Title: ARV Complications and Management
1ARV Complications and Management
- Michael Thompson PharmD, BCNSP
- Professor of Pharmacy Practice
- Florida AM University
- College of Pharmacy
2Disclosure 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.
3Todays 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
4Therapeutic 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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7Indications 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
8Initiation 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
9Goal 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
10Goal 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
11Tools to Achieve Goals
- Maximal adherence to prescribed regimens
- Rational sequencing of drugs
- Resistance testing
12Antiretroviral 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)
13Antiretroviral Drugs continued
- Nucleotide Reverse Transcriptase Inhibitor
- Tenofovir Disoproxil Fumurate (Viread)
- Nonnucleoside Reverse Transcriptase Inhibitors
(NNRTI) - Nevirapine (Viramune)
- Delavirdine (Rescriptor)
- Efavirenz (Sustiva)
14Antiretroviral Drugs continued
- Protease Inhibitors
- Indinavir (Crixivan)
- Ritonavir (Norvir)
- LopinavirRitonavir (Kaletra)
- Nelfinavir (Viracept)
- Saquinavir (Invirase or Fortovase)
- Amprenavir (Agenerase)
- Fosamprenavir (Lexiva)
- Atazanavir (Reyataz)
- Tipranavir (Aptivus)
15Treatment Options to Consider
- HIV Infection
- antiretroviral agents
- Opportunistic infections
- viral infection CMV
- protozoa toxoplasma
- Pneumocystis, candidiasis
- MAI infection
- others
16Pharmacotherapy 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
17Goal 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
18Selection 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
19Evaluation 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
20Problems Associated with Antiretrovirals
- Adverse Effects
- Drug Interactions
- Resistance
- Genotyping
- Phenotyping
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22Common 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
23Summary 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
24Mechanism of Development of Lactic Acidosis in
HAART
25Mechanism 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)
26continued
- 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
27Common 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)
28Lactic 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
29Adverse 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.
30Adverse 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
31Adverse 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
32Example of Buffalo Hump
33Adverse 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
34Other Adverse Effects
- Pancreatitis
- Bleeding in Hemophiliacs
- Skin Rash/Dermatologic Effects
- NRTIs (zidovudine and nails, rash)
- NNRTIs (eg nevirapine)
- Others see handout
35Understanding 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
36Interactions 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
37Drug 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)
38Nonnucleoside 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
39Protease 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
40Effects 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
41Food 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
42Food 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
43Effect 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.
44Effect 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
45Effect 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
46Examples 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
47Antiretroviral 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
48Drug 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
49Interactions Between HAART and Recreational/Other
Drugs
- Alcohol
- Marijuana
- Ecstasy
- Heroin
- Benzodiazepines
- Barbiturates
- Amphetamines
50Drug Interactions with Antiretrovirals
- Antifungal agents
- Antilipidemic agents
- Antimycobacterial agents
- Anticonvulsants
- Herbal Products
- St Johns Wort
- Kava Kava
- Other herbals that cause hepatotoxicity
51Therapeutic 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
52Summary
- 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