Transcript Clinical Pharmacology of Antiretroviral Therapy

Changing Anti-Retroviral
Therapy
HIV Care and ART: A Course for
Pharmacists
Introductory Case: Mikael
 Mikael is a 28 year-old male diagnosed with AIDS
who has been taking his triple drug ART regularly for
the past 6 months without difficulties. He began
therapy one year ago, during a bout of PCP
pneumonia and oral thrush
 CD4/TLC and VL monitoring is not available in his
region
 Today Mikael is diagnosed with toxoplasmosis and is
hospitalized for treatment with Fansidar
2
Introductory Case: Mikael (cont.)

Which of the following statements about changing
therapy are true?
1. ART should not be changed because this patient is not
experiencing side effects from his regimen
2. A change in ART should be done for a patient who
experiences a new opportunistic infection on ART
3. ART should be changed as soon as a patient starts to
miss doses to avoid treatment failure
4. ART should only be changed when a patient experiences
virologic failure
3
Unit Learning Objectives
 Identify reasons for changing ART
 List factors in ART failure
 Determine how to change ART due to toxicity,
treatment failure or concomitant disease
 Describe factors to consider when changing ART
 Describe appropriate laboratory monitoring
procedures for ART
4
Factors to Consider When
Changing Regimen





Ethiopia ARV guidelines
Prior antiretroviral history
Antiretroviral resistance
Side effects
Number of drugs needing
replacement
 Barriers to adherence
 Patient life-style and
preferences
 Ability to follow-up in clinic
 Drug interactions
 Cost and sustainability
5
Reasons for Changing ART
 ART is not changed unless absolutely necessary!
 ART may be changed because of:
 Treatment Failure
• Clinical failure
• Immunologic failure
• Virologic failure
 Toxicity or intolerance
 Co-morbid conditions
 Non-adherence/compromised quality of life
6
Treatment Failure
 Treatment failure is defined by
 Clinical failure
• New or recurrent OI
• Onset or recurrent WHO Stage III condition
Note: Should not be confused with immune reconstitution inflammatory
syndrome
 Immunologic failure
• Fall of CD4 count by >50% from the peak
• Return of the CD4 count to baseline or below
7
Introductory Case: Mikael (cont.)
1. ART should not be changed because this patient is
not experiencing side effects from his regimen
FALSE
 Where CD4 counts and viral load tests are unavailable,
the WHO recommends using clinical evaluation to define
treatment failure
 This patient is experiencing clinical failure defined as the
development of a new opportunistic infection (in this case
toxoplasmosis) while on ART
8
Introductory Case: Mikael (cont.)
2. A change in ART should be done for a patient who
experiences a new opportunistic infection on ART
TRUE
Where CD4 counts and viral load tests are
unavailable, the WHO recommends using clinical
evaluation to define treatment failure
9
Treatment Failure (2)
 Virologic failure:
 Failure to suppress viral load to undetectable
 Reappearance of detectable virus after a period of
undetectability (loss of virologic control)
 Less than one log (10-fold) decrease in viral load from
baseline after 8-12 weeks of ART
10
Antiretroviral Therapy: Failure to Suppress
100000
Medications Started
HIV RNA
10000
1000
100
50
10
50
TIME
Courtesy of David H. Spach, MD; NW AETC, University of Washington
11
Antiretroviral Therapy: Viral Failure
100000
Medications
Started
HIV RNA
10000
1000
100
10
50
TIME
50
12
Courtesy of David H. Spach, MD; NW AETC, University of Washington
Reasons Treatment May Fail
Treatment fails if:
 Drugs are not strong enough to control the virus
 Patient is too sick (clinical failure) or has serious infections
which are not treatable
 Patient has poor adherence
• Missing more than three doses/month increases risk of
treatment failure
• Missing additional doses causes drug levels to fall, making HIV
resistant
13
Treatment Failure and IRIS
 Must differentiate treatment failure from
Immune Reconstitution Inflammatory
Syndrome (IRIS)
 Clinical manifestation of a sub-clinical infection
present at baseline. Brought on by ART-induced
reconstitution of the immune system
 Typically seen within several weeks of initiating
ART
14
Introductory Case: Mikael (cont.)
3. ART should be changed as soon as a patient starts
to miss doses to avoid treatment failure
FALSE
 If it is determined that a patient is missing doses, it is best
to try to determine the cause and to identify a solution to
assist the patient with adherence
 Changing ART should only be done when absolutely
necessary
15
Reasons Treatment May Fail (2)
 Other medicines may stop ART from working
 Reduce levels of ARVs in the blood
• e.g. TB drug rifampicin is a potent liver enzyme inducer
 Important:
 Patients must be warned that herbal medicines could
reduce ARV drug levels
 Traditional healers must be told that their medicines could
reduce ARV drug levels
16
Reasons Treatment May Fail (3)
 Patient cannot tolerate the available drugs
 Liver damage, nerve damage and anemia are possible
serious side effects
 Diarrhea, nausea and vomiting caused by the drugs may
sometimes be too much to bear
 Treatment may have to be stopped if these side effects
become serious and replacement drugs are not available
17
Introductory Case: Mikael (cont.)
4. ART should only be changed when a patient experiences
virologic failure
FALSE


