Response Rates in Heavily Pretreated HIV Patients

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Response Rates in Heavily Pretreated HIV Patients

• Roy M. Gulick, MD, MPH
• Cornell Clinical Trials Unit

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Clinical Cohort Studies Virologic Failure
Rates
3
Clinical Cohort Studies Predictors of Virologic
Failure

• prior antiretroviral treatment
• higher baseline/peak viral load level
• lower baseline/nadir CD4 cell count
• specific antiretroviral regimen used
• more missed clinic appointments

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GART HIV RNA Changes by Number of Active Drugs
Change (log)
HIV RNAchanges(log)
0
-0.25
-0.50
-0.75
of patients
GART n78 No GART n75
-1.00
-1.25
?
?
No. of active drugs
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Therapeutic Drug Monitoring VIRADAPT
HIV RNA Decreases in PI-Treated Patients
Time, mo 0 3 6
0.05 -0.15 -0.35 -0.55 -0.75 -0.95 -1.05 -1.35 -1.
55
SOC
SOC GT
HIV RNA, log decrease
OC
OC GT
S/OC suboptimal/optimal drug concentration GT
genotypic testing done
Control Standard of care. Source Garraffo.
Antiviral Ther 19994(1)75.
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Clinical Cohort Studies Limitations

• Heterogeneous patient populations
• (e.g., prior antiretroviral experience)
• Reflects antiretroviral rx use in 1996-98
• Fewer antiretrovirals available
• More complex regimens
• Sequential monotherapy
• ?virologic immunologic clinical failure

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UCSF Cohort (N380)Virologic Immunologic
Responses
8
French Cohort (N2236)Viro., Immun. Clinical
Responses
100
IR/VR
95
IR/VR-
90
IR-/VR
Percent alive and AIDS-free
85
IR-/VR-
80
75
6 12 18
24 30
.
Months since introduction of PI
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Treatment Failure at 2 years EuroSIDA Cohort
(N8507)
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Prospective Studies of Salvage Rx First
Failures

• ACTG 333 SQV-experienced
• ACTG 372b IDV-experienced
• ACTG 359 IDV-experienced
• ABT-765 Single PI-experienced

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ACTG 333 SQV-experienced

• Study population gt48 wks SQVhc, no other PI,
  stable antivirals X 2 mos (N72)
• Baseline HIV RNA 21K, CD4 222
• Results (interim analysis at 8 wks)

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ACTG 372b IDV-experienced

• Population HIV, on AZT or d4T 3TC IDV with
  VL gt500 cps/ml (N 84)
• Duration 48 weeks
• Rx EFV ADV ABC (or new NRTI) /- NFV
• Results Overall, 29 (35) had HIV RNA lt500
  copies/ml at week 16
• Factorial analyses
• ABC (37) vs. 1-2 new NRTIs (32) (p0.62)
• NFV (45) vs. placebo (24)
• favored nelfinavir group (p0.046)

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ACTG 359 IDV-experienced

• Population HIV, gt 6 mo prior IDV, HIV RNA
  2-200K, naïve to other PI and NNRTI, (N 277)
• Baseline VL 32K, CD4 229
• Rx SQVsgc RTV or NFV DLV, ADV, or both
• Overall, 77 (30) had HIV RNA lt500 copies/ml at
  week 16
• Factorial analyses
• SQV/RTV (28) vs. SQV/NFV (33) (p0.50)
• DLV (40) vs. ADV (18) vs. both (33)
• favored DLV-containing regimens (p0.006)

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Abbott M97-765 PI-experienced

• Study population HIV, single PI failure, NNRTI
  naïve, HIV RNA 1-100K (N70)
• Baseline VL 4.1 logs, CD4 372
• Study treatment lopinavir 400 mg bid
  ritonavir 100 or 200 mg bid NVP nucs X 96
  weeks
• Preliminary results 4 d/c for rx-related
  effects (3 GI, 1 rash)

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M97-765 HIV RNA Mean Change from Baseline
At Baseline, PI was switched to lopinavir/r
At Week 2, NRTIs were switched and NVP added
log10 copies/mL
Week
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M97-765 HIV RNA lt400 copies/mL (ITT MF)
65 61
Percent
Sample Size 400/100 mg 36 400/200 mg 34
Week
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Abbott M97-957 gt2 PI-experienced

• Study population HIV, gt2 PI failure, NNRTI
  naïve, HIV RNA gt1000 (N57)
• Baseline VL 4.5 logs, CD4 245
• Study treatment lopinavir 400 or 533 mg bid
  ritonavir 100 or 133 mg bid EFV nucs X 48
  weeks
• Preliminary results 3 d/c for rx-related
  effects (2 CNS sx, 1 lactic acidosis)

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M98-957 Proportion lt400 copies/mL (ITT MF)
71 59
Percentage of patients
Week
400/100mg n 29 533/133mg n 28
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Heavily Pretreated PatientsA Definition

• Patients with
• a loss/lack of virologic response to at least 2
  HAART regimens
• have taken at least one member of each of the
  approved antiretroviral drug classes (NRTI,
  NNRTI, PI)

