11/7/2016. Jeanne M. Marrazzo, MD, MPH Professor of Medicine University of Alabama at Birmingham Birmingham, Alabama

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1 HIV Preexposure Prophylaxis: Pills, Rings, Injectables, and Gels Oh My! Jeanne M. Marrazzo, MD, MPH Professor of Medicine University of Alabama at Birmingham Birmingham, Alabama FORMATTED: 10/17/16 Financial Relationships With Commercial Entities Dr Marrazzo was awarded research grants, paid to her institution, from Curatek Pharmaceuticals and Symbiomix Therapeutics. She has also served as a consultant for Cepheid. (Updated 11/4/16) Slide 2 of 38 Learning Objectives After attending this presentation, participants will be able to: Describe the differences in delivery of tenofovir and emtricitabine to the rectal epithelium and the cervical epithelium, and the implications for dosing and efficacy Describe the recent clinical trial results that demonstrate the efficacy of the dapivirine vaginal ring in preventing HIV acquisition Name at least 1 antiretroviral drug currently under study as a long-acting injectable preexposure prophylaxis (PrEP) agent Slide 3 of 38 1

2 Which of the following is true regarding the safety of the use of daily TDF- FTC as pre-exposure prophylaxis for HIV acquisition? 10% 1. Irreversible decreases in bone density are common. 2. Acquisition of the K65R mutation occurs in the majority of persons 10% who fail this regimen and acquire HIV. 76% 3. Gastrointestinal intolerance is usually mild and limited to the first weeks of initiation. 5% 4. Proteinuria occurs within the first three months of use. Approximately how long does a woman need to take daily oral TDF-FTC to achieve protective levels in the cervix and vaginal tissues? 2% 1. 2 days 49% 2. 7 days 42% days 6% days Discussion Slide 4 of 38 The PrEP experience with TDF-FTC: current status Access, adherence, adherence, access Testing biomedical interventions Addressing challenges with adherence & user preferences The end of the placebo arm Evolving evidence New products & potential indications Long-acting delivery platforms Combination prevention 2

3 What is your practice with regard to TDF-FTC HIV PrEP? 24% 1. I prescribe it at least once a week. 21% 2. I prescribe it about once a month. 25% 3. I have only prescribed it a few times (less than once a month). 30% 4. I ve never prescribed it. What We Learned from Placebo Controlled RCTs of Daily TDF FTC PrEP: Percent of Samples with Detectable TFV & Efficacy Slide 8 of 38 FEM PREP 6 26 iprex TDF PARTNERS PrEP Protection of PrEP vs Placebo % with detected TDF Randomized, open-label trial of daily oral TDF/FTC PrEP in HIV- MSM in 13 clinics in London Immediate (n = 267) vs Deferred for 12 mos (n = 256) Primary endpoint: HIV infection in 12 mos 86% reduction in risk over 60 wks with immediate PrEP (90% CI: 58% to 96%, P =.0002) Number needed to treat to prevent 1 infection: 13 (90% CI: 9-25) Slide 7 of 38 Group HIV Incidence Infected, n Incidence/100 PY (90% CI) Immediate ( ) Deferred ( ) DMSB interrupted trial; recommended that all participants be offered PrEP Lancet

4 A 22 year old man is going to Miami for a weekend two weeks from now. He wants to use TDF-FTC HIV PrEP, and has never taken it. How would you advise him? 66% Start immediately and continue throughout the time of risk. 30% Start 5 to 7 days before and continue throughout the time of risk. 1% See how things go, and use it on demand why take it if you don t need it? 4% Just use condoms. NEJM 14 Dec 2015 Slide 9 of 38 Randomized double-blind trial of event-driven oral TDF/FTC* (n = 199) vs placebo (n = 201) (both with prevention services) in France 2 tablets taken 2-24 hrs before sex 1 tablet 24 hrs after sex 1 tablet 48 hrs after first event-driven dose Primary endpoint: HIV seroconversion Probability of HIV-1 Infection Slide 12 of 38 86% reduction in risk in PrEP arm (95% CI: 40% to 99%, P =.002) Number needed to treat for 1 yr to prevent 1 infection: 18 Median of 16 pills taken per mo in each arm Molina J-M et al. N Engl J Med 2015;373:

