Transcript 6_ARV_Drug_Toxicity

KITSO AIDS Training Program
Lecture 6:
ARV Drug Side Effects and
Toxicities
delivered by
Dr. J.H. Mukendi Kazadi, BHP
Adverse Effects of Antiretroviral Drugs
• Do occur commonly.
• Can be a potential barrier to successful therapy.
• May lead to a reduction in the quality of life.
• May be an important cause of non-adherence to
therapy.
REMEMBER: Overall experience in Botswana has
shown that ARV medications are very well tolerated
by the vast majority of patients!
Outline
•
Common side effect profiles of each ARV drug
(grouped by class).
•
Serious and rare toxicities of each ARV drug.
•
Recognition & management strategies.
•
Brief review of long-term complications of PIs.
•
Food requirements of ARV drugs.
•
Summary / Conclusions.
Side Effects and Toxicities
• Side effects are usually self-limited and not
life-threatening, and usually resolve over a
short period of time and with symptomatic
support. Side effects usually occur early after
ARV initiation.
• Toxicities are more severe, potentially lifethreatening effects of ARVs and can occur at
anytime.
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Recommended Drug Regimens
NRTIs
NNRTIs
PIs
1st Line AZT+3TC NVP* or
EFV**
2nd Line ddI + d4T
NFV or
LPV/r
*Age < 3 years or woman with reproductive potential
**Age > 3 years or women with no reproductive potential
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Potential Toxicities of NRTIs
AZT
3TC
ddI
d4T
Zidovudine
Retrovir™
Lamuvidine
Epivir™
Didanosine
Videx™
Stavudine
Zerit™
AZT (Zidovudine)
• Most common:
-- Nausea, vomiting, headaches, fatigue, myalgias
• Common:
-- Macrocytosis -- not significant, but a marker for
adherence
• Serious:
-- Anemia and neutropenia
-- Myositis (elevated CPK) and myopathy
-- Lactic Acidosis
• Other:
-- Darkening of skin, mucous membranes, nails
AZT Pigmentation (nail beds)
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AZT Pigmentation of the Mucosa
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AZT Pigmentation (hard and soft palate)
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AZT Anemia
• Modification of AZT therapy must be
considered when patients have substantial
drop in HB (< 7.0 gm/dL) or more than 25%
decrease from their baseline.
• AZT-induced anemia can occur as early as
2-4 weeks following initiation, but typically
occurs after 4-12 weeks, sometimes later.
Severe AZT Anemia
If significant drop in HB from baseline:
STOP AZT

