Go Undetectable Why LowLevel Viremia Is Not an Option

1
Go Undetectable Why Low-Level Viremia Is
Notan Option
Charles Hicks, M.D.Duke University Medical
Center Durham, North Carolina, USA
2
3 Million Years of Life Saved With HIV Treatment
PCP Pneumocystic jiroveci pneumonia MAC
Mycobacterium avium complexART antiretroviral
therapy OI opportunistic infection
Walensky R et al. JID 200619411-19
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Viral Replication in HIV-Infected Cell
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Frequency of Latently Infected CD4 Cells as a
Function of Time on HAART
10,000
1,000
100
10
95 CI
1
Decay Rate t1/2 44.2 mo.
Frequency (IUPM)
0.1
0.01
0.001
0.0001
0.00001
0
1
2
3
4
5
6
7
8
Time on HAART (years)
Total reservoir 10c cells Infection units per
million

• Time needed for eradication of HIV estimated as
  73.4 years!

Siliciano JD et al. Nature Medicine 20039727-728
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The Essential Reality of HIV Managementin 2007

• Despite enormous improvements in the management
  of HIV-infected persons, cure is still not a
  possibility.

6
2006/2007 Guideline Paradigm Shift for
Treatment-Experienced Patients Undetectability
The goal for patients with treatment failure is
to re-establish maximal virologic suppression,
i.e. a plasma HIV-1 RNA level below 50 copies/mL.
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Goal for Treatment-Experienced Patients

• To achieve plasma HIV-1 RNA levels below assay
  detection
• If 2 or more potent drugs available goal should
  be HIV-1 RNA lt 50 copies/mL1
• If not possible partial suppression by selection
  of optimal regimen based on resistance testing2

• Resistance and transmitted resistance continue to
  challenge HIV management.

1 Hammer S et al. JAMA 2006296827-843 2 DHHS
Guidelines 2006. www.aidsinfo.nih.gov
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Consequences of Low-Level Viremia
Accumulation of resistance mutations
Reduced future treatment options
Increase in viral load (VL) over time
Increasingrisk of AIDSor death
Declinein CD4 cell count over time
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Mutation Rate on Stable Antiretroviral Therapy
With Detectable Viral Load

• 98 patients from UNC CAR (n 1,605)
• 2 genotype resistance tests (GT) at baseline (BL)
  and follow-up (F/U) gt 30 days apart
• Initiated ART lt 30 days before BL
• Stable ART from baseline to F/U
• Interpretation IAS-USA panel for drug resistance

Edwards D et al. 44th IAAC, Washington 2004.
Abstract H-176
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60 of Patients With Detectable Viral Replication
Selected for New Mutations (1.5/Year)
1/3 patients selected 2 mutations
Edwards D et al. 44th ICAAC, Washington 2004.
Abstract H-176
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Risk of Delayed Switch On Stable ART

• SCOPE cohort of ART-experienced subjects (n
  106)
• Stable ART for 120 days
• HIV RNA gt 1,000 copies/mL
• 1 resistance mutation
• Resistance testing every 4 months until ART
  modification

Hatano H, et al. 13th CROI, Denver 2006. Abstract
615
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At One Year 30 of Patients Lost the Phenotypic
Equivalent of One Susceptible Drug
Hatano H, et al. 13th CROI, Denver 2006. Abstract
615
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44 of Patients Developed at Least One New Drug
Resistance Mutation Over One Year
-18 (95 CI 934)
-23 (95 CI 1534)
-44 (95 CI 3356)
Hatano H, et al. 13th CROI, Denver 2006. Abstract
615
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No Evolution for Resistance With HIV RNA lt 50
copies/mL

• Longitudinal, clonal genotypic analysis of plasma
  samples of HIV-1 infected adults with
  undetectable viral loads (lt 50 copies/mL) for a
  period of 15 months

• No accumulation of new mutations was detected in
  all patients for more than one year with
  undetectable viral loads ( lt 50 copies/mL)
• In addition, no existing mutations were shown to
  increase over the study period

Kieffer TL et al. J Infect Dis 20041891452-65
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Consequences of Low-Level Viremia
Accumulation of resistance mutations
Reduced future treatment options
Increase in viral load (VL) over time
Increasingrisk of AIDSor death
Declinein CD4 cell count over time
16
Development of ART Resistance DuringLow-Level
Viremia

• Database study of 1,200 HIV subjects
• 22 persons met following criteria
• HIV RNA 501,000 copies/mL
• At least 2 genotype resistance tests (GT)
  performed
• No change in ART

