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1 Serodiscordant Couples Deborah Cohan, MD, MPH University of California San Francisco Department of Obstetrics, Gynecology, and Reproductive Sciences Bay Area Perinatal AIDS Center National Perinatal HIV Hotline and Clinicians Network Disclosure The following people have no relevant financial, professional or personal relationships to disclose: Faculty: Deborah Cohan, MD, MPH CNE Program Planner(s): Marsha Marecki, EdD, WHNP-BC Melanie Steilen, RN, BSN, ACRN Iris Stendig-Raskin, MSN, CRNP, WHNP-BC CNE Program Reviewer(s): Iris Stendig-Raskin, MSN, CRNP, WHNP-BC There are no commercial supporters of this activity. Accreditation status does not imply endorsement by NJSNA, CAI, or ANCC of any commercial products or services. Let s be in touch! Natl Perinatal HIV Hotline & Clinicians Network hour/day coverage Reproductive Infectious Disease pager (24/7) ReproID_HIV listserv: sweber@nccc.ucsf.edu

2 Overview Epidemiology of serodiscordance HIV prevention: Pre-Exposure Prophylaxis Reproductive rights and desires Contraception: condoms, IUDs Conception HIV+ female/hiv- male (H+F/H-M) HIV- female/hiv+ male (H-F/H+M) Will not discuss same-sex serodiscordance Epidemiology of HIV Heterosexual Serodiscordance HIV Cost and Services Utilization Study (1996) Probability sample, n=1421 (34,833, 53,177 ) Currently married or with heterosexual partner HIV + WOMEN HIV+ MEN 54% 52% Chen et al. Family Planning Perspectives, 2001 Heterosexual HIV Transmission Partners in Prevention Study (ACV vs plac.) 3297 couples with 86 linked transmissions Unadjusted risk per-unprotected act Male-to-female Female-to-male Each log viral load: 2.9-fold risk per-act Condom use: 78% risk per-act Hughes et al, JID 2012

3 PRE-EXPOSURE PROPHYLAXIS ( PREP ) Pre-Exposure Prophylaxis ARVs for HIV-uninfected prior to exposure Single or dual ARV Daily or intermittent Oral or topical iprex (n=2499 men/mtf sex with men) 44% (p < 0.005) 92% (p < 0.001) if detectable Rx Grant NEJM 2010 DOES PREP WORK FOR HETEROSEXUAL SERODISCORDANT WOMEN AND MEN?

4 Phase III RCT CAPRISA 004 Vaginal TDF 1% gel (2 pericoital doses/24hrs) 889 women, South Africa Efficacy 39% HIV 54% if >80% adherence 51% HSV Karim Science July 2010 VOICE Study (MTN 003) 5,029 women, 15 sites Phase IIb RCT (proof of concept; safety and efficacy) TDF gel vs oral TDF vs oral TDF/FTC vs plac gel/pills DSMB Oral TDF vs. placebo=futile comparison (9/16/2011) TDF gel vs. placebo=futile comparison (11/25/2011) Continuation of TDF/FTC vs. placebo Follow-up planned: open-label CHOICE study if protective effect found FEM-PrEP: Preliminary Results Phase III RCT: daily TDF/FTC vs. placebo Women, yo Study closure reported Feb 18, women screened 2056 enrolled HIV incidence: 4.7/100 P-Y (68 cases): HR 0.94 ( ) Adherence: 95% self report; 86% pill count Level 10ng/ml at 2 visits: 26% non-converters; 15% converters ~75% "not at high risk of HIV" Pregnancy: 11.2% TDF/FTC vs. 7.5% placebo Highest if OCPs Van Damme L et al. CROI; Seattle, 2012; Abst. 32LB.; Taylor D et al. International Microbicides Conference, Sydney, 2012.

5 Partners PrEP Study Phase 3 RCT: oral TDF vs. TDF/FTC vs. placebo 4758 HIV men/women in serodiscordant couples 9 trial sites in Africa July 10, 2011 DSMB meeting placebo arm closed HIV incidence: TDF 67% ; TDF/FTC 75% Partners PrEP Study >80% adherence, 95% efficacy Baeten/Donnell, CROI, 2012 TDF-2/Bostwana Phase III RCT: oral TDF/FTC vs. placebo yo men and women; n=1200 final analysis Overall HIV incidence: 62.6% with TDF/FTC 9/601 TDF/FTC vs. 24/599 placebo Women: 7 vs. 14 cases = 49.4% (p=0.11) Men: 2 vs. 10 cases = 80.1% (p=0.026) If drug supply confirmed, 77.9% with TDF/FTC Women: 3 vs. 13 cases = 75.5% (p=0.021) Men: 1 vs. 6 cases = 82.4% (p=0.065) Thigpen et al IAS, Rome, 2011

