1. Benefits of PrEP as an adjunctive method of HIV prevention during attempted conception between HIV-uninfected women and HIV- infected male partners: A modeling approach R. Hoffman 1, R. Vardavas 2, A. Jaycocks 2, G. Wagner 2, J. Lake 1, D. Mindry 3, J. Currier 1, R. Landovitz 1 1 David Geffen School of Medicine at University of California, Los Angeles, 2 RAND Corporation, Santa Monica, 3 University of California, Los Angeles, Center for Culture and Health, Department of Psychiatry and Behavioral Sciences

2. Background Globally, HIV-infection is estimated to affect over 34 million individuals, with 2/3 of infections heterosexually acquired 1 20-75% desire to conceive 2-6 Serodiscordant couples engage in transmission-risk behavior in order to conceive 7 1 UNAIDS Global Summary of HIV Infection, 2011 2 Stanwood NL et al., Contraception 2007 3 Finocchario-Kessler S et al., AIDS Behavior 2010 4 Cooper D et al., AIDS Behavior 2009 5 Schwartz SR et al., AIDS Behavio, 2012 6 Landovitz RJ et al., 20 th CROI 2013, Abstract #1069 7 Brubaker SG et al., HIV Medicine 2010

3. Background Options include self insemination or assisted reproduction Optimal procedures are often prohibitive due to cost and lack of widespread availability (sperm washing+adjunctive) Protection against HIV transmission during conception among serodiscordant couples remains challenging Less costly menu of options : Timing of intercourse, STI treatment, PrEP, ART for positive partner. And of course, the good-old-fashioned approach

4. Aims To evaluate the additive benefit of PrEP for successful conception, without HIV transmission in the setting of an HIV+ male and HIV- female – To explore the relative benefits of ART and PrEP, singly and in combination across multiple clinical scenarios – To evaluate the impact of maternal age on annual successful conception/HIV non-transmission probabilities Primary outcome of interest is a previously HIV- woman remaining HIV-uninfected and successfully conceiving and delivering a child

5. Methods – 1: Model Inputs 1 Quinn TC et al., NEJM 2000 2 Hughes JP et al., J Inf Dis 2012 3 Gray RH et al., J Inf Dis 2012 4 Hollingsworth TD et al., J Inf Dis 2008 5 Wawer MJ et al., J Inf Dis 2005 6 Cohen MS et al., NE Engl J Med 2011 7 Grosskurth H et al., Lancet 1995 8 Baeten JM et al. N Engl J Med 2012 Base Transmission RateEstimate (per sex act) RangeNotes Male-female transmissability per unprotected sex act 1,2,3 0.00220.0010-0.0031 Assumes early stage HIV Multiplicative FactorsEstimate (per sex act) RangeNotes Transmissability in late-stage HIV 4,5 1.821.29-2.35 Only applies if male not on ART Male on ART 6 0.040.01-0.27 STIs 7 2.32.0-23.0 Accounts for both increased susceptibly and transmissibility Pre-exposure Prophylaxis 8 0.340.16-0.72 Data on subset of women

6. Methods – 1: Model Inputs 1 Quinn TC et al., NEJM 2000 2 Hughes JP et al., J Inf Dis 2012 3 Gray RH et al., J Inf Dis 2012 4 Hollingsworth TD et al., J Inf Dis 2008 5 Wawer MJ et al., J Inf Dis 2005 6 Cohen MS et al., NE Engl J Med 2011 7 Grosskurth H et al., Lancet 1995 8 Baeten JM et al. N Engl J Med 2012 Base Transmission RateEstimate (per sex act) RangeNotes Male-female transmissability per unprotected sex act 1,2,3 0.00220.0010-0.0031 Assumes early stage HIV Multiplicative FactorsEstimate (per sex act) RangeNotes Transmissability in late-stage HIV 4,5 1.821.29-2.35 Only applies if male not on ART Male on ART 6 0.040.01-0.27 STIs 7 2.32.0-23.0 Accounts for both increased susceptibly and transmissibility Pre-exposure Prophylaxis 8 0.340.16-0.72 Data on subset of women

7. Methods – 1: Model Inputs Base Transmission RateEstimate (per sex act) RangeNotes Male-female transmissability per unprotected sex act 1,2,3 0.00220.0010-0.0031 Assumes early stage HIV Multiplicative FactorsEstimate (per sex act) RangeNotes Transmissability in late-stage HIV 4,5 1.821.29-2.35 Only applies if male not on ART Male on ART 6 0.040.01-0.27 STIs 7 2.32.0-23.0 Accounts for both increased susceptibly and transmissibility Pre-exposure Prophylaxis 8 0.340.16-0.72 Data on subset of women 1 Quinn TC et al., NEJM 2000 2 Hughes JP et al., J Inf Dis 2012 3 Gray RH et al., J Inf Dis 2012 4 Hollingsworth TD et al., J Inf Dis 2008 5 Wawer MJ et al., J Inf Dis 2005 6 Cohen MS et al., NE Engl J Med 2011 7 Grosskurth H et al., Lancet 1995 8 Baeten JM et al. N Engl J Med 2012

