Strategies for the fully suppressed patients

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Strategies for the fully suppressed patients
Dr. José R Arribas HIV Unit
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Simplification in guidelines
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DHHS Candidates for Regimen Simplification

• Patients on suppressive antiretroviral therapy
  may be considered candidates for this strategy,
  especially if
• They are receiving treatments that are no longer
  recommended as preferred or alternative choices
  for initial therapy
• They were prescribed a regimen in the setting of
  treatment failure at a time when there was an
  incomplete understanding of resistance or
  drug-drug interaction data
• They were prescribed a regimen before the
  availability of newer options that might be
  easier to administer and/or more tolerable

DHHS guidelines. Available at http//www.aidsinfo
.nih.gov. Accessed January 27, 2009.
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Reasons for regimen switch in fully suppressed
patients
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Considerations Before Modifying Antiretroviral
Therapy

• Genetic barrier of the new regimen in the context
  of possible archived antiretroviral resistance
  mutations
• Duration of virologic suppression prior to
  considered switch
• Expected level of adherence

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Barriers to resistance PK and genetics
High trough
High trough
Low trough
Increasing EC50
EC50
EC50
Increasing number of mutations
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Patients with NNRTI resistance mutations (IAS) at
median 12 days postpartum. Nevirapine Monotherapy
Jourdain G. et al New Engl J Med, July 15, 2004
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Rapid Emergence of Enfuvirtide Resistance in
HIV-1 Infected Patients.
Lu J et al. J Acquir Immune Defic Syndr
20064360-64)
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Change from Baseline in HIV RNA With GS-9137 125
mg Influence of Activity of OBT
Zolopa et al. CROI 2007. 143LB
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Development of resistance in Subject 311 (LPV/r)
Norton M et al XV International Drug Resistance
Workshop, 13-17 June 2006, Sitges, Spain.
Abstract 74.
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NEFA Switch from PI to NNRTI or NRTI
Month 36
Switch PI to NVP continue 2 NRTIs (n 155)
HIV-infected patients on stable PI-based
regimen with HIV-1 RNA lt 200 copies/mL (N
460)
Switch PI to EFV continue 2 NRTIs (n 156)
Switch PI to ABC continue 2 NRTIs (n 149)

• Primary endpoints death, progression to AIDS, VF

Martinez et al, et al. N Engl J Med
20033491036-46.
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NEFA Switch from PI to NNRTI or NRTI
Significantly higher rate of death, AIDS
progression, or VF with switch to ABC vs switch
to NNRTIs at Month 36 (P .031 ITT, M F)
Martinez et al, et al. N Engl J Med
20033491036-46.
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NEFA
Ochoa de Echagüen A, et al. AIDS. 2005 Sep
219(13)1385-91
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Simplification with abacavir-based triple
nucleoside therapy versus continued protease
inhibitor-based highly active antiretroviral
therapy in HIV-1-infected patients with
undetectable plasma HIV-1 RNA.
CNA 30017. Clumeck N, et al. AIDS.
2001151517-1526.
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ANRS 138 EASIER Switch From ENF to RAL in
Virologically Suppressed Pts
Week 24 primary analysis
Week 48 study end
Maintain ENF (n 85)
Switch ENFto RAL (n 85)
HIV-infected patients with triple-class
resistance or intolerance HIV-1 RNA lt 400
copies/mL for 3 months on stable
ENF-containing regimen (N 170)
Switch ENF to RAL (n 85)
Median duration on ENF therapy ENF arm (2.2
yrs) RAL arm (2.5 yrs).
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ANRS 138 EASIER Virologic Outcomes at Week 24
100
88
89
90
88
85
HIV-1 RNA lt 50 c/mL ()
80
ENFRAL
10
0
0
4
8
24
16
Week
No. of Pts
ENF 85 85 85
85
84RAL 84 84
84 84
84

• Low incidence of grade 3/4 laboratory
  abnormalities and adverse events in both arms

De Castro N, et al. CROI 2009. Abstract 572.
Graphic reproduced with permission.
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SWITCHMRK -1 and -2 Switch From Stable LPV/RTV-
to RAL-Based HAART
HIV-1 RNA lt 50 copies/mL at Week 24
Stratified by duration of previous LPV/RTV
therapy ( vs gt 1 yr)
Mean change in lipids at Week 12
Switch to RAL (Protocol 032 n 174 Protocol
033 n 176)

• HIV-infected patients with undetectable
• HIV-1 RNA for 3 months
• on LPV/RTV-based regimen
• (Protocol 032 N 348
• Protocol 033 N 354)

Continue LPV/RTV (Protocol 032 n 174
Protocol 033 n 178)
All patients continued treatment with background
regimen including at least 2 NRTIs. No exclusion
for number of previous regimens or history of
previous virologic failure.
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SWITCHMRK -1 and -2 Virologic Outcomes at Wk 24,
NC F

• Predefined criteria for noninferiority lower
  limit of the 95 CI for treatment difference gt
  -12

RAL ARVs, n 174 166 169
173 172
176 176 176 176
175LPV/RTV ARVs, n
174 171 171 171
174 178
178 177 177 178
Eron J, et al. CROI 2009. Abstract 70aLB.
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Protocols 032, 033Confirmed Virologic Failures
In combination with background antiretroviral
therapy Virologic failure required confirmed
viral rebound at least 1-week apart

