Kaiser Permanente San Francisco Medical Center San Francisco CA USA Disclosure THE PHASE 3 DISCOVER STUDY DAILY FTAF OR FTDF FOR HIV PREEXPOSURE PROPHYLAXIS CoAuthors Brad Hare 1 Pep Coll ID: 919518
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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
Slide2Co-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
Slide3Thank 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
Slide4Background
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
Slide5DISCOVER: 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
Slide6Assessments
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
Slide7201
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
Slide8Baseline 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.
Slide9DISCOVER 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
Slide10DISCOVER 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])
Slide11Overall 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.
Slide12Common 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
Slide13DISCOVER 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
Slide14Bone 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
Slide15Renal 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
Slide16Comparing 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)
Slide17Conclusions
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