2/21/2014

HIV AND ANTIRETROVIRALS: A DISPENSERS PERSPECTIVE WITH A FOCUS ON DRUG INTERACTIONS DR. M.M. PEZA MBCHB (UCT) PG DIPLOMA (HEALTH ECONOMICS) (UCT)

2

HIV STATISTICS IN SOUTH AFRICA

• One in every 10 South Africans is HIV-positive, according to Statistics South Africa 2013 mid-year population estimate.

• Other interesting statistics about the SA population:

– The total number of South Africans living with HIV is about 5.26 million.

– In the age group 15 – 49, the HIV prevalence is 15.9%.

– Stats SA estimates that 200 000 people will die from Aids-related complications in 2013.

– The total number of people living with HIV has gone up by more than a million – from 4 million in 2002, to more than five million in 2013.

– The life expectancy of South Africans has increased by a year to 59.6 (57.7 for males and 61.4 years for females.

– The province with the lowest life expectancy is the Free State.

– Over 1.9 million adults and children are receiving antiretroviral treatment nationwide.

– In May 2012, the government said it had cut the mother-to-child transmission rate from 3.5% in 2010 to less than 2%.

(Source: Statistics South Africa

HIV

HIV proteins

RNA DNA

Reverse transcriptase

inhibitors

Protease inhibitors

Fusion inhibitors Integrase inhibitors (in development)

CD4+ cell

1

2

3

4 5

HIV REPLICATION CYCLE

4

DISEASE PROGRESSION OF HIV

INFECTED PATIENT

SEROCONVERSION

AIDS

5

WHEN TO START TREATMENT

• All pregnant women

• Any child with the virus

• Adult with AIDS defining condition

– (TB & CCM)

• Any Medical Scheme member with

– CD4 < 350

• DOH < 250

• Patient MUST want to start ARV’s

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THE SAD REALITY……

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SA Treatment Guidelines:

First Line Therapy

1 NNRTI 2 NRTI

Efavirenz

Nevirapine Abacavir

FIXED DOSE

COMBINATIONS

OR AND

OR

OR

OR

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GOALS OF ANTI-RETROVIRAL THERAPY

(ART)

• Improve quality of life

• Reduce HIV-related morbidity and mortality

• Provide maximal and durable suppression

of viral load

• Restore and/or preserve immune function.

9

HOW TO ACHIEVE GOALS OF ART

MAXIMAL TREATMENT ADHERANCE

COMPLETE SUPRESSION

OF VIRAL REPLICATION

ACHIEVE GOALS OF

ART

10

FACTORS LEADING TO ADHERANCE

DIFFICULTIES

27%

57%

14%

42%

54%

33%

32%

56%

5%

6%

11%

19%

46%

51%

68%

72%

Integration of ART in everyday life

Need for long-life treatment

Need to take medication with food

Need to take medication while fasting

Side-effects

Tablet size

Number of daily intakes

Number of tablets

Patient and Doctors perspective on adherence difficulties

Doctors Patients(1599 patients)

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A SOLUTION: FIXED DOSE

COMBINATIONS (FDC)

• Decrease tablet burden thus improving adherence levels

• Improved efficacy

• Fewer side effects

• Decreased cost

• Decreased risk of incorrect dosing as patient only takes one tablet

once a day

• Decreased risk of patients defaulting a single tablet to avoid certain

side effects (e.g. avoiding Efavirenz to avoid central nervous system

side effects)

• Regimen and stock management simplification

The benefits of ART in the form of a FDC results in maximal treatment

adherence levels and thus HIV viral suppression

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An Introduction To Drug Interactions

• Definition: When the effects of one drug are altered by the effects of another drug

– Precipitant drug: precipitates an interaction

– Object drug: drug whose action is affected by the precipitant drug

• Drug interactions can either increase or decrease the effect of the object drug

– Example of increased effect:

• Amiodorone (Precipitant) inhibits a cytochrome P 450 isoenzyme CYP2C9

• Reduced metabolism of warfarin (Object)

• Result: Increased anti-coagulant effect

13

Drugs likely to be involved in drug interactions: Precipitants

• Drugs likely to cause (precipitant) drug interactions

– drugs that are highly protein-bound therefore displacing object drugs from protein-binding sites

• E.g. : Aspirin and sulphonamides, Sodium Valproate

• Drugs that alter (stimulate/inhibit) the metabolism of other drugs

– Stimulate:Anticolvulsants, rifampicin, griseofulvin, St John’s wort

– Inhibit: allopurinol, cimetidine, erythromycin, metronidazole monoamine oxidase inhibitors, quinolone antibiotics (e.g. ciprofloxacin)

• Drugs that affects renal function and alter renal clearance

– E.g. diuretics

It is possible to predict the type of drugs that will be involved in important reactions

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Drugs likely to be objects of drug interactions

• Drugs for which a small change in dose can result in a relatively large change in therapeutic effect

• Change in therapeutic effect

– Reduced efficacy

– Low toxic: therapeutic ratio

• Examples of such drugs are

– Aminoglycoside antibiotics

– Anti-coagulants

– Anti-convulsants

– Antihypertensives

– Oral contraceptive

– Drugs that act on the CNS

It is possible to predict the type of drugs that will be affected by the effects of other drugs

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Types of drug interactions

• Pharmacokinetic interactions

– Absorption interactions

– Protein binding displacement interactions

– Cellular distribution interactions

– Metabolism interactions

– Excretion interactions

• Pharmacodynamic interactions

– Direct pharmacodynamic interactions

– Indirect pharmacodynamic interactions

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Pharmacokinetic interactions

• Absorption interactions

– Reduced gastrointestinal motility

• Drugs with anti-cholinergic effects ( e.g. antidepressants)

• Slows the speed of absorption of drugs

• Usually does not affect the extent of absorption

• Binding interactions can be avoided if two drugs are taken an hour or two apart

• Sometime beneficial

– Use of activated charcoal in drug-poising

When the Absorption, Distribution, Metabolism or Excretion of the object drug is altered by the precipitant drug

Do not take milk, iron preparations or indigestion remedies at the same time of day as this medicine

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Pharmacokinetic interactions

• Protein binding displacement interactions

– Displacement of one drug by another from its sites of binding to

plasma proteins

– Increased circulation of unbound drug

– Increased system effect of the displaced drug

– Object drug must be highly protein bound

• Important protein-bound object drugs

– Warfarin

• Important precipitant drugs involved in protein binding displacement

interactions

– Sulfonamides

• Cellular distribution interactions

– E.g. rifampicin inhibits the uptake of certain drugs by hepatocytes

– Reducing metabolism

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Pharmacokinetic interactions

• Metabolism interactions

– Metabolism of object drug is inhibited/increased by a precipitant drug

– Often involve the cytochrome P 450 system

– Happens when two drugs are metabolised by the same system

• Excretion interactions

– Mostly occur in the kidneys

– Drugs that inhibit renal tubular excretion increase the blood concentration of object drugs

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Pharmacodynamic Interactions

• When the precipitant drug alters the effect of the object drug at the site of action

• Direct pharmacodynamic interactions

– When two drugs act

• On the same site

• Two different sites with similar end result

• Indirect pharmacodynamic interactions

– A pharmacological, therapeutic or toxic effect of the precipitant drug alters the pharmacological, therapeutic or toxic effect of the object drug

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A Focus on Common Antiretroviral (ARV) Drug Interactions

Nucleoside Reverse Transcriptase Inhibitors

Drug Interactions

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Nucleoside Reverse Transcriptase Inhibitors

• Zidovudine (AZT/ZDV)

• Didanosine (ddI)

• Lamivudine (3TC)

• Stavudine (d4T)

• Abacavir (ABC)

• Emtricitabine (FTC)

