Why do patients develop virologic failure

1
Why do patients develop virologic failure?
Sharon WalmsleyCanada
2
Good news treatment response after first 6
months of HAART is improving
100

• Data from 12 cohort studies across Europe and
  North America
• Patients starting HAART between 1995 and 2003
  (total n 22,217)

82
83
82
81
76
73
80
58
60
Patients with viral load 500 HIV RNA copies/mL
()
40
20
0
1995-1996
1997
1998
1999
2000
2001
2002-2003
Year of starting HAART
ART Cohort Collaboration Lancet 2006 368451458
3
Why do patients stop first-line treatment?
Reason N CD4 VL Unknown 49 312
2.26 Other 112 391 2.60 Choice
189 364 2.60 Toxicities 190 386
2.28 Failure 86 328 3.78
p0.27 plt0.0001
p0.18
100
80
60
40
20
0
1999
2000
2001
2002
Calendar year of starting HAART
Mocroft A et al. AIDS Res Hum Retroviruses 2005
21527536
4
Factors that may prevent patients achieving or
maintaining an undetectable viral load
Inconvenientregimen
Toxicities
Non-adherence
Reducedefficacy
Drugdruginteractions
Resistance
VIROLOGIC FAILURE
5
Factors that may prevent patients achieving or
maintaining an undetectable viral load
Inconvenientregimen
Toxicities
Non-adherence
Reducedefficacy
Drugdruginteractions
Resistance
VIROLOGIC FAILURE
6
Some regimens are not recommended due to
suboptimal antiviral potency

• US DHHS guidelines advise against the following
  regimens because of suboptimal antiviral potency

didanosine tenofovir efavirenz (or
nevirapine) not recommended as initial therapy
3-NRTI REGIMENS COMPRISING
abacavir tenofovir lamivudine (or
emtricitabine)
didanosine tenofovir lamivudine (or
emtricitabine)
DHHS Guidelines for the use of antiretroviral
agents in HIV-infected adults and adolescents.
http//aidsinfo.nih.gov/guidelines
7
Factors that may prevent patients achieving or
maintaining an undetectable viral load
Inconvenientregimen
Toxicities
Non-adherence
Reducedefficacy
Drugdruginteractions
Resistance
VIROLOGIC FAILURE
8
Prevalence of drug resistance in treatment-naive
patients
France512
UK79
Canada210
US(33 States)4 13
Germany111
Switzerland3 8
Mexico94
Australia8 (Victoria) 13
Brazil67
Botswana10(estimated) lt 5
Rates cannot be cross-compared. Duration of
infection prior to resistance testing varies by
study. Definition of resistance may vary by study
1. Oette M, et al. J Acquir Immune Defic Syndr
2006 41573581. 2. Brooks JI, et al. Antivir
Ther 2006 11 (suppl 1)S119 (abstract
106) 3. Yerly S, et al. Antivir Ther 2006 11
(suppl 1)S118 (abstract 105) 4. Ross LL, et al.
Antivir Ther 2006 11 (suppl 1)S120 (abstract
107) 5. Chaiz ML, et al. Antivir Ther 2006 11
(suppl 1)S123 (abstract 110)
6. Brindeiro RM, et al. AIDS 2003
1710631069 7. Health Protection Agency. CDR
Weekly 2006 16 8. Middleton T, et al. Antivir
Ther 2004 9S110 9. Escoto-Delqadillo M, et al.
XV International AIDS Conference 2004 abst
B11496 10. Vardavas R Blower S. Antivir Ther
2005 10 (suppl 1)S154 (abstract 141)
9
Prevalence of drug resistance in treatment-naive
patients
France512
UK79
Canada210
US(33 States)4 13
Germany111
Switzerland3 8
Mexico94
Australia8 (Victoria) 13
Brazil67
Botswana10(estimated) lt 5
Resistance Before You Start HAARTThursday,
10451215, Session Room 9
Rates cannot be cross-compared. Duration of
infection prior to resistance testing varies by
study. Definition of resistance may vary by study
1. Oette M, et al. J Acquir Immune Defic Syndr
2006 41573581. 2. Brooks JI, et al. Antivir
Ther 2006 11 (suppl 1)S119 (abstract
106) 3. Yerly S, et al. Antivir Ther 2006 11
(suppl 1)S118 (abstract 105) 4. Ross LL, et al.
Antivir Ther 2006 11 (suppl 1)S120 (abstract
107) 5. Chaiz ML, et al. Antivir Ther 2006 11
(suppl 1)S123 (abstract 110)
6. Brindeiro RM, et al. AIDS 2003
1710631069 7. Health Protection Agency. CDR
Weekly 2006 16 8. Middleton T, et al. Antivir
Ther 2004 9S110 9. Escoto-Delqadillo M, et al.
XV International AIDS Conference 2004 abst
B11496 10. Vardavas R Blower S. Antivir Ther
2005 10 (suppl 1)S154 (abstract 141)
10
Factors that may prevent patients achieving or
maintaining an undetectable viral load
Inconvenientregimen
Toxicities
Non-adherence
Reducedefficacy
Drugdruginteractions
Resistance
VIROLOGIC FAILURE
11
How much adherence?
patients with HIV-1 RNA lt 400 copies/mL
100
90
80
70
60
patients
50
40
p 0.00001
30
20
10
0
gt 95
9095
8090
7080
lt 70
Level of adherence ()
Paterson D, et al. Ann Intern Med 2000 1332130
12
Boosted PIs may be more forgiving with regards to
non-adherence

