Charles "Chuck" Hicks, M.D., of UC San Diego Owen Clinic, presents "8th IAS Conference - Update from Vancouver" at AIDS Clinical Rounds

1. The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinicians, physicians and
researchers. The goal of these presentations is to provide the most
current research, clinical practices and trends in HIV, HBV, HCV, TB
and other infectious diseases of global significance.
The slides from the AIDS Clinical Rounds presentation that you are
about to view are intended for the educational purposes of our
audience. They may not be used for other purposes without the
presenter’s express permission.
AIDS CLINICAL ROUNDS

2. 8th IAS Conference on HIV Pathogenesis,
Treatment, and Prevention, July 19-22, 2015
Vancouver, British Columbia

3. Speaker and Disclosure Information
Charles Hicks, MD
Professor of Clinical Medicine
Director, Owen Clinic
University of California, San Diego
San Diego, California
Disclosures:
Scientific Advisory Board: Bristol-Myers Squibb, Gilead Sciences,
Janssen Virology, Merck, and ViiV
Royalties: UpToDate, Inc.
Authorship/Editorial Board: Journal Watch-ID, Massachusetts
Medical Society

4. Vancouver 2015

5. HPTN 052:
Updated Analysis on Interim Results
Cohen M, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOAC0101LB.
April 2005-May 2011
Person-
years
F/U
All Partner
Infections #
(Rate)
Linked
Partner
Infections #
(Rate)
Total 3482 46 (1.32) 37 (1.06)
Early Arm 1751 4 (0.23) 1 (0.06)
Delayed Arm 1731 42 (2.43) 36 (2.08)
Rate Ratio 0.09 0.03
Risk Reduction 91% 97%
Rate = # of events / 100 PY
Risk reduction = 1 – rate ratio
Linked = index-to-partner transmission likely

6. HPTN 052:
Updated Analysis on Interim Results
April 2005-May 2011 May 2011-May 2015
Person-
years
F/U
All Partner
Infections #
(Rate)
Linked
Partner
Infections #
(Rate)
Person-
years
F/U
All Partner
Infections #
(Rate)
Linked
Partner
Infections #
(Rate)
Total 3482 46 (1.32) 37 (1.06) 5012 32 (0.64) 9 (0.18)
Early Arm 1751 4 (0.23) 1 (0.06) 2563 15 (0.59) 2 (0.08)
Delayed Arm 1731 42 (2.43) 36 (2.08) 2449 17 (0.69) 7 (0.29)
Rate Ratio 0.09 0.03 0.86 0.28
Risk Reduction 91% 97% 14% 72%
Cohen M, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOAC0101LB.
Rate = # of events / 100 PY
Risk reduction = 1 – rate ratio
Linked = index-to-partner transmission likely

7. HPTN 052:
Updated Analysis on Interim Results
April 2005-May 2011 May 2011-May 2015
Person-
years
F/U
All Partner
Infections #
(Rate)
Linked
Partner
Infections #
(Rate)
Person-
years
F/U
All Partner
Infections #
(Rate)
Linked
Partner
Infections #
(Rate)
Total 3482 46 (1.32) 37 (1.06) 5012 32 (0.64) 9 (0.18)
Early Arm 1751 4 (0.23) 1 (0.06) 2563 15 (0.59) 2 (0.08)
Delayed Arm 1731 42 (2.43) 36 (2.08) 2449 17 (0.69) 7 (0.29)
Rate Ratio 0.09 0.03 0.86 0.28
Risk Reduction 91% 97% 14% 72%
Cohen M, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOAC0101LB.
8 transmissions on treatment:
4 prior to or at start of ART; 4 during VL failure
Overall risk reduction – 93%

8. UNAIDS 90-90-90:
2020 HIV Treatment Targets
! 90% of HIV+ people
diagnosed
! 90% of those
diagnosed on ART
! 90% of those on ART
with Undetectable
HIV RNA
100%
90%
81%
73%
0%
20%
40%
60%
80%
100%
HIV Positive People Diagnosed On ART Viral Suppression
35.0
million
31.5
million
28.4
million
25.6
million
Levi J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOAD0102.
Ref: The Joint United Nations Program on HIV/AIDS.
90-90-90 An ambitious treatment target to help end the AIDS epidemic. 2014; JC2684

9. UNAIDS 90-90-90:
Percent of HIV+ Population Aware of Diagnosis
87% 86%
86% 85% 84%
81% 80%
76%
73%
71%
52%
49%
45%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Estonia Australia USA Denmark Switzerland France Brazil United
Kingdom
Netherlands British
Columbia
(Ca)
Georgia Russia Sub
Saharan
Africa
UNAIDS 90-90-90 Target of 90% Diagnosed
Global Average
(Estimate 2013) – 48%
Levi J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOAD0102.

10. 71%
68%
66%
64%
62%
60%
51%
48%
39% 37%
29%
26%
11%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Switzerland United
Kingdom
Australia Netherlands Denmark France British
Columbia
(Canada)
Brazil Sub Saharan
Africa
USA Estonia Georgia Russia
UNAIDS 90-90-90 Target of 81% on ART
Global Average (Estimate 2013)
UNAIDS 90-90-90:
Percent of HIV+ Population on ART
Levi J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOAD0102.

11. UNAIDS 90-90-90:
Percent of HIV Population w/ Viral Suppression
68%
62% 61%
59% 58%
52%
40%
35%
30% 29%
20% 19%
9%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Switzerland Australia United
Kingdom
Denmark Netherlands France Brazil British
Columbia
(Ca)
USA Sub
Saharan
Africa
Georgia Estonia Russia
UNAIDS 90-90-90 Target of 73% Viral Suppression
Levi J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOAD0102.

