Injectable Pre-exposure Prophylaxis Myron S. Cohen, MD Yeargan-Bate Eminent Professor Medicine, Microbiology and Epidemiology Director, Institute for Global Health & Infectious Diseases
Transmission of HIV Josephs, Swanstrom and Cohen et al Nature Micro (June 2015)
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?
Slide 4 of 47 Component Risk assessment Recommendation PrEP indicated for those at substantial HIV risk Eligibility MMWR May 16, 2014 / 63(19);437 HIV negative, adequate renal function, no HBV Dosing 1 FDC tablet, once daily; not intermittent* (??) Follow-up Discontinuation Testing for HIV every 3 mos Counseling on risk reduction and testing creatinine at 3 mos and then annually Testing for STIs every 6 mos, even if asymptomatic PrEP not meant for lifelong administration but rather for periods of highest risk *caveat on discussion for peri-conception counseling
Optimization of FTC/TDF in MSM IPERGAY (CROI 2015) PROUD (CROI 2015) HPTN 067: varying dosage schedule for FTC/TDF (R4P, Late Breaker IAS) HPTN 073: Client centered care coordination (C4) to enhance update and adherence with FTC/TDF among Black MSM
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. Spreen 1 1 GlaxoSmithKline, Infectious Diseases, Research Triangle Park, NC, USA; 2 Central Texas Clinical Research, Austin, TX, USA; 3 Maple Leaf Medical Clinic, Toronto, ON, Canada; 4 Living Hope Foundation, Long Beach, CA, USA; 5 Chatham County Health Department, Savannah, GA, USA; 6 ViiV Healthcare, Research Triangle Park, NC, USA; 7 Janssen R&D, Beerse, Belgium 22nd Conference on Retroviruses and Opportunistic Infections; February 23-26, 2015; Seattle, WA
Long-acting rilpivirine for HIV prevention Akil Jacksona and Ian McGowan Curr Opin HIV AIDS 2015, 10:253 257
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
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
Selection of 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: EVALUATION OF TMC278LA (RILPIVIRINE LA) 88 TMC278LA 132* Women (ages 18-45) 44 Placebo Objectives: Safety of long-term dosing Tolerability Acceptability Pharmacokinetics 2:1 randomization active :placebo
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, 7 th IAS, 2013; Min, ICAAC, 2009 Taoda, International Congress on Drug Therapy in HIV Infection, 2012
Percent survival CAB LA (GSK744) is an Effective PrEP Agent in Vaginal Challenge in Rhesus and Pigtail Macaques Drug+virus challenges Washout Drug + virus challenges Washout GSK744 GSK744 GSK744 GSK744 GSK744 (last dose) 100 100 Aviremic (%) 80 60 40 20 0/4 GSK744 LA Control 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Weeks 6/8 p=0.0003 75 50 25 GSK744 (n=6) Placebo controls (n=6) p = 0.0005 0 0 2 4 6 8 10 12 14 16 30 Weeks SHIV 162p3 300xTCID50 Intravaginal Challenge in Female Rhesus Macaques, with DMPA (viral challenge Week 1, 5 and 7) SHIV 162p3 50xTCID50 Intravaginal Challenge in Female Pigtail Macaques, no DMPA (biweekly viral challenges x 22) Andrews et al. 21 st CROI 2014 Radzio et al. 21 st CROI 2014 13
