1 Dermatological Toxicities of ART HAIVN Harvard Medical School AIDS Initiative in Vietnam
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Dermatological Toxicities of ART
HAIVNHarvard Medical School AIDS
Initiative in Vietnam
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Learning Objectives
By the end of this session, participants should be able to:
Explain how to grade dermatological toxicity Describe the clinical manifestation of rash
and explain how to manage rash caused by:• NNRTI• Cotrimoxazole• Abacavir
Explain the management of a patient with Stevens-Johnson Syndrome
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Differential Diagnosis of Rash in PLHIV
Drug toxicity or allergy
• ARVs• Cotrimoxazole• Other drugs
Allergic reactions to:
• Foods• Contact dermatitis
Systemic infection
• Penicilliosis• Syphilis • Viral infection (i.e. Dengue)• Scabies
Other dermatological diseases
• Eczema• Eosinophilic folliculitis• Papulo-Pruritic Eruption (PPE)
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Grading Rash
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Four Grades of Rash (1)Grade 1: Mild •Erythema, with or without pruritisGrade 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)
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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 multiforme Exfoliative dermatitis
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Evaluating the Possible Causes of Rash
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Evaluating the Rash (1) –How to Find the Etiology?
Take a thorough history of the rash and concomitant symptoms:• ask about other possible allergens• find out where and when exactly the
rash started on the body Get a good medication history Do a thorough medical and
laboratory evaluation to exclude other etiologies
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Evaluating the Rash (2) – Is Rash Caused by ARV?
Did the patient recently start an ARV likely to cause rash?
Does the patient has a known history of allergies to other medications that he/she is taking?
Is the treatment of other causes of rash not helpful?
Are evaluations of other causes of rash negative?
Which Medications are Likely to Cause Rash?
Least likely
• Fluconazole• 3TC • D4T• TDF• LPV/r• Pyrazinamide• Ethambutol
Somewhat likely
• ABC• Rifampicin • Isoniazid
Most likely
•CTX •NVP•EFV
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Medications Likely to Cause Rash
DrugIncidence of Rash
Mild to severe*
Severe Rash-
Stop Drug**
CTX
NVP
EFV
19%
17%
15-27%
< 3%
6%
< 1%
t 2007; **AIDS 2007, 21:2293–2301, Lancet 2004; 363: 1253–63
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NNRTI Rash
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NNRTI Rash
Rash is common with both NVP (37%) and EFV (26%)
Most rashes are mild, requiring treatment with antihistamines without stopping the NNRTI
NVP is more likely to cause severe (grade 3-4) rash
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Management of NNRTI Rash: Stage 1- 2
Continue ARV; Give antihistamines Delay escalating dose of NVP Closely monitor for development of
systemic symptoms, worsening rash, LFT elevations:• Stop CTX if this was started around same
time as ARV and allergy can’t be ruled out• Stop or change ARV if rash progresses to
stage 3 or 4
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Management of NNRTI Rash: Stage 3 (1)
If NNRTI (e.g. NVP) is the most likely cause, stop it and continue the 2 NRTI drugs for up to 7 days
Stop CTX if this was started around the same time as ARV, and allergy to it is also possible
Give antihistamines
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Management of NNRTI Rash: Stage 3 (2)
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If much improved (rash almost gone)
• substitute EFV for NVP and continue treatment
If improved but still with generalized rash after 7 days
• stop the NRTIs• restart with EFV when rash
and other signs and symptoms resolved
If not improving
• stop all ARV & continue to monitor
• restart ARV when patient improving and clinically stable
Follow-up in 3-7 days:
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Management of NNRTI Rash: Stage 4
Stop all medications Close monitoring and care Restart ARV and CTX when rash,
fever and other symptoms have resolved:• NNRTI should be changed to another
NNRTI or PI or TDF• Start CTX 2 weeks after starting ARV
and patient stable
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Management of NNRTI Rash:Vietnam MOH Guidelines (1)
Regimen Side EffectMedication
Change
AZT/D4T+ 3TC + NVP
Moderate (grade 3) rash due to NVP Change NVP to
EFV
Severe, life threatening rash due to NVP (e.g. Stevens Johnson Syndrome)
Change NVP to EFV, PI, or TDF
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Management of NNRTI Rash:Vietnam MOH Guidelines (2)
Regimen Side EffectMedication
Change
AZT/D4T+ 3TC + EFV
Moderate (grade 3) rash due to EFV
Severe, life threatening rash due to EFV (e.g. Stevens Johnson Syndrome)
Change to PI or TDF
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Cotrimoxazole Rash
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Cotrimoxazole Allergy
Clinically:• Maculopapular rash • Can have fever• Usually within first few weeks of
treatment Epidemiology
• No studies in Asia• In Africa, about 2% had allergy to CTX*
Resolves when drug is stoppedLancet. 2004 Oct 16-22;364(9443):1428-34.
