ARV Complications and Management

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ARV Complications and Management

• Michael Thompson PharmD, BCNSP
• Professor of Pharmacy Practice
• Florida AM University
• College of Pharmacy

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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 are no conflicts of interest
represented in the presentation.
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Todays Lecture Objectives

• To discuss the current therapeutic approach to
  the management of HIV infection
• To identify and discuss key monitoring parameters
  to insure therapeutic success
• To discuss key adverse effects and drug
  interactions associated with antiretroviral use

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Therapeutic Management and MonitoringWhere are
We??

• Do we really understand how to treat HIV-infected
  patients?
• Do we really understand the role of the
  healthcare provider in proper management?

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Indications for Initiating Therapy

• AIDS Defining illness
• CD4treat any value
• HIVRNAtreat any value
• Asymptomatic
• CD4 lt 200
• HIVRNA-any value
• Treat
• Asymptomatic
• CD4gt200 but lt 350 and HIV RNA any value
  treatment should be offered

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Initiation of therapy..continued

• Asymptomatic
• CD4 gt350 and HIVRNA gt 100,000 most clinicians
  recommend deferring therapy but some clinicians
  will treat
• CD4gt350 and HIVRNA lt100,000 defer treatment

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Goal of Antiretroviral Therapy

• To achieve maximum and durable suppression of HIV
  replication
• Interpreted to mean an HIV RNA level in plasma
  that is less than the lower limit of quantization
  (i.e. undetectable)
• Increase in CD4 lymphocytes
• Improved quality of life
• Decreased morbidity and mortality

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Goal of Therapy continued

• Decreasing viral load below level of sensitivity
  depends upon assay procedure
• RTPCR (Amplicor)---lt 50 copies/ml
• Versant----lt 75 copies/ml
• Nuclisens---lt 80 copies/ml
• Should be achieved within 16-24 weeks should see
  a 1log10 reduction within 8 weeks
• Increase in CD4
• Adequate suppression is an increase by 100-150
  cells/mm3 per year

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Tools to Achieve Goals

• Maximal adherence to prescribed regimens
• Rational sequencing of drugs
• Resistance testing

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Antiretroviral Drugs

• Nucleoside Reverse Transcriptase Inhibitors NRTI
• Zidovudine (AZT,ZDV)-Retrovir
• Stavudine (d4T)-Zerit
• Lamivudine (3TC)-Epivir
• Zalcitabine (ddC)- HIVID
• Didanosine (ddI)-Videx
• Abacavir (ABC)-Viagen
• Emtricitabine (Emtriva)

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Antiretroviral Drugs continued

• Nucleotide Reverse Transcriptase Inhibitor
• Tenofovir Disoproxil Fumurate (Viread)
• Nonnucleoside Reverse Transcriptase Inhibitors
  (NNRTI)
• Nevirapine (Viramune)
• Delavirdine (Rescriptor)
• Efavirenz (Sustiva)

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Antiretroviral Drugs continued

• Protease Inhibitors
• Indinavir (Crixivan)
• Ritonavir (Norvir)
• LopinavirRitonavir (Kaletra)
• Nelfinavir (Viracept)
• Saquinavir (Invirase or Fortovase)
• Amprenavir (Agenerase)
• Fosamprenavir (Lexiva)
• Atazanavir (Reyataz)
• Tipranavir (Aptivus)

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Treatment Options to Consider

• HIV Infection
• antiretroviral agents
• Opportunistic infections
• viral infection CMV
• protozoa toxoplasma
• Pneumocystis, candidiasis
• MAI infection
• others

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Pharmacotherapy of HIV Infection

• Highly reactive antiretroviral therapy (HAART)
  consists of 2 reverse transcriptase inhibitors
  and one protease inhibitor to initiate therapy
• Experts consider HAART as one of several factors
  that lead to 47 decline in US mortality in 1997
• In 1997, fell from 8 to 14 cause of death in US

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Goal of Antiretroviral Therapy

• To achieve maximum and durable suppression of HIV
  replication
• Interpreted to mean an HIV RNA level in plasma
  that is less than the lower limit of quantitation
  (i.e. undetectable)
• Increase in CD4 lymphocytes
• Improved quality of life
• Decreased morbidity and mortality

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Selection of HAART Regimens

• Three basic categories now
• NNRTI category
• Protease Inhibitor Category
• Triple NRTI category
• Advantage Takes class sparing into account
• Know what agent combinations are not recommended

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Evaluation of Therapeutic Outcomes

• Following the initiation of therapy, patients are
  usually monitored at 3 month intervals with
  immunologic (CD4 count), viral load and clinical
  assessments
• Change therapy if toxicity develops OR if
  treatment failure occurs

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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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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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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
  oxidatiave 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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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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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

• 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
• 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
• 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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Example of Buffalo Hump
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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

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Other Adverse Effects

• Pancreatitis
• Bleeding in Hemophiliacs
• Skin Rash/Dermatologic Effects
• NRTIs (zidovudine and nails, rash)
• NNRTIs (eg nevirapine)
• Others see handout

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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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Drug Interactions HAART

• Nucleoside and Nucleotide drugs not eliminated
  via cytP450 therefore these interactions are
  minimal
• Drug interactions here may occur via other
  mechanisms (eg GI absorption, renal elimination)

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Nonnucleoside 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

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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
• Note Fusion inhibitors 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
• 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
• Boosting not recommended Do not use

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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 increase
• 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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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
• Antilipidemic agents
• Antimycobacterial agents
• Anticonvulsants
• Herbal Products
• St Johns Wort
• Kava Kava
• Other herbals that cause hepatotoxicity

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Therapeutic Issues Affecting HAART

• Adherence Issues
• HIV Resistance
• Tipranivir and Enfurtivide (Fuzeon) shows promise
  against PI resistant strains
• Community Education
• Lack of Understanding Among Health Professionals
• Not understanding the role of triple therapy
• Not understanding drug interaction potential
• Not understanding where to refer people who
  cannot afford therapy

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Summary

• Understand the role of the pharmacist in
  providing care to HIV infected patients
• Understand the role of triple therapy
• Be conscious of potential adverse effects through
  simple patient complaints
• Be sensitive to potential drug-drug interactions
• Serve as a source of information concerning
  prevention and treatment for the community