Second Line ART: Doses & Side Effects

1. Second Line ART: Doses & Side Effects HAIVN Harvard Medical School AIDS Initiative in Vietnam

2. Learning Objectives By the end of this session, participants should be able to: • Explain the choice of second line regimens based on first failure regimens • Describe common side effects of second line drugs

3. Overview of Second Line ARVs in Vietnam

4. Switching for Treatment Failure AZT + 3TC or ddI + ABC TDF + 3TC or ddI + ABC + LPV/r EFV/NVP + ddI Vietnam MOH, HIV/AIDS Treatment Guidelines, 2009.

5. Second Line ARVs Available in Vietnam Lamivudine (3TC) Tenofovir (TDF) Zidovudine (AZT) Abacavir (ABC) Didanosine (DDI) Lopinavir/ritonavir (LPV/r) Indinavir*

6. Second-Line ARV: NRTI

7. Tenofovir (TDF)

8. TDF – Dosing

9. 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 • Should monitor creatinine every 6 months • Acute renal failure rare: reduce TDF dose or switch to another NRTI

10. 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

11. Lamivudine (3TC)

12. 3TC – Dosing

13. 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 Mandell et al. Principle and practice of infectious diseases

14. Zidovudine (AZT)

15. AZT - Dosing and Contraindications

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

17. Abacavir (ABC)

18. ABC - Dosing and Contraindications

19. Abacavir Hypersensitivity (1) • ABC hypersensitivity is a multi-organ systemic illness • Occurs in approximately 5 to 8% of HIV-infected patients who start ABC • More than 90% of cases occur within the first 6 weeks • Median time to onset of symptoms is 8 to 11 days • Can cause life-threatening complications if ABC is continued despite worsening symptoms ClinTher. 2001;23:1603-14

20. Abacavir Hypersensitivity (2): Symptoms/Signs • ABC hypersensitivity reaction presents with signs or symptoms from at least 2 of the following groups: • fever • rash • gastrointestinal (nausea, vomiting, diarrhea, abdominal pain) • constitutional (fatigue, myalgias, malaise) • respiratory (dyspnea, cough, pharyngitis) • Abnormal laboratory findings are nonspecific ClinTher. 2001;23:1603-14

21. Abacavir Hypersensitivity (3) • Clinical suspicion should be high if symptoms: • appear within first 6 weeks of abacavir therapy • appear together as both constitutional and organ specific (particularly gastrointestinal symptoms) • worsen with each successive dose

22. AbacavirHypersensitivity (4): Treatment • Stop ABC immediately if hypersensitivity is suspected • Symptoms usually improve within days • Never give ABC again • Note ABC hypersensitivity in patient record • Notify patient of reaction and counsel them not to take ABC again • For severe reactions or hypotension: • Admit to hospital or ICU

23. Didanosine (DDI)

24. DDI – Dosing

25. DDI – Side Effects • Pancreatitis • Peripheral Neuropathy • Lipoatrophy • Lactic acidosis • Noncirrhotic portal hypertension Avoid combination: DDI + D4T due to increased toxicities

26. Second-Line ARVs: PI

27. LPV/r – Dosing

28. Ritonavir (RTV) High-dose: (600mg twice a day) • Treatment dose for HIV • Not used due to high rate of patient intolerance (GI side effects) and liver toxicity Low-dose: (< 400 mg/day) • No anti-HIV activity • Used to “boost” or increase the level of other PI drugs • Nomenclature: /r (LPV/r, SQV/r)

29. Ritonavir Boosting • Most potent CYP 450 3A4 inhibitor available • Used to boost other PI: • “boosted PI” • Increases AUC of the other PI • Can use lower dose of other PI • Increases the Cmin (trough concentration) of other PI, decreasing risk for resistance • Allows once or twice daily dosing of PI

30. Benefits from Using Ritonavir to Boost Other PIs High levels increase risk of side effects Peak levels Drug Levels Ritonavir smoothes out the peak and trough levels of the active PI Trough levels Low levels increase risk of resistance Without ritonavir trough levels are lower and peak levels are often higher Time (Hours)

31. LPV/r – Side Effects (1) Short Term Side Effects • Diarrhea • Occurs in 15-25% of patients • Treat with loperamide 2mg • Nausea and vomiting • Take with food • Ginger tea • If severe, prescribe metoclopramide 10mg

32. LPV/r – Side Effects (2) Long Term Side Effects

33. Fat Accumulation Increase in visceral adipose tissue “Humpback”

34. Lipodystrophy – Treatment • Difficult to treat or reverse • Low-fat diet • Exercise • Switch PI to NNRTI (if not resistant to NNRTI already)

35. Metabolic Effects • Insulin resistance, hyperglycemia • Check fasting glucose every 6-12 months • Treat for diabetes as in non-HIV patient • Elevated Cholesterol • Check lipid panels yearly • Treatment: same as non-HV patient • Exercise, low-fat diet • Stop smoking • Lipid lowering drugs

36. LPV/r – Drug Interactions

37. Case Scenarios

38. Key Points • The preferred MOH second-line ARV regimens are TDF+3TC+LPV/r and AZT+3TC+LPV/r • Patients with ABC hypersensitivity should never take ABC again • Patients on PI should have glucose and lipid tests done at least yearly to screen for metabolic side effects

39. Thank you! Questions?