• HOMER cohort
• n 1,634
• 19962003
• Patients suppressed on first-line HAART
• Failure defined as HIV RNA 1000 copies/mL on
  two consecutive occasions

Risk of failure with lt 95 adherence
Unboosted PI (n 752)
NNRTI (n 631)
Boosted PI (n 251)
0
0.5
1
1.5
2
2.5
3
Adjusted hazard ratio (95 CIs)
Adjusted for sex, age, IDU, CD4 cell count,
AIDS diagnosis, physician experience
Gross R, et al. 13th CROI 2006 abstract 533
13
Factors that may prevent patients achieving or
maintaining an undetectable viral load
Inconvenientregimen
Toxicities
Non-adherence
Reducedefficacy
Drug-druginteractions
Resistance
VIROLOGIC FAILURE
14
Patient survey important factors in choosing ARVs

• The least-tolerable side effects were reported
  as
• Diarrhoea 75
• Nausea 49
• Fatigue 47
• Body-shape changes 45
• Neuropathy 41

50
44
45
40
35
27
30
Responses ()
25
20
20
15
10
5
0
Potency
Side effects
Convenience
Survey n 357
Boyle BA, et al. XV International AIDS Conference
2004 abstract WePeB5815
15
Lipodystrophy syndrome has a major impact on
patient well-being
Lipoatrophy Wasted arms, legs, buttocks and face
Lipohypertrophy Pot-belly, buffalo-hump,
enlarged breasts
Profound effect on psychosocial well-being of
patients

• 67 of patients questioned would rather lose a
  year of life gained by HAART than have
  lipodystrophy1
• gt 95 adherence was significantly greater in
  patients without lipodystrophy2

1. Echavez M Horstman W. AIDS Reader 2005
15369375 2. Marin A, et al. 3rd IAS Conference
2005 abstract WePe12.7C34
16
Many ARVs are associated with increased lipid
levels

• NRTI especially d4T
• NNRTI especially EFV
• PI especially LPV/r

17
Many ARVs are associated with increased lipid
levels

• NRTI especially d4T
• NNRTI especially EFV
• PI especially LPV/r

30
25
Grade 34(gt 300 mg/dL)
20
Incidence of abnormal fasting cholesterol levels
15
11
9
10
5
0
FPV/r(n 436)
LPV/r(n 443)
KLEAN studytreatment-naive patients
Eron J, et al. Lancet 2006 368 47682.
18
Many ARVs are associated with increased lipid
levels

• NRTI especially d4T
• NNRTI especially EFV
• PI especially LPV/r

30
25
Grade 34(gt 300 mg/dL)
20
Incidence of abnormal fasting cholesterol levels
15
11
9
New IAS-USA guidelines for boosted PIs in
patients with lipid concerns suggest use of ATV/r
or SQV/r
10
5
0
FPV/r(n 436)
LPV/r(n 443)
KLEAN studytreatment-naive patients
Eron J, et al. Lancet 2006 368 47682.
Adapted from Hammer et al. JAMA 2006 296827-43
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• N 310, fully enrolled
• Canada
• USA
• Thailand
• France
• Puerto Rico
• Duration 48 weeks
• Inclusion criteria
• Treatment naive
• CD4 lt 350 cells/mm3
• HIV RNA gt 10,000 copies/mL

Saquinavir/r 1000/100 mg bid TDF/FTC

• 11 randomization

Lopinavir/r 400/100 mg bid TDF/FTC
20
BASICBoosted Atazanavir- or Saquinavir-Induced
lipid Changes

• N 120
• Netherlands, UK, USA, Germany, France, Poland
• Duration 48 weeks
• Inclusion criteria
• Treatment naive with treatment indication
• Effects on lipid profile
• Effects on body fat distributionby CT and DEXA

Saquinavir/r 2000/100 mg qd TDF/FTC

• 11 randomization

Atazanavir/r 300/100 mg qd TDF/FTC
Investigational dosage the approved dose of
saquinavir/r is 1000/100 mg bid.
21
Factors that may prevent patients achieving or
maintaining an undetectable viral load
Inconvenientregimen
Toxicities
Non-adherence
Reducedefficacy
Drugdruginteractions
Resistance
VIROLOGIC FAILURE
22
Patients on HAART frequently use products that
increase gastric pH
100
n 200
77
80
60
51
Total respondents ()
39
40
20
0
Since startingHAART
Adapted from Luber A et al. 7th Conf. Drug
Therapy in HIV Infect. 2004, Poster 294
23
The impact of acid-reducing agents on PI drug
exposure
FPV ranitidine
ATV/r omeprazole
0
0
20
20
-30
40
40
()
60
60
80
80
-75
100
100
US prescribing information for each drug ATV/r
300/100 mg qd
24
Factors that may prevent patients achieving or
maintaining an undetectable viral loads
Inconvenientregimen
Toxicities
Non-adherence
Reducedefficacy
Drugdruginteractions
Resistance
VIROLOGIC FAILURE
25
HAART is becoming more convenient

• Improved formulations
• Fixed-dose combinations
• Once-daily regimens

26
Factors that may prevent patients achieving or
maintaining an undetectable viral load
Inconvenientregimen
Toxicities
Non-adherence
Reducedefficacy
Drugdruginteractions
Resistance
VIROLOGIC FAILURE
27
Factors that may contribute to patients achieving
or maintaining an undetectable viral load
Good adherence
Convenientregimen
Low toxicity
Reduced likelihoodof resistance
Improvedefficacy
Minimal drugdruginteractions
VIROLOGIC SUPPRESSION