Biomedical Interventions and Risk Compensation Jean-Michel Molina Saint-Louis Hospital, University of Paris Diderot, ANRS (National Agency for AIDS Research) Inserm U941, Paris, France STI 2018 Understanding and Adressing the HIV and STI syndemics Amsterdam, July 21-22, 2018 1

Disclosures Advisory boards: Gilead, Merck, ViiV, Teva Grants: Gilead Stock: none

Biomedical Interventions to Prevent HIV-Infection Condoms Male Circumcision Post-Exposure Prophylaxis (PEP) Treatment of HIV-infection (TASP) Pre-Exposure Prophylaxis (PrEP) Vaccine

Risk Compensation Critical issue in the public health implementation of biomedical interventions: Could increased risky sexual behavior counteract the biological efficacy against HIV? Risk management plan: Assess the public health impact of PrEP Risk compensation: Adjustment of behavior in response to a perceived reduction in risk Behavioral adaptation: Behavioral changes triggered by a safety measure: reduction in condom use Behavioral disinhibition: Lack of restraint with more risk taking behaviors: increasing Nb of partners, Nb of sexual acts, chemsex… STIs: Best objective measure of risk compensation and most feared consequence of risk compensation Individual vs. population impact of biomedical interventions: risk compensation among people not using PrEP/TASP Cassell BMJ 2006

PEP and Changes in Sexual Behavior 76% 85% 397 adults (92% MSM) enrolled in a PEP study in SF with 4 weeks of PEP and 5 counseling sessions Over 12 months of follow-up significant reduction in condomless sex and no increase in STIs rates 17% needed an another course of PEP 4 HIV seroconversion, 3 in MSM with an HIV incidence of 1.2/100 PY Martin JN et al. AIDS 2004

Effect of Antiretroviral Therapy on Sexual Behavior Unprotected sex lower in pts on ART vs no ART OR: 0.73 (95%CI: 0.6-0.8) STI diagnoses lower in pts on ART vs no ART OR: 0.58 (95% CI: 0.3-1.0) No change in injection risk-taking behavior (OR: 0.90 (95% CI: 0.6-1.3) Doyle JS. Et al CID 2014

Condomless Sex with HIV Negative (or unknown status) Partners in MSM IMM ART (N=1314) DEF ART (N=1306) P Value Heterosexual (N=1012) (N=1053) P Value Baseline 19.8% 20.0%   13.2% 11.7% 12 mths 12.7% 13.1% 0.76 10.8% 8.3% 0.066 24 mths 16.3% 14.7% 0.32 9.5% 5.6% 0.004 CLS-D declined over time in both arms CLS-D did not differ in MSM by randomisation arm at 12 or 24 months CLS-D in heterosexuals at 24 months higher with immediate ART Rodger A et al. Presented at AIDS 2016, Durban $Baseline 2 estimates exclude those diagnosed less than 3 months before completing the baseline TRB CRF, who may be reporting pre-diagnosis sexual behaviour. I MM ARM =randomised to immediate ART. DEF ARM = randomised to deferred ART. P values by Chi-squared tests.

New diagnoses of HIV and STIs from 1996 to 2015 in MSM in England Figure 10 New diagnoses of HIV and STIs from 1996 to 2015 in MSM in England Unemo M et al. Lancet Infect Dis 2017

PrEP and Risk Compensation What about PrEP:

Condom Use in Ipergay Proportion Pts with Condomless Sex at Last Receptive Anal Intercourse P for Trend = 0.0003 No significant change in median Nb of partners or sexual acts during the open-label phase (p=0.42 and p=0.12) No significant increase in incidence rate of a first STI (49 vs 59 per 100 PY in the double-blinded and OLE phases (p=0.11) Molina et al Lancet HIV 2017

Community-Level Changes in Condom use with Casual Partners Among MSM Figure 11 30% 1% 46% The Lancet Infectious Diseases 2017 17, e235-e279DOI: (10.1016/S1473-3099(17)30310-9) Holt M. et al . Lancet HIV 2018 Copyright

Trends in STIs and HIV Testing and Treatment Uptake among MSM 2013 2014 2015 2016 2017 PrEP use in past 6 months 2% 7% 24% Any STI in past 12 months 17% 18% 20% 23% 31% HIV test in past 6 months 59% 65% 66% 72% 77% HIV+ on ART 79% 86% 87% 90% 94% HIV+ with VL undetectable 84% 88% 89% Crystalmet in past 6 months 15% 16% 13% 14% Increase in PrEP uptake and decrease in condom use coincided with a reduction in new HIV diagnoses in MSM by 16% in Victoria and 11% in NSW Holt M. et al. Lancet HIV 2018