Median CD4 cell counts and viremia
Lafeuillade A et al. XV IAC, Bangkok 2004.
Abstract WeOrB1293
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After Median of 28 Months 15/22 Patients WithNew
Mutations
NNRTI
PI

• 9 with increase in HIV RNA gt 1 log10

Lafeuillade A et al. XV IAC, Bangkok 2004.
WeOrB1293
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Consequences of Low-Level Viremia
Accumulation of resistance mutations
Reduced future treatment options
Increase in viral load (VL) over time
Increasingrisk of AIDSor death
Declinein CD4 cell count over time
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Class-Wide Resistance Represents a Risk Markerof
Disease Progression
Zaccarelli M et al. AIDS 2005191081-1089
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Class-Wide Resistance Represents a Risk Marker of
Death

• Class-wide resistance, particularly if extended
  to all 3 ARV classes is related to poor outcomes.

Zaccarelli M et al. AIDS 2005191081-1089
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Increased Options for Sustained Undetectability
in All Patients
Accumulation of resistance

• Increased options
• Fusion inhibitor enfuvirtide
• Integrase inhibitors raltegravir
• CCR5 inhibitors maraviroc
• 2nd generation NNRTI

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Antiretroviral Agents 2007
23
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Clinical Case Clinical History

• 40-year-old gay male
• CD4 cell count 25 cells/µL
• HIV RNA 84,600 copies/mL
• Opportunistic Infections
• Cryptosporidium
• Kaposi sarcoma
• Bacterial pneumonia
• Additional information
• Hepatitis C
• Amphetamine use

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Clinical Case Past ARV

• Summary prior treatment
• 3 class exposure
• 10 years NRTI
• 7 years PI
• 15 drugs used in the past

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Clinical Case Course of HIV RNA and CD4 Cell
Count
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Clinical Case Resistance Testing

• Genotype

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Clinical Case Resistance Testing

• Phenotype-genotype

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Clinical Options in Patients With 3-Class
Resistance

• 1. Stop all ARV
• 2. Maintain current regimen and wait for better
  options
• 3. Switch now to best available option

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Effective Viral Load Reduction With Active PI and
New Class Drug
TORO 1 21
POWER 1 23
RESIST 1 22
58
45
43
44
27
18
Patients ()
Patients ()
Patients ()
lt 50 copies/mL Week 48
lt 400 copies/mLWeek 48
lt 400 copies/mL Week 48

• Nelson M et al. JAIDS 200540(4)404-412
• Hicks CB et al. Lancet 2006368466-75
• Lazzarin A et al. XVI IAC, Toronto 2006. Abstract
  TuAB0104

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Viral Load Reduction in Treatment-Experienced
Patients on Tipranavir/r at 24 Weeks
MVC Combined StudiesA4001027 A40010283
Combined RESIST1 21,2
0
-0,5
-1
Mean VL reduction (log10) from baseline
-1,5
-2
-2,5
1. Hicks CB et al. Lancet 2006 368466-475 2.
Cahn P et al. Clin Infect Dis 2006431347-1356 3.
MVC FDA Antiviral Drugs Advisory Committee
Briefing Document, April 24, 2007
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Clinical Case Resistance Testing

• Phenotype-genotype

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Clinical Case Selected Regimen

• Selected Regimen
• FTC
• TDF
• ZDV
• TPV/RTV
• T-20

• Rationale
• Extensive prior treatment
• Broad 3-class cross-resistance
• Limitations from prior toxicity
• Choice for recycle agents based on lowest
  (relative) phenotype fold change accounting for
  clinical cut-points
• Trying to play off competing resistance pathways
  of TAMs with K65R

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Clinical Case Course of HIV RNA and CD4 Cell
Count after Regimen Switch
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Clinical Case Summary

• Regimen switch resulted in
• Excellent HIV RNA response, achieving
  undetectable viral load
• Remarkable increase in CD4 cell count
• Patient benefit as CD4 increase and undetectable
  viral load are associated with improved survival
• Realistic goal in highly experienced, 3 class
  resistant patients previously was to maintain
  CD4 lymphocyte counts
• But with the availability of better agents,
  including new classes, long-term viral
  suppression is increasingly possible even for
  these patients

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The ARV Pipeline 20072010
Note Estimated earliest US launch dates
All dates are subject to adjustment Expanded
Access Program (EAP)Available
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Survival Gains of ART Compared With Other Disease
Interventions
200
180
160
140
120
100
Survival Gains (months)
80
60
40
20
0
Node
Node
2 vessel
3 vessel
BMT
OI Proph
ART
Chemo/breast
CABG/PTCA
Lymph-
AIDS Care
cancer
oma
Walensky R et al. JID 200619411-19