PrEP: Is Longer Better? Myron S. Cohen, MD

Transcription

1 PrEP: Is Longer Better? Myron S. Cohen, MD Yeargan-Bate Eminent Professor Medicine, Microbiology and Epidemiology Director, Institute for Global Health & Infectious Diseases

2 TDF/FTC was FDA Approved for use for Prevention on July 16, 2012 Success depends entirely on adherence Alternatives to daily dosing are possible Truvada PrEP uptake has been limited to date Perhaps longer acting agents will prove more attractive?

3 Long Acting Parenteral PrEP

4 Cabotegravir Nanosuspension Drug nanocrystal suspended in aqueous vehicle Nanomilled to increase surface area and drug dissolution rate Allows ~100% drug loading vs. matrix approaches for lower injection volumes Cabotegravir 200 mg/ml Mean Concentration-Time Profile Following Single Dose Injection Spreen, et al. JAIDS 2015 Müller, et al. European Journal of Pharmaceutics and Biopharmaceutics 78 (2011) 1-9

5 LATTE-2: Cabotegravir IM + Rilpivirine IM for Long-Acting Maintenance ART Multicenter, open-label phase IIb study Primary endpoints: HIV-1 RNA < 50 c/ml by FDA snapshot, PDVF, and safety at maintenance Wk 32 Induction Phase* Maintenance Phase ART-naive HIVinfected pts with CD4+ cell count > 200 cells/mm 3 Wk 16: RPV PO Added CAB 30 mg PO QD + ABC/3TC Wk 20 Wk 32 primary analysis; Wk 1 dose selection Wk 96 CAB 400 mg IM + RPV 600 mg IM Q4W (n = 115) CAB 600 mg IM + RPV 900 mg IM Q8W (n = 115) (N = 309) CAB 30 mg PO + ABC/3TC PO QD (n = 56) *Pts with HIV-1 RNA < 50 c/ml from Wk 16 to Wk 20 continued to maintenance phase. In snapshot induction analysis, 14 pts had virologic nonresponse and 13 pts had no virologic data in window, including 6 pts who discontinued for AEs or death and 7 pts who discontinued for other reasons. Margolis DA, et al. CROI Abstract 31LB. Slide credit: clinicaloptions.com

6 HPTN 083: CAB LA to Prevent HIV Acquisition in MSM and TGW Step 1 Step 2 Step 3 Daily oral CAB and TDF/FTC placebo CAB LA at two time points 4 weeks apart and every 8 weeks thereafter and TDF/FTC placebo Open-label TDF/FTC to cover the PK tail, for up to 48 weeks TDF/FTC and oral CAB placebo TDF/FTC and injectable placebo at two time points 4 weeks apart and every 8 weeks thereafter Open-label TDF/FTC for up to 48 weeks Primary Objective: HIV Incidence, double blind double dummy, non-inferiority N=4500; Study duration: Enrollment months; follow-up up to 4.5 y Enrollment goals: Minimum 50% of US enrollment Black MSM (~ 950) Overall minimum 10%TGW (~ 450) Overall > 50% under age 30

7 45 HPTN 083 Research Sites Worldwide As of October Sites in the U.S. 1 Site in India 3 Sites in Thailand 1 Site in Vietnam 5 Sites in Peru 4 Sites in Brazil 1 Site in South Africa 2 Sites in Argentina

8 HPTN 084: CAB LA Prevent HIV Acquisition in Females Delaney-Moretlwe and Hossinipour Step 1 Oral 5 Weeks Daily oral CAB 30 mg TDF/FTC 300 mg/ 200 mg Step 2 Injection Phase CAB LA 600 mg IM at two time points 4 weeks apart / every 8 weeks TDF/FTC Daily Visits every 8 weeks TDF/FTC use measured Step 3 Follow Up Phase TDF/FTC for all subjects N= 3600 HIV negative women Primary outcome: Reduce HIV incidence (superiority)

9 The Cabotegravir PrEP Partnership HIV Prevention Trials Network National Institutes for Health OGAC/PEPFAR United States Agency for International Development Bill & Melinda Gates Foundation ViiV Healthcare Gilead Sciences, Inc.

