10/05/2016. Long-Acting Antiretroviral Agents For Prevention. Dr Paul Benn MB ChB FRCP

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1 Long-Acting Antiretroviral Agents For Prevention Dr Paul Benn MB ChB FRCP 1

2 Disclosures Paul Benn is a full time employee of ViiV Healthcare and an honorary HIV Consultant at the Mortimer Market Centre, Central and North West London NHS Foundation Trust, London 2

3 Outline UNAIDS fast-track targets and role of PrEP Summary of PrEP studies to date Long-acting PrEP agents under investigation Considerations for the management of long-acting PrEP Conclusions 3

4 UNAIDS Fast-Track Targets UNAIDS advocates for optimal scaling up of PrEP as an additional effective HIV prevention intervention 1 1/ Oral PrEP putting a new choice in context 4

5 WHO policy brief on PrEP 2015 Offering PrEP should be a priority for populations with an HIV incidence of about 3 per 100 person-years or higher. WHO policy brief on PrEP 2015 available at 5

6 AVAC at accessed

7 AVAC at accessed

8 Effectiveness (%) Adherence has a critical impact upon effectiveness CAPRISA 004 iprex TDF2 PartnersPrep (TDF) PartnersPreP (FTC) FemPrEP VOICE (TDF) VOICE (Truvada) VOICE (TFV gel) -60 Percentage of Participants Samples with detectable drug levels (Analysis based on a subset of total trail participants, Pearson correlation = 0.86, p=0.003) Landovitz CROI

9 Long-acting PrEP agents in development Agent Class Administration Dosing interval Phase of development Dapivirine 1,2 NNRTI IVR 4 weekly III Cabotegravir LA 3 INI IM 4-12 weeks IIb/III Rilpivirine LA 4 NNRTI IM 4-8 weeks IIb Monoclonal antibodies 4-6 Ibalizumab, PRO 140, VRC01 CCR5 mab CD4 bs mab IV, SC or both 1-4 weeks 1-III EFdA (MK 8591) 7 NRTTI PO 1 weekly Ib Tenofovir NR(t)I Implant? I alafenamide 8 NRTTI Nucleoside reverse transcriptase translocation inhibitor 1/ Nel A et al. CROI 2016 Abstr 110LB; 2/ Baeten JM et al. CROI 2016 Abstr 109LB; 3/ Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.,4/ Pace C, Markowitz M. Curr Opin HIV AIDS 2015, 10: ; 5/ Lynch RM et al. Sciencetranslationalmedicine 2015, 7; 319;;7/ Grober J et al. CROI 2016; Boston MA, Abstract 98, 8/ Schlesinger E.B. Et al. CROI 2016 Abstr 879 9

10 Long-acting PrEP agents and delivery systems Slow release vaginal rings (DPV, TDF, MVC, DRV) and vaginal films (IQP-0528, NNRTI) Long-acting injectable agents (RPV, CAB, mabs) Subcutaneous implants and transdermal patches (TAF, RPV, CAB, MVC) Multipurpose technologies for prevention 10

11 Long-acting PrEP agents and delivery systems Slow release vaginal rings (DPV, TDF, MVC, DRV) 11

12 Dapivirine (DPV) Intra-Vaginal Ring studies Participants Design The Ring Study 1 (IPM 027) N= sites: S Africa, Uganda Median age 25 (18-45 yrs) RCT DPV vs PBO ring (2:1) (replaced every 4 weeks) ASPIRE 2 (MTN 020) N= sites:malawi, S Africa, Uganda, Zimbawae Median age 26 (18-45 yrs) RCT DPV vs PBO ring (replaced every 4 weeks) Relative reduction in incidence overall Reduction in an asrandomized among > 21 yo 31% (95% CI 1-52, p=0.04) 37% (95% CI , p=0.1) 27% (95% CI 1-46, p=0.046) 56% (95% CI 31-71, p=0.0003) no safety concerns or clinically relevant differences in safety parameters were observed between study arms 1/ Nel A et al. CROI 2016 Abstr 110LB; 2/ Baeten JM et al. CROI 2016 Abstr 109LB 12

