Transcript Toxicity

Clinical Pharmacology of
Antiretroviral Therapy
HIV Care and ART: A Course for Physicians
Learning Objectives
• Understand the mechanism of action for
the different antiretroviral classes.
• List the common ARV doses and reasons
for dose modifications.
• List the common side effects of ARVs and
identify how to help patients cope with
these side effects.
• Recognize the types and mechanisms of
drug interactions between ARVs and other2
Learning Objectives (2)
• Discuss pharmacokinetic drug
enhancement and protease inhibitor
combinations
• Describe how incomplete viral suppression
can lead to resistant strains of HIV
• Describe strategies for avoiding
development of resistance
3
Goals of HAART
• Viral: reduce viral load to < 50 c/ml at 6
mos
• Immune: Increase CD4 to 100-150/yr
• Prevent HIV-related complications:
– Expected at >= 3 months
– Source of confusion: Immune
Reconstitution Inflammatory Syndrome
4
Principles of Therapy
1. Want 3 active drugs / 2 classes
– “Triple Therapy”
– 2NRTIs + 3rd drug : PI, PI/r, NNRTI
2. Failure of Therapy
– Transmitted resistance
– Failure of drug to reach target
3. Change in Therapy: 60-70%
– Treatment failure
– Drug intolerance / toxicity
4. Critical Issues: Adherence & resistance
5
Classes of Antiretrovirals
• NRTIs
– Nucleoside reverse transcriptase inhibitors
– Nucleotide reverse transcriptase inhibitors
(NtRTI)
• NNRTIs – non-nucleoside reverse
transcriptase inhibitors
• PIs – protease inhibitors
• Entry Inhibitors (not generally available)
– Fusion inhibitors
– CCR5 attachment inhibitors (in
development)
6
HIV life cycle
Fusion-Inhibitors
7
Nucleoside Reverse
Transcriptase Inhibitors (NRTIs)
RNA
DNA
Nucleus
Host
Cell
8
Types of NRTIs
•
•
•
•
•
•
•
•
Zidovudine (AZT)
Stavudine (d4T)
Lamivudine (3TC)
Didanosine (ddI)
Abacavir (ABC)
Zalcitabine (ddC)
Emtricitabine (FTC)
Tenofovir (TDF)-Nucleotide RTI
9
Zidovudine (AZT, ZDV) *
• Dosing: 300mg BID
• Food Interactions
– None – with or without food is ok
– Food decreases AZT-related
nausea
• Resistance: TAMS (d4T also)
10
Zidovudine Toxicity *
• Nausea
• Bone Marrow
Suppression
– Anemia
– Neutropenia
• Headaches
•
•
•
•
Myalgias
Myopathy
Insomnia
Pigmentation of
nail beds
• Lactic acidosis,
fatty Liver
11
AZT-associated marrow suppression
• Correlates with: Marrow reserve, dose,
duration, and stage of disease
• Anemia: After 4-6 weeks
• Neutropenia: After 12-24 weeks
• Marrow: Normal or ↓ RBC precursors
• Rx: stop AZT
• Hemoglobin usually recovers in 1-2 weeks
12
ZDV-Related Fingernail
Discoloration
13
Lamivudine (3TC) *
•
•
•
•
Dosing: 150mg BID or 300mg QD
Food Interactions: no food interactions
Toxicity : very rare
Part of all first line regimens
• Also indicated for Hep B, dose=100300mg qd; but high rate of HBV
resistance
14
Lamivudine: Key Issues
• Tolerance: best tolerated ART agent, once
daily, no food effect
• Resistance: 184V mutation as early as 3
weeks and reduces activity vs. HIV 1000x
BUT continues to show antiretroviral activity
and the 184V mutation promotes AZT and
d4T activity
• HBV: Active but high rate of HBV resistance
25% at 1 year
15
Emtricitabine (FTC)
• Dosing: 1 x 200mg capsule QD
• Food Interactions: no food interactions
• Toxicity
– Mild abdominal discomfort
– Occasional nausea
16
Emtricitabine (FTC)
• Activity: nearly the same as 3TC
FTC
3TC
Dose
200 mg /day
300 mg / day
Half life
39 hours
12 hours
HBV
Active
Active
Resistance
184V
184V
Toxicity
None
None
17
Hepatitis B Co-infection
•
Drugs active vs. HBV & HIV: 3TC, FTC, TDF
•
Rapid resistance: 3TC / FTC
•
Rx: HBV+ HIV
– TDF + (3TC or FTC)
•
Serious hepatic disease:
– 3TC Rx  3TC or FTC resistance
– “HBV flair” after stopping 3TC, FTC, TDF
– ART: Hepatoxocity (AZT, d4T, ddI, EFV, NVP,
All PIs)
– Immune reconstitution syndrome
18
Stavudine (d4T, Avostan®) *
• Dosing
– 40 mg BID for weight > 60 kg
– 30 mg BID for weight < 60 kg
• Food Interactions: None
• Toxicity
– Peripheral Neuropathy (5-15%, pain,
tingling, and numbness in extremities)
– Lactic acidosis, fatty liver *
– Pancreatitis *
– Lipoatrophy *
– Hypertriglyceridemia
19
Stavudine (d4T, Avostan®) *
• Resistance: TAMS (AZT also)
• Avoid AZT/d4T as they are antagonistic
• When used with ddI – must dose adjust
ddI
20
Facial Lipoatrophy
21
Abacavir (ABC)
• Dosing: 1 x 300mg tablet BID
• Food Interactions: no food interactions
• Toxicity
– Hypersensitivity reaction - 5% *
– Occurs within first 6 weeks of therapy
22
Hypersensitivity to Abacavir *
• Genetic basis: Prevalence of the gene is 7% in
Americans and Europeans; 1% in Asians and
Africans
• Multi-organ system involvement
• Most common signs and symptoms:
– Fever > 80%
– Rash (maculopapular or urticarial) 70%
– Fatigue >70%
– Flu-like symptoms 50%
– GI (nausea, vomiting, diarrhea, abdominal
pain) 50%
23
Abacavir Hypersensitivity Signs
and Symptoms Reported (n=636)
100
90
80
% of Cases
70
60
50
40
30
20
10
al
ai
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ar e
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ad s
ac
h
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u
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ya
lg
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m
ou c h
th ills
/th
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m
iti
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0
Symptoms
Hetherington S et al. In: Abstracts of the 7th Conference of Retroviruses and Opportunistic
Infections. San Francisco, CA. January 30- February 2, 2000, Poster No. 60.
