Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
ART for Prevention… What Happens Next? Myron S. Cohen, MD Yeargan-Bate Eminent Professor Medicine, Microbiology and Epidemiology Director, Institute for Global Health & Infectious Diseases Long Acting Parenteral PrEP Drug Development Phases • Non Human Primate PROTECTION • Phase 1 studies (HIV negative people) -Safety -Preliminary PK/PD AGA Jackson, LJ Else, PMM Mesquita, D Egan, DJ Back, Z Karolia, L Ringner-Nackter, CH Higgs, BC Herold, BG Gazzard and M Boffito Clin Pharmacol Ther. 314, 2014 Rilpivirine Resistance: The Tail Penrose KJ, Parikh UM, Hamanishi KA, Panousis C, Else L, Back D, Boffito M, Jackson A, Mellors JW. Selection of rilpivirine resistant HIV-1 in a seroconverter on long-acting rilpivirine (TMC278LA) from the lowest dose arm of the SSAT 040 trial. HIV R4P Meeting 2014, Cape Town, South Africa, Abstract OA27.01. HPTN 076 HPTN 076: Safety and acceptability of injectable rilpivirine for PrEP 136 HIV-uninfected, women ages 18-45 years WEEKS 4 ARM 1 N = 91 Daily Oral TMC278 ARM 2 N = 45 Daily oral placebo 52 Six injections of TMC278 LA every 8 weeks Six injections of TMC278 LA placebo every 8 weeks 76 Follow-up phase (tail phase) Primary objective: Evaluate the safety of injectable rilpivirine through 48 weeks in women in SSA and the U.S. HPTN 076 HPTN 076 – Rilpivirine Study Sites US Sites Bronx, NY Newark, NJ International Sites Cape Town, South Africa Harare, Zimbabwe Study Fully Enrolled CABOTEGRAVIR: GSK126744 Long Acting (744LA) Favorable attributes for PrEP: • High genetic barrier to resistance • PK profile – half life of 21-50 days -allows once-daily oral or 1-3 month injectable dosing using nanosuspension formulation Muller et al, European Journal of Pharmaceutics and Biopharaceutics,2011 Spreen, 7th IAS, 2013; Min, ICAAC, 2009 Taoda, International Congress on Drug Therapy in HIV Infection, 2012 CAB LA (GSK744) is an Effective PrEP Agent in Rectal Challenge in Rhesus Macaques Drug+virus challenges Drug+virus challenges GSK744 GSK744 100 10 8/8 protected 80 Placebo GSK744LAP 60 40 p<0.0001 20 8/8 infected 0 0 2 4 6 8 Plasma GSK744 (mg/mL) Percent Aviremic in Plasma GSK744 Washout 1 0.10 0.01 10 12 14 16 Weeks Post First Challenge Weekly SHIV 162p3 50xTCID50 Intrarectal Challenge in Male Rhesus Macaques (viral challenge weekly 0-7) Andrews et al. 20th CROI 2013 0 2 II33 IP0 Range of GSK744 exposure in POC study FH3 IK9 IK7 IH7 HI0 Open symbols =EP5 point of infection IG7 HV3 4 6 8 10 12 14 16 18 HN II64 Weeks post first challenge SHIV 162p3 50xTCID50 Intrarectal Challenge in Male Rhesus Macaques (weekly viral challenge starting at Week 0) Andrews et al. 21st CROI 2014 9 ÉCLAIR: Cabotegravir LA for PrEP in Low-Risk, HIVUninfected Men Oral Phase Injection Phase Phase 2a Double-blind Men 18 to 65 years of age Low-risk of acquiring HIV No PEP or ART No liver disease 5:1 randomization Cabotegravir 30 mg qd (n=105) Cabotegravir LA 800 mg IM every 12 weeks (n=94) Placebo (n=21) Saline Placebo IM every 12 weeks (n=21) Week 0 Baseline characteristics (cabotegravir oral phase): Median age: 31 years. White/black race/ethnicity: 56%/31%. Hispanic/Latino race/ethnicity: 15%. Median height: 176 cm. Median BMI: 26 kg/m2. Risk for HIV acquisition: Homosexual contact: 85%. Heterosexual contact: 21% Occupational exposure: 2%. Markowitz M, et al. 23rd CROI. Boston, 2016. Abstract 106. 