6 Summary of PrEP among Women: Adherence is everything! 1% TDF gel VOICE: no difference vs. placebo (why?) CAPRISA: 54% if >80% adherent Oral TDF VOICE: no difference vs. placebo (why?) Partners PrEP: 67% vs. placebo Oral TDF/FTC FEM-PrEP: no difference vs. placebo; adherence! Partners PrEP: 95% if >80% adherent TDF-2: 76% if drug supply confirmed Oral PrEP likely works if taken, but Who is a good candidate? Only SDC? Who will prescribe, monitor? HIV clinics not equipped to manage HIV-neg pts Women s health clinics not equipped to manage PrEP Who will pay (public, private sector)? How to optimize adherence in clinical setting? Alternative PrEP formulations? RAL vaginal gel, Injectable rilpivirine, Dapivarine ring WHAT ABOUT REPRODUCTIVE HEALTH AND SERODISCORDANT COUPLES?

7 A SERODISCORDANT COUPLE DOESN T WANT TO GET PREGNANT! Unintended pregnancy US general population 49% pregnancies unintended US, WIHS 232 adults 77% pregnancies while using contraception (vs. 60% HIV-) US 1090 adolescents 83.3% unplanned 49-52% HIV status known Italy 334 on ARV 57.6% unplanned Finer/Henshaw Perspec Sex Repro Health 2006; Massad AIDS 2004; Koenig AJOG 2007; Floridia Antivir Ther 2006 Contraception Failure (1st Year) Withdrawal/Rhythm Diaphragm Condom Pill 3% 6% 9% 14% 19% 20% Copper IUD 0.5% 0.8% Tubal Ligation 0.5% Injectable Progestin 0.2% Implants 0.1% Vasectomy 0.02% Typical Lowest Expected 0% 5% 10% 15% 20% Hatcher: Contraceptive Technology 16th Edition 1994.

8 IUDs are safe for HIV+ women No evidence of infectious complications 156 HIV+, 493 HIV- (Kenya; Copper IUD) Overall 24 mos: HR 1.0 ( ) No evidence of genital tract shedding of HIV Copper IUD n=98 (Kenya): 4 mos s/p insertion: OR 0.6 ( ) LNG-IUS (Mirena) n=12: no difference pre vs. post-insertion WHO Medical Eligibility Criteria category 2 Benefits generally outweigh theoretical or proven risk Morrison BJOG 2001; Sinei Lancet 1998; Richardson AIDS 1999; Heikinheimo Human Repro 2006 WE WANT TO GET PREGNANT! Fertility desires among HIV+ US reproductive-aged women 35% Cross-sectional, n=118 Rochester 20% yes, 15% unsure 12% tubal regret (4% tubal regret in US) Cross-sectional, n=182 Cross-sectional, n=181 HCSUS probability sample, n=1421 British Columbia 25.8% Baltimore 59% US, HCSUS 29% women (51% if in SDC) 28% men (46% if in SDC) ¹Chen Fam Plann Persp 2001, ²Stanwood Contraception 2007, ³Ogilvie AIDS 2007, 4 Oladapo J Natl Med Assoc 2005, Finocchario Kessler AIDS Behav 2010

9 Being infected with HIV dampens but does not come close to eliminating individuals desires and intentions to have children. Chen et al. Family Planning Perspectives, 2001 Conception for HIV+ female/hiv- male Timed coitus PrEP to HIV- man Vaginal insemination Timed, Unprotected Intercourse Timing unprotected sex with ovulation Barriero et al 62 HIV serodiscordant couples, 22 H+F/H-M Female receiving suppressive ART No cases of sexual HIV transmission P. Barriero, A. Duerr, K. Beckerman et al. Reproductive options for HIV-serodiscordant couples, AIDS Reviews, vol. 8, pp , 2006.