24
Time to Onset of 636 Cases
60
50
Median time to onset 11 days
No. of Cases
40
93% of reported cases occurred
within the first 6 weeks of initiating
abacavir
30
20
10
0
1
15
29
43
57
71
85
99
Days
113 127 141 155 169
One additional ABC HSR Reported at
318 days
*
Hetherington S et al. In: Abstracts of the 7th Conference of Retroviruses and Opportunistic
Infections. San Francisco, CA. January 30- February 2, 2000, Poster No. 60.
25
Hypersensitivity to Abacavir (2)
• Must warn patient
• Symptoms progressive with each
subsequent dose
• May be fatal (19 deaths)
• NEVER rechallenge
• Similar to life-threatening reaction to
NVP
26
Tenofovir disoproxil fumarate
(TDF) *
• Dosing: 1 x 300mg tablet QD
• Food Interactions: no important effect
• Toxicity
– Renal insufficiency – Fanconi syndrome
(rare) *
– Must dose adjust with renal failure
27
Tenofovir disoproxil fumarate
(TDF) (2)
• Also has activity against Hepatitis B
– Dose 300 mg QD
– Active vs. Lamivudine resistant HBV
strains
– HBV resistance 1% at 1 year
– If stop TDF, may have HBV hepatitis
flare
28
Didanosine (ddI)
• Requires a basic environment for absorption
• Take on an empty stomach
• Dosing
– 1 x 400mg enteric coated capsule QD (if
<60kg: 250mg QD), or
– 2 x 100mg buffered tab BID or 4 x 100mg QD
(if <60kg: 125 mg BID or 250mg QD)
 NOTE: If use buffered tablets, 2 or more tablets
must be used at each dose to provide adequate
buffer. Or,
– 250mg of reconstituted buffered powder BID
(if <60kg: 167mg BID)
29
Didanosine (ddI) (2)
• If taken with TDF must reduce ddI dose:
– > 60 kg
– 250 mg/d
< 60 kg
200 mg/d
• Without dose adjustment – blunted CD4
response
• Toxicity
– Peripheral Neuropathy
– GI intolerance
– Pancreatitis (2%  7%)
– Lactic acidosis, fatty liver
30
NRTI Class Side Effects
• Peripheral Neuropathy: ddI + d4T
– With continued treatment may be
irreversible
• Lactic Acidosis, fatty liver:
– d4T > ddI > AZT
• Lipoatrophy: d4T > AZT
• Pancreatitis: ddI > d4T
• Marrow Suppression: AZT
31
NRTI Mitochondrial Toxicity
• Inhibition of mitochondrial DNA polymerase-
–  oxidative metabolism,  ATP
generation
• Implicated in lactic acidosis with hepatic steatosis
• Other possible manifestations:
– Neuropathy (d4T, ddI)
– Lipoatrophy (d4T)
– Pancreatitis (ddI)
– Myopathy (AZT)
– Cardiomyopathy (AZT)
32
Hyperlactatemia/Lactic Acidosis
• Common with long term use of d4T, ddI or AZT
- potentially fatal syndrome (1/1000 pt/yrs)
• Linked to prolonged use of NRTIs, especially ddI and d4T
• Acute or subacute onset
• Symptoms: GI side effects -- anorexia, weight loss
• Lab: ↑ anion gap or lactate level
• US: fatty liver
• Management: d/c AZT, ddI, d4T – may take months to
reverse. No specific treatment
33
Neucloside Pairings
YES
NO
AZT + 3TC *
AZT + d4T (Antagonistic)
d4T + 3TC *
d4T + ddI
TDF + 3TC *
TDF + ddI (High failure rate)
ddI + 3TC *
AZT + ddI (Toxicity)
ABC + 3TC*
FTC + 3TC (overlap activity)
(Toxicity)
ddC + any (toxicity)
*FTC = 3TC
ABC+TDF+3TC (high failure rate)
34
Non-Nucleoside Reverse
Transcriptase Inhibitors (NNRTIs)
RNA
DNA
Nucleus
Host
Cell
35
Non-Nucleoside Reverse
Transcriptase Inhibitors
• NNRTIs
– Nevirapine (NVP, Nevipan®)