13 AVAC at accessed

14 Acceptability of the Intra-Vaginal Ring High levels of acceptability of IVR for HIV prevention among: African women 1,2 Post menopausal US women (99% VR was very easy/easy to use) 3 High levels of acceptability of IVR contraceptive 4 1/Van d Straten et al. AIDS Behav (2012) 16: , 2/ Nel A et al. PLoS ONE 11(3):e ; 3/ Van de Straten et al. CROI 2016 Abstr 873; 4/ Schurmans C et al. BMC Public Health 2015;15:348 14

15 Long-acting PrEP agents and delivery systems Slow release vaginal rings (DPV, TDF, MVC) Long-acting injectable agents (RPV, CAB, mabs) Subcutaneous implants and transdermal patches (TAF, RPV, CAB, MVC) Multipurpose technologies for prevention 15

16 CAB LA and RPV LA: Comparative information Attribute Cabotegravir LA Rilpivirine LA Drug concentration 200 mg/ml 300 mg/ml Refrigeration/stability No; store up to 30 C 24 months Yes; store at 2 8 C 36 months (>8 25 C for 24 hours) Protect from light No Yes Dose monthly 400 mg (2 ml) 600 mg (2 ml) Dose bimonthly 600 mg (3 ml) 900 mg (3 ml) Dosage instructions/needle gauge t 1/2 with single dose (range or SD) Drug interactions HCP, healthcare professional; SD, standard deviation; t 1/2, half-life HCP administration Gluteal IM 25 G ~40 days (25 54 days) Low liability as perpetrator or victim HCP administration Gluteal IM 21 G days (±24 days) Low liability as perpetrator; victim of CYP3A4 induction/inhibition 16

17 Rilpivirine phase I study Study design HIV negative volunteers, aged yrs, low HIV risk Single IM dose RPV 20 women per arm 300mg, 600mg, 1200mg 6 men 600mg Primary objectives: Plasma PK through day 84 post dose PK in genital tract and rectal fluid/tissues Jackson A et al. Clin Pharmacol Ther 2014; 96:

18 Rilpivirine PK following single IM dose in healthy volunteers Jackson A et al. Clin Pharmacol Ther 2014; 96(3):

19 Aviremic (%) Aviremic (%) Aviremic (%) Cabotegravir LA NHP preclinical proof of principle for PrEP Rectal Drug + virus challenges Washout Vaginal Drug + virus challenges Washout Vaginal Drug + virus challenges Washout CAB LA CAB LA /8 protected GSK744 LA Untreated 8/8 infected P= Time after first challenge (weeks) Weekly SHIV 162p3 50xTCID50 intrarectal challenge in male rhesus macaques (viral challenge weekly at weeks 0 7) CAB LA CAB LA /8 protected P= /4 infected GSK744 LA Control Time (weeks) SHIV 162p3 300xTCID50 Intravaginal challenge in female rhesus macaques, with DMPA (viral challenge weeks 1, 5 and 7) CAB LA CAB LA CAB LA GSK744 (n=6) Placebo controls (n=6) P= Time (weeks) SHIV 162p3 50xTCID50 Intravaginal challenge in female pigtail macaques, no DMPA (biweekly viral challenges x 22) Andrews et al. 20 th CROI 2013; Andrews et al. 21 th CROI 2013; Radzio et al. 21 st CROI

20 Plasma CAB (µg/ml) Cabotegravir LA single injection provides detectable drug in plasma for 48 weeks Mean concentration time profile (n=6/cohort) 100 mg IM 200 mg IM 400 mg IM 800 mg IM (split) 100 mg SC 200 mg SC 400 mg SC (split) x PA-IC 90 PA-IC 90 (0.67 μg/ml) CAB 5mg/day PO C tau = 0.6 μg/ml 0 CAB LA apparent t 1/2 ~40 days vs CAB oral t 1/2 ~40 hours Time (weeks) 16th HIV-HEPPK CAB, cabotegravir; C tau, trough concentration; IM, intramuscular; LA, long acting; PA-IC 90, proteinadjusted 90% inhibitory concentration; PO, oral; SC, subcutaneous; t 1/2, half-life Spreen et al. JAIDS 2014; Aug 21, Epub 20

