1. PrEP in the US: Where are we now? Where are we going?
Raphael J. Landovitz, MD MSc
Associate Professor of Medicine
UCLA Center for Clinical AIDS Research & Education
April 25, UCI

2. Disclosure
Raphael J. Landovitz has received research grants awarded to his institution from Gilead Sciences, has served as a consultant to Gilead Sciences.

3. 2.1 Million New Infections in 2015 5,600 New Infections per Day
13,000 [9,600 – 17,000]
22,000 [13,000 – 33,000]
85,000 [48,000 – 130,000]
87,000 [70,000 – 100,000]
140,000 [110,000 – 160,000]
340,000 [240,000 – 480,000]
1.4 million [1.2 – 1.5 million]
New HIV Infections
UNAIDS. Fact Sheet: 2015 Statistics; 2016.

4. Prevention Modalities
Condoms
PEP
Voluntary Male Circumcision
Needle Exchange
Abstinence
Vaccine
HIV Treatment
PrEP
Microbicides
STI Treatment
Harm Reduction
HIV & STI Testing

5. Effectiveness of Daily TDF/FTC in Clinical Trials
iPrEx
(TDF/FTC)
CI: 15-63
42%
FEM-PrEP
(TDF/FTC)
CI: 6%
TDF2
(TDF/FTC)
CI:
CI: 25-97
49%
80%
99%
VOICE
(TDF)
(TDF/FTC)
-49%
-4.4%
CI: +3 to -129
CI: +27 to -149
Partners PrEP
(TDF/FTC)
CI: 28-84
CI: 54-94
63%
CI: 20-83
CI: 37-87
(TDF)
71%
66%
84%
PROUD
(TDF/FTC)
CI: 58-96
86%

6. Relationship Between Effectiveness and Adherence in Microbicide & PrEP Trials
Pearson correlation = 0.86, p=0.003
Pearson correlation = 0.86, p=0.003
Partners PrEP (TDF)
Partners PrEP (Truvada)
IPERGAY(Truvada)
PROUD(Truvada)
SS Abdool Karim, personal communication

7. Maximizing the Potential Effectiveness
TDF/FTC (7x/week)
TDF/FTC (~1x/24°)
99%
94%
Plasma TFV 14 h 2-3 days
PBMCs TFV-DP 150h 14 days
RBCs TFV-DP 17 days 3-4 months
Hair TFV durable weeks-months
CI:
CI:
Some adherence forgiveness with retained protection
6-7 doses per week likely required
Donnell D et al, JAIDS
Cottrell ML et al, JID, 2016.
Anderson P et al, Sci Transl Med

8. PrEP Demonstration: High Adherence in STD/Community-Based Clinics
AE, adverse event; BLQ, below level of quantification; DBS, dried blood spots; FTC, emtricitabine; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; STD, sexually transmitted disease; STI, sexually transmitted infection; TDF, tenofovir disoproxil fumarate; TFV, tenofovir; TGW, transgender women.

9. Unique Individuals Starting PrEP in US, 2012 to 2016(by quarter)
98,732 Unique Individuals Starting TRUVADA for PrEP™
Increase from 1,715 in Q to 11,827 in Q3 2016
6.9 times increase
2012
2013
2014
2015
2016
2012
2013
2014
2015 9
Mera R, et al. IAS Paris, France. Poster #WEPEC0919

10. TDF/FTC for PrEP Utilization Compared With Population and New HIV Infections
Estimated Population Distribution by Race/Ethnicity,
2015b
Estimated New HIV Infections,
2015c
Total FTC/TDF for PrEP Utilization by Race/Ethnicity,
Sept 2016a AA
White
Hispanics
Asians
Multiracial/Other*
FTC/TDF for PrEP use among AA and Hispanics is low relative to the rate of new HIV infections
a. These data represent 41% of unique individuals who have started TVD for PrEP from Q2016. b.
c. based on CDC Surveillance Report 2015 .
* Other indicates American Indian or Alaska Native, Native Hawaiian or Pacific Islander
Mera R, et al. IAS 2017; Paris, France. A

11. PrEP use in the United States
National Prescription Database
Since 2012, 140,000 prescribed PrEP in US
Women, <25, southern and non-Medicaid expansion states all ↓ rx and rx:need
Siegler, CROI 2018, Abstract 1022LB,

12. A phase 2 safety study designed to answer:
HPTN 069 / ACTG A5305
A phase 2 safety study designed to answer:
Could daily oral maraviroc, a CCR5 receptor antagonist, be a next-gen PrEP agent for men and/or women?