– Efavirenz (EFV, Stocrin®)
– Delavirdine (DLV, Rescriptor®), rarely
used
36
Non-Nucleoside Reverse
Transcriptase Inhibitors
37
Class Issues NNRTIs
•
•
•
•
•
Dosing: 1-2 / day; no food effect
Pharmacology: long half life
Toxicity: Infrequent after 4-6 weeks
Potency: Unbeaten in clinical trials
Drug interactions: less frequent than with
PIs
• RESISTANCE: SINGLE MUTATION
(K103N) ELIMINATES CLASS FOREVER
38
Nevirapine (NVP, Nevipan®)
•
•
•
•
Dosing: 200 mg QD x 2 weeks, then 200 mg BID
Food Interactions: None
Potency: Unbeaten in clinical trials of efficacy
Toxicity: two serious ADRs in first 6 weeks & more
common with CD4 > 300
– Rash – MP (17%); SJS (1%)
– Hepatitis – liver necrosis
• Drug interactions: Few
• Metabolic side effects: None
39
Nevirapine (2)
• Nevirapine rash
– Milder form – erythematous,
maculopapular rash
• continue medication with close observation
• antihistamines may be administered
– Severe form – with mucous membrane
involvement, SJS & TEN
• DRESS: Drug rash, eosinophilia, systemic
symptoms
• D/C if fever, blisters mucous membrane,
conjunctivitis, edema, arthalgias
40
Nevirapine-Induced Rash
41
NNRTI Rash
• Often diffuse, slightly raised, itchy
• Vary in redness and distribution
• Can be severe - Steven’s Johnson
Syndrome
42
Hepatotoxicity: NVP + PIs
• NVP:
– Hepatic necrosis 1st 6-16 weeks after
starting Rx
– Esp. among women w/ CD4> 250 and
low BM
– Always symptomatic – fever, rash,
nausea, vomiting
– May be fatal
• PI & NNRTIs: All cause ↑ ALT/AST
in 10-15%
43
Hepatotoxicity: NVP & PI (2)
NVP
PI/r
When
First 6-12 weeks
Late
Risk
Female, CD4 >
250, low BMI
HBV, HCV coinfection
Sxs
Fever, rash, GI
sxs
Asymptomatic
Treatment
Stop drug
“treat through”
Outcome
May be lethal
No clear sequelae
44
NVP: Hepatotoxicity
“symptomatic hepatitis”
CD4 count
Rate of Hep
Women CD4 > 250
*
CD4 < 250
11%
0.9%
Men *
CD4 > 400
6.4%
CD4 < 400
2.3%
* Analysis of 607 treatment naïve patients (2NN)
45
Efavirenz (EFV, Stocrin®)
• Dosing: 600 mg tab QHS
• Food Interactions
– Take on empty stomach or with low-fat
meal
• High-fat meals increase absorption
50%  increases side effects
• Resistance: K103 N (100, 181, 188)
• Drug Interactions: Rifampin ↓ EFV by
25%
46
Efavirenz (EFV, Stocrin®) (2)
• Toxicity (WARN PATIENT)
– CNS Changes (52%): Insomnia, nightmares,
poor concentration, mood change, dizziness,
dysequilibrium, depression, psychosis
– Rash (17%): usually does not require
discontinuation
– CONTRAINDICATED DURING PREGNANCY
– Teratogenic – Class D
47
Efavirenz CNS Toxicity
• Sxs: confusion, impaired concentration, bad
dreams, dizziness, “disconnected”
• Onset: first dose
• Course: usually resolves in 2-3 weeks
• Long-term sequelae: none
• Cause: Unknown
• Management: warn patient
48
Efavirenz Pharmacology
• Half-life: 36-100 hours
• Metabolism:
– p450 CYP 2B6 genetic differences at codon 516
determines half-life;
– Pattern GG is common in African Americans and
gives therapeutic levels EFV at 2-3 weeks
– Prolonged monotherapy when stop EFV
– Increase CNS toxicity
49
50
NVP vs. EFV
NVP
EFV
Potency
Never beaten
Never beaten
Daily doses
2
1
Efficacy
Similar
Similar
Pregnancy
Yes
No
TB (Rifampin)
No (?)
