COMPLICATIONS OF ANTIRETROVIRAL THERAPY Michael Thompson

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COMPLICATIONS OF ANTIRETROVIRAL THERAPY

• Michael Thompson PharmD, BCNSP
• Faculty Florida/Caribbean AETC
• Professor of Pharmacy Practice
• College of Pharmacy
• Florida AM University

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Disclosure of Financial Relationships

• This speaker has no significant financial
  relationships with commercial entities to
  disclose.

This slide set has been peer-reviewed to ensure
that there areno conflicts of interest
represented in the presentation.
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Objectives

• To review mechanisms of action of commonly used
  antiretroviral agents
• To discuss common adverse effects associated with
  antiretroviral use
• To discuss drug-drug interactions associated with
  antiretroviral use
• Highlight the role of the clinician in
  prevention, detection and monitoring of adverse
  drug-related outcomes in patients receiving ARVs

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ART Options

• NRTIs (Nucleoside OR Nucleotide Reverse
  Transcriptase Inhibitors, aka Nukes)
• NNRTIs (Non-Nucleoside Reverse Transcriptase
  Inhibitors, aka Non-Nukes)
• PIs (Protease Inhibitors)
• Fusion Inhibitors
• Entry Inhibitors
• Integrase Inhibitors

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Nucleoside/Nucleotide Reverse Transcriptase
Inhibitors (NRTIs)
Agent
Approved

• Zidovudine (AZT, ZDV, Retrovir?) 3/87
• Didanosine (ddI, Videx?, Videx EC?) 10/91
• Zalcitabine (ddC, Hivid?) 6/92
• Stavudine (d4T, Zerit?) 6/94
• Lamivudine (3TC, Epivir?) 11/95
• Abacavir (ABC, Ziagen?) 12/98
• Combivir? (AZT/3TC) 9/97
• Trizivir? (AZT/3TC/ABC) 11/00
• Tenofovir (TDF, Viread?) 10/01
• Emtricitabine (FTC, Emtriva ?) 7/03
• Epzicom? (ABC/3TC) 8/04
• Truvada? (FTC/TDF) 8/04

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Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)
Agent
Approved

• Nevirapine (NVP, Viramune?)
  6/96
• Delavirdine (DLV, Rescriptor?) 4/97
• Efavirenz (EFV, Sustiva?) 9/98
• Etravirine (Intelence)
  1/08

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Protease Inhibitors (PIs)

• Saquinavir-HGC (SQV-HGC, Invirase?)
  12/95
• Ritonavir (RTV, Norvir?) 3/96
• Indinavir (IDV, Crixivan?) 3/96
• Nelfinavir (NFV, Viracept?) 3/97
• Saquinavir-SGC (SQV-SGC, Fortovase?) 11/97
• Amprenavir (APV, Agenerase?) 4/99
• Lopinavir/ritonavir (KAL, Kaletra) 9/00
• Atazanavir (ATV, Reyataz) 6/03
• Fosamprenavir (fos-APV, Lexiva) 10/03
• Tipranavir (TPV, Aptivus) 6/05
• Darunavir (DRV, Prezista) 6/06

Approved
Agent
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Fusion and Entry Inhibitors

• Agent Approved
• Fusion Inhibitor
• Enfuvirtide (T-20, Fuzeon?) 3/03
• Entry Inhibitor (CCR5 Inhibitor)
• Maraviroc (Selzentry) 8/07

Integrase Inhibitor
Agent Approved Raltegravir
(Isentress)
10/07 Mechanism of Action
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Multi-Class Product

• Atripla (emtricitabine/tenofovir/efavirenz)
• Emtricitabine/tenofovir (Truvada) efavirenz
  (Sustiva)
• Approved July 12, 2006
• First collaborative effort between 2 companies to
  develop combination pill for HIV treatment
• Not new drugs!

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Problems Associated with Antiretrovirals

• Adverse Effects
• Drug Interactions
• Resistance
• Genotyping
• Phenotyping

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Common Adverse Effects of Antiretrovirals

• Lactic Acidosis
• Hepatotoxicity
• Hyperglycemia
• Fat Maldistribution
• Hyperlipidemia
• Pancreatitis
• Peripheral Neuropathy
• Others (bone marrow suppression, gastric
  intolerance)
• Common effects due to shared toxicity of
  mitochondria in human cells

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Common Adverse Effects of Antiretrovirals

• Lactic Acidosis
• Thought to be secondary to mitochondrial damage
  associated with hepatic steatosis
• Increased risk in
• females,
• obesity,
• prolonged NRTI therapy,
• nutritional depletion of cofactors/vitamins
  (riboflavin and thiamine)- required for normal
  mitochondrial function
• HIV itself (lower numbers of cellular
  mitochondria even prior to NRTI use)