12. Vancouver 2015

13. IPERGAY pK Sub-study:
Concentrations of TDF in Rectal Tissue
Concentrations of TFV and FTC After TDF 600 mg and FTC 400 mg – One Double Dose
Molina JM, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0102.
In explant cultures – 10/10 biopsies with productive infection vs 6/10 post-dose
0
5
10
15
20
0.0 0.5 1.0 2.0 4.0 8.0 24.0 30.0
Time (hours)
FTC
TFV
Concentration
(ng/mg)
Control

14. HPTN 067:
Daily vs Intermittent PrEP Trial Design
Primary Outcome: Sex Coverage with Drug:
≥1 dose within 4 days of sex and ≥1 dose within 24 hours after sex
Grant R, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0103.
Final
study
Visit
Week 34
4
weeks
off
drug
24 Weeks
Self-administered
dosing
6 Weeks
DOT
period
Women
(incl.TGW)
& MSM
Daily - One tablet/day
Time driven – 1 tablet /2x week with a post sex boost
Event driven -1 tablet pre-sex and 1 tablet post-sex
No more than 2 tablets daily or 7 tablets/week
FTC/TDF
Randomized
D
E
T
Sex Coverage
Subjects:
Women in Cape Town
MSM, TGW in Harlem
and Bangkok

15. HPTN 067:
Primary Outcome
0
10
20
30
40
50
60
70
80
90
Cape Town Harlem Thailand
Daily
Time Driven
Event Driven
PercentCompleteCoverage
WSM MSM
! 10 Outcome: Percent Complete Coverage by PrEP Strategy
! Post Sex Dose Most Frequently Missed
Grant R, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0103; Holtz T, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0104;
Mannheimer S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0104.

16. Percent with TFV-DP >9.1 fmol/M PBMC*
HPTN 067:
Waning Adherence Over Time in Cape Town
Time Period Daily
Event
Driven
Time
Driven
Week 10
(with sex in the past 7 days)
81%
(33/41)
52%
(12/23)
54%
(20/37)
Week 30
(with sex in the past 7 days)
66%
(19/29)
46%
(11/24)
32%
(10/31)
Grant R, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0103.
*Indicative of > two doses per week
Seroconversions:
- 2 during pre-study pK eval (8.9/100 PYs)
- 5 in study: 1 in daily, 2 in Time-d, 2 in Event-d (5.4/100 PYs)
- All seroconversions w/ no detectable TDF pK

17. 47%
11%
21%
21%
1%
Black Hispanic/Latino
White Other/Mixed
Asian/PI
ATN 110:
PrEP Demonstration Project in Young MSM in US
Age (range 18-22) 20.18 (SD 1.34)
Sexual identity
Gay – 77.8%
Bisexual – 13.7%
Highest grade
completed
High school – 33.8%
Some college – 45.5%
Not currently working 30.1%
Kicked out of home 17.2%
Been paid for sex 28.6%
Exchange sex for
shelter
9%
CRAI* w/ last partner 58%
Positive STI test
Rect. Gonorrhea – 8%
Rect. Chlamydia – 18%
Syphilis – 6.5%
Decided to take PrEP 98%
Hosek S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAC0204LB.
* CRAI = condomless receptive anal intercourse
Baseline Characteristics

18. 0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
WK 4 WK 8 WK 12 WK24 WK 36 WK 48
ATN 110:
Adherence Rates
Adherence:
TFV-DP via DBS* and Dosing Estimates
>1250
(daily)
>700-1250
(4+ days)
350-700
(2-3 days)
LLQ-350
(<2 days)
BLQ
Hosek S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAC0204LB. * DBS = dried blood spot

19. US PrEP Demonstration Project:
Adherence to PrEP by TDF Levels in Dried Blood Spots
Open Label PrEP among MSM and transgender women in San
Francisco (n=300), Miami (n=157), and Washington DC (n=100)
Hosek S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAC0204LB.
0%
20%
40%
60%
80%
100%
4 12 24 36 48
Engagement(Percentage)
Visit Week
No Visit BLQ <2 doses 2-3 doses 4-7 doses

20. US PrEP Demonstration Project:
Predictors of Protective Levels of TFV
Characteristic % PL* AOR (95% CI) P value
Site
San Francisco
Miami
DC
90
65
88
Ref
0.32 (0.17-0.60)
1.08 (0.54-2.19)
<0.001
0.82
Race/Ethnicity
White
Latino
Black
Asian
Other
91
77
57
84
82
Ref
0.81 (0.41-1.61)
0.28 (0.12-0.64)
0.72 (0.17-3.03)
0.42 (0.13-1.38)
0.55
0.003
0.65
0.15
Living situation
Rent or own housing
Other
87
70
2.02 (1.14-3.55)
Reference
0.02
# Condomless Anal Sex Partners, Past 3 mo
0-1
≥2
75
89
Reference
1.82 (1.14-2.89) 0.01
Liu A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAC0202.
*PL = Protective DBS levels (TFV-DP in DBS consistent with ≥4 doses/week)
OR for protective levels did not differ by age, education, alcohol, or drug use

21. US PrEP Demonstration Project:
STI Rate Over Time
0
2
4
6
8
10
12
14
16
18
Screening 12 24 36 48
STIPositivityRateatEachVisit(%)
Visit interval
Rectal STI (GC/CT) Urethral STI (GC/CT)
Pharyngeal STI (GC/CT) Primary, secondary, or early latent syphilis
Liu A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAC0202.

