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Limitations of Antiretroviral Therapy
Marshall J Glesby MD PhDAssociate Professor of Medicine and Public Health
Weill Medical College of Cornell UniversityMarch 2006
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Limitations of Current Antiretrovirals
Adherence
Resistance
Cost
Drug-drug interactions
Side effects
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Adherence
A major determinant of degree and duration of viral suppression
Poor adherence associated with virologic failure Optimal suppression requires excellent adherence Suboptimal adherence is common
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What Degree of Adherence is Needed? Data From Unboosted PIs
Adherence to a PI-containing regimen correlates with HIV RNA response at 3 months
% V
L <
400
co
pie
s/m
L
PI Adherence, % (MEMS caps)
0
20
40
60
80
100
< 70 70–-0 80-90 90–-5 > 95
Paterson DL et al. Ann Intern Med. 2000;133:21-30
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NNRTI Regimens May Be More Forgiving of Suboptimal Adherence
109 indigent patients in San Francisco• 56 unboosted PI, 53 NNRTI regimen
Bangsberg DR et al. 12th CROI, 2005; abstract 616
PINNRTI
0-53 54-73 74-93 94-1000
20
40
60
80
100
% V
L <
400
co
pie
s/m
L
% Adherence (Pill Count)
0-53 54-73 74-93 94-1000
20
40
60
80
100
% Adherence (Electronic Measurement)
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Predictors of Inadequate Adherence
Regimen complexity and pill burden Poor clinician-patient relationship Active drug use or alcoholism Unstable housing Mental illness (especially untreated depression) Lack of patient education Medication adverse effects (or fear of them)
Not age, race, sex, educational level, socioeconomic status, past history of alcoholism or drug use
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3-Drug Combination ART: 1996
8AM 4PM 12 MID
fasting (1 hour before/2 hours after meals)1.5 liters of hydration/day
AZT +
3TC
+
IDV
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3-Drug Combination: 2006
At Bedtime
TDF/FTC
+
EFV
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Improving Adherence
Establish readiness to start therapy
Provide education on medication dosing
Review potential side effects
Anticipate and treat side effects
Utilize educational aids including pictures, pillboxes, and calendars
Individualized adherence programs
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Limitations of Current Antiretrovirals
Adherence
Resistance
Cost
Drug-drug interactions
Side effects
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Mutations Occur Spontaneously in the HIV Genome
HIV makes copies of itself very rapidly ~ 1-10 billion new virus particles/day
During its replication, HIV is prone to make errors when copying itself
This results in mutations or errors in the genetic material of the virus which make the structure of the offspring virus slightly different to that of the parent virus
Some of these mutations will result in an increased ability of the virus to grow in the presence of antiretroviral drugs
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Partial Viral Suppression Leads to Selection of Resistant Virus
When HIV replication is not blocked completely….
• Sub-optimal therapy regimens (e.g. partially suppressive regimens)
• Adherence problems
• Pharmacokinetic problems: poor drug absorption, inadequate dosing, drug-drug interactions, interperson differences in PK
….drug-resistant virus, already present in the population, is selected for and ultimately dominates
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Drug Levels and Resistance 1
dose
Increased risk of side effects
0
Increased risk of resistance
dose dose dose
MEC(Minimum Effective Concentratin)
Drug concentration
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Drug Levels and Resistance 2
dose misseddose
dosedose latedose
Increased risk of side effects
0
Increased risk of resistance
MEC(Minimum Effective Concentratin)
Drug concentration
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CDC Surveillance of Resistance Mutations In Naive Patients
633 newly diagnosed patients genotyped at 89 sites in 6 states in 2003-2004
14.5% prevalence of resistance mutations
• NRTI, 7.8%
• NNRTI, 3.0%
• PI, 0.7%
• Multiclass, 0.7%
Bennett D et al. 12th CROI 2005; abstract 674
Pre
vale
nce
(%
)
7.8%
3.0%
0
2
4
6
NRTI NNRTI PI Multi
0.7%
8
0.7%
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HAART Observational Medical Evaluation & Research Study
Pts who initiated HAART from 8/96-9/99 in B.C.