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Summary of NRTI Related Lactic Acidosis

• NRTIs prevent DNA elongation and viral
  reproduction
• Once incorporated into the viral DNA chain, their
  presence in the DNA halts transcription
• These drugs unfortunately can also function as
  substrates for other enzymes like DNA polymerase
  gamma this enzyme is involved in the replication
  of mitochondrial DNA
• Disruption of DNA polymerase gamma is thought to
  result in a wide variety of adverse effects
  ranging from lactic acidosis to hepatic steatosis

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Mechanism of Development of Lactic Acidosis in
HAART
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Lactic Acidosis Continued

• Symptoms nonspecific GI complaints of nausea,
  abdominal pain, bloating, nausea and vomiting,
  diarrhea, anorexia, weakness, tachypnea,
  myalgia,paresthesia and weight loss with
  hepatomegaly
• Labs hyperlactemia, increased anion gap,
  elevated aminotransferases, LDH, lipase and
  amylase
• Routine testing of lactic acid not recommended
  due to technical problems in reliably assaying
  for lactate

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Adverse Effects Hepatotoxicity

• Defined as 3 to 5 times increase in serum
  transaminases with or without clinical hepatitis
• All marketed NNRTIs and Protease Inhibitors have
  been associated with elevations in transaminases

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Nevirapine Hepatotoxicity

• Of the NNRTIs, nevirapine has highest incidence
  of hepatoxicity and patients should be monitored
  especially throughout the first 18 weeks.
  Patients with hepatitis B and C may be at
  increased risk.
• The two week lead in with nevirapine may reduce
  incidence of hepatotoxicity. Patients should be
  monitored every 2 weeks for the first month then
  monthly for the first 18 weeks. If rash occurs,
  patients should be monitored for hepatotoxicity
  as well.

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Adverse Effects Hepatotoxicity

• Protease Inhibitors can cause hepatoxicity at ANY
  time during therapy
• Other antiretrovirals and hepatotoxicity
• Co infection with Hepatitis C or B, alcohol and
  stavudine use can increase potential for toxicity

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Adverse Effects Continued

• Hyperglycemia
• Seen in Protease Inhibitors
• Glucose intolerance and insulin resistance can
  occur without Diabetes
• Fat maldistribution
• Lipodystrophy is part of a metabolic syndrome
  that includes dyslipidemias, insulin resistance
  and accelerated bone loss

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HAART Toxicities Lipodystrophy

• Body habitus changes
• Central fat accumulation
• Peripheral fat wasting
• Risk factors
• Female gender
• Older age
• HAART
• Protease Inhibitor use

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Lipodystrophy
http//www.thebody.com/pinf/wise_words/mar05/lipod
ystrophy.html?m89o
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Proposed Case Definition of Lipodystrophy

• Primary Characteristics
• Age gt 40 years
• HIV infection gt 4 years
• AIDS (Class C)
• Increased waisthip ratio
• Decreased HDL
• Change in anion gap

• Secondary Characteristics
• Increased total cholesterol
• Increased triglycerides
• Decreased lactate

http//www.hivforum.org/publications/Lipodystrophy
.pdf http//www.med.unsw.edu.au/nchecr
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Lipodystrophy Unclear Etiology

• Mitochondrial toxicity?
• Interference w/ adipocyte differentiation?
• Pro-inflammatory activation of the immune system
  during reconstitution?

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Lipodystrophy Syndrome NRTIs versus PIs
PIs
NRTIs d4TgtZDV
Intra-abdominal fat Cholesterol
TG Insulin resistance
Lactic acid
SC fat wasting TG Buffalo hump
John M, et al. Antiviral Ther. 200169-20.
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Lipodystrophy Treatment Options

• Switch patient to NNRTI regimen
• Anti-hyperglycemic agents
• Metformin and Thiazolidindiones
• Growth hormone

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Lipodystrophy Illustrations
Buffalo hump
Facial wasting
Crix belly
http//www.hivandhepatitis.com/recent/lipo/fataccu
mulation/1.htmlbuf
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Severe Wasting
http//bayloraids.org/atlas/images/14.jpg
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Treatment of Facial Wasting
Sculptra
http//www1.sculptra.com/US/hcp/Works.jsp
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Example of Buffalo Hump
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Other Adverse Effects