Yes
Side Effects
Liver *; Rash *
CNS
Resistance
Low barrier -- kills
class forever
Low barrier – kills
class forever
51
* May be lethal
Co-Formulated Reverse
Transcriptase Inhibitors - FDC
– AZT/3TC
(Combivir, Duovir, Virocomb, Zidolam )
– D4T/3TC
(Lamivir-S, Viro LIS, Lamistar)
– Abacavir/AZT/3TC
(Trizivir or Trisivir, Generic Brands: Virol LZ )
– Nevirapine/d4T/3TC
(Generic Brands: Triomune, Viro LNS,
Nevilast)
– Nevirapine/AZT/3TC
(Generic brand: Duovir-N)
52
Protease Inhibitors (PIs)
DNA
Host
Cell
53
Protease Inhibitors
•
•
•
•
•
Lopinavir + Ritonavir (Kaletra) *
Nelfinavir *
Ritonavir *
Indinavir *
Saquinavir-HGC **
•
•
•
•
Fosamprenavir
Atazanavir
Tipranavir
Darunavir
*Available in Ethiopia ** on National drug list
54
Ritonavir (RTV, Norvir)
• Pharmacology: Potent inhibitor of CYP 3A4
and 2D6 enzyme pathways
• Hx: introduced as PI but 1200 mg/d was
poorly tolerated and now used to “boost” PIs
in doses from 100-400 mg/day
• Drug interactions: Extensive based on P450
metabolic pathway
55
Ritonavir (RTV)
• GI intolerance prevents full dose
• Now used to boost other PIs
• Doses < 400 mg/day – no anti-HIV
activity
• Terms used is: /r (LPV/r, SQV/r)
• Requires refrigeration
• Hard to make
56
Lopinavir/ritonavir (LPV/r) *
• Dosing: 3 caps (400 mg lopinavir/100 mg ritonavir)
BID with food
– New formulation: 2 tabs vs 3 tabs bid, no
food effect, don’t need refrigeration
• Toxicity
– GI intolerance, Diarrhea
– Lipodystrophy
– ALT/AST increase
• Refrigeration recommended, but OK at room
temperature for up to 2 months
• Resistance: requires > 4 mutations
57
LPV/r vs. NFV; * M98-683 trial
• Method: LPV/r /3TC / d4T vs. NFV / 3TC /
d4T
• N=653 treatment naive patients
Results (48 weeks) VL < 50
LPV/r
67%
NFV
52%
* NEJM 2002; 346:2039
58
Nelfinavir (NFV)
• Dosing: 1250 mg po bid with food
• Toxicity
– Diarrhea (10%-30%)
– Nausea
– Lipodystrophy
– ALT/AST increase
– Only PI that doesn’t boost with RTV
– Least potent PI
59
Saquinavir-Hard Gel Capsules (SQV)
Invirase
• Dosing:
– Must take with Ritonavir
– 1000 mg /100 mg bid with food
• Toxicity
– GI intolerance
– Lipodystrophy
– ALT /AST increase
• Refrigeration recommended, but OK at
room temperature for up to 3 months
60
Indinavir (IDV)
• Dosing:
– 2 x 400mg q 8
hours OR
– With RTV 800 /
100 mg bid or
400/400 mg bid
• Toxicity
– Nausea
– Diarrhea
– Nephrolithiasis (flank pain, ↑
SrCr, hematuria, pyuria)
– Dry lips, dry skin
– Hyperbilirubinemia
– Lipodystrophy
– ALT /AST increase
• Food Interactions:
take on empty
stomach, or with low • Capsules are sensitive to
moisture
fat snack (e.g. non61
fat milk)
PIs: Resistance Mutations
 Genetic barrier to resistance
 Usually requires multiple mutations
 Resistance mutations are “signature” and
“class”
Signature: NFV – 30N, FPV – 50V, ATV –
50L
 Many PIs require multiple mutations to get
resistance.
Continued use with failure will get there
62
NNRTI vs. PI: Resistance
Adherence
NNRTI
PI
0 - 53%
68%
23%
54 - 94%
40%
36%
> 95%
11%
42%
Bangsberg D: AIDS 2004;20:223
63
PI Class Side Effects
• Metabolic Disorders
– Hepatotoxicities
– Hyperglycemia,
insulin resistance
– Lipid
abnormalities
– Fat redistribution
• Rash, esp: FPV,
ATV, TPV
• GI Intolerance
• Drug Interactions
– CYP450 3A4
Inhibition: RTV,
LPV > IDV = NFV =
APV >SQV
64
Hepatotoxicity
• Increased LFT’s observed with all PI’s.
• More common in pts with chronic viral
hepatitis (HBV, HCV).
• Data do not support withholding PI’s from
pts co-infected with HBV or HCV.
• Increased ALT/AST is common (10-20%),
asymptomatic and unclear consequence
65
Lipodystrophy
Agents
Monitori
ng
Conse quence
Rx
Fat
redistribution
All PIs
(all classes)
Appearance
Cosmetic
None
d/c drug
Insulin
resistance
All PIs
FBS
monitoring
Diabetes
Standard
metformin
Lipids
Increase
All PIs, except
ATV
Lipids
CVD
Standard
66
HIV/HAART Toxicities Lipid Abnormalities
• Hypertriglyceridemia; risk of pancreatitis
• Low HDL, high LDL
• Increased deaths from coronary artery
disease noted among persons on HAART
• Generally treated w/ fibrates and/or statins
• Best results from switch studies are with
NVP, EFV or ATV
• Avoid d4T
• Beware of drug interactions between ART,
statins, and fibrates  risk of myositis
67
Management of hyperlipidemia
LDL Goal Life
Style
Drug
Rx
Cardiovascular
Disease or
Diabetes
< 70
< 100
> 130
> 2 risks *
< 100 –
130
< 130
> 130
0-1 risk *
< 160
< 190
> 190
* Risk = HBP, Age > 45-55 yrs, smoking, genetics
68
Risk of MI with HAART
• Method: D:A:D 23,400 pts with 345 MIs
• Results: 94,469 pt/yrs of data
– RR = relative risk
– RR = 0.5 (2003-4 cohort vs 1999 cohort)
– RR for PIs = 1.16 per yr
– RR for NNRTIs = 1.05 per yr
* Friss-Moller 2006 CROI, Abstract 519
69
Lipodystrophy – Morphologic Changes
• Fat Accumulation (lipohypertrophy) PIs
– Dorsocervical fat
– Visceral adiposity
– Breast enlargement
• Fat Loss (lipoatrophy) – d4T
– Facial fat loss
– Subcutaneous fat loss of extremities
70
Dorsocervical Fat Pad
“Buffalo hump” in HAART-treated patient
71
Lipoatrophy
72
Buffalo Hump – side view
73
Central Fat Accumulation
74
Fat Redistribution Syndromes
75
Hepatic Toxicity
