Lecture 7: Drug-Drug Interactions in ARV Therapy delivered by Dr. Daniel J. Baxter, ACHAP

1. Lecture 7:Drug-Drug Interactions in ARV Therapydelivered byDr. Daniel J. Baxter, ACHAP KITSO AIDS Training Program

2. Drug Interactions • Potential for drug interactions is significant in the HIV infected patient. • May be an important cause of treatment failure. • Overlapping toxicities may increase the risk of adverse events. • Beneficial drug interactions are increasingly being used to enhance efficacy and reduce toxicity.

3. Lecture Overview • Review of mechanisms of drug interactions. • Interactions between antiretroviral agents and other drugs. • Interactions between antiretroviral agents. • Overlapping toxicities. • Management principles.

4. Drug Therapeutics • In order for any drug, including ARVs, to exert a therapeutic effect, the blood and tissue level of that drug must be at a certain therapeutic level over a certain period of time. • If the blood and tissue levels of ARVs are not at a therapeutic level, viral replication will not be suppressed and treatment failure will result.

5. Drug Blood Level Time

6. NRTI Metabolism • NRTIs are cleared through the kidneys. • Dose adjustment of NRTIs is necessary in patients with significant renal failure. • Consult with pharmacist or HIV specialist concerning dose adjustment.

7. Absorption Gastrointestinal pH acid environment:NFV neutral environment: ddI

8. Interactions between ARV Drugs and other Drugs

9. Drugs cleared by Cytochrome P450 Antiretroviral drugs NNRTI Protease Inhibitors Anti-infectious agents e.g. Ketoconazole Rifampicin Dapsone Oral contraceptives Anti-histamines Anticoagulants Warfarin Lipid lowering drugs Simvastatin Lovastatin Anticonvulsive drugs Carbamazepine Phenytoin Phenobarb ACTIVE DRUG Cytochrome P450 InactiveDRUG

10. Enzyme Induction/Inhibition New substances e.g., proteins Broken down in the body, with the help of ENZYMES Food, drinks, drugs, etc. Waste products INDUCED (increased) OR INHIBITED (blocked)

11. Hepatic Metabolism of Drugs • The liver’s metabolism of drugs is not at a fixed rate and varies from drug to drug and from person to person. • One of the things which can increase or decrease the rate of the liver’s metabolism of a given drug is other drugs. • Many drug-drug interactions involve the way one drug affects the liver’s metabolism of another drug.

12. Enzyme Induction/Inhibition • Drugs such as Rifampicin or NVPinduce (activate) the P450 enzyme system and therefore increase the liver’s metabolism of drugs that use the P450 enzyme system, thereby decreasing their blood level more rapidly. • Drugs such as protease inhibitors or Ketoconazoleinhibit(suppress) the P450 enzyme and therefore decrease the liver’s metabolism of drugs that use the p450 enzyme system, thereby keeping their blood level higher for a longer period of time.

13. NVP Drug Interactions

14. EFV Drug Interactions

15. Protease Inhibitor Drug Interactions *Pravastatin can be used safely with protease inhibitors.

16. NRTI Drug Interactions

17. Interactions between ARV Drugs

18. Interactions between ARV drugs

19. SQV & LPV RTV Inactive drug PI Boosting Among the PIs, RTV is the most potent inhibitor of the P450 enzyme system. A low dose of RTV (“r”) will increase the level of SQV or LPV when given concurrently.

20. PI boosting • The combination RTV/ SQV or LPV/r has multiple benefits: • Reducing the pill burden and dosing frequency. • Improving the medication adherence. • Reducing risk of toxicity. • Reducing cost.

21. Interactions of Anti-TB Treatment and ARV Therapy

22. Anti-tuberculosis Agents and ARVs Rifampicin • Rifampicin is the most potent P450 inducer and lowers plasma levels of NNRTIs and PIs. • NNRTI levels are lowered from 30-37%; this reduction is usually not clinically significant. However, there may be occasional patients in whom rifampicin lowers the blood level of NVP or EFV to a greater extent, such that treatment failure could result. • PI levels are lowered by up to 90%, which is clinically significant.

