What to Start With?

1

Initial Antiretroviral Therapy Choosing the
First Regimen
Joel E. Gallant, MD, MPH Professor of Medicine
and EpidemiologyJohns Hopkins University School
of Medicine
International AIDS SocietyUSA
2
The Initial RegimenDHHS Guidelines, 11/3/2008
US Department of Health and Human Services.
Available at http//aidsinfo.nih.gov/Default.aspx
.
From JE Gallant, MD, MPH, at Los Angeles, CA
February 23, 2009, IASUSA.
3
The Initial Regimen IAS-USA Guidelines, 7/2008
Except during first trimester of pregnancy or in
women with high pregnancy potential. Or
lamivudine. Possible increased risk of CVD
possible increased risk of failure with high
viral load. Or emtricitabine.
Hammer SM, et al. JAMA. 2008300555-570.
From JE Gallant, MD, MPH, at Los Angeles, CA
February 23, 2009, IASUSA.
4
EFV vs. Boosted PI?
From JE Gallant, MD, MPH, at Los Angeles, CA
February 23, 2009, IASUSA.
5
Which Boosted PI?
From JE Gallant, MD, MPH, at Los Angeles, CA
February 23, 2009, IASUSA.
6
CASTLE Week 96 Response to ATV/r vs LPV/r in
Naive Patients
ATV/r (n 440)
ITT-CVR, NC F
Primary endpoint
LPV/r (n 443)
100
78
80
74
76
68
60
VL lt 50 ()
40
Estimated Difference 1.7 (95 CI, -3.8 to 7.1)
Estimated difference 6.1 (95 CI 0.3 to
12.0 P lt .05)
20
0
0
84
60
96
4
36
72
12
48
24
Weeks

• Higher discontinuation rate with LPV/r vs ATV/r
  (16 vs 21, respectively)

Molina JM, et al. ICAAC/IDSA 2008. Abstract 1250d.
From JE Gallant, MD, MPH, at Los Angeles, CA
February 23, 2009, IASUSA.
7
ARTEMIS Week 96 Response to DRV/r vs LPV/r in
Naive Patients
DRV/r (n 343)
Primary endpoint
LPV/r (n 346)
100
84
80
79
78
71
60
Week 48 Estimated difference in response vs
LPV/RTV for noninferiority PP 5.6 (95 CI
-0.1 to 11.3 P lt .001) Estimated difference in
response vs LPV/RTV for superiority ITT 5.5
(95 CI -0.3 to 11.2 P .062)
Week 96 Estimated difference in response vs
LPV/r for noninferiority PP 8.4 (95 CI 1.9
to 14.8 P lt .001) Estimated difference in
response vs LPV/r for superiority ITT 8.3 (95
CI 1.8 to 14.7 P lt .012)
VL lt 50 SE
40
20
0
84
60
96
8
36
72
0
16
48
24
Weeks

• Superiority at Week 96 also observed when DRV/r
  (n 343) compared with subset of patients
  treated with twice-daily LPV/r only (n 258)
• 79 vs 72 (P .038)

Mills A, et al. ICAAC/IDSA 2008. Abstract 1250c.
From JE Gallant, MD, MPH, at Los Angeles, CA
February 23, 2009, IASUSA.
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STARTMRK Virologic and Immunologic Efficacy at
Week 48

• Significantly shorter time to virologic response
  with RAL vs EFV (P lt .001)
• Significantly greater CD4 count increase with RAL
  vs EFV
• 189 vs 163 ? 26 (95 CI 4-47)
• Fewer CNS events by Week 8 with RAL vs EFV (10.3
  vs 17.7 P .015)

Lennox J, et al. ICAAC/IDSA 2008. Abstract 896a.
From JE Gallant, MD, MPH, at Los Angeles, CA
February 23, 2009, IASUSA.
9
Which NRTI Backbone?
From JE Gallant, MD, MPH, at Los Angeles, CA
February 23, 2009, IASUSA.
10
ACTG 5202 Shorter Time to VF in Pts With High VL
Receiving ABC/3TC
1.0
0.8
0.6
Probability (Remaining free of Virologic Failure)
ABC/3TC (57 events)
0.4
TDF/FTC (26 events)
0.2
Log rank test P value .0003HR (95CI) 2.33
(1.46 - 3.72)
0.0
0
4
16
24
84
96
108
36
48
60
72
Weeks from Randomization

• Similar proportions in each arm with VL lt 50 at
  Wk 48 (P .20) by ITT (switching NRTIs ?
  failure)
• Post hoc analysis for subjects achieving 2 VL lt
  50 on therapy, no significant difference in risk
  of viral rebound between arm (P .247)

Sax PE, et al. IAS 2008. Abstract THAB0303.
From JE Gallant, MD, MPH, at Los Angeles, CA
February 23, 2009, IASUSA.
11
DAD Study Recent Use of ABC, ddI Associated
With Increased Risk of MI

• Current or recent (within 6 mos) use of ABC or
  ddI associated with ? relative risk of MI
• 90 ? risk of MI with recent ABC
• 49 ? risk of MI with recent ddI
• Risk most prominent in individuals with
  underlying CVD risk factors
• ? risk no longer observed in patients who had
  discontinued ABC or ddI for gt 6 mos

CHD (n 639)
Stroke (n 195)
ZDV
RR 1.40 (P .005)
ddI
d4T
3TC
RR 1.63 (P .0001)
ABC
0.50
0.75
1.00
1.25
1.50
1.75
2.00
2.25
Adjusted Relative Rate (95 CI)
Sabin C, et al. CROI 2008. Abstract 957C.
From JE Gallant, MD, MPH, at Los Angeles, CA
February 23, 2009, IASUSA.
12
SMART Current Use of ABC But Not ddI Associated
With Increased CV Risk

• Increased risk of CVD events with use of ABC
  detected only among patients with 5 CV risk
  factors at baseline (adjusted HR 3.1)
• However, difference in risk between patients with
  vs without these factors failed to reach
  statistical significance

Lundgren J, et al. IAC 2008. Abstract THAB0305.
From JE Gallant, MD, MPH, at Los Angeles, CA
February 23, 2009, IASUSA.
13
Examples of NRTI-Sparing Options

• PI/r NNRTI
• LPV/r EFV well studied and effective, but
  poorly tolerated with significant hyperlipidemia
• ATV/r EFV not well studied, easier and likely
  to be better tolerated with better lipid profile
  need for increased ATV/r dose (400/100 mg QD)
• DRV/r EFV not studied ARTEMIS dose of DRV/r
  (800/100 QD) OK?
• PI or PI/r RAL
• Under study, including RAL ATV 300 mg BID
• RAL NNRTI
• No data low barrier to resistance with both
  drugs

From JE Gallant, MD, MPH, at Los Angeles, CA
February 23, 2009, IASUSA.
14
Starting Therapy The Basic Questions

• Is the patient ready?
• Does the patient meet guidelines criteria for
  starting?
• If not, is there a reason to start anyway?
• Is there baseline resistance?
• Assuming no resistance, which regimen?
• EFV, a boosted PI, or RAL?
• If a PI, which one?
• Which NRTI backbone?

From JE Gallant, MD, MPH, at Los Angeles, CA
February 23, 2009, IASUSA.