Transcript HIVART_7 - I-Tech

Pharmacology
Unit 7
HIV Care and ART:
A Course for Physicians
Learning Objectives
 Describe the mechanism of action of
antiretroviral (ARV) drugs
 List the common side effects of ARVs
 List the standard ARV doses
 Identify the ARVs that require dose adjustment
for patients with renal or hepatic disease
 List the ARVs that have food requirements
2
Learning Objectives (2)
 Describe the mechanisms of drug interactions
relevant to ARVs
 Identify commonly used drugs that may have
important interactions with ARVs
 Describe the principles and mechanisms of drug
resistance
3
Antiretroviral Drugs
Ethiopian ART Guideline
First Line
Second Line
AZT or d4T
and
3TC
and
NVP or EFV
ABC, TDF, or AZT
and
ddI
and
Lop/r, SQV/r, NFV,
IND/r
5
2003 vs. 2005 WHO Guidelines
6
Classes of Antiretrovirals
 NRTIs
 Nucleoside reverse transcriptase inhibitors
 Nucleotide reverse transcriptase inhibitors (NtRTI)
 NNRTIs – non-nucleoside reverse transcriptase
inhibitors
 PIs – protease inhibitors
 Fusion Inhibitors
7
ARVs and the HIV Lifecycle
8
Nucleoside Reverse
Transcriptase Inhibitors (NRTIs)
RNA
DNA
Nucleus
Host
Cell
9
Types of NRTIs








Zidovudine (AZT)
Stavudine (d4T)
Lamivudine (3TC)
Didanosine (ddI)
Abacavir (ABC)
Zalcitabine (ddC)
Emtricitabine (FTC)
Tenofovir (TDF)-Nucleotide RTI
10
Zidovudine (AZT, ZDV)
 Dosing: 300mg BID
 Food Interactions
 None – can take with or without food
 Food decreases AZT-related nausea
11
ZDV: Toxicity
 Nausea
 Bone Marrow
Suppression
 Anemia
 Neutropenia
 Headache




Myalgia
Myopathy
Insomnia
Pigmentation of nail
beds
 Lactic acidosis, fatty
liver
12
ZDV: Bone Marrow Suppression
 Correlates with drug dose & duration, marrow
reserve, and stage of disease
 Anemia occurs after 4-6 weeks
 Neutropenia occurs after 12-24 weeks
 Marrow histology shows normal or reduced RBC
precursors
 Management
 Stop AZT if Hgb <8 gm/dl
 Hgb typically recovers in 1 to 2 weeks
13
ZDV-Related Fingernail Discoloration
 Nail Hyperpigmentation




Can be seen on hands and feet after 2-6 weeks
Usually dark bluish-black vertical-line discoloration
More common among African population
This is NOT an indication to stop ZDV
14
Lamivudine (3TC)






Dosing: 150mg BID or 300mg QD
Food Interactions: none
Toxicity: very rare
Component of all first-line regimens
Also active against Hepatitis B
Main disadvantage: rapid development of
resistance
15
Emtricitabine (FTC)
 Dosing: 1 x 200mg capsule QD
 Food Interactions: no food interactions
 Toxicity
 Mild abdominal discomfort
 Occasional nausea
 Emtricitabine is the fluorinated version of
lamivudine
16
Hepatitis B Co-infection




Drugs active against both HBV & HIV: 3TC, FTC, TDF
HBV develops rapid resistance to 3TC and FTC
TDF + (3TC or FTC) is the optimal NRTI backbone
Differential diagnosis of exacerbation of hepatic disease
in these patients:




Development of 3TC or FTC resistance
“HBV flair” secondary to stopping 3TC or FTC
ART related hepatoxocity (AZT, d4T, ddI, EFV, NVP, All PIs)
Immune reconstitution syndrome
17
Lamivudine + Zidovudine
 Dosing: 1 tablet (150 / 300mg) BID
 Food Interactions
 None – with or without food is ok
 Food decreases ZDV-related nausea
18
Stavudine (d4T)
 Dosing
 40 mg BID for weight > 60 kg
 30 mg BID for weight < 60 kg
 Food Interactions: None
 Toxicity (use lower dose to reduce risk of S/E
development for patients < 60kg)
 Peripheral Neuropathy (5-15%, pain, tingling, and numbness in
extremities)
 Lactic acidosis, fatty liver
 Lipoatrophy
 Pancreatitis
 Hypertriglyceridemia
19
d4T: Dose-related Side Effects
 Peripheral Neuropathy:
 Onset usually after 2-6 months of therapy.
 If develops: discontinue d4T at onset (or reduce dose
to 20mg Q12H if weight > 60kg, or 15mg Q12H if <
60kg)
 Lipoatrophy:
 loss of fat tissue on arms, legs, and face
 Pancreatitis:
 If develops, discontinue therapy.
 When symptoms resolve, do not re-challenge with
stavudine
20
Facial Lipoatrophy
21
© ITECH, 2006
Abacavir (ABC)




Dosing: 1 x 300mg tablet BID
Food Interactions: no food interactions
Generally well tolerated
Toxicity
 Hypersensitivity reaction
• Occurs within first 6 weeks of therapy
22
Hypersensitivity to Abacavir
 Observed in approximately 5% of all patients
receiving abacavir
 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
Hypersensitivity to Abacavir (2)
 Counsel and prepare patient for hypersensitivity
symptoms and to contact provider/pharmacist
immediately
 Especially during first month of therapy
 Provider/pharmacist determines cause of
symptoms: abacavir or not
 Hypersensitivity may be fatal (19 deaths)
 NEVER rechallenge
 Genetic predisposition
 Similar to life-threatening reaction to NVP
24
Abacavir Re-challenge
 20% risk of anaphylactic-like reaction upon re-challenge
 Death can occur with hours of restarting
 Symptoms may include include:
 hypotension
 bronchoconstriction
 renal failure
 Laboratory changes may include
 Increased CPK
 Elevated liver function tests
 Reduced lymphocyte count
Abacavir should never be re-challenged!
25
Tenofovir Disoproxil Fumarate (TDF)




Dosing: 1 x 300mg tablet QD
Food Interactions: None
Very well tolerated, side effects are minimal
Toxicity
 Renal insufficiency (rare)
• Must dose adjust with renal failure
 Also has activity against Hepatitis B




Dosed 300mg QD
Active against Lamivudine resistant HBV strains
HBV resistance 1% at 1 year
If TDF is stopped, may have HBV hepatitis flare
26
Didanosine (ddI)
 Requires a basic environment
 Food Interactions: take on empty stomach
 Dosing (one of the following)
 1 x 400mg enteric coated capsule QD (if <60kg: 250mg QD)
 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
 250mg of reconstituted buffered powder BID (if <60kg: 167mg
BID)
• Mix pediatric powder with liquid antacid
27
Didanosine (ddl) (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 (7%2%)
Lactic acidosis, fatty liver
28
NRTI Class Side Effects
 As with all antiretrovirals, side effects are worst
during the first 1 to 2 weeks of therapy.
 Counsel patients
 Potential for side effects
 How to handle side effects
 Don’t give up
29
NRTI Class Side Effects (2)
 Peripheral Neuropathy: ddl + d4T
 With continued treatment may be irreversible