5 TFV-PrEP Safety Slide 11 of 38 Rates of death, serious adverse events, and laboratory abnormalities (including renal dysfunction) very low Not significantly different between those on PrEP and placebo Well tolerated GI adverse effects (e.g., nausea) more common in those receiving PrEP than placebo (< 10%, primarily during the first month only) PrEP safe during pregnancy (Mugo JAMA 2014) No reduction in contraceptive efficacy (Murnane AIDS 2014) Rare acquired resistance (about 3%); 12 infections averted for each case of resistance PrEP in the Real World Slide 12 of 38 The Good News: No new HIV infections in over 600 PrEP initiators at Kaiser Permanente San Francisco Volk et al. CID 2015; Image courtesy J Volk 60% 50% 40% 30% PrEP and STIs in >600 MSM Kaiser Permanente San Francisco 50% STI Incidence After 12 Months of PrEP Use 33% 33% 28% Slide 13 of 38 Expected HIV incidence with this STI incidence: 8.9% 20% 10% 0% 5.5% Any STI Rectal STI Chlamydia Gonorrhea Syphilis HIV 0% Volk et al. CID 2015 Slide courtesy J. Volk 5

6 Should We Go Beyond Oral PrEP? No Why Bother? Stabilization of the epidemic likely attainable with combination of ART & oral PrEP (TDF-FTC, TDF) Sustained delivery systems for ARV PrEP advancing in investigative pipeline Rilpivirine, cabotegravir Low adherence in clinical trials suggests limited marketability & uptake for some products (gel) Yes! Slide 14 of 38 Bridge to critical threshold of ART/PrEP coverage Need on-demand protection Expand choice for personalized protection Aim for low / minimal systemic absorption, low systemic toxicity Different PK for cervix vs. rectum Possibility for co-protection (HSV) Multi-purpose prevention (contraception) Slide 15 of 38 Science, October 17, 2014 Slide 16 of 38 J Infect Dis

7 MTN-020/ASPIRE MTN-020/ASPIRE was a multi-center, randomized, doubleblind, placebo-controlled phase III trial of a vaginal matrix ring containing the NNRTI dapivirine Primary objectives were to determine the effectiveness and safety of dapivirine (25 mg) administered in a silicone elastomer vaginal matrix ring, inserted once every 4 weeks, in preventing HIV-1 infection among healthy sexually active HIV-1 uninfected women Slide 17 of 38 February 22, 2016 nejm.org HIV-1 Protection Slide 18 of 38 After excluding data from two sites with lower adherence, the dapivirine ring reduced HIV 1 acquisition by 37%. Primary HIV-1 effectiveness intention-to-treat analysis (13 sites) Dapivirine Placebo # HIV-1 infections HIV-1 incidence, per 100 person-years HIV-1 protection effectiveness 95% CI, p-value % (12, 56) p=0.007 Age and HIV-1 Protection Slide 19 of 38 HIV 1 protection effectiveness was explored in additional age stratified categories, and lack of HIV 1 protection was limited to those 21 years of age: Age % ( 133,31) placebo incidence 5.4%/yr Age % (19,76) placebo incidence 6.1%/yr Age % (8,74) placebo incidence 3.0%/yr 7

