Update from the 23rd Conference on Retroviruses and Opportunistic Infections (CROI), Boston, MA 22-25 Feb 2016 Charles Hicks, M.D. April 1, 2016 UCSD HIV & Global Health Rounds

2. Update from the 23rd
Conference on Retroviruses and
Opportunistic Infections (CROI),
Boston, MA
22-25 Feb 2016
Charles Hicks, M.D.
Professor of Clinical Medicine
Director, Owen Clinic
University of California, San Diego

3. Speaker Disclosures – April 2016
Charles Hicks, MD
• Royalties: UpToDate, Inc.
• Consulting Fees: BMS, ViiV, Merck, Janssen Virology
• IDMC: Medimmune (D5170C00002 Study)
• Other: Massachusetts Medical Society/NEJM: Associate
Editor and Contributor for Journal Watch-ID

5. HIV Outcomes

6. CDC Estimated Lifetime Risk for HIV Infection
for Men in the United States
64
20
48
82
129 132
174
0
20
40
60
80
100
120
140
160
180
200
Risk(1inn)
Total Black Hispanic NHOPI AI/AN White Asian
Hess K, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 52.

7. CDC Estimated Lifetime Risk for HIV Infection
for Women in the United States
Risk(1inn)
Total Black Hispanic NHOPI AI/AN White Asian
227
48
227
385 399
880 883
0
100
200
300
400
500
600
700
800
900
1000
Hess K, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 52.

8. U.S. Clinics: Changes in Viral Load Over Time
CFAR Network of Integrated Clinical Systems (CNICS)
Cohort 29,467 Participants at 8 HIV Clinics
0
10
20
30
40
50
60
70
80
90
100
1997 1999 2001 2003 2005 2007 2009 2011 2013
Calendar Year
Percentage of Suppressed Viral Load Over Time
30%
87%
OR Std Err 95% CI P-value
Integrase Use 2.40 0.12 [2.17-2.66] <0.01
Male 1.42 0.09 [1.23-1.61] <0.01
Age (per year) 1.05 0.00 [1.04-1.05] <0.01
Race (White=Ref)
Black 0.48 0.03 [0.43-0.53] <0.01
Hispanic 1.09 0.08 [0.94-1.26] 0.27
Other/Missing 1.24 0.14 [0.99-1.55] 0.06
Years from Baseline 2.95 0.10 [2.76-3.14] <0.01
Simoni J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 1034.
PercentofSubjects

9. Increasing Rates of Viral Suppression in
United States From 2009 to 2013
 Medical Monitoring Project 2009-2013: surveillance data on
ART prescription and viral suppression in adults
Bradley H, et al. CROI 2016. Abstract 53.
*HIV-1 RNA < 200 c/mL at last test. †HIV-1 RNA < 200 c/mL at all tests from previous 12 mos.
100
80
60
40
20
0
Patients(%)
2009 2010 2011 2012 2013
Yr
βtrend = .01
βtrend = .02
βtrend = .03
58 60 62 66 68
72 74 76 77 80
89 90 92 93 94
ART prescription Viral suppression* Sustained viral suppression†
Slide credit: clinicaloptions.com

10. CDC: Change in Rates of HIV Suppression
in the United States: 2009 - 2013
2009 2013
% 95% CI % 95% CI
β
trend
change
Overall 72 69-74 80 78-83 0.02 +8
Women 66 62-70 77 73-80 0.02 +11
18-29 year olds 56 50-62 68 63-72 0.03 +12
30-39 year olds 62 58-65 75 70-80 0.03 +13
African Americans 64 61-68 76 72-79 0.03 +12
Bradley H, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 53.
OVERALL

11. 0 0.5 1 1.5 2 2.5 3 3.5
1996-99
2000-03
2004-07
2008-10
1996-99
2000-03
2004-07
2008-10
1996-99
2000-03
2004-07
2008-10
1996-99
2000-03
2004-07
2008-10
1996-99
2000-03
2004-07
2008-10
1996-99
2000-03
2007-04
2008-10
Mortality Hazard Ratios (95% CI)
ARTStartYearGroup
1
0.82 (0.75,0.91)
0.65 (0.58,0.73)
0.47 (0.40,0.55)
1
0.77 (0.64,0.93)
0.48 (0.39,0.60)
0.20 (0.14,0.30)
1
1.28 (0.84,1.94)
0.78 (0.47,1.28)
0.23 (0.09,0.59)
1
0.66 (0.46,0.96)
0.92 (0.65,1.31)
0.36 (0.21,0.63)
1
1.05 (0.69,1.59)
0.47 (0.27,0.82)
0.18 (0.06,0.51)
1
1.36 (0.83,2.24)
1.01 (0.58,1.76)
0.29 (0.11,0.76)
All Cause
AIDS
Non-AIDS Infection
Non-AIDS, Non-Liver Cancer
Liver-Related
Cardiovascular
ART-CC Cohort: Lower Mortality Among Patients
Starting ART from 2008-2010
Trickey A, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 941.

