HIV Prevention: Assisted Reproduction & Preconceptional Counseling

1. HIV Prevention: Assisted Reproduction & Preconceptional Counseling Marya Zlatnik, MD UCSF Perinatal Medicine & Genetics

2. Thanks to: Deborah Cohan Ruth Greenblatt Maureen Shannon

3. Outline • Preconceptional counseling • Sexual transmission findings • Semen & HIV • HIV & fertility • ART methods & outcomes • Local information on perinatal transmission • Legal considerations

4. Preconceptional Counseling • “Prenatal” history • Medical/OB/MFM referrals • Prenatal labs/screening • CBC, RPR, Rubella, T&S, HBsAg, Pap/cx, hgb electrophoresis, CF • Folic acid supplementation • 400ug/d

5. Preconceptional Counseling • HIV disease issues • Medical • Psychosocial • What to expect with pregnancy • Rx issues • Delivery • Breastfeeding • Method of conception

6. Mode of Conception • HIV+ ♀With HIV- ♂ • Syringe/turkey baster • Fertility cup • IUI • Timed coitus +/- PEP • Adoption, surrogacy

7. Options for HIV- ♀With HIV+ ♂Desiring Children • Adoption • Sperm donation • Sperm banks • Designated donor • Insemination by partner • Timed coitus (+/- PEP) • Artificial insemination • ICSI (intracytoplasmic sperm injection)

8. Heterosexual Transmission • “Heterosexual” sex (CDC, cumulative 2001) • Among ♀: 41% AIDS cases; 39% HIV cases • Risk of HIV transmission • HIV + ♂  HIV- ♀ • 1.1/1000 coital acts (95% CI 8/10,000 – 1.5/1000) • n=174 couples; Uganda • Gray, et al, Lancet 2001 • 5-25/100 P-Y • n=228 couples; Uganda • Quinn, et al, NEJM 2000 • 2.5-8.4/100 P-Y • n=121 couples; Europe • De Vincenzi, et al, NEJM 1994

9. Routes & “Efficiency” of Transmission

10. Factors Influencing Sexual Transmission of HIV • Quantity of HIV RNA in plasma • Treatment effects • Presence of foreskin • Presence of STDs • Genital ulcer diseases • Recruitment of leukocytes • Other epithelial abnormalities • Trauma or bleeding • ? Exogenous hormones • Depo-provera • Oral contraceptive pills

11. Other Issues • Site of transmission is unknown • Vagina, cervix or endometrium • Some resistance mutants may be less fit • Treatment benefits despite viral rebound on therapy • Possible reduced transmissibility • Super-infection appears to be rare • Co-infections • HCV, HHV-8, CMV, HSV

12. Semen Components • Where is HIV in semen?: • Spermatozoa fraction has lowest frequency of HIV RNA • White cell component has highest frequency of HIV RNA & highest concentrations of RNA • Seminal fluid has next highest frequency of HIV RNA • Unclear: • CD4 may be present on sperm • CCR5 & CXCR4 do not appear to be present on sperm

13. Sperm Washing • Rationale: • No HIV inside spermatozoa • HIV in seminal plasma (free virus) & non-sperm cells (cell-associated virus) • Semen as distinct viral reservoir • Kiessling et al, AIDS Res Hum Retro, 1998 • Washing can isolate sperm from semen • Undetectable HIV despite HIV in semen • Bujan, Fert Ster, 2002; Lasheeb, Genit Med, 1997 • Hanabusa, AIDS, 2000; Pasquier, AIDS, 2000

14. Sperm Washing • Technique: • Gradient centrifugation, sperm washing, swim up • PCR of seminal fluid, non-sperm cells & sperm • If negative, frozen sperm  insemination • New methods are being developed • Outcome: • No clinical trials • Prior studies used differing PCR methods • Washing does not eliminate all bacterial pathogens • 6% of sperm samples + HIV RNA PCR after optimal processing • Actual risk of transmission small, but not zero

