Antiretroviral Therapy Drug Drug Interactions

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Antiretroviral Therapy Drug- Drug Interactions

• Todd Wills, MD
• Assistant Professor of Internal Medicine
• Division of Infectious Disease and International
  Medicine
  
• University of South Florida
• Faculty, Florida Caribbean AETC

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Disclosure of Financial RelationshipsThis
speaker has the following significant financial
relationships with commercial entities to
disclose

• Research Support
• Tibotec
• Pfizer
• Gilead

This slide set has been peer-reviewed to ensure
that there are no conflicts of interest
represented in the presentation.
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Why are HIV/AIDS Patients at Risk?

• Use of 3 and 4 drug antiretroviral regimens
• Multiple agents for treatment/prevention of
  various opportunistic infections
  
• Patient living longer and being treated for other
  chronic diseases (e.g. diabetes, CAD)
  
• Many antiretroviral agents have a profound effect
  on the cytochrome P450 enzyme system

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Metabolism

• Drugs enter GI tract
• P-glycoproteins
• Transporter proteins- pumps
• Meds may promote decrease drug levels
• Meds may inhibit increase drug levels

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Metabolism

• After leaving GI tract
• May be bound or unbound to proteins
• Bound not bioavailable to tissues
• Nutritional deficits
• Efficiency and site of action may be altered
• Hepatic Metabolism
• Cytochrome P450 system
• Enzymes to facilitate metabolism
• 20 variants

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Hepatic Metabolism

• Metabolism may occur by one or more of the
  enzymes
  
• CYP3A4 most frequently utilized by ART
• Inhibitors
• Inducers

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Drug Interactions

• Multifactorial
• Sex
• Age
• Race/ ethnicity
• Pregnancy
• Hormone levels
• Body size
• Alcohol use
• Co-morbidities

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Drug Interactions

• Co-infection with Hepatitis B or C
• Reduces enzyme activity in liver
• Up to 80 reduction for some enzymes
• PIs affected
• Need to consider when prescribing 2nd and 3rd
  line therapies
  
• NNRTIs and NRTIs less affected

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Classifications of Interactions

• Pharmacokinetic
• Absorption
• Mg and Al antacids impair IDV absorption
• Distribution
• TMP/SMX displaces warfarin from protein binding
• Metabolism
• Rifampin induces CYP450 metabolism of PIs
• RTV boosting
• Excretion

• Pharmacodynamic
• Additive
• Increased bone marrow toxicity of ZDV GCV
• Synergistic
• HAART effect greater than additive monotherapy
• Antagonistic
• ZDV and D4T reduces antiviral effect

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NRTI Related Interactions

• Both additive and synergistic
• Eliminated by the kidneys
• Minimal impact from CYP450
• No interactions with NNRTIs or PIs
• Abacavir alcohol use may increase level
• Tenofovir
• Can decrease Atazanavir levels must boost
• Atazanavir/Lopinavir minimal increase of TDF

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NRTI Related Interactions

• Zidovudine and Stavudine Antagonistic
• Didanosine
• Buffered formulations (solution and tablet)
• Impair absorption of quinolones, tetracyclines,
  atazanavir
  
• Must be taken at separate times
• Enteric Coated
• Increased DDI AUC with tenofovir
  co-administration
  
• Must lower DDI EC dose
• Watch for emergence of didanosine related
  toxicities

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NNRTI Related Interactions

• Can increase or decrease PIs (especially EFV)
• Nevirapine CYP3A4 induction
• Requires dose escalation
• May decrease efficacy of OCPs
• Levels may be reduced with rifampicin
  co-administration (rifabutin preferred)
  
• Efavirenz CYP3A4 induction /- inhibition
• EFV dose increase required with rifampicin
• Rifabutin dose increase when used with EFV
• Very long half-life

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PI Related Interactions

• Potent inhibitors of CYP3A4
• Ritonavir
• Most potent inhibitor of CYP3A4 among PIs
• Used clinically to pharmacokinetically enhance
  other PIs
  
• Inhibits P-glycoprotein transport in the GI
  tract, increases absorption of other meds thereby
  enhancing boosting effect

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PI Related Interactions

• Saquinavir mildest inhibitory effect
• ATV,f-AMP, IDV, NFV moderate inhibitors
• RTV and NFV induce their own metabolism
• f-AMP LPV reduced levels of both
• Tipranavir CYP3A4 inducer
• Decreases levels of other PIs

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Drugs That Should Not Be Given With PIs

• Simvastatin
• Lovastatin
• Astemizole
• Terfenadine
• Cisapride
• Pimozide
• Bepridil

• St. Johns Wort
• Rifampin (except ritonavir)
• Rifapentine
• Midazolam
• Triazolam
• Ergot alkaloids

• Additionally the following should not be given
  with ritonavir amiodarone, flecainide,
  propafenone, quinidine, alfuzosin, voriconazole
  
• Proton pump inhibitors and Irinotecan should not
  be used with atazanavir

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Fusion Inhibitors

• Enfuvirtide
• No known interactions with other antiretrovirals

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Antimicrobials

• Macrolides
• Erythromycin and Clarithromycin
• Inhibit CYP3A4 and p-glycoproteins
• Erythro with other inhibitors
• 5x increased risk of sudden cardiac death
• Study not related directly to ART
• Azithromycin has minimal impact

