Virologic Failure Workshop Advanced

1






Use of Resistance Testing and Salvage Therapy
Joel E. Gallant, MD, MPHProfessor of Medicine
and EpidemiologyJohns Hopkins University School
of MedicineRoy M. Gulick, MD, MPHProfessor of
MedicineChief, Division of Infectious
DiseasesWeill Medical College of Cornell
University
From JE Gallant, MD, MPH, and RM Gulick, MD, MPH,
at 12th Annual Ryan White HIV/AIDS Program
Clinical Conference, IASUSA.
2
Goals of Therapy Guidelines

• The goal of treatment for patients with prior
  drug exposure and drug resistance is to
  re-establish maximal virologic suppression.
• Use the rx history and resistance test results to
  identify at least 2 (and preferably 3) fully
  active agents to design a new regimen.

U.S. DHHS Guidelines http//www.aidsinfo.nih.gov/,
11/3/08
3
Importance of NRTI in Rx-Exp Pts.

• 22 pts with high-level PT resistance to PI and
  NRTI on multidrug regimens
• Median VL -1.1 log cps/ml below baseline (21/22)
  median CD4 203 over baseline
• Non-randomized comparison

Deeks, JID 20051921537
4
Study 1029 MVC for D/M-tropic virus
Study pop Non-R5 tropic virus (dual/mixed, X4,
or indeterminate) median CD4 40 and HIV RNA
gt100,000 c/mL (N167 with dual/mixed)

• No difference in adverse events
• Conclusion No differences in VL or CD4 responses

Saag JID 20091991638
5
DRV/r ETR RAL
6
Slide 6
Improved CD4 Recovery with boosted PIsACTG 5142
VLlt50 at Week 96
? CD4 at Week 96
Riddler SA et al. N Engl J Med.
2008358(20)2095-2106.
From JE Gallant, MD, MPH, and RM Gulick, MD, MPH,
at 12th Annual Ryan White HIV/AIDS Program
Clinical Conference, IASUSA.
7
Slide 7
MERIT MVC associated with greater CD4
increase than EFV
MERIT Study 48 Weeks
169 cells/mm3
142 cells/mm3
Mean ? from Baseline CD4 count
Unclear whether difference due to distribution or
a real decrease in inflammation and cell death
Time (weeks)
n 331 346 348
348 348 348 348
348 348 348
n 336 350 351 352
352 352 352
352 352 352

Saag M et al. 4th Annual IAS Meeting. Sydney,
Australia July 22-25, 2007. Abstract WESS104
From JE Gallant, MD, MPH, and RM Gulick, MD, MPH,
at 12th Annual Ryan White HIV/AIDS Program
Clinical Conference, IASUSA.
8
ESPRIT No Significant Effect of IL-2 on
Incidence of OI or Death
Slide 8
15
10
Cumulative Probability (x 100) of Event
ART IL-2ART
5
HR 0.93 (95 CI 0.75-1.16)
0
1
2
3
4
5
6
0
7
8
Years
No. PtsART IL-2ART
2071 2030 1997 1947 1909 1873
1552 971 3222040 2003 1962
1918 1883 1825 1483 910 272

• Addition of IL-2 associated with significantly
  more grade 4 adverse events

Losso M, et al. CROI 2009. Abstract 90aLB.
Graphic reproduced with permission.
From JE Gallant, MD, MPH, and RM Gulick, MD, MPH,
at 12th Annual Ryan White HIV/AIDS Program
Clinical Conference, IASUSA.
9
DUET-1 -2 Predictors of ETR Response

• ETR mutations (n 17) weighted based upon impact
  on response (weighting factor)
• 3.0 Y181I/V
• 2.5 L100I, K101P, Y181C, M230L
• 1.5 V106I, V179F, E138A, G190S
• 1.0 V90I, A98G, K101E/H, V179D/T, G190A

100
74
80
70
60
52
HIV-1 RNA lt 50 copies/mL at Wk 24 ()
50
38
40
30
20
10
0
0-2.0
gt 3.5
2.5-3.5
Weighted Score Category
Vingerhoets Resistance Workshop 2008 24
10
ETR Rash

• Postmarketing reports of
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis, including fatality
• HSR, sometimes with hepatic failure
• Guidance
• Stop ETR for
• severe skin reactions (blistering, oral lesions,
  conjunctivitis)
• HSR reactions (rash, fever, malaise, fatigue,
  muscle/joint aches, facial edema, hepatitis,
  eosinophilia)

Updated Package Insert, August 2009
11
MOTIVATE 1 2 VL lt50 at Wk 24 by Number of
Active Drugs in OBR
Slide 11
MVC QD OBR
MVC BID OBR
PBO OBR
100
90
Combined Analysis MOTIVATE 1 and 2
80
70
61
58
55
53
60
52
Patients,
43
43
50
40
29
30
19
18
20
9
10
3
0
51
56
44
N
35
130
134
59
104
64
132
121
88
Number of active drugs in OBR
0
1
2
3
Nelson M, et al. CROI 2007. Abstract 104aLB.
Lalezari J, et al. CROI 2007. Abstract 104bLB.
From JE Gallant, MD, MPH, and RM Gulick, MD, MPH,
at 12th Annual Ryan White HIV/AIDS Program
Clinical Conference, IASUSA.
12
BENCHMRK-1 -2 Undetectable VL at Week 48,
Overall and by GSS
Slide 12

• Rates of virologic suppression also greater with
  RAL vs PBO when analyzed by baseline PSS
• Similar results when assessing PSS by number of
  fully active drugs and by number of fully or
  partially active drugs

RAL
PBO
n
443
64
Overall
34
228
By GSS
112
45

• 0

3
65
67
166

• 1

92
37
158
75

• 2

68
59
0
20
40
60
80
100
Patients ()
1. Cooper DA, et al. CROI 2008. Abstract 788 2.
Steigbigel R, et al. CROI 2008. Abstract 789.
From JE Gallant, MD, MPH, and RM Gulick, MD, MPH,
at 12th Annual Ryan White HIV/AIDS Program
Clinical Conference, IASUSA.
13
DUET-1 and -2 VL lt 50 at Wk 48,by Active Agents
in OBR
Slide 13
ETR (n 599)
PBO (n 604)
1. Haubrich R, et al. CROI 2008. Abstract 790 2.
Johnson M, et al. CROI 2008. Abstract 791 3.
Winters B, et al. CROI 2008. Abstract 873.
From JE Gallant, MD, MPH, and RM Gulick, MD, MPH,
at 12th Annual Ryan White HIV/AIDS Program
Clinical Conference, IASUSA.