21 ECLAIR Study Design (phase IIa) Phase IIa, randomized, multi-site, 2-arm, double-blinded study in men at low risk of acquiring HIV Oral phase Injection phase Follow-up phase D1 W2 W4 W5 W17 W29 W41 W53 W65 W77 W81 CAB 30 mg PO QD Placebo PO QD 5:1 Randomization CAB LA 800 mg IM Q12W Saline placebo IM Q12W Follow-up Follow-up Note: not all scheduled study visits are shown in this study schematic. PO, orally; Q12W, every 12 weeks; QD, once daily. Markowitz et al. CROI 2016; Boston, MA. Abstract

22 Baseline Characteristics of the Randomized Population PBO CAB (N=21) (N=106) Median age, years (min-max) 30 (21-57) 31 (20-61) Race White African American/African 57% 33% 56% 31% Hispanic/Latino ethnicity 14% 15% Median height, cm (min-max) 175 ( ) 176 ( ) Median weight, kg (min-max) 79 (48-132) 81 (52-167) Median BMI, kg/m 2 (min-max) 25 (18-40) 26 (18-48) Risk factors for HIV acquisition Homosexual contact Heterosexual contact Occupational exposure 76% 29% 5% 85% 21% 2% BMI, body mass index; PBO, placebo. Markowitz et al. CROI 2016; Boston, MA. Abstract

23 ISR Symptoms Injection Phase PBO (N=21) n (%) CAB (N=94) n (%) Subjects with any ISR event 12 (57) 87 (93) Total number of injections ISR events by maximum toxicity a Number of events (%) Mean duration (days) Number of events (%) Mean duration (days) Pain 17/62 (27) /272 (92) 5.4 Grade 1 16 (26) 122 (45) Grade 2 1 (2) b 101 (37) Grade (10) Pruritus 4 (6) (10) 2.5 Swelling 0 22 (8) 3.8 Nodule/Bump 0 21 (8) 9.7 Warm to touch 0 19 (7) 3.2 Bruising 1 (2) (6) 3.3 Induration 0 15 (6) 4.3 No subjects discontinued due to AEs during the injection phase; 4 subjects who withdrew consent cited injection tolerability as a reason a Percentages are out of total number of injections. With the exception of Grade 3 pain, all ISRs listed were Grade 1-2. b Subject was misdosed with CAB on third injection. Markowitz et al. CROI 2016; Boston, MA. Abstract

24 Predicted and Observed Mean (SD) CAB Concentration C T, concentration at the end of the dosing interval; PA-IC 90, protein binding adjusted 90% inhibitory concentration; SD, standard deviation. Markowitz et al. CROI 2016; Boston, MA. Abstract

25 ÉCLAIR Study Medication Satisfaction Questionnaire (Week 18 LA Compared With Oral) Markowitz et al. CROI 2016; Boston, MA. Abstract

26 Considerations for LAI PrEP Acceptability 26

27 Familiarity with and Preferences for Oral versus Long-acting Injectable PrEP in a US National Sample of Gay and Bisexual Men N=948 MSM USA 41% considered themselves suitable candidates for PrEP 84% had never heard of LA PrEP (12 weekly) Parsons JT 10 th IAPAC Maimi, June

28 Attitudes and Acceptance of Oral and Parenteral HIV Pre-exposure Prophylaxis among Potential User Groups: A Multinational Study N=1,790 (FSWs, MSM, IDUs, SDCs & YW) in seven countries: Peru, Ukraine, India, Kenya, Botswana, Uganda and South Africa 61% said they would use PrEP PrEP preference: 8/52 IM buttock> 4/52 IM deltoid > daily pill & event driven pill Eisingerich AB et al. PLoS ONE 7(1): e doi: /journal.pone