10 MK-8591 Michailidis et al (2009) JBC Non-obligate chain terminator; inhibits reverse transcriptase by preventing translocation Potent activity (PBMC EC 50 = 0.2 nm) with broad subtype and mutant coverage (HIV-1, HIV-2, MDR strains) MK-8591-TP exhibits persistence (t 1/2 = 103 hr) in human PBMCs allowing for extendedduration dosing Parenteral formulations exhibited >180-day extended release after a single injection in rats Ongoing studies suggest the potential to provide coverage for durations up to 1 year 10

11 Subcutaneous PrEP Implants Simple insertion AND removal Long-acting (months to years) PrEP + contraception? Current development: TAF, EFdA (MK-8591) Schlesinger, et al, Pharm Res 2016; Gunawardana, et al., AAC 2015

12 Neutralizing Ab to HIV-1 V3-glycan gp41 MPER V1V2-glycan CD4 binding site gp120/41 interface V1V2-Glycan bind to trimer cap V3-glycan, N332 supersite gp41 MPER near membrane gp120/41 interface bind to parts of both gp120 and gp41 CD4 binding site of gp120 where the virus attaches to CD4 VRC01, 3BNC11 Christina Corbaci, Andrew Ward,

13 BnABs Prevent SHIV in Non-Human Primates PGb126 protects against rectal/vaginal challenge Moldt, AIDS 2016 VRC01 delivered by AAV prevents infection Saunders, JV 2015 Combination BnABs selected through modeling Wagh, PLOS Path 2016 Single dose BnaB(s) protect repeated challenges Gautam, Nature 2016 PG121 protection is distal to the mucosa Liu, Science 2016

14 Antibody-mediated protection against SHIV challenge includes systemic clearance of distal virus Jinyan Liu, Khader Ghneim, Devin Sok, William Bosche, Yuan Li, Elizabeth Chipriano, Brian Berkemeier, Kelli Oswald, Erica Borducchi, Crystal Cabral, Lauren Peter, Amanda Brinkman, Mayuri Shetty, Jessica Jimenez, Jade Mondesir, Benjamin Lee, Patricia Giglio, Abishek Chandrashekar, Peter Abbink, Arnaud Colantonio, Courtney Gittens, Chantelle Baker, Wendeline Wagner, Mark Lewis, Wenjun Li, Rafick-Pierre Sekaly, Jeffrey Lifson, Dennis Burton, Dan H. Barouch Animals infused with PGT121 (or placebo) day -1 Vaginal exposure to SHIV on day 0 SHIV RNA and DNA detected in tissues 1-3 days after exposure (distal to the site of infection) SHIV was then eliminated by PGT 121 (and inflammation) over 7 days, but not in controls Science Sep 2;353(6303):

15 Current mabs are More Potent and Broadly Reactive than Previous mabs F ra c tio n n e u tra liz e d IC 5 0 c u to ff (u g /m l) 1 0 E 8 V R C B N C P G b G 1 2 (PGT121) Since 2009 CAVD David Montefiori (PI) NVITAL Bailer, Louder et al. 190 diverse Env-pseudoviruses

16 VRC01 Protects against Mucosal SHIV162P3 Challenge in NHP 20 mg/kg infusion of VRC01 Percent uninfected RECTAL CHALLENGE 4/4 protected VRC01 Control 0/4 protected Days post challenge P e r c e n t u n in f e c t e d VAGINAL CHALLENGE 4/4 protected 1/4 protected V R C 0 1 C o n t r o l D a y s p o s t c h a lle n g e

17 The AMP Studies: Highlights Cohort IV Treatment n= Schedule North + South American MSM (2400) HVTN 704 / HPTN 085 VRC01 10 mg/kg 800 VRC01 30 mg/kg 800 Placebo Control 800 Every 8 wks x 10 doses Sub-Saharan African women (1500) HVTN 703 / HPTN 081 VRC01 10 mg/kg 500 VRC01 30 mg/kg 500 Placebo Control 500 Every 8 wks x 10 doses Two different infusion doses: Important to know if lower dose of 10 mg/kg can protect Powered to associate mab serum level with protection

18 45 AMP Research Sites Worldwide As of September 2016 HVTN 704/HPTN 085, MSM + TG HVTN 703/HPTN 081, Women

19 HVTN 704/HPTN 085 (MSM+TG) 3000 AMP MSM+TG: Cumulative Enrollment vs Projections (as of 19 September 2016) Target Cumulative Enrolled 20

20 THANK YOU