22. Vancouver 2015

23. Vancouver 2015
Review from the 8th IAS Conference on HIV
pathogenesis, treatment, and prevention
Studies in Treatment-Naïve Patients
19-22 July 2015
Vancouver, British Columbia

24. Case%
A"27"year"old"male"presents"for"care"
• Diagnosed"with"HIV"infec;on"less"than"1"month"ago"
• Iden;fied"through"contact"tracing"a?er"his"partner"tested"
posi;ve"for"HIV"and"syphilis"
• Asymptoma;c"on"presenta;on"but"concerned"about"his"
new"diagnosis"
• He"is"interested"in"treatment"but"wants"to"know"more"
about"the"medica;ons"
• Ini;al"laboratory"data"
– CD4"796"cells/mm3"(43%)"
– HIV"RNA"level"9,700"copies/ml"

25. When%would%you%start%an1retroviral%
therapy%in%this%pa1ent?%
A. Immediately"if"he"
consents"to"
treatment""
B. A?er"the"results"of"
HIV"genotyping"are"
available"
C. A?er"one"or"more"
clinic"visits"to"assess"
pa;ent"readiness"
D. When"the"CD4"count"
falls"below"500"cells/
mm3"
Im
m
ediately*w
hile*hospit...
After*the*results*of*HIV*g...
After*one*or*m
ore*clinic*v...
W
hen*the*CD4*count*falls...
0% 0%0%0%

26. START%Design%%
HIVTinfected"individuals"who"are"ARTTnaïve"with"CD4+"
count">"500"cells/mm3"
Immediate>Ini1a1on%Group%
"
Ini;ate"ART"immediately""
following"randomiza;on"
"
"
N"="2326"
Deferred>Ini1a1on%Group%
"
Defer"ART"un;l"the"CD4+"count"
declines"to"<"350"cells/mm3"or"
"AIDS"develops"
"
N"="2359"
The"INSIGHT"START"Study"Group,"N"Engl"J"Med"2015;%DOI:"10.1056/NEJMoa1506816"

27. START%Methods%
• Study"required"use"of"an"approved"
combina;on"of"medica;ons"from"the"DHHS"
ART"treatment"guidelines"
• Primary"composite"endpoint:""
– AIDS"event"(1993"defini;on"plus"Hodgkin’s)"or"
– Serious"nonTAIDS"event"(CV"disease,"ESRD,"liver"
disease,"nonTAIDS"cancer)"or""
– Death"due"to"any"cause"
The"INSIGHT"START"Study"Group,"N"Engl"J"Med"2015;%DOI:"10.1056/NEJMoa1506816"

28. START Study:
Baseline Characteristics
Characteristics
Immediate-Initiation
Group
(N=2326)
Deferred-Initiation
Group
(N=2359)
All Patients
(N=4685)
Median Age (IRQ)-yr 36 (29-44) 36 (29-44) 36 (29-44)
Female Sex – no. (%) 624 (26.8) 633 (26.8) 1,257 (26.8)
Mode of Infection with HIV – no. (%)
Sexual Contact
Men Having Sex with Men 1,300 (55.9) 1,286 (54.5) 2,586 (55.2)
With Person of Opposite Sex 873 (37.5) 917 (38.9) 1,790 (38.2)
Injection-drug Use 37 (1.6) 27 (1.1) 37 (1.6)
Blood Products, Other, or Unknown 116 (5.0) 129 (5.5) 116 (5.0)
Median Time Since HIV Diagnosis (IQR) – yr 1.0 (0.4-3.0) 1.1 (0.4-3.1) 1.0 (0.4-3.0)
Median CD4+ count (IQR) – cells/mm 651 (585-765) 651 (582-764) 651 (585-765)
Median HIV RNA (IQR) – copies/ml
13,000
(3133-43,808)
12,550
(2963-42,567)
13,000
(3133-43,808)
Median CHD Risk at 10yr (IQR) - % 1.9 (0.5-5.0) 1.9 (0.5-5.3) 1.9 (0.5-5.0)
Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.
No significant differences between groups

29. 0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60
PercentageofParticipants
Months
START Study:
Proportion on ART
% of Follow-up
on ART
Immediate 94
Deferred 28
Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.
Deferred Arm:
Median time to ART
3 years (IQR 1.6-4.8)
(projected 4 years)
Immediate ART, % with HIV RNA ≤ 200 c/mL
Deferred ART, % using ART
Deferred ART, % with HIV RNA ≤ 200 c/mL
Immediate ART, % using ART

30. START Study:
Initial ART Combinations
Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.
Deferred
TDF/FTC/EFV
TDF/FTC/ATV/r
ZDV/3TC/EFV
TDF/FTC/DRV/r
TDF/FTC/RPV
TDF/FTC/RAL
Other
Immediate
N=2287 (98%) N=1134 (48%)
EFV: 73% vs 51%
TDF: 89% in both groups

31. START%Results%
• 4685"subjects"were"enrolled"and"followed"for"a"
mean"of"3"years"
• Based"on"an"interim"analysis"in"March"of"2015,"
the"Data"Safety"Monitoring"Board"concluded"that"
the"study"had"answered"the"ques;on"
• The"DSMB"recommended"that"the"deferredT
ini;a;on"arm"be"offered"ART"
• The"results"were"announced"in"an"NIH"press"
release"on"May"27,"2015"
• The"results"were"published"in"the"NEJM"and"
presented"at"the"IAS"conference"on"July"20,"2015"
The"INSIGHT"START"Study"Group,"N"Engl"J"Med"2015;%DOI:"10.1056/NEJMoa1506816"