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Heavily Pretreated PatientsEuroSIDA Cohort (1)

• 266 pts had 3-class experience had taken gt2
  HAART regimens and started new salvage rx
• 40 decreased VL lt1000, and 30 maintained this
  decrease at 6 months
• 55 had gt1 log decrease and 45 maintained this
  decrease at 6 months
• (55-70 virologic failure at 6 months)
• 55 decreased CD4 below baseline (imm.failure at
  1 year)
• 5 had a new AIDS event/death (clinical failure
  at 1 year)

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Heavily Pretreated PatientsEuroSIDA Cohort (2)

• Predictors of virologic response
• Prior VL lt500 cps/ml
• Less prior rx (28 decline in probability/year
  rx)
• Higher latest CD4 count
• Central Europe resident
• Predictors of immunologic/clinical response
• Female
• Lower latest VL
• Fewer prior antiretrovirals

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CNAA 2007 PI-experienced

• Population HIV, gt20 weeks combination therapy
  with a PI HIV RNA gt500 cps/ml (N99)
• Baseline experience 72 4-5 NRTI, 44 NNRTI 60
  3-4 PI
• Duration 48 weeks
• Treatment open label ABC EFV APV
• Primary endpoint safety/tolerability, antiviral
  activity at 16 weeks

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CNAA 2007 PI-experiencedResults

• Overall, 19 (26) had HIV RNA lt400 copies/ml at
  week 16
• Subgroup analyses
• NNRTI naïve, VL lt40K (53)
• NNRTI naïve, VL gt40K (23)
• NNTRI experienced, VL lt40K (33)
• NNRTI experienced, VL gt40K (7)

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ACTG 398 PI-experienced

• Population HIV, gt4 months of up to 3 prior PI
  
• HIV RNA gt1000 prior NNRTI OK (N481)
• Duration 72 weeks
• Treatment
• open label APV ABC EFV ADV with
• SQV sgc 1600 mg bid
• IDV 1200 mg bid
• NFV 1250 mg bid or
• matching placebo (for 2nd PI)
• Primary endpoint safety/antiviral activity/24
  wks

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ACTG 398 PI-experiencedResults

• Overall, 149 (31) had HIV RNA lt200 copies/ml at
  week 24
• Subgroup analyses
• NNRTI-naïve (43) vs. experienced (16)
• favors naïve subjects (plt0.001)
• 1 PI exp (37) vs. gt2 PI exp (29)
• no difference (p0.16)
• Dual PI rx (35) vs. APV alone rx (23)
• favors dual PI rx (p0.002)

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New Drug in Experienced Pts DAPD (nucleoside
analog)

• DAPD-101 Study
• Study population Failed prior ZDV or d4T 3TC
  VL 5-250K cps/ml, CD4 gt50 (N24)
• Baseline VL 5 logs, CD4 350
• Prior treatment experience
• average number of antivirals 6
• average prior length of rx -- 4 years
• 100 NRTI, gt60 NNRTI, gt80 PI
• Rx DAPD at 200, 300, 500 mg bid 3 groups
  washed out X 7d, 1 group added on X 15 days

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DAPD-101 Median Change in HIV-1 RNA Treatment
Experienced Cohorts
0.5
DAPD BID TREATMENT
WASHOUT
0
-0.5
HIV-1 RNA Median Change from BL
-1
200 mg BID 300 mg BID 500 mg BID 500 mg BID Add-On
-1.5
-2
0
5
10
15
20
Study Day
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New Drug in Experienced Pts Tenofovir
(nucleotide analog)

• Gilead 902 Study
• Study population On stable antiretroviral
  regimen with VL gt5K (N189)
• Baseline VL 3.7 logs CD4 350
• Prior treatment experience
• average prior length of rx 4.6 years
• Baseline mutations 97 NRTI, 32 NNRTI, 57 PI
• Rx tenofovir at 75, 150, or 300 mg qd (or
  placebo) X 48 weeks

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Tenofovir Gilead 902 Study
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New Drug in Experienced Pts T-20 (fusion
inhibitor)

• T-20 205 Study
• Study population Prior T-20 experience (N71)
• Baseline VL 4.8 logs, CD4 133
• Prior treatment experience
• average number of antivirals 10
• 80 were three-drug class experienced
• Rx T-20 50 mg bid sq other antiretrovirals
  chosen by hx and genotype X 48 wks
• Results 14/71 (20) had lt0.5 log reduction
• 23/70 (33) had gt1 log reduction or VL lt400

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T20-205 Phase I follow-upViral Load Reduction
-- Week 32
n71
Viral Load Change from Baseline (log10 copies /
mL)
n66
n64
n46
n50
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Salvage Therapy Conclusions

• Virologic failure occurs commonly immunologic
  and clinical failure also occur all should be
  evaluated.
• Predictors of response include adherence, VL,
  CD4, resistance profile, number of active drugs,
  drug levels.
• Newer drugs with novel resistance patterns and/or
  mechanisms demonstrate activity, even in heavily
  pretreated patients.
• Novel study design may demonstrate activity AND
  provide benefit for the subjects.
• Further clinical research is needed.