NRTI: Lactic acidosis with steatosis – d4T,
ddI and AZT
NNRTI:
NVP – 1) Hepatic necrosis
2) Transaminitis*
EFV – 1) Transaminitis*
PI: Transaminitis*
*Significance is unclear; may resolve with
continued treatment; more common with
HBV or HCV
76
Recommendation: D/C if ALT >5-10 ULN
Nephrotoxicity
TDF: Fanconi syndrome
U/A – protein, glucose
Creatine/BUN increased
IDV: Renal calculi of IDV crystals. Renal
failure and/or renal colic
Risks: High levels
77
Dosing considerations in patients with renal failure
CrCl
>60
CrCl
30-59
CrCl
10-29
CrCl
<10
AZT
300mg bid
300mg bid
300mg bid
100mg tid
3TC
150mg bid
150mg qd
100mg qd
50mg qd
d4T*
40mg bid
20mg bid
20mg qd
20mg qd
ddI*
400mg qd
200mg qd
125mg qd
125mg qd
TDF
300mg qd
300mg q48
300mg
twice/wk
300mg qwk
*dosing for patients > 60kg
78
Significant Drug Interactions
with Antiretroviral Therapy
79
Basic Definitions
Pharmacokinetic
• Refers to what the
body does to the drug
• “LADME” principle
– Liberation
– Absorption
– Distribution
– Metabolism
– Elimination
Pharmacodynamic
• Refers to what the
drug does to the body
• Examples
– Mitochondrial Toxicity
• Nucleoside analogues
– Bone Marrow Toxicity
caused by ganciclovir
or AZT
– Peripheral Neuropathy
– DDI, D4T, DDC
– Pancreatitis – DDI, 80
pentamidine, Alcohol
Mechanisms for Drug
Interactions (1)
• Pharmacokinetic Interactions
– Altered intracellular activation
• Impairment of phosphorylation (D4T, ZDV)
– Altered drug absorption and tissue
distribution
• Chelation, pH, P-gp
– Altered drug metabolism
• Induction/inhibition, GT,P-gp
– Reduced renal excretion (P-gp)
81
Mechanisms for Drug
Interactions (2)
• Pharmacodynamic interactions
– Additive or synergistic interactions
– Antagonistic or opposing interactions
82
First Pass Effect
83
Drug Metabolism/Elimination
84
Cytochrome (CYP450)
• >30 isoenzymes identified in humans
• Present in liver, small intestines, lungs, and brain
• Primary function is to alter toxins (drugs) to speed
excretion
• Nomenclature: Family<subfamily<individual gene (called
isoenzyme)
– Enzyme 3A4 (3 =family, A= subfamily, 4= isoenzyme)
• Isoenzymes:1A2, 2C9/19, 2D6, 3A4 are primarily
responsible for drug metabolism
• Also metabolize steroid hormones, vitamins, toxins,
prostaglandins, fatty acids
• Knowledge of substrates, inhibitors and inducers helps
predict drug interactions
85
Cytochrome P450 Enzymes
Patient Factors
•Genetics
Outcome of
Drug
Interaction
Drug Factors
•Dose
•Diseases
•Duration
•Diet/Nutrition
•Dosing Times
•Environment
•Sequence
•Smoking
•Route
•Alcohol
Variability
•Dosage Form
Adapted from Philip D. Hansten, Science & Medicine 1998
86
P450 Drug Interactions
• Substrate
• Medication depends on enzymatic pathway(s)
for metabolism
• Object drug which is affected by inducer or
inhibitor
• Inducer
• Speeds up metabolism
• Decreases substrate level (lack of efficacy is
concern)
• Onset/offset is gradual
• Inhibitor
• Slows metabolism
• Increases substrate level (toxicity is concern) 87
CYP P450 Drug-Drug
Interactions
• Pharmacologic action of drug is altered by
coadministration of second drug
• Co-administration may: effect (eg ritonavir + saquinavir;
 ritonavir + simvastatin)
Drug B
New effect (eg, ritonavir +
amitriptyline;)
Drug A
No
Consequences
 effect (eg,rifampin +
protease inhibitors, indinavir +
coumadin)
88
CYP P450 Drug-Drug
Interactions
• Pharmacologic action of drug is altered by
coadministration of second drug
• Co-administration may: effect (eg ritonavir + saquinavir;
 ritonavir + simvastatin)
Drug B
New effect (eg, ritonavir +
amitriptyline;)
Drug A
No
Consequences
 effect (eg,rifampin +
protease inhibitors, indinavir +
coumadin)
89
Cytochrome P450 Caveats
• A potent enzyme inhibitor
is likely to inhibit the
metabolism of ANY drug
that is metabolized by
that enzyme
• Some substrates for a
particular enzyme are
also inhibitors or inducers
of that same enzyme
• Some inhibitors affect
more than one enzyme
• Magnitude of inhibition
may depend upon the
dose
• An inhibitor may produce
inhibition of an isozyme at
one dose, but require a
larger dose to inhibit
another isozyme
• Most CYP450 inhibitors are
eliminated by the liver, but
some are not
• Enantiomers may be
metabolized by different
enzymes
• Some ARVs have mixed
effect: EFV, Lop/r, RTV
90
Remember
• A drug interaction can occur
– Whenever a new medication is started
– Whenever a medication is discontinued
– Whenever a dose is changed
• Remember:
– Inducing interactions
• Gradual onset/offset
– Inhibiting interactions
• Quick onset/offset
91
Red Flags for Potential
Interactions
• PIs or NNRTIs +
– Statins
– Azole antifungals
– Antihistamines
– Ergot alkaloids
– Anticonvulsants
– Anti-TB
(Rifampicin)
– Warfarin
– Benzodiazepines
– Methadone
– Alternative
medicine
– Cardiac medicine
– Macrolide
antibiotics
– Oral contraceptives
– Antidepressants
92
PI/ NNRTI/ Antidepressant Drug
Interactions
Antidepressant
Potential for
Interaction
Effects
Management
Amitriptyline
ritonavir,
lopinavir/r,
amprenavir,
Levels of
amitriptyline may
be increased
Start with lower dose
(50%) of amitriptyline,
adju0st dose when
adding ritonavir.
