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
Background Globally, HIV-infection is estimated to affect over 34 million individuals, with 2/3 of infections heterosexually acquired % desire to conceive 2-6 Serodiscordant couples engage in transmission-risk behavior in order to conceive 7 1 UNAIDS Global Summary of HIV Infection, Stanwood NL et al., Contraception Finocchario-Kessler S et al., AIDS Behavior Cooper D et al., AIDS Behavior Schwartz SR et al., AIDS Behavio, Landovitz RJ et al., 20 th CROI 2013, Abstract # Brubaker SG et al., HIV Medicine 2010
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
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
Methods – 1: Model Inputs 1 Quinn TC et al., NEJM Hughes JP et al., J Inf Dis Gray RH et al., J Inf Dis Hollingsworth TD et al., J Inf Dis Wawer MJ et al., J Inf Dis Cohen MS et al., NE Engl J Med Grosskurth H et al., Lancet 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, Assumes early stage HIV Multiplicative FactorsEstimate (per sex act) RangeNotes Transmissability in late-stage HIV 4, Only applies if male not on ART Male on ART STIs Accounts for both increased susceptibly and transmissibility Pre-exposure Prophylaxis Data on subset of women
Methods – 1: Model Inputs 1 Quinn TC et al., NEJM Hughes JP et al., J Inf Dis Gray RH et al., J Inf Dis Hollingsworth TD et al., J Inf Dis Wawer MJ et al., J Inf Dis Cohen MS et al., NE Engl J Med Grosskurth H et al., Lancet 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, Assumes early stage HIV Multiplicative FactorsEstimate (per sex act) RangeNotes Transmissability in late-stage HIV 4, Only applies if male not on ART Male on ART STIs Accounts for both increased susceptibly and transmissibility Pre-exposure Prophylaxis Data on subset of women
Methods – 1: Model Inputs Base Transmission RateEstimate (per sex act) RangeNotes Male-female transmissability per unprotected sex act 1,2, Assumes early stage HIV Multiplicative FactorsEstimate (per sex act) RangeNotes Transmissability in late-stage HIV 4, Only applies if male not on ART Male on ART STIs Accounts for both increased susceptibly and transmissibility Pre-exposure Prophylaxis Data on subset of women 1 Quinn TC et al., NEJM Hughes JP et al., J Inf Dis Gray RH et al., J Inf Dis Hollingsworth TD et al., J Inf Dis Wawer MJ et al., J Inf Dis Cohen MS et al., NE Engl J Med Grosskurth H et al., Lancet Baeten JM et al. N Engl J Med 2012
Methods – 1: Model Inputs 1 Quinn TC et al., NEJM Hughes JP et al., J Inf Dis Gray RH et al., J Inf Dis Hollingsworth TD et al., J Inf Dis Wawer MJ et al., J Inf Dis Cohen MS et al., NE Engl J Med Grosskurth H et al., Lancet 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, Assumes early stage HIV Multiplicative FactorsEstimate (per sex act) RangeNotes Transmissability in late-stage HIV 4, Only applies if male not on ART Male on ART STIs Accounts for both increased susceptibly and transmissibility Pre-exposure Prophylaxis Data on subset of women
Methods – 1: Model Inputs 1 Quinn TC et al., NEJM Hughes JP et al., J Inf Dis Gray RH et al., J Inf Dis Hollingsworth TD et al., J Inf Dis Wawer MJ et al., J Inf Dis Cohen MS et al., NE Engl J Med Grosskurth H et al., Lancet 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, Assumes early stage HIV Multiplicative FactorsEstimate (per sex act) RangeNotes Transmissability in late-stage HIV 4, Only applies if male not on ART Male on ART STIs Accounts for both increased susceptibly and transmissibility Pre-exposure Prophylaxis Data on subset of women
Methods – 1: Model Inputs Base Transmission RateEstimate (per sex act) RangeNotes Male-female transmissability per unprotected sex act 1,2, Assumes early stage HIV Multiplicative FactorsEstimate (per sex act) Range Notes Transmissability in late-stage HIV 4, Only applies if male not on ART Male on ART STIs Accounts for both increased susceptibly and transmissibility Pre-exposure Prophylaxis Data on subset of women 1 Quinn TC et al., NEJM Hughes JP et al., J Inf Dis Gray RH et al., J Inf Dis Hollingsworth TD et al., J Inf Dis Wawer MJ et al., J Inf Dis Cohen MS et al., NE Engl J Med Grosskurth H et al., Lancet Baeten JM et al. N Engl J Med 2012
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
Potential Outcomes
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
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
Results - 1: Optimal Scenario * 27.6% 29.5% 30.6%30.7% p = NS ⌘ ⌘ All other pair-wise comparisons p < *Assumes STIs diagnosed and treated in both partners
Results - 2: Suboptimal Scenario * ⌘ 17.0% 24.1% 29.3% 30.3% ⌘ All pair-wise comparisons p <
*Assumes STIs diagnosed and treated in both partners Results - 3: Both Scenarios * 17.0% 24.1% 29.3% 30.3% p < % 29.5% 30.6%30.7% 17.0% 24.1% 29.3% 30.3%
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
Clinical Application Prototype
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
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)
Acknowledgements UCLA AIDS Institute and the UCLA Center For AIDS Research, AI28697 NIH/NIDA K23DA (PI: Landovitz) NIH/NIAID K24AI56933 (PI: Currier) NIH/NICDH R01HD (PI: Wagner)
Thank You!
Outcome: HIV+, no child 7.4% 2.9% 0.6%0.2% 31.1% 15.1% 3.5% 1.3%