Limitations of Antiretroviral Therapy

1
Limitations of Antiretroviral Therapy

• Marshall J Glesby MD PhD
• Associate Professor of Medicine and Public Health
• Weill Medical College of Cornell University
• March 2006

2
Limitations of Current Antiretrovirals

• Adherence
• Resistance
• Cost
• Drug-drug interactions
• Side effects

3
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

4
What Degree of Adherence is Needed? Data From
Unboosted PIs
Adherence to a PI-containing regimen correlates
with HIV RNA response at 3 months
100
80
60
VL lt 400 copies/mL
40
20
0
lt 70
70-0
80-90
90-5
gt 95
PI Adherence, (MEMS caps)
Paterson DL et al. Ann Intern Med. 200013321-30
5
NNRTI Regimens May Be More Forgiving of
Suboptimal Adherence

• 109 indigent patients in San Francisco
• 56 unboosted PI, 53 NNRTI regimen

100
PI
100
NNRTI
80
80
60
60
VL lt 400 copies/mL
40
40
20
20
0
0
0-53
54-73
74-93
94-100
0-53
54-73
74-93
94-100
Adherence (Pill Count)
Adherence (Electronic Measurement)
Bangsberg DR et al. 12th CROI, 2005 abstract 616
6
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
7
3-Drug Combination ART 1996
8AM
4PM
12 MID
AZT 3TC IDV
fasting (1 hour before/2 hours after meals)1.5
liters of hydration/day
8
3-Drug Combination 2006
At Bedtime
TDF/FTC EFV
9
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

10
Limitations of Current Antiretrovirals

• Adherence
• Resistance
• Cost
• Drug-drug interactions
• Side effects

11
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

12
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

13
Drug Levels and Resistance ?1
Increased risk of side effects
Drug concentration
MEC (Minimum Effective Concentratin)
Increased risk of resistance
0
dose
dose
dose
dose
14
Drug Levels and Resistance ?2
Increased risk of side effects
Drug concentration
MEC (Minimum Effective Concentratin)
Increased risk of resistance
0
missed dose
late dose
dose
dose
dose
15
CDC Surveillance of Resistance Mutations In
Naive Patients
7.8
8

• 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

6
Prevalence ()
4
2
0
NRTI
NNRTI
PI
Multi
Bennett D et al. 12th CROI 2005 abstract 674
16
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 2005191339-47
Murphy et al. EACS 2005
17
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 (lt 10 of viral
  population)

18
Mutations Selected by PIs
ltwww.iasusa.orggt
19
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
20
Recommendations for Resistance Tests
Clinical Setting

• Virologic failure
• Suboptimal virologic suppression
• Acute HIV infection

Recommended

• Chronic HIV infection prior to starting ART

Consider

• gt4 weeks after ART drugs are stopped
• Viral load levels lt1000 cpm

Not generally recommended
DHHS Guidelines, 4/7/05
21
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.

22
Limitations of Current Antiretrovirals

• Adherence
• Resistance
• Cost
• Drug-drug interactions
• Side effects

23
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

24
Drug Interactions with ARVs Dose Modification
or Cautious Use

• Oral contraceptives (may require second method)
• Methadone
• Erectile dysfunction agents
• Herbs - St. Johns wort
• Lipid-lowering agents
• Anti-mycobacterials, especially rifampin
• Psychotropics midazolam, triazolam
• Ergot Alkaloids
• Antihistamines astemizole
• Anticonvulsants

25
Limitations of Current Antiretrovirals

• Adherence
• Resistance
• Cost
• Drug-drug interactions
• Side effects

26
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

Virologicalfailure 14.1
Toxicity58.3
n 312
Non-adherence19.6
Other 8.0
Monforte A et al. AIDS 200014499-507d'Arminio
MA et al. AIDS 2000 14499-507O'Brien ME et al.
JAIDS 2003 34407-14Reisler RB et al. JAIDS
2003 34379-86
27
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 lt 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.
28
Adverse Effects of NNRTIs

