1. 1 Antiretroviral Drugs: Dosages and Side Effects of first-line ARV HAIVN Harvard Medical School AIDS Initiative in Vietnam

2. 2 Learning Objectives At the end of this lecture, each trainee should: Know the names and dosages of the first-line ARVs in Vietnam. Be able to recognize, diagnose and manage rash due to nevirapine. Be able to recognize, diagnose and manage ARV related hepatotoxicity. Know the common short-term and long-term toxicities of NRTI

3. 3 Content First-line antiretrovirals recommended in Vietnam First-line ARV regimens and their side effects –NRTIs and Mitochondrial Toxicity –NNRTIs

4. 4 Side Effects, Adverse reactions and toxicities Adverse reactions: –All effects of drugs other than intended therapeutic effect –Includes side effects and toxicities –Some are predictable (occur in most people to a greater or lesser extent) e.g. nausea –Some are unpredictable (occur only in some people) e.g. hypersensitivity Side effects: –E.g. nausea, anemia, dizziness –Mostly occur early and subside with time –May be managed without switching drug depending on nature and severity –Symptomatic treatment should be offered Toxicities: –Organ or tissue damage or metabolic problems caused medications –May occur more slowly than side effects and progress continuously –Often require switching of the drug

5. 5 Importance of recognizing side effects and toxicities Quality of life: –Cause suffering and ill health –Can be prevented, managed or controlled Adherence: –Side effects and toxicities cause non-adherence and loss to follow up

6. 6 Antiretroviral dosages and side effects for first line ARV regimens in Vietnam

7. 7 First line ARV Regimens in Vietnam + 3TC D4T or AZT NVP or EFV or ABC + Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.

8. 8 First-Line ARV regimens: AZT/3TC/NVP AZT/3TC/EFV D4T/3TC/NVP D4T/3TC/EFV AZT/3TC/ABC D4T/3TC/ABC First line ARV Regimens in Vietnam Preferred regimen: AZT/3TC/NVP Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.

9. 9 Drugs are given on the basis of weight and need to be adjusted as the child grows

10. 10 AZT Dosing Individual –Syrup: 10 mg/ml –Capsules: 100 mg 250 mg –capsule: 300 mg Fixed Dose Combination –AZT/3TC –AZT/3TC/NVP Baby 60/30/50 Adult 300/150/200 Food restrictions: none (food may improve tolerability) Contraindications: –Hb ≤ 8.0 mg/dL –AZT should not be given with d4T (antagonistic)

11. 11 AZT Side Effects and Toxicities Common Anemia Neutropenia Headache Nausea and Vomiting Altered taste Fatigue Anorexia Insomnia Myalgia Long-Term Use Myopathy Nail pigmentation Lipoatrophy Rare Fever Rash Hepatitis Steatosis/lactic acidosis

12. 12 AZT: Anemia Very common side effect of AZT therapy. –1%-18% of patients experienced anemia grade 1 or 2 –0-3% of patients develop moderate/severe anemia (grade 3 or 4) Do not use AZT if baseline Hb < 80g/L Requires monitoring: –Symptoms and signs of anemia –Checking Hb levels (month 1, 3, 6 after starting AZT, and every 6 months thereafter) If severe anemia develops (Hg < 70 g/L), change to d4T

13. 13 AZT: Neutropenia Less common than anemia but can occur in children If mild-moderate (ANC 500 – 1000/mm 3 ) and no concerning signs and symptoms (i.e., no fever or infection), then can continue AZT with repeat CBC after 1 month. If severe (ANC < 500), then exclude other causes of neutropenia or bone marrow suppression and, if no other treatable cause is identified, change AZT to d4T or ABC

14. 14 Nausea and Vomiting Very common at start of therapy Improves with time and often resolves within 2-4 weeks Management: –Reassure patient/caregiver –Recommend taking ARVs with food and small meals frequently between doses. –Anti-nausea medication as needed or 30 min prior to ART Metoclopramide: < 6 years old: 0.1 mg/kg three times a day if required Metoclopramide: 6-14 years old: 2.5-5 mg taken 30min before ARV dose if the patient experiences vomiting with ARV –Rehydration therapy if persistent vomiting

15. 15 Fatigue, Headache, Myalgias Common at start of therapy Improves with time Paracetamol for headache and myalgias.