15. Insemination by HIV+ ♂ • Timed coitus • 4.3% seroconversion in 92 serodiscordant couples, 104 pregnancies over 10 yrs • Conversions: 2/4 antepartum; 2/4 postpartum • Assisted insemination • Sperm washing, with: • Intrauterine insemination (IUI) • In-vitro fertilization (IVF) • Intracytoplasmic Sperm Injection (ICSI) Mandelbrot, et al, 1998

16. HIV & Fertility • Decreased fertility • Most data from developing countries • Increased miscarriages & stillbirths • Most data from developing countries • Male factors • Semen WBC increase with falling CD4 • Motility abnormal with falling CD4 • Androgen levels may be low • STDs may confound these findings

17. HIV & Female Fertility • Decreased fertility • Uganda:  fertility by 25% (Ross, 1999) • Longitudinal cohort; 80 HIV+, 96 HIV- • 7% pregnancy rate (HIV+) vs. 9.5% (HIV-) over 3 mos • Cote d’Ivoire:  fertility by 17% (Desgrees, 1999) • Cross-sectional; 1201 pregnant women • Interval btwn pregnancies; Cox regression

18. HIV & Female Fertility • Increased miscarriages/stillbirths • Cote d’Ivoire:OR 1.28 (1.02-1.60)(Desgrees, 1998) • Uganda: OR 1.50 (1.01-2.27)(Gray, 1998) • Longitudinal cohort; 4813 women; 18.5% HIV+ vs. 12.2% HIV- • Italy: OR 1.67 (D’Ubaldo, 1998) • Retrospective cohort; 217 HIV+ vs. 132 HIV-

19. HIV & Female Fertility • Possible etiologies of  fertility • PID/tubal factor (STIs) • Menstrual disorders • Polymenorrhea: OR 1.45 (1.0-2.11) (Harlow, 2000) • Longitudinal cohort; 802 HIV+ vs. 273 HIV- • Oligomenorrhea: OR 1.32 (0.68-2.58) (Chirgwin, 1996) • Cross-sectional; 248 HIV+ vs. 82 HIV - • direct effects of HIV on uterus, tubes, ovaries? • HAART improves fertility?

20. HIV & Male Fertility • Politch et al, 1994 • Cross-sectional chart review; 166 HIV+ men • No ZDV, CD4>200=nl semen analysis • No ZDV, CD4<200=all with abnl semen analysis • ZDV, regardless of CD4= wbc • Normal, regardless of AZT • Muller et al, 1998 • Cross-sectional; 250 HIV+ vs. 38 HIV- fertile men • HIV+ (vs. HIV-) •  volume,  concentration,  motility,  nl morphol • CD4<200: Abnl morphology, motility,  wbc

21. Arguments Against Offering Assisted Reproduction • HIV is potentially fatal, but survival on Rx is now comparable to many chronic diseases • 4-6 yrs increased life expectancy vs. pre-HAART • CD4 > 200 15.4 years • CD4  200 8.5 years • CD4  50 5.5 years • King, Med Decis Making 2003 • Risk of adverse effects of antiretroviral Rx may be increased by pregnancy • Risk to medical & laboratory staff may be increased • Legal constraints on use of body fluids

22. Arguments Against Offering Assisted Reproduction • High risk of adverse neonatal outcome, yet… • <1% transmission if VL <1000 • Comparable to other chronic conditions: diabetes, lupus • Compare with life expectancy of aged but healthy parents

23. Arguments for Offering Assisted Reproduction • Assisted reproduction may decrease HIV transmission among discordant couples • Reduce frequency of exposures • Reduce level of contamination of body fluids • Improved survival with treated HIV infection • Parents • Offspring

24. Results of Assisted Reproduction • Intrauterine Insemination (IUI) • Cases prior to 1990 • Case of seroconversion during washing/IUI (1990) • MMWR: no density gradient, no semen VL prior to IUI • European summary • 3166 inseminations, 1263 women • 393 births, no seroconversions • Politch, Repro Immun, 2002 • Semprini, 1992, 1998

