Projeto Praça Onze Universidade Federal do Rio de Janeiro Pre-Sexual Exposure Prophylaxis (PrEP) Mauro Schechter Principal Investigator, Projeto Praça Onze Professor of Infectious Diseases Universidade Federal do Rio de Janeiro 1st Andean Pacific Workshop on HIV&Hepatitis Santiago, Chile, 30 June - July 1, 2017
Reducing HIV Infections Antiretrovirals for Prevention PrEP PEP Treatment as prevention Uninfected Person Drug use Behavior Change Condom Use Sexual behavior change Behavior Change for Prevention
PEP for HIV: Rio de Janeiro Prospective Cohort Study Most common reasons for not starting PEP: Did not consider as high-risk practice Sex with a steady partner Worried about side effects
What is PrEP? (Pre-Exposure Prophylaxis) PrEP as a concept is to take a medicine or product to prevent disease for the period of risk exposure Malaria prophylaxis PCP prophylaxis For HIV, PrEP is the use of antiretroviral medications or other products to reduce the risk of HIV acquisition in HIV-negative people
Why Tenofovir/Emtricitibine Truvada Limited side effects and strong safety profile Relatively long duration of action in the body Less likelihood of drug resistance Strong protective effect against in animal models
Initial PrEP Trials 2004-2005 Location Population Outcome Cambodia 960 high risk women Oral TDF Safety and efficacy Nigeria 400 women Oral TDF, safety Cameroon 400 women Oral TDF, safety Ghana 936 women Oral TDF, safety Malawi 400 men Oral TDF, safety Study halted 2004 Study halted 2005 after enrolling 120 Study halted; 400 enrolled Comparable safety and AE profile Stopped before enrolling
Initial PrEP Trials 2004-2005 International AIDS Conference 2004
CAPRISA 004 Safety and effectiveness of 1% tenofovir gel Coitally-related gel use Insert 1 gel up to 12 hours before sex, insert 1 gel as soon as possible within 12 hours after sex, no more than two doses in 24 hours Karim S, XVIII International AIDS Conference in Vienna, Austria, on July 20, 2010
Caprisa 004: HIV infection rates in the tenofovir and placebo gel groups 0.20 Probability of HIV infection 0.18 0.16 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0.00 Months of follow-up 0.0 0.5 6 1.0 12 1.5 18 2.0 24 2.5 30 Cumulative HIV endpoints 37 65 Years 88 97 98 Cumulative women-years 432 833 1143 1305 1341 HIV incidence rates (Tenofovir vs Placebo) Effectiveness (p-value) 6.0 vs 11.2 5.2 vs 10.5 5.3 vs 10.2 5.6 vs 9.4 5.6 vs 9.1 47% (0.069) 50% (0.007) 47% (0.004) 40% (0.013) Placebo Tenofovir 39% (0.019) p=0.019 p=0.017 Karim S, XVIII International AIDS Conference in Vienna, Austria, on July 20, 2010
4,905 Screened 842 Eligible, Not Enrolled 2,499 3,341 Randomized Eligible 1,564 (32%) Ineligible 410 HIV Positive 405 Lab Ineligible 247 Low HIV Risk 502 Other Reasons 1,251 (50%) Randomized to FTC/TDF 1,248 (50%) Randomized to Placebo 25 No Follow Up HIV Test 23 No Follow Up HIV Test 1,226 (98%) Followed 1,225 (98%) Followed
Efficacy(MITT) 44% (15-63%) Number of infections: 64 36
Divergent PrEP efficacy trial results Study Population N Results iprex MSM 2499 44% efficacy FTC/TDF TDF2 Study Young men and women 1200 62% efficacy FTC/TDF Partners PrEP Study Heterosexual couples 4758 67% efficacy TDF 75% efficacy FTC/TDF FEM-PrEP Women 2021 6% efficacy FTC/TDF VOICE Women 5029 No efficacy TDF or FTC/TDF or vaginal TFV gel