32. START Study:
CD4 Cell Counts
Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.
450
500
550
600
650
700
750
800
850
900
950
1000
12 24 36 48 60
MeanCD4+Count(cells/mm3)
Months
B CD4+ Count
Immediate Initiation
Deferred Initiation
CD4 at the start of ART
in deferred.
Median 408
Estimated difference
194 cells

33. START Study:
Primary Endpoint
Immediate ART Deferred ART
No. with Event (%) 42 (1.8%) 96 (4.1%)
Rate/100PY 0.60 1.38
HR (Imm/Def) 0.43 (95% CI: 0.30 to 0.62, p<0.001)
Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.
0
2
4
6
8
10
0 6 12 18 24 30 36 42 48 54 60
CumulativePercentwithanEvent
Months
Immediate ART
Deferred ART
5.3
2.5

34. 0
2
4
6
8
10
0 6 12 18 24 30 36 42 48 54 60
CumulativePercentwithanEvent
Months
Immediate ART
Deferred ART
START Study:
Serious AIDS Events
Immediate ART Deferred ART
No. with Event (%) 14 50
Rate/100PY 0.20 0.72
HR (Imm/Def) 0.28 (95% CI: 0.15 to 0.50, p<0.001)
Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.

35. START Study:
Serious NON-AIDS Events
Immediate ART Deferred ART
No. with Event (%) 29 47
Rate/100PY 0.42 0.67
HR (Imm/Def) 0.61 (95% CI: 0.38 to 0.97, p=0.04)
Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.
0
2
4
6
8
10
0 6 12 18 24 30 36 42 48 54 60
CumulativePercentwithanEvent
Months
Immediate ART
Deferred ART

36. START Study:
Primary and Secondary Endpoints
End Point
Immediate-
Initiation
Group
(N=2326)
Deferred-
Initiation
Group
(N=2359)
Hazard Ratio
(95% CI)
P Value
No.
No. /100
person-
yr
No.
No. /100
person-
yr
Composite Primary End Point 42 0.60 96 1.38 0.43 (0.30-0.62) <0.001
Components of the Primary End Point
Serious AIDS-Related Event 14 0.20 50 0.72 0.28 (0.15-0.50) <0.001
Serious Non-AIDS-Related Event 29 0.42 47 0.67 0.61 (0.38-0.97) 0.04
Death From Any Cause 12 0.17 21 0.30 0.58 (0.28-1.17) 0.13
Tuberculosis 6 0.09 20 0.28 0.29 (0.12-0.73) 0.008
Kaposi’s Sarcoma 1 0.01 11 0.16 0.09 (0.01-0.71) 0.02
Malignant Lymphoma 3 0.04 10 0.14 0.30 (0.08-1.10) 0.07
Cancer Not Related to AIDS 9 0.13 18 0.26 0.50 (0.22-1.11) 0.09
Cardiovascular Disease 12 0.17 14 0.20 0.84 (0.39-1.81) 0.65
Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.

37. START Study:
Primary Endpoint Subgroup Analysis
Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.
Subgroup
Percentage
in Group
Immediate
Initiation
Deferred
Initiation
Hazard Ratio (95% CI)
P Value for
Interaction
no. of patients with event
(rote per 100 person-yr)
Age 0.98
≤35yr 48.8 I5 (0.43) 31 (0.91) 0.47
>35yr 51.2 27 (0.78) 65 (1.85) 0.42
Sex 0.38
Male 73.2 35 (0.66) 74 (1.40) 0.47
Female 26.8 7 (0.42) 22 (1.34) 0.31
Race 0.65
Black 30.1 I5 (0.82) 28 (1.52) 0.57
White 44.5 21 (0.63) 53 (1.54) 0.40
Other 25.4 6 (0.34) 15 (0.91) 0.37
Geographic region 0.55
High income 46.0 20 (0.56) 51 (1.42) 0.39
Low or moderate income 54.0 22 (0.65) 45 (1.35) 0.48
Baseline CD4+ 0.71
<600 cells/mm3 31.5 10 (0.44) 35 (1.54) 0.28
600-800 cells/mm3 48.6 24 (0.70) 46 (1.38) 0.50
>800 cells/mm3 19.9 8 (0.63) 15 (1.14) 0.56
Baseline HIV RNA 0.25
<5000 copies/ml 31.8 12 (0.56) 18 (0.83) 0.66
5000-30,000 copies/ml 35.5 13 (0.53) 36 (1.41) 0.38
>30.000 copies/ml 32.5 17 (0.72) 42 (1.92) 0.37
Smoker 0.93
Yes 31.9 18 (0.78) 43 (1.81) 0.43
No 68.1 24 (0.52) 53 (1.16) 0.44
Framingham 10-yr CHD risk 0.56
<0.8 32.7 8 (0.35) 17 (0.77) 0.46
0.8-3.6 32.3 11 (0.48) 27 (1.23) 0.39
>3.6 33.5 23 (1.00) 50 (2.05) 0.50
0.25 0.50 1.00 2.00
Immediate Initiation
Better
Deferred Initiation
Better

38. 0
10
20
30
40
50
60
PercentofFollow-upTime
Latest CD4+ Count (Cells per Cubic Millimeter)
START Study:
CD4 at the Time of Events
Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.
2 3 6 11 20
(4.7) (0.8) (0.4) (0.6) (0.6)
5 34 34 9 14
(1.8) (2.0) (1.5) (0.6) (1.1)
<350 350-49
9
500-64
9
650-79
9
≥ 800 <350 350-49
9
500-64
9
650-79
9
≥ 800
Immediate ART Deferred ART
Immediate Defer
Percent 88% 59%
Rate (/100 PY) 0.6 1.1
No. of Participants with Events (Rates per 100 PY)
Primary Events at Latest
CD4 count >500 c/mm3

39. START Study:
Adverse Events
End Point
Immediate-
Initiation
Group
(N=2326)
Deferred-Initiation
Group
(N=2359)
Hazard
Ratio
(95% CI)
P Value
No.
No. /100
person-yr No.
No. /100
person-yr
Other Secondary End Points
Grad 4 Event 73 1.06 73 1.05
1.01
(0.73-1.39)
0.97
Unscheduled Hospitalizations 262 4.02 287 4.40
0.91
(0.77-1.08)
0.28
Grade 4 Event, Unscheduled
Hospitalizations, or Death
from Any Cause
283 4.36 311 4.78
0.91
(0.77-1.07)
0.25
Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.