Lactic Acidosis, fatty liver: d4T > ddl > AZT
Lipoatrophy: d4T > AZT
Pancreatitis: ddl > d4T
Marrow Suppression: AZT
30
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)
31
Hyperlactatemia/Lactic Acidosis
 Rare but potentially fatal syndrome (1/1000 pt/yrs)
 Linked to prolonged use of NRTIs, especially ddI and
d4T
 Acute or subacute onset
 Symptoms: nausea, vomiting, weight loss, fatigue
 Lab: increased anion gap (or lactate level)
 Ultrasound: fatty liver
 Management: discontinue NRTI – may take months to
reverse. No specific treatment
32
Neucloside Pairings
YES
NO
AZT + 3TC *
AZT + d4T
d4T + 3TC *
d4T + ddI
TDF + 3TC *
(TDF + ddI)
ddI + 3TC *
(AZT + ddI)
* Can use FTC same as 3TC
33
Non-Nucleoside Reverse
Transcriptase Inhibitors (NNRTIs)
34
Non-Nucleoside Reverse
Transcriptase Inhibitors
 NNRTIs
 Nevirapine (NVP)
 Efavirenz (EFV)
35
Nevirapine (NVP)
 Dosing: 200 mg QD x 2 weeks, then 200 mg BID
 Food Interactions: None
 Toxicity
 Rash (17%)
 Nausea & vomiting
 Hepatitis (8-18%)
• Risk is greatest in first 6 weeks of therapy
• Could be benign or fatal
 Black Box warning by FDA (USA):
 Do not use NVP in women w/ starting CD4>250
 Do not use NVP in men w/ starting CD4> 400
36
Hepatotoxicity: NVP & PIs
 NVP:
 Hepatic necrosis 1st 6-16 weeks after starting Rx
 Those at higher risk for hepatitis include:
• Patients with a history of alcohol abuse, coinfection with
hepatitis B or C and in patients who are older or are
women.
• Persons with higher CD4 cell counts or elevated LFTs
at baseline
 PI & NNRTIs: All cause ↑ ALT/AST in 10-15%
37
Hepatotoxicity: NVP & PI (2)
NVP
Others
When
First 6-16 weeks
Late
Sxs
Rash, GI Sxs
No Sxs
Long term
consequence
Serious
Unknown
When to d/c
drug
Promptly
ALT> 5-10 x ULN
38
NVP: Hepatotoxicity
“Symptomatic Hepatitis”
Women
Men
CD4 count
Rate
CD4 > 250
11%
CD4 < 250
0.9%
CD4 > 400
6.4%
CD4 < 400
2.3%
Analysis of 607 treatment naïve patients (2NN)
39
NVP for PMTCT
 Issue is RESISTANCE and EFFICACY
 No SAFETY concerns
40
Nevirapine-Induced Rash
41
Courtesy of HIV Web Study, www.hivwebstudy.org
Nevirapine-Induced Rash (2)
 To reduce the risk
 The dose should be escalated over the first 2 weeks
• Starting at 200mg QD for 2 weeks and then increasing
to 200mg BID
 This dosing makes sense because nevirapine
autoinduces hepatic cytochrome P450 enzymes
(CYP3A4)
• Which reduces its own half-life over 2 to 4 weeks from
45 to 25 hours.
42
Efavirenz (EFV)
 Dosing: 3 x 200mg capsules or 600mg tab QHS
 Food Interactions
 Take on an empty stomach or with low-fat meal
• High-fat meals increase absorption by 50%
increases side effects

 Consistent results: persistent activity after >5
years
 Never surpassed in clinical trial
43
Efavirenz Toxicity
 CNS Changes (52%)
 Rash (15-27%) usually does not require
discontinuation
 Hepatotoxicity (2-8% experience increase in
LFTs > 5 ULN)
 Contraindicated during pregnancy
 Teratogenic—Class D
44
Efavirenz CNS Toxicity
 Symptoms: confusion, Insomnia, nightmares,
poor concentration, mood change, dizziness,
dysequilibrium, depression, psychosis,
“disconnected”
 Onset: first dose
 Course: usually resolves in 2-3 weeks
 Cause: Unknown
 Management: warn patient
45
Which Third Drug to Use?
Advantage
Disadvantage
NNRTI
↓ pill burden
Potency
Rifampin
Low barrier to
resistance
Rash
EFV & pregnancy
PI
Potency
Less resistance
Boost with RTV
Metabolic effects
Drug intolerance
GI intolerance
46
EFV vs. NVP
NVP
EFV
Daily doses
2
1
Efficacy
Similar
Similar
Pregnancy
Yes
No
TB (Rifampin)
No (?)
Yes
Side Effects
Liver *; Rash *
CNS
Resistance
Low barrier
Low barrier
47
* May be lethal
NNRTI Class Effects
 Side effects
 Rash
 Hepatotoxicity
 Cross resistance:
 A single mutation, the K103N, causes high-level
resistance to all 3 drugs in this class: EFV, NVP, and
DLV
 Latent pool forever
 Importance of adherence
48
NNRTI Rash
 Often diffuse, slightly
raised, itchy
 Vary in redness and
distribution
 Can be severe Steven’s Johnson
Syndrome
Courtesy of the Public Health Image Library/CDC/ J.
Pledger, BSS/VD
49
Protease Inhibitors (PIs)
DNA
Host
Cell
50
Protease Inhibitors (2)