12. HIV positive
Expected
yrs of life
remaining
at age 20
(dots)
Slide credit: clinicaloptions.com
Kaiser Permanente: Life Expectancy in
HIV-Infected vs Uninfected Persons
 Analysis of life expectancy in 24,768 HIV-infected and 257,600 HIV-uninfected
adult pts in Kaiser Permanente California 1996-2011
 2 groups matched for age, sex, medical center, year
Marcus JL, et al. CROI 2016. Abstract 54.
HIV negative
Deaths
per
100,000
person-
yrs (lines)
8000
6000
4000
2000
0
80
60
40
20
0
439
19
63
7077
65
53
1054
381
P < .001
P = .062
13-Yr Gap
1996-
1997
1998-
1999
2000-
2001
2002-
2003
2004-
2005
2006 2007 2008 2009 2010 2011

13. Slide credit: clinicaloptions.com
Kaiser Permanente: Factors Contributing to
Reduced Life Expectancy With HIV (2008-11)
Marcus JL, et al. CROI 2016. Abstract 54.
Factor
Expected Years of Life Remaining at Age 20 Years
HIV Infected and
Began ART With
CD4+ ≥ 500
cells/mm3
HIV Uninfected
Difference
(95% CI)
Overall 54.5 62.3 7.9 (5.1-10.6)
 No HBV or HCV 55.4 62.6 7.2 (4.4-10.0)
 No drug or
alcohol abuse
57.2 63.8 6.6 (3.9-9.3)
 No smoking 58.9 64.3 5.4 (2.2-8.7)
 None of the
above
59.2 65.0 5.7 (2.4-9.0)

14. ACTG A5257: Sex and Racial Disparities in
Virologic Outcomes With ART
 ACTG A5257: randomized phase III comparison of ATV/RTV vs RAL
vs DRV/RTV (each with FTC + TDF) in ART-naive pts
 Current analysis compared virologic outcomes in A5257 by sex and
race/ethnicity
Ribaudo HJ, et al. CROI 2016. Abstract 476.
0.5
0.4
0.3
0.2
0.1
0.0
CumulativeVFProbability
Wks since study entry
0 19224 48 64 80 128 16096
Women
Men
Wk 96 Unadjusted HR Women vs Men:
1.4 (95% CI: 1.1-1.9; P = .026)
Slide credit: clinicaloptions.com
0.5
0.4
0.3
0.2
0.1
0.0
Wks since study entry
0 19224 48 64 80 11212814416017696
Black
Hispanic
White
Wk 96 Unadjusted HR Black vs White:
2.8 (95% CI: 2.0-3.8; P < .001)
Wk 96 Unadjusted HR Hispanic vs
White: 2.0 (95% CI: 1.4-2.8; P = .001)
112 144 176

15. ACTG A5257: Multivariable Analysis of
Risk Factors Assoc. With Virologic Failure
 Race/ethnicity adjustment eliminated excess VF risk
for women (P = .20)
 Sociodemographic factor adjustment eliminated excess
VF risk for Latinos, but not for black pts
– aHR for Latinos: 1.16 (95% CI: 0.74-1.84)
– aHR for black pts: 1.68 (95% CI: 1.14-2.46)
 Additional factors associated with increased VF risk
– Younger age
– Recent nonadherence
– High baseline HIV-1 RNA
– Underweight
Ribaudo HJ, et al. CROI 2016. Abstract 476.
– Low income
– Less education
– History of IV drug use
Slide credit: clinicaloptions.com

16. Pre-exposure Prophylaxis
(PrEP)

17. BMD Substudy of iPrEx: TDF/FTC PrEP vs
Placebo in HIV-Neg. High-Risk MSM/TGW
 iPrEx: double-blind, randomized trial (N = 2499): 44% relative
reduction in cumulative HIV risk TDF/FTC vs PBO (P = .005)[1]
 iPrEx DXA BMD substudy: (N = 498)[2]
– Small net decrease in spine (-0.91%) and total hip (-0.61%) BMD
with TDF/FTC vs PBO at Wk 24 (P = .001 for both); no difference
in fracture rate between groups (P = .62)
 Current analysis evaluated BMD changes after PrEP stop visit[3]
Slide credit: clinicaloptions.com
1. Grant RM, et al. NEJM. 2010;363:2587-2599. 2. Mulligan K, et al. Clin
Infect Dis. 2015;61:572-580. 3. Grant R, et al. CROI 2016. Abstract 48LB.
DXA:
iPrEx RCT
Median: 1.2 yrs
PrEP Gap
Median: 1.5 yrs
iPrEx OLE
1.4 yrs
BL Every 24 Wks PrEP
Discont.
6 Mos Post
Discont.
OLE
Enroll
…

