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Antiretroviral Therapy Drug Drug Interactions

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Title: Antiretroviral Therapy Drug Drug Interactions


1
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

2
Disclosure of Financial Relationships This
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.
3
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

4
Metabolism
  • Drugs enter GI tract
  • P-glycoproteins
  • Transporter proteins- pumps
  • Meds may promote decrease drug levels
  • Meds may inhibit increase drug levels

5
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

6
Hepatic Metabolism
  • Metabolism may occur by one or more of the
    enzymes
  • CYP3A4 most frequently utilized by ART
  • Inhibitors
  • Inducers

7
Drug Interactions
  • Multifactorial
  • Sex
  • Age
  • Race/ ethnicity
  • Pregnancy
  • Hormone levels
  • Body size
  • Alcohol use
  • Co-morbidities

8
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

9
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

10
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

11
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

12
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

13
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

14
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

15
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

16
Fusion Inhibitors
  • Enfuvirtide
  • No known interactions with other antiretrovirals

17
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

18
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

19
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

20
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

21
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

22
(No Transcript)
23
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

24
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

25
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

26
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

27
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

28
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

29
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

30
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

31
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)
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