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• Tenofovir

Nucleotide Reverse Transcriptase Inhibitors

Flexner C. Antiretroviral agents and treatment of HIV infection. In: Brunton LL, editor. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th edition. The McGraw Hill Companies Inc; 2011

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Tenofovir

• Tenofovir DF

Diester hydrolysis

• Tenofovir

AMP Kinase • TFV-MP

NDP Kinase

• TFV-DP

Active

incorporated into

HIV DNA to

cause chain

termination

because it has

incomplete

ribose ring

Reverse

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Tenofovir: Pharmacokinetics

Parameter Tenofovir DF

Tmax 1.0 ± 0.4 hrs

Bioavailability 25%

Metabolism Tenofovir and Tenofovir DF are not

metabolized via CYP450 enzymes

Excretion 70−80% as unchanged drug in the

urine

Half-life 17 hours

Effect of food Increase in AUC and Cmax by 35%

and 15%

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Tenofovir Drug Interactions

• Didanosine is best avoided

• Lopinavir-ritanovir coadministration needs close monitoring

• Monitor closely for adverse events

• Avoid drugs that reduce renal function

• Avoid drugs that compete for active tubular secretion

• Aciclovir and Valaciclovir (Herpes simplex 1 and 2; Varicellar-zoster viruses)

• Gangiclovir and Valganciclovir ( Cytomegalovirus CMV infection)

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Emtricitabine

Reverse

• FTC

Deoxycytidine kinase

• FTC-MP

CMP/dCMP Kinase

• FTC-DP

NDP Kinase

• FTC-TP

Active

Incorporated into HIV DNA to cause chain termination

Emtricitabine lacks 3’ hydroxyl group

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Emtricitabine: Pharmacokinetics

Parameter Emtricitabine

Absorption Rapid

Tmax 1 – 2 hours

Bioavailability 93%

Metabolism Limited metabolism via oxidation and

glucuronidation

Excretion approximately 86% in the urine and 13% as

metabolites

Half-life 10 hours (intracellular up to 39 hours)

Effect of food No change

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Emtricitabine Drug Interactions • Avoid drugs that reduce renal function

• Avoid drugs that compete for active tubular secretion

• Aciclovir and Valaciclovir (Herpes simplex 1 and 2; Varicellar-zoster viruses)

• Gangiclovir and Valganciclovir ( Cytomegalovirus CMV infection)

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Lamivudine

• 3TC

Deoxycytidine kinase

• 3TC-MP

CMP/dCMP Kinase

• 3TC-DP

NDP Kinase

• 3TC-TP

Active

Reverse

Incorporated into HIV DNA to cause chain termination

Lamivudine lacks 3’ hydroxyl group

30

Lamivudine: Pharmacokinetics

Parameter Lamivudine

Tmax 1-1.5 hours

Bioavailability 82% to 87%

Metabolism is the minor route of

elimination

Excretion Renal Excretion 70%,

Excreted unchanged in the

urine

Half-life 3 to 7 hours (intracellular half

life is 12-18 hours)

Effect of food No change

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Lamivudine Drug Interactions • The likelihood of interactions is low due to the limited metabolism and plasma protein

binding and almost complete renal clearance.

• Not significantly metabolised by cytochrome P450 enzymes (such as CYP 3A4, CYP 2C9 or CYP

2D6)

• Lamuvudine may inhibit the intracellular phosphorylation of zalcitabine when the two

medicinal products are used concurrently.

• Used in peripheral neuropathy

• History of pancreatitis

• Administration of trimethoprim, a constituent of co-trimoxazole causes an increase in

lamivudine plasma levels. Unless the patient has renal impairment, no dosage adjustment of

lamivudne is necessary.

• Lamivudine has no effect on the pharmacokinetics of co-trimoxazole.

• The possibility of interactions with other medicines administered concurrently should be

considered, particularly when the main route is renal.

