1. 1 Dermatological Toxicities of ART HAIVN Harvard Medical School AIDS Initiative in Vietnam

2. 2 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

3. 3 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)

4. 4 Grading Rash

5. 5 Four Grades of Rash (1) 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) 5

6. Four Grades of Rash (2) Grade 3: Severe  Vesiculation  Moist desquamation  Ulceration  Systemic symptoms Fever Blistering Muscle and/or joint pain, edema Elevated transaminases

7. Four Grades of Rash (3) Grade 4: Potentially life- threatening  Mucous membrane involvement: Ulceration in mouth, eyes, genitals  Suspected Stevens-Johnson syndrome  Erythema multiforme  Exfoliative dermatitis

8. 8 Evaluating the Possible Causes of Rash

9. 9 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

10. 10 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?

11. 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

12. 12 Medications Likely to Cause Rash Drug Incidence 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

13. 13 NNRTI Rash

14. 14 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

15. 15 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

16. 16 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

17. 17 Management of NNRTI Rash: Stage 3 (2) 17 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:

18. 18 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

19. 19 Management of NNRTI Rash: Vietnam MOH Guidelines (1) RegimenSide Effect Medication 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

20. 20 Management of NNRTI Rash: Vietnam MOH Guidelines (2) RegimenSide Effect Medication 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

21. 21 Cotrimoxazole Rash

22. 22 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 stopped Lancet. 2004 Oct 16-22;364(9443):1428-34.

23. 23 Management of CTX Rash 23 GradeManagement 1 – 2 Continue CTX Give antihistamines Follow closely 3 Stop CTX Consider desensitization or switch to alternate prophylaxis 4 Stop and do not use CTX again Use alternate prophylaxis regimen with dapsone Vietnam MOH guidelines on treatment of HIV/AIDS, 2009

24. 24 Cotrimoxazole Desensitization (1) 24 WHO August 2006: Guidelines on co-trimoxazole prophylaxis StageDosePediatric syrup (240mg/5ml ) Tablets Day 196mg2ml~1/8 SS Day 2192mg4ml~1/4 SS Day 3288mg6ml~1/2 SS Day 4384mg8ml~3/4 SS Day 5480mg-1 SS Day 6 onwards 960mg-1 DS or 2 SS

25. 25 Cotrimoxazole Desensitization (2) Offer antihistamines Review daily or give specific instructions on how to respond to any reaction: 25 Type of reactionAction 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

26. 26 Abacavir Hypersensitivity Rash

27. 27 Abacavir Hypersensitivity (1) Incidence: 3 - 6% Time of presentation: Median = 11th day 93% of cases occur in the first 6 weeks

28. 28 Abacavir Hypersensitivity (2) Clinical symptoms: Most common: fever, maculopapular rash, fatigue GI Symptoms: nausea, vomiting, diarrhea, abdominal pain Respiratory symptoms: cough, shortness of breath

29. Abacavir Hypersensitivity (3)

30. 30 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

31. 31 Stevens Johnson Syndrome (SJS)

32. 32 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%

33. 33 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

34. 34 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

35. Fein, J. D. et al. N Engl J Med 2005;352:1696 Stevens Johnson Syndrome

37. 37 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

38. 38 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

39. 39 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

40. 40 Thank you! Questions?