Faculty: Relationships with financial sponsors: Speakers Bureau/Honoraria: Advisory board/consulting Fees:

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1 Faculty/Presenter Disclosure Faculty: Joss de Wet Relationships with financial sponsors: Speakers Bureau/Honoraria: Gilead, ViiV, Merck. Advisory board/consulting Fees: Gilead, ViiV, Merck. Dr Joss de Wet Clinical Assistant Professor Family Medicine UBC Mitigating Potential Bias Discuss principles and not specific drugs Follow guidelines Only one drug approved for PREP, namely Truvada which now is generic PREP Present BC program & stastistics Evidence Daily vs Ondemand How to apply, follow STD BC program Truvada (generic) covered as of Jan 2018 September: n = 2490 Prescribers: n = 49 Zero HIV infections 3 4 Why PREP? New infections in all risk groups have declined except MSM STD rates increasing in MSM Condom use at best is 70% 6 1

2 VAX004 study: HIV vaccine study EXPLORE study: Largest behavioural HIV prevention N = 772 men VAX: Per one act: No condom use 1:90 to 100% condom use 1:667 EXPLORE Per one act: No condom use 1:244 to 100% condom use 1: 44 Real life setting 70% efficacy Long term consistent condom use very difficult 13% able to maintain 100% condom use over 3 years cosmith DK, Herbst JH, Zhang XJ, Rose CE. Condom effectiveness for HIV prevention by consistency of use among men who have sex with men (MSM) in the US. J Acquir Immune Defic Syndr, e-publication ahead of print. Doi: /QAI December PROUD: Pragmatic Open-Label Randomized Trial of Pre-Exposure Prophylaxis mitt a efficacy of % Adherence-adjusted efficacy reduction in acquisition based on TDF detection in blood Clinical Participants Number Drug of HIV infection b c trial (9% % % (9% CI) CI) Men who have iprex 2499 TVD* 42 (18-60) 92 (40-99) sex with men TDF 67 (44-81) 86 (67-94) Partners HIV discordant 4747 PrEP couples TVD* 7 (-87) 90 (8-98) Heterosexually TDF 2 active men and 1200 TVD* 62 (22-83) 84 NS women Bangkok Tenofovir IDU 2413 TDF 49 (10-72) 74 (2-91) Study Heterosexually Fem-PrEP 191 TVD* NS < 40% active women Heterosexually VOICE 029 TVD* NS <30% active women a. Modified Intent to Treat b. Excluded only those enrolled patients later found to be infected at randomization and those with no follow-up visit or HIV test 11 c. The percentage of reduction in HIV incidence among those with TFV detected in blood, compared with those without detectable TFV *TVD = FTC/TDF High-risk, HIV-uninfected MSM engaging in CAI N=44 PROUD Immediate (IMM) TVD (n=27) Deferred (DEF) TVD (start at Month 12) (n=269) Primary endpoint: HIV seroconversion between randomisation and Month 12 Secondary endpoints: Randomised, multicentre, open-label pilot study in the UK All subjects received comprehensive HIV prevention services, including condoms, riskreduction counseling, testing and treatment for sexually transmitted infections, and HIV preand post-test counseling Safety, adherence, sexual behavior, resistance development Oct 2014: the PROUD Trial Steering Committee announced that participants on the deferred arm of the study, who had not yet started PrEP, would be offered the opportunity to begin PrEP ahead of schedule McCormack S. & al. Lancet 2016;387,3-60 ClinicalTrials.gov Identifier: NCT CAI: Condomless anal intercourse 12 2

