Download Limitations of Antiretroviral Therapy

Limitations of
Antiretroviral Therapy
Marshall J Glesby MD PhD
Associate Professor of Medicine and Public Health
Weill Medical College of Cornell University
March 2006
Limitations of Current Antiretrovirals
 Adherence
 Resistance
 Cost
 Drug-drug interactions
 Side effects
2
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
3
What Degree of Adherence is Needed?
Data From Unboosted PIs
Adherence to a PI-containing regimen correlates
with HIV RNA response at 3 months
% VL < 400 copies/mL
100
80
60
40
20
0
< 70
70–-0
80-90
90–-5
> 95
PI Adherence, % (MEMS caps)
4
Paterson DL et al. Ann Intern Med. 2000;133:21-30
NNRTI Regimens May Be More Forgiving
of Suboptimal Adherence
 109 indigent patients in San Francisco
• 56 unboosted PI, 53 NNRTI regimen
% VL < 400 copies/mL
100
100
PI
NNRTI
80
80
60
60
40
40
20
20
0
0
0-53
54-73
74-93
0-53
54-73
74-93
94-100
% Adherence (Electronic Measurement)
94-100
% Adherence (Pill Count)
5
Bangsberg DR et al. 12th CROI, 2005; abstract 616
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
6
3-Drug Combination ART: 1996
8AM
4PM
AZT
+
3TC
+
IDV
fasting (1 hour before/2 hours after meals)1.5 liters of hydration/day
7
12 MID
3-Drug Combination: 2006
At
Bedtime
TDF/FTC
+
EFV
8
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
9
Limitations of Current Antiretrovirals
 Adherence
 Resistance
 Cost
 Drug-drug interactions
 Side effects
10
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
11
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
12
Drug Levels and Resistance
1
Increased risk of side effects
Drug
concentration
MEC
(Minimum
Effective
Concentratin)
Increased risk of resistance
0
dose
dose
dose
13
dose
Drug Levels and Resistance
2
Increased risk of side effects
Drug
concentration
MEC
(Minimum
Effective
Concentratin)
Increased risk of resistance
0
dose
missed
dose
dose
14
late
dose
dose
CDC Surveillance of Resistance Mutations
In Naive Patients
8
Prevalence (%)
 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%
7.8%
6
4
3.0%
2
0.7%
0.7%
PI
Multi
0
NRTI NNRTI
15
Bennett D et al. 12th CROI 2005; abstract 674
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
16
Harrigan et al. J Infect Dis 2005;191:339-47
Murphy et al. EACS 2005
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)
17
Mutations Selected by PIs
Multi-PI
IDV
L
10
V
M
32
46
54
FIRV
I
IL
VML
L
10
K
20
IRV MR
RTV
SQV
NFV
APV
LPVRTV
ATV
TPVRTV
I
A
G
54
71
73
77
V
VT SA
I
54
VL
A
71
VT
I
A
G
V
M
M
I
32
36
46
I
I
I
IL
M
36
I
M
46
IL
V
32
I
L
33
F
I
L
82 84
AFT
S
V V
L
24
L
K
10 20
FIRV MR
V
90
V
M
I
L
82 84
90
AFT
V
M
V V
77 82
I AFT
S
V V
I
V
L
90
M
I
L
I
84
L
G
10
48
54
71
73
77
82
84
90
IRV
V
VL
VT
S
I
A
V
M
V
I
L
D
M
M
A
V
10
FI
30
36
I
46
IL
71
VT
77 82 84
I AFT V
S
I
N
L
V
M
I
I
10
FIRV
32
I
46
IL
47
V
50
I
54
G
73
V
LVM
S
M
I
L
K
L
10 20 24
FIRV MR
L
10
10
K
I
I
L
V
20 24
24
20
IFV RMI
L
K
10 20
IV MLT
V
I
L
32 33
F
IL
32
L M
33 36
M
46
I
IFV ILV
I
L
33
IFV
I
46 47
VA
V
G
48
48
V
M
46
I
F
I
I
50
L
L
VL P
MTS
I
54
L
I
54
V
18
L
50 53 54 63
A
G
V
N
L
88
DS
90
M
84
L
90
V
M
I
L
71 73
82 84
90
VT
S
M
A
G
73
AFT V
S
I
V
84
82
88
L
90
A
V
S
M
V
I
71
V CSTA
82 84
AFL
T
V
N
L
90
M
<www.iasusa.org>
Genopheno: An Example
RT: Q102K, D123E, I142V, C162S, V179I, T200A, I202V, R211Q, R277K, T286P, E297A
PR: K14R, I15V, M36A, R41K, K55R, I62V, I66L, G68E, H69Y, K70KIK, I93L
19
Recommendations for Resistance Tests
Clinical Setting
Recommended
 Virologic failure
 Suboptimal virologic suppression
 Acute HIV infection
Consider
 Chronic HIV infection prior to starting
ART
Not generally
recommended
 >4 weeks after ART drugs are stopped
 Viral load levels <1000 cpm
20
DHHS Guidelines, 4/7/05
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.
21
Limitations of Current Antiretrovirals
 Adherence
 Resistance
 Cost
 Drug-drug interactions
 Side effects
22
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
23
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
24
Limitations of Current Antiretrovirals
 Adherence
 Resistance
 Cost
 Drug-drug interactions
 Side effects
25
Treatment-Limiting Side Effects
Reasons for treatment switch /
discontinuation of 1st HAART regimen
 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
Toxicity
58.3%
n = 312
26
Virological
failure 14.1%
Other Non-adherence
19.6%
8.0%
Monforte A et al. AIDS 2000;14:499-507
d'Arminio MA et al. AIDS 2000; 14:499-507
O'Brien ME et al. JAIDS 2003; 34:407-14
Reisler RB et al. JAIDS 2003; 34:379-86
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.
27
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)
28
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
29
Adverse Effects of Entry Inhibitors
 Enfuvirtide (T-20)
• Injection-site reactions
• Hypersensitivity reaction
• Increased incidence of bacterial pneumonia
30
Metabolic Complications of HIV/Antiretroviral
Therapy
Lipid
abnormalities
Mitochondrial
toxicity
Disordered
glucose
metabolism
Body fat
redistribution
 One syndrome or several?
 One etiology or multifactorial?
31
Bone
Disorders
Multifactorial Etiology of Dyslipidemia
Traditional risk
factors
HIV-related
factors
Familial
hypercholesterol
emia; obesity
Antiretroviral-related
factors
↑ TGs, ↓ HDL, ↓
total chol, ↓ LDL
in untreated
advanced HIV
Most PIs & d4T: ↑ TGs, ↑
total chol, ↑ LDL;
NNRTIs: ↑ total chol, ↑
HDL; EFV: ↑ LDL
32