16. 16 Myopathy Most commonly presents within 6-12 months of initiating AZT Can have an insidious onset Typically involves proximal muscle weakness and exercise-induced myalgias Serum creatine kinase (CK) levels are often elevated Stopping AZT generally results in a gradual resolution of symptoms over 6 to 8 weeks

17. 17 Nail pigmentation Rahav et al. (1992) Scandinavian Journal of Infectious Diseases,24:5,557

18. 18 AZT Adverse Effects: Other Lactic acidosis, Lipoatrophy, Hepatotoxicity –All can occur with AZT therapy –Less frequent than with d4T –If present, stop AZT and change to ABC

19. 19 D4T/Stavudine Individual –Syrup: 1 mg/ml –Capsules: 15, 20, 30 mg Fixed Dose Combination –D4T/3TC/NVP Baby 6/30/50 Junior 12/60/100 Adult 30/150/200 Food restrictions: none Contraindications: –Peripheral neuropathy –D4T should not be given with AZT (antagonistic) or ddI (increased toxicity) –Pregnancy: AZT is preferred

20. 20 d4T – Adverse reactions Short term side effects: –Few or no short term side effects –Very well tolerated in the short term Long term toxicities: –Common and severe Peripheral neuropathy Lipodystrophy Lactic acidosis To avoid d4T long term toxicities: –AZT preferred –Substitute AZT after one year of D4T use or change earlier if signs of toxicity appear.

21. 21 Peripheral Neuropathy Appears to occur less frequently in children compared to adults. Onset typically occurs after many months of d4T use Symptoms include numbness, tingling, and/or burning Symptoms begin distally (toes and/or fingers) and move proximally over time D4T-related peripheral neuropathy may resolve if therapy is withdrawn promptly. However, severe and permanent disability can occur.

22. 22 Lipoatrophy Lipoatrophy is the loss of subcutaneous body fat; most commonly in the extremities, face, and buttocks It is closely associated with d4T use in both adults and children. Studies of children on d4T-based ART estimate the prevalence of body fat changes from 18 to 33%. The presence of lipoatrophy can be stigmatizing, can reduce quality of life, and can adversely affect adherence to ART.

23. 23 Lipoatrophy (Peripheral Fat Wasting) Prominence of blood vessels Sunken Cheeks

24. 24 Lactic Acidosis Lactic acidosis is caused by NRTI-induced mitochondrial dysfunction in tissues Mild asymptomatic hyperlactatemia is common in children (17-32%), but symptomatic severe hyperlactatemia (> 5.0 mmol/L) is less common than in adults. Symptoms include fatigue, weight loss, nausea, vomiting, abdominal pain, shortness of breath Can lead to multi-organ failure, coma, and death

25. 25 NRTIs and Mitochondrial Toxicity NRTI’s are nucleoside analogues: –inhibit of HIV reverse transcriptase enzyme –Inhibit of 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 and cell dysfunction Different NRTIs effect different cells, tissues and organs Symptoms of mitochondrial toxicity vary according to the tissues affected

26. 26 mtDNA Polymerase γ function mitochondrion mtDNA NRTIs mtDNA encoded protein dysfunction nDNA encoded proteins mtDNA encoded proteins The NRTI and Mitochondrial Toxicity Hypothesis Adapted slide from Dr. Cecilia Shikuma

27. 27 NRTIs and Mitochondrial Toxicity: Spectrum of Disease Nerve tissue: d4T, ddI –Peripheral Neuropathy Bone Marrow: AZT –Anemia –Neutropenia Body fat: d4T –Lipoatrophy Pancreas: ddI –pancreatitis Liver: d4T, ddI –Hyperlactatemia –Lactic acidosis –Hepatic Steatosis Muscle: AZT –Myopathy

