HIV AND ANTIRETROVIRALS: A DISPENSERS PERSPECTIVE WITH A FOCUS ON DRUG INTERACTIONS DR. M.M. PEZA MBCHB (UCT) PG DIPLOMA (HEALTH ECONOMICS) (UCT) 2/21/2014
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 2
HIV REPLICATION CYCLE Fusion inhibitors Integrase inhibitors (in development) 1 RNA 2 DNA 3 HIV proteins HIV CD4+ cell 4 5 Reverse transcriptase inhibitors Protease inhibitors
DISEASE PROGRESSION OF HIV INFECTED PATIENT SEROCONVERSION AIDS 4
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 5
THE SAD REALITY 6
SA Treatment Guidelines: First Line Therapy 1 NNRTI 2 NRTI Efavirenz OR OR AND OR Nevirapine OR Abacavir FIXED DOSE COMBINATIONS 7
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. 8
HOW TO ACHIEVE GOALS OF ART MAXIMAL TREATMENT ADHERANCE COMPLETE SUPRESSION OF VIRAL REPLICATION ACHIEVE GOALS OF ART 9
FACTORS LEADING TO ADHERANCE DIFFICULTIES Patient and Doctors perspective on adherence difficulties Doctors Patients(1599 patients) Number of tablets 56% Number of daily intakes 32% Tablet size 51% 33% Side-effects 46% 54% Need to take medication while fasting 19% 42% Need to take medication with food 11% 14% Need for long-life treatment 6% 57% Integration of ART in everyday life 5% 27% 68% 72% 10
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 11
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 12
Drugs likely to be involved in drug interactions: Precipitants It is possible to predict the type of drugs that will be involved in important reactions 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 13
Drugs likely to be objects of drug interactions It is possible to predict the type of drugs that will be affected by the effects of other drugs 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 14
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 15
Pharmacokinetic interactions When the Absorption, Distribution, Metabolism or Excretion of the object drug is altered by the precipitant drug 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 Do not take milk, iron preparations or indigestion remedies at the same time of day as this medicine Sometime beneficial Use of activated charcoal in drug-poising 16
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 17
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 18
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 19
A Focus on Common Antiretroviral (ARV) Drug Interactions 20
Nucleoside Reverse Transcriptase Inhibitors Drug Interactions
Nucleoside Reverse Transcriptase Inhibitors Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Zidovudine (AZT/ZDV) Didanosine (ddi) Lamivudine (3TC) Stavudine (d4t) Abacavir (ABC) Emtricitabine (FTC) Nucleotide Reverse Transcriptase Inhibitors Tenofovir Flexner C. Antiretroviral agents and treatment of HIV infection. In: Brunton LL, editor. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12 th edition. The McGraw Hill Companies Inc; 2011
Tenofovir Tenofovir DF AMP Kinase Tenofovir TFV-MP Active TFV-DP Diester hydrolysis NDP Kinase Revers e incorporated into HIV DNA to cause chain termination because it has incomplete ribose ring
Tenofovir: Pharmacokinetics Tmax Parameter 1.0 ± 0.4 hrs Tenofovir DF 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%
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)
Emtricitabine FTC Deoxycytidine kinase CMP/dCMP Kinase FTC- MP FTC- DP NDP Kinase Active FTC- TP Revers e Incorporated into HIV DNA to cause chain termination Emtricitabine lacks 3 hydroxyl group
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 Effect of food 10 hours (intracellular up to 39 hours) No change
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)
Lamivudine 3TC Deoxycytidine kinase CMP/dCMP Kinase 3TC- MP 3TC- DP NDP Kinase Active 3TC- TP Revers e Incorporated into HIV DNA to cause chain termination Lamivudine lacks 3 hydroxyl group
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
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 P 450 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.
Zidovudine Zidovudine Thymidylate Kinase ZDV-MP ZDV-DP Active ZDV-TP Thymidine kinase NDP Kinase Revers e Incorporated into HIV DNA to cause chain termination Zidovudine lacks 3 hydroxyl group
Zidovudine: Pharmacokinetics Parameter Zidovudine Absorption Well absorbed Tmax 0.5 to 1.5 hours Bioavailability 60-70% Metabolism Liver, extensive with significant firstpass 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
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
Abacavir Abacavir Cytosolic enzyme ABC-MP CBV-MP Kinase CBV-DP CBV-TP Adenosine phorphortransferase Kinase Active Rever se incorporated into HIV DNA to cause chain termination because lacks 3 hydroxyl
Abacavir: Pharmacokinetics Parameter Absorption Tmax Rapid 0.7 to 2 hours Abacavir 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
Abacavir Drug Interactions Not significantly metabolised by cytochrome P 450 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
Drugs Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Nevirapine (NVP) Efavirenz (EFV) Delavirdine Etravirine Rilpivirine (RPV)
NNRTIs Mechanism of Action Noncompetitive 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
Efavirenz Pharmacokinetics Administration with fatty meals increases bioavailability 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%)
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
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
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
Thank you 45