Antiretroviral Therapy: Pharmacology

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Antiretroviral Therapy Pharmacology

• Cristina Gruta, PharmD,Asst. Clinical Professor
  of Clinical Pharmacy and FCM

San Francisco AIDS Education and Training Center
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HIV Life Cycle
Step 1 Fusion
Step 3 Integration
reverse transcriptase
HIV
Step 5 Packaging and Budding
Step 2 Transcription
Step 4 Cleavage
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Nucleoside Analogues (NAs) or NRTIs
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Nucleoside Analogues Food Constraints

• ddI (didanosine/Videx) only one that requires an
  empty stomach, i.e. at least one hour before or
  two hours after a meal
• For buffered tablets, need at least two tabs/dose
  for adequate buffering capacity
• Enteric-coated still requires empty stomach
• All other NRTIs can be taken with food best
  for GI tolerability

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Nucleotide Analogues

• Tenofovir (VireadTM), TFV
• Dose 300 mg once daily
• Take with food for optimal absorption

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Nucleoside/Nucleotide AnaloguesCommon Adverse
Effects

• AZT HAs, n/v, fatigue, bone marrow suppression
• ddI, ddC, d4T peripheral neuropathy,
  pancreatitis
• 3TC HAs, nausea (generally well-tolerated)

• Abacavir (ABC) n/v/d, perioral paresthesias,
  hypersensitivity rxn in 4-5 (FEVER, malaise,
  myalgia, arthralgia, GI sxs, rash) ? not advise
  re-challenge
• Tenofovir (TFV) Nausea, vomiting, flatulence
  (generally well-tolerated)

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Case

• 44 yo male recently diagnosed with HIV, VL75,000
  copies/mL, CD4230 /mm3. After several
  discussions of HAART therapy, side effects and
  adherence, AZT/3TC/ABC was started one week ago.
  Today he calls your clinic complaining of a rash.

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Abacavir hypersensitity

• Occurs in up to 5 of patients
• Most common symptoms
• Fever, rash, nausea, malaise/fatigue, GI symptoms
• Respiratory symptoms may occur
• Onset usually first two weeks of therapy
• Symptoms worsen with each dose
• Can be fatal if continued or restarted
• NEVER re-challenge
• Patient counseling and follow-up mandatory

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HIV/HAART Toxicities Lactic Acidosis

• Rare but potentially fatal syndrome
• Linked to prolonged use of NRTIs
• Symptoms include lethargy, fatigue, abdominal
  pain, respiratory distress
• Etiology ?mitochondrial dysfunction, possibly
  due to inhibition of key mitochondrial
  replication enzyme by antiretroviral agents

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Lactic Acidosis- Potential Lab Findings

• Anion gap, ? lactate, ? AST/ALT, CPK, LDH,
  lipase, amylase, ? HCO3, liver bx steatosis,
  necrosis, and inflammation
• Venous lactate level gt 2.5 nmol/L (normal 0.5-2.5
  mmol/L) and normal pH
• Lactic acidosis arterial pHlt 7.35 mmol/L with
  venous lactate gt 2.0 plus HCO3 lt 20 mmol/L
• Mild 2.1-5.0 mmol/L
• Severe gt 5-10 mmol/L

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Lactic Acidosis Management

• Draw serum lactate levels if suspected
• If serum lactate gt2 and symptomatic, d/c
  antiretrovirals until Sx resolve and lactate
  levels normalize (may take months)
• Anecdotal reports of help from supplemental
  L-carnitine, riboflavin, coenzyme Q
• Consider NRTI-sparing regimen if resumption of
  HAART indicated

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NRTI Mitochondrial Toxicity

• MOA Inhibition of mitochondial DNA polymerase-?,
  ? oxidative metabolism, ? ATP generation
• Implicated in lactic acidosis with hepatic
  steatosis
• Other possible manifestations
• Myopathy (AZT)
• Neuropathy (d4T, ddI, ddC),
• Lipoatrophy (d4T)
• Pancreatitis (ddI)

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Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)
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NNRTIs Adverse Effects

• RASH!!
• ? LFTs
• EFV CNS effects (e.g. sedation, insomnia, vivid
  dreams, dizziness, confusion, feeling of
  disengagement)

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Nevirapine New Data

• September 2000 two instances of life-threatening
  HEPATOTOXICITY in health-care workers taking NVP
  for PEP reported to CDC
• One of the two HCWs required a liver
  transplantation for fulminant hepatic failure
• Serious adverse effects associated with
  NVP-containing PEP regimens reported in 22 cases
  (16 occupational expsures)

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ARV Complications-- Case

• 33 y.o. male with CD4 539 and viral load
  44,000. Pt is HCV with chronically elevated
  LFTs. Current LFTs AST588 ALT 860. ARV
  regimen is d4T/ 3TC/NVP.
• What should be done about ARV regimen in light of
  LFTs?