40. TEMPRANO:%A%Trial%of%Early%An1retrovirals%and%
Isoniazid%Preven1ve%Therapy%in%Africa%
• Subjects"with"CD4"less"than"800"cells/mm3"but"
did"not"meet"treatment"per"WHO"guidelines"
• 41%"of"the"2056"subjects"had"an"ini;al"CD4">"500"
cells/mm3"
• Assigned"to"4"treatment"groups:"deferred"ART,"
deferred"+"IPT,"early"ART,"early"+"IPT"
• Risk"of"death"or"severe"HIVTrelated"illness"lower"
with"both"early"ART"and/or"IPT"
The"TEMPRANO"ANRS"12136"Study"Group,"N"Engl"J"Med"2015;%DOI:"10.1056/NEJMoa1507198"

41. TEMPRANO:%A%Trial%of%Early%An1retrovirals%and%
Isoniazid%Preven1ve%Therapy%in%Africa%
The"TEMPRANO"ANRS"12136"Study"Group,"N"Engl"J"Med"2015;%DOI:"10.1056/NEJMoa1507198"

42. Implica1ons%of%START%Trial%and%Other%
Studies%of%“Early%ART”%
• A?er"decades"of"debate,"the"benefits"of"
immediate"ART"are"now"clear"in"large,"
randomized"interna;onal"trials"
• The"data"suppor;ng"a"personal"health"benefit"
are"now"as"strong"as"the"data"to"support"
treatment"as"preven;on"
• Harmoniza;on"of"countryTspecific"and"global"
guidelines"should"soon"follow"

43. 15%million%of%the%World’s%36.9%Million%
Persons%with%HIV%Infec1on%are%on%ART%
41%%
59%% On"ART"
Not"on"ART"
As of March 2015, UNAIDS.org"

44. Week 48
ATV+RTV+FTC/TDF Placebo QD
EVG/COBI/FTC/TDF QD
EVG/COBI/FTC/TDF Placebo QD
ATV+RTV+FTC/TDF QD(n=575)
WAVES 1:1
Key Eligibility Criteria:
! HIV infected womem
! HIV-1 RNA ≥ 500 copies/mL
! Estimated GFR ≥ 70 mL/min
! No history of prior antiretroviral therapy
! Sensitivity to FTC, TDF, and ATV
! Stratification:
" HIV-1 RNA (<=100,000, >100,000-<=400,000, >400,000 copies/mL)
" Race (Black or non-Black)
Baseline
Open Label
Extension
WAVES Study:
Design in HIV+ ART Naïve Women
Squires K, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOLBPE08.

45. STB
(n=289)
ATV+RTV+TVD
(n=286)
Age (years), median (Q1,Q3) 34 (28,43) 35 (29,42)
Race
White
Black
Asian
44%
49%
3%
42%
47%
6%
Mode of Infection
Heterosexual 96% 94%
HIV Disease
Asymptomatic
AIDS
81%
4.2%
75%
4.5%
Body Mass Index (BMI), Mean (SD) 26 (7.02) 26 (5.69)
Positive HBsAg 3.1% 2.4%
Positive HCV Antibody 7.6% 8.7%
HIV-1 RNA (log10 copies/mL), Median (Q1,Q3)
< 100,000 c/mL
>100,000-400,000 c/mL
> 400,000 c/mL
4.46 (4.09,4.97)
76%
15%
9%
4.56 (4.02,5.00)
75%
17%
8%
CD4 cell count (cells/mm3), Median (Q1,Q3)
<200 cells/mm3
344 (246,466)
17%
370 (244,489)
18%
WAVES Study:
Baseline Characteristics of HIV+ Women
Squires K, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOLBPE08.

46. HIV-1RNA<50c/mL,%
ATV+ RTV + FTC/TDF (n=286)
EVG/COBI/FTC/TDF (n=289)
Favors ATV+ RTV Favors STB
12.6%
-12%
+12%
0.4%
0
Treatment Difference
(95% CI)
6.5%
Mean CD4 Cell Increase (cells/mm3) was 196 (EVG/COBI/FTC/TDF & ATV/RTV + FTC/TDF)
WAVES Study:
Virologic Outcomes
RESISTANCE
STB: Only one pt with emergent D67D/N
ATV/r: 3 with M184V/I
Squires K, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOLBPE08.
87
9
4
81
12
7
0
20
40
60
80
100
Virologic Success Virologic Failure No Virologic Data

47. 87 86
90 88 86
81 82
78
82 79
0
20
40
60
80
100
Overall VL
≤ 100,000
VL
> 100,000
CD4
≤ 350
CD4
> 350
EVG/COBI/FTC/TDF ATV+RTV+FTC/TDF
VirologicSuccess(%)
HIV-1 RNA (c/mL) CD4 Cell Count (/µL)
WAVES Study:
Efficacy by Baseline HIV-1 RNA & CD4 Count
Squires K, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOLBPE08.
N 289 286 220 214 69 72 146 131 143 154
AERs leading to d/c: E/C/F/T - 7 vs ATV/r - 20