iprex TDF intracellular levels and incidence Predefined pharmacology substudy Levels measured in all active arm participants Estimated number of doses based on STRAND trial (open-label crossover study of oral TDF in 24 HIV negative adults, each of whom received two, four, and seven doses per week for 6 weeks.) Quantification of concentrations of drugs associated with protection Estimated reduction in risk of infection (95% CI) 2 doses/week 76% (56-96%) 4 doses/week 96% (90->99%) 7 doses/week 99% (96->99%) Anderson, Sci Transl Med 2012
Drug levels and Efficacy in Oral PrEP Randomized Clinical Trials (TDF/FTC)) BTS
PROUD Pilot GMSM reporting UAI last/next 90days; 18+; and willing to take a pill every day Randomize HIV negative MSM (exclude if treatment for HBV/Truvada contra-indicated) Risk reduction includes Truvada NOW Risk reduction includes Truvada AFTER 12M Follow 3 monthly for HIV and STIs up to 24 months McCormack, Dunn et al, Lancet, 09 September 2015
Participant randomization 544 enrolled 275 assigned to IMMEDIATE 269 assigned to DEFERRED
HIV Incidence Group No. of infections Follow-up (PY) Incidence (per 100 PY) 90% CI Overall 23 465.6 4.9 3.4 6.8 Immediate 3 243.5 1.2 0.4 2.9 Deferred 20 222.1 9.0 6.1 12.8 Effectiveness =86% (90% CI: 64 96%) P value =0.0001 Rate Difference =7.8 (90% CI: 4.3 11.3) Number Needed to Treat =13 (90% CI: 9 23)
www.ipergay.fr Study Design Double-Blinded Randomized Placebo-Controlled Trial HIV negative high risk MSM Condomless anal sex with > 2 partners within 6 m egfr > 60 ml/mn Full prevention services* TDF/FTC before and after sex Full prevention services* Placebo before and after sex * Counseling, condoms and gels, testing and treatment for STIs, vaccination for HBV and HAV, PEP End-point driven study : with 64 HIV-1 infections, 80% power to detect a 50% relative decrease in HIV-1 incidence with TDF/FTC (expected incidence: 3/100 PY with placebo) Follow-up visits: month 1, 2 and every two months thereafter
Ipergay : Event-Driven iprep 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 Friday Saturday Sunday Monday Tuesday Wednesday Thursday Friday Saturday Sunday
KM Estimates of Time to HIV-1 Infection (mitt Population) 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
Adherence by Pill Count TDF/FTC Nb pills/month Placebo Nb pills/month 4.00 0 or missing ]1 4] 2.00 ]4 11] 3.00 ]11 18] 4.00 ]18 25] ]25 30] 4.00 0 or missing ]1 4] 2.00 ]4 11] 3.00 ]11 18] 4.00 ]18 25] ]25 30]
PrEP Effectiveness by Adherence in Open-label and Observational Studies Intervention (TDF/FTC) MSM (iprex OLE) Heterosexual discordant couples (Partners PrEP OLE) MSM (NIAID Demo Project) MSM (Kaiser SF) Prevention effectiveness 0 seroconversions with protective drug levels 96% reduction from expected incidence 0 seroconversions with protective drug levels 0 seroconversions over 388 persons/years of PrEP use Adherence by drug level testing Protective drug levels found at 33% of visits 2 seroconversions in inconsistent PrEP users, neither with positive partners on ART 80% with protective drug levels at 48 weeks - Sources: Grant 2014, Baeten CROI 2015 http://www.croiwebcasts.org/console/player/25541?mediatype=slidevideo&liu 2015, Volk 2015,
32 US PrEP Demonstration Projects Seroconversion Rates Men n=7002 Women n=1388 Transgender Women* n=76 Total exposure, p-y 6214 788 48 Number of HIV-1 seroconversions 64 2 1 Rate/100 p-y (95% CI) 1.03 (0.80-1.32) 0.25 (0.03-0.92) 2.07 (0.05-11.52) *Includes genderqueer, androgynous designations. McCallister, ASM Microbe 2016, Abs 371LB.