8 Age and HIV-1 Protection Slide 20 of 38 HIV 1 protection effectiveness was explored in additional age stratified categories, and lack of HIV 1 protection was limited to those 21 years of age: Age % ( 133,31) placebo incidence 5.4%/yr Age % (19,76) placebo incidence 6.1%/yr Age % (8,74) placebo incidence 3.0%/yr Among women >21 years of age, HIV 1 protection effectiveness was 56% (95% CI 31 71%, p<0.001) MTN-020/ASPIRE Subcohort: Adherence by Residual DAP Levels in Vaginal Ring Slide 21 of 38 Expected level of ring used for 28 days: mg Expected level of unused ring: mg A lower level of residual DAP in the returned ring is indicative of higher adherence DAP Remaining (mg) Outcome Placebo Nonadherent ( 23.5 mg*) Brown E, et al. AIDS Abstract TUAC005LB. Reproduced with permission. Low-High Adherence (< 23.5 mg*) Med-High Adherence (< 22 mg*) Infections, n HIV incidence/100 PY Risk reduction vs PBO, % (95% CI; P value) (-28 to 63;.24) (20 to 76;.007) (22 to 84;.01) *Residual levels of DAP remaining in returned rings. MTN-020/ASPIRE Subcohort: Adherence vs HIV Protection 3 Mos Before Detection Slide 22 of 38 Sustained adherence associated with 92% reduction in risk of HIV infection 100 HIV Infection Risk Reduction (%) Risk reduction 11% (95% CI: -78 to 55) Risk reduction 29% (95% CI: -52 to 66) Risk reduction 58% (95% CI: -7 to 83) Risk reduction 92% (95% CI: 38 to 99) No use Bottom third Middle third Top third Adherence* *For seroconversions, adherence level taken from visit with lowest adherence of 3 months (3 visits) before HIV detection. Brown E, et al. AIDS Abstract TUAC0105LB. 8

9 Slide 23 of 38 Renewed Interest in Vaginal Ring Delivery for ARV, hormones ASPIRE data have revitalized discussion of ARV delivery by rings Numerous products under evaluation TDF; TFV; Vicriviroc (MK-4176) & MK-2048 (II) Combo rings have varying HC component Etonogestrel/ethinylestradiol vaginal ring has ENG; proprietary Different components may have varying effects on menses; estrogen needed to suppress menses Etonogestrel/ethinyl estradiol vaginal ring studies in Kenya, Seattle (Marrazzo), Rwanda (Jespers et al) & Cape Town (Bekker; adolescents) Data on microbiome effects at HIV R4P meeting, Chicago, October 2016 Long-Acting Injectable Prep Slide 24 of 38 Cabotegravir: integrase inhibitor (dolutegravir analogue) formulated as a nanosuspension for injection ÉCLAIR study established safety, tolerability, dosing schedule Good for PrEP because: High genetic barrier to resistance PK profile: half life of days allows once-daily oral or 1-3 month injectable dosing Cabotegravir: HPTN 077 Slide 25 of 38 Phase 2A study of quarterly injectable CAB compared to placebo in 200 men / women: fully enrolled, in follow up 9

10 Cabotegravir: HPTN 083 Slide 26 of 38 Phase 2B/3 safety / efficacy study of quarterly injectable CAB compared to daily oral TDF/FTC for PrEP in 4500 MSM / TGW Step 1: Oral TDF/FTC or oral CAB 30 mg daily x 5 weeks Step 2: Oral TDF/FTC daily or injectable CAB 800 mg every 3 mos Continues until 286 seroconversions reached Step 3: Open label TDF/FTC daily to cover PK tail / post-trial access HPTN 083 Design Slide 27 of 38 Cabotegravir: HPTN 084 Slide 28 of women in an open-label Phase 3 trial testing hypothesis that CAB-LA is superior to daily oral TDF/FTC 10

11 Slide 29 of 38 Thoughts & Next Steps Slide 30 of 38 PrEP works, when taken consistently, and is the most effective tool for preventing sexual HIV transmission we have so far Only one ARV (TFV) available; data for women still limited Critically dependent results coming up: HPTN studies of long-acting ARV (cabotegravir, rilpivirine) Rectal microbicide development Combination product development Antiretroviral + hormonal contraceptive Slide 33 of 38 11

