Brad Hare Nothing to Disclose - PowerPoint Presentation

Slide1

Brad Hare

Nothing to Disclose

Kaiser Permanente San Francisco Medical CenterSan Francisco, CA, USA

Disclosure:

THE PHASE 3 DISCOVER STUDY: DAILY F/TAF OR F/TDF FOR HIV PREEXPOSURE PROPHYLAXIS

Co-Authors

Brad Hare

1, Pep Coll2, Peter Ruane3

, Jean-Michel Molina4, Kenneth Mayer5

,

Heiko Jessen

6

, Robert Grant

7

, Joss De Wet

8

, Melanie Thompson

9

, Edwin DeJesus

10

,

Ramin Ebrahimi

11

, Robertino Mera

11

, Moupali Das

11

, Diana Brainard

11

, Scott McCallister

11

1

Kaiser-Permanente, San Francisco, CA;

2

Institut de

Recerca

de la

Sida

, Barcelona, Spain;

3

Ruane Clinical Research, Los Angeles, CA;

4

University of Paris Diderot, France;

5

Harvard T.H. Chan School of Public Health, Boston, MA;

6

Praxis Jessen, Academic Teaching Clinic of

Charité

,

Universitätsmedizin

, Berlin, Germany;

7

University of California, San Francisco, San Francisco, CA;

8

Spectrum Health, Vancouver, Canada;

9

AIDS Research Consortium of Atlanta, Atlanta, GA;

10

Orlando Immunology Center, FL;

11

Gilead Sciences, Inc., Foster City, CA

Thank You!

AUSTRIA

FRANCE

SPAIN

UNITED STATES

B Haas

E

Cua

J

Coll D AsmuthJ GladsteinK MounzerA RiegerJ-M MolinaM CrespoA AveryRM GrantO OgbuaguP PhilibertJ del RomeroP Benson R Grossberg A PetrollCANADA G PialouxD PodzamczerM BerheJ HalperinJ PhoenixJ BrunettaI Brar CB HareMN RamgopalJJ de WetGERMANYUNITED KINGDOM C BrinsonS HasslerB RashbaumB TrottierH JessenV Apea JH BurackR Hengel GJ RichmondJ SzaboG KnechtA ClarkeT Campbell K Henry PJ RuaneC TremblayI Krznaric O Dosekun M CespedesS Hosek L SalazarC Spinner R GilsonM ColemanM IandorioAJ ScarsellaDENMARKS KeggCM CreticosA LaMarca M ScottJ Gerstoft ITALYC Leen GE CrofootC LucastiP ShalitG KronborgA AntinoriN Nwokolo FA CruickshankS Mannheimer JL StephensC Larsen A LazzarinF PostE DaarCT MartorellMA Thompson D LarsenI Reeves E DeJesusM MarkowitzG VoskuhlNETHERLANDSG Schembri S Doblecki-LewisK MayerBH WadeM PrinsS Taylor T DonovanA MillsDA WohlJ FlammS MorrisK Workowski

Community advisors

Investigators and site staff

Study participants, partners, families

3

Background

F/TDF is the only approved drug for HIV pre-exposure prophylaxis (PrEP)

Where PrEP uptake is high, a greater decline in HIV infections is observed1,2

TAF achieves more rapid and higher intracellular TFV-DP levels than TDF in plasma PBMCs, and has lower plasma TFV levels3,4In HIV treatment, TAF-based regimens have similar high virologic suppression rates and improved renal and bone safety as compared to TDF-based regimens

5,6

The Phase 3 DISCOVER study evaluated the efficacy and safety of F/TAF for PrEP among cis-MSM and TGW at high risk of HIV infection

F (or FTC)/TDF, emtricitabine/tenofovir (TFV) disoproxil fumarate; F (or FTC)/TAF, emtricitabine/tenofovir alafenamide; MSM, men who have sex with men; PBMC, peripheral blood mononuclear cells; TFV-DP,

TFV-diphosphate;

TGW, transgender women.

1. Sullivan IAC 2018. 2. Grulich Lancet HIV 2018. 3. Ruane JAIDS 2013. 4. Custodio EACS 2017. 5. Sax Lancet 2015. 6. Gupta AIDS 2019.4

DISCOVER: A Randomized, Noninferiority Trial of F/TAF for

PrEP

5

F/TAF dose: 200/25 mg; F/TDF dose: 200/300 mg. eGFR, estimated glomerular filtration rate.