• Rash, including Stevens-Johnson syndrome with
  nevirapine
• Elevated liver enzymes (nevirapine gt efavirenz,
  delavirdine)
• Incidence of hepatotoxicity highest in women with
  pre-nevirapine CD4 counts gt250 cells/mm3 and men
  with gt400 cells/mm3
• Efavirenz - neuropsychiatric, teratogenic in
  primates (FDA Pregnancy Class D)

29
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

30
Adverse Effects of Entry Inhibitors

• Enfuvirtide (T-20)
• Injection-site reactions
• Hypersensitivity reaction
• Increased incidence of bacterial pneumonia

31
Metabolic Complications of HIV/Antiretroviral
Therapy
Disordered glucose metabolism
Lipid abnormalities
Body fat redistribution

• One syndrome or several?
• One etiology or multifactorial?

32
Multifactorial Etiology of Dyslipidemia
Traditional risk factors
HIV-related factors
Familial hypercholesterolemia obesity
? TGs, ? HDL, ? total chol, ? LDL in untreated
advanced HIV
Antiretroviral-related factors
Most PIs d4T ? TGs, ? total chol, ? LDL
NNRTIs ? total chol, ? HDL EFV ? LDL
33
Cardiovascular and cerebrovascular events (CVE)
in the DAD Study
Incidence of CVE according to duration of ART
exposure

• Follow-up of ongoing, prospective, multinational
  cohort study1
• 36,151 pt-years follow up
• Endpoints include documented
• Myocardial infarction (n127)
• CAD on angiography (n42)
• Stroke (n30 )
• Estimation of theincidence of MI based upon the
  Framingham algorithm2
• Observed rate exceeded predicted rate by
  approximately 25

12 10 8 6 4 2 0
Incidence/1000 PY (95 Cl)
Test for trend plt0.00001
ART exposure (yrs) None lt1 1-2
2-3 3-4 gt4 Total
Events 7 15
22 30 49 76
199 PYFU 5711
4139 4795 5841 7210 8456
36151
http//hin.nhlbi.nih.gov/atpiii/calculator.asp?use
rtypeprof Law MG et al. 11th CROI 2004
abstract 737
34
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 311467-75 Brown TT
et al. Arch Intern Med 20051651179-84
35
Carr A Cooper DA. N Engl J Med 19983391296
36
Abdominal MRI Scans
Control subject
Increased Visceral Fat
37
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 200540121-131
38
Potential Etiologies
Antiretroviral therapy

• HIV infection

Host factors
Hormonal influence
Etiology?
Mitochondrial dysfunction
Immune dysregulation
Non-HIV causes
39
Prometheus Study d4T Clinician Reported
Lipodystrophy
1.00
SQV/RTV
P 0.003
0.75
SQV/RTV/d4T
0.50
Lipodystrophy-free survival
0.25
0.00
48
36
96
84
72
60
24
12
0
Time (weeks)
82
85
n 87
75
88
n 88
No. of patients not reported at 96 weeks
van der Valk M, et al. AIDS 2001 15847855
40
Role of Different NRTIs on Morphologic Changes
Change in Limb Fat (A5005)
N156 analysis by intent to treat
3TC/ZDV
ddId4T
20


10


IQR
0
Median change from baseline


-10



-20
-30
Entry
16
32
48
64
80
Study Week
Plt0.05 between groups Plt0.05 within groups.
Dube M, et al. 4th Lipo Wkshp 2002 abstract 27
41
Dube MP et al. AIDS 2005191807-18
42
(No Transcript)
43
MITOX Limb Fat over 18 months
HIV-infected patients with moderate to severe
lipoatrophy
1.29 kg (36)
Mean change (kg)
0.55 kg (15)
0.16 kg (4)
Week
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 181029
44
Will Non-Thymidine Analog Based RegimensPrevent
Lipoatrophy? Gilead 903 Study
10
9
8.6
7.9
8
7
6
Kilograms
5.0
5
4.5
4
3
2
1
0
48
96
144
Weeks
TDF 3TC EFV 128 115 d4T 3TC EFV 134 117
Gallant JE et al. JAMA 2004292191-201
45
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 200132130
Hadigan et al, JCEM 200186939-43
46
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 200014F63-7 Mondy K et al,
Clin Infect Dis 2003 36482-90
47
(No Transcript)
48
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 2003171-9
49
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