3 PROUD: Pragmatic Open-Label Randomised Trial of Pre-Exposure Prophylaxis Use of post-exposure prophylaxis by arm: IMM: 12 subjects (4.4%); 14 prescriptions DEF: 8 subjects (31.%); 174 prescriptions HIV Incidence Efficacy results Group Infections, n Follow-up (PY) Incidence/100 person-years (90% CI) Overall * Immediate ( ) Deferred ( ) 86% (90% CI: 64-96) Relative Risk Reduction; p= Number needed to treat to avert one HIV infection = 13 (90% CI: 9-23) McCormack S. & al. Lancet 2016;387,3-60 * The overall incidence was 4.9 infections/100 person-years, 90%CI ( ) at 1 st communication in McCormack S, et al. CROI 201; Seattle, WA. #22LB 13 IPERGAY: High-risk, HIV-uninfected MSM with Condomless anal sex with 2 partners within 6 months N=400 egfr > 60 ml/min Primary endpoint: Secondary endpoints: ONDEMAND PREP Randomised, multicentre, double-blind study in France and Québec On-demand regimen constitutes: 2 TVD or 2 placebo 2-24 hrs prior to sexual intercourse exposure 1 TVD or placebo 24 hrs after first intake 1 TVD or placebo 48 hrs after first intake HIV seroconversion «On-demand» TVD (n=199) «On-demand» TVD placebo (n=201) Sexual behavior, safety events, adherence Oct. 2014, the DSMB recommended that the placebo arm be discontinued and patients be offered switching into the treatment arm. Molina JM et al. CROI 201; Seattle, WA. #23LB Molina JM & al. N Engl J Med 201;373, IPERGAY : Sex-Driven iprep FTC/TDF is only licensed as a daily dosage for PrEP All participants received a package of preventative measures: counseling repeated HIV testing screening & treatment for other STIs HBV and HAV vaccination condoms and gel IPERGAY : Sex-Driven iprep IPERGAY : Sex-Driven iprep Efficacy results 2 tablets (TDF/FTC or placebo) 2-24 hours before sex 1 tablet (TDF/FTC or placebo) 24 hours later 1 tablet (TDF/FTC or placebo) 48 hours after first intake 16 subjects infected Placebo = 14 (incidence: 6.60/100 PY) FTC/TDF =2 (incidence: 0.91/100 PY) Mean follow-up= 9.3 months (IQR ) Average 1 pills / month (TVD : IQR 11-21; PBO : IQR 9-21) 6 subjects received post-exposure prophylaxis : PBO = 2 p=0.37 TVD = 31 Friday Saturday Sunday Monday Tuesday Wednesday Thursday Friday Saturday Sunday 4 pills of TDF/FTC taken over 3 days to cover one sexual intercourse 86% (9% CI: 40-98, p=0.002) Relative Risk Reduction Number needed to treat for 1 year to avert 1 HIV infection: 18 (9% CI : 11- Molina JM et al. CROI 201; Seattle, WA. #23LB Molina JM & al. N Engl J Med 201;373, ) 16 FTC/TDF is only licensed as a daily dosage for PrEP Conclusions On Demand oral PrEP with TDF/FTC was very effective with a 86% (9% CI: 40-99) reduction in HIV-incidence Adherence was good Safety of on demand TDF/FTC was overall similar to placebo except for gastrointestinal AEs No evidence of risk compensation ANRS Prevenir: Daily vs On-Demand TDF/FTC Oral PrEP Multicenter, open-label, prospective cohort study in Paris HIV-negative adults at high risk of HIV infection with inconsistent condom use; CrCl 0 ml/min; HBsAg negative in on-demand arm (N = 194)* Beginning of Study May 3, 2017 Daily TDF/FTC PrEP (n = 724) On-Demand TDF/FTC PrEP (2-1-1: 2 doses before sex, 1 dose QD for 2 days after sex) (n = 870) *Participants enrolled in arm of their choice with ability to switch; target enrollment, N = 3000 (8% MSM). Plus condoms, gels, risk reduction and adherence counseling, questionnaire on sexual behavior. Follow-up every 3 mos with STI and/or HIV testing, plasma creatinine measurement. Current Analysis July 2, 2018 End of Study May 31, 2020 Predominantly MSM (98.8%), white (8.2%); median age: 36 yrs Primary endpoint: 1% reduction in new HIV diagnoses among MSM in Paris vs rate reported by National Surveillance network in 2016 Secondary endpoints: PrEP adherence, sexual behavior, safety Molina J-M, et al. AIDS Abstract WEAE0406LB. 3