Lopinavir + Ritonavir
Nelfinavir
Saquinavir-HGC
Indinavir
Fosamprenavir
Atazanavir
Ritonavir
51
Ritonavir (RTV)
 Substantial GI intolerance prevents use at full,
original dose
 Now used to boost other PIs
 Doses < 400 mg/day – no anti-HIV activity
 Nomenclature: /r (LPV/r, SQV/r)
 Requires refrigeration
 Hard to make
52
Ritonavir Boosting
AUC
Saquinavir
30 – 74 x
Lopinavir
15 – 20 x
Indinavir
3–6x
Nelfinavir
1.5 x
53
Pharmacokinetic Rationale for
Dual PI Therapy
 Single PI is used:
 Peaks may reach well above the desired
concentration for effectiveness
• This may lead to drug toxicity
 Levels of the drug may become too low
• Permitting viral replication
 PIs are used together
 Lower peak levels achieved
• Reduces the chance of side effects
 Higher trough levels acheived
• Increases potency and reduces the chance of viral
replication
54
Clinical Pharmacology of ART
54
Lopinavir/ritonavir (LPV/r)
 Dosing: 3 caps (400 mg lopinavir/100 mg ritonavir) BID
 Each capsule contains LPV 133mg / RTV 33mg
 Food Interactions: take with food
 Toxicity





Nausea
Weakness
Diarrhea (mild to moderate)
Lipodystrophy
ALT/AST increase
 Refrigeration recommended
 Stable at room temperature for up to 2 months
 Hot temperatures should be avoided
55
Nelfinavir (NFV)
 Dosing: 1250 mg PO BID
 Food Interactions: take with meal
 Toxicity







Diarrhea (10%-30%)
Abdominal pain
Flatulence
Nausea
Rash
Lipodystrophy
ALT/AST increase
56
Saquinavir-Hard Gel Capsules
(SQV) Invirase
 Dosing:
 Must take with Ritonavir
 1000 mg /100 mg bid with food
 Toxicity






Diarrhea
Nausea
Abdominal pain
Headache
Lipodystrophy
ALT /AST increase
 Refrigeration recommended, but OK at room
temperature for up to 3 months
 Hot temperatures should be avoided
57
Indinavir (IDV)
 Dosing:
 2 x 400mg q 8 hours OR
 With RTV 800 / 100 mg bid
 Food Interactions: take on empty stomach, or
with low fat snack (e.g. non-fat milk)
 Capsules are sensitive to moisture
58
Indinavir (IDV): Toxicity
 Nausea
 Diarrhea
 Nephrolithiasis (flank pain, ↑ SrCr, hematuria, pyuria)
(2%)
 Dry lips, dry skin
 Bald patches in hair
 Ingrown toe or finger nails
 Acid reflux (3%)
 Hyperbilirubinemia (10-15%)
 Lipodystrophy
 ALT /AST increase
59
PI Class Side Effects
 Metabolic Disorders
 Hepatotoxicity
 Hyperglycemia, insulin
resistance
 Lipid abnormalities
 Fat redistribution
 GI Intolerance
 Drug Interactions
 CYP450 3A4 Inhibition: RTV,
LPV > IDV = NFV = APV
>SQV
 Bone Disorders
60
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 coinfected with HBV or HCV.
 Increased ALT/AST is common (10-20%),
asymptomatic and unclear consequence
61
HIV Lipodystrophy Syndrome
 Definition
 A complex medical condition
 Including abnormal fat redistribution and metabolic disturbances
 Seen in HIV patients receiving ART
 Metabolic complications (primarily PI therapy)