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Antifungals

• azoles
• CYP3A4 and p-glycprotein inhibitors
• Increases levels of other meds
• Other CYP3A4 inhibitors can increase azoles
• Care with combination of voriconazole with RTV or
  EFV
  
• Change voriconazole to 400 bid, efavirenz 300 mg
  qhs when combined
  
• Flucon

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Antimycobacterial Drugs

• Rifampicin is potent inducer of CYP450 system
• Leads to clinically significant reduction in most
  PI levels
  
• Clinically significant reductions of nevirapine
  levels
  
• May be used with NRTIs, efavirenz, and
  enfuvirtide
  
• With proper dose adjustments Rifabutin can be
  used with most antiretrovirals
  

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Acid-Lowering Drugs

• Proton Pump Inhibitors
• Do not use with Atazanavir
• Up to 76 reduction in plasma concentration
• OTC antacids
• Can use within 1-2 hrs of ART
• Buffered or enteric coated medications
• Caution with Atazanavir

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Other Drug Classes

• Anticonvulsants
• Monitor drug levels
• Avoid phenytoin, carbamazapine, and phenobarbitol
  (inducers) with PIs and NNRTIs
  
• Depakote, gabapentin, lamotrigine, and Keppra
  have minimal interactions

• HMG-CoA Reductase Inhibitors
• Metabolized by CYP450 system
• Simvastatin levels increased up to 40-fold with
  concurrent PI use
  
• Safest drugs pravastatin, low dose atorvastatin,
  rosuvastatin, fluvastatin

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Other Drug Classes

• Calcium Channel Blockers
• Levels may increase with PIs
• Immunosuppressives PIs increase levels
• Benzodiazepines
• Midazolam and triazolam inc. levels with CYP450
  inhibitors
  
• Fatal respiratory depression
• Caution with alprazolam (Xanax), diazepam
  (Valium), zolpidem (Ambien)
  
• Lorazepam (Ativan) and temazepam (Restoril) safer

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Other Drug Classes

• Antidepressants
• Tricyclics more likely to be involved
• SSRIs - Prozac, Paxil, Zoloft, Lexapro
• Levels may be increased by inhibitors leading
  to seizures, arrhythmias, coma
  
• PIs, especially RTV- may need to decrease SSRIs

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Other Drug Classes

• Erectile Dysfunction Drugs
• Metabolized by CYP3A4
• Sildenafil, vardenafil, tadalafil
• Concentrations increased by four-fold with PIs
• Low BP, dizziness, fainting, headaches, vision
  disturances, and priapism
  
• May have decreased levels of ED drugs with EFV

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Other Drug Classes

• Oral Contraceptives
• Impacted by CYP34A agents
• EFV, NVP, NFV, RTV, LPV decrease levels of
  estrogen
  
• May use OCP that contain progesterone only

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Recreational and Street Drugs

• Few studies
• RTV can increase ecstasy (MDMA) levels
• Agitation, seizures, tachycardia, cardiac arrest
• Liver disease may worsen
• Other amphetamines crystal meth
• GHB RTV SQV death
• Opiates including Methadone PIs, NNRTIs
  reduce plasma conc.
  
• Monitor for withdrawl
• Cocaine no significant interactions with ART

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Alternative Remedies

• Few studies
• Garlic inhibits /- induces CYP3A4
• Potential 50 reduction in SQV levels (gel caps)
• Limited information with NNRTIs and PIs
• Milk Thistle used for Hep C and Hep B
• unknown
• St.Johns Wort inducer of CYP3A4 and
  p-glycoproteins
  
• One study decreased levels of IDV
• US guidelines no use with NNRTIs and NRTIs

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Adverse Effects

• NRTIs
• Zidovudine HA, GI, bone marrow suppression
• Didanosine GI intolerance, pancreatitis
• Stavudine peripheral neuropathy
• Zalcitabine - peripheral neuropathy
• Abacavir HA, GI, hypersensitivity reaction

• NNRTIs
• Nevirapine - rash, liver
• Delavirdine - rash
• Efavirenz teratogenic in primates, CNS, rash
• PIs
• Indinavir nephrolithiasis
• Ritonavir GI intolerance
• Nelfinavir diarrhea
• Fosamprenavir GI intolerance, HA
• Lopinavir/ritonavir GI intolerance

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Summary

• ART is not an emergency
• Patients need to bring all medications, both
  prescribed and OTC to clinic before prescribing
  ART
  
• Complete medication list should be reviewed every
  visit to detect potential interactions
  
• Entire hospital team should be aware of ART
  toxicities and interactions
  
• Patient education is necessary to ART success

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Drug Interaction Resources

• www.hiv-druginteractions.org
• hivinsite.ucsf.edu
• http//hivinsite.ucsf.edu/insite?pagear-00-02
• www.aidsinfo.nih.gov (DHHS HIV Treatment
  Guidelines, TB Guidelines)