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Protease Inhibitors (PIs)
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Dual Protease Inhibitor Combinations

• Exploits the enzyme inhibition properties of
  PIs, specifically RTV
• Lessens pill burden
• Theoretical ability to suppress resistant HIV
  strains by enhancement of PI plasma levels

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Basic Pharmacology Principles
Cmax
Drug Level
Cmin
IC90
Area of Potential HIV Replication
IC50
Dosing Interval
Time
Dose
Dose
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Indinavir/Ritonavir Pharmacokinetics
10,000
IDV/RTV q12h 800/200 High-fat Meal
800/100 High-fat Meal 400/400 High-fat
Meal IDV q8h 800 mg Fasted
IndinavirPlasmaConcentration(nM)
1,000
100
0
2
4
6
8
10
12
Time Postdose (hours)
6th Conference on Retroviruses and Opportunistic
Infections 1999. Abstract 362.
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Dual Protease Inhibitor Combinations-- Dosing

• RTV 400 mg SQV 400 mg BID
• RTV 400 mg IDV 400 mg BID
• RTV 200 mg IDV 800 mg BID
• RTV 100-200 mg APV 600 mg BID
• Kaletra 3 pills BID
• Not as common.
• RTV 400 mg NFV 750 mg BID
• NFV 1250 BID SQV 1600 mg BID

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Protease Inhibitors Adverse Effects
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PI Class-Wide Effects

• Hepatotoxicities
• Lipodystrophy
• Lipid abnormalities (?T chol, ?triglycerides)
• Hyperglycemia, insulin resistance

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Hepatotoxicity

• RTV use linked to increased risk of severe
  hepatotoxicity (Sulkowski, JAMA 2000 28374)
• Increased LFTs observed with all PIs
• More common in pts with chronic viral hepatitis
  (HBV, HCV)
• Data do not support witholding PIs from pts
  co-infected with HBV or HCV

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ARV Complications-- Case

• 34 y.o. female with CD4 545 (nadir 150) with
  undetectable VL presents as a new pt with ARV
  regimen of d4T/3TC/SQV/RTV and c/o intermittent
  loose stools, abdominal cramping negative stool
  w/u.
• Primary MD denotes prominent central obesity,
  enlarged breasts, and peripheral wasting.
• Total cholesterol 250-300 triglycerides 1230

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HAART Toxicities Lipodystrophy

• Body habitus changes
• central fat accumulation
• peripheral fat wasting
• Risk factors
• female gender (maybe get it worse)
• older age
• HAART
• Protease Inhibitor use

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Dorsocervical fat pad (buffalo hump) in
HAART-treated patient
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Dorsocervical fat pad and gynecomastia in patient
on HAART
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Peripheral Lipoatrophy
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Facial Lipoatrophy
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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 Treatment Options

• Switching Protease Inhibitors out of HAART
  regimen inconsistent results
• Metformin?
• Thiazolidinediones?
• Growth hormone?

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HIV/HAART Toxicities Lipid Abnormalities

• Hypertriglyceridemia risk of pancreatitis
• Low HDL, high LDL
• Increased CAD not yet documented
• Generally treated w/ fibrates and/or statins
• Inconsistent results from switch studies
• Beware of drug interactions, risk of myositis

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HIV/HAART Toxicities Insulin Resistance

• Progression to frank diabetes mellitus possible
• Monitor with fasting glucose values
• Improvement often seen with switching out of
  PI-based regimens
• Some success w/ metformin (Glucophage)

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Case

• T.C. is a24 y.o. male diagnosed with HIV
  infection 2 years ago. Back then, CD4 count
  565, viral load 13,500. Pt chose to defer
  therapy.
• Pt was lost to follow-up until 6 months ago. CD4
  count 349 and viral load 60,000. He admits to
  not always practicing safe sex.
• He seeks your advice about antiretrovirals how
  would you counsel him?