~25% developed drug resistance mutations during 30 m of f/u
However, with 7-year f/u of lopinavir/r + d4T/3TC in naïve pts: no d4T or LPV resistance; 3% 3TC resistance
Harrigan et al. J Infect Dis 2005;191:339-47
Murphy et al. EACS 2005
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Resistance Testing
Genotypic resistance test• Perform test that gives mutations in viral genes
Phenotypic resistance test• Perform test that describes growth of virus in the presence
of anti-HIV drugs Limitations:
• Cannot detect minority species (< 10% of viral population)
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Mutations Selected by PIs
APV 32 46 47 50 54 73 908410
L V M I G I LII
FIRV I VIL S V MLVMV
9077 82 84 887146363010
FI N I IL I AFTS
VT V MDS
L D M M V VA I LN
NFV
48 9077 82 8473715410
IRV VL I A V MV SVT
L I V VA I LG G
SQV
10 20 32 33 36 46 54 82 847771 90
FIRV I F IL VL I AFTS
VT V MMR IRTV
L K V M M I V VA I LL
IRV II I IL V I AFTVT SA V MMR
82 84777371544632 3610 20 24 90
L K VL M M I V VA G I L
IDV
AFTS
FIRV MR VA VI F IL VLMTS
VT V MI L P S
L K VL M I VA G I LL I I F L8273 84 9046 54 7147 50 53 6332 3310 20 24
LPV-RTV
10 20 33 46 54 82 84 90IV IFV I V AFL
TV MMLT
TPV- RTV
L K M I V I LL
FIRV IL VML AFTS
V M
82 84544610 90L M I V I L
Multi-PII
V
32
A
20RMI
K
10IFV
L
24I
L
33
IFV
L
36
ILV
M
V S
48
V
G II A V
ATV 50 8410
VL
71
I
M46
L
I54 82
M
L9088
N
I
V
32 73
CSTA
G
20 24 33 36 48
<www.iasusa.org>
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Genopheno: An Example
RT: Q102K, D123E, I142V, C162S, V179I, T200A, I202V, R211Q, R277K, T286P, E297APR: K14R, I15V, M36A, R41K, K55R, I62V, I66L, G68E, H69Y, K70KIK, I93L
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Recommendations for Resistance Tests
>4 weeks after ART drugs are stopped Viral load levels <1000 cpm
Not generally recommended
Chronic HIV infection prior to starting ART
Consider
Virologic failure Suboptimal virologic suppression Acute HIV infection
Recommended
Clinical Setting
DHHS Guidelines, 4/7/05
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Antiretroviral Resistance: Conclusions
HIV growth leads to diversity. Not suppressing viral load levels in the presence
of antiretroviral drugs leads to resistant virus. HIV drugs have unique resistance patterns, but
cross-resistance may occur. Resistance testing offers benefits in choosing the
next drug combination.
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Limitations of Current Antiretrovirals
Adherence
Resistance
Cost
Drug-drug interactions
Side effects
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Metabolism of PIs/NNRTIs
Metabolized by cytochrome P450, especially CYP 3A4
Levels of PIs and NNRTIs may be affected by concurrently administered drugs
PIs, especially ritonavir, inhibit CYP 3A4 potentially leading to increased levels of concurrently administered drugs
Efavirenz and nevirapine can induce and inhibit CYP 3A4
Fewer drug-drug interactions with NRTIs
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Drug Interactions with ARVs: Dose Modification or Cautious Use
Oral contraceptives (may require second method)
Methadone
Erectile dysfunction agents
Herbs - St. John’s wort
Lipid-lowering agents
Anti-mycobacterials, especially rifampin
Psychotropics – midazolam, triazolam
Ergot Alkaloids
Antihistamines – astemizole
Anticonvulsants
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Limitations of Current Antiretrovirals
Adherence
Resistance
Cost
Drug-drug interactions
Side effects
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Treatment-Limiting Side Effects
Cohort data from pts on older PI-based HAART regimens (e.g. IDV, NFV) indicated that 20-25% or more stopped or changed their 1st regimen due to side effects
Appears to be less frequent with current regimens
Rate of life-threatening adverse events exceeded AIDS events among ~3,000 pts in 5 multicenter trials
Toxicity58.3%
Virologicalfailure 14.1%
Non-adherence19.6%
Other8.0%
Reasons for treatment switch / discontinuation of 1st HAART regimen
n = 312
Monforte A et al. AIDS 2000;14:499-507d'Arminio MA et al. AIDS 2000; 14:499-507
O'Brien ME et al. JAIDS 2003; 34:407-14Reisler RB et al. JAIDS 2003; 34:379-86
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Adverse Effects of NRTIs*
Zidovudine (AZT)- headache, GI intolerance, bone marrow suppression
Abacavir - hypersensitivity reaction
Didanosine (ddI) - GI intolerance, pancreatitis, peripheral neuropathy
Stavudine (d4T) - peripheral neuropathy, pancreatitis, lipoatrophy
Zalcitabine (ddC) - peripheral neuropathy, oral ulcers
Lamivudine (3TC) – rare side effects
Emtricitabine (FTC) – side effects uncommon; hyperpigmentation of palms/soles < 2% (non-Whites)
Tenofovir - headache, GI intolerance, renal insufficiency
*Lactic acidosis is a class effect, most strongly associated with d4T/ddI; 3TC, FTC, and tenofovir are active against HBV. Development of HBV resistance may lead to flare of hepatitis.
