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New Drugs and Formulations: Effect on Therapeutic Paradigms

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New Drugs and Formulations: Effect on Therapeutic Paradigms
Slide 1 of 12
Update from the 2013
Conference on Retroviruses and
Opportunistic Infections:
Focus on ART
Roy M. Gulick, MD, MPH
Professor of Medicine
Weill Cornell Medical College
New York, NY
From RM Gulick, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
IAS–USA
Oh, Baby!
Slide 2 of 12
• Mother presented in labor, unaware of HIV status, found HIV+
• Baby treated with 3-drug ART (ZDV/3TC + NVP) within 30 hours
• Mother VL 2K, baby VL 20K
• Matched wild-type virus, subtype B
• Baby HIV RNA decreased at days 7, 12, 20, then <20 at day 29
• HIV RNA continued <20 cps/ml X 16 determinations
• Mother and baby lost-to-follow-up; ART stopped at 18 months
• Re-presented for follow-up
• HIV RNA <20 copies/ml (1 copy/ml) at 24 months
• HIV DNA 4 copies / 1 million PBMC at 26 months
• No replication-competent virus
• HIV Antibody negative
• Cure(?)
From RM Gulick, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Persaud CROI 2013 #48LB
Slide 3 of 12
CDC: U.S. ART Drug Resistance 2007-2010
• Study population: Convenience sample of newly diagnosed
HIV+ without prior ART use in 10 U.S. surveillance areas
reported to the CDC through 6/11
• Assessed NRTI, NNRTI and PI mutations
• 18,144 patients had viral sequences assessed
• 2932 (16%) of patients had 4788 drug mutation sequences
• Of these viral sequences –
• 14% 1-class resistance; 2% 2-class; 0.5% 3-class
• 7% to NRTIs; 8% to NNRTIs; 4% to PIs
• Estimated annual change for any 1 mutation not
significant (3%, p=0.06)
• Significant increases in
• 1-class mutations (4%, p=0.01)
• NNRTI mutations (5%, p=0.03)
From RM Gulick, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Kim CROI 2013 # 149
Slide 4 of 12
TAF vs TDF Phase 2, Week 24 Analysis
% Subjects VL <50 c/mL
Study population: Rx-naïve, VL >5000, CD4 >50 (N=170)
TDF/FTC/EVG/c 90% (n=58)
100
90
80
70
60
50
40
30
20
10
0
TAF/FTC/EVG/c 88% (n=112)
2
12
4
8
Time (Weeks)
16
24
 Change in serum creatinine at Week 24
– TAF +0.07 mg/dL
– TDF +0.12 mg/dL (p=0.02)
From RM Gulick, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Zolopa CROI 2013 # 99LB
Slide 5 of 12
Percent Change in Bone Mineral Density (DEXA)
GS-US-292-0102 – Week 24 Analysis
HIP
2
0
-0.8%
p = 0.002
-2
Mean % change in BMD
Mean % change in BMD
SPINE
2
0
-0.3%
p < 0.001
-2
-2.0%
-2.5%
0
12
Time (Weeks)
24
0
12
Time (Weeks)
24
 Proportion of subjects with no decrease in BMD
– Spine: TAF 38% TDF 12%
– Hip: TAF 41% TDF 23%
From RM Gulick, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Zolopa CROI 2013 # 99LB
Slide 6 of 12
Second-Line Study: LPV/r + [NRTIs or RAL]
• Design: Randomized, open-label non-inferiority study (margin 12%)
• Study population: HIV+ patients who failed a 2 NRTI + NNRTI
regimen with no prior PI or RAL (N=541)
• Baseline: 55% men; 42% Asian, 36% African, 14% Hispanic;
VL 4.2 log; CD4 211; 47% prior AIDS illness
• Study rx: LPV/r + 2-3 NRTIs (most common regimen TDF +
FTC/3TC 46%; genotyping used in 73%) or RAL
• Results (week 48):
• HIV RNA <200: 81% (NRTIs) vs. 83% (RAL) p=0.59
• HIV RNA <50: 70% (NRTIs) vs. 71% (RAL)
• CD4: +114 (NRTIs) vs. +150 (RAL) (p=0.01)
• Treatment d/c: 29 (NRTIs) vs. 28 (RAL)
• Grade 3/4 events: 28 (NRTIs) vs. 19 (RAL)
• Conclusion: RAL non-inferior to NRTIs as second-line rx with a PI/r
From RM Gulick, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Boyd CROI 2013 #180LB
Slide 7 of 12
MK-1439: Phase Ib
Double-blind, randomized, placebo-controlled
Study population: HIV+, treatment-naïve (N=18)
From RM Gulick, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Anderson, CROI 2013; #100
Slide 8 of 12
BMS-663068: Oral HIV Attachment Inhibitor
Study pop: CD4 >200, VL >5000 off ART X >8 wks or ART-naive (N=50)
• Prodrug of BMS-626529
• Inhibits CD4 binding by
binding to gp120
• PK suggest QD or BID
dosing without boosting
• ↓ baseline susceptibility
in some pts due to
envelope polymorphisms;
screened by baseline IC50
From RM Gulick, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Nettles JID 2012;206:1002
Slide 9 of 12
Cenicriviroc (CVC) 202: Phase 2
VL <50 copies/mL (ITT-FDA Snapshot)
Subjects with HIV-1 RNA
<50 c/mL, % (±SE)
100
Study population: Rx-naïve, VL >1000,
CD4 >200, documented R5 virus (N=143)
All arms with TDF/FTC
80
76%
73%
71%
60
CVC 100 mg
CVC 200 mg
EFV
40
20
randomized
2:2:1
BL 1
CVC 100 mg (N=59)
CVC 200 mg (N=56)
EFV (N=28)
2
0 3
2 2
0 4
4
8
11
4
5
25
17
12
12
Weeks
16
37
28
16
44
13
18
From RM Gulick, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
20
42
40
19
24
45
41
20
Gathe CROI 2013 #106LB
Slide 10 of 12
Cenicriviroc (CVC) Study 202
Mean change from baseline in
sCD14 levels,a x 106 ng/L (±SE)
sCD14 Changes from Baseline
CVC 100 mg
CVC 200 mg
EFV
EFV
CVC 100 mg
CVC 200 mg
55
54
28
51
50
22
From RM Gulick, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
47
44
21
Gathe CROI 2013 #106LB
Slide 11 of 12
GSK744 LAP: PrEP Study in Macaques
• Study population: male macaques (N=16)
• Study treatment:
– GSK 744LAP 50mg/kg X 2, 4 weeks apart
– Placebo
• Weekly SHIV rectal challenge X 8
• Results (preliminary)
– GSK 744LAP: no infections
– Placebo: all infected
Andrews CROI 2013 #24LB
From RM Gulick, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 12 of 12
TDF Intravaginal Ring for PrEP
• Polyurethane drug reservoir ring that contains 130 mg
of TDF and delivers 2.3 mg/day; replaced every 28
days over 16 weeks
• 18 macaques (6 ring, 12 controls -- 6 real-time, 6 hx)
• Low-dose challenge model: once-weekly SHIV
vaginally up to 16 weeks
• Results (over 16 weeks):
– 0/6 macaques with rings vs. 11/12 without rings
infected (after median 4 exposures) (P<0.0004)
– Rings well retained and well-tolerated X 5 months
From RM Gulick, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Smith, CROI 2013 #25LB
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