4 ANRS Prevenir: HIV Incidence Primary Endpoint HIV incidence/100 PY (9% CI) Mean follow-up: 7 mos Daily PrEP (443 PYFU) On-Demand PrEP* (06 PYFU) 0 (0-0.8) 0 (0-0.7) Overall HIV infections averted, n = 8 Assuming incidence of 9.17/100 PY as reported for ANRS IPERGAY study among participants in Paris Overall incidence of study discontinuation: 3.3/100 PY, including PrEP discontinuations of 1./100 PY Molina J-M, et al. AIDS Abstract WEAE0406LB. *On-demand PrEP strategy not FDA approved. Slide credit: clinicaloptions.c At Last Sexual Encounter, n (%) PrEP use Total Correct* ANRS Prevenir: PrEP Adherence, Sexual Behavior, Safety Daily PrEP (1088 Acts) 1068 (98.2) 1024 (9.8) On-Demand PrEP (1191 Acts) 967 (81.2) 931 (96.2) Condom use 206 (18.9) 28 (21.6) Incidence/10 0 PY (9% CI) Drug-related AEs Daily PrEP (443 PYFU) 11. ( ) Median episodes of condomless sex in previous 4 wks: 3-6 with daily PrEP, Grade ( with on-demand PrEP creatinine 19.7) Median sexual partners in CrCl (11.7- previous ml/min 19.2) 3 mos: 10-1 with daily PrEP, 6-10 with on-demand PrEP Most drug-related AEs were On-Demand PrEP (06 PYFU) 12. ( ) Grade 3/4 AEs 3.6 (2.1-.9) 4.7 ( ) Viral hepatitis 1.1 ( ) 1.2 ( ) ALT abnormality Grade 3/4 4.6 ( ) 2.3 ( ) 40.3 ( ) 2.0 ( ) 17.6 ( ) 17.6 ( ) Participants with adherence data, n = gastrointestinal *Per protocol, or at least 1 pill before and after within 24 hrs. No discontinuations due to drug-related Molina J-M, et al. AIDS Abstract WEAE0406LB. AEs Slide credit: clinicaloptions.c BC-CfE PrEP Enrolment & Prescription Request Form 1. Their identifiers 2. Your identifiers/location for Pickup 3. HIV Risk Category 4. Baseline Blood work Current negative HIV Ag/Ab test (within previous 1 days), egfr 60mL/min, Hepatitis B surface antigen status. Prior PrEP 6. Prescription quantity Initial Script: 30 days Prior PrEP: 90 days 4

5 PrEP Monitoring Baseline: HIV, renal, urine ACR, Hep B/C Serology, STI screen Start prescription for 30 days First Follow-up: Just before end of first month of use Check HIV, renal function again Get prescription refill: 90 days Every 3 months HIV/renal/STI checks STI screening We recommend STI screens q3months US PrEP demonstration project: 0.9% STI during followup If screening had been conducted only semi-annually or based on symptoms, 62 (34.3%) of participants with GC, 86 (41.0%) of participants with CT and 11 (20.4%) of participants with syphilis would have been missed, extending the period of infectivity by up to 3 months/case. Cohen, S. CROI 2016 Abstract 870. BC CfE PrEP Guidelines 2017 PrEP refills Book followup and review blood work prior to each fill easiest if scheduled a week before medications to run out Confirm HIV negative, adequate renal function, other STI monitoring A new signed prescription required for each fill Pre-printed PrEP refill form (sent automatically to prescriber) or any legal prescription format Nurse practitioners can be designated to refill 90 day maximum refill Fax and Allow at least business days for preparation Refill must be picked up within 30 days of prescription date PrEP monitoring Renal safety assessment of 2499 HIV-negative subjects in iprex study A mild, non-progressive decrease in Mean Change in CrCL (ml/min) creatinine clearance (Cockcroft-Gault), that was reversible and readily managed with routine monitoring Did not vary by race, age, or HTN history Affected by NSAID use -3.4 ml/min (+NSAID) vs ml/min (no NSAID), P = 0.04 Wk 4 At Stop Post-stop FTC/TDF Placebo P-value Change in Creatinine Clearance from Baseline (ml/min)* 0 10 FTC/TDF Placebo 2 9 * in 1,137 subjects Week Solomon M, et al. CROI 2013; Atlanta, GA. #998 30

