Lecture 7:

Drug-Drug Interactions in ARV Therapy

delivered byDr. Daniel J. Baxter, ACHAP

KITSO AIDS Training Program

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.

Lecture Overview

• Review of mechanisms of drug interactions.

• Interactions between antiretroviral agents and other drugs.

• Interactions between antiretroviral agents.

• Overlapping toxicities.

• Management principles.

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.

Drug Blood Level

Time

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.

Absorption

Gastrointestinal pH

acid environment: NFV

neutral environment:ddI

Interactions between ARV Drugs and

other Drugs

Drugs cleared by Cytochrome P450

Cytochrome P450

Antiretroviral drugsNNRTIProtease Inhibitors

Anti-infectious agents e.g.KetoconazoleRifampicin Dapsone

Oral contraceptivesAnti-histaminesAnticoagulants

Warfarin

Lipid lowering drugsSimvastatin Lovastatin

Anticonvulsive drugsCarbamazepine Phenytoin

Phenobarb

ACTIVE

DRUG

InactiveDRUG

Enzyme Induction/Inhibition

Food, drinks, drugs,

etc.

Broken down in the body, with the help of ENZYMES

New substances e.g., proteins

Waste products

INDUCED (increased)

OR

INHIBITED (blocked)

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.

Enzyme Induction/Inhibition

• Drugs such as Rifampicin or NVP induce (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 Ketoconazole inhibit (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.

NVP Drug InteractionsDrug NVP

InteractionComment

Rifampicin NVP No dose adjustment of NVP.

Oral Contraceptives

O/C Use alternative or additional contraception.

Ketoconazole NVP , Keto Not recommended, use alternate antifungal drug.

Ergotamine Compounds

CONTRAINDICATED

EFV Drug Interactions

Drug EFV Interaction Comment

Rifampicin EFV Dose adjustment of EFV may or may not be indicated.

Ergotamine compounds CONTRAINDICATED

Protease Inhibitor Drug InteractionsDrug Interaction Comment

Rifampicin PI Boosted RTV/SQV recommended

Ketoconazole RTV: Keto IDV: IDV

Do not exceed Keto dose of 200 mg/day

Dose adjust IDV

NFV no adjustment

Oral Contraceptives

O/C RTV, NFV: Use alternative or additional contraception

IDV: no adjustment

Ergotamine Compounds

St John’s Wort

Lovastatin, Simvastatin, *

CONTRAINDICATED

*Pravastatin can be used safely with protease inhibitors.

NRTI Drug Interactions

AZT Do not combine with d4T.

ddI Antacids and cimetidine might increase absorption.

3TC No significant drug interactions.

d4T Do not combine with AZT.

Interactions between ARV Drugs

Interactions between ARV drugs

Drug Combinations

Comments

NRTI combinations Do not combine AZT and d4T

NRTI + NNRTI No significant interactions

NRTI + PI ddI + NFV: optimal absorption environment differs

PI combinations Possible pharmacological enhancement

PI Boosting

SQV & LPV

Inactive drug

RTV

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.

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.

Interactions of

Anti-TB Treatment and ARV Therapy

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.

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

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.

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.

Overlapping Toxicities

Overlapping Toxicities

Bone Marrow Toxicity

Pancreatitis Nephrotoxicity Hepatotoxicity

AZT

Hydroxyurea Anti-cancer

drugs

Sulfonamides

Pyrimethamine

Primaquine

Gancyclovir

ddI

3TC

d4T

RTV

Sulfonamides

Alcohol

Aminoglycosides

Amphotericin

Foscarnet

EFV

NVP

Protease

Inhibitors

Fluconazole

Ketoconazole

INH

Rifampicin

alcohol

Overlapping Toxicities (2)

Neuropathy Rash Diarrhea Eye Toxicity

DDI

d4T

INH

Alcohol

NVP

EFV

Sulfonamides

Dapsone

NFV

ddI

RTV

LPV/r

Clindamycin

Ethambutol

ddI

Case 1A 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

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

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

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

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.

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.

Case 7A 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

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.

Summary

Recommended Dosing with Regard to Meals

Take on empty stomach:

– ddI

Take with food

– NFV

Food independent

– AZT

– 3TC

– d4T

– NVP

– EFV

– LPV/r

Review Drug Interactions when Prescribing…

• ATT

• Oral contraceptives

• Ketoconazole

• Ergotamine

• Protease inhibitors and ATT

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.

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.