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Management of CTX Rash
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Grade Management
1 – 2• Continue CTX• Give antihistamines• Follow closely
3• Stop CTX• Consider desensitization or switch to
alternate prophylaxis
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• Stop and do not use CTX again• Use alternate prophylaxis regimen
with dapsone
Vietnam MOH guidelines on treatment of HIV/AIDS, 2009
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Cotrimoxazole Desensitization (1)
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WHO August 2006: Guidelines on co-trimoxazole prophylaxis
Stage Dose Pediatric syrup
(240mg/5ml )
Tablets
Day 1 96mg 2ml ~1/8 SS
Day 2 192mg 4ml ~1/4 SS
Day 3 288mg 6ml ~1/2 SS
Day 4 384mg 8ml ~3/4 SS
Day 5 480mg - 1 SS
Day 6 onwards
960mg - 1 DS or 2 SS
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Cotrimoxazole Desensitization (2)
Offer antihistamines Review daily or give specific
instructions on how to respond to any reaction:
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Type of reaction Action
No reaction • Progress to the next stage
Minor reaction • Continue same dose for 1 extra day or until the reaction subsides• Once reaction subsides: progress
to the next stage
Severe, worsening or persistent reaction
• Stop CTX
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Abacavir Hypersensitivity Rash
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Abacavir Hypersensitivity (1)
Incidence: 3 - 6% Time of presentation:
• Median = 11th day• 93% of cases occur in the first 6 weeks
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Abacavir Hypersensitivity (2)
Clinical symptoms: • Most common: fever, maculopapular
rash, fatigue• GI Symptoms: nausea, vomiting,
diarrhea, abdominal pain • Respiratory symptoms: cough, shortness
of breath
Abacavir Hypersensitivity (3)
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Abacavir Hypersensitivity (4): Treatment
Stop ABC immediately if hypersensitivity is suspected:• Symptoms will usually improve within a few
days• Note ABC hypersensitivity in the patient
record• Never give ABC again• Notify the patient of the reaction and
counsel them not to take ABC again For severe reactions or hypotension:
• Admit to hospital or ICU
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Stevens Johnson Syndrome (SJS)
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What is Stevens Johnson Syndrome?
Severe reaction, most commonly triggered by medications
Characterized by:• fever and mucocutaneous lesions • necrosis and sloughing of the epidermis
HIV positive patients are at higher risk for SJS than HIV negative
Mortality rate usually less than 5%
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SJS: Skin Lesions (1)
Begins 1-3 weeks after drug initiation Typically fever and flu-like symptoms
occur 1-3 days before rash onset Initial skin lesions:
• Poorly defined macules with purpuric centers that coalesce to form blisters
• Symmetrically distributed• Located on face and upper trunk• Lesions may burn or be painful
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SJS: Skin Lesions (2)
Lesions then progress to epidermal detachment• Rash is most severe on 4th day
Nikolsky's sign shows extensive epidermal detachment:• separation of the outer layer of the
epidermis from the basal layer when lateral pressure is applied to the skin
Fein, J. D. et al. N Engl J Med 2005;352:1696
Stevens Johnson Syndrome
Stevens Johnson Syndrome
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Stevens Johnson Syndrome: Other Findings
Mucosal involvement • conjunctiva, oral cavity, genital mucosa• esophagus occasionally involved
Ophthalmologic involvement: • conjunctival lesions
Pulmonary involvement:• dyspnea, cough with sputum, hypoxemia • interstitial infiltrates, pulmonary edema,
bronchiolitis obliterans
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Stevens Johnson Syndrome: Management
Early recognition and immediate withdraw of any potential causative agent
ICU transfer (burn unit) Topical antibacterial ointments or silver
sulfadiazine Surgical debridement to remove
necrotic epidermis Ophthalmologic care
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Key Points
Common drugs that cause rash in PLHIV include NNRTIs, CTX, and Abacavir
Skin rashes are graded by severity using grades 1 - 4• Grade 1-2 may resolve with antihistamines and
continuation of the drug• Grades 3 and 4 usually necessitate medication
withdrawal or change SJS is best managed by early recognition
and withdrawal of causative drug
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Thank you!
Questions?