Pre-exposure Prophylaxis (PrEP) Kenneth Mayer, MD Fenway Health Beth Israel Deaconess Medical Center Harvard Medical School and School of Public Health Treatment As Prevention in Africa Workshop May 2 nd, 2014
Why Chemoprophylaxis Post-HPTN 052? TasP long term effectiveness not fully understood HIV incidence has not in several resource rich countries despite access (Birrell, 2013; Audelin, 2013) U.S. Cascade < 30% PLHIV virologically suppressed Serostatus awareness is limited among many Not all PLHIV want to start meds with high CD4 counts, and virologic suppression rates vary HIV stigma limits willingness to disclose Cost effectiveness of PrEP : 44 PubMed cites Not either/or, especially if PreP is limited to the riskiest people, e.g. women in South Africa (Walensky, et al, CID, 2012)
PrEP works, but adherence is critical Study Efficacy overall Drug detected overall Estimated Risk reduction with drug iprex 42% ~50% 92% Partners PrEP 67-75% 82% 86% (TDF) 90% (FTC/TDF) TDF-2 62% 80% 78% Fem-PrEP No efficacy 26% adherence too low to assess efficacy VOICE No efficacy 29% Thai IDU 49% N/A N/A
Residual PrEP Concerns Risk Compensation: not seen in trials Renal insufficiency: rare, reversible -but pts had to have normal function for trials Bone demineralization: statistically significant, not clinically significant at 18 months, needs f/u Transmission of resistance -Primarily in pts started on PrEP with acute HIV -Most were 184V (3TC/FTC R, less fit virus) Role of Genital Tract Inflammation and PK need f/u (Naranbhai, JID, 2012; Hendrix, CROI, 2014)
Buchbinder et al, Lancet ID, 2014
Strategies to improve PrEP delivery and adherence New PrEP drugs and dosing strategies Novel adherence strategies Alternative delivery systems and formulations Topical Microbicides: TFV vaginal or rectal gel Intra-vaginal rings: ASPIRE (Dapivirine) Injectables: Rilpivirine-LA GSK744
TFV- DP Concentra0ons in IPrEx and STRAND TFV-DP (fmol/10 6 Cells) 100 10 STRAND 16 iprex Regression analysis in iprex: 90% reduction in HIV acquisition when TFV-DP>16 fmol/10 6 cells Predicted risk reduction: 76% with 2 pills / week 96% with 4 pills / week 99% with 7 pills/ week 1 2/Wk 4/Wk 7/Wk n = 21 n = 21 n = 22 BLQ: 0% 0% 0% Median: IQR: 11 6 13 32 25 39 42 31 47 Cases Controls n = 42 n = 144 93% 64% 11 4 15 16 9 27 * nt * Visit when HIV was first discovered Anderson et al, Science Translational Medicine 2012 4:151ra125
Tenofovir PBMC v. Plasma (HPTN 066) (Hendrix C et al, CROI, 2014) PBMC Tenofovir diphosphate Plasma Tenofovir TFV-DP fmol/m cells PBMC 80 70 60 50 40 30 20 10 Weekly 1x Twice weekly 2x Twice Weekly Daily TFV ng/ml Plasma 80 70 60 50 40 30 20 10 Weekly 1x Twice weekly 2x Twice Weekly Daily 0 0 0 7 14 21 28 35 42 49 0 7 14 21 28 35 42 49 Days Days
HPTN 067/ADAPT (Alterna0ve dosing to augment PrEP pill taking) Phase II, Randomized, Open-Label, Pharmacokinetic and Behavioral Study of the Use of Intermittent Oral PrEP with TDF/FTC Wk 24 primary endpoint 6-week lead-in period 1 pill/week DOT before randomization Daily Truvada 1 tablet/d Regarless of sexual activity (n = 180) High risk women and MSM (New York, Bangkok, Cape Town) Time driven Truvada: 1 tablet 2 days/week + 1 post-exposure dose within 2 hours after sex (n = 180) Event driven Truvada: 1 tablet prior to sex + 1 post-exposure dose within 2 hours after sex (n = 180) Primary Objective: Is intermittent vs. daily dosing associated with equivalent coverage of sex events, lower number of pills used and decreased side effects R. Grant, F. Van Griensven, et al.