• Pancreatitis
• Bleeding in Hemophiliacs
• Skin Rash/Dermatologic Effects
• Examples
• NNRTIs (nevirapine, efavirenz)
• NRTIs (abacavir)
• Others

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Steven Johnson Syndrome or Toxic Epidermal
Necrolysis
http//www.fromthewilderness.com/images/stevenJohn
sonSyndrome2.jpg
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Drug Interactions
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Understanding Drug Interactions with
Antiretrovirals

• Mechanisms of Drug Interactions Pharmacokinetic
  Interactions
• These interactions affect
• Absorption of drugs
• Distribution of drugs
• Metabolism
• Elimination of drugs
• Considered clinically significant if there is
  more than a 30 change in the blood levels or
  area under the concentration curve

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Interactions Affecting Drug Metabolism Most Common

• Cytochrome P450 is an enzyme system containing
  many enzyme families
• The majority of interactions reported involve
  CYP3A4
• Medications can induce OR inhibit the action of
  enzymes responsible for their own metabolism or
  the metabolism of other drugs
• Inducing enzymes result in lower drug levels
  Inhibiting enzymes result in increased levels

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Effect of ARVs on Drug Metabolism
Fichtenbaum CJ. Clin Pharmacokinet.
2002411195-1211 Product labels.
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Drug Interactions HAART

• Nucleoside and Nucleotide drugs not eliminated
  via cytochrome P450 therefore these interactions
  are minimal
• Drug interactions here may occur via other
  mechanisms (eg GI absorption, renal elimination)

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Non-nucleoside Interactions

• Drugs involved
• Efavirenz can induce or inhibit CYP3A4 (most
  often acts as an inducer and can also induce
  others)
• Nevirapine acts as an inducer to CYP3A4
• Delavirdine acts as an inhibitor of CYP3A4
• Etravirine is an inducer of CYP3A4 (inhibits
  CYP2C, and CYP2C19)

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Protease Inhibitor Interactions

• All PIs inhibit CYP3A4
• Ritonavir is the most potent inhibitor while
  Saquinavir is the least potent
• Ritonavir can inhibit other cytochrome P450
  inhibitors and can induce CYP1A2
• Tipranavir can also be an inducer

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Other classes

• Fusion inhibitors and integrase inhibitors are
  not metabolized by these systems

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Effects of Food on Absorption of Antiretrovirals

• Didanosine
• Levels decrease by 55
• Take ½ hour before or 2 hours after meals
• Efavirenz
• Empty stomach, food increases levels as high as
  39-79
• Amprenavir
• High fat meal decreases blood levels
• Can take with food but avoid high fat
• f-Amp not affected as much

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Food Effects Continued..

• Ritonavir
• Take with food increases bioavailability
• Indinavir
• Food decreases levels by 77 (not a problem if
  boosted with ritonavir)
• Take 1 hr before or 2 hr after or may take with
  skim milk or low fat meal
• Nelfinavir
• Levels increase 2-3 fold with food Take with food

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Food Effects Continued..

• Saquinavir (eg Fortovase, Invirase)
• Levels increase 6-fold if taken with food
• Take with or up to 2 hours after a meal as sole
  PI or with RTV
• Lopinavir/Ritonavir (Kaletra)
• Take with food
• AUC increased when taken with food

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Effect of Buffering Agents on PI Concentrations

• Mechanism
• PI absorption is related to its solubility
  properties
• For weak bases-solubility increases in gastric
  acid
• When pH is less acidic, PIs become less soluble
  to varying degrees

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Effect of Buffering Agents on Gastric pH

• Buffering agents
• Proton-pump inhibitors (PPIs)
• Histamine-2 (H2) blockers
• Antacids
• calcium carbonate and magnesium hydroxide in
  didanosine buffered tablets (Videx)
• Duration of action
• Decrease in gastric acidity varies by drug class
• PPI gt H2 blockers gt antacids
  24 - 72h 10 12h a few hours

References Product Monographs
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Effect of Buffering Agents on Antiretroviral Drug
Absorption

• Didanosine (ddI)
• Contains buffering agents that can affect
  absorption of
• Atazanavir
• Tetracyclines
• Quinolones
• Itraconazole
• Proton Pump Inhibitors, H2 antagonists and
  Antacids
• Atazanavir absorption decreased
• Note manufacturers dosing recommendation as
  follows

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Dosing Recommendations for Use of PPIs with
Atazanivir

• Treatment Naïve Patients
• PPI max dose equal to 20mg omeprazole given 12
  hrs before atazanvir 300mg with ritonavir 100mg
• Treatment Experienced Patients
• Avoid use as per manufacturers recommendations

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Examples of Noted Interactions Between
Antiretrovirals