48. Vancouver 2015

49. Vancouver 2015
Review from the 8th IAS Conference on HIV
pathogenesis, treatment, and prevention
Studies in Treatment-Experienced Patients
including investigational agents
19-22 July 2015
Vancouver, British Columbia

50. TDF/FTC + Doravirine vs EFV:
Study Design
Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB04.
Part 1
Dose Ranging Phase
(N=210)
Part 1
Extension Phase
DOR 25 mg
DOR 50 mg
DOR 100 mg (n=42) DOR 100 mg
DOR 200 mg
EFC mg (n=42) Continue EFV
Part 2
Additional Patients
(N=132)
DOR 100 mg (n=66)
EFC 600 mg (n=66)
Week 24 Week 96Week 48
Week 24 Week 96Week 48
Note: blinding maintained through Week 96 study visit
Patients:
HIV-1+ ART-naïve
HIV RNA ≥1,000 c/ml
CD4 count ≥100 cells/µL

51. TDF/FTC + Doravirine vs EFV:
Baseline Characteristics
Doravirine 100 mg
(N=108)
Efavirenz 600 mg
(N=108)
% Male 91.7 93.5
Age (years), median (range) 35 (19 – 67) 34 (20 – 57)
% White 79.6 79.6
% with AIDS 3.7 6.5
HIV RNA (log10 c/mL), median (range) 4.6 (2.6 – 6.5) 4.6 (3.0 – 6.7)
% with HIV RNA >100,000 c/mL, at screening 35.2 37.0
CD4 Count (cells/µL), median (range) 402 (92 – 1110) 430 (118 – 1121)
% with CD4 count ≤ 200 cells/µL 6.5 9.3
% with Clade B viral subtype 69.4 79.6
Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB04.

52. 3.7
15.7
27.8
42.1
63.6 72.2
6.5 12
26.9
47.2
57.5
73.1
0
10
20
30
40
50
60
70
80
90
100
0 4 8 12 16 20 24
Treatment Week
Doravirine 100mg
Efavirenz
Δ (95% CI):
-1.2 (-13.0, 10.5)
TDF/FTC + Doravirine vs EFV:
Primary Endpoint
Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB04.
Percentage < 40 cop/mL at 24 weeks

53. 83.3
92.4
60.5
92.1
85.7
92.1
65.8
94.7
0
20
40
60
80
100
% <40 c/mL % <200 c/mL % <40 c/mL % <200 c/mL
Doravirine 100 mg q.d. Efavirenz 600 mg q.d.
≤100,000%c/mL% >100,000%c/mL%
n/N:%%%%%55/66%%%%%%%54/63%
TDF/FTC + Doravirine vs EFV:
Results by Baseline HIV RNA
Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB04.
25:%%%%%51/66%%%%%%58/63% 11:%%%%%23/38%%%%%%25/38% """""35/38""""""36/38"
Virologic failures: DRV 17, EFV 11 -- mostly due to low-level viremia at week 24 (no resistance detected)
1 or more CNS adverse events: DRV 27%, EFV 46% -- difference -19.4% (95% CI -31.7, -6.6)

54. Switch to E/C/F/TAF in Virologically
Suppressed Adults
Primary Endpoint
HIV-1 RNA <50 c/mL
Week 0
Switch to E/C/F/TAF
Continue TDF-Based
Regimen
9648
Virologically
Suppressed
Adults
E/C/F/TDF
(n=459)
EFV/FTC/TDF
(n=376)
Boosted ATV + FTC/TDF
(n=601)
Randomized (2:1), active-controlled,
open-label study
n=959
n=477
Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.
Baseline Characteristics E/C/F/TAF
n=959
TDF-Based Regimen
n=477
Median age, years 41 40
Female, % 11 11
Race, %
White 68 66
Black or African descent 18 21
Hispanic/Latino ethnicity 26 17
Median CD4 count, cells/mm3 675 662
Patients with <200 cells/mm3, % 0.5 0.8
Median estimated GFR, mL/min* 106 108
Dipstick proteinuria, %
Grade 1 8.5 9.2
Grade 2 0.4 0.6

55. 97
1 2
93
1
6
0
20
40
60
80
100
Success Failure No Virologic Data
E/C/F/TAF
n=959
TDF-Based Regimen n=477
Virologic Outcome
TDF Based E/C/F/TAF
0
HIV-1RNA<50c/mL,%
‒12% +12%
6.71.6
4.1
Switch to E/C/F/TAF in Suppressed Adults:
Results
54
932 444 10 6 17 27n=
Treatment Difference (95% CI)
Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.

56. 97 96 97 98
93
90 92
97
0
20
40
60
80
100
All Prior Regimens Prior
EFV/FTC/TDF
Prior
Boosted
ATV + FTC/TDF
Prior
E/C/F/TDF
Switch to E/C/F/TAF in Suppressed Adults:
Virologic Outcome By Prior Treatment
55
PatientsWithHIV-1RNA<50c/mL,%
p <0.001 p=NSp=0.02 p=0.02
932
959
444
477
301
306
149
153
241
251
112
125
390
402
183
199
0.5—12.3 0.9—9.2 -1.9—3.91.6—6.795% CI =
TDF-Based RegimenE/C/F/TAF
Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.
Primary Endpoint