Substitute d4T for AZT
Transfuse if HB < 5.5 gm/dL
Do not treat with AZT again, unless
absolutely necessary and hemoglobin has
substantially improved.
3TC (Lamivudine)
• Common:
-- None (well-tolerated)
• Less common:
-- Occasional nausea, headaches,
vomiting, and diarrhea
• Serious:
-- Pancreatitis (very rare)
D4T (Stavudine)
• Common side effects:
- Peripheral neuropathy (up to 20%)
- Lipid elevations
- Lipoatrophy
• Uncommon:
- Lethargy, myalgia, headache
• Serious:
- Liver toxicity, pancreatitis (rare)
- Lactic acidosis (rare)
ddI (Didanosine)
• Common:
Nausea
Bloating
Diarrhoea
Peripheral neuropathy (up to 20%)
• Serious:
Pancreatitis, optic neuritis
Recognition of ARV Drug-induced
Peripheral Neuropathy
• ARV drugs implicated: d4T > ddI > > AZT
• Document presence of PN at baseline visit since HIV alone
can cause significant PN, which often improves with ARV
therapy.
• Typical symptoms (parasthesia, numbness)
-- Usually in hands / feet (“stocking-glove distribution”)
-- As progresses, can cause loss of reflexes and vibratory
sense
-- Important to assess how PN affects activities of daily living
(walking, sleeping, working, etc.)
Management of ARV Drug-induced
Peripheral Neuropathy
• Mild/Moderate PN
-- Treat side effects and continue same regimen.
-- Treat with amitriptyline (begin at 25 mgs), carbamazepine,
phenytin, or gabapentin.
NOTE: [Need to document presence of PN at baseline visit
since HIV alone can cause significant PN].
• Severe PN
-- Discontinue causative ARV drugs (d4T and/or ddI)
-- May take weeks-months for symptoms to resolve even after
discontinuing causative ARV drugs.
Recognition of ARV Drug-induced
Pancreatitis
• Symptoms of pancreatitis typically during first 1-6
months
• Begins with abdominal pain, nausea and vomiting
• More common with ddI, but also reported with d4T,
rarely with 3TC.
• Elevated amylase/lipase (asymptomatic
hyperamylasemia may be due to parotid/salivary
gland source).
Management of ARV Drug-induced
Pancreatitis
• Treat abdominal pain, nausea, vomiting.
• Bowel rest with IVF’s (stop all ARVs, until
pancreatitis resolves); consider imaging with
abdominal ultrasound / CT scan.
• Do not re-challenge with offending ARV(s) if
pancreatitis is confirmed.
Lactic Acidosis Syndrome
• Entire NRTI class implicated:
-- Recently described / reported
-- Probably due to mitochondrial toxicity
-- Very rare.
-- Presentation is very vague (fatigue, nausea,
vomiting, abdominal pain, weight loss, malaise,
dyspnea, and motor weakness).
Recognition of Lactic Acidosis
Syndrome
• Laboratory Clues:
-- Increased anion gap: Na – [Cl + CO2]
-- Increased lactic acid (check with a grey-top tube
on ice), modest elevation in SGOT/SGPT, and low
HCO3
NOTE: If lab is not able to perform HCO3 on U/E, can run
heparinised blood specimen on blood gas analyzer.
• Diagnosis:
-- Above symptoms with elevated lactate level
(> 5.0 mmol/L in adults)
Management of Lactic Acidosis
Syndrome
• High mortality rate (60%)



Consider administering bicarbonate and vitamin
supplements (riboflavin).
Discontinue all ART; administer NRTI-sparing
HAART after patient recovers and lactate levels
return to normal. Consult HIV specialist.
Recovery from elevated lactic acid levels may be
prolonged.
Potential Toxicities of NNRTI Class

EFV (Efavirenz)