STIs in PROUD - Randomized Phase Mc Cormack et al Lancet 2015 13

PROUD - Post-Randomized Phase Rate of sexually transmitted infections (STIs)   Randomized phase Post-randomized phase Rate (n/100PY) IMM DEF Rectal GC 35.3 (81/229) 33.0 (67/203) 31.4 (129/411) 32.6 (116/356) Rectal CT 33.6 (77/229) 21.7 (44/203) 33.1 (136/411) 29.8 (106/356) Syphilis 19.4 (46/237) 13.2 (28/212) 31.1 (132/424) 25.9 (93/359) The incidence of rectal infections was high in both groups and phases There was an increase in syphilis in the post-deferred phase White E et al. IAS 2017. Paris, France. Oral #TUAC0101

Meta-Analyis of Effect of PrEP on STIs Diagnosis among MSM Significant increase in any rectal STI diagnosis (OR: 1.39, 95% CI: 1.03-1.87) Significant increase in rectal chlamydia (OR: 1.59, 95% CI: 1.19-2.13) Increase in STIs rates in more recent studies (OR: 1.47, 95% CI: 1.05-2.05) Traeger MW et al. CID 2018

Experience from a PrEP Clinic in Paris Prospective Open-label Cohort Follow-up and HIV incidence 1069 pts came for a first visit from 11/2015 to 05/2017 HIV-infection at first visit n=10 (0.9%) 1049 started PrEP: 75% « On Demand » 486 PY of FU (median follow-up of 5.6 months) 15% lost to FU (changed center, moved, stable couple, other) 4 breakthrough HIV-infection (2 daily) HIV incidence: 0.8/100 PY Changes in Sexual behavior (from Baseline to Month 12) Condomless sex at last intercourse increased from 53% to 79% Modest increase in overall STIs rates from 14.6% to 19.2% Significant increase in rectal chlamydia or gonorrheal infections (11% to 20.4%, p<10-4) Noret M. et al. AIDS 2018 (in press)

Increase in Rectal Chlamydia Infections in France among MSM before PrEP Nb rectal chlamydia infections 1600 1400 non L strains 1200 LGV Non L 1000 LGV % HIV + 76 36 800 600 400 200 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Chlamydia French Reference National Center LGV Network 2002-2016

Partners not Condom Use Predicting Factors of STIs Drive STIs Rates SPARK: Community-based PrEP demonstration project in NYC 261 MSM followed until M12 after PrEP intitiation Decrease in condom use: 61% to 46% Predicting Factors of STIs aOR 95% CI p Age < 25 years old 3.67 1.11-12.25 < 0.05 > 5 casual partners at BL 2.80 1.43-5.50 < 0.01 STIs in 6 months pre-PrEP 2.22 1.07-4.59 <0.05 Increase in Nb casual partners 2.16 1.07-4.38 Neither overall condom use nor change in condom use were associated with STIs diagnosis in the 12 months following PrEP uptake Golub S et al. CROI 2018 Boston 18

Testing for STIs in Last 12 months among MSM – an eCDC/Hornet Survey Of those currently not on PrEP Of those currently on PrEP Men taking PrEP test more often for STIs Noori T. et al EACS 2017

Increases in Extra-Genital Testing in the US (2013-2015) % increase in Ct and GC NAAT volume at LabCorp, Specimen type /pathogen Male rectal Ct/GC (n) o/p GC (n) Female urogenital CT/GC. ages 15-24 (n) urethral Ct/GC, (n) 2013 (Q2) 4,942 6,603 249,854 138,393 2015 (Q4) 12,973 18,458 384,047 209,243 Schillinger JA et al. 2018 National STD Prevention Conference

Incidence of Gonorrhea and Chlamydia among MSM using PrEP Over the next decade, 40% of NG and CT infections would be averted (40% PrEP coverage) Jenness et al CID 2017

Summary TASP/PrEP implementation: high rates of condomless sex and STIs did not undermine high efficacy against HIV transmission or acquisition New interventions should be accompanied by measures to reinforce individual perception of STIs risk and behavioral changes including condom use Frequent testing, early diagnosis and treatment and better partner notification should help reduce HIV and STIs incidence PrEP cohorts are a unique opportunity to assess new strategies (behavioral and biomedical) to prevent STIs STIs should not be an excuse to deny PrEP access Community and individuals empowerment is key to counter the increase in STIs associated with biomedical interventions

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