28. 28 Hyperlactatemia and Lactic Acidosis Aerobic metabolism (mitochondria dependent) –uses oxygen and glucose and releases carbon dioxide Anaerobic metabolism –Releases lactic acid or lactate into the blood stream –Lactic acid is processed by the liver. Hyperlactatemia: –High blood levels of lactate –Caused by mitochondrial dysfunction in tissues –Causes symptoms of shortness of breath, nausea, malaise, fatigue, abdominal pain. (8-21% of NRTI treated patients) Lactic acidosis –With hepatic steatosis –Multiorgan failure, coma, and death (1-2 % in prospective analyses)

29. 29 Lamivudine (3TC) Individual –Syrup: 10 mg/ml –Tablet: 150 mg Fixed Dose Combination –AZT/3TC, d4T/3TC –AZT/3TC/NVP Baby 60/30/50 Adult 300/150/200 –D4T/3TC/NVP Baby 6/30/50 Junior 12/60/100 Adult 30/150/200 Food restrictions: none

30. 30 3TC/lamivudine Side effects and toxicites Few/rare Other effects: Active against Hep B Cessation may cause Hep B flares Patients with chronic HBV taking 3TC may have false-negative HBsAg test results

31. 31 Nevirapine (NVP) Individual –Syrup: 10 mg/ml –Tablet: 200 mg Fixed Dose Combination –AZT/3TC/NVP –D4T/3TC/NVP Dose escalation instructions: Dose by weight once per day for the first 2 weeks Then, Increase to twice per day or change to FDC (twice daily) If rash occurs at lower dose, delay dose escalation for up to one week Food restrictions: none

32. 32 Example of NVP Dosing

33. 33 Nevirapine – Side Effects Rash –Incidence: 20-25% 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 High CD4 count (> 250 for females or > 400 for males) –Clinical presentation: Gradual onset Begins on trunk later extending to whole body (if severe) Commence around 10 days commonest but any time in first 1-6 weeks May worsen after dose escalation

34. 34 Grading the rash 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)

35. 35 Grade 1-2 NVP Rash

36. 36 Grading the Rash Grade 3: Severe –Vesiculation –Moist desquamation –Ulceration –Systemic symptoms Fever Blistering Muscle and/or joint pain, edema Elevated transaminases

37. 37 Grading the Rash Grade 4: Potentially life-threatening –Mucous membrane involvement Ulceration in the mouth, eyes, genitals –Suspected Stevens-Johnson syndrome –Erythema multiform –Exfoliative dermatitis

38. 38 Stage IV NVP Rash

39. 39 Stage IV NVP Rash

40. 40 Nevirapine – Rash Practice points: –Warn patient to return immediately if rash develops and then review frequently –If mild or moderate (Grade 1 – 2) Continue nevirapine Delay dose escalation up to 1 week Antihistamines Steroids not proven to be helpful –If Grade III or persistent grade I-II: Replace NVP with EFV (if age > 3 and weight > 10 kg): 90% will tolerate EFV without allergy –If grade IV Admit to hospital, cease all drugs

41. 41 Grade 1-2 Assess rash Check for systemic symptoms and signs and systemic Check LFTs Grade 3 Reassess Frequently Delay dose escalation for up to one week Grade 4 Stop NVP Continue NRTIs Start EFV* after 3-7 days Admit to hospital Stop all drugs Start different combination later Dose escalate and continue regimen Resolves Continues Nevirapine Rash: Treatment Protocol * If age > 3 and weight > 10 kg

42. 42 Nevirapine – Hepatotoxicity Hepatotoxicity –Risk factors: LFTs > 2.5x ULN before treatment Higher CD4 counts HBV and/or HCV co-infection –Clinical presentation Fever, malaise With or without rash High LFTs

43. 43 Grading Hepatotoxicity GRADE  LFT > normal mild 11.25 – 2.50 22.60 - 5 severe 35 - 10 4> 10

44. 44 Nevirapine – Hepatotoxicity Check LFTs: –After one month in all patients –In all patients with rash –In all patients with fever or illness Management: –LFTs < 5x ULN (Grade 1-2) Continue nevirapine Monitor LFTs and clinical symptoms frequently –LFTs > 5x ULN (Grade 3-4) Switch to EFV if appropriate Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.

