Dosages and Side Effects of First-line ART

1. Dosages and Side Effects of First-line ART HAIVN Harvard Medical School AIDS Initiative in Vietnam

2. Learning Objectives By the end of this session, participants should be able to: • Describe the importance of recognizing side effects and toxicities • Describe the side effects caused by NRTIs and NNRTIs • Explain dosing for NRTIs and NNRTIs • Explain how to change or stop NNRTIs

3. Why is it Important to Recognize Side Effects and Toxicities? Quality of life: • Cause suffering and ill health • Can be prevented, managed, and controlled Adherence: • Side effects and toxicities cause non-adherence and loss to follow up

4. Help Patients Manage Side Effects: Warn Them in Advance • To help patients deal with side effects, counsel them about: • Which side effects to expect • How to contact ARV clinic if side effects occur • When to return to clinic or to hospital • The fact that most side effects are mild and will resolve with continued use of the medications

5. Overview of First-line ARVs in Vietnam

6. NRTIs

7. Overview of NRTI Toxicity • All NRTIs cause some amount of side effect or toxicity • Majority of NRTI toxicities are related to drug’s effect on mitochondrial cells • These toxicities include: • Peripheral neuropathy • Pancreatitis • Lipoatrophy/dystrophy • Lactic acidosis • Hepatic steatosis

8. NRTIs and Mitochondrial Toxicity (1) • NRTIs are nucleoside analogues and inhibit: • HIV reverse transcriptase enzyme • 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 • cell dysfunction

9. NRTIs and Mitochondrial Toxicity (2) • Different NRTIs affect different cells, tissues and organs • Symptoms of mitochondrial toxicity vary according to tissues affected

10. NRTIs and Mitochondrial Toxicity (3) - Spectrum of Disease d4T, ddI AZT d4T • ddI d4T, ddI AZT

11. Dosing and Side Effects of Specific NRTIs

12. d4T – Dosing

13. d4T – Contraindications • AZT + d4T are antagonistic: • Do not use together • D4T + ddI = increased toxicity: • Avoid combination • Pregnancy: • AZT preferred over d4T • Increased toxicity of d4T in pregnancy, but can use if necessary • Peripheral neuropathy

14. d4T – Adverse Reactions Switch to AZT or TDF after 1 year treatment or earlier if symptoms or side effects appear

15. d4T – Side Effects: Peripheral Neuropathy • Clinical presentations: • Onset after many weeks or months • “Stocking and glove” distribution: starts at fingertips/toes and spreads inward • Symptoms: numbness, tingling, pain • Progressive and irreversible if left untreated • Management: switch to AZT or TDF

16. d4T – Side Effects:Lipoatrophy (1) • Lipoatrophy, or fat atrophy, involves the loss of subcutaneous fat in the face, arms, legs, and buttocks • Related to NRTI-induced mitochondrial toxicity • d4T is the NRTI most closely associated with lipoatrophy

17. d4T – Side Effects:Lipoatrophy(2) Management: switch to AZT or TDF

18. d4T – Side Effects:Lactic Acidosis (1) Hyperlactatemia and lactic acidosis are caused by mitochondrial dysfunction in tissues • Hyperlactatemia refers to elevated blood levels of lactate • Lactic acidosis, the severe form, occurs in the setting of liver dysfunction, typically hepatic steatosis

19. d4T – Side Effects:Lactic Acidosis (2) • Risk factors: • NRTIs, particularly ddI combined with d4T • Female, pregnancy, obesity • Symptoms include: • Abdominal discomfort, loss of appetite, nausea, vomiting, diarrhea, fatigue, weight loss, dyspnea • Can progress to multi-organ failure, coma, death • Labs: • Increased lactate level • Other labs: CPK, LDH, AST/ALT, low albumin, low pH or bicarbonate

20. Lactic Acidosis: Treatment

21. d4T – Side Effect Management

22. AZT - Dosing and Contraindications

23. AZT – Side Effects • Headache, nausea, bloating, dyspepsia • Anemia • Lipoatrophy • Proximal myopathy • Skin hyperpigmentation (face) • Nail discoloration • Lactic acidosis (rare)

