Pre-Exposure Prophylaxis for HIV Prevention

Size: px

Start display at page:

Download "Pre-Exposure Prophylaxis for HIV Prevention"

Lizbeth Marsh
5 years ago
Views:

1 Pre-Exposure Prophylaxis for HIV Prevention Raphael J. Landovitz, MD MSc Associate Professor of Medicine UCLA Center for Clinical AIDS Research & Education April 15, 2016

2 Million New Infections in 2014 5,600 New Infections per Day New HIV Infections 13,000 [9,600 17,000] 22,000 [13,000 33,000] 85,000 [48,000

2 2 Million New Infections in ,600 New Infections per Day New HIV Infections 13,000 [9,600 17,000] 22,000 [13,000 33,000] 85,000 [48, ,000] 87,000 [70, ,000] 140,000 [110, ,000] 340,000 [240, ,000] 1.4 million [ million] UNAIDS. Fact Sheet: 2014 Statistics; 2015.

3 Vaccine Prevention Modalities Condoms PEP Voluntary Male Circumcision Needle Exchange Abstinence HIV Treatment PrEP Microbicides HIV & STI Testing STI Treatment Harm Reduction

4 Vaccine Prevention Modalities Condoms PEP Voluntary Male Circumcision Needle Exchange Abstinence HIV Treatment PrEP Microbicides HIV & STI Testing STI Treatment Harm Reduction

5 Today s Agenda What is PrEP? Origins of PrEP Effectiveness Trials and Aspirational Modeling Implementation Considerations and Debate Progress and Challenges to Scale-up Looking Forward

6 Pre-Exposure Prophylaxis (PrEP) PrEP (Pre-exposure prophylaxis) Strategy of administering ART to uninfected, at-risk individuals Think of: Malaria prevention, birth control pill Tenofovir Disoproxil Fumarate (TDF) +/- Emtricitabine (FTC) Safe and well-tolerated Daily dosing of co-formulated tablet supported by PK/PD Relatively high barrier to resistance Rapid concentration in genital/rectal tissues Nonhuman Primate Models Suggest TDF + FTC offers better protection than TDF alone Effective protection from IV, rectal, and vaginal challenges Lower concentrations in CV vs. rectal compartments with oral Intermittent dosing may be possible Garcia-Lerma JG et al, PLoS Med Hendrix CW et al, PLoS One Von Rompay Lehman KK DA et et al, al, JAIDS. JID Von Rompay Grant RM KK et al, al. AIDS. JID Subbarao S et al JID Garcia-Lerma JG et al. Transl Med

7 TDF/FTC Mechanism of Action Nucleos(t)ide RTI s Entry/Fusion Inhibitors Non-Nucleoside RTI s Integrase Inhibitors Protease Inhibitors Castillo-Mancilla J et al. JAIDS 2015.

8 How did we get here? Time 0 24h 48h 72h 96h 120h 144h HIV Exposure-To-Dose Time Efficacy Tsai CC et al., J Virol Wade NA et al, NEJM Otten RA et al, J Virol

9 How did we get here? -48h -24h Time 0 24h 48h 72h 96h 120h 144h HIV Exposure-To-Dose Time Efficacy Tsai CC et al., J Virol Wade NA et al, NEJM Otten RA et al, J Virol

10 How did we get here? -48h -24h Time 0 24h 48h 72h 96h 120h 144h HIV Exposure-To-Dose Time Efficacy Tsai CC et al., J Virol Wade NA et al, NEJM Otten RA et al, J Virol

11 Effectiveness of Daily TDF/FTC in Clinical Trials iprex (TDF/FTC) FEM-PrEP (TDF/FTC) TDF2 (TDF/FTC) 99% VOICE (TDF) 99% (TDF/FTC) 42% 6% 49% 80% -49% -4.4% CI: CI: CI: CI: CI: +3 to -129 CI: +27 to -149 (TDF) Partners PrEP (TDF/FTC) PROUD (TDF/FTC) 63% 71% 66% 84% 86% CI: CI: CI: CI: CI: 58-96

12 Effectiveness (%) Relationship Between Effectiveness and Adherence in Microbicide & PrEP Trials Pearson correlation = 0.86, p=0.003 Pearson correlation = 0.86, p= CAPRISA 004 iprex TDF2 PartnersPrep PrEP (TDF) PartnersPreP PrEP (FTC) (Truvada) FemPrEP VOICE (TDF) VOICE (Truvada) VOICE (TFV gel) IPERGAY(Truvada) PROUD(Truvada) -60 Percentage of Participants Samples with detectable drug levels SS Abdool Karim, personal communication

13 TDF Concentrates x More in Rectal Tissue than in Cervico-vaginal Tissues Days post single-dose Patterson KB et al. Sci Transl Med

14 Maximizing the Potential Effectiveness TDF/FTC (7x/week) TDF/FTC (~1x/24 ) 99% 94% CI: Some adherence forgiveness with retained protection Anderson P et al, Sci Transl Med CI: doses per week likely required Donnell D et al, JAIDS Cottrell ML et al, JID, 2016.