29 Considerations for LAI PrEP Acceptability 4 week oral lead in to establish safety and tolerability RPV requires cold chain storage and protection from light Injection site reactions over long term Long tail requiring coverage with oral PrEP Service implications e.g. training, recall systems 29

30 Theoretical Infection-Exposure-Resistance Relationship CAB and RPV LA concentrations wane over months Monitor for HIV acquisition during tail Oral PrEP to cover tail 30

31 HIV seroconversions and LAI PrEP Rilpivirine LA 1 N=1 female subject, single dose 300mg RPV LA seroconverted day 84 Low plasma RPV 6.8 ng/ml at presumed HIV acquisition, RPV detectable for 9 months post dose Commenced TDF, FTC, rdrv Cabotegravir LA 2 ECLAIR study n=2 Male subject, PBO arm, HIV seroconversion at week 23 Male subject, CAB LA arm, seroconversion at week 53 (24 weeks after final injection), no CAB detectable. No NRTI, NNRTI, INI mutations Commenced TDF, FTC, rdrv 1/ Jackson A Curr Opin HIV AIDS 2015; 10: ; 2/ Markowitz et al. CROI 2016; Boston, MA. Abstract

32 On going studies of LA PrEP agents Agent Study design Population Anticipated completion HTPN 077 Cabotegravir LA 1 HTPN 076 Rilpivirine LA 1 PhIIa RCT IM CAB 600mg vs PBO 8 weekly Or IM CAB 800mg vs PBO 12 weekly (3:1) 3-5 inj, FU 52 weeks 4 week oral lead in PhII RCT IM RPV 1200mg vs PBO (2:1) 5 inj 8 weekly, FU 32 weeks 4 week oral lead in HIV negative men and women (low risk) N=194 HIV negative females SSA & US N=132 Q Q / accessed April

33 Planned studies of LA PrEP agents Study name Agent HTPN Study design Ph IIb/ III RCT IM CAB 600mg 8/52 vs TVD QD PO Design TBC Population 4500 HIV-uninfected MSM in Asia, South Africa, and North and South America HTPN 084 Ph III RCT Design TBC HIV negative High risk women SSA 1/ Accessed April

34 Monoclonal antibodies for prevention Pegu et al. ScienceTranslationalMedicine.org 2014; 6,

35 Planned studies of LA PrEP agents Study name Agent HVTN 703 HTPN 081 VRCO1 Study design Population Anticipated completion PhIIb RCT IV VRC01 vs PBO 8 weekly 72 weeks & 20 weeks FU HIV negative women SSA N=1500 Q HVTN 704 HTPN 085 VRCO1 PhIIb RCT IV VRC01 vs PBO 8 weekly 72 weeks & 20 weeks FU HIV negative MSM TG US, Brazil, Peru N=2700 Q / accessed April

36 Subcutaneous implants and transdermal patches Several groups are developing/testing long acting delivery systems 1,2 Reservoir implants, degradable implants, and controlled release injectables ARV agents include rilpivirine, cabotegravir, tenofovir alafenamide, maraviroc 1/ 2/ 3/ 36

37 Multipurpose technologies for prevention Considerable interest in multipurpose technologies (MPT), i.e. combination of ARV and hormonal contraceptive in one product 1 Intra-vaginal ring, long-acting injectables, implants e.g. Dapivirine / levonorgestrol ring (IPM) 90 days Tenofovir / levonorgestrol ring (CONRAD) 90 days Dapivirine / Maraviroc ring (ph I) 2 1/ Malcolm R.K. BJOG 2014; 121, 5, 62 69; 2/ Chen BA et al. J Acquir Immune Defic Syndr Nov 1;70(3):

38 Conclusions PrEP poses an important effective prevention strategy Adherence is key to the effectiveness of PrEP Long-acting PrEP may offer individuals alternative options with less frequent dosing Further data regarding the efficacy, tolerability, cessation and implementation of long-acting PrEP are required New delivery systems and multipurpose technologies are being explored 38

39 Questions? 39