Monitor for side effects
fluoxetine
ritonavir,
lopinavir/r, all
other PIs,
efavirenz
Levels of both
fluoxetine and
ARVs may be
increased
As above
sertraline
ritonavir,
lopinavir/r, all
other Pis,
efavirenz
Levels of
As above
sertraline may be
increased. ARV
levels
not likely to
change.
93
PI/ NNRTI/ Antidepressant Drug
Interactions
Antidepressant
Potential for
Interaction
Effects
Management
Amitriptyline
ritonavir,
lopinavir/r,
amprenavir,
Levels of
amitriptyline may
be increased
Start with lower dose
(50%) of amitriptyline,
adju0st dose when
adding ritonavir.
Monitor for side effects
fluoxetine
ritonavir,
lopinavir/r, all
other PIs,
efavirenz
Levels of both
fluoxetine and
ARVs may be
increased
As above
sertraline
ritonavir,
lopinavir/r, all
other Pis,
efavirenz
Levels of
As above
sertraline may be
increased. ARV
levels
not likely to
change.
94
Pharmacological
enhancement
Pharmacokinetic Enhancement
• Ritonavir used to
“boost” Cmin and
increase t½ of other
protease inhibitors
– Allows for extended
dosing intervals
– Decreases pill burden
– Reduces adverse
effects
– May allow salvage in
patients with
resistance and
• Ritonavir (cont.)
– Overcomes enzyme
induction caused by
other drugs
– Increase drug
exposure
– Remove meal
requirements
• Activity primarily via
inhibition of CYP450
3A4
96
• May also inhibit MDR-
Pharmacokinetics Principles
Concentration (ug/mL)
10
Cmax
maximum concentration
correlates with some short-term
side effects, e.g. nausea
8
6
4
AUC
area under the curve
overall drug exposure
2
0
2
4
6
8
10
12
97
Pharmacokinetics Principles (2)
Concentration (ug/mL)
10
Cmin
minimum, or trough concentration
occurs at the end of the dosing interval
correlates with anti-HIV effect for all PIs
8
6
4
2
0
2
Clinical Pharmacology of ART
4
6
8
10
12
98
98
99
Clinical Pharmacology of ART
99
An Example of Ritonavir Boosting:
Indinavir/Ritonavir BID PK Study
10,000
IDV/RTV q12h:
800/200 High-fat Meal
Indinavir
Plasma
Concentration
(nM)
800/100 High-fat Meal
1,000
400/400 High-fat Meal
IDV q8h:
800 mg Fasted
100
0
2
4
6
8
Time Postdose (hours)
10
12
100
6th Conference on Retroviruses and Opportunistic Infections; 1999. Abstract 362.
Indinavir Concentration (µg/mL)
Steady-State IDV Plasma Profile
After IDV + RTV 400 mg Q12H with Food
100
IC90
IDV + RTV 400/400 mg q12h (regular 35%-fat meal)
IDV 800 mg q8h (Fasting)
10
1
0.1
0.01
0
4
8
12
16
20
24
Time (h)
E981561A
101
[Hsu et al. AAC 98;42:2784-91]
Ritonavir Boosting
AUC
Saquinavir
30 – 74 x
Lopinavir
15 – 20 x
Indinavir
3–6x
Nelfinavir
1.5 x
102
PI – Safer Choices
• Rifabutin, if possible
– Requires dose reduction with all PIs and dose
increase with efavirenz
• Rifampin (only use with adjusted doses of EFZ, LPV/r or
RIT/SAQ)
• Anticonvulsants
– Use sodium valproate, gabapentin or
lamotrigene, if possible
• Migraine therapy
– Use sumatriptan
• Antihistamines
– Use loratadine or cetirizine
103
PI – Safer Choices (2)
• Rifabutin, if possible
– Requires dose reduction with all PIs and dose
increase with efavirenz
• Rifampin (only use with adjusted doses of EFZ, LPV/r or
RIT/SAQ)
• Anticonvulsants
– Use sodium valproate, gabapentin or
lamotrigene, if possible
• Migraine therapy
– Use sumatriptan
• Antihistamines
– Use loratadine or cetirizine
104
NNRTIs- Do NOT CoAdminister
•
•
•
•
•
Ergot derivatives (ergotamine)
Benzodiazepine: midazolam
Rifampin (Nevirapine)
Terfenadine (Efavirenz)
Herbal – Interaction unknown in Ethiopian
context
105
PI and NNRTI Drug Interactions
Nevirapine (NVP)
• NVP (standard dose) +
– Indinavir (increase IDV to 1000 mg q8h or
consider IDV/RTV)
– Ritonavir (dose RTV standard)
– Saquinavir (use with RTV)
– Nelfinavir (NFV dose standard)
– Amprenavir, fos-Amprenavir (no data)
– Lopinavir/r (use 4 caps bid)
– Atazanavir ( no data, most clinicians would
use with ritonavir)
106
