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ARV Complications and Management

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Accumulation of fat centrally in abdomen and breast and over dorsocervical spine (buffalo hump) ... Proton Pump Inhibitors, H2 antagonists and Antacids ... – PowerPoint PPT presentation

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Title: ARV Complications and Management


1
ARV Complications and Management
  • Michael Thompson PharmD, BCNSP
  • Professor of Pharmacy Practice
  • Florida AM University
  • College of Pharmacy

2
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.
3
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

4
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?

5
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6
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7
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

8
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

9
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

10
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

11
Tools to Achieve Goals
  • Maximal adherence to prescribed regimens
  • Rational sequencing of drugs
  • Resistance testing

12
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)

13
Antiretroviral Drugs continued
  • Nucleotide Reverse Transcriptase Inhibitor
  • Tenofovir Disoproxil Fumurate (Viread)
  • Nonnucleoside Reverse Transcriptase Inhibitors
    (NNRTI)
  • Nevirapine (Viramune)
  • Delavirdine (Rescriptor)
  • Efavirenz (Sustiva)

14
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)

15
Treatment Options to Consider
  • HIV Infection
  • antiretroviral agents
  • Opportunistic infections
  • viral infection CMV
  • protozoa toxoplasma
  • Pneumocystis, candidiasis
  • MAI infection
  • others

16
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

17
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

18
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

19
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

20
Problems Associated with Antiretrovirals
  • Adverse Effects
  • Drug Interactions
  • Resistance
  • Genotyping
  • Phenotyping

21
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22
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

23
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

24
Mechanism of Development of Lactic Acidosis in
HAART
25
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)

26
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

27
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)

28
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

29
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.

30
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

31
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

32
Example of Buffalo Hump
33
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

34
Other Adverse Effects
  • Pancreatitis
  • Bleeding in Hemophiliacs
  • Skin Rash/Dermatologic Effects
  • NRTIs (zidovudine and nails, rash)
  • NNRTIs (eg nevirapine)
  • Others see handout

35
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

36
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

37
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)

38
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

39
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

40
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

41
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

42
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

43
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.

44
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
45
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

46
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

47
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

48
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

49
Interactions Between HAART and Recreational/Other
Drugs
  • Alcohol
  • Marijuana
  • Ecstasy
  • Heroin
  • Benzodiazepines
  • Barbiturates
  • Amphetamines

50
Drug Interactions with Antiretrovirals
  • Antifungal agents
  • Antilipidemic agents
  • Antimycobacterial agents
  • Anticonvulsants
  • Herbal Products
  • St Johns Wort
  • Kava Kava
  • Other herbals that cause hepatotoxicity

51
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

52
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
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