15 Modeled Adherence Required for Protection Cottrell ML et al, JID 2016.

16 The Issues Holding us Back What is the effect of PrEP on risk behavior? What are the resistance implications of seroconversion on PrEP? What is the onset of protection? How quickly does protection wane? Long Term Safety in diverse populations? Optimal deployment? How do we best support adherence? Are less-than-daily dosing regimens protective? Is something better coming? Can we make PrEP available to, and will people most at risk use it and adhere to it?

17 Safety: Youth Bone Health Mulligan,K et al. Comorbidities and Adverse Drug Reactions

18 How Do We Best Support PrEP Adherence? Next Step Counseling 1 CDC Guidance 2 Text messaging 3,4 Smart devices 5,6 1. Amico KR, et al. AIDS Behav CDC 2014 Clinical Practice Guideline 3. Finitsis DJ, et al. PLoS ONE Mbuagbaw L, et al. BMJOpen Grant RM, et al. HPTN Gulick RM, et al. HPTN 069

19 What about ipergay? or Does less-than-daily dosing work?

94 per 100 PY) 86% relative reduction in the incidence of HIV-1 (95% CI:

20 ipergay Efficacy Results Mean follow-up of 13 months: 16 subjects infected 14 in placebo arm (incidence: 6.6 per 100 PY), 2 in TDF/FTC arm (incidence: 0.94 per 100 PY) 86% relative reduction in the incidence of HIV-1 (95% CI: 40-99, p=0.002) NNT for one year to prevent one infection : 18 Molina JM, NEJM 2015

21 Percentage of participants ipergay TDF/FTC Usage Nb pills used / month ]25-30] ]18-25] ]11-18] ] 4-11] ] 0-4 ] 0 : full bottles returned (all tablets) missing : 294/2798 visits (10.5%) Visits N part.. 0 M1 M2 M4 M6 M8 M10 M12 M14 M16 M18 M20 M22 M24 M26 M28 M Median number of pills/month (IQR): 16 pills (10-23) in the placebo arm and 16 pills (12-24) in the TDF/FTC arm (p=0.84) 48 participants (12%) received PEP 25 (13%) in the TDF/FTC arm and 23 (11%) in the placebo arm (p=0.73) Molina JM, NEJM 2015

22 ipergay Adherence: CASI PrEP use during the last sexual intercourse 1212 sexual intercourses assessed in 319 participants % PrEP Use (min-max) TDF/FTC n = 649 acts Placebo n = 563 acts Total % (min-max) Correct use* 45 (36-57) 40 (22-49) 43 (35-51) Suboptimal use 27 (14-35) 31 (18-44) 29 (20-38) No PrEP 27 (15-37) 29 (24-44) 28 (20-38) * According to the protocol, or at least one pill before and one pill after sex Molina JM, NEJM 2015

23 TFV and FTC Concentration in Rectal Tissue Molina JM, IAS 2015, Abstract MOSY0102

24 HPTN 067 Bekker LG. CROI 2015, Abstract 978LB.

25 Percentages Daily vs Nondaily PrEP Dosing Reported sexual acts protected by PrEP Daily 40 Twice Weekly 30 Event Driven Cape Town Women Bangkok MSM Harlem MSM Adherence was higher for the daily rather than non-daily doses Bekker L, et al. CROI 2015; Seattle, WA. #978LB Holtz TH et al. IAS 2015, Vancouver, BC #MOAC0306LB Mannheimer S et al. IAS 2015, Vancouver, # MOAC0305LB

26 HIV Incidence per 100 Person- Yrs Open-label data suggest that Perfect Adherence Not Required for High levels of protection iprex OLE Open label extension study of daily oral PrEP (TDF/FTC) in MSM and transgender women (N = 1,603) PrEP provides protection even when adherence is 100%: Efficacy of 4 6 tablets/wk similar to 7 tablets/wk (100% risk reduction) 2 3 tablets/wk also associated with significant risk reduction (84%) Participants at highest risk had the greatest levels of adherence HIV Incidence and Drug Concentrations < 2 Tablets/W k 0 LLOQ Tablets/W k 4 6 Tablets/Wk TFV-DP in fmol/punch Tablets/W k Off PrEP On PrEP Follow-up (%) 26% 12% 21% 12% Risk Reduction (%) 44% 84% 100% 100% % CI (%) -31 to 77% 21 to 99% 86 to 100% (combined) Grant R, et al. Lancet Infect Dis. 2014;14(9): ; Grant RM, et al. 20th International AIDS Conference. July 20 25, Melbourne Abstract TUAC0105LB.