18. BMD Substudy of iPrEx: BMD Recovery
After Discontinuation of TDF/FTC PrEP
Slide credit: clinicaloptions.comGrant R, et al. CROI 2016. Abstract 48LB.
*P < .05; **P < .001.
ChangeinBMDFrom
iPrExEnrollment(%)
ChangeinBMDFrom
iPrExEnrollment(%)
SpineHip
BL Wk 24 Discont. 6-mos Post
Discont.
OLE
Enroll
BL Wk 24 Discont. 6-mos Post
Discont.
OLE
Enroll
2.0
1.5
1.0
0.5
0
-0.5
-1.0
-1.5
2.0
1.5
1.0
0.5
0
-0.5
-1.0
-1.5
3.0
2.0
1.0
0
-1.0
-2.0
-3.0
3.0
2.0
1.0
0
-1.0
-2.0
-3.0
Age younger than 25 yrs
Placebo
TFV-DP < 16 at Wk 24
TFV-DP ≥ 16 at Wk 24
Age 25 yrs or older
Age younger than 25 yrs
Age 25 yrs or older
**
**
** *
**
**
 Data compared for TVF-DP < or ≥ 16 fmol/M viable PBMC, concentration associated
with 90% reduction in HIV infection risk in MSM/TGW

20. HPTN-069/A5305: Maraviroc-Based PrEP
for MSM
 Randomized, double-blind phase II trial
– Primary endpoints: safety (grade ≥ 3 AEs), tolerability
(rate/time to discontinuation of study drug)
Gulick R, et al. CROI 2016. Abstract 103.
Maraviroc*
(n = 101)
Maraviroc + FTC*
(n = 106)
- HIV-uninfected adults
- Condomless anal
intercourse with ≥ 1
HIV+ or HIV unknown
man in previous 90
days (N = 406)
Wk 48
*All standard dosing.
Maraviroc + TDF*
(n = 99)
FTC + TDF*
(n = 100)
Slide credit: clinicaloptions.com

21. HPTN-069/A5305
Safety, Tolerability, and Efficacy
 67 grade 3/4 AEs; rates similar across arms
 9% discontinued study drug early
– Rates of study drug discontinuation (P = .6) and time to permanent
discontinuation (P = .6) similar across arms
 5 new HIV infections occurred during study for annual incidence rate
of 1.4% (95% CI: 0.8-2.3); all R5 tropic; no transmitted drug resistance
Age and Race of
Newly Infected Pt
Study Arm
First HIV+
Test (Wk)
HIV-1 RNA
(c/mL)
Plasma Drug Conc. at
Seroconv. Visit (ng/mL)*
20, black MVC + TDF 4 122,150 MVC: 0† TFV: 0
61, Asian MVC alone 16 981 MVC: 145
21, mixed race MVC alone 24 106,240 MVC: 0†
35, white MVC alone 32 13,626 MVC: 6.7
36, black MVC alone 48 52,191 MVC: 0.7
Gulick R, et al. CROI 2016. Abstract 103.
*Anticipated predose steady-state MVC concentration: 32 ng/mL. †Undetectable plasma drug
concentrations at every study visit.
Slide credit: clinicaloptions.com

22. McGowan I, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 104.
Maraviroc Less Effective at Inhibiting HIV
Following Infection of Tissue Explants
0
100
200
300
400
500
MVC only
MVC + FTC
MVC + TDF
TDF + FTC
HIV-1p24(pg/mL)
Baseline Week 24 Week 48 Week 49

24. ÉCLAIR: Cabotegravir LA in HIV-Negative
Men at Low Risk for HIV Infection
 Cabotegravir: potent InSTI formulated as oral tablet and for
long-acting (LA) IM injection
 Randomized, double blind, phase IIa trial
– Primary endpoint: safety, tolerability of CAB LA IM injections
– No HIV seroconversions occurred during CAB LA dosing period
CAB LA 800 mg IM Q12W
(n = 106)
Saline Placebo IM Q12W
(n = 21)
Healthy adult
men at low risk
of HIV infection
(N = 127)
Oral Phase Injection Phase
CAB 30 mg
PO QD
Placebo
PO QD
Wk 4 Wk 5 Wk 41
Markowitz M, et al. CROI 2016. Abstract 106.
40-Wks of
follow-up
Slide credit: clinicaloptions.com

25. ÉCLAIR: Predicted vs Observed
Cabotegravir LA Pharmacokinetics
 Peak CAB LA exposure higher and trough exposure lower than
predicted because of more rapid absorption rate after injection
– 15% to 31% Ctrough measures < protein-binding adjusted IC90; Q8W
dosing now under investigation
Mean(SD)PlasmaCAB
Concentration(μg/mL)
Time From First IM Dose (Wks)
Markowitz M, et al. CROI 2016. Abstract 106.
Geometric mean
Ctrough with 10 mg PO
QD: 1.35 μg/mL
(LATTE)
4 x Protein-binding
adjusted IC90: 0.664
μg/mL
Protein-binding
adjusted IC90: 0.166
μg/mL
10
1
0.1
0.01
0 1 4 8 1213 18 2425 30 36
Observed CAB 800 mg IM Q12W (ÉCLAIR; n = 94)
Simulated CAB 800 mg IM Q12W (males)
Slide credit: clinicaloptions.com