12 Case Report: Multiclass Resistant HIV Infection Despite High Adherence to PrEP Slide 32 of yr-old MSM with multiclass resistant HIV-1 infection after 2 y of daily TDF/FTC Pharmacy records, plasma TFV analyses, clinical history support recent & long-term adherence PrEP failure likely result of exposure to PrEP-resistant, multiclass resistant HIV-1 strain Drug Class Mutations Detected on Day 7 Following p24-positive Test Estimated Fold-Change in IC 50 or Change in Response (Drug) NRTI 41L, 67G, 69D, 70R, 184V, 215E 1.9x (ABC), 61x (3TC), 38x (FTC), 1.3x (TDF) NNRTI 181C 43x (NVP) PI 10I No relevant change INSTI 51Y, 92Q Reduced (RAL), resistant (EVG), reduced (DTG) Knox DC, et al. CROI Abstract 169aLB. Slide 33 of 38 BMD Substudy of iprex: TDF/FTC PrEP vs Placebo in HIV-Neg High-Risk MSM/TGW iprex: double-blind, randomized trial (N = 2499): 44% relative reduction in cumulative HIV risk with TDF/FTC vs PBO (P =.005) [1] iprex DXA BMD substudy (N = 498) [2] : Small net decrease in spine (-0.91%) and total hip (-0.61%) BMD with TDF/FTC vs PBO at Wk 24 (P =.001 for both); no difference in fracture rate between groups (P =.62) Current analysis evaluated BMD changes after PrEP stop visit [3] DXA: BL iprex RCT Median: 1.2 yrs Every 24 Wks PrEP d/c 6 Mos Post d/c OLE Enroll iprex OLE 1.4 yrs 1. Grant RM, et al. N Engl J Med. 2010;363: Mulligan K, et al. Clin Infect Dis. 2015;61: Grant R, et al. CROI Abstract 48LB. ÉCLAIR: Cabotegravir LA in HIV-Negative Men at Low Risk for HIV Infection Slide 34 of 38 Cabotegravir: potent INSTI formulated as oral tablet and for LA IM injection Randomized, double-blind phase IIa trial Primary endpoint: safety, tolerability of CAB LA IM injections 2 HIV seroconversions, none during CAB LA dosing period Oral Phase Injection Phase Wk 4 Wk 41 Healthy adult men at low risk of HIV infection (N = 127) CAB 30 mg PO QD Placebo PO QD CAB LA 800 mg IM every 12 wks (n = 106) Saline Placebo IM every 12 wks (n = 21) 40-Wks of follow-up Markowitz M, et al. CROI Abstract

