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

2. 2 Learning Objectives At the end of this lecture, each trainee should know: The second-line ARV regimen recommended by the Vietnam MOH The common side effects of second line drugs How to manage side effects

3. 3 Content Second-line ARV regimen Second-line ARV drugs  Formulations  Dosing  Common Side effects

4. Switching from 1st line to 2nd line regimens Failure on 1 st regimensChange to 2 nd regimens AZT or d4T + 3TC + NVP AZT or d4T + 3TC + EFV ABC +3TC/ddI + LPV/r AZT or d4T + 3TC + ABCddI + EFV + LPV/r ddI + NVP + LPV/r ABC + 3TC + NVP or EFVAZT + 3TC/ddI + LPV/r

5. Second-Line ARV NRTIs  Abacavir (ABC)  Didanosine (ddI) Protease Inhibitors  Lopinavir / ritonavir (LPV/r)

6. Didanosine (ddI; Videx) Formulations*:  Liquid mixed in antacid (usually Maalox)  Chewable/dispersible tablet (with an antacid buffer)  Extended release, enteric coated capsule (Videx EC) * Absorption of ddI in the stomach is affected by acid.

7. ddI: Dosing Vietnam MOH HIV/AIDS Treatment Guidelines, 2009.

8. ddI: Pharmacokinetics DDI should be given on an empty stomach (1 hour before or 2 hours after a meal) DDI liquid should be stored under refrigerated conditions DDI tablets: minimum dose is two tablets at a time.  Tablets contain an antacid and two tablets are needed to supply enough antacid to provide adequate buffering. EC capsules: enteric coating protects the ddI during its transport through the stomach

9. ddI: Side Effects Peripheral neuropathy:  Presents as paresthesias, most often of the feet  May appear as a gait disturbance in younger children Pancreatitis:  Presents as abdominal pain, nausea, and vomiting  Associated with a rise in amylase and lipase levels Lipoatrophy:  d4T+ddI > d4T > ddI Lactic acidosis:  d4T+ddI > d4T > ddI

10. Abacavir (ABC; Ziagen) Formulations:  Capsule 300 mg  Syrup 20 mg/ml Administered on an every 12-hour schedule. There is no food effect on absorption.

11. ABC: Dosing Vietnam MOH HIV/AIDS Treatment Guidelines, 2009.

12. 12 Abacavir – Hypersensitivity Incidence: 3 - 6% Time of presentation:  median = 11 th day  93% of cases occur in the first 6 weeks Clinical symptoms:  Most common: fever, maculopapule rash, fatigue  GI Symptoms: nausea, vomiting, diarrhea, abdominal pain  Respiratory symptoms: cough, shortness of breath Contraindications:  Previous ABC hypersensitivity Hypotension or death upon re-challenge! Patients with hypersensitivity should never receive ABC again!

13. 13 Abacavir Hypersensitivity – Laboratory Abnormalities Common  Lymphopenia: redistribution effect  elevated liver enzymes Less frequent  elevated creatine phosphokinase: may be pronounced  mild thrombocytopenia: not clinically significant  renal: increased serum creatinine  lungs: chest X-ray may be normal or display diffuse bilateral or lobar infiltrates Laboratory abnormalities resolve a few days after discontinuing abacavir

14. 14 Abacavir Hypersensitivity – Treatment Stop Abacavir immediately if hypersensitivity is suspected  Symptoms will usually improve within a few days  Never give Abacavir again  Note Abacavir hypersensitivity in the patient record  Notify the patient and caregiver of the reaction and counsel them not to take abacavir again For severe reactions or hypotension:  Admit to hospital or ICU

15. Lopinavir/ritonavir (LPV/r; Aluvia) Formulations*:  Syrup ((LPV 80mg / RTV 20 mg) per ml)  Coated tablet (LPV 100 mg / RTV 25 mg)  Coated tablet (LPV 200 mg / RTV 50 mg) * LPV/r should be taken with food, both to enhance absorption and improve tolerability

16. LPV/r: Dosing Vietnam MOH HIV/AIDS Treatment Guidelines, 2009.

17. LPV/r: Dosing

18. 18 LPV/r: Pharmacokinetics Ritonavir boosting Most potent liver enzyme (Cytochrome P 450 3A4) inhibitor available  inhibits the break down of drugs in the liver, including other protease inhibitors Now used to boost other PIs  “boosted PI”  Increases AUC of the other PI  Can use lower dose of other PI  Increases the Cmin (trough concentration) of other PI, decreasing the risk for resistance  Allows once or twice daily dosing of PI

19. 19 Ritonavir Boosting AUC increased: Saquinavir20x Lopinavir15 – 20 x Indinavir2 – 5 x Nelfinavir1.5 x Atazanavir2.4 x

20. 20 LPV/r: Pharmacokinetics

21. LPV/r: Drug interactions Rifampin:  LPV by 75%  Generally should avoid combination  If necessary can give additional ritonavir to “super” boost the LPV (consult with expert) Clarithromycin levels   Adjust clarithromycin dose only in renal failure Itraconazole levels   Use with caution at itraconazole doses > 200 mg/day

22. LPV/r: Side Effects GI intolerance (nausea, vomiting) Diarrhea Long-term side effects:  Fat accumulation (lipodystrophy)  Lipids: increased cholesterol, triglycerides  Insulin resistance, increased glucose

23. LPV/r Side Effects: Lidodystrophy Changes in body fat distribution (lipodystrophy) have been reported to occur in 1%–33% of children with HIV infection. Lipohypertrophy or central fat accumulation is most often associated with protease inhibitor therapy. In children, physical examination showa increased abdominal girth, dorso-cervical fat accumulation, and/or breast enlargement.

24. LPV/r Side Effects: Lidodystrophy Development of lipohypertrophy is probably related to:  Genetic and developmental characteristics  Lifestyle factors (diet and exercise/activity)  ARV exposure and duration Treatment:  Low-fat diet  Exercise  Switch PI to NNRTI (if not resistant to NNRTI already) Support of the patient and family is an important aspect of care.

25. PI: Metabolic Effects Elevated Cholesterol  Check lipids yearly (Cholesterol, LDL, HDL, Triglycerides)  Treatment: Dietary changes Exercise Lipid lowering drugs Change in ARV regimen if possible

26. Lipid-Lowering Medications in Pediatric Patients with HIV DHHS Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection, Feb 2008

27. PI: Metabolic Effects Insulin resistance, hyperglycemia  When starting PIs, caregivers and patients should be educated about the signs and symptoms of diabetes mellitus  Check glucose every 6-12 months  Lifestyle modification if impaired glucose tolerance 27

28. 28 Key Points The MOH second-line ARV regimens for children is ABC-DDI-LPV/r Patients with abacavir hypersensitivity should never take abacavir again due to the risk of recurrent reaction and death. Be aware of potential drug interactions with patients on LPV/r. Patients on LPV/r should have glucose and lipid tests done at least once a year to screen for metabolic side effects.

29. Thank you! Questions?