57. ! Eligible
" HIV virologically suppressed
on any regimen
" HBSAg +
" Estimated GFR > 50
! Primary efficacy
endpoints (week 24)
" HIV RNA < 50
" HBV DNA < 29
Switch to E/C/F-TAF in HIV/HBV Co-infection:
Baseline Characteristics
N = 72
Demographi
cs
Median age, y (Q1, Q3) 51 (45, 55)
Male, n (%) 66 (92)
Asian, n (%) 7 (10)
Black, n (%) 13 (18)
HIV
Median Cockcroft-Gault eGFR, mL/
min (Q1, Q3)
95 (77,117)
Median CD4 count, cells/mm3 (Q1,
Q3)
605 (438,
789)
Median duration of HIV infection, y
(Q1, Q3)
18 (9, 24)
ART regimen characteristics
TDF-based ART (TDF and FTC or
3TC), n (%)
69 (96)*
FTC or 3TC only as part of ART, n 1
No TDF, FTC, or 3TC in ART, n 2
HBV
HBsAg+, n (%) 71 (99)†
HBeAg+, n (%) 30 (42)
HBV DNA <29 IU/mL, n (%) 62 (86)
Median duration of HBV, y (Q1, Q3) 12 (5, 20)
ALT ≤ULN, n (%) 62 (86)
FibroTest category moderate/severe
(F1-F2→F4), n (%)
43 (60)
Baseline Demographics and Disease Characteristics
Gallant J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. WELBPE13.

58. ! All 10 patients with detectable HBV DNA had declines, 7/10 < 29 at week 48
! By week 48, 2/70 lost HBSAg/gained HBSAb; 2/30 lost HBEAg
! Renal function, tubular proteinuria improved; markers of bone turnover decreased
Switch to E/C/F-TAF in HIV/HBV Co-infection:
HIV and HBV Results
94
1 4
92
3 6
0
20
40
60
80
100
Virologic Success Virologic Failure No Data
Patients(%)
HIV-1 RNA <50 Copies/mL (FDA Snapshot)
Week 24 Week 48
86
10
4
92
3 6
0
20
40
60
80
100
<29 IU/mL ≥29 IU/mL Missing
Patients(%)
HBV DNA <29 IU/mL (Missing=Failure)
Week 24 Week 48
Antiviral Efficacy at Weeks 24 (Primary Endpoint) and 48
Gallant J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. WELBPE13.
Outcomes of 3 patients on non-TDF-based regimens
LPV/r+ABC/3TC: HIV RNA <50 copies/mL; HBV DNA declined from 143 to <20 IU/mL
RAL+ATV/r: HIV RNA remained <50 copies/mL; HBV DNA declined from 259,000,000 to 51 IU/mL
ATV/r: HIV RNA remained <50 copies/mL; HBV DNA remained <30 IU/mL

59. ! Eligible: Virologically suppressed for >6 months
on TDF/FTC or ABC/3TC
! N = 60 (30 per study arm)
Randomization
PROBE Study:
DRV/r + RPV as Maintenance Therapy
Maggiolo F, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUPEB270.
RPV + DRV/r
Continuing ongoing cART
24 48
weeks
Primary Secondary
0
Non inferiority
95%CI ± 12%
Snapshot analysis
VL <50 copies for ≥6 months
No resistance for NNRTI
HBsAg negative
Any 3 drugs,
boosted PI based cART

60. PROBE Study:
DRV/r + RPV as Maintenance Therapy
! No virologic failures in DRV/r + RPV arm
! BMD outcomes numerically better in DRV/r + RPV arm,
renal and lipid outcomes no different
HIV-RNA <50 copies/ml HIV RNA >50 copies/ml No data
0
10
20
30
40
50
60
70
80
90
100
T0 T24 T48 T24 T48 T24 T48
proportion
RPV + DRV/r Controls
Primary Endpoint: Virologic Response
Favors
Controls RPV+DRV/r
24 weeks
48 weeks
-12 +12
+13,5
+20,7-0,7
-7,5
Maggiolo F, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUPEB270.

61. HIV-1 Life Cycle
Budding
Assembly/
cleavage
Release
Maturation
inhibitor
Maturation
Lataillade et al. CROI 2015, Abstract 114LB.

62. BMS-955176
40 mg
+ ATV 300 mg
+ RTV 100 mg
N=8
BMS-955176
80 mg
+ ATV 400 mg
N=8
BMS-955176
40 mg
+ ATV 400 mg
N=8
Dosing period
Furloughed
Outpatient visits
Discharge
Day 30
Days 35‡
Day 42
Days 1–28
TDF/FTC
300/200 mg
+ ATV 300 mg
+ RTV 100 mg
N=4†
Inpatient days: Day -1 to Day 30
Hwang C, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0106LB
Objectives
Change in plasma HIV-1 RNA levels from baseline to
Day 28
Safety and tolerability of BMS-955176 during combination
therapy
Key Inclusion Criteria
HIV-1 subtype B-infected subjects Plasma HIV-1 RNA ≥5,000 c/mL
Treatment-naïve (<1 week of
antiretroviral treatment) or -
experienced (PI naïve) subjects
CD4+ T-cell count ≥200 cells/µL
BMS-955176 Maturation Inhibitor:
Study Design

63. TDF/FTC 300 mg/200 mg + ATV 300 mg + RTV 100 mg
BMS-955176 40 mg + ATV 300 mg + RTV 100 mg
BMS-955176 40 mg + ATV 400 mg
BMS-955176 80 mg + ATV 400 mg
! Median change in HIV-1 RNA at Day 29 was between -1.66 and -2.18 log10 c/mL
for the BMS-955176 arms and was -2.22 log10 c/mL for the standard of care arm
–2.5
–2
–1.5
–1
–0.5
0
0.5
1
MedianChangeinHIV-1
RNA(log10c/mL)fromBaseline
Study Day
10 15 20 25 30 35 40 45 5050
Dosing Period
Hwang C, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0106LB
BMS-955176 Maturation Inhibitor:
Median Change in HIV-1 RNA