13. Enrollment and Randomization
HPTN 069 / ACTG A5305
Screening
Enrollment and Randomization
N = 600
(400 MSM/TGW; 200 ciswomen)
MVC (active) +
FTC (placebo)
TDF (active)
Arm 3, N=150
100/50
MVC (placebo)
FTC (active)
Arm 4, N=150
TDF (placebo)
Arm 2, N=150
Arm 1, N=150
Gulick RM, JID 2016,
Gulick RM, Annals 2017

14. HPTN 069 / A5305: HIV Infections
In MSM/TGW Cohort: 5 new HIV infections during the study
Annual incidence rate 1.4% [95% CI: 0.8%, 2.3%] #
Demos. (age, race/ ethnicity, HIV risk)
Study arm
First reactive HIV+ test (week)
HIV RNA (cps/mL)
CD4 cells (/mm3)
HIV trop-ism
Geno-typic drug resis-tance
Plasma drug conc. at serocon-version visit (ng/mL)* 1
20, black MSM
MVC+TDF 4
122,150
357 R5
none
MVC=0† TFV=0 2
61, Asian MSM
MVC alone 16
981
294
MVC=145 3
21, mixed MSM 24
106,240
325
MVC=0†
35, white MSM 32
13,626
828
MVC=6.7 5
36, black MSM 48
52,191
804
MVC=0.7
* expected pre-dose steady state MVC = 32 ng/ml
† undetectable plasma drug concentrations at every study visit

15. HPTN 069 / A5305: Study Drug Concs. in New HIV Infections
MVC ng/mL
Note: 2 others with new HIV infection had undetectable study drug at every visit.

16. Pre-Clinical and Animal Models of TAF for PrEP
Will it be equi-efficacious as
TDF-based PrEP?
Perhaps
Perhaps not

17. Prodrug Pharmacology of TDF and TAF
LYMPHOCYTE
TFV
OAT
1 & 3
RENAL TUBULAR CELL
PLASMA
91% LESS
plasma TFV 1
TDF
TAF
greater plasma stability
Less Plasma Stability
GI TRACT
HIV
TAF 25 mg results in >90% lower TFV plasma levels
Sax P, et al. Lancet 2015
Wohl D, et al. CROI Boston, MA. #681
OAT, organic anion transporter; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV, tenofovir.

18. Concentrations of TFV and TFV-DP in Female Mucosal Tissues After Single Dose of TAF
TAF 25mg,
Tissue Samples BLQ, % n
TDF 300mg
TFV
TFV-DP
CVF 58
n/a 40 23 95
Genital Tissue 6 75 16 25
Rectal Tissue 63 8
BLQ=below the level of quantification. 0=all the samples had detectable TFV (none were BLQ)
Garrett K, et al. CROI Boston, MA. #102LB

19. TAF/FTC for PrEP in SHIV-Challenged Macaques
SHIV challenge repeated weekly for up to 19 weeks
FTC/TAF
PBO
-24h
SHIV
+2h
Treatment arm (n=6)
Placebo arm (n=6)
F/TAF prevents rectal SHIV infection in macaques to a degree similar to that previously found with F/TDF but with a substantially reduced TFV dose1
F/TAF protected 100% of macaques (N=6) challenged with SHIV in a similar, pre-clinical trial2
SHIV challenges (weeks, n)
Percent protected 20 40 60 80
100
Placebo
FTC/TAF 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
100% 0%
Massud I, et al. CROI Boston, MA. #107
Heneine W, et al. CROI Denver, CO. #32LB

20. TAF/FTC for vaginal SHIV prevention
Massud, CROI 2018, Abstract 85

21. DISCOVER: FTC/TAF vs TDF/FTC
Primary Endpoint: Seroconversion rate/100 p-y
Week 0 48 72 96
n=2500
FTC/TAF (200/25 mg) QD
F/TAF
FTC/TDF (200/300 mg) QD
Switch option
Cis MSM or transwomen
n=2500
Eligibility: HIV and HBV negative, eGFR ≥60 mL/min, and at least one of the following:
2+ episodes condomless anal intercourse (past 12 wks),
or rectal gonorrhea/chlamydia (past 24 wks)
or syphilis (past 24 wks)
Sample size N=5000 to show noninferiority (FTC/TDF vs FTC/TAF) assumes 1.4/100 p-y seroconversion rate for F/TDF arm; 144 seroconversions needed to demonstrate NI
Sites: sexual health clinics, medical offices (North America, EU)

22. A phase 2 safety study designed to answer:
HPTN 076
A phase 2 safety study designed to answer:
Could injectable rilpivirine, a FDA-approved NNRTI in its oral formulation, be a useful sustained-release PrEP agent?

23. Long Acting Rilpivirine (TMC278) HPTN 076: Phase 2 Safety
TMC278 LA is a novel poloxamer 338-containing formulation of TMC278. TMC278 LA is long-acting suspension and well-suited for delivery via IM injection
HPTN 076 enrolling at 4 sites, low-risk HIV-uninfected women (NY, NJ, Zim, SA)

24. HPTN 076: Safety and acceptability of injectable rilpivirine(TMC278 LA) for PrEP
136 HIV-uninfected, women ages years
WEEKS
ARM 1
N = 91
Daily oral
TMC278
Six injections of TMC278 LA
1200 mg every 8 weeks
Follow-up phase
(tail phase)
ARM 2
N = 45
placebo
Six injections of TMC278 LA placebo every 8 weeks

25. HPTN 076: Phase 2 Safety Results
Safe and well-tolerated
Acceptable to women
Cold chain required
Unclear interest of sponsor in pursuing PrEP indications
Bekker LG, CROI Abstract 421 LB.