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Adverse Effects of NNRTIs
Rash, including Stevens-Johnson syndrome with nevirapine
Elevated liver enzymes (nevirapine > efavirenz, delavirdine)• Incidence of hepatotoxicity highest in women with
pre-nevirapine CD4 counts >250 cells/mm3 and men with >400 cells/mm3
Efavirenz - neuropsychiatric, teratogenic in primates (FDA Pregnancy Class D)
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Acute Adverse Effects of PIs
GI intolerance, diarrhea
Hyperbilirubinemia –atazanavir, indinavir
Hepatotoxicity
Increased bleeding in hemophiliacs
Adverse metabolic effects • Dyslipidemia• Insulin resistance• ? Lipodystrophy/fat redistribution• Atazanavir has favorable metabolic profile
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Adverse Effects of Entry Inhibitors
Enfuvirtide (T-20)• Injection-site reactions
• Hypersensitivity reaction
• Increased incidence of bacterial pneumonia
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Metabolic Complications of HIV/Antiretroviral Therapy
One syndrome or several? One etiology or multifactorial?
Body fatBody fatredistributionredistribution
LipidLipidabnormalitiesabnormalities
Bone Bone DisordersDisorders
Mitochondrial Mitochondrial toxicitytoxicity
DisorderedDisorderedglucose glucose
metabolismmetabolism
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Multifactorial Etiology of Dyslipidemia
Antiretroviral-relatedfactors
Traditional risk factors
HIV-relatedfactors
↑ TGs, ↓ HDL, ↓ total chol, ↓ LDL in untreated advanced HIV
Familial hypercholesterolemia; obesity
Most PIs & d4T: ↑ TGs, ↑ total chol, ↑ LDL; NNRTIs: ↑ total chol, ↑ HDL; EFV: ↑ LDL
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Cardiovascular and cerebrovascular events (CVE) in the D:A:D Study
Follow-up of ongoing, prospective, multinational cohort study1
36,151 pt-years follow up
Endpoints include documented:
• Myocardial infarction (n=127)
• CAD on angiography (n=42)
• Stroke (n=30 )
Estimation of theincidence of MI based upon the Framingham algorithm2
• Observed rate exceeded predicted rate by approximately 25%
http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof Law MG et al. 11th CROI 2004; abstract 737
12
10
8
6
4
2
0Inci
den
ce/
100
0 P
Y (
95%
Cl)
Incidence of CVE according to duration of ART exposure
ART exposure (yrs) None <1 1-2 2-3 3-4 >4 Total Events 7 15 22 30 49 76 199 PYFU 5711 4139 4795 5841 7210 8456 36151
Test for trendp<0.00001
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Disordered Glucose Metabolism
Prevalence of diabetes mellitus increased among HIV+ pts on protease inhibitors• Prevalence ~2-14%
Insulin resistance (higher concentrations of insulin required for usual effects) more common
MACS: Risk of new onset DM ~ 4 x higher in HIV+ men vs. HIV- men (adjusted for age, BMI)
Dube M Clin Infect Dis 2000; 31:1467-75 Brown TT et al. Arch Intern Med 2005;165:1179-
84
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35 Carr A Cooper DA. N Engl J Med 1998;339:1296
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Abdominal MRI Scans
Control subject Increased Visceral Fat
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“Lipodystrophy Syndrome”
No generally accepted case definition of syndrome(s) Initial reports suggested clustering of:
• Central fat accumulation/adiposity
• Lipoatrophy/fat wasting
• Dyslipidemia
• Insulin resistance/type 2 diabetes mellitus Recent cross-sectional epidemiological data question
linkage of lipoatrophy and fat accumulation
Fram J Acquir Immune Defic Syndr 2005;40:121-131
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Potential Etiologies
Etiology?
