Management of Treatment Failure

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Updates on Treatment Failure and New Drugs
Roy M. Gulick, MD, MPHAssociate Professor of
MedicineWeill Medical College of Cornell
University
The International AIDS SocietyUSA
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Question 1

• What percentage of your patients have
  multidrug-resistant (MDR) HIV?
• lt10
• 10-30
• 30-50
• 50-70
• 70-90
• gt90

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Question 2

• What is your goal for using ART in late
  antiretroviral failure?
• Suppress HIV RNA below detection
• Preserve CD4 cell count
• Prevent clinical progression
• 1 and 2
• 2 and 3
• All of the above

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What to change to DHHS Guidelines (10/6/05)

• Review goals of therapy
• maximal virologic suppression (HIV RNA lt50 c/ml)
• for some pts with extensive prior rx/no rx
  options preserve immune fx and avoid
  clinical progression
• Review ART history
• Assess adherence, tolerability, and PK
• Perform resistance testing while on drugs
• Consider novel strategies (e.g., TDM?)
• Identify susceptible drugs/drug classes and
  consider newer agents -- expanded access or
  clinical trials
• Design a regimen with at least 2 fully active
  agents

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Resistance Test Recommendations
DHHS Guidelines, 10/6/05
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Question 3

• Do you use therapeutic drug monitoring?
• Yes, I send drug levels routinely.
• Yes, but only in special cases.
• Its not available to me, but I would if I could.
• No, Im unconvinced of the clinical value.

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Use of TDM

• IQ inhibitory quotient
• drug concentration (e.g, measured AUC or trough)
• resistance (e.g., measured IC50 or fold change)
• Some studies have correlated IQ with virologic
  responses
• Protease inhibitor levels are the most amenable
  to manipulation
• Increased doses or
• RTV enhancement of SQV, IDV, APV, LPV, ATV, TPV,
  darunavir (TMC 114)
• However, current consensus in the U.S. is that
  routine use of TDM is premature

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RTV-Boosted PI Regimens

• SQV/RTV vs. IDV/RTV
• MaxCmin1 Dragsted JID 2003188635
• Mixed study population (N306)
• ITT analysis similar responses 75 both arms
• ITT (switch failure)
• 70 (SQV/r) vs. 50 (IDV/r)
• SQV/RTV vs. LPV/RTV
• MaxCmin2 Dragsted Antivir Ther 2005 10735
• Mixed study population (N324)
• Treatment failure at wk 48 (ITT/discontinuation
  failure)
• 61 (SQV/r) vs. 75 (LPV/r) (p0.005)
• On treatment analysis no difference (p0.27)

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BMS 045 HIV RNA Change
Study pop VF on gt2 ART regimens (at least 1 PI)
(N347)
0 -1 -2 -3
ATV 300/RTV LPV/RTV ATV 400/SQV
Mean HIV RNAchange from baseline(log10 c/mL)
-1.6 -1.9 -1.9
BL2 4 8 12 16 24
32 40 48
Weeks
Time Averaged Difference Estimate ATV 300/RTV
LPV/RTV 0.13 log10 c/mL (97.5 CI -0.12,
0.39) ATV 400/SQV LPV/RTV 0.33 log10 c/mL
(97.5 CI 0.07, 0.60)
Johnson, AIDS 200519685
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Context Study HIV RNA change
Study pop PI-experienced (?2 PIs) VL gt1,000
(N315)
Statistical Results (97.5 CI) FOS/r QD -
LPV/r 0.184 (-0.065, 0.433) FOS/r BID - LPV/r
0.171 (-0.082, 0.424)
Mean HIV-1 RNA AAUCMB Values (log10 copies/mL)
ITT Exposed
-1.48
-1.50
-1.66
BL 1 2 4 8 12 16 20 24
FPV/r BID
LPV/r BID
FPV/r QD
DeJesus E, et al. 10th CROI, Boston, 2003.
Abstract 178.
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Use of 3 PIs ACTG 5143 FPV with LPV/r in
Rx-exp. Pts PK Results
µg/mL
Arm A (n8) LPV/RTV 3caps BID Arm B (n8)
FPV/RTV 700mg/100mg BID Arm C (n17) LPV/RTV
3caps BID FPV 700mg BID
Kashuba, AIDS 200519145-152.
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Interactions Between 3 PIs (Compared to PI/r)

• Summary of Interactions
• LPV ? APV ?
• LPV ? FPV ?
• LPV ? IDV ?
• LPV ? NFV ?
• LPV ? SQV ?
• SQV ? APV ?
• SQV ? ATV ?
• SQV ? FPV ?

