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

THE PHASE 3 DISCOVER STUDY: DAILY F/TAF OR F/TDF FOR HIV PREEXPOSURE PROPHYLAXIS. Brad Hare. Nothing to Disclose. Kaiser Permanente San Francisco Medical Center San Francisco, CA, USA. Disclosure:. Co-Authors.

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

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  1. THE PHASE 3 DISCOVER STUDY: DAILY F/TAF OR F/TDF FOR HIV PREEXPOSURE PROPHYLAXIS Brad Hare Nothing to Disclose Kaiser Permanente San Francisco Medical Center San Francisco, CA, USA Disclosure:

  2. Co-Authors Brad Hare1, Pep Coll2, Peter Ruane3, Jean-Michel Molina4, Kenneth Mayer5, Heiko Jessen6, Robert Grant7, Joss De Wet8, Melanie Thompson9, Edwin DeJesus10, Ramin Ebrahimi11, Robertino Mera11, Moupali Das11, Diana Brainard11, Scott McCallister11 1Kaiser-Permanente, San Francisco, CA; 2Institut de Recerca de la Sida, Barcelona, Spain; 3Ruane Clinical Research, Los Angeles, CA; 4University of Paris Diderot, France; 5Harvard T.H. Chan School of Public Health, Boston, MA; 6Praxis Jessen, Academic Teaching Clinic of Charité, Universitätsmedizin, Berlin, Germany; 7University of California, San Francisco, San Francisco, CA; 8Spectrum Health, Vancouver, Canada; 9AIDS Research Consortium of Atlanta, Atlanta, GA; 10Orlando Immunology Center, FL; 11Gilead Sciences, Inc., Foster City, CA

  3. Thank You! Study participants, partners, families Investigators and site staff Community advisors

  4. 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 levels3,4 • In HIV treatment, TAF-based regimens have similar high virologic suppression rates and improved renal and bone safety as compared to TDF-based regimens5,6 • 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.

  5. DISCOVER: A Randomized, Noninferiority Trial of F/TAF for PrEP Primary analysis: HIV incidence/100 PY when 100% complete W48 & 50% complete W96 F/TAF QD n=2694 At entry and Q12W: Adherence counseling Prevention services • Risk reduction counseling • Condoms/lubricant Randomized 1:1 Double-blinded Active controlled MSM or TGW participants Open-label switch for 48 weeks 96 weeks F/TDF QD n=2693 • 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 Study conducted in NA, EU in cities/sites with high HIV incidence • 94 sites in 11 countries • Participants: US, 60%; EU, 34%; Canada, 7% • 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 F/TAF dose: 200/25 mg; F/TDF dose: 200/300 mg. eGFR, estimated glomerular filtration rate.

  6. Assessments Visits every 12W Safety HIV Lab Testing • General adverse events (AEs) • AE-related discontinuations • Prespecified secondary endpoints: • BMD sub-study • Renal biomarkers • Rapid HIV testing on-site • Central lab AllDISCOVERParticipants N=5387 HIV Risk Behavior • Confidential CASI questionnaire • Number and type of recent sexual events • Alcohol and recreational drug use Adherence • Self-report (CASI) • Pill counts • Drug levels • Dried blood spots (DBS) • STI assessment at every visit: • GC/CT: rectum, urethra, oropharynx (NAAT) • Syphilis testing BMD, bone mineral density; CASI, computer-aided self-interview; GC/CT, gonococcus/chlamydia trachomatis; NAAT, nucleic acid amplification test; STI, sexually transmitted infection.

  7. DISCOVER Participant Disposition Enrollment period: Sep 2016–May 2017 Randomized and treated n=5387 Randomized, not treated: n=12 F/TAF n=2694 F/TDF n=2693 Still on study drug n= 2242 (83%) Still on study drug n= 2263 (84%) Most frequent reasons provided: withdrew consent, moved, monogamous relationship, reduced sexual risk, work/school/military obligations. Includes protocol violation, investigator discretion, HIV infection, death.

  8. Baseline Demographics and HIV Risk Factors *Includes mixed black race; † ≥6 drinks on ≥1 occasion, at least monthly.

  9. DISCOVER Primary Endpoint Analysis: HIV Incidence 22 HIV infections in 8756 PY of follow-up F/TAF is noninferior to F/TDF for HIV prevention HIV Incidence Incidence Rate Ratio [95% CI] Favors F/TAF Favors F/TDF Noninferiority 15 infections 4386 PY HIV Incidence Rate/100 PY 0.47 7 infections 0.19 1.15 4370 PY F/TAF n=2694 F/TDF n=2693 1.62 RR = 1, no difference NI margin CI, confidence interval; RR, rate ratio.

  10. DISCOVER Adherence and Resistance Analyses of HIV Infections • 7 F/TAF infections: 1 suspected baseline infection, 5 low levels of TFV-DP in DBS,1 medium level • 15 F/TDF infections: 4 suspected baseline infections, 10 low levels of TFV-DP in DBS, 1 high level • In a sensitivity analysis that excluded suspected baseline infections, noninferiority was maintained (0.55 [0.20, 1.48]) Participants, n 15 TFV-DP in DBS medium/high 1 TFV-DP in DBS low Suspected baseline infection 10 7 1 5 4 1 *3 samples could not be amplified; †All 4 participants with resistance were suspected baseline infections.

  11. Overall Safety Summary *Reasons: traffic accident, metastatic squamous cell carcinoma, unknown. SAE, serious AE.

  12. Common Adverse Events (≥10%)

  13. 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 Lab Assessed GC/CT Lab Assessed GC/CT Incidence Participants, % Week

  14. Bone Safety at Week 48: Bone Mineral Density Sub-study (n=383)Secondary Endpoint Spine p <0.001* Hip p <0.001* Mean % Change From BL (95% CI) Mean % Change From BL (95% CI) n=159 n=160 n=158 n=158 *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.

  15. Renal Safety Through Week 48Secondary Endpoint • Renal discontinuations: F/TAF, n=2; F/TDF, n=6 • Fanconi syndrome: F/TAF, n=0; F/TDF, n=1 eGFRCG Proximal Tubular Protein to Creatinine Ratios F/TDF F/TAF RBP:Cr β2M:Cr p <0.001 p <0.001 p <0.001 +1.8 Median % Change From BL (Q1, Q3) Median Change From BL,mL/min (Q1, Q3) -2.3 Weeks Weeks Weeks Baseline Baseline β2M, β2-microglobulin; Cr, creatinine; eGFRCG, 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.

  16. 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] HIV Rate Comparison (US MSAs & US DISCOVER sites) HIV Incidence/100 PY (95% CI) MSM Not on PrEP F/TAF F/TDF *CDC-defined persons with an indication for PrEP use (Smith Ann Epidemiol 2018). 1. Mera JIAS 2019, under review.

  17. 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 PY • The 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 discontinuations • F/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

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