HIV infection
Hormonal influence
Immune dysregulation
Non-HIV causes
Mitochondrial dysfunction
Host factors
Antiretroviral therapy
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4836
Lipo
dyst
roph
y-fr
ee
surv
ival
Time (weeks)
P = 0.003
Prometheus Study: d4T & Clinician Reported Lipodystrophy
7588n = 888285n = 87
van der Valk M, et al. AIDS 2001; 15:847–855
96847260241200.00
0.25
0.50
0.75
1.00SQV/RTV
SQV/RTV/d4T
No. of patients not reported at 96 weeks
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Role of Different NRTIs on Morphologic Changes: Change in Limb Fat (A5005)
IQR
** *
†
††
†
††
N=156; analysis by intent to treat
Me
dia
n %
ch
ang
e f
rom
ba
sel
ine
*P<0.05 between groups; †P<0.05 within groups.
Dube M, et al. 4th Lipo Wkshp 2002; abstract 27
-30
-20
-10
0
10
20
Study Week
3TC/ZDV ddI+d4T
Entry 16 32 48 64 80
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41 Dube MP et al. AIDS 2005;19:1807-18
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MITOX: Limb Fat over 18 months
0
0.5
1
1.5
0 12 24 36 48 60 72
ABC
ABC from week 24
d4Tor ZDV
Me
an
ch
an
ge
(kg
)
Week
1.29 kg (36%)
0.55 kg (15%)
0.16 kg (4%)
n= ABC 47 42 35 33
ABC week 24 23 19 15 13 d4T or ZDV 29 25 22 19
Martin A et al. AIDS 2004; 18:1029
HIV-infected patients with moderate to severe lipoatrophy
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Will Non-Thymidine Analog Based RegimensPrevent Lipoatrophy? Gilead 903 Study
TDF + 3TC + EFV 128 115d4T + 3TC + EFV 134 117
Weeks
*p < 0.001
TDF + 3TC + EFVd4T + 3TC + EFV
Kil
og
ram
s
8.6*
4.5
0
1
2
3
4
5
6
7
8
9
10
48 96 144
5.0
7.9*
Gallant JE et al. JAMA 2004;292:191-201
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Cardiovascular Risk Factors in Lipodystrophy
Compared with age and BMI matched controls from the Framingham Offspring Study, HIV+ pts with self-reported lipodystrophy had:
• higher prevalence of impaired glucose tolerance/diabetes
• higher diastolic blood pressure
• elevated triglycerides, total cholesterol (not LDL-C)
• lower HDL-C
• increased PAI-1 and tPA (markers of impaired fibrinolysis-- ability to break down blood clots )
Some pts with lipodystrophy appear to have a metabolic syndrome that theoretically could predispose to accelerated atherosclerosis and diabetes
Hadigan et al, Clin Infect Dis 2001;32:130 Hadigan et al, JCEM 2001;86:939-43
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Osteopenia/Osteoporosis
Decreased bone mineral density (BMD) initially reported in HIV+ on PIs (plus NRTIs)
Subsequent reports of higher prevalence of decreased BMD in ARV naïve pts and increases in BMD while on PI-containing HAART
Multifactorial etiology: HIV, cytokines, endocrine factors, liver disease, smoking, ? antiretrovirals
Tebas P et al, AIDS 2000;14:F63-7 Mondy K et al, Clin Infect Dis 2003 ;36:482-90
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Osteonecrosis
Avascular necrosis = aseptic necrosis = osteonecrosis• death of cellular constituents of bone & marrow due to ischemia
(decreased blood supply)
Associated with corticosteroid use, possibly duration of antiretroviral therapy & immune recovery
Most commonly presents as hip pain
MRI is test of choice if symptoms suggest dx
Conservative management for early stages of disease
Surgery• total hip replacement vs. core decompression
Allison et al, AIDS 2003;17:1-9
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Conclusions
Adherence, resistance, drug-drug interactions, and side effects (short- and long-term) are important limitations of antiretroviral therapy
Regimen choices usually based on potential advantages/options• Decreased dosing frequency and pill burden
• Tolerability
• Pharmacokinetic profiles
• Resistance considerations
• Improved metabolic profiles