26. 0
10
20
30
40
50 Injection 1
Injection 2
Injection 3
ÉCLAIR Study: CAB Trough Concentrations
Following Each Injection
Desired trough
concentration
Markowitz M, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 106.
<1 x PA-IC90 1 x to <4 x PA-IC90 ≥4 x PA-IC90
24%
31%
15%
45%
37%
31%
30%
32%
55%
PercentofSubjects

27. ÉCLAIR: Patient Satisfaction With IM
Therapy vs Oral Phase
Slide credit: clinicaloptions.com
1. Markowitz M, et al. CROI 2016. Abstract 106.
2. Andrews CD, et al. CROI 2016. Abstract 104.
Patients(%)
How satisfied are you with your
current treatment?
100
80
60
40
20
0
Placebo (n = 21)CAB (n = 91)
More Neutral Less
100
80
60
40
20
0
How satisfied would you be to continue
with your present form of treatment?
62
23
71 29 74
81
15
24
5
Placebo (n = 21)CAB (n = 91)
15 11
19
0
 Pt satisfaction assessed by questionnaire at Wk 18 of IM treatment
(one week after second injection)

29. Baeten J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 109LB.
ASPIRE Study:
Phase III Trial of Dapivirine Vaginal Ring

30. MTN-020/ASPIRE & IPM-027: Dapivirine
Vaginal Ring for HIV Prevention in Women
 Silicone elastomer vaginal matrix ring containing NNRTI dapivirine 25
mg; new ring inserted Q4W
 Randomized, double-blind, placebo-contolled, phase III trials
– MTN-020/ASPIRE[1,2]: Malawi, S. Africa, Uganda, Zimbabwe
– IPM-027 (The Ring Study)[3]: S. Africa, Uganda
– Primary endpoints: efficacy and safety
1. Baeten JM, et al. CROI 2016. Abstract 109LB. 2. Baeten JM, et al. N
Engl J Med. 2016;[Epub ahead of print]. 3. Nel A, et al. CROI 2016.
Abstract 110LB.
Dapivirine 25 mg Vaginal Ring Q4W
+ HIV Prevention Service Package
(ASPIRE: n = 1313; IPM-027: n = 1300)
Placebo Vaginal Ring Q4W
+ HIV Prevention Service Package
(ASPIRE: n = 1316; IPM-027: n = 650)
Sexually active HIV-
uninfected adult
women
(ASPIRE: N = 2629;
IPM-027: N = 1959)
≥ 1 Yr; Endpoint-
driven duration
Slide credit: clinicaloptions.com

31. ASPIRE Study:
Primary HIV-1 effectiveness ITT (15 sites)
Baeten J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 109LB.
Dapivirine Placebo
# HIV-1 infections 71 97
HIV-1 incidence
(Per 100 person-years)
3.3 4.5
HIV-1 Protection Effectiveness
(95% CI)
[p-value]
27%
(1, 46)
[0.046]

32. ASPIRE: Phase III Trial of Dapivirine Vaginal Ring
Efficacy and Adherence
Adherence by Plasma Drug Concentration
and Concentration in Returned RingEfficacy
Age 18 – 21
-27% (-133, 31)
Placebo incidence – 5.4%/y
Age 22 – 26
+56% (19, 76)
Placebo incidence – 6.1%/y
Age 27 – 45
+51% (8, 74)
Placebo incidence – 3.0%/y
Baeten J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 109LB.
Age 27-45
Age 22-26
Age 18-21
3 6 9 12 16 18 21 24 27 30 33
100
90
80
70
60
50
Month since randomization
PercentofSubjects

33. IPM027 Study:
Phase III Trial of Dapivirine Vaginal Ring
Nel A, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 110LB.
Variable
Dapivirine
(N = 1300)
Placebo
(N = 650)
Number of confirmed seroconversions 77 (5.9%) 56 (8.6%)
Total person years of follow-up (years) 1888 917
HIV-1 seroconversion rate
(per 100 person-years)
4.1 6.1
% reduction in HIV-1 seroconversion
(95% Cl)
[p-value]
31%
[0.9%, 51.5%)
[0.040]

34. IPM027 Study:
Efficacy by Residual Drug Level
Nel A, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 110LB.
Cut-off ring residual
level (mg)
Adherent vs. Non-adherent
% Reduction in HIV-
1 seroconversion
95% Cl
20 65% 21% to 84%
21 44% 7% to 67%
22 36% -8% to 62%
23.5 22% -40% to 56%

35. Cure

37. -10
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9
%VirologicSuppression
Weeks post-ATI
Prior ACTG studies A5340
ACTG 5340: Time to Rebound in Viral
Load After Infusions with VRC01
• 38% vs. 13% suppression at 4 weeks, p=0.04
• 8% vs. 3% suppression at 8 weeks, p=0.44
• compared to historical controls on non-NNRTI regimens undergoing ATI in ACTG studies
Bar K, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 32LB.
Number at risk
8 (90% CI 0.4-32)
38 (90% CI 17-65)
13 13 13 10 8 5 2 2 2 1

