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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?