23. Anti-tuberculosis Agents and ARVs (2) Favorable clinical experience: • 2 NRTIs + EFV (600 mg OD) / NVP (200 mg BD) + Rifampicin regimen (Guidelines recommend EFV 800mg dose if weight is greater than 60kg. Other specialists believe 600mg dose is adequate.) • Combination RTV/SQV (400mg/400mg BD) + Rifampicin regimen

24. Anti-tuberculosis Agents and ARVs (3) Because of serious drug-drug interactions between rifampicin and protease inhibitors, patients who develop TB while on second-line regimen must be referred to a specialist for evaluation.

25. Anti-tuberculosis Agents and ARVs (4) • Rifampicin can lower LPV/r (Kaletra) levels by 75%. • Possible options include: - Extra RTV boosting - Change to SQV/RTV(400mg/400mg BD) • HIV specialist should be consulted.

26. Overlapping Toxicities

27. Overlapping Toxicities

28. Overlapping Toxicities (2)

29. Case 1 A patient has recovered well from severe immune deficiency (baseline CD4 56, weight 41 kg) since started on (AZT+3TC) + NVP. Her weight is now 59 kg. She is now menstruating regularly and has a partner. What contraception do you recommend? Interaction O/C and NVP: possible advice O/C plus condom

30. Case 2 A patient with a CD4 of 63 and severe oral candidiasis is started on (AZT+3TC) + NVP. She also receives Ketoconazole 200mg. Interaction Ketoconazole and NVP: Oral suspension antifungal preparation or Fluconazole recommended

31. Case 3 A patient with known migraine and on treatment with Dihydroergotamin will start HAART with (AZT+3TC) + EFV. Interaction Ergotamin and EFV: Ergotamine CONTRAINDICATED Prophylaxis with propranolol or amitriptyline

32. Case 4 A patient with KS is started on ART with (AZT+3TC) + NVP. Six weeks after HAART initiation, the patient presents with pallor and a HB of 3.9 g%. He also receives cotrimoxazole and chemotherapy for his KS. Overlapping toxicity: Cotrimoxazole, AZT, and chemotherapy

33. Case 5 • A patient has been on (AZT+3TC) + NVP. Five months after initiation symptoms of TB appear, and the sputum AFB result comes back positive. Interaction between Rifampicin and NVP:Potentially decreased NVP effect. National Program guidelines recommend NO drug modification.

34. Case 6 • Female patient on 3rd month of ATT should now be initiated on first line HAART. What regimen do you recommend? Potential Interaction between Rifampicin and NVP, but no dose adjustment recommended.

35. Case 7 A patient presents with a CD4 of 36, wasting syndrome and oral candidiasis. You want to initiate HAART. On questioning about other medications he takes, he mentions that he also receives a tea from a traditional doctor which he takes every morning. Traditional medicine and ARV drugs Unknown interactions

36. Traditional Medicine None of the medications (teas, herbs, tablets, concoctions, etc.) given within the context of traditional/spiritual healing in Botswana have been studied with regard to their content and/or potential effect on ARV medications and their toxicities.

37. Summary

38. Take on empty stomach: ddI Take with food NFV Recommended Dosing with Regard to Meals • Food independent • AZT • 3TC • d4T • NVP • EFV • LPV/r

39. Review Drug Interactions when Prescribing… • ATT • Oral contraceptives • Ketoconazole • Ergotamine • Protease inhibitors and ATT

40. Management of Drug Interactions • Knowledge of drug-drug interactions continues to evolve. Consult guidelines i.e., www.hiv-druginteractions.org or www.HIVinsite.org • Potentially harmful interactions occur in a small proportion of patients.

41. Management of Drug Interactions (2) • A thorough drug history including non-prescription drugs and alternative or traditional therapies must be taken at each follow-up visit. • Drug-drug interactions are one of the causes of treatment failure.