Kaiser-Permanente The PATH-PrEP iprex DEMO OLE Project Clinical

76% 657 uptake (82%) 301 Initiated MSM/TG PrEP at Greater No

seroconversions at DBS levels suggesting mean 4-7 doses per week

follow-up African-American participants 30% of PrEP users were

seroconversions stable during at follow-up DBS levels 50% of

suggesting mean 4-7 doses per week Uses real-time drug levels to

higher-risk populations Decreases in risk-behavior over time

Grant Cohen JE RM S et et al, al. al, CID. Lancet JAIDS. 2015.

27 Kaiser-Permanente The PATH-PrEP iprex DEMO OLE Project Clinical Cohort 1603 Enrolled MSM/TGW MSM/TG/Women 60% Enrolled 76% 657 uptake (82%) 301 Initiated MSM/TG PrEP at Greater No seroconversions uptake in higher-risk 2 sites in Los Angeles No seroconversions at DBS levels suggesting mean 4-7 doses per week Lower populations High rates engagement of STIs at among follow-up African-American participants 30% of PrEP users were diagnosed with any STI at 6 month follow-up STIs No seroconversions stable during at follow-up DBS levels 50% of PrEP users were diagnosed with any STI at 12 month follow-up suggesting mean 4-7 doses per week Uses real-time drug levels to implement staged adherence intervention No seroconversions at DBS levels suggesting mean 4-7 doses per week Adherence better in higher-risk populations Decreases in risk-behavior over time Similar for on- and off- drug participants Demo Projects Volk, Grant Cohen JE RM S et et al, al. al, CID. Lancet JAIDS Inf Dis Liu, AY et al, JAMA

implementation provided at no cost for hjgh risk MSM and TGW in the context of the

28 PrEP Brasil Demonstration project Clinicaltrials.gov NCT Main Objectives Assess uptake, safety and feasibility of PrEP implementation provided at no cost for hjgh risk MSM and TGW in the context of the Brazilian public health system Secondary objectives PrEP awareness Adherence pattern TDF levels in DBS Social harm Risk compensation Adherence patterns

29 Uptake Approached N=986 Potentially elegible N=798 Screened N=490 Enrolled N=409 % uptake= # Enrolled *100 # Potentially eligible 51.25% Grinsztejn B, IAS 2015.

30 Predictors of uptake aor 95%CI p-value Age (per year increase) Schooling <12 years vs. > 12 years Site CRT-SP vs. FIOCRUZ USP-SP vs. FIOCRUZ <0.01 Steady partner Yes vs. No Gender TGW vs. Male <0.01 Perceived likelihood of getting HIV on the next year % vs. 0-25% Previous HIV test (last 12 months) Yes vs. No Prior PrEP awareness Yes vs. No <0.01 # Male condomless anal sex partners (last 12 months) 2 or more vs. < <0.01 Anal sex with HIV-positive partners(12 months) Yes vs. No I do not know vs. No Grinsztejn B, IAS 2015.

31 Are there PrEP Failures? Two MSM in UK taking TDF (alone) for HBV rx One suppressed viremia but had significant reservoir seeding by DNA PCR One had VL 158,899, also with reservoir seeding (GT WT) Both had plasma levels consistent with regular dosing One Example: Canadian A Tale MSM of taking 2 PrEP TDF/FTC Trials Drug Detection (subset) Risk vs. Drug detection iprex VOICE HIV test 2 months prior to PrEP initiation DBS levels c/w 51% daily dosing 30% Seroconversion with R5, Clade B RT 41L, Higher 215E, 67G, 69D, 70R, 184V, 181C INI 51Y, 92Q 1.3 fold change in TDF Overall phenotypic 42% susceptibility Effect. (15 to 63%) Rx TDF/FTC/RAL/r/DRV -> DTG/COB/DRV/RPV Lower -4.4% (-149 to 27%) Fox J, Inf Dis Ther Knox DC, CROI 2016.

32 Finding a PrEP Provider/ Building Infrastructure for PrEP Delivery Provider lists Crowd Sourcing Leadership from CBO s Clinician hotlines/warmlines CDC and WHO Guidance Academic Detailing - NYC

33 What Does the Future Hold? Maraviroc HPTN 069/ACTG A TAF Macaque protection (?) but low tissue levels 2 Long Acting Therapies Rilpivirine (TMC278) HPTN 076 Cabotegravir (GSK ) HPTN 077/HPTN 083/ ÉCLAIR 3 Immunotherapies VRC01 Implantable devices More on Intermittent (i)prep Special populations ATN 110/113 Youth 5,6 Combinations of interventions 1. Gulick RM, CROI Garrett K, CROI Markowitz M, CROI Wheeler D, CROI Hosek S, IAS 2016; Mulligan K Compl 2016.