13 ÉCLAIR: Predicted vs Observed Cabotegravir LA Pharmacokinetics Slide 35 of 38 Peak CAB LA exposure higher and trough exposure lower than predicted because of more rapid absorption and release after injection ~ 70% of pts had C trough < 4 x protein-binding adjusted IC 90 ; every-8-wk dosing now under investigation 10 Geometric mean C trough with 10 mg PO QD: 1.35 μg/ml (LATTE) Mean (SD) Plasma CAB Concentration (μg/ml) Time From First IM Dose (Wks) Markowitz M, et al. CROI Abstract 106. Reproduced with permission. Observed CAB 800 mg IM every 12 wks (ÉCLAIR; n = 94) Simulated CAB 800 mg IM every 12 wks (males) 4 x Protein-binding adjusted IC 90: μg/ml Protein-binding adjusted IC 90: μg/ml ÉCLAIR: Injection Safety and Pain Outcomes Slide 36 of 38 ISR events occurred in 93% of pts with IM CAB vs 57% with placebo No discontinuations for AEs during inj. phase; however, 4 pts who withdrew consent noted inj. tolerability as reason On 0 (none of time) to 6 (all of time) pain/discomfort scale assessed at Wk 30, 6% of pts in CAB arm reported pain/ discomfort all of the time 21% of pts in CAB arm reported being dissatisfied with study medication AEs CAB (n = 94) Placebo (n = 21) Mean Mean ISR Event Events, Events, % Duration, Duration, % Days Days Pain Gr Gr Gr Pruritus Swelling Nodule/ bump Warmth Bruising Induration Markowitz M, et al. CROI Abstract 106. Murray M, et al. CROI Abstract 471. Reproduced with permission. HPTN-069/A5305: Maraviroc-Based PrEP for MSM Slide 37 of 38 Randomized, double-blind phase II trial Primary endpoints: safety (grade 3 AEs), tolerability (rate/time to discontinuation of study drug) Wk 48 HIV-uninfected men with condomless anal intercourse with 1 HIV+ or HIV unknown man in previous 90 days (N = 406) *Standard dosing. Gulick R, et al. CROI Abstract 103. MVC 300 mg (n = 101) MVC 300 mg + FTC* (n = 106) MVC 300 mg + TDF* (n = 99) FTC + TDF* (n = 100) Slide credit: clinicaloptions.com 13

14 HPTN-069/A5305: Safety, Tolerability, and Efficacy Slide 38 of grade 3/4 AEs; rates similar across arms 9% discontinued study drug early Rates of study drug discontinuation (P =.6) and time to permanent discontinuation (P =.6) similar across arms 5 new HIV infections occurred during study for annual incidence rate of 1.4% (95% CI: ); all R5 tropic; no transmitted drug resistance Age (Yrs), Race of Newly Infected Pt Study Arm First HIV+ Test, Wk HIV-1 RNA, c/ml Plasma Drug Conc. at Seroconv. Visit (ng/ml)* 20, black MVC + TDF 4 122,150 MVC: 0 TFV: 0 61, Asian MVC alone MVC: , mixed race MVC alone ,240 MVC: 0 35, white MVC alone 32 13,626 MVC: , black MVC alone 48 52,191 MVC: 0.7 *Anticipated predose steady-state MVC concentration: 32 ng/ml. Undetectable plasma drug concentrations at every study visit. Slide credit: clinicaloptions.com Gulick R, et al. CROI Abstract 103. Reproduced with permission. Which of the following is true regarding the safety of the use of daily TDF-FTC as pre-exposure prophylaxis for HIV acquisition? 0% 1. Irreversible decreases in bone density are common. 2. Acquisition of the K65R mutation occurs in the majority of 0% persons who fail this regimen and acquire HIV. 100% 3. Gastrointestinal intolerance is usually mild and limited to the first weeks of initiation. 0% 4. Proteinuria occurs within the first three months of use. Which of the following is true regarding the safety of the use of daily TDF FTC as pre exposure prophylaxis for HIV acquisition? Irreversible decreases in bone density are common. 0% 10% Acquisition of the K65R mutation occurs in the majority of persons who fail this regimen and acquire HIV. 0% 10% Gastrointestinal intolerance is usually mild and limited to the first weeks of initiation. 76% 100% Proteinuria occurs within the first three months of use. 0% 5% First Slide Second Slide 14

15 Approximately how long does a woman need to take daily oral TDF-FTC to achieve protective levels in the cervix and vaginal tissues? 1% 1. 2 days 46% 2. 7 days 49% days 4% days Approximately how long does a woman need to take daily oral TDF FTC to achieve protective levels in the cervix and vaginal tissues? 2 days 1% 2% 7 days 46% 49% 25 days 42% 49% 90 days 4% 6% First Slide Second Slide HIV Preexposure Prophylaxis: Pills, Rings, Injectables, and Gels Oh My! Jeanne M. Marrazzo, MD, MPH Professor of Medicine University of Alabama at Birmingham Birmingham, Alabama FORMATTED: 10/17/16 15