Virologic failure is only one possible reason that a change in therapy
may be necessary
Other reasons to change therapy include:
• Intolerable toxicities or side effects
• Treatment failure (clinical failure or immunologic failure)
• Co-morbidities
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Causes of ART Failure: Summary
Pre-existing Resistance
Poor Absorption
Limited Potency of Regimen
Rapid Elimination
Drug-Drug Interactions
Imperfect Adherence
Persistent Viral Replication
Drug Failure
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Toxicity
 About 50% of patients treated for three years with
good viral suppression will require a change in
therapy due to an adverse reaction to antiretroviral
drugs
 Intolerable side effects
 Organ Dysfunction
 Interventions:
 If the offending drug can be identified, replace just that drug
 If the offending drug cannot be identified, replace entire
regimen
20
Clinical Indications to Change ART
Due to Toxicity
Symptom
Clinical Indication
Nausea
Severe discomfort or minimal intake for > 3 days
Vomiting
Severe vomiting of all foods/fluids in 24 hrs, orthostatic
hypotension or need of IV fluids
Diarrhea
Bloody diarrhea, orthostatic hypotension or need of IV fluids
Fever
Headache
Allergic
Reaction
Unexplained fever of > 39.6 C
Severe or requires narcotics
Generalized urticaria, angioedema or anaphylaxis
Peripheral Severe discomfort, objective weakness, loss of 2-3
Neuropathy previously present reflexes or sensory dermatomes
Fatigue
Normal activity reduced > 50%
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Lab Indications to Change ART Due to Toxicity
Parameter
Grade 3 Toxicity
< 750/mm3
M: 13.8 – 17.2 g/dL
F: 12 – 15.6 g/dL
1500 to 7000/mm3
Platelet count
< 49 x 103/µL
130-400 x 103/µL
Total Bilirubin
> 3-7.5 x ULN*=
3.9-9.75mg/dL
≤ 1.3 mg/dL
SCr
> 1.7-2.0 (adult)
≤ 1.2 mg/dL
Hemoglobin (Hgb) < 7.0 g/dL
Hematology
ANC
Chemistries
AST / ALT
LFTs
Pancreatic
Enzymes
Normal Reference Values
5-10 x ULN* =
≤ 42 U/L , ≤ 48U/L
210-420 U/L, 240480 U/L
Amylase, Lipase
> 2-3 x ULN*
23-85 U/L, 0-160 U/L
Triglyceride (TG)
8.49- 13.56
mmol/L
< 200 mg/dL
1.6-2.0 X ULN
< 200 mg/dL
Lipids
Cholesterol
* ULN = Upper Limit of Normal
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Toxicity: Changing One Drug
 Regimen: d4T/3TC/NVP
 d4T-related neuropathy or pancreatitis: Switch d4T to ZDV
 NVP-related rash or hepatotoxicity:
• Switch NVP to EFZ (except pregnancy)
• Switch NVP to PI’s (in cases of pregnancy or severe adverse
effect)
 Regimen: d4T/3TC/EFV
 EFZ-related persistent CNS toxicity: Switch EFZ to NVP
 Regimen: ZDV/3TC/EFV
 ZDV-related anemia or neutropenia: Switch ZDV to d4T
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Co-morbidities
 A change in clinical status of patients may mandate
change in ART
 Pregnancy:
• If on EFV based regimen – change EFV to NVP
 Occurrence of active TB:
• If on NVP based regimen – change to EFV (with adjusted
dose), to LPV/r, or SQV/r
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Minimizing Viral Resistance
 Never prescribe ARVs in the absence of adherence
counseling and support
 Work with patients and their families to minimize
barriers to medication adherence
 Never prescribe ARV monotherapy or dual therapy
 If ARV medications are to be discontinued, stop all
drugs at the same time
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Minimizing Viral Resistance (2)
 Do not prescribe ZDV (zidovudine) and d4T
(stavudine) together (antagonistic)
 Pay meticulous attention to other medications and
treatments and their potential to interact with ARV
therapies
 Never add a single drug (alone) to a failing regimen
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Improving Adherence and Enhancing QOL
 Reduce pill burden
 Changing to fixed dose combinations
 Replace PIs with NNRTI’s or abacavir
 Minimize food/water restrictions
 Revisit co-morbid conditions that might be interfering,
e.g. mental health; substance abuse
 Inquire about side effects that may have contributed to
poor adherence
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Changing Regimen
 When changing regimen due to treatment failure:
 Evaluate for resistance through resistance testing or
empiric decision-making based on clinical history
 Change to an entirely new regimen, with at least one drug
from a new class
 Anticipate some cross-resistance (e.g. ZDV and d4T)
 Try to determine and correct reasons for failure of the first