4 5 41 HPTN 077 HPTN 077: Safety, tolerability and pharmacokinetics of injectable cabotegravir (CAB) in men and women 4 WEEKS Cohort 1 194 ARM 1 N = 79 ARM 2 N = 27 HIVuninfected, ages 18-65 Cohort 2 41 81 Daily Oral Injections of CAB 800 mg every 12 weeks x 3 CBT Follow-up 30mg Phase (Tail Phase) Daily Injections of CAB placebo Oral every 12 weeks x 3 Placebo 4 WEEKS 41 ARM 1 N = 66 Daily Oral CBT 30mg Injections of CAB 600 mg every 4 weeks x 2 then every 8 weeks X3 ARM 2 N = 22 Daily Oral Placebo Injections of CAB placebo every 4 weeks x 2 then every 8 weeks x 3 85 Follow-up Phase (Tail Phase) Primary objective: Evaluate the safety and tolerability of the injectable CAB in HIV-uninfected men and women HPTN 077 HPTN 077 – Cabotegravir Study Sites US Sites Los Angeles, California San Francisco, California Washington, DC Chapel Hill, North Carolina International Sites Soweto, South Africa Durban, South Africa Lilongwe, Malawi Rio de Janeiro, Brazil Enrollment complete Cabotegravir and Rilpivirine As Two-Drug Oral Maintenance Therapy: LATTE Week 96 Results David A. Margolis,1 Cynthia C. Brinson,2 Graham H.R. Smith,3 Jerome de Vente,4 Debbie P. Hagins,5 Sandy K. Griffith,1 Marty H. St. Clair,1 Kimberly Smith,6 Peter E. Williams,7 William R. Spreen1 1GlaxoSmithKline, Infectious Diseases, Research Triangle Park, NC, USA; Texas Clinical Research, Austin, TX, USA; 3Maple Leaf Medical Clinic, Toronto, ON, Canada; 4Living Hope Foundation, Long Beach, CA, USA; 5Chatham County Health Department, Savannah, GA, USA; 6ViiV Healthcare, Research Triangle Park, NC, USA; 7Janssen R&D, Beerse, Belgium 2Central 22nd Conference on Retroviruses and Opportunistic Infections; February 23-26, 2015; Seattle, WA HPTN 083 HPTN 083: Efficacy of injectable cabotegravir (CAB) for PrEP in MSM and transgender women • • • • N = 4500; Goals: 10% TGW overall; 50% of US BMSM; 50% overall < 30 year old Study duration: 3-5 years Sites in North and South America; Asia; SSA (limited) CAB TDF/FTC Step 1 Daily oral CAB and oral TDF/FTC placebo Daily oral TDF/FTC and oral CAB placebo Step 2 CAB injection x 2, 4 weeks apart then every 8 weeks plus daily oral TDF/FTC placebo Placebo injection x 2, 4 weeks apart then every 8 weeks plus daily oral TDF/FTC Step 3 Open-label daily oral TDF/FTC to cover the PK tail, for up to 48 weeks Primary objective: HIV Incidence HPTN 084: Cabotegravir PrEP for Women • Dr. Sinead Delaney Protocol Chair • Study design under discussion NOTE PARTNERSHIP BETWEEN NIH/HPTN and VIIV, PEPFAR, USAID, and BMGF HPTN 084: Efficacy of Injectible Cabotegravir for PrEP in HIV-uninfected Women • In the early stages of protocol development • Sites will be in sub-Saharan Africa • Team currently discussing: • • • Superiority study Open-label 1:1 Randomization Primary objective: HIV Incidence Blinded versus Unblinded Blinded • Participants – Receive both injection and pills – Know if pill is active, will only work if taken • Question answered – Closer to efficacy of drug itself – Difference in characteristics of adherers minimal Unblinded • Participants – Receive either injection or pill – Those on pill know it will work only if taken • Question answered – Closer to effectiveness of intervention – Adherer characteristics will differ between arms – Behavior changes are possible MK-8591 (Efda) CROI 2016! -EC50 in PBMCs of 0.2 nM -Half life in PBMCs100 hours HIV treatment? Peroral weekly prevention? Development of a long acting implant BC and PrEP implant combined? The best drug development plan? THANK YOU FOR LISTENING