27. Formerly known as GSK1265744 Or “744”
CABOTEGRAVIR
Formerly known as GSK
Or “744”

28. Cabotegravir development
Early Phase Indication Phase Phase 3
LATTE-1
LATTE-2
ATLAS
FLAIR
NHP Models
Treatment
First-in-human/Phase 1
Prevention
cis women
HPTN 077*
HPTN 084
Cardiac Safety, DDI
Prevention MSM/TGW
ÉCLAIR
HPTN 077*
HPTN 083
*INCLUDES BOTH MEN AND WOMEN

29. HPTN 077 Study Design Follow-up Phase 3:1 Follow-up Phase
Oral
Injection Phase
(800mg ever 12 weeks)
Follow-up Phase
3:1
HIV-uninfected men and women
at low risk for acquiring HIV infection,
ages 18 to 65
(n=199)
Oral
Injection Phase
(800mg ever 12 weeks)
Follow-up Phase
Oral
Injection Phase
(600mg ever 8 weeks)
Follow-up Phase
3:1
Oral
Injection Phase
(600mg ever 8 weeks)
Follow-up Phase
Landovitz R, et al, 9th IAS, Paris, Abstract #TUAC0106LB

30. Grade 2 or Higher AE’s Experienced by >5% of Any Arm During Injection Phase
n=177 (CAB 134, PBO 43)
>
p <
p = 0.03
* Grade 2: < 90 to 60 ml/min or 10 to < 30% decrease from participant’s baseline.
Grade 3: < 60 to 30 ml/min or 30 to < 50% decrease from participant’s baseline.
Landovitz R, et al, 9th IAS, Paris, Abstract #TUAC0106LB

31. Percentage of Participants with ISR
Landovitz R, et al, 9th IAS, Paris, Abstract #TUAC0106LB

32. HPTN 083 Sites – Phase 2b/3 45 Sites in 8 Countries
Anticipated Start – Q US Sites
Non-US Sites TBD*
*Based on local regulatory approvals

33. HPTN 083: Study Visit Schema
Blinded Injections
& Safety Visits
Week 2
Week 4
Week 5
Week 9
Week 17
Week 25
Week 33
Week 41
Week 49
Injections: Every 8 weeks
Safety visits: Two weeks after each injection
≈ Week 187
Week 6
Week 10
Week 19
Week 27
Week 35
Week 43
Arm A
CAB LA 600 mg IM at Weeks 5, 9, and Q8 Weeks thereafter Plus Daily Oral Placebo for TDF/FTC W W 12 W 24 W 36 W 48
Screening +
Enrollment +
Daily Oral TDF/FTC Plus Placebo for CAB LA IM at Weeks 5, 9, and Q8 Weeks thereafter
Arm B
Step 1
Step 2
Step 3
Oral Phase
Injection/Oral Phase
Open Label Follow Up
Cabotegravir oral
TDF/FTC oral
Cabotegravir injection
Key
Cabotegravir Oral
placebo
TDF/FTC placebo
Cabotegravir placebo injection

34. Cabotegravir

35. Cabotegravir and Intralipid

36. Slides adapted from Shelly Karuna/HVTN and Phil Andrew/HPTN

37. Study Schema for The Study
REGIMEN
MSM & TG in the Americas
Women in
sub-Saharan Africa
TOTAL
VRC mg/kg
900
500
1300
10 infusions total
&
Infusions every 8 weeks
Study duration:
~22 months
VRC mg/kg
Control
Total
2700
1500
4200

38. Subcutaneous PrEP Implants Modeled After Implanon/Nexplanon Contraception
Simple insertion AND removal
Long-acting (months to years)
PrEP + contraception?
Current development:
TAF, CAB, EFdA (MK-8591)
Schlesinger, et al, Pharm Res 2016
Gunawardana, et al., AAC 2015

39. MK-8591 protects against rectal SHIV
Dose achievable with 250mcg weekly or 10 mcg daily in humans
Markowitz, CROI 2018, Abstract 89LB

40. Topical agents for PrEP: As Good as Systemic PrEP?
“…a less efficacious barrier (one that fails more often than another on each sexual encounter), if frequently used, might serve the public health as well or better than a more efficacious but less frequently used barrier, and could in the end play an important role in preventing transmission at the population level.”
(Am J Pub Health, 1990)

41. Open label dapivirine rings
Expected incidence derived from 10,000 samplings from MTN-020/ASPIRE placebo group.
Across 10,000 samplings, there was none with an HIV-1 incidence of ≤1.9 per person-years
Observed incidence was during open- label ring use from MTN-020/ASPIRE participants
In a second trial using similar methods, expected HIV-1 incidence was 3.9 per PY (95% CI: ) vs. 1.8 per PY (95% CI: ) in the open-label doravirine ring period
MTN-020/ASPIRE
placebo
EXPECTED
HIV-1 incidence = 4.1
(95% CI )
54% reduction
P=0.01
MTN-025/HOPE
OBSERVED
HIV-1 incidence = 1.9
(95% CI )
Baeten, CROI 2018, Abstract #1 43LB, Nel, CROI 2018Abstract #144LB

42. Los Angeles

43. Thank you!