Hepatic insulin resistance
Impaired glucose tolerance
Type 2 diabetes
Hypertriglyceridemia
Hypercholesterolemia
Decreased high density lipoprotein (HDL)
62
Fat Redistribution
 Fat accumulation (lipohypertrophy) --PIs
 Dorsocervical fat
 Visceral adiposity
 Breast enlargement
 Fat loss (lipoatrophy) – d4T
 Facial fat loss
 Subcutaneous fat loss of extremities
63
Fat Redistribution Syndromes
Fonte: Dominic C. Chow, MD, University of Hawaii; Larry J. Day, MD,
University of Michigan; Cecilia M. Shikuma, MD, University of Hawaii
64
HIV Lipodystrophy Syndrome (2)
Abnormality
Assoc.
agent
Monitoring
Conse quence
Rx
Fat redistribution
All
ARVs
Appearance
Cosmetic
None;
d/c drug
Insulin
resistance
All PIs
Blood
glucose
Diabetes
Standard
Lipid Increase
All PIs,
except
ATV
Lipids
Cardiovascular
disease
Standard
65
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
66
Fusion Inhibitor: Enfuvirtide (T-20)
 First fusion inhibitor
 Binds to gp41 and prevents HIV entry into host cell
 Used as part of salvage regimen for ART experienced
patients
 Dosing: 90 mg BID by subcutaneous injection
 Food interaction: None
 Toxicity
 Injection site reactions (98%)
 Nausea, diarrhea, fatigue, hypersensitivity (< 1%)
67
Dosing Considerations in Patients with
Liver Disease
Drug
Hepatic impairment
NRTIs
No dosage recommendation
NVP
No data available; avoid use in patients with
moderate to severe hepatic impairment
EFV
No recommendation; use with caution in patients
with hepatic impairment
LPV/r
SQV
NFV
IND
No recommendation; use with caution in patients
with hepatic impairment
Reduce dose from 800mg to 600mg in moderate
cirrhosis
68
Dosing Considerations in Patients with
Renal Failure
AZT
CrCl
>60
300mg bid
CrCl
30-59
300mg bid
CrCl
10-29
300mg bid
CrCl
<10
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
69
Significant Drug Interactions with
ART
70
Mechanisms for Drug Interactions
 Altered intracellular activation
 D4T combined with ZDV
 Altered drug absorption and tissue distribution
 Flouroquinolones combined with antacids form
insoluble complex
 Altered drug metabolism
 Rifampicin combined with NVP
 Reduced renal excretion
71
First Pass Effect
 Orally administered drugs
 Absorbed in the gastrointestinal tract
 Pass through the portal venous system to the liver
 Subject to first pass effect in the liver
• May limit systemic circulation
 Once in the systemic circulation, drugs interact with
receptors in target tissues
72
Drug Metabolism/Elimination

Goal of metabolism:
 To change the active part of the medication, making
them more water-soluble and more readily excreted
by the kidney

Metabolism occurs via two types of reactions:
1. Phase I reactions involve:
 Oxidation, hydrolysis, and reduction, take place
primarily in the liver CYP450
2. Phase II reactions involve:
 Conj (adding another compound) to form glucuronides
73
Cytochrome (CYP450)
 Present in liver, small intestines, lungs, and brain
 Primary function is to alter toxins (drugs) to speed
excretion
 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
 important as PIs are metabolized 80-95% by the CYP450
isoenzymes in liver and small intestine
74
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
75
P450 Drug Interactions
 Substrate
 Any drug that is metabolized by one or more of the P450
enzymes
 It is the 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 of substrate drug
Increases level of drug in blood (toxicity is concern)
Quick onset
This process is almost always competitive and reversible
76
CYP P450 Drug-Drug Interactions
 Pharmacologic action of drug is altered by
coadministration of second drug
 Co-administration may:
effect (e.g. ritonavir + saquinavir;
 ritonavir + simvastatin)
Drug B
New effect (e.g., ritonavir +
amitriptyline;)
Drug A
No
Consequences
 effect (e.g.,rifampin +
protease inhibitors, indinavir +
coumadin)
77
Drugs with Potential to Interact with
PIs or NNRTIs
 Statins (simvistatin &
lovastatin)
 Azole antifungals
 Anticonvulsants
 Anti-TB (Rifampicin)
 Warfarin