regimen (e.g. adherence issues)
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Alternative Regimen
First Line Regimen
2nd Line Regimen for Tx Failure
D4T or ZDV
+
3TC
+
NVP or EFV
ABC or TDF or ZDV (if not taken)
+
DDI
+
LPV/r or SQV/r OR NFV or IDV/r
Source: Guideline for Use of Antiretroviral Drugs in Ethiopia. MOH, January 2005. p. 16
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Changing Regimen (2)
 Second-line therapy for patients with drug failure on
d4T/3TC/nevirapine or efavirenz:
• ZDV + DDI + IDV/r or
• TDF +DDI + LPV/r
 Second-line therapy for patients with drug failure on
ZDV/3TC/nevirapine or efavirenz:
• TDF + DDI + IDV/r or
• TDF +DDI + LPV/r
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Monitoring Therapy
First-Line Regimen: Laboratory Monitoring
 Baseline: ALT and CD4 or TLC
 Additional lab monitoring varies with regimen
 NVP: ALT/AST at 2, 4, 6, 8 weeks, 3 months, then q 6
months and symptom directed
 EFV: symptom directed thereafter for ALT, pregnancy test
at baseline for women of childbearing age
 ZDV: CBC/diff at baseline, 2, 4, 8 and 12 wks, then q 3-6
months and symptom directed
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Laboratory Monitoring Guideline
Regimen
ART
Lab Test
1
D4T/3TC/NVP
ALT
Other
Frequency
TLC or CD4
Baseline, 2, 4, & 8 wks, then q 6 months & symptom
directed for toxicity
Baseline & q 6 months
D4T/3TC/EFV
ALT
TLC or CD4
Symptom directed
Baseline & q 3-6 months
ZDV/3TC/EFV
ALT
TLC or CD4
CBC + diff/
Hgb/Pltc
Symptom directed
Baseline & q 3-6 months
Baseline, 4, and 12 wks, & thereafter symptom directed
ZDV/3TC/NVP
ALT
TLC or CD4
CBC + diff/
Hgb/Pltc
Refer to slide at end of handbook.
Baseline, 2, 4, & 8 wks, then q 6 months then q 6 months &
symptom directed for toxicity
Baseline & q 3-6 months
Baseline, 4, and 12 wks, & thereafter symptom directed
Source: Guideline for Use of Antiretroviral Drugs in Ethiopia. MOH, January 2005.
Second-Line Regimen:
Laboratory Monitoring
 Baseline: CBC/diff, ALT, SCr and CD4 or TLC
 Other lab monitoring varies with regimen
 ZDV: CBC/diff at baseline, 2, 4, 8, 12 wks, then q 3-6
months and symptom directed
 DDI: amylase at baseline and symptoms of abdominal
pain, CBC with diff and LFTs q 12 months
 TDF: urine protein dipstick and SCr at baseline, 3 months
and q 6 months, CBC/diff and AST/ALT q 12 months
 PIs: lipids at baseline and q 12 months, AST/ALT at
baseline, 3 months then q 6 months, fasting glucose at
baseline, then q 12 months
 Indinavir: urine dipstick for RBCs with symptoms of flank
pain, SCr at baseline then q 6 months
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Case Studies
Case 1
Case Study: Kasahun
 Kasahun is a 25 year-old male (CD4 count 56) who
presents to clinic for follow-up 2 weeks after starting
ZDV, 3TC and NVP. He learned his HIV status two
months ago, during a hospitalization with CNS
toxoplasmosis. He is currently receiving treatment
for toxoplasmosis and has tolerated his medication
over the past two months
 At diagnosis he had significant lower leg numbness
and weakness due to INH therapy for TB
 Pyridoxine 40 mg was started to replace his B-complex
vitamin. Why would this be necessary?
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Case Study: Kasahun (2)
 He had some nausea the first week on meds, which
he has resolved by eating small meals before doses.
He claims to take his medications every day as
directed. He has lost weight and is now 51 kg
 Today he presents complaining of a mildly itchy red
rash over his trunk and arms which began 2 days
ago. He says he feels tired all day. He proudly states
that he has taken his NVP twice daily since his first
day on medications
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Case Study: Kasahun (3)
1.
2.
3.
4.
What do you think is occurring with Kasahun?
Should his ART regimen be changed?
What additional information would you like to know?
What are the laboratory tests that should be done at
today’s visit to monitor Kasahun’s therapy?
39
Case Study: Kasahun Follow-up (4)
 Laboratory Values
 WBC: 5.6
H/H: 6.9 / 27
LFTs: 31 / 26
 How would you interpret these lab results?
 He has had only minor headaches over the past 3
weeks. What does this tell us?
 He does not have any other areas of the rash, oral
blisters, myalgias or fever. What should you do?
 Did he take NVP QD x 2 weeks, then increase to
BID?
40
Case Study: Kasahun (5)

