CPCRA GART Study (046) A Randomized Study of Antiretroviral Management Based on Plasma Genotypic Antiretroviral Resistance Testing (GART) in Patients Failing Antiretroviral Therapy

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CPCRA GART Study (046) A Randomized Study of
Antiretroviral Management Based on Plasma
Genotypic Antiretroviral Resistance Testing
(GART) in Patients Failing Antiretroviral Therapy
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Study Design
3-fold rise in HIV RNA on gt16 weeks 2 NRTIs PI
Baseline
Virologists review genotype AR HxPrepare GART
report with Tx suggestions
Randomization (N 153)
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Algorithm For Interpretation Of Resistance
Mutations RTIs
Reverse Transcriptase Mutation
Expected Drug Resistance
75T
stavudine
215F/Y (41L, 67N, 70R, 210W, 219E/Q)
zidovudine
74V or 65R or 69D
didanosine, zalcitabine
184V
lamivudine, didanosine, zalcitabine
215F/Y 74V or 65R or 69D
zidovudine, didanosine, zalcitabine
151M (62V, 75I, 77L, 116Y)
zidovudine, didanosine, zalcitabine, stavudine
possible lamivudine
103N or 106A or 181C/I or 188C
nevirapine, delavirdine
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Algorithm For Interpretation Of Resistance
Mutations PIs
Protease Mutation
Expected Drug Resistance
90M or 48V (63P, 71T/V)
saquinavir
possible nelfinavir
30N (36I/L, 46I/L, 71T/V, 77I, 88D)
nelfinavir
50V (46
I
/L, 47V)
amprenavir
90M 48V
saquinavir
possible ritonavir, indinavir, nelfinavir
gt Any 3 of the following
indinavir, ritonavir
possible nelfinavir, saquinavir
10
I/
R/V, 20M/R, 24I, 36I/L, 46I/L, 48V, 54V,
63P, 64V, 71T/V, 82A/F/T, 84V, 90M
(either 46
I
/L, 82A/F/T or 84V must be present)
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Baseline GART Report

• PID 023-0004
• Date 05-23-97

Resistance Mutations
These mutations indicate the following drug
sensitivities
RT gene
Protease gene
67N 48V ZDV resistance 70R 90M 3TC resistance
184V 215Y SQV resistance IDV/RTV possible
resistance

Based on a review of this patients genotypic
resistance mutations and antiretroviral history,
we suggest the following treatment
recommendations 1. ddI HU nevirapine
indinavir 2. ddI HU delavirdine
nelfinavir 3. d4T nevirapine nelfinavir
indinavir 4. d4T delavirdine nelfinavir
indinavir
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Baseline Characteristics
GART
No-GART

• CD4 (mean cells/mm3) 230 229
• HIV RNA (median copies/mL) 28,785 25,860
• Entry regimen ()NRTI Component
• ZDV 3TC 45 44 d4T 3TC 41 39PI
  Component
• Indinavir 54 53
• Nelfinavir 33 33
• Ritonavir 6 8
• Saquinavir 6 5
• Failing on first PI () 53 44

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Distribution of Major Mutations
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Impact of GART Report on RegimenPrescribed in
the GART Group
Percent

• GART report influenced choice of 83 regimen
• A regimen suggested by the study 54 virologists
  was prescribed

After review of the GART report, the site
clinician altered their initial proposed regimen
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HIV RNA (log10) Change from Baseline
No-GART
GART
P-value
Dif.
Avg (4 8 wks) -1.19 -0.61 -0.53 .00001
95 CI (-0.29 to -0.77)
Adjusted for baseline HIV RNA and baseline
regimen.
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Mean HIV RNA by Study Week
5.0
Study Group
10
4.5
4.0
HIV RNA (log )
3.5
p .003
p .0001
p .0003
3.0

Study Week
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Percent of Patients with Undetectable HIV RNA,
by Study Week
P.0001
P.004
Percent
P.10
No-GART
No-GART
No-GART
GART
GART
GART
Week 4 (N 150)
Week 8 (N 148)
Week 12 (N 148)
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HIV RNA Changes byNumber of Active Drugs
Prescribed
Change (log10)
0
HIV RNAChanges(log10)
-0.10
-0.25
-0.59
-0.50
-0.75
-1.04
-1.00
-1.25
Percent
-1.25
GART
No-GART
Number of Active Drugs
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No. Drugs Prescribedby Randomization Group
3 or moreactive drugs
No. Patients
67
30
91
62
100
60
3
gt5
4
Total No. Drugs
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Treatment Differences by Selected
Baseline-Defined Subgroups
CD4 Count (cells/mm )
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Baseline HIV RNA
(log10 RNA)
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Treatment Differences by Selected
Baseline-Defined Subgroups
Prior PI Treatment
Protease Inhibitor
(log10 RNA)
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Treatment Differences by Selected
Baseline-Defined Subgroups
Major RT/PI Mutations
NNRTI Proposed by Site Clinician

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Change in HIV RNA (from Baseline to Average of 4
and 8 Weeks) Associated with Selected Protease
Mutations
Unadjusted for Prior PI Treatment
Adjusted for Prior PI Treatment
Protease Mutation
30N -0.41 0.04 -0.47 0.06 46I/L -0.03 0.84 -0.01 0
.93 82A/F/T 0.11 0.48 0.15 0.36 84V -0.22 0.39 -0.
22 0.40 90M 0.31 0.04 0.25 0.13
Adjusted for baseline HIV RNA and CD4 count
positive change indicates increase from baseline
relative to those without the indicated mutation
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Conclusion

• GART with expert advice in patients failing
  antiretroviral therapy was superior to No-GART,
  as measured by short-term viral load responses

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Conclusions (continued)

• The greater viral load reduction with GART is
  attributed to a greater number of active drugs
  prescribed in the GART arm
• The impact of GART was similar for patients
  failing their first protease inhibitor and for
  those who had received multiple protease
  inhibitors
• Baseline genotype was associated with virologic
  response to salvage therapy

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Protocol Team

• John Baxter, M.D., Chair
• Douglas Mayers, M.D., Co-chair
• Thomas Merigan, M.D., Co-chair
• Donald Abrams, M.D.
• Barbara Brizz, B.S.N., M.H.S.Ed.
• Kathy Canaday, R.N.
• Timothy Day
• Marie Hoover, Ph.D.
• John Ioannidis, M.D.

Leslie Johnston-Dow, Ph.D. Sharon Mannheimer,
M.D. Ana Martinez, R.Ph. Robert Munk, Ph.D. James
Neaton, Ph.D. Elizabeth Perelli, R.N., M.S. Carla
Pettinelli, M.D., Ph.D. Melanie Thompson,
M.D. Deborah Wentworth, M.P.H.