NVP (Nevirapine)
EFV (Efavirenz)
• Common (not class-related):
Central nervous system side effects
Headaches
Light-headedness
Confusion
Sleep disturbances (abnormally vivid dreams)
These side effects typically resolve within the
first 14-21 days of treatment and are lessened
by taking EFV at bedtime.
EFV (Efavirenz)
• Serious (class-related):
-- Skin rash; progressing to Steven’s
Johnson Syndrome
-- Hepatotoxicity
• The above toxicities are less common with
EFV than with NVP.
EFV (Efavirenz)
• EFV is the only ARV absolutely
contra-indicated in pregnancy
(not recommended for use in women with childbearing potential).
• Contraindicated in children under 3 years.
• Safe to administer with ATT medications.
EFV (Efavirenz)
• Other possible side effects:
Lipodystrophy (body habitus changes)
-- Elevated triglycerides/cholesterol
-- Breast enlargement
NVP (Nevirapine)
• Common:
-- Cutaneous
-- Skin rash, reported up to 20%, usually appears
in the first few weeks to months of therapy.
-- Progresses to Stevens-Johnson Syndrome (SJS)
in < 1.0%.
• Less Common:
-- Liver toxicity
(more common than with EFV)
Mild NVP Rash
Moderate maculopapular rash, typically on face,
trunk, and/or extremities, with or without pruritus.
• Usually appears within the first few weeks to months of
therapy.
• Treat with antihistamines, topical skin creams, do not use
systemic steroids.
• Usually resolves within a few weeks.
• Safe to continue NVP, but if patient is still on OD dose, do not
dose escalate until rash resolves.
• Advise patient to return if rash worsens or mucous membrane
involvement appears.
Severe NVP Rash (1)
Severe Hypersensitivity Reaction
SJS is quite rare, occurs within the first 6-8 weeks
of ARV therapy, and can be fatal.
Treat with steroids and stop ALL ARV drugs
until patient recovers, and do not rechallenge with NVP.
Severe NVP Rash (2)
Any of the following signs/symptoms suggest
impending SJS:
- Fever
- Conjunctivitis
- Extensive, moist, peeling rash
- Mucous membrane involvement (lip
sores/ulcers/swelling, new vaginal
lesions)
- Patient appears unwell
NVP-Related SJS
Stevens-Johnson Syndrome
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Management of NVP-induced Severe
Skin Reaction
• Discontinue ARVs and all other medications
• Treatment:
-- Prednisone (40-60 mgs, taper)
-- Chlorpheniramine
-- Brufen
-- Paracetamol
-- Close observation, realizing that patient may
deteriorate over next 72-96 hours.
• After recovers, new ARV regimen may substitute
EFV or a PI for NVP. Do not re-challenge with NVP.
NNRTI Liver Toxicity
If LFT’s up to 2x upper limit of normal values,
monitor closely.
If LFT’s ≥ 5x upper limit of normal values:
• Stop all medications, including ARVs, and monitor LFTs.
• When LFTs have normalized, restart HAART but without
NVP.
• If previously on NVP, substitute EFV or a PI for NVP.
• If previously on EFV, substitute a PI for EFV (do not use
NVP).
Practical Considerations with NVP
Treatment
• LFTs should be drawn at 2 week follow-up
visit after initiation of NVP.
• NVP: Need to monitor patients closely during
first 6-8 weeks on ART.
• If possible, try to avoid simultaneous initiation of
NVP with other drugs having potential
hepatotoxicity, eg., ATT, IPT, cotrimoxazole.
• However, INH and cotrimoxazole may safely be
used with NVP.
Toxicities of Protease Inhibitors
To be used for first/second treatment failures
(cost, pill burden, interactions with TB
meds, and side effects).
Nelfinavir
Kaletra
Ritonavir
Saquinavir
NFV
LPV/r
RTV
SQV
NFV (Nelfinavir)
• Common side effects:
Diarrhea
- Up to 20%, usually mild
- Treat with loperamide, change dosing
schedule; may need to take with porridge or
calcium carbonate.
• Less common side effects:
Nausea / vomiting / abdominal bloating
LPV/r (Kaletra)
• Common side effects:
Diarrhea, nausea, vomitting, increased lipids
• Less common side effects:
hepatitis, pancreatitis
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Long-Term Metabolic
Complications of PIs
Insulin Resistance /Diabetes Mellitus
(elevated blood glucose)
Lipodystrophy Syndrome
(body habitus changes)
Lipid Abnormalities
(increased cholesterol/triglyceride levels)
Osteoporosis / Avascular Necrosis (rare)
Lipodystrophy: Body Habitus Changes
Fat accumulation:
Fat loss (lipoatrophy*):
(lipodystrophy*)
Facial fat loss
Neck fat pad
Breast enlargement
(gynecomastia in men)
Visceral / central obesity
Lipomas
*EFV and PIs
Subcutaneous fat loss in the
extremities
Fat loss in buttocks
*NRTIs, especially D4T
Lipodystrophy 1
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Lipodystrophy 2
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Lipid Monitoring of Patients
on HAART
• Patients should have baseline and then 6monthly lipid assessments if on PIcontaining or EFV-containing HAART, or if
on d4T.
• Check fasting glucose if diabetes is
suspected.
Food Requirements of ARV Meds
• Most ARV drugs may be taken with or without food.
• However, side effects may be less if taken with
some food (AZT-induced nausea).
• ddI must be taken on empty stomach (otherwise
poorly absorbed), 1 hour before or 2 hours after
meals.
• NFV and SQV (PIs) should be taken with food.
Summary / Conclusions
• Adverse effects of antiretroviral agents are
common and may be a cause of therapy
change, non-adherence, and treatment failure.
• Mild to moderate side effects, and those that
resolved with time, may be managed with
symptomatic therapy.
• Serious or disabling side effects or toxicities may
necessitate discontinuation of the offending
drug.
Summary / Conclusions (2)
• It is important to EDUCATE patients about the
potential adverse effects of these medications.
• It is important to be vigilant to these adverse
effects when initiating therapy and also during
follow-up.
• It is important to perform careful, comprehensive
evaluations at baseline to see what side effects
are pre-existing.