24. AZT – Side Effects Nausea and vomiting: • Common at start of therapy • Improve with time • Management: • Take with food • Anti-nausea medication • Ginger tea Fatigue, headache, tiredness • Common at start of therapy • Improves with time • Management: • Paracetamol for headache

25. AZT – Side Effects (1)Anemia • Anemia is the most common side effect of AZT (due to bone marrow suppression) • Two patterns: • Acute drop of Hgb after a few months of therapy, sometimes necessitating transfusion • Slowly declining of Hgb, 0.5-1.0 gm, over several months • Management: • CBC monitoring required • Change AZT to d4T/TDF if severe • Avoid AZT if Hb < 80g/L

26. AZT – Side Effects (2)Finger Nail Discoloration

27. AZT – Side Effects (3) Myopathy • Progressive proximal muscle weakness • Proximal muscle weakness and atrophy (legs > arms) • Muscle tenderness and myalgias • No sensory findings, reflexes intact • ↑ creatininekinase levels • Management: • Stop AZT • Responds to prednisone

28. AZT - Side Effect Management

29. 3TC – Dosing

30. 3TC – Side Effects • Side effects and toxicities: • Well tolerated • Headache, dizziness, malaise, fatigue • Rash/allergy (rare) • Other effects: • Active against Hepatitis B • Cessation may cause Hepatitis B flares • Patients with chronic HBV taking 3TC may have false-negative HBsAg test results Mandell et al. Principle and practice of infectious diseases

31. TDF – Dosing

32. TDF – Side Effects • Usually very well tolerated • Most common side effects are minor: nausea, vomiting, flatulence • Most concerning is renal dysfunction • Usually mild, asymptomatic • Reverses when TDF stopped • Creatinine should be monitored every 6 months • Acute renal failure is rare: reduce TDF dose when renal failure or switch to another NRTI

33. TDF Dosing in Renal Failure • TDF should be dosed by Creatinine Clearance (CrCl) • CrCl is measured in milliliters/min (ml/min) • Normal values are: • Male: 97 to 137 ml/min • Female: 88 to 128 ml/min

34. NRTI Case Studies

35. NNRTIs

36. NVP – Dosing

37. NVP – Side Effects • Rash • Hepatotoxicity

38. NVP – Rash (1) Incidence: • 25-37% 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 • CD4 counts > 250 for females, > 400 for males

39. NVP – Rash (2) • Clinical presentation: • Gradual onset • Begins on trunk; extends to whole body (if severe) • Most commonly starts after 10 days but commonly occurs any time in first 4-6 weeks • May worsen after dose escalation

40. Grading Rash

41. Four Grades of Rash (1)

42. Four Grades of Rash (2)

43. Four Grades of Rash (3)

44. NVP Rash - Management Practice points: Warn patient to return immediately if rash develops and then review frequently

45. NVP – Hepatotoxicity (1) • Risk factors: • LFTs > 2.5x ULN before treatment • Women with CD4 > 250 • Man with CD4 > 400 • HBV and/or HCV co-infection • Clinical presentation: • Fever, malaise • With or without rash • High LFTs • Severe hepatotoxicity occurs in 2-4% of patients on NVP

46. NVP – Hepatotoxicity (2) • Need to check LFTs: • After one month in all patients • In all patients with rash • In all patients with fever or illness • Management: Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.

47. EFV – Dosing

48. EFV - Side Effects (1) • Psychologic disturbances: depression, psychosis, mania • Sleep disturbances • Headache, lightheadedness, dizziness • Rash, usually mild, self-limited • Increase in lipids • Teratogenic in first trimester

49. Efavirenz – Side Effects (2) • Central Nervous System: • Sleep disturbance, vivid dreams, insomnia, dizziness, drowsiness (> 50% of pts) • Unsteady walking: Particularly at night • Progression: • Onset 1 - 2 days • Peak 4 - 7 days • Resolution over 2 - 4 weeks

50. Efavirenz – Side Effects (3) • Rash: • Usually mild • SJS << 1% • Hepatotoxicity: • Much less than NVP • Safe in patients with raised LFTs, HBV and/or HCV