• Efavirenz and Nevirapine
• Decrease Atazanavir levels
• Tenofovir and ddI
• ddI levels are elevated (exact mechanism not
  known fully)
• Recommend 250mg ddI-EC (gt60 kg)
• Some reports to suggest decreased virologic
  control when this combination used as NRTI
  backbone with EFV or NVP

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Antiretroviral Interactions Continued

• Tenofovir and Atazanavir
• Atazanavir levels are decreased
• Tenofovir concentrations increased
• Atazanavir should be boosted with RTV when
  combined
• Does not seem to be clinically significant with
  PIs such as lopinavir/ritonavir (Kaletra)
• Tenofovir may compete for tubular secretion for
  wide variety of drugs as well

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Other Interactions Maraviroc

• When given with strong CYP3A inhibitors (with or
  without CYP3A inducers) including PIs (except
  tipranavir/ritonavir), delavirdine 150 mg twice
  daily
• With NRTIs, tipranavir/ritonavir, nevirapine, and
  other drugs that are not strong CYP3A inhibitors
  or CYP3A inducers 300 mg twice daily (i.e. that
  do not have a net CYP3A inhibition or induction
  effect)
• With CYP3A inducers including efavirenz (without
  a strong CYP3A inhibitor) 600 mg twice daily

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Drug Interactions with Drugs Used in Treating
Addiction

• Methadone
• Efavirenz and nevirapine decreases methadone
  levels Delavirdine effects unknown
• Abacavir decreases methadone clearance
• Methadone decreases stavudine levels but
  increases zidovudine
• PIs decrease levels and patients can have
  symptoms of withdrawal

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Interactions Between HAART and Recreational/Other
Drugs

• Alcohol
• Marijuana
• Ecstasy
• Heroin
• Benzodiazepines
• Barbiturates
• Amphetamines

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Drug Interactions with Antiretrovirals

• Antifungal agents
• Review of specific agents with dosage adjustments
• Antilipidemic agents
• Selection of proper agents to avoid interactions.
  Avoid simvastatin (Zocor) and lovastatin
  (Lescol)
• Dosage adjustment when using rosuvastatin
  (Crestor) with lopinavir, do not exceed 10
  mg/day of rosuvastatin
• Antimycobacterial agents
• Major interactions to consider
• Management Issues

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Drug Interactions Continued

• Anticonvulsants
• Carbamazepine, Phenobarbital and Phentyoin
• Effect on serum concentrations of ARV
• Concomitant effects on anticonvulsant levels

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Drug Interactions

• Herbal Products
• St Johns Wort
• Kava Kava
• Other herbals that cause hepatotoxicity
• Other herbal products to consider

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Role of the Clinician in Drug Interaction
Detection and Prevention

• Question patients concerning
• Nonprescription Drug Usage
• Herbal and Natural Product Usage
• Use appropriate literature sources to obtain
  reliable and consistent information
• www.aidsinfo.nih.gov
• www.hivinsite.com
• www.hiv-druginteractions.org
• Prescribing information on web
• Communication among providers is key

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Summary

• Talk with patients to stress adherence to therapy
• Review all medications with patients
• Function in an interdisciplinary environment

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Thank you
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Mechanism of NRTI Associated Lactic Acidosis
Specifics

• During normal glycolysis, glucose is converted to
  pyruvate in the cytosol and is transferred into
  the mitochondria
• Once the pyruvate is in the mitochondria, most of
  it is converted into acetylcoenzyme A, which in
  turn enters the tricarboxylic acid cycle to form
  NADH (nicotinamide adenine dinucleotide)
• NADH is used by the mitochondria to produce ATP
  through oxidative phosphorylation DNA polymerase
  is inhibited in the presence of NRTIs which
  diminishes mitochondrial function (especially
  oxidative phosphorylation)

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Continued

• Pyruvate and NADH accumulate and the conversion
  of pyruvate to lactate is enhanced
• Impaired oxidation leads to decreased fatty acid
  oxidation resulting in accumulation of free fatty
  acids
• Free fatty acids are converted to triglycerides
  and accumulate in liver causing hepatic steatosis

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Facial Wasting
http//www.emedicine.com/derm/topic877.htmsection
pictures
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Adverse Effects

• Clinical Features of Peripheral Fat Loss
• Peripheral fat loss in face, limbs, buttocks
• Accumulation of fat centrally in abdomen and
  breast and over dorsocervical spine (buffalo
  hump)
• Dyslipidemia
• Elevation in triglyceride and cholesterol levels
• Can respond to antihyperlipidemics