38. ART

40. 0.2 0.5 1.0 2.0 5.0 10
START Trial: Impact on Cancer
• Results: Immediate vs. deferred ART initiation and the risk of any type cancer, infection-related
and infection-unrelated cancers in the START study
Borges A, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 160.
74% reduction in risk of infection related cancers (KS, HL & NHL,HPV)
Factors associated with  risk of Infection-related cancers
• Older age and Higher baseline HIV RNA
Factors associated with risk of Infection-related cancers
• Residence in high income country
A: univariable, estimated in a Cox
proportional hazards model with a single
treatment indicator
B: adjusted for baseline covariates; age,
gender, race, geographical region,
smoking, BMI, hepatitis B/C, CD4 cell
count and baseline log10 HIV RNA
C: adjusted for latest HIV RNA,
modelled as <200 copies/mL vs HIV
RNA >200 copies/mL
D: adjusted for latest CD4 cell count and
latest HIV RNA (<200 copies/mL)
Model A
Model B
Model C
Model D
Model A
Model B
Model C
Model D
Model A
Model B
Model C
Model D
Any type cancer
(n=53)
Infection-related
cancer
(n=53)
Infection-unrelated
cancer
(n=53)

41. -4
-2
0
2
4
0 12 24 36 48 60
ChangefromBaseline
Months from Randomization
Current Health
(Visual Analog Scale, 0-100)
Immediate ART
Deferred ART
No of Participants:
Imm,: 2253 2150 1797 1038 559 146
Def.: 2287 2121 1773 1026 529 156
No of Participants:
Imm,: 2091 1977 1698 1014 555 145
Def.: 2119 1949 1677 993 521 153
-4
-2
0
2
4
0 12 24 36 48 60
ChangefromBaseline Months from Randomization
General Health
(SF-12 v2, Scaled 0-100)
Lifson A, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 475.
START Trial: Increased Quality of Life with
Immediate ART Initiation

42. • Review of resistance testing results in British Columbia since 2009
• Significant decline in detected PI an RT resistance; despite increase in use of integrase
inhibitors, rate of resistance remains very low
• Declining prevalence of drug resistant strains, and low prevalence of integrase inhibitor
resistance, to date
BC Cohort: Trends in Drug Class Resistance in
Recent Treatment Era
Lepik K, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 492LB.
331
316
304 300 292 290 285
1.07 1.67 3.26 4.28 4.84 6.14 6.8
0
50
100
150
200
250
300
350
2009 2010 2011 2012 2013 2014 2015
HIVDrugresistance/1000ART-
TreatedPersons*
Year
Prevalence of Drug Resistance
RT, PI resistance/1000 ART-treated
INI resistance/1000 ART-treated
Decreasing prevalence of RT, PI resistance,
trend p<0.001, R2 0.98
Increasing prevalence of INI resistance,
trend p<0.001, R2 0.98

43. Pooled E/C/F/TAF Studies: Pooled 48 Analysis of
HIV-1 Drug Resistance
Resistance Mutations Emerging (Final Resistance Analysis Population - RAP)
Abram M, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 496.
Subject Category
E/C/F/TAF
N=866
E/C/F/TDF
N=867
RAP (%; N with data) 24 (2.8; 22) 24 (2.8; 23)
Final RAP (%; N with data) 19 (2.2; 19) 16 (1.8; 15)
Any Primary Genotypic Resistance (%) 10 (1.2) 8 (0.9)
NRTI Resistance (%) 10 (1.2) 7 (0.8)a
M184V/I 9 (1.0) 6 (0.7)
K65R/N 2 (0.2) 3 (0.3)
K70R 1 (0.1) 1 (0.1)
INSTI Resistance (%) 8 (0.9) 6(0.7)
T66I/A/V 2 (0.2) 0
E92Q 4 (0.5) 2 (0.2)
Q148R 1 (0.1) 2 (0.2)
N155H/S 2 (0.2) 2 (0.2)
No Resistance (%) 9 (1.0) 7 (0.8)
a The subject without NRTI resistance had RT assay failure

44. TenoRes: Survey of Tenofovir Resistance
Following First-Line ART
Gregson J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 503.
Lancet 2016.
TDF + NNRTI + M184V/I TDF + NNRTI
TDF + M184V/I TDF only
49%
71%
61%
42%
60%
74%
42%
71%
59%59%
71%
82%
34%
48%
0%
20%
40%
60%
80%
100%
Numberwithresistance(%)
39%
57%
Key for tenofovir mutations
Asia
(n=365)
Eastern Africa
(n=143)
Latin America
(n=68)
North America
(n=94)
South Africa
(n=404)
West/central
Africa (n=107)
Western Europe
(n=754)
35% 22%
56%
60%
20%
• 1926 patients with treatment failure from 36 countries; all treated with TDF plus FTC or 3TC, and NVP or
EFV
• Highest rates of tenofovir resistance in Africa (56-60%)
• Significant predictors of TDF resistance: Low CD4 cell count, use of 3TC vs FTC, and NVP vs EFV
• Study results demonstrate a substantial global reservoir of TDF resistance among patients with treatment
failure