• Regimen
• LPV/RTV APV
• LPV/RTV FPV
• LPV/RTV IDV
• LPV/RTV NFV
• LPV/RTV SQV
• SQV RTV APV
• SQV RTV ATV
• SQV RTV FPV

if RTV 100 mg ? if 200 mg Courtesy of David
Back, PhD
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Importance of NRTI in Rx-Exp Pts.

• 22 patients with hi-level phenotypic resistance
  to PI and NRTI on multidrug regimens
• Median HIV RNA -1.1 log cps/ml below baseline
  (21/22) median CD4 203 over baseline
• Non-randomized comparison of stopping PI (n17)
  or RTI (n6)

n6
n17
Deeks, JID 20051921537
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TORO 1 2 48 Weeks
HIV RNA at week 48 lt400 / lt50
Optimized background (OB) alone
12 / 8
OB enfuvirtide (T-20)
30 / 18
(Plt.0001 for both)
Nelson, JAIDS 200540404
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Tipranavir RESIST-1
Study pop gt3 mos rx with NRTI, NNRTI, 2 prior
PI regimens gt1 1º PI mutation but ?2 mutations
at codons 33, 82, 84, or 90 (N620) Baseline VL
67K, CD4 123, 15 PI mutations, 12-77X resistance
to current PIs
CPI/r -0.28
TPV -0.88
Intent-to-treat LOCF
HIV RNA log10 change from baseline
P lt 0.001
OBR
Hicks, ICAAC 2004, abstract H-1137a
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TPV RESIST T-20 in Optimized Background Regimen
(OBR)
TPV arm 27 on T-20 CPI arm 22 on T-20
70
70
70
58
60
60
50
50
35
37
Pts with VL reduction ?1 log10 copies/mL
Pts with VL reduction ?1 log10 cps/mL
40
40
31
29
26
30
30
18
18
17
20
20
8
9
10
10
0
0
TPV/r
CPI/r
TPV/r
CPI/r
T-20 Included in OBR
T-20 Not Included in OBR
T-20 Experienced
Overall
T-20 Naive
Cooper, CROI 2005, abst. 560
OBR Optimized regimen background.
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Question 4
How do you currently use T-20?

• Only in selected patients who have no other
  options.
• Only in selected patients who have at least one
  other active drug to use.
• Routinely, as part of a salvage regimen.
• I dont (or hardly ever) use T-20.
• Another way.

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Model for VL lt400 copies/mL at week 24on the
TORO studies
Montaner, IAS 2003, abst 116
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Investigational Drugs 2006
(partial list)

• NRTI amdoxovir, apricitabine, dexelvucitabine
• NNRTI etravirine (TMC-125), TMC-278
• PI brecanavir, darunavir (TMC-114)
• Entry inhibitors
• CD4 attachment inh BMS cpds, PRO-542, TNX-355
• Chemokine receptor inhibitors
• CCR5 maraviroc, PRO-140, vicriviroc
• CXCR4 AMD-070
• Integrase inhibitors GS-9137, MK-0518
• Assembly inhibitors PA-457

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Dexelvucitabine (DFC) In vitro activity
25
23.5
Average Wild Type EC
1.6 ?M
90
20
18.4
15
Cmax at 200 mg dose 6.2 fold WT (9.8 ?M)
Fold Change from Average Wild Type
10
5
3.2
2.7
1.4
0.6
0.4
0.4
0.2
0.2
-0.3
-0.4
-0.6
-0.8
-0.8
-0.6
-0.9
-5
L74V
K65R
T215Y
M184V
Q151 MDR
K65RV179D
M41L/T215Y
M184V/T215Y
Average Wild Type
K65RF214LK122E
D69 Serine Insertions
D67N/K70R/T215Y/K219Q
D67N/K70R/K103N/T215Y
M41L/D67N/M184V/T215Y
M41/K103N/M184V/T215Y
6 others
D67N/K70R/M184V/T215Y/K219Q
10 others
Geleziunas AAC 20031449-59
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DFC Study RVT-203

• Phase IIb, placebo-controlled study 50, 100, 200
  mg QD (n199)
• Rx-experienced VL gt2000 cps/mL on ART
• Results best VL response in 200 mg group
• -0.7 log10 (week 2), independent of TAMs
• -1.2 log10 (week 16)
• Use of 3TC/FTC decreased response
• Pancreatitis with ddI (3 clinical cases and 12/35
  34 with grade 4 ? lipase)
• No emergence of novel resistance mutations no
  K65R