US PrEP Demonstra0on Project: Implementa0on of PrEP (2012-2014) STD clinics in San Francisco, Miami, Washington, DC (n=831) - MSM, transgender women (1.4%) - Clinic referrals (63%) - Self- referrals (37%): more likely to be white, higher educa0on level, higher sexual risk behaviors and risk percep0on versus clinic referrals Offered up to 48 weeks of open- label emtricitabine/tenofovir DF - Accepted PrEP: 60.4% 77% had TDF- DP levels consistent with taking >4 doses/week PrEP uptake associated with - Self- referral, prior PrEP awareness, higher- risk sexual behaviors BLD: below limit of detecfon. Cohen SE, et al. 21 st CROI. Boston, 2014. Abstract 954. Samples (%) 60 50 40 30 20 Tenofovir- DP Levels (Week 4) Miami (n=157) Washington, DC (n=100) San Francisco (n=300) 27% 18% 43% 43% 40% 10 11% 0 5% 4% 4% 2% 2% 0% BLD <250 250-550 >550-950 Doses/Week: <2 <2 2 4 >4 Tenofovir- DP (fmol/punch)* *femtomole/punch: measure of flux density. 14% 35% >950 52%
PrEP Proof-of-Concept: Long-Acting Integrase Inhibitor in Nanosuspension for Injection Macaque model of SHIV transmission Study 1 (vaginal transmission) - Low-dose SHIV (50 TCID 50 ) twice a week - GSK744 LA (50 mg/kg) 3 injections at week 0, 4, 8-6 of 6 pigtail macaques (lunar menstrual cycles) protected against SHIV infection Study 2 (rectal transmission) - Weekly SHIV (50 TCID 50 ) until systemic infection detected - One GSK744 LA (50 mg/kg) injection at week 0 - After 1 to 2 challenges, placebo macaques became infected - With a single GSK744 injection, infection was delayed by 5 to 10 challenges with SHIV Radzlo J, et al. 21 st CROI. Boston, 2014. Abstract 40LB. Andrews CD, et al. 21 st CROI. Boston, 2014. Abstract 39. Andrews CD, et al. Science. 2014;343:1151-1154. Aviremic (%) Aviremic (%) 100 80 60 40 20 0 100 80 60 40 20 0 Vaginal SHIV Exposure P=0.0005 GSK744 LA (n=6) Placebo (n=6) 0 2 4 6 8 10 12 14 16 30 Week Rectal SHIV Exposure P<0.0001 GSK744 LA (n=12) Placebo (n=4) 0 2 4 6 8 10 12 14 16 18 20 22 24 Week
Project PrEPare (NIMH R34,Fenway) Modeled after Life-Steps, (Safren et al) ART adherence intervention Modular intervention: 4 weekly visits and 2 booster sessions (nurse-delivered). Intervention content: CBT-oriented adherence problem-solving Brief motivational interviewing Identification of barriers and solutions Sexual risk-reduction strategies Optional modules: Mental health and substance use concerns 13 Adherence to PrEP was measured daily via Wisepill Sexual risk taking was assessed by text messages (Lester, 2010)
To implement PrEP successfully, it will be essenfal to engage pracfcing clinicians Fenwayfocus.org
Candidates for PrEP studies in Africa HIV discordant couples: HIV+ partner does not want to start ART Bridge for newly initiating HIV+ (Partners PrEP Demo) PrEP-ception MSM HPTN 075: MSM in Kenya, Malawi, South Africa MSM with wives: how can they explain condoms? FSW: which ones? High risk heterosexuals? Botswana: yes; VOICE, FEMPrEP: questions.
Combination Antiretroviral Prevention Interventions to Increase Testing HIV Negative Risk Assessment PrEP, Adherence Counseling Test HIV Positive Positive Prevention Linkage To Care Address concomitant concerns, e.g. depression, substance use, relationship dynamics Enroll in Care Treat ART Initiation Adherence to ART Maintain Viral Suppression. Decrease in HIV Transmission
Thank You Fenway Clinical, Epidemiological and Behavioral Research Teams Fenway Medical Department Slim and Quarraisha Abdool Karim Susan Buchbinder Connie Celum Robert Grant Doug Krakower Albert Liu Jim Rooney Steve Safren Dawn Smith NIAID, NIMH, NIDA, NICHD, CDC, HRSA, Mass DPH, Gilead www.thefenwayinstitute.org