45. -3
-2.8
-2.6
-2.4
-2.2
-2
0 2 4 8 12 24
ChangeinViralLoadfrombaseline(Log10)
Week
PADDLE
SPRING
SINGLE
-3
-2.8
-2.6
-2.4
-2.2
-2
0 2 4 8 12 24
ChangeinViralLoadfrombaseline(Log10)
Week
PADDLE
SPRING-1
SINGLE
pVL change at each time point
(Mean ±Standard error of the mean)
0.0 0.0
Sued O, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 947.
Cross Study PK Comparison: Comparable Viral
Decay in Dual and Triple Dolutegravir-based ART
pVL Change at Each Timepoint
(Mean=standard Error of the Mean)
pVL Change at Each Timepoint
(Mean=standard Error of the Mean),
Normalized per Baseline pVL

46. Future ART

48. RCT,DB,
dose-finding,
2-part study
Patients:
• HIV-1+ ART naïve
• RNA ≥1,000 c/mL
• CD4 ≥100 cells/µL
• Stratified by screening
RNA (≤/>100k c/mL)
Part 2 began after
dose selection based
on Part 1 week
24 results.
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
EFV 600 mg (n=43) Continue EFV
Part 2: Additional Patients, DOR Selected Dose vs EFV
(N=132)
DOR 100 mg (n=66)
EFV 600 mg (n=66)
Study 007: DOR 100 mg QD vs. EFV +TDF/FTC in
Naive HIV+ Patients – Week 48 Results
Gatell J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 470.
Study Design
Week 48
Week 48
Week 96
Week 96

49. Study 007: Results
HIV RNA <40 copies/mL
Gatell J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 470.
3,7
15,7
27,8
42,1
63,0
73,1
77,8
78,7
6,5 12,0
26,9
47,2
57,5
72,9
81,5
77,8
0
10
20
30
40
50
60
70
80
90
100
0 4 8 12 16 20 24 28 32 36 40 44 48
%ofpatients(95%CI)
Treatment Week
DOR 100 mg + TDF/FTC
EFV 600 mg + TDF/FTC
Week 48 n/N (%)
DOR 84/108 (77.8)
EFV 85/108 (78.7)
Difference (95% CI): -1.1 (-12.2, 10.0)
(NC=F Approach)

50. Study 007: Results
Virologic Response by Screening RNA
Gatell J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 470.
88,6 89,6
74,3
91,487,1 91,9
83,8
91,9
0
20
40
60
80
100
% <40 c/mL % <200 c/mL % <40 c/mL % <200 c/mL
DOR 100 mg + TDF/FTC EFV 600 mg + TDF/FTC
≤100,000 c/mL >100,000 c/mL
n/N: 58/67 54/62 60/67 57/62 26/35 31/37 32/35 34/37
Week 48 (OF Approach)
PercentofSubjects(95%CI)

51. Study 007: Adverse Events
DOR 100 mg
(N=108)
EFV 600 mg
(N=108)
Difference
[DOR – EFV]
(95% CI)
One or more adverse events (AE) 87.0 88.9 -1.9 (-10.9, 7.1)
Serious AE 6.5 8.3 -1.9 (-9.5, 5.6)
Death 0 0
Discontinued due to AE 2.8 5.6 -2.8 (-9.2, 3.0)
Drug-related AE 31.5 56.5 -25.0 (-37.3, -11.8)
Diarrhea 0.9 6.5 --
Nausea 7.4 5.6 --
Dizziness 6.5 25.9 --
Headache 2.8 5.6 --
Abnormal dreams 5.6 14.8 --
Insomnia 6.5 2.8 --
Nightmares 5.6 8.3 --
Sleep disorder 4.6 6.5 --
Gatell J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 470.

52. LATTE-2 Study: Maintenance Therapy with
Injectable Cabotegravir and Rilpivirine
Induction period
Week 32
Primary analysis
Dosing regimen
selection
Day 1
Randomization
2:2:1
Week 48
Analysis
Dosing regimen
confirmation
CAB 400 mg IM + RPV 600 mg IM
Q4W (n=115)
CAB 600 mg IM + RPV 900 mg IM
Q8W (n=115)
CAB 30 mg + ABC/3TC PO QD (n=56)
Week 96
CAB loading dose at Day 1
CAB loading doses at Day 1 and Week 4
CAB 30 mg +
ABC/3TC for
20 weeks
(N=309)
Maintenance period
Add RPV
4 weeks
Margolis D, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 31LB.