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Zidovudine

• Zidovudine

Thymidine kinase

• ZDV-MP

Thymidylate Kinase • ZDV-DP

NDP Kinase

• ZDV-TP

Active

Reverse Incorporated into HIV

DNA to cause chain termination

Zidovudine lacks 3’ hydroxyl group

33

Zidovudine: Pharmacokinetics

Parameter Zidovudine

Absorption Well absorbed

Tmax 0.5 to 1.5 hours

Bioavailability 60 - 70%

Metabolism Liver, extensive with significant first-

pass metabolism

Excretion Renal: Urinary recovery of oral

zidovudine 14%, metabolite 74%

Half-life 1 hour (intracellular half life is 3-4

hours)

Effect of food Unchanged, may be taken with or

without a meal

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Zidovudine Drug Interactions

• Ganciclovir

• Use has caused severe haematological toxicity

• Radiation therapy

• Increased risk of bone marrow suppression

• Probenecid

• Delayed excretion of Zidovusine

• Valproate

• Significantly increases zidovudine levels

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Abacavir

Rever

se

• Abacavir

Adenosine phorphor-

transferase

• ABC-MP

Cytosolic enzyme • CBV-MP

Kinase

• CBV-DP

Kinase

• CBV-TP

Active

incorporated

into HIV DNA

to cause

chain

termination

because lacks

3’ hydroxyl

group

36

Abacavir: Pharmacokinetics

Parameter Abacavir

Absorption Rapid

Tmax 0.7 to 2 hours

Bioavailability >80%

Metabolism Extensive. Not a substrate or

inhibitor of CYPs

Excretion Renal 1%, Feces 16%

Half-life 1 – 1.5 hours (intracellular

carbovir TP up to 21 hours)

Effect of food No significant difference

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Abacavir Drug Interactions

Not significantly metabolised by cytochrome P450 enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6) nor do they inhibit or induce this enzyme system

Potential for clinically significant interactions is low

Non-Nucleoside Reverse Transcriptase Inhibitors

Drug Interactions

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Drugs

• Nevirapine (NVP)

• Efavirenz (EFV)

• Delavirdine

• Etravirine

• Rilpivirine (RPV)

Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

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NNRTIs Mechanism of Action

Non-competitive inhibitors of HIV Reverse Transcriptase

enzyme

Binds to hydrophobic pocket in the p66 subunit

Binding site is distant from

the active site

Induces conformational

change that reduces its

activity

41

Efavirenz Pharmacokinetics

• Administration with fatty meals increases bio-availability by 50%

• Highly protein bound: 99% to albumin

• Half-life is prolonged in liver disease

• Metabolised in the liver : cytochrome P450 system

• Excreted in urine (14-34%) and faeces (16-69%)

42

Efavirenz Drug Interactions

• Efavirens may either inhibit or induce metabolism of hepatically metabolised drugs

• Protease Inhibitors

• Do not give concurrently

• Midazolam, triazolam, ergot alkaloids, terfenamide

• Increased plasma levels: avoid

• Rifampicin

• Induces metabolism of EFV therefore increase EFV dose

• Anticonvulsants (Phenytoin, Carbamazepine, Phenobarbitone)

• Serum levels of both EFV and anticonvulsants reduced

• Warfarin

• May require warfarin dose adjustment/ monitor INR regularly

• Oral contraception

• Reduced efficacy therefore recommend barrier contraception

• St John Wart

• Induces EFV metabolism therefore decreases EFV plasma levels

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Nevirapine Pharmacokinetics and Drug Reactions

• Pharmacokinetics

• Extensively metabolised by the cytochrome P450 system

• Drug Interactions

• Rifampicin (use Rifambuten instead)

• Oral contraception

• Ketoconazole

• Should not be given concomitantly

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Take home message

You can’t remember all drug to drug interactions

– Make use of resources available to you

South African Medicines Formulary (SAMF)

University of Liverpool

– HIV iChart

Work from first principles

– It is possible to predict potential drug to drug

interactions

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Thank you