Study conducted in NA,

EU in cities/sites with

high HIV incidence

94 sites in 11 countries

Participants: US, 60%;

EU, 34%; Canada, 7%

Eligibility required high sexual

risk of HIV

2+ episodes

condomless anal sex

in past 12W

or

rectal gonorrhea/

chlamydia, syphilis in past 24W

HIV & HBV negative

, eGFR ≥60 mL/min

Prior use of

PrEP

allowed

Primary efficacy endpoint:

HIV incidence

Evaluated by rate ratio with noninferiority (NI) margin <1.62

Expected incidence of 1.44/100 PY based on pooled studies:

iPrEx

, PROUD, IPERGAY

Randomized

1:1

Double-blinded

Active controlled

Primary analysis:

HIV incidence/100 PY

when 100% complete W48

& 50% complete W96

MSM or TGW

participants

96 weeks

Open-label

switch

for 48 weeks

At entry and Q12W:

Adherence counseling

Prevention services

Risk reduction counseling

Condoms/lubricant

F/TAF QD

n=2694

F/TDF QD

n=2693

Assessments

6

BMD, bone mineral density; CASI, computer-aided self-interview; GC/CT, gonococcus/chlamydia trachomatis; NAAT, nucleic acid amplification test; STI, sexually transmitted infection.

HIV Risk Behavior

Visits every 12W

STI assessment at every visit:

GC/CT: rectum, urethra, oropharynx (NAAT)

Syphilis testing

Confidential CASI questionnaire

Number and type of recent sexual eventsAlcohol and recreational drug useSelf-report (CASI)Pill countsDrug levelsDried blood spots (DBS)AdherenceSafetyGeneral adverse events (AEs)AE-related discontinuationsPrespecified secondary endpoints:BMD sub-studyRenal biomarkers

HIV Lab Testing

Rapid HIV testing on-site

Central lab

All

DISCOVER

Participants

N=5387

201

Lost to follow-up

170

193

Participant decision

1

175

36

Adverse event

498Non-adherence1214Other224DISCOVER Participant Disposition7Most frequent reasons provided: withdrew consent, moved, monogamous relationship, reduced sexual risk, work/school/military obligations.Includes protocol violation, investigator discretion, HIV infection, death.F/TAFn=2694F/TDFn=2693Still on study drugn= 2242 (83%)Still on study drugn= 2263 (84%)Randomized and treated n=5387Randomized, not treated: n=12452 (17%)Discontinued study drug430 (16%)Enrollment period: Sep 2016–May 2017

Baseline Demographics and HIV Risk Factors

8

F/TAF

n=2694

F/TDF

n=2693

Demographics

Median age, y (range)

34 (18–76)

34 (18–72)Race, n (%)White2264 (84)2247 (84)Black*240 (9)234 (9)Asian113 (4)120 (5)Hispanic or Latinx ethnicity, n (%)635 (24)683 (25)Proportion TGW, n (%)45 (2)29 (1)HIV risk factors, %≥2 condomless anal sex (receptive), past 12W6058Rectal gonorrhea, past 24W1010Rectal chlamydia, past 24W1312Syphilis, past 24W910Recreational drug use, past 12W 6767Binge drinking†2322Taking F/TDF for PrEP at baseline1716*Includes mixed black race; † ≥6 drinks on ≥1 occasion, at least monthly.

DISCOVER Primary Endpoint Analysis: HIV Incidence

F/TAF is noninferior to F/TDF for HIV prevention

9

HIV Incidence

Incidence Rate Ratio

[95

%

CI]

HIV Incidence Rate/100 PY

F/TAFn=2694F/TDFn=26937 infections15 infections4370 PY4386 PYCI, confidence interval; RR, rate ratio.1.150.190.471.62NI marginRR = 1, no differenceNoninferiorityFavors F/TDFFavors F/TAF22 HIV infections in 8756 PY of follow-up

DISCOVER Adherence and Resistance Analyses of HIV Infections

10

*3 samples could not be amplified;

†

All 4 participants with resistance were suspected baseline infections.

7

1

1

15

54110TFV-DP in DBS lowTFV-DP in DBS medium/highSuspected baseline infectionnF/TAFn=7F/TDFn=15Resistance genotyped*613Resistance to study drugsFTC04†TFV00Participants, n7 F/TAF infections: 1 suspected baseline infection, 5 low levels of TFV-DP in DBS,1 medium level15 F/TDF infections: 4 suspected baseline infections, 10 low levels of TFV-DP in DBS, 1 high levelIn a sensitivity analysis that excluded suspected baseline infections, noninferiority was maintained (0.55 [0.20, 1.48])

Overall Safety Summary

11

%

F/TAF

n=2694

F/TDF

n=2693

Any AEs

93

93Study drug-related AEs2023Grade ≥2 AEs4745Grade ≥3 AEs66SAEs65Study drug-related SAEs0.10.2AEs leading to discontinuation12Deaths, n*12*Reasons: traffic accident, metastatic squamous cell carcinoma, unknown. SAE, serious AE.