• Based upon post-hoc data collection
• 84 (27/32) of patients with confirmed VF (gt50
  c/mL) in the RAL group reported that their
  regimen at study entry was not their 1st ART
  regimen
• 66 (18/27) reported a history of VF on prior
  regimen(s)

Eron J, et al. CROI 2009. Abstract 70aLB.
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Strategies for the fully suppressed patients

• The primary goal of therapy modification is
  maintenance of virologic suppression
• The risk of virologic failure with treatment
  modification is low in patients who do not have
  archived antiretroviral resistance.
• In virologically suppressed patients with
  archived antiretroviral resistance, treatment
  modification has to be performed very carefully,
  and the overall genetic barrier to resistance of
  the regimen must be maintained.

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Strategies for the fully suppressed patients

• A boosted PI should be switched to unboosted
  atazanavir, an NNRTI, or raltegravir only if the
  full activity of the 2 NRTIs (or other agents)
  remaining in the regimen can be guaranteed.

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Considerations Before Modifying Antiretroviral
Therapy

• Genetic barrier of the new regimen in the context
  of possible archived antiretroviral resistance
  mutations
• Duration of virologic suppression prior to
  considered switch
• Expected level of adherence

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BMS-089 RTV-boosted vs unboosted ATV in
ART-naïve patients
48-week results

• 3TC d4T XR ATV RTV vs ATV
• Total bilirubin elevation (gt2.5 x ULN) 59 (ATV
  RTV), 20 (ATV)

• ATV RTV noninferior to ATV

Malan N, et al. 13th CROI, Denver 2006, 107LB
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ARIES Boosted vs Unboosted ATV Maintenance in
Naive Pts
Wk 36 randomization if HIV-1 RNA lt 50 c/mL
Wk 84primary endpoint
ATV 400 mg QD ABC/3TC FDC (n 210)
Antiretroviral-naive pts with HIV-1 RNA 1000
c/mL no CD4 cell count restrictions
HLA-B5701 negative (N 515)
ATV/RTV 300/100 mg QD ABC/3TC FDC (n 515)
Wk 144
ATV/RTV 300/100 mg QD ABC/3TC FDC (n 209)
Stratified by BL HIV-1 RNA lt or 100,000 c/mL
Squires K, et al. IAS 2009. Abstract WELBB103.
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ARIES Boosted vs Unboosted ATV Maintenance Wk
84 Results
ATV (n 210)
ATV/RTV (n 209)
100
87
86
85
82
80.8
79
80
60
HIV-1 RNA lt 50 c/mL at Wk 84 ()
40
20
0
BL HIV-1 RNA lt 100,000 c/mL
BL HIV-1 RNA 100,000 c/mL
Overall Results
Squires K, et al. IAS 2009. Abstract WELBB103.
Graphic used with permission.
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Monotherapy with LPV/r
MONARK LPV/r Initial therapy
Study 613 LPV/r Induction/maintenance
OK LPV/r Simplification
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COOL Study Lamivudine-Sparing Maintenance
Regimen (contd)

• Tenofovir DF efavirenz with lamivudine
• More efficacious as a maintenance regimen versus
  without lamivudine
• Tenofovir DF efavirenz without lamivudine
  demonstrated lower efficacy due to
• Virologic failure
• Higher discontinuation rate

Girard PM, et al. 46th ICAAC. San Francisco,
2006. Abstract H-1383.
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INCAS TRIAL
JAMA. 1998 Mar 25279(12)930-7..
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Risk of virologic failure based on adherence

• REACH
• 221 subjects identified from cohort of HIV
  marginally housed or homeless individuals
• Subjects on stable HAART (NNRTI 37, BPI 29, PI
  25, PINNRTI 7, NRTI only 3)
• Virologic failure (VF) defined as HIV-RNA gt50
  c/mL
• Adherence measured by unannounced pill counts and
  categorized into 049, 5074, 7589, 90100
• Statistically significant decrease in the
  probability of virologic failure for subjects in
  top 3 strata

Rosenblum M, et al. 16th CROI, Montreal 2009, 583
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Considerations Before Modifying Antiretroviral
Therapy

• Genetic barrier of the new regimen in the context
  of possible archived antiretroviral resistance
  mutations
• Duration of virologic suppression prior to
  considered switch
• Expected level of adherence

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Lopinavir/ritonavir monotherapy. OK04
Pulido F. Antivir Ther. 200914(2)195-201.
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Strategies for the fully suppressed patients

• A longer duration of virologic suppression and an
  expectation of high adherence are very important
  considerations before modifying a suppressive
  antiretroviral regimen in a manner that may
  result in lower overall potency or genetic
  barrier to resistance.

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Modifying Antiretroviral Therapy to Increase
Tolerability and/or Decrease Toxicity
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Modifying Antiretroviral Therapy to Increase
Tolerability and/or Decrease Toxicity
Not proven in clinical trials
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Modifying Antiretroviral Therapy to Increase
Tolerability and/or Decrease Toxicity
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Modifying Antiretroviral Therapy to Increase
Tolerability and/or Convenience
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Modifying Antiretroviral Therapy to Preserve
Treatment Options, Avoid Nucleoside Toxicity, or
Decrease Cost