8. Methods – 1: Model Inputs 1 Quinn TC et al., NEJM 2000 2 Hughes JP et al., J Inf Dis 2012 3 Gray RH et al., J Inf Dis 2012 4 Hollingsworth TD et al., J Inf Dis 2008 5 Wawer MJ et al., J Inf Dis 2005 6 Cohen MS et al., NE Engl J Med 2011 7 Grosskurth H et al., Lancet 1995 8 Baeten JM et al. N Engl J Med 2012 Base Transmission RateEstimate (per sex act) RangeNotes Male-female transmissability per unprotected sex act 1,2,3 0.00220.0010-0.0031 Assumes early stage HIV Multiplicative FactorsEstimate (per sex act) RangeNotes Transmissability in late-stage HIV 4,5 1.821.29-2.35 Only applies if male not on ART Male on ART 6 0.040.01-0.27 STIs 7 2.32.0-23.0 Accounts for both increased susceptibly and transmissibility Pre-exposure Prophylaxis 8 0.340.16-0.72 Data on subset of women

9. Methods – 1: Model Inputs 1 Quinn TC et al., NEJM 2000 2 Hughes JP et al., J Inf Dis 2012 3 Gray RH et al., J Inf Dis 2012 4 Hollingsworth TD et al., J Inf Dis 2008 5 Wawer MJ et al., J Inf Dis 2005 6 Cohen MS et al., NE Engl J Med 2011 7 Grosskurth H et al., Lancet 1995 8 Baeten JM et al. N Engl J Med 2012 Base Transmission RateEstimate (per sex act) RangeNotes Male-female transmissability per unprotected sex act 1,2,3 0.00220.0010-0.0031 Assumes early stage HIV Multiplicative FactorsEstimate (per sex act) RangeNotes Transmissability in late-stage HIV 4,5 1.821.29-2.35 Only applies if male not on ART Male on ART 6 0.040.01-0.27 STIs 7 2.32.0-23.0 Accounts for both increased susceptibly and transmissibility Pre-exposure Prophylaxis 8 0.340.16-0.72 Data on subset of women

10. Methods – 1: Model Inputs Base Transmission RateEstimate (per sex act) RangeNotes Male-female transmissability per unprotected sex act 1,2,3 0.00220.0010-0.0031 Assumes early stage HIV Multiplicative FactorsEstimate (per sex act) Range Notes Transmissability in late-stage HIV 4,5 1.821.29-2.35Only applies if male not on ART Male on ART 6 0.040.01-0.27 STIs 7 2.32.0-23.0 Accounts for both increased susceptibly and transmissibility Pre-exposure Prophylaxis 8 0.340.16-0.72 Data on subset of women 1 Quinn TC et al., NEJM 2000 2 Hughes JP et al., J Inf Dis 2012 3 Gray RH et al., J Inf Dis 2012 4 Hollingsworth TD et al., J Inf Dis 2008 5 Wawer MJ et al., J Inf Dis 2005 6 Cohen MS et al., NE Engl J Med 2011 7 Grosskurth H et al., Lancet 1995 8 Baeten JM et al. N Engl J Med 2012

11. Methods-2 Additional Model Inputs: – Probability of conception by age – Probability of successful delivery by age – Number of unprotected sex acts to achieve successful conception Classification and Regression Tree (CART) analysis was used to establish hierarchy of importance of parameters to outcome of interest

12. Potential Outcomes

14. 0-60 Sex Acts distributed over Entire Menstrual Cycle (Sampled around 15) Sub-optimal Scenario 0-12 Sex Acts localized to Ovulation Period (Sampled around 3) Optimal Scenario

15. 0-60 Sex Acts distributed over Entire Menstrual Cycle (Sampled around 15) Sub-optimal Scenario 0-12 Sex Acts localized to Ovulation Period (Sampled around 3) Optimal Scenario

16. Results - 1: Optimal Scenario * 27.6% 29.5% 30.6%30.7% p = NS ⌘ ⌘ All other pair-wise comparisons p < 0.0001 *Assumes STIs diagnosed and treated in both partners

17. Results - 2: Suboptimal Scenario * ⌘ 17.0% 24.1% 29.3% 30.3% ⌘ All pair-wise comparisons p < 0.0001

18. *Assumes STIs diagnosed and treated in both partners Results - 3: Both Scenarios * 17.0% 24.1% 29.3% 30.3% p < 0.0001 27.6% 29.5% 30.6%30.7% 17.0% 24.1% 29.3% 30.3%

19. Results - 2 CART analysis of the outcome of an HIV- uninfected woman delivering a child – In the optimal clinical scenario, age is the most influential factor – In the sub-optimal clinical scenario, for women <40, ART treatment is next-most important parameter

20. Clinical Application Prototype

21. Conclusions Based upon our inputs to our model, PrEP provides little added benefit when all are true: – The HIV-infected male partner is on ART – Unprotected intercourse is limited to the period of ovulation – STIs are diagnosed and treated in both partners In the timing-optimized scenario, there is little absolute difference between any of the 4 strategies In the non-timing optimized scenario, ART treatment of the HIV+ male partner drives the differences between strategies The model highlights that younger age is associated with the desired outcome

22. Public Health Implications and Caveats Model results are limited by inputs, and do not substitute for clinical decision making on individual basis These data are reassuring that patients can have desired results without the addition of PrEP if they are motivated to optimize other modifiable risk factors (provided ART is available)

23. Acknowledgements UCLA AIDS Institute and the UCLA Center For AIDS Research, AI28697 NIH/NIDA K23DA026308 (PI: Landovitz) NIH/NIAID K24AI56933 (PI: Currier) NIH/NICDH R01HD072633 (PI: Wagner)

24. Thank You!

25. Outcome: HIV+, no child 7.4% 2.9% 0.6%0.2% 31.1% 15.1% 3.5% 1.3%