – Dosing
Adult dose
600mg daily before sleep
Food restriction
• Take on empty stomach or with light snack• High-fat meal will quicken drug
absorption and increase side effects
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EFV - Side Effects (1)
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
Toxicity Management - NNRTIToxicity Action
NVP: rash,hepatotoxicity
mild to moderate(grade 1-2)
•Continue NVP;•Switch to EFV if persistent/progressive
Severe(grade 3)
Switch to EFV
life threatening (grade 4)
Switch to EFV, PI, or TDF
EFV: severe or persistent CNS symptoms
Switch to NVP, PI or TDF
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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.
Additive Side Effects – Not Just ARVs
Side Effect Medications
RashCotrimoxazole, TB drugs and NVP
Liver toxicityINH, RIF, PZA and NNRTIs or PIs
Bone marrow suppression
AZT and Cotrimoxazole
Peripheral Neuropathy
Isoniazid and d4T
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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