Midazolam, trizolam
Alternative medicine
Clarithromycin
Oral contraceptives
Amitriptyline
78
Drug interactions - Key Points
 A drug interaction may occur when
 A new medication is started
 A medication is discontinued
 A dose is changed
 Use reference manuals when starting / changing
therapy
 Beware of food requirements with certain ARVs
79
Drug Resistance
Case Study: Berhan
 A 50 year old male patient completed 9 months of TB
therapy (with rifampicin and isoniazid along with
pyridoxine) 3 weeks ago and is continuing with ARV
(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?
81
Principles of HIV Drug Resistance
 Not all drug failure is due to resistance
 Partial HIV suppression promotes resistance
 Resistance can be delayed by suppressing the
virus completely
 RT and protease are flexible (highly mutable)
 Resistance may fade but not disappear when
a drug is stopped
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Principles of Resistance (2)
 Some mutations allow certain viruses to resist
the effects of one or more antiretroviral drugs
 Each infected person has a mixture of viruses,
some of which are resistant to some medications
 The drug resistant virus usually grows faster and
better than the drug susceptible virus
 The drug resistant virus replaces the drug
susceptible virus in the patient
83
Resistance Testing
 Two types:
 Genotyping
• Less expensive
• Can usually be completed in 1-2 weeks
 Phenotyping
• More expensive
• Generally takes 2-3 weeks to complete
84
Suspect Resistance in the Setting of
Treatment Failure
 Due to HIV’s high transcription error rate and
high level of replication, mutant HIV variants
constantly generated
 These variants often contain mutations that
confer variable levels of resistance to
antiretroviral agents
 Poor adherence or suboptimal regimens can
lead to resistance and ‘viral breakthrough’
85
How Does Resistance Develop?
 Results from changes (mutations) in the genetic
information in the virus
 These changes occur whenever HIV is
replicating
 Every possible mutation occurs tens of
thousands of times each day
86
Resistance Mutations
 For some drugs (NNRTIs and 3TC), a single
mutation causes high-level resistance.
 Resistance to these drugs occurs very quickly
 For other drugs (most NRTIs and PIs), many
mutations must occur before high-level
resistance is observed.
 Resistance to these drugs occurs more slowly
87
Cross-Resistance
 Resistance to one drug can cause resistance to
others of the same class
 NNRTI: complete cross-class resistance
 NRTI: partial cross-class resistance
 PI: partial cross-class resistance
• Partly overcome by ritonavir boosting
88
Minimize Emergence of
Viral Resistance
 Never prescribe ARVs in the absence of
adherence counseling and support
 Never prescribe monotherapy or dual therapy
 Ensure optimal serum drug concentrations
 Avoid drug interactions
 Diagnose and manage malabsorption
 If ARV medications are to be discontinued, stop
all drugs at the same time
 Possible exception: NNRTI-based regimen
89
Case Studies
Case Study: Mulu
 48 yo woman has received NVP/3TC/d4T. The
pharmacy has no NVP in stock
 What should she do?
 Continue 3TC/d4T until the NVP becomes available,
then add NVP
 Stop all drugs
 Stop NVP for 7 days then stop 3TC/d4T
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Case Study: Mengistu


A 50 year old man has taken EFV/AZT/3TC for
1 year. He now presents with thrush.
What should he take now?
1.
2.
3.
4.
5.
NVP / 3TC / ddI
NFV / 3TC / d4T
NVP / 3TC / AZT / ABC
LPV/r / d4T / AZT
NFV / TDF / ddI
92
Case Study: Senait


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.
2.
3.
4.
NVP / AZT / 3TC
NFV / AZT / 3TC
NVP / d4T / ddI
NVP / TDF / ABC
93
Case Study

Which of the following is the best regimen for a
patient with HIV who failed EFV/3TC/AZT and
now has active TB?
1.
2.
3.
4.
5.
LPV/r / d4T / ddI
NFV / ddI / TDF
NVP / ddI / TDF
NFV / d4T / TDF
Stop ART; resume after completion of Rifampicin
94
Key Points
 Goals of ART include:
 Suppression of viral replication
 Restoration of immunologic function
 Effective ART requires
 strict adherence,
 proper monitoring of side effects and disease
progression,
 recognition and treatment of co-morbidities.
95
Key Points (2)
 ART involves a combination of at least 3 drugs,
usually 2 NRTIs + 1 NNRTI or 1 PI.
 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.
96
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 receive
a change in dose of their medications.
97
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.
98