53. LATTE-2 Study: Week 32 Primary Endpoint:
HIV-1 RNA <50 c/mL by Snapshot (ITT-ME)
• No resistance detected in any study arm
• 82% experienced grade 1 injection site reactions, 17% grade 2 (moderate) – most
commonly pain, swelling, or nodules; one death (epilepsy), cause unclear
• Suppressive ART with IM cabotegravir and rilpivirine appears safe and effective;
further studies planned
Virologic Outcomes Treatment Differences (95% CI)
Oral
-4.8 12.2
Q8W
-5.8 11.5
Q4W
IM
Margolis D, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 31LB.
4 5
91
4 5
0
20
40
60
80
100
Virologic
success
Virologic
non-response
No virologic
data
HIV-1RNA<50c/mL,%
Q8W (n=115)
Q4W (n=115)
oral CAB (n=56)
95* 94*
<1 <1

54. How satisfied are you with
your current treatment?
How satisfied would you be to continue
with your present form of treatment?
97% 96% 71%
29%
0%
20%
40%
60%
80%
100%
Q8W (n=106) Q4W (n=100) Oral CAB (n=49)
More Neutral Less
98% 98% 71%
29%
0%
20%
40%
60%
80%
100%
Q8W (n=106) Q4W (n=100) Oral CAB (n=49)
More Neutral Less
3%
3% 2%
1%
1%
1%
Margolis D, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 31LB.
LATTE-2 Study: Patient Outcomes Comparing
Maintenance with Oral Induction Treatment
PatientPercent

55. Long-term follow-up through Week 96 (BMS-663068 1200 mg QD)Week 96
BMS-663068 1200mg QD was selected as the open-label continuation dose after Week 48
AI438011 Study:
BMS-663068 Oral HIV Attachment Inhibitor – 96 Week Results
DeJesus E, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 472.
Primary study – start of combination therapyDay 1
Data monitoring committee assessmentDay 8
Primary endpointWeek 24
Long-term follow-up through Week 48 (secondary endpoint)Week 48
BMS-663068 monotherapy sub-study: 10 subjects per study arm
BMS-663068
400 mg BID
+ RAL +TDF
N=50
BMS-663068
800 mg BID
+ RAL +TDF
N=50
BMS-663068
600 mg QD
+ RAL +TDF
N=50
BMS-663068
1200 mg QD
+ RAL +TDF
N=50
ATV/r
300/100 mg OD
+ RAL +TDF
N=50
Study Design

56. AI438011 Study: Results
DeJesus E, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 472.
ProportionofsubjectsachievingHIV-1RNA<50
c/mL,%(95%Cl)
0 2 4 8 12 16 20 24 32 40 48 56 64 72 80 88 96
100
90
80
70
60
50
40
30
20
10
0
Week
Proportion of subjects with
<50 c/mL through Week 96
BMS-663068
1,200 mg QD 90%
ATV/r 300 mg/
100 mg QD 90%

57. • NRTI with unique mechanism of action and unusual PK
• Active phosphorylated metabolite has prolonged intracellular persistence in human PMBCs,
with half-life of 150-160 hours
• Exploratory study of single 10 mg dose in HIV infected volunteers
• MK-8591, a novel NRT translocation inhibitor, suppresses HIV RNA by 1.75 log after a single
dose – long half life could lead to novel dosing or administration strategies
MK-8591: Long-acting NRTI
Grobler J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 98;
Friedman E, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 437LB.
-2.5
-2
-1.5
-1
-0.5
0
0.5
0 5 10 15 20
ChangeFromBaselineHIV-1RNA
(log10c/mL)
Time (days)
TDF - 300 mg QD
TAF - 25 mg QD
MK-8591 - 10 mg QW

58. Other stuff

59. Slide credit: clinicaloptions.com
EuroSIDA: Impact of TDF Exposure on
Risk of Fractures in HIV-Infected Patients
 Prospective analysis of 11,820 HIV-infected pts
 Followed from baseline (Jan 2004) to last visit or death to
assess for fractures, femoral osteonecrosis
Borges AH, et al. CROI 2016. Abstract 46.
TDF Exposure
Any Fracture
IRR (95% CI)
Osteoporotic Fracture*
IRR (95% CI)
Univariate Multivariate† Multivariate†
Ever used vs never
used
1.71‡ (1.42-2.06) 1.40‡ (1.15-1.70) 1.10 (0.76-1.58)
On TDF vs not on
TDF
1.38‡ (1.16-1.64) 1.25‡ (1.15-1.70) 1.12 (0.79-1.60)
Cumulative TDF
exposure/5 yrs
1.28‡ (1.13-1.50) 1.08 (0.94-1.25) 0.99 (0.69-1.43)
*Fracture of the spine, arm, wrist, or hip. †Adjusted for demographics, HIV-specific variables, and
comorbidities. ‡P < .05.

60. Switch from F/TDF to F/TAF Efficacy at Week 48
F/TDF F/TAF
0
HIV-1RNA<50c/mL,%
94.3
0.3
5.4
93.0
1.5
5.5
0
20
40
60
80
100
Success Failure No Data
F/TAF (n=333) F/TDF (n=330)
‒10% +10%
5.1-2.5
1.3
Non-success
Treatment Difference (95% CI)Virologic Outcome
Gallant J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 29.