Follow-up of ongoing,
prospective, multinational
cohort study1

36,151 pt-years follow up

Endpoints include
documented:

Incidence/1000 PY (95% Cl)
Cardiovascular and cerebrovascular events
(CVE) in the D:A:D Study
Incidence of CVE according to
duration of ART exposure
12
10
8
6
• Myocardial infarction
4
(n=127)
2
• CAD on angiography
0
(n=42)
ART exposure (yrs)
• Stroke (n=30 )
Events
PYFU
Estimation of the
incidence of MI based upon
the Framingham algorithm2
• Observed rate exceeded
predicted rate by
approximately 25%
Test for trend
p<0.00001
None
7
5711
<1
15
4139
1-2
22
4795
2-3
30
5841
3-4
49
7210
>4
76
8456
Total
199
36151
http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof
Law MG et al. 11th CROI 2004; abstract 737
33
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)
34
Dube M Clin Infect Dis 2000; 31:1467-75
Brown TT et al. Arch Intern Med 2005;165:1179-84
35
Carr A Cooper DA. N Engl J Med 1998;339:1296
Abdominal MRI Scans
Control subject
Increased Visceral Fat
36
“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
37
Fram J Acquir Immune Defic Syndr 2005;40:121-131
Potential Etiologies
Antiretroviral
therapy
HIV
infection
Host factors
Hormonal
influence
Etiology?
Mitochondrial
dysfunction
Immune
dysregulation
Non-HIV
causes
38
Prometheus Study: d4T & Clinician Reported
Lipodystrophy
1.00
SQV/RTV
Lipodystrophy-free
survival
P = 0.003
0.75
SQV/RTV/d4T
0.50
0.25
0.00
0
12
24
48
36
60
72
84
96
Time (weeks)
n = 87
n = 88
85
88
82
75
No. of patients not reported at 96 weeks
39
van der Valk M, et al. AIDS 2001; 15:847–855
Role of Different NRTIs on Morphologic
Changes: Change in Limb Fat (A5005)
N=156; analysis by intent to treat
3TC/ZDV
20
†
10
ddI+d4T
†
†
†
IQR
0
†
*
-10
†
*
-20
*
-30
Entry
16
32
48
64
80
Study Week
*P<0.05 between groups; †P<0.05 within groups.
40
Dube M, et al. 4th Lipo Wkshp 2002; abstract 27
41
Dube MP et al. AIDS 2005;19:1807-18
42
MITOX: Limb Fat over 18 months
Mean change (kg)
HIV-infected patients with moderate to
severe lipoatrophy
1.29 kg (36%)
1.5
ABC
ABC from week 24
d4Tor ZDV
1
0.5
0.55 kg (15%)
0
0.16 kg (4%)
0
12
24
36
48
60
72
Week
n= ABC
47
ABC week 24 23
d4T or ZDV
29
42
19
25
35
15
22
43
33
13
19
Martin A et al. AIDS 2004; 18:1029
Will Non-Thymidine Analog Based Regimens
Prevent Lipoatrophy? Gilead 903 Study
10
9
8
8.6*
7.9*
TDF + 3TC + EFV
d4T + 3TC + EFV
*p < 0.001
7
6
5.0
5
4
4.5
3
2
1
0
48
96
144
Weeks
TDF + 3TC + EFV
d4T + 3TC + EFV
128
134
115
117
44
Gallant JE et al. JAMA 2004;292:191-201
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
45
Hadigan et al, Clin Infect Dis 2001;32:130
Hadigan et al, JCEM 2001;86:939-43
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
46
Tebas P et al, AIDS 2000;14:F63-7
Mondy K et al, Clin Infect Dis 2003 ;36:482-90
47
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
48
Allison et al, AIDS 2003;17:1-9
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
49