CAB LA (GSK744) is an Effective PrEP Agent in Rectal Challenge in Rhesus Macaques Drug+virus challenges Washout Drug+virus challenges Percent Aviremic in Plasma GSK744 100 80 60 40 20 GSK744 8/8 protected Placebo GSK744LAP p<0.0001 8/8 infected 0 0 2 4 6 8 10 12 14 16 Weeks Post First Challenge Plasma GSK744 (mg/ml) GSK744 10 1 0.10 0.01 Range of GSK744 exposure in POC study 0 2 4 6 8 10 12 14 16 18 Weeks post first challenge Open symbols = point of infection II33 IP0 FH3 IK9 IK7 IH7 HI0 EP5 IG7 HV3 HN II64 Weekly SHIV 162p3 50xTCID50 Intrarectal Challenge in Male Rhesus Macaques (viral challenge weekly 0-7) Andrews et al. 20 th CROI 2013 SHIV 162p3 50xTCID50 Intrarectal Challenge in Male Rhesus Macaques (weekly viral challenge starting at Week 0) Andrews et al. 21 st CROI 2014 14
ÉCLAIR GSK1265744 in US Men N=120 Randomized 2:1 744:placebo Similar structure to 077 (4 week oral lead-in, 3 injections, 52 week follow-up) Goal 60% MSM low-to-moderate risk 10 US-based sites Aaron Diamond Research Center, NY NY Blood Center, NY Fenway Institute, Boston University of Pennsylvania, Philadelphia Gladstone Institute of Virology, SF Southwest Care Center: Santa Fe Whitman Walker Clinic, DC Piedmont Hospital, Atlanta Columbia University, NY Health Research of Hampton Roads, Newport News Nearing Completion leading to HPTN 083
HPTN 077 HPTN 077 8 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
HPTN 077 A Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the Investigational Injectable HIV Integrase Inhibitor, Cabotregravir, in HIV-uninfected Men and Women 176 HIV-uninfected, Ages 18-65 WEEKS 4 41 81 ARM 1 N = 132 ARM 2 N = 44 Daily Oral 744 Daily Oral Placebo Injections of 744LA at 3 timepoints (every 12 weeks) Injections of 744LA placebo at 3 timepoints (every 12 weeks) Follow-up Phase (Tail Phase) Primary objective: Evaluate the safety and tolerability of the cabotegravir LA injectable through Week 41 in HIV- uninfected men and women
HPTN 077 Current Status HPTN 077 As of August 1, 2015: 7/8 sites activated and enrolling; Lilongwe to be activated soon 60/176 enrolled to date (34%), 25 men and 35 women Note: These numbers will change since enrollment is currently ongoing
HPTN 083 PHASE 2B/3 DOUBLE BLIND SAFETY AND EFFICACY STUDY OF QUARTERLY INJECTABLE GSK 1265744 (CABOTEGRAVIR) COMPARED TO DAILY ORAL TENOFOVIR/EMTRICITABINE (TRUVADA), FOR PRE-EXPOSURE PROPHYLAXIS IN HIV UNINFECTED MSM AND TRANSGENDER WOMEN
HPTN 083 STUDY SCHEMA 4500 HIV-uninfected MSM in North & South America, Asia will be randomized 1:1 to: Step 1: Oral TDF/FTC or Oral 744 30 mg daily x 5 weeks (DB) Step 2: Oral TDF/FTC daily or Injectable 744 800 mg every 3 months (DB) Continues until 286 seroconversions reached (mean 3.5 py) Step 3: Open label TDF/FTC daily to cover PK tail / post-trial access if locally unavailable STEP 1 STEP 2 STEP 3 Screen 0 2 4 5 0 1 4 1316 25 28 3740 4952 6164 7376 8588 +1w+4w 12 24 36 48 60 72 84 96 +12w +12w 0 12 24 36 48 TDF/FTC tail coverage of last injection Blinded Injections ARM A 1:1 ARM B 744 30 mg PO QD TDF/FTC PBO QD TDF/FTC PO QD 744 PBO PO QD 744LA 800 mg IM Q12Weeks + TDF/FTC PBO PO QD TDF/FTC PO QD + PBO IM Q12Weeks Open label TDF/FTC PO QD Blinded study duration 101-231 weeks PK tail coverage/ole 48 weeks
Long Acting PrEP: Concerns Tolerance of two injections (4 ml) Safety, as drug removal is not possible Managing discontinuation (the tail) - subtherapeutic levels of ART threaten resistance if HIV is acquired
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