He has not been having trouble remembering
doses
 He has been taking doses with meals (breakfast and
dinner)


Peripheral neuropathy symptoms have improved
However, he has been missing work due to fatigue
41
Case Study: Kasahun (6)
1. How would you interpret his results?
2. Would you change his ART?
3. How would you counsel Kasahun?
42
Case Study: Kasahun (7)
 Follow up at 3 months shows:





CD4 count = 110 (10%) cell/mm3
Hemoglobin/Hematocrat = 13 / 38%
WBC = 5.8
55 kg
He is tolerating medications except for occasional
numbness in lower extremities. His symptoms have
somewhat improved over last 3 months. Occasional
nausea after taking meds
 Claims he is taking all his medications. He takes his
morning dose at work during his break and takes his
evening dose with dinner
43
Case Study: Kasahun (8)
 Therapeutic goals are being met




Patient energy increased and he’s feeling better
Appetite is good and he has gained 4 Kg
CD4 increasing (was 56/5% 2 months ago)
H/H normalized
 However, he reports side effects:
 If possible, decrease dose of stavudine to 30mg BID for
neuropathy
 Encourage food before doses
44
Case 2
Case Study: Yared
 Yared is a 30 year-old man who has been stable on
stavudine, lamivudine and nevirapine for the past
four years
 History: PCP pneumonia 4 years ago
 Today his CD4 cell count is 140 cells/mm3, his
previous CD4 count was 300 and his viral load has
risen from undetectable levels to 50,000 copies/ml
 He feels well and has no complaints today
46
Case Study: Yared (2)
1.
2.
3.
4.
What do you think is happening to Yared?
What additional information would you like to know?
Does he require a change in his regimen?
What possible regimen can you give to Yared,
based on your local situation?
47
Case Study: Yared Follow-up (3)
 Yared had been taking his medication as prescribed
but missed doses recently while he was visiting his
brother in Jimma
 What are the factors to consider before starting a
new regimen?
48
Case Study: Yared (4)
 Side effects
 Educate Yared on the potential side effects of each
potential regimen
 Patient preference
 Yared is very fearful of the ABC hypersensitivity syndrome
and would prefer to avoid ABC in his next regimen
 Review drug-drug interactions
 Cost and sustainability
 Barriers to adherence
 Plan ahead for changes in schedule, vacations, etc
49
Case Study: Yared (5)
 He will begin TDF 300 mg qd +DDI 250 mg qd
+LPV/r 3 caps bid
 How will you monitor his therapy?
 Clinical
 Laboratory
 Does he have to take his DDI apart from LPV/r
and/or tenofovir?
50
Key Points
 Treatment failure occurs because of
preexisting resistance, limited regimen
potency, imperfect adherence, poor
absorption, rapid elimination, or drug-drug
interactions
 Therapy should not be changed unless
absolutely necessary
 The main reasons for changing ART are
treatment failure and drug toxicity
51
Key Points (2)
 Other reasons for changing ART include
problems with adherence or other medical
conditions or illnesses
 Ongoing laboratory monitoring is necessary to
detect all side effects and to monitor
success/failure of therapy
52