34 Maraviroc HPTN 069/ACTG A5305

HPTN 069 Screening Enrollment and Randomization N = 600 (400 men; 200 women) Arm 1, N=150 100 men; 50 women Arm 2, N=150 100 men; 50 women Arm 3, N=150 100 men; 50 women Arm 4, N=150 100 men; 50

35 HPTN 069 Screening Enrollment and Randomization N = 600 (400 men; 200 women) Arm 1, N= men; 50 women Arm 2, N= men; 50 women Arm 3, N= men; 50 women Arm 4, N= men; 50 women MVC (active) + FTC (placebo) + TDF (placebo) MVC (active) + FTC (active) + TDF (placebo) MVC (active) + FTC (placebo) + TDF (active) MVC (placebo) + FTC (active) + TDF (active) Tissue Subset N = 30 15m; 15w Drug Interaction Subset N = 18 Tissue Subset N = 30 15m; 15w Drug Interaction Subset N = 18 Tissue Subset N = 30 15m; 15w Drug Interaction Subset N = 18 Tissue Subset N = 30 15m; 15w Drug Interaction Subset N = 18

36 Long Acting Rilpivirine (TMC278) HPTN 076: Phase 2 Safety TMC278 LA is a novel poloxamer 338- containing formulation of TMC278. TMC278 LA is long-acting suspension and well-suited for delivery via IM injection HPTN 076 enrolling at 4 sites, low-risk HIVuninfected women (NY, NJ, Zim, SA) Fully enrolled, Data available 2017

37 Long Acting Rilpivirine (TMC278) HPTN 076: Phase 2 Safety Williams, P. HIV DART 2014

38 Williams, P. HIV DART 2014

39 Cabotegravir (GSK ) development Early Phase Indication Phase 2a Phase 2b ± 3 NHP Models Treatment LATTE-1 LATTE-2 Pivotal Phase 3 First-inhuman/Phase 1 Prevention cis women HPTN 077* HPTN 084 Cardiac Safety, DDI Prevention MSM/TGW ECLAIR HPTN 083 *INCLUDES BOTH MEN AND WOMEN

40 Long Acting Cabotegravir HPTN 077 Phase 2a Cabotegravir is a novel strand-transfer integrase inhibitor Nanomolar activity against clinical HIV strains Chemical congener of dolutegravir Pure nanosuspension, suitable for IM injection HPTN 077 low-risk HIV-uninfected women and men Planned >60% women

41 Long Acting Cabotegravir HPTN 077 Phase 2a A Phase 2a Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the Investigational Injectable HIV Integrase Inhibitor, Cabotregravir, in HIV-uninfected Men and Women HIV-uninfected, Ages WEEKS Cohort 1 ARM 1 N = 79 ARM 2 N = 27 Daily Oral mg Daily Oral Placebo Injections of 744LA 800 mg every 12 weeks at three time points Injections of 744LA placebo every 12 weeks at three time points Follow-up Phase (Tail Phase) WEEKS Cohort 2 ARM 1 N = 66 ARM 2 N = 22 Daily Oral mg Daily Oral Placebo Injections of 744LA 600 mg every 8 weeks after monthly load at five time points Injections of 744LA placebo every 8 weeks after monthly load at five time points Follow-up Phase (Tail Phase)

Carolina International Sites Soweto, South Africa Durban, South Africa

42 Long Acting Cabotegravir HPTN 077 Phase 2a 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 as of April : 152

43 HPTN 083 Cabotegravir Ph 2b/ HIV-uninfected MSM in Asia, South Africa, North & South America

44 Dapivirine Rings

45 Conclusions PrEP is highly effective when taken as prescribed We need to target most at-risk populations We need more data in transgender populations and women at risk, including peri-conception In partnership with communities TDF-based PrEP is the first example of successful PrEP we await generational improvements PrEP scale-up is a global health imperative as part of combination prevention efforts

46 Thank you!

11/8/2016. Moving Beyond Truvada: The (Current) Future Pipeline for PrEP. Prevention Modalities

11/8/2016. Moving Beyond Truvada: The (Current) Future Pipeline for PrEP. Prevention Modalities Moving Beyond Truvada: The (Current) Future Pipeline for PrEP Raphael J. Landovitz, MD MSc Associate Professor of Medicine UCLA Center for Clinical AIDS Research & Education November 18, 2016 2 Million