PI and NNRTI Drug Interactions
Efavirenz (EFV)
• EFV (standard dose) +
– Indinavir (increase IDV to 1000 mg q8 or consider IDV/RTV)
– Ritonavir (dose standard)
– Saquinavir (SQV nt recommended as sole PI when used with
EFV- use with RTV)
– Nelfinavir (dose standard)
– Amprenavir (add RTV 200 mg to standard APV of consider using
APV/RTV 450/200 mg
– Fos-Amprenavir (use 1400 mg APV with 300 mg RTV once daily
or 700 mg APV with 100 mg RTV bid
– Atazanavir (use ATV 300 mg with RTV 100 mg qd
– Lopinavir/r (use 4 caps of LPV/r bid)
107
Antiretroviral-Food
Interactions
Take with food:
• Lopinavir:  50-130%
• Saquinavir: 7 fold 
(fatty meal)
• Nelfinavir: 2-3 fold 
• Ritonavir: 15% ,
decreased GI toxicity
• Itraconazole caps
• Atazanavir 70 
Ganciclovir  up to
5%
• atovaquone 24% 
Avoid food:
• Amprenavir:  23% with
high fat meal (regular
food OK)
• Indinavir: 77%  (fatty
meal; light snack OK)
• DDI: 47%  with meal
• Efavirenz:  79% high fat
meal inc. toxicity
• Rifampin (food may
levels)
• Itraconazole liquid
• Isoniazid
108
Antiretroviral-Food
Interactions (2)
Take with food:
• Lopinavir:  50-130%
• Saquinavir: 7 fold 
(fatty meal)
• Nelfinavir: 2-3 fold 
• Ritonavir: 15% ,
decreased GI toxicity
• Itraconazole caps
• Atazanavir 70 
Ganciclovir  up to
5%
• atovaquone 24% 
Avoid food:
• Amprenavir:  23% with high
fat meal (regular food OK)
• Indinavir: 77%  (fatty meal;
light snack OK)
• DDI: 47%  with meal
• Efavirenz:  79% high fat meal
inc. toxicity
• Rifampin (food may levels)
• Itraconazole liquid
• Isoniazid
109
Grapefruit & Saquinavir
• Specific constituents in juice inhibit
CYP3A4, 1A2, 2A6
• Impact of grapefruit juice on saquinavir
concentrations:
– double-strength: 200%  in SAQ
– normal-strength: 40%  in SAQ
• Comparative effects:
– ritonavir > grapefruit juice > high-fat breakfast
>normal breakfast
110
Avoid Antacids
• PIs
– indinavir
– (fos)amprenavir
– amprenavir
– atazanavir
• Ketoconazole
– luoroquinolones
– isoniazid
– dapsone
– zalcitabine
– delavirdine
111
Case Study
• A 50 year old male patient who has just
completed 9 months of TB therapy (with
rifampicin and isoniazid along with
pyridoxine) 3 weeks ago continues on
ARVs (EFV 800 mg qhs, 3TC 150 mg bid
and ZDV 300 mg bid) therapy. He
presents to the ER with a bloody nose and
bruises on his arm.
• Other current medications include:
• coumadin for atrial fibrillation
• atenolol for blood pressure
What do you suspect has happened?
112
Drug Resistance
113
How Drug Resistance Arises
“Selection Process”
114
Development of Drug Resistance
115
Sequence of resistance mutations
AZT/3TC → 184V → TAMS
d4T/3TC → 184V →TAMS
ddI/3TC → 184V → 65R, 74V
→ → 65R,74V
ABC/3TC → 184V
TDF/3TC → 184V → 65R
119
NRTI Resistance
Mutations
Selected by
Comment
TAMS (41, 67, 70,
210, 215, 219)
AZT , d4T
Reduce activity of
all NRTIs
184V
3TC
Reduces activity
ddI, FTC, 3TC;
increases activity
AZT
K65R, 74V
ddI, TDF, ABC
Protects against
TAMS
120
WHO Regimen: Need Salvage Rx
• Toxicity:
■ NVP  EFV (?) or PI
■ EFV  NVP (CNS) or PI
■ d4T  AZT, TDF
■ AZT  d4T, ddI, TDF
• Viral Failure: AZT, d4T  ddI
■ 3TC  Keep
■ AZT, d4T  ABC, TDF
■ EFV, NVP  PI
121
Tale of Two Mutations
Induction
Requirement
184V
3TC or FTC
> 3 wks
103N
NVP or EFV
single dose
Increase resistance
3TC
1000 fold
------------
------------
1000 fold
Cross-resistance
3TC/FTC
NNRTI
Fitness
Decreased
NNRTI
Collateral effect
Utility of Drug
↑ AZT, d4T activity
Great
No change
No benefit
None
122
Resistance of the “Third Drug”
NNRTI
Potency
Excellent
 Failure
PI
Excellent
Single mutation
Kills class
 Options in class
None
Requires multiple
mutations
 Continued use
with failure
 Protection
Increasing PI
mutations
Genetic
No benefit
Pharmacology
Many
123
Case # 1
• Hx: 48 yo woman has received
NVP/3TC/d4T. The pharmacy has no
NVP in stock
• What should she do?