45. 45 Grade 1-2 and No systemic symptoms and No rash Assess rash Check for systemic symptoms and signs and systemic Check LFTs Grade 3 or with fever/rash Grade 4 or with fever, rash Stop NVP Continue NRTIs Start EFV* after 3-7 days Admit to hospital Stop all drugs Start different combination later Dose escalate and continue regimen Continue NVP Check LFTs every 1-2 weeks Nevirapine Hepatotoxicity: Treatment Protocol * If age > 3 and weight > 10 kg

46. 46 Stopping drugs with different half lives 0 244836 12 Time (hours) Drug concentration IC 90 IC 50 Last DoseDay 1Day 2 Zone of potential replication Taylor S, et al. 11th CROI, San Francisco, 2004, #131 MONOTHERAPY NNRTI

47. 47 Efavirenz (EFV) Individual –Capsule: 50, 200, 600 mg Food restriction: Take on empty stomach or with light snack. High-fat meal will quicken drug absorption and increase side effects. Contraindications: Children < 3 years old or weight < 10 kg Pregnant adolescent in 1 st trimester

48. 48 Efavirenz – Side Effects Central Nervous System: –Sleep disturbance, vivid dreams, dizziness, drowsiness. –Unsteady walking: particularly at night –Timing Onset 1 - 2 days Peak 4 - 7 days Resolution over 2 - 4 weeks

49. 49 Efavirenz – Side Effects Rash: –Commonly reported in children (30–40%) –Most often a maculopapular eruption –Typically mild; the rash usually resolves with continued treatment. –Antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of the rash.

50. 50 Efavirenz – Side Effects Hepatotoxicity: –Much less than NVP –Safe in patients with raised LFTs, HBV and/or HCV. Teratogenic in first trimester –Avoid in women of childbearing age if other options available. –Consider pregnancy test before starting. –Contraception mandatory for women of child bearing age –Never give to pregnant women in 1st 12 weeks of pregnancy

51. 51 Hepatotoxicity: Differential Diagnosis ARV toxicity Hepatotoxicity, hypersensitivity: –NNRTI (NVP, EFV) –Abacavir (hypersensitivity) –Indinavir (rare) Lactic acidosis with hepatic steatosis –nRTIs (d4T, ddI, AZT, ABC) Non-ARV drugs TB drugs – PZA, RIF, INH Antifungal drugs –Ketoconazole, fluconazole, itraconazole Others- –Paracetamol Alcohol Infectious diseases Viral: CMV, HAV, HBV, HCV, HDV, HEV, dengue Bacterial: TB, MAC, sepsis Fungal: Penicillium, candida Parasitic: Amoebiasis Other causes IRS (HBV) Steatosis (fatty liver) Tumor: lymphoma Autoimmune hepatitis

52. 52 Additive Side Effects – Not Just ARVs Rash: Cotrimoxazole, TB drugs and NVP Liver toxicity: INH, RIF, PZA and NNRTI’s or PI’s Bone marrow suppression: AZT and Cotrimoxazole Peripheral Neuropathy: Isoniazid and D4T

53. 53 Key Points Counseling patient/caregiver on early side effects is critical for good adherence. –What side effects to expect –How to contact ARV clinic if side effects occur. –When to return to clinic or to hospital –Most side effects are mild and will resolve with continued use of the medications The most common side effects in first line treatment are rash and hepatotoxicity from NNRTI –Side effects more common with NVP than EFV –Delay dose escalation of NVP if rash occurs. –Severe hepatotoxicity occurs in 2-4% of patients on NVP. –The risk higher in Hepatitis B and/or Hepatitis C. –EFV preferred when LFTs > 2.5 x ULN (AST,ALT > 100)

54. 54 Key Points Side effects of NRTI: –Short term toxicities: AZT: nausea, vomiting, anemia d4T: usually well tolerated in the short term –Long term toxicities More common with d4T Related to inhibition of mitochondrial polymerase gamma –Lactic acidosis –Lipodystrophy –Peripheral neuropathy

55. 55 Thank you Questions?