6 Do not use daily TRUVADA in HIV-uninfected individuals for PrEP if CrCl is below 60 ml/min. If a decrease in CrCl is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use. Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in all individuals with mild renal impairment. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of VIREAD. TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) Do not use TRUVADA in HIV-uninfected individuals for PrEP if CrCl is below 60 ml/min. If a decrease in CrCl is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use. Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in all individuals with mild renal impairment. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of VIREAD. TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) Do not use TRUVADA in HIV-uninfected individuals for PrEP if CrCl is below 60 ml/min. If a decrease in CrCl is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use. Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in all individuals with mild renal impairment. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of VIREAD. TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) Do not use TRUVADA in HIV-uninfected individuals for PrEP if CrCl is below 60 ml/min. If a decrease in CrCl is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use. Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in all individuals with mild renal impairment. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of VIREAD. TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs)

7 Change from baseline, % 9/28/ P l a ce b o FT C/ T DF Spine (L1-L4) P = P = P = Mean, SE and P-values by linear mixed model Total Hip Week Week P l a ce bo FT C/ T D F Small but significant decreases in BMD at the spine, but not the hip, were observed in HIV-negative men randomized to FTC/TDF relative to placebo There were no differences in bone fractures between the groups (P=0.41) P l a ce b o FT C/ T DF P < P = P = 0.40 Mulligan K, et al. CROI Boston. # 94LB 37 In iprex, mean number of partners decreased and condom use increased over time 1,2 In Partners PrEP, unprotected sex decreased over time 3 1. Grant R, et al. CROI Boston. Oral # Grant R, et al. N Engl J Med 2010;30: Baeten J, et al. IAS 2011; Rome. Oral #MOAX Study iprex (36 on FTC/TDF, 64 on 1. Grant R, et al. N Engl J Med 2010;30: Lehman D, et al. CROI 2014; Boston. #90LB 3. Thigpen M, et al. N Engl J Med 2012;367: Van Damme L, et al. N Engl J Med 2012;367: Parikh, et al. CROI 2014; Boston. #94 Infected on Study Resistant to Infected, n FTC or TDF, n placebo) 103 Partners PrEP *2 (21 on FTC/TDF, 30 on TDF, 2 on placebo) TDF (9 on FTC/TDF, 24 on placebo) FEM-PrEP 4 68 (33 on FTC/TDF, 3 on placebo) None 3 on FTC/TDF (2 M184I/V, 1 M184I/V + K6R) * ; 1 on TDF (M184I/V); 2 on placebo (M184I/V) 1 on placebo (K6R <1%) 1 on placebo (M184V)*; 4 on FTC/TDF (M184V/I) VOICE on FTC/TDF (M184V/I) Unrecognized Baseline Infections d Infected, n 10 (2 on FTC/TDF, 8 on placebo) 18 (4 on FTC/TDF, 8 on TDF, 6 on placebo) 3 (1 on FTC/TDF, 2 on placebo) (1 on FTC/TDF, 4 on placebo) Resistant to FTC or TDF, n 2 on FTC/TDF (M184V/I); 1 on placebo (M184V) * 2 on FTC/TDF (M184V); 1 on TDF (K6R/K70E) 1 on FTC/TDF (K6R, M184V, A62V) Resistance development was rare but likely to occur when PrEP was given during unrecognized/acute infection None 22 2 on FTC/TDF (M184V) * Using ultra-deep sequencing Transmitted (primary) resistance can occur independent of PrEP, which likely explains resistance in the placebo arm 1 probable and 2 possible transmitted resistance; 1 uncertain timing of infection (HIV RNA detectable at first follow-up visit) Infection + incomplete suppression of replication by FTC/TDF selects resistance; transmitted (primary) resistance can occur, independent of PrEP, which likely explains resistance in the placebo arm 39 Conclusions We have the tools for HIV elimination expanding ART uptake and PrEP PrEP must be integrated into sexual health and primary care services as a component of HIV Prevention programming for MSM and other populations at risk Need to evaluate mechanisms to identify at-risk individuals and linkage to care STI services as entry point HIV testing services Develop linkages to primary care if PrEP not offered on-site 7