Common Adverse Events (≥10%)

12

%

F/TAF

n=2694

F/TDF

n=2693

Rectal chlamydia

29

29Oropharyngeal gonorrhea2827Rectal gonorrhea 2625Exposure to communicable disease1716Diarrhea 1616Nasopharyngitis 1313Upper respiratory tract infection1312Syphilis 1312Urethral chlamydia1010

DISCOVER Sexually Transmitted Infections Through Week 96

Incidence of gonorrhea, chlamydia, or syphilis while on study (based on AE reporting)

F/TAF = 145.1/100 PY

F/TDF = 138.8/100 PY

13

n (Rate: n/100 PY)

F/TAF

F/TDF

Gonorrhea (any site)

1053 (47.1)1059 (45.3)Rectal651 (21.6)662 (20.5)Chlamydia (any site)1049 (41.9)1071 (41.6)Rectal810 (27.5)835 (28.2)Syphilis365 (10.3)370 (9.5)WeekParticipants, %Lab Assessed GC/CTLab Assessed GC/CT Incidence

Bone Safety at Week 48: Bone Mineral Density Sub-study (n=383)

Secondary Endpoint

Mean % Change From BL (95% CI)

Change from BL,

%

F/TAF

F/TDF

p-value

†

≥3% increase1790.052≥3% decrease1027<0.001*p-values from analysis of variance model with baseline F/TDF for PrEP and treatment as fixed effects; †p-value was based on a dichotomized response (ie, ≥3% vs <3%) from Cochran-Mantel-Haenszel test for nominal data (general association statistic) adjusting for baseline F/TDF for PrEP. BL, baseline. n=159n=160n=158n=158Mean % Change From BL (95% CI)Change from BL, %F/TAFF/TDFp-value†≥3% increase960.5≥3% decrease418<0.001Hipp <0.001*Spinep <0.001*14

Renal Safety Through Week 48

Secondary Endpoint

Renal discontinuations: F/TAF, n=2; F/TDF, n=6

Fanconi syndrome: F/TAF, n=0; F/TDF, n=1

β2M, β2-microglobulin; Cr, creatinine;

eGFR

CG

, eGFR by Cockcroft Gault; Q, quartile; RBP, retinol-binding protein.

p

-values were from the Van Elteren test stratified by baseline F/TDF for PrEP to compare the 2 treatment groups.84 μg/g 86 μg/g 101 µg/g 104 µg/g Median % Change From BL (Q1, Q3)β2M:CrRBP:CrF/TAFF/TDFWeeksWeeksWeeks eGFRCGMedian Change From BL,mL/min (Q1, Q3)123 mL/min 121 mL/min p <0.001p <0.001p <0.001+1.8-2.3Proximal Tubular Protein to Creatinine RatiosBaselineBaseline15

Comparing DISCOVER Results to HIV Infection Rate In MSM at HIV Risk but Not on PrEP

In the absence of placebo control, we sought to contextualize the HIV incidence rates in DISCOVER to the rate in MSM not on PrEP

Using CDC-reported HIV surveillance data, we calculated the background infection rate for MSM at HIV infection risk* in US metropolitan statistical areas (MSAs) that overlapped with DISCOVER sites1

HIV infection rate for MSM not on PrEP in 2016:

4.02/100 PY

95%CI

[

3.96

,

4.09]HIV incidence rates in US DISCOVER sites:F/TAF = 0.08/100 95%CI [0.01, 0.28]F/TDF = 0.45/100 95%CI [0.23, 0.78]16*CDC-defined persons with an indication for PrEP use (Smith Ann Epidemiol 2018). 1. Mera JIAS 2019, under review.HIV Incidence/100 PY (95% CI)F/TAFF/TDFMSM Not on PrEPHIV Rate Comparison (US MSAs & US DISCOVER sites)

Conclusions

F/TAF was noninferior to F/TDF in preventing HIV infection in high-risk cis-MSM and TGW

F/TAF HIV incidence was 0.16/100 PY, and F/TDF HIV incidence was 0.34/100 PYThe majority of HIV infections occurred prior to study entry or in participants with low or undetectable drug levels

Both drugs were well tolerated, with low rates of adverse events related discontinuationsF/TAF had significantly better bone and renal safety outcomes as compared to F/TDF

Study participants had consistent high rates of sexual risk behavior, with a lack of risk compensation

F/TAF is an effective and safer option for

PrEP

in cis-MSM and TGW at risk for HIV infection

17