Effect of NRTIs on 2-week VL decline with DFC
200 mg
Cohen, IAS 2005, WeOaLB0103
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TMC-125 Activity on NNRTI-resistant clinical
isolates (N 1,081)
De Bethune, AIDS 200014S17
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TMC-125-C223 Study Rx-Experienced
Study pop VL 48K, CD4 100, resistance to EFV
(41-fold), NVP (68-fold), TMC-125 (1.6-fold),
extensive PI resistance (N199)
0.5
ITT analysis (non-completer failure)
Active control (N 40)
0.0
0.2
-0.5
400 mg bid (N 80)
Mean change in log10 viral load ( SE)
1.0, P lt 0.05
-1.0
1.2, P lt 0.05
-1.5
800 mg bid (N 79)
P values versus active control
-2.0
0
2
4
8
12
16
20
24
Time (weeks)
Grossman, ICAAC 2005, abstract H-416c
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Susceptibility of 5601 Clinical Isolates to
Darunavir (TMC-114)
3 or More Primary Mutations
100
80
60
Percent Isolates
FC gt 4
FC lt 4
40
20
0
IDV
NFV
SQV
APV
LPV
ATV
TMC114
De Meyer, et al. CROI 2004. Abst. 620. De Meyer
AAC 2005492314
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Power Studies Subset Analysis-- VL lt50 at Wk
24 (ITT NC F)
TMC-114 600 bid
Control PI
67 (n 27)
T-20 Used (Naïve)
16 (n 25)
37 (n 27)
T-20 Not Used
8 (n 39)
48 (n 40)
?3 Primary PI Mutation
5 (n 56)
45 (n 38)
TMC-114 FC gt4
5 (n 42)
31 (n 16)
No Sensitive ARV in OBR
0 (n 13)
20
40
60
80
Haubrich, et al. 12th CROI, 2005 Abst. 164LB.
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Chemokine Receptor Inhibitors

• CCR5 inhibitors
• maraviroc (UK-427, -857)
• PRO-140
• vicriviroc (SCH-417690)
• TAK-652
• CXCR4 inhibitors
• AMD-070

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Chemokine Receptor Tropism
1Demarest ICAAC 2004, H-1136 2Brumme JID 2005
3Moyle JID 2005 4Wilkin CROI
2006, 655 5Melby EI Workshop 2005
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Maraviroc Phase I
Study pop asymp R5-tropic (N82)
Last day of dosing
0.5
0.0
-0.5
Change from baseline (log10 HIV-1 copies/mL)
-1.0
-1.5
-2.0
5
10
15
20
25
30
35
40
Baseline
Time (day)
Study A4001007/1015
Fätkenheuer, Nat Med 2005111170
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Vicriviroc (SCH-D, SCH-417690) Phase I
Study population Off ART X 8 weeks, CD4 gt200
(N48, 16/cohort 12 on study rx, 4 on placebo)
Schurmann, 11th CROI, abst. 140LB
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HIV Integrase Mechanism
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MK-0518 Phase II in Rx-Experienced
Study pop 3-class resistance VL gt5K, CD4 gt50,
at baseline 50 phenotypically resistant to all
ART (N167)
(cells/mm3)
MK-0518 200 mg
MK-0518 600 mg
MK-0518 400 mg
OBT Alone
Grinstezjn CROI 2006 abst 159LB
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GS-9137 Phase I
Study pop VL 56K, CD4 442, mix of rx-naïve and
-exp (N40)
0.0
-0.5
Change HIV-1 RNA
-1.0
Placebo
800 QD
-1.5
200 BID
10
400 BID
Log
-2.0
800 BID
50 RTV QD
10d
Dosing
Dosing
-2.5
BL
1
2
3
4
7
10
11
14
21
Day
DeJesus CROI 2006 abst. 160 LB
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Slide 33
Viral Budding and Maturation
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PA-457 Assembly Inhibitor

• Randomized, double-blind, PBO-controlled
• Study pop no ART X gt12 wks CD4 gt200 VL 5-250K
  (N32)
• Rx PA-457 (oral liquid) 25, 50, 100, or 200
  mg monotherapy (loading dose on day 1) vs.
  placebo over 10 days
• Results
• Dose-dependent PK
• VL (log cps/ml) change at day 11
• placebo, 25 mg (no change) 50 mg (-0.2)
  100 mg (-0.5) 200 mg (-1.1)

Smith CROI 2006 abst 52
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New ART Agents Stage of Development