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

Switching for Treatment Failure 1 st Line ARV2 nd Line ARV TDF + 3TC + NVP/EFV AZT/d4T + 3TC + NVP/EFV AZT/d4T + 3TC +TDF/ABC Vietnam MOH, HIV/AIDS Treatment Guidelines, AZT + 3TC or ddI + ABC + LPV/r TDF + 3TC or ddI + ABC EFV/NVP + ddI

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

6 Second-Line ARV: NRTI

7 Tenofovir (TDF)

TDF – Dosing Adult Dosing  300mg tab, once daily  Dose reduction recommended for Cl cr < 50 mL/minute PreparationsIndividual drug Indications First-line ARV Second-line ARV when AZT used in first line Food restrictions None

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 Creatinine Clearance (ml/min) and TDF dose ( TDF 300 mg) > 50ml/min30 – 49 ml/min10 – 29 ml/min< 10 ml/min Once dailyEvery other day Every 3- 4 days or twice a week Contra-indicated

11 Lamivudine (3TC)

12 3TC – Dosing Adult Dosing  150 mg twice daily or 300 mg once daily  Dose reduction recommended for Cl cr < 50 mL/minute Preparations  Individual component 150mg tablets  Part of FDC: AZT + 3TC, AZT+3TC+NVP d4T + 3TC, d4T+3TC+NVP Indications First-line ARV Second-line ARV Food restrictions None

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 Adult Dosing 300 mg tab twice daily Preparations Individual drug Fixed dose combination: AZT+3TC AZT+3TC+NVP Food restrictions None (food may improve tolerability) Contra- indications Hb < 80g/L Should not be given with D4T (antagonistic)

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 Adult Dosing 300 mg twice daily Formulations 300 mg tablet Food restrictions None Indications Second line therapy Can be used in 1 st line if other NRTIs are not tolerated Contraindications Previous ABC hypersensitivity

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 Clin Ther. 2001;23:

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 Clin Ther. 2001;23:

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 Abacavir Hypersensitivity (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 Adult Dosing <60 kg: 250 mg once daily >60 kg: 200 mg twice daily Dose reduction recommended for Clcr <60 mL/minute Formulations DDI: 25mg, 50mg DDI EC: 125, 200 and 250mg Food restrictions Take 30 min before or 2h after a meal for 25mg tablets (levels decrease if taken with food)

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 Adult Dosing 400/100 mg twice a day (2 tablets ALUVIA twice per day) Formulations Aluvia: 200/50 mg Kaletra: 133/33 mg Oral solution Food restrictions Increased absorption if taken with food

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 Time (Hours) Low levels increase risk of resistance Drug Levels High levels increase risk of side effects Peak levels Trough levels Without ritonavir trough levels are lower and peak levels are often higher Ritonavir smoothes out the peak and trough levels of the active PI

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 Lypodystrophy fat redistribution Hyperlipidemia increased cholesterol, triglycerides Dysglycemia insulin resistance hyperglycemia diabetes

33 Fat Accumulation “Humpback” Increase in visceral adipose tissue

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

LPV/r – Drug Interactions Interaction of LPV/r with: ResultsManagement Rifampicin  level of LPV by 75% Avoid combination Methadone  level of methadone Monitor closely for signs of withdrawal Lovastatin Simvastatin  levels of these drugs Contra-indicated. Use other lipid lowering agents

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?