10 Vaginal Insemination #1: Ovulation detection #2: Semen collected into condom or clean cup #3: Semen aspirated into needleless syringe #4: Vaginal insemination by her or partner Vaginal Insemination by Female Vaginal Insemination by Male Partner

11 CONCEPTION FOR HIV- FEMALE/ HIV+ MALE Options for safe conception? COST=yes EFFECTIVENESS=?? Timed coitus PrEP/PEP for HIV- ARV for HIV+ Sperm washing + IUI Sperm washing + IVF-ICSI Adoption, sperm donation, not having children Timed Coitus Sex without a condom during ovulation Ovulation prediction: BBT, spinnbarkeit, urine kit French cohort 104 pregnancies among 92 HIV- ( ) ARV use in 21 men Monthly HIV testing during pregnancy 1/3 inconsistent or no condom use 4 conversions (all inconsistent condom use) 2 at 7 months gestation 2 postpartum Data pre-haart Mandelbrot Lancet 1997

12 Options for safe conception? COST=yes EFFECTIVENESS=?? Timed coitus PrEP/PEP for HIV- ARV for HIV+ Sperm washing + IUI Sperm washing + IVF-ICSI Adoption, sperm donation, not having children Semen and HIV Components HIV present? Spermatozoa NO Seminal fluid possible Non-sperm cells (wbc) possible Spermatozoa No CD4, CCR5 and CXCR4 receptors Electron microscopy suggesting HIV viral particles in sperm not replicated Baccetti J Cell Biol Assisted Reproduction: Sperm Washing Gradient centrifugation separates out 3 components Sperm washed x 2 Use in setting of HIV pioneered by Deborah Anderson & Augusto Enrico Semprini

13 What is done with washed sperm? Intrauterine Insemination (IUI) Europe/Israel (CREAThE), South America MA, CO, OR, MO, TX, CA In-vitro fertilization (IVF) Intracytoplasmic sperm injection (ICSI) Results of Assisted Reproduction Single case of seroconversion with sperm washing/iui (1990) No density gradient, no semen VL prior to IUI CDC recommends against insemination with semen from HIV-infected men IUI IVF/ ICSI 3900 cycles 1184 couples 11 studies 738 cycles 579 couples 10 studies Pregnancy/ cycle Cumulative pregnancy Spont. Abortion 18% 50% 15.6% 38.1% 52.9% 20.6% No seroconversions at birth, 3 months, 6 months Vitorino Fert Ster 2011; Sauer Hum Reprod. 2007, Savasi Hum Repro 2007, Politch, Repro Immun, 2002 Assisted Reproductive Services

14 Options for safe conception? COST=yes EFFECTIVENESS=?? Timed coitus PrEP/PEP for HIV- ARV for HIV+ Sperm washing + IUI Sperm washing + IVF-ICSI Adoption, sperm donation, not having children PrEP for Conception: PrEP-ception Observational cohort HIV+ men on ARVs; HIV-RNA <50 copies/ml x >3 mos HIV-RNA in semen undetectable at baseline Ovulation predictor kit TDF 36 hrs and 12 hours before sex Outcomes: March 2004-March H-F/H+M couples, 46 opted for PrEP Pregnancy rate per # attempts 1 attempt 26% 5 attempts 66% 12 attempts 75% No seroconversions or adverse events Vernazza et al AIDS 2011 Options for safe conception? COST=yes EFFECTIVENESS=?? Timed coitus PrEP/PEP for HIV- ARV for HIV+ Sperm washing + IUI Sperm washing + IVF-ICSI Adoption, sperm donation, not having children

15 Antiretrovirals=Enough? Transmission Barriero, 2006 Cohort 62 SDC 0 Attia, 2009 Meta-analysis 11 cohorts 5021 SDC Donnell Partners in Prevention, 2010 RCT ACV vs. placebo 3381 SDC 349 initiated ARVs 0 (HAART and VL <400) 1 case/273 P-Y w/in 18 days of ARV initiation (vs. 102/4558 P-Y) 92% HPTN 052, 2011 RCT immediate vs. delayed ARV (CD ) 1763 SDC Delayed: 3.1% Immediate: 0.1% 96% Barriero JAIDS 2006; Attia AIDS 2009, Donnell Lancet 2010; Cohen NEJM 2011 The future is now. Numerous methods to decrease HIV transmission while trying to conceive. Logistical, financial barriers Mindset that CD4 count should guide ART initiation Swiss Federal Commission for HIV/AIDS HIV-positive people with no other STIs and on effective antiretroviral therapy do not transmit HIV sexually Antiretroviral therapy is taken consistently. Viral load has been undetectable for at least six months. January 2008

16 Take it home Call the perinatal hotline available 24/7 Serodiscordance common in heterosexual HIV-affected couples PrEP for WSM and MSW likely effective if good adherence (adherence probably driven by perception of risk) Safer conception options = harm reduction Couples will try to conceive with or without your help so, you may as well help Thank you! Do we have to fill our patients lives with years or those years with life? Augusto Enrico Semprini