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Considerations in Initiating Therapy HIV
Asymptomatic

• Theoretical benefit
• No proven long-term clinical benefit for CD4 gt200
  cells/ml3
• Expert opinion advises initiation of therapy for
  CD4 lt350 cells/ml3 at any viral load
• Consider the viral load when gt 350 cells/ml3 CD4
  T cell
• The downside of antiretroviral regimens
• ? QOL
• Short- and long-term toxicities

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Considerations in Initiating Therapy HIV
Asymptomatic

• Willingness of patient to begin and the
  likelihood of adherence
• Degree of immunodeficiency
• Plasma HIV RNA
• Risk of disease progression
• Potential risks and benefits

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Prognosis without HAART
Viral load gt60,000 20 - 60,000 6 - 20,000 1 -
5,000 lt1000
3-year probability of AIDS in 1604 men enrolled
in the Multicenter AIDS Cohort Study (MACS)
1984-1985 from Mellors Ann Int Med 1997
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Goals of Therapy Tools to Achieve Goals

• Goals
• Maximal and durable suppression of viral load
• Restoration and/or preservation of immunologic
  function
• Improvement of quality of life
• Reduction of HIV-related morbidity and mortality

• Tools
• Maximize adherence
• Rational sequencing of therapy
• Preservation of future treatment options
• Use of resistance testing in selected clinical
  settings

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ARV Therapy in the Chronically HIV Infected
Patient

• CLINICAL CATEGORY
• Symptomatic
• (AIDS, severe symptoms)
• Any CD4 T cell
• Any Plasma HIV RNA
• Asymptomatic,
• AIDS CD4T cells
• Asymptomatic
• Asymptomatic
• Asymptomatic

CD4 Count Any lt200/mm3 gt200/mm3 but
lt350/mm3 gt350 gt350
Plasma HIV RNA Any Any Any gt55,000
(RT-PCR or bDNA)) lt55,000 (RT-PCR or bDNA)
RECOMMENDATION Treat Treat Offer treatment
but controversy exists Clinical experts differ
in their recommendations many experts would
treat Many experts defer therapy and observe
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Indications for ART in the Chronically
HIV-Infected Patient

• TREAT ALL
• (regardless of viral load)
• Symptomatic (AIDS, severe symptoms)
• Asymptomatic, CD4 lt200 cells/mm3
• Asymptomatic, CD4 gt200/mm3 but lt350 cells/ mm3
  
• Treatment should generally be offered, though
  controversy exists

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Indications for ART in the Chronically
HIV-Infected Patient

• TREAT
• Asymptomatic,
• CD4 gt350/mm3 and
• HIV RNAgt55,000(RT-PCR or bDNA)
• Some experts would recommend initiating
  therapy, recognizing that the 3 year risk of
  developing AIDS in untreated patients is gt30.
  In the absence of very high levels of plasma HIV
  RNA, some would defer therapy and monitor the
  CD4 and level of plasma HIV RNA more frequently.
  Clinical outcomes data after initiating therapy
  are lacking.

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Indications for ART in the Chronically
HIV-Infected Patient

• DEFER TREATMENT
• Asymptomatic
• CD4 cells gt 350/mm3
• HIV RNA lt55,000(RT-PCR or bDNA)
• Many experts would defer therapy and observe,
  recognizing that the 3 year risk of developing
  AIDS in untreated patients is lt15.

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Initial TreatmentStrongly Recommended
One Choice Each From Column A and B

• Column B
• Didanosine Lamivudine
• Stavudine Lamivudine
• Stavudine Didanosine
• Zidovudine Lamivudine
• Zidovudine Didanosine

• Column A
• Efavirenz
• Indinavir
• Nelfinavir
• Ritonavir Saquinavir (SGC or HGC)
• Ritonavir Lopinavir
• Ritonavir Indinavir

Saquinavir-SGC, soft-gel capsule (Fortovase)
Saquinavir-HGC, hard-gel capsule (Invirase)
Co-formulated as Kaletra Based largely on
expert opinion
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Initial TreatmentAlternative Recommendation
One Choice Each From Column A and B

• Column B
• Zidovudine Zalcitabine

• Column A
• Abacavir
• Amprenavir
• Delavirdine
• Nelfinavir Saquinavir-SGC
• Nevirapine
• Ritonavir
• Saquinavir-SGC

• CONTRAINDICATED
• ART monotherapy
• Zidovudine and Stavudine
• exception for prevention of perinatal
  transmission (see ACOG guidelines)

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The Advantage of Sequencing Drugs

• To extend the overall long-term effectiveness of
  the available therapy options
• Delay the risk of certain side effects uniquely
  associated with a single class of drugs
• Anticipates up to 50 of failure rate and
  preserves future treatment options

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Case

• T.C. is a24 y.o. male diagnosed with HIV
  infection 2 years ago. Back then, CD4 count
  565, viral load 13,500. Pt chose to defer
  therapy.
• Pt was lost to follow-up until 6 months ago. CD4
  count 349 and viral load 60,000. He admits to
  not always practicing safe sex.
• He seeks your advice about antiretrovirals how
  would you counsel him?