64. ! BMS-955176 80 mg + ATV and BMS-955176 40 mg + ATV + RTV had similar
maximum median changes in HIV-1 RNA compared with the standard of care arm
! Greatest elevations in bilirubin seen in maturation inhibitor plus boosted ATV (arm 2)
MaximummedianchangeinHIV-1
RNA(log10copies/mL)
-2.39
-2.02
-1.86
-2.23
-2.5
-2
-1.5
-1
-0.5
0
TDF/FTC
300/200 mg
+ ATV 300 mg
+ RTV 100 mg*
(n=4)
BMS-955176
40 mg
+ ATV 300 mg
+ RTV 100 mg
(n=8)
BMS-955176
40 mg
+ ATV 400 mg
(n=8)
BMS-955176
80 mg +
ATV 400 mg
(n=8)
Hwang C, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0106LB
BMS-955176 Maturation Inhibitor:
Maximum Median Decline in HIV-1 RNA from Baseline

65. Vancouver 2015

66. Comorbidities and
Adverse Events

67. Rising Rates of Comorbidities at
HIV Diagnosis in USA
0
10
20
30
40
50
60
70
Medicare (over 65 years)
2003 2013
0
2
4
6
8
10
12
14
16
18
Medicaid
2003 2013
Meyer N, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOPEB157.

68. ACTG: Pharmacogenomics and EFV Suicidality May Be
Predicted by CYP 2B6 and 2A6 Slow Metabolizer Genotypes
Weeks Since EFV Initiation
ProbabilityofSuicidality
0 48 96 144 192
0.000.010.020.030.040.05
Extensive (levels: 1-2)
Intermediate (3-7)
Slow (8-12)
Unweighted
No. at risk:
Extensive 623 506 435 233 52
Mid 838 659 566 276 45
Slow 195 152 124 62 8
9 events
18 events
7 events*
Mollan K, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUPEB273.
* Hazard ratio (95% CI): 1.85 (1.05, 3.26), P= 0.03

69. Study GS-US-292-0112 - Switch to FTC/TAF in Subjects with
Renal Dysfunction (Stable eGFR CG 30–69 mL/min):
Design and Baseline Characteristics
Primary Endpoint
E/C/F/TAF QDN=242
24 96480 12Week
Total
N=242
TDF
n=158
Non-TDF
n=84
Median age, years 58 59 58
≥ 65 years, % 26 22 33
Female, % 21 23 17
Black or African descent, % 18 22 12
Median CD4 count, cells/µL 632 661 585
Hypertension, % 40 34 49
Diabetes, % 14 13 14
Median eGFRCG, mL/min 56 58 53
eGFRCG ≥60 mL/min, % 34 40 24
Dipstick proteinuria, %
Grade 1 23 27 16
Grade 2 10 10 10
Grade 3-4 0 0 0
Gupta S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0103.

70. 59
63
50
57
62
48
58
63
49
0
20
40
60
80
BL W2/4/8 W24
Switch to FTC/TAF in Pts with Renal Dysfunction:
Actual GFR by Iohexol Clearance (1º Endpoint)
aGFR(mL/min)
% GLSM Ratio, % (90% CI)*%
TDF (n=21)
Week 2, 4, or 8 vs baseline 98 (94, 102)
Week 24 vs baseline 100 (96, 105)
Non-TDF (n=10)
Week 2, 4, or 8 vs baseline 96 (86, 108)
Week 24 vs baseline 98 (87, 111)
Total Non-TDFTDF
BL W2/4/8 W24 BL W2/4/8 W24
Gupta S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0103.
*Lack of alteration boundary: 80–125% (GLSM).
Actual GFR unaffected by E/C/F/TAF switch, regardless of previous regimen

71. Week 24
n=225
Baseline
n=236
Week 48
n=216
Switch to FTC/TAF in Pts with Renal Dysfunction:
Change in BMD from Baseline to Week 48
-2
0
2
4
Hip
Mean(SD)%ΔSpineBMD
1.85*
1.47*
0.70
Mean(SD)%ΔHipBMD
Week 24
n=226
Baseline
n=236
Week 48
n=214
Gupta S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0103.
Total TDF Non-TDF
-2
0
2
4
Spine
*p<0.05 by two-sided Wilcoxon signed-rank test.
2.95*
2.29*
0.99

72. 3.6 3.7
<0.001 0.010
19
7
1
12
-11
-5
-4
-1
-15
-10
-5
0
5
10
15
20
Switch to FTC/TAF in Pts with Renal Dysfunction:
Fasting Lipids at Week 48MedianChangeFromBaseline(mg/dL)
0.3
0.2
0
0.5
MedianChange
FromBaseline
Total
Cholesterol LDL HDL Triglycerides Total: HDL Ratio
Gupta S, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0103.
Baseline 194 205 122 126 54 55 122 165
P-value*
0.001 0.028
0.002 0.011 0.36 <0.001 0.028 0.73
*Wilcoxon signed-rank test.
TDF
Non-TDF

73. Effectiveness of Contraception with ART
0
5
10
15
20
25
No Contraception Implant Injectable Oral
Incidence of Pregnancy/100pyrs
ART No ART
Pyra M, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOPD103.
Data from 5,282 HIV+ women in 3 longitudinal studies in Africa

74. Vancouver 2015 – the end of the talk!