1. Continue 3TC/d4T until the NVP
becomes available, then add NVP
2. Stop all drugs
3. Stop NVP for 7 days then stop
3TC/d4T
124
Case # 1
• Hx: 48 yo woman has received
NVP/3TC/d4T. The pharmacy has no
NVP in stock
• What should she do?
1. Continue 3TC/d4T until the NVP
becomes available, then add NVP
2. Stop all drugs
3. Stop NVP for 7 days then stop
3TC/d4T
125
Case # 2
• Hx: A 50 year old man has taken
EFV/AZT/3TC for 1 year. He now
presents with thrush.
• What should he take now?
1. NVP / 3TC / ddI
2. NFV / 3TC / d4T
3. NVP / 3TC / AZT / ABC
4. LPV/r / d4T / AZT
5. NFV / TDF / ddI
126
Case # 2
• Hx: A 50 year old man has taken
EFV/AZT/3TC for 1 year. He now
presents with thrush.
– May have NNRTI resistance, making NVP
poor choice; Also likely developed M183V
mutation for 3TC; may have mutation for
AZT and d4T resistance
• What should he take now?
1. NVP / 3TC / ddI (essentially 1 drug)
2. NFV / 3TC / d4T (essentially 2 drugs)
3. NVP / 3TC / AZT / ABC (adding 1 drug)
127
Case # 3
• Hx: 20 year old woman has received
EFV/AZT/3TC and has done well with a
CD4 increase from 180  280 /mm3.
She becomes pregnant.
• What should she take?
1. NVP / AZT / 3TC
2. NFV / AZT / 3TC
3. NVP / d4T / ddI
4. NVP / TDF / ABC
128
Case # 3
• Hx: 20 year old woman has received
EFV/AZT/3TC and has done well with a
CD4 increase from 180  280 /mm3.
She becomes pregnant.
• What should she take?
1. NVP / AZT / 3TC (WHO recs)
2. NFV / AZT / 3TC (USA most experience)
3. NVP / d4T / ddI (not rec. due to toxicity)
4. NVP / TDF / ABC (little data in
pregnancy)
129
Case # 4
• Which of the following is the best
regimen for a patient with HIV who is
doing well with NVP/3TC/AZT and now
has active TB?
1. LPV/r / d4T / ddI
2. NFV / ddI / TDF
3. EFV/3TC/AZT
4. NFV / d4T / TDF
5. Stop ART; resume after completion
of Rifampcin
130
Case # 5
•
Which of the following is the best regimen for a patient with
HIV who failed EFV/3TC/AZT and now has active TB?
1. LPV/r / d4T / ddI (do not combine d4T/ddI)
2. NFV / ddI / TDF (ddI/TDF not best
regimen)
3. NVP / ddI / TDF (no NVP + Rif)
4. NFV / d4T / TDF (Might be OK but
substituting D4T for AZT – which may
have same mutation)
5. Stop ART; resume after completion of
131
Rifampcin
Case 6
A man with HIV has been treated with
NVP/AZT/3TC. In one year the CD4 count
incrased from 105/mm3 to 260/mm3. He now
has active TB. What should he get beside 4
drugs for TB?
1. LPV/r/d4T/3TC
2. EFV/3TC/AZT
3. AZT/3TC/ABC
4. Stop ART until he is on maintenance
treatment for TB
132
1. LPV/r/d4T/3TC: PIs can’t be used with
standard TB treatment – interaction with
rifampin
2. EFV/3TC/AZT: Best option. Major question is
dose of EFV
3. AZT/3TC/ABC: Not a bad option if we didn’t
have #2
4. Stop ART: CD4 count is high enough to do
this for 2 months to get through the induction
of TB treatment, but when you stop the CD4
count goes down fast
133
Case 7
A patient taking NVP/d4T/3TC and develops
PCP.
What would be the next best regimen?
1.
2.
3.
4.
5.
EFV/AZT/ddI
NFV/AZT/ddI
LPV/r/TDF/ABC
LPV/r/ABC/ddI
NFV/AZT/3TC/ABC
134
1.
2.
3.
4.
5.
EFV/AZT/ddI – one new drug (ddI)
NFV/AZT/ddI – two new drugs (NFV, ddI)
LPV/r/d4T/ddI – avoid drT/ddI
LPV/r/ABC/ddI – WHO recommendation
NFV/AZT/3TC/ABC – two new drugs
(NFV/ABC)
135
Key Points
• Goals of ART include:
– Suppression of viral replication
– Restoration of immunologic function:
increased TLC and CD4 cell counts
• Effective ART requires strict adherence to
the regimen, proper monitoring of side
effects and disease progression, and
recognition and treatment of comorbidities.
136
Key Points (2)
• ART involves a combination of at least
3 drugs, usually 2 NRTIs + 1 NNRTI or
1-2 PIs.
• First line regimen for Ethiopia is
d4T/3TC/NVP.
• A drug interaction can occur whenever
a medication is started or discontinued
or whenever a dose is changed.
137
Key Points (3)
• Physicians must be knowledgeable about
potential drug-drug and drug-food
interactions.
• Physicians should question a patient about
their current medications whenever filling a
prescription that is new for them, when a
dose is changing or when a medication is
being discontinued.
• Patients should be educated that drug
interactions can also occur if they stop or
138
receive a change in dose of their
Key Points (4)
• Drug resistance occurs when HIV
continues to grow in the presence of
medications.
• A patient with HIV will develop drug
resistance if treated with only 1-2 drugs
or if they regularly miss doses.
• Drug resistance limits activity of
current drug regimen and limits future
options.
139
Thank you!