61. 20
10
0
-10
0 12 24 36 48
F/TDF to F/TAF:
Changes in eGFR and Renal Biomarkers
Gallant J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 29.
F/TAF (n=333)
F/TDF (n=330)
Weeks
Median*Q1,Q3)change
eGFR(mL/min)
8.4 mL/min
2.8 mL/min
P<0.001
F/TAF
F/TDF
AlbuminProtein β2MRBP
-14.6
-7.7
-16.3
-39.6
7.7
12.3
18.2
22.0
-40
-20
0
20
40
Median%change

62. Baseline 24 48
4
2
0
4
2
0
F/TDF to F/TAF:
Change in Bone Mineral Density through Week 48
Gallant J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 29.
F/TAF, n 321 310 300
F/TDF, n 320 310 306
F/TAF, n 321 309 300
F/TDF, n 317 305 303
Spine
WeeksWeeks
Hip
Mean%change(95%Cl)
1.1
-0.2
P<0.001
1.5
-0.2
P<0.001
Baseline 24 48

63. ACTG 5298: Quadrivalent HPV Vax of Limited Utility
in Older HIV+ Adults
No Prevention of New Anal HPV Infections or Improvement
in HSIL Treatment Outcomes Over 2Yrs FU
Wilkin T, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 161.
qHPV (n=288) Placebo (n=287) Hazard ratio ‡ (99.99% CI)
Persistent anal HPV
infection or single
detection at final visit
23/286 (8.0%) 28/283 (9.9%) 0.78 (0.31, 1.97)
Persistent anal HPV infection 9/286 (3.1%) 13/283 (4.6%) 0.66 (0.16, 2.75)
Persistent oral HPV infection
or single detection at final visit
3/288 (1.0%) 8/286 (2.8%) 0.36 (0.04, 3.33)
Persistent oral HPV Infection 0/288 (0%) 6/286 (2.1%) 0.00 (not able to calculate)
Anal HSIL on histology:
week 52 and beyond
38/288 (13.2%) 36/286 (12.5%) 1.03 (0.52, 2.05)
Abnormal cytology at baseline 182/285 (64%) 188/284 (66%) 0.96 (0.79, 1.16)
Abnormal cytology at week 52 123/231 (53%) 121/229 (53%) 1.00 (0.75, 1.33)
Abnormal cytology at week 104 94/191 (49%) 103/187 (55%) 0.90 (0.65, 1.24)

64.  Variations across models anticipated given differences in outcome
 ART use (ie, D:A:D score) did not improve discrimination vs ASCVD
 Discrimination greater with ASCVD vs other models for all outcomes
Slide credit: clinicaloptions.com
Comparison of CVD Risk Scores in HIV-
Infected Patients
 Compared expected and observed MI event rates using 4 risk scores
in 10,832 HIV-infected pts with 229 incident MI events in CNICS
– 3 general population CVD risk scores (Framingham, ATP3, 2013
ACC/AHA ASCVD) plus HIV-specific D:A:D score in CNICS pts
Crane HM, et al. CROI 2016. Abstract 42.
Risk of MI
Framingham ATP3 D:A:D ASCVD
HC CI HC CI HC CI HC CI
Type 1 MI 0.73* 0.69, 0.77 0.74* 0.70, 0.78 0.73* 0.68, 0.78 0.77 0.73, 0.81
Type 2 MI 0.63* 0.57, 0.69 0.63* 0.56, 0.69 0.62* 0.55, 0.68 0.72 0.67, 0.78
All MI 0.68* 0.65, 0.72 0.69* 0.65, 0.72 0.68* 0.64, 0.71 0.74 0.71, 0.77
*Harrell’s C significantly different vs ASCVD HC.

65. IMPAACT P1026s: DTG in Pregnancy[1]
 Ongoing, nonrandomized,
open-label, phase IV study in
HIV+ pregnant women
 DTG 50 mg QD: PK assessed
during 2nd trimester, 3rd
trimester, 3-12 wks postpartum,
and in infants
 N = 21 women
– HIV-1 RNA ≤ 50 c/mL in 2nd
and 3rd trimester: 100%
– Med gestational age at birth:
38.9 wks
– 9/18 infants HIV-neg; HIV
status pending in 9/18
 DTG trough and AUC exposure
lower in 2nd and 3rd trimester
vs postpartum
 Antepartum DTG exposure
similar to levels observed in
nonpregnant adults
 DTG elimination half-life > 2-
fold higher in infants vs
nonpregnant adults
 Congenital anomalies in 4
infants
 APR: 0/10 (1st trimester) and
1/18 (2nd or 3rd trimester) birth
defects with DTG exposure[2]
1. Mulligan N, et al. CROI 2016. Abstract 438.
2. APR. http://www.apregistry.com.
Slide credit: clinicaloptions.com