TDF/FTC Both are cleared by the kidney Neither are metabolized in the liver No important drug interactions, including with methadone, buprenorphine, or naloxone Appears to be safe in pregnancy and breastfeeding
PrEP: No evidence of increases in behavioral risk Sexual risk-msm Injection risk Source: Marcus, Julia L., et al. PloS One 2013 Source: Martin, Michael, et al. PloS One 2014
PrEP: Side Effects and Safety Start-up syndrome <10% with nausea, vomiting, cramps Lasts a few days in most patients Renal safety Small decrease in creatinine clearance Returns to normal after PrEP use discontinued Bone safety Small decrease in bone mineral density Not associated with increased fractures Returns to normal after PrEP use discontinued
Drug resistance in PrEP users who acquire HIV infection Most PrEP patients remain HIV-uninfected PrEP patients who stop taking their drug or take it infrequently have a risk of developing resistance or acquiring a drug-resistant virus from a partner 2 cases of acquiring a multiple-drug resistant virus out of ~100,000 persons currently on PrEP PrEP patients who are fully adherent to daily dosing can (very rarely) acquire HIV infection 1 case reported out of ~100,000 persons currently on PrEP Virus had no drug resistance mutations
CDC PrEP Guidelines Summary Component Risk assessment Lab screen before prescribing Prescribing Follow-up Discontinuation Recommendation PrEP is indicated for adult MSM, heterosexually-active women and men, and PWID who are at substantial risk for HIV infection through ongoing exposures HIV test, test for acute HIV infection if symptomatic Adequate renal function (ecrcl 60 ml/min) 1 daily TDF/FTC tablet (Truvada) Prescribe no more than 90 day supply Test for HIV and pregnancy every 3 months Test for sexually transmitted infections (STIs) every 6 months, even if asymptomatic Counsel on risk reduction and medication adherence Test creatinine clearance at 3 months and then every 6 months At least every 12 months, assess risk behavior, medication adherence, and need for continuing PrEP use
People at Substantial Risk of HIV Infection (Meet Indications for PrEP) MSM Heterosexual Men and Women PWID In the past 6 months: HIV-positive sexual partner Bacterial STI (esp. GC or syphilis) More than one sex partner not known to have HIV infection Inconsistent or no condom use Commercial sex work In the past six months HIV-positive injecting partner Sharing injection equipment In high-prevalence area
Excluding Acute or Established HIV Infection Preferred www.cdc.gov/hiv/pdf/guidelines/prepguidelines2014.pdf
Discontinuing PrEP For HIV seroconversion Offer immediate transition to treatment regimen Document HIV resistance test results For HIV negative persons Document HIV and creatinine test results Assure that HIV prevention plan is in place If chronic hepatitis B infection, monitor liver function and if a flare occurs, treat in consultation with expert
PrEP Uptake in the US Unique individuals starting TDF/FTC for PrEP in US by gender (1Q2013-1Q2016) Bush,S. et al. HIV Drug Therapy 2016; Glasgow, Scotland
PrEP Vs Estimated New HIV Infections Total PrEP Utilization by Race/Ethnicity, Sept 2015, US a Estimated New HIV Infections, 2014, US b AA White Hispanics Asians Multiracial/Other a. These data represent 43.7% (n=21,463) of unique individuals who have started TVD for PrEP from 2012-3Q2015. b. Other indicates American Indian or Alaska Native, and Native Hawaiian or other Pacific Islander. CDC. HIV Surveillance Report, 2014 Bush S, et al. ASM/ICAAC 2016; Boston, MA. #2651
PrEP Care Continuum, Young MSM, Washington DC, 2016 R4P 2016 Levy Poster P09.15
Product pipeline for PrEP Pill Gel Vaginal film Vaginal ring Injectable Ideal: long acting, safe, effective, low cost and user-friendly Maximize choice & optimize effectiveness Potential for combinations of drugs to increase effectiveness
Acknowledgments Simon Collins Ken Dominguez Bob Grant Esper Kallás Andréa Lemos Ken Mayer Sheena McCormick Jean-Michel Molina Kimberly Page Dawn Smith