Fertility Desires/Management of Serodiscordant HIV + Couples

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1 Fertility Desires/Management of Serodiscordant HIV + Couples William R. Short, MD, MPH Assistant Professor of Medicine Division Of Infectious Diseases Jefferson Medical College of Thomas Jefferson University

2 Outline Epidemiology of HIV In Women Serodiscordant Couples Management of Serodiscordant couples Focus on ART as prevention Male + Female Male Female + Prep-ception

3 Global Impact of HIV on Women Worldwide (2013) 30 million adults living with HIV 49% are women United States Proportion of HIV/AIDS cases in women have tripled from 1985 to 2013 (7% to 24%) Racial and regional differences in prevalence and severity of disease UNAIDS. Available at: CDC. HIV Surveillance Report, Available at:

4 Introduction Efforts to prevent HIV transmission are critical HIV prevention campaigns typically focus prevention on high risk individuals A significant proportion of infections may occur in stable relationships because of either prior infection or infidelity So it is essential to identify serodiscordant couples

5 Serodiscordant Couples The risk of transmission depends on a number of things: Frequency of intercourse Sexual practices (anal vs vaginal) Male circumcision HIV viral load Use of antiretrovirals Host genetic factors (co-receptors, immune system)

6 Concurrent STIs Asymptomatic and symptomatic HSV infection is associated with increased HIV- 1 levels in the blood, cervical and rectal secretions, and semen HSV-2 is associated with a fold increased risk of acquiring HIV

7 Quality of the Inoculum Strong relationship between HIV-1 viral load and transmission rates The risk of transmission is low if the vial load is <1500 copies/ml, but the plasma viral load may underestimate the viral load in the genital tract

8 Management of Serodiscordant Couples Serodiscordant couples face a number of social, sexual, and relationship challenges Both individuals need counseling and support, but different couples will have different needs

9 Management of Serodiscordant Couples Provide information and support for both individuals Encourage regular follow up Facilitate planned pregnancies Discuss sexual practices

10 What are my patients thinking? Am I able to have children? What will people think if I become pregnant with HIV? Will I be around to watch my children grow? Will I infect my partner if he is negative? How will getting pregnant affect my HIV? What is the risk of my baby getting infected? Will they have a sign outside my door saying that I have HIV? Will HIV make my baby abnormal?

11 HIV and Women: HIV Transmission and Serodiscordant Partners HIV-Positive Woman HIV-Negative Man ART to achieve virologic suppression Artificial insemination Low-cost/ low-tech alternatives HIV-Negative Woman HIV-Positive Man Unprotected intercourse ART to achieve virologic suppression and timed insemination Semen processing In vitro fertilization Hormonal stimulation for oocyte recruitment, egg retrieval under ultrasound guidance, fertilization via intracytoplasmic sperm injection

12 Evidence Supports Combination ART for Prevention of HIV Transmission Transmission only occurs from persons with HIV HIV RNA level is single greatest risk factor for HIV transmission Combination ART can lower HIV RNA level to undetectable levels Observational evidence in heterosexual couples Previous modeling work suggests considerable potential Knowing one s HIV status is key to prevention with combination ART When to start combination ART is not known for certainty

13 Antiretroviral treatment as prevention Observational studies AIDS 20:85-92; BMJ 340:c2205; Lancet 375: Randomized controlled trial HPTN 052: 96% reduction in transmission of HIV among serodiscordant couples (ARVs started if CD cells/mcl) N Engl J Med Aug 11;365(6):

14 Viral Load and Heterosexual Transmission of HIV NEJM Volume 342 Number

15 Viral Load Predicts Heterosexual Transmission Source: Quinn et al. (2000). N Engl J Med, 342, 13,

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17 HPTN 052: Stable Heterosexual Couples Phase 3 study Americas, African, Asian sites (n=1763 couples) Stable, healthy, sexually active, serodiscordant couples CD cells/mm 3 Randomization 1:1 Early ART CD4 350 to 550 cells/mm 3 Primary Endpoints Transmission Clinical Delayed ART CD4 <250 cells/mm 3 Similar baseline demographic characteristics and sexual history/behavior both arms and between HIV-negative partner and HIVpositive, treatment naïve index patient - Virologically linked transmission events - WHO stage 4 clinical events - Pulmonary TB - Severe bacterial infection and/or death Cohen MS, et al. N Engl J Med. 2011;365:

18 Cumulative Probability HPTN 052: HIV Prevention in Stable Heterosexual Couples DSMB halts trials after a median followup: 1.7 years HIV RNA <400 copies/ml Early ART: 90% Delayed ART: 93% Linked HIV transmission to HIV-negative partner (n=28) Early therapy (n=1) 0.1 per 100 person-years Delayed therapy (n=27) 1.7 per 100 person-years Early ART led to a 96% reduction of sexual transmission of HIV in serodiscordant couples Linked HIV Transmission HR: 0.04 (95% CI ) (P<0.001) Delayed ART Early ART Years Cohen MS, et al. N Engl J Med. 2011;365:

19 One Transmission Event on ART Index begins ART AZT/3TC/EFV Index VL<400 Partner HIV+ (WB) Screening Enrollment Days Partner VL < 400 Index CD4 = 482 Index VL = 87,202 Single Genome Analysis: 1-2 viruses transmitted Analysis of Transmission: >50 days earlier ( days)

20 PARTNER Study: HIV Transmission Risk Through Condomless Sex in Serodiscordant Couples Observational study (interim analysis) Serodiscordant couples (n=767; 894 couple-years follow-up) in international multi-centered settings HIV positive: on ART (HIV RNA <200 copies/ml) HIV negative: not on PEP or PrEP Condomless sex Phylogenetically linked transmissions HIV negative: condomless penetrative sex during follow-up MSM Receptive anal: 70% Receptive anal with ejaculation: 40% Only insertive anal sex: 30% Heterosexual Vaginal sex with ejaculation: 73% Study entry HIV(-): condomless sex (years) HIV(+): on ART (years) During follow-up HIV(-): years in study Diagnosed with STI (%) HIV(-) HIV(+) HIV(-): condomless sex Number of acts/year Total number Characteristics (Couples With Eligible Follow-Up) MSM (n=282) ,400 Heterosexual (n=445) Male (n=245) ,000 Female (n=240) ,000 Rodger A, et al. 21 st CROI. Boston, Abstract 153LB.

21 HIV Transmission According to Sexual Behavior Reported by HIV-Negative Partner Overall HIV transmission rate Zero through condomless sex with a partner on ART (HIV RNA <200 copies/ml), despite a significant number of sex acts Uncertainty over the upper limit of risk remains Particularly with receptive anal sex with ejaculation Additional follow-up needed to provide more precise estimates for transmission risk Duration of prior ART without transmission may have selected for lowest risk discordant couples Rate of Couple Transmission (per 100 Couple-Years Follow-Up) Heterosexual (Male) Vaginal sex with ejaculation (192 CYFU) Heterosexual (Female) Vaginal sex (272 CYFU) MSM Receptive anal sex: With ejaculation (93 CYFU) Without ejaculation (157 CYFU) Insertive anal sex (262 CYFU) Rate (95% CI) Rodger A, et al. 21 st CROI. Boston, Abstract 153LB.

22 Female positive Male negative

23 HIV and Women: HIV Transmission and Serodiscordant Partners HIV-Positive Woman HIV-Negative Man ART to achieve virologic suppression Artificial insemination Low-cost/ low-tech alternatives HIV-Negative Woman HIV-Positive Man Unprotected intercourse ART to achieve virologic suppression and timed insemination Semen processing In vitro fertilization Hormonal stimulation for oocyte recruitment, egg retrieval under ultrasound guidance, fertilization via intracytoplasmic sperm injection

24 Safe conception: HIV+ woman and HIV- man 1. Predict ovulation (kit, BBT, cervical mucus) 2. Ejaculate into cup or spermicide-free condom 3. Home insemination with 5-10 cc syringe + + or

25 Female negative Male positive

26 HIV and Women: HIV Transmission and Serodiscordant Partners HIV-Positive Woman HIV-Negative Man ART to achieve virologic suppression Artificial insemination Low-cost/ low-tech alternatives HIV-Negative Woman HIV-Positive Man Unprotected intercourse ART to achieve virologic suppression and timed insemination Semen processing In vitro fertilization Hormonal stimulation for oocyte recruitment, egg retrieval under ultrasound guidance, fertilization via intracytoplasmic sperm injection

27 Semen and HIV Components Spermatozoa Seminal fluid Non-sperm cells (wbc) HIV present? NO possible possible Spermatozoa No CD4, CCR5 and CXCR4 receptors Electron microscopy suggesting HIV viral particles in sperm not replicated Baccetti J Cell Biol 1994

28 Sperm washing Sperm washing involves separating sperm from seminal fluid. The sperm is then used for insemination, usually IUI. AIDS. 20(7): , April 24, 2006.

29 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)

30 Costs Columbia University in New York (2008) -ICSI US Dollars -IVF-6600 US Dollars -Medication Dollars -Consultation

31 Periconceptional PrEP (PrEPception) Is there a standard of care in the US? (No) 2-dose peri-ovulatory TDF (36 &12h prior to sex) Daily TDF/FTC (efficacy data) Initiation: at menses onset vs 1 wk s/p LMP vs 36h before sex Continuation: No PEP component vs 28 days after last sex vs continue until pregnant vs continue through pregnancy if sex without condom Early embryonic exposure No known risks but data limited Antiretroviral Pregnancy Registry Vernazza AIDS 2011; Matthews Curr Opin HIV AIDS

32 PrEP for Conception: PrEPception Observational cohort HIV+ men on ARVs; HIV-RNA <50 copies/ml for >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 AIDS

33 Thank you!!