25. Additional Observational Findings • In vitro fertilization (IVF) • 93 cycles, 75 women, no conversions • Politch, Repro Immun, 2002 • Intracytoplasmic Sperm Injection (ICSI) • Minimize exposure to contaminated fluids • 189 cycles, 130 women • 46 births, no conversions

26. Complications of IVF-ICSI • 132 IVF-ICSI cycles in 74 seropositive-male discordant couples • 43 pregnancies • Ovarian hyperstimulation syndrome: • Moderate/severe = 4.5% of IVF cycles • Higher-order multiple gestations • 7/43 (16%) of pregnancies • 1 quadruplet, 6 triplet pregnancies • Reduction to twins in 4 women • 3 sets triplets, 3 sets twins Pena, Arch Gynecol Obstet 2003

27. Published Selection Criteria • Level of infirmity in HIV+ partner • Untreated viral load • CD4>350 • No hx of AIDS defining illnesses/prophylaxis • Undetectable blood HIV RNA on Rx with stable CD4 • Regimen does not include teratogenic drugs • Regimen is well tolerated & adhered to • Both partners are aware of HIV infection • Adequate counseling & consent • Satisfactory Pap in woman • Hepatology clearance in setting of HCV infxn

28. Other Considerations (?) • Resources for treatment of HIV infection in parents & child • Abstinence from unprotected intercourse during pregnancy • Clear understanding that transmission to woman & to child is possible

29. Local Cases and Referrals

30. HIV Disease: Women • n = 56 • AIDS defining condition: 17% • CD4 <200: 13% • Detectable viral load: 41% • HAART: 78% • Protease inhibitor regimen 75% Maureen Shannon, ’94-’03

31. Partner’s HIV Status (n = 70) MEN WOMEN Data from 1/94 – 4/03

32. Clinical Implications • Majority of couples (87%) are HIV discordant • Minimize risk of transmission during conception • PEP after exposure • Improve access to ART • Majority (78%) of HIV+ women on HAART • Minimize adverse embryo/fetal effects • Maximize control of HIV disease • Large % of women >35 years of age • Genetic issues

33. ART Referral Options • Northern California: • HIV+ women with HIV- partners (limited access) • Out of state: • Mark Sauer (Columbia U.) HIV+ male partner/HIV- female partner only • Ann Kiessling (Boston) • Arizona, Oregon, Nevada, etc

34. Provision of ART to HIV-affected Couples • American Society for Reproductive Medicine Ethics Committee • “Unless health care workers can show that they lack the skill & facilities to treat HIV-positive patients safely…, they may be legally as well as ethically obligated to provide requested reproductive assistance.” (Fert Ster 2002)

35. Ethical Principles • Respect for autonomy: another’s values, preferences, & decisions • Beneficence (or nonmalefeasance): promote the well-being of others • Justice: treat individuals fairly

36. Issues in Accessing ART for HIV-affected Couples • Legal restrictions prevent access to care & biomedical technology that can significantly reduce HIV transmission risk • Withholding ART from HIV+ women because of PNT risk (NY) • Couples in lower SES category unable to afford access to ART programs

37. California Law, HIV & Assisted Reproduction in CA • CA Health & Safety Code 1644.5 (1989) • “No tissues shall be transferred into the body of another person…unless the donor of the tissues has been screened & found nonreactive…(to) HIV, agents of viral hepatitis (HBV & HCV), HTLV-1, & syphilis, where “tissue” is defined to include sperm” • ACOG-sponsored AB 525 amendment (1993) • “May waive…repeat testing…if the recipient is informed…& signs a written waiver” California Health & Safety Code Section 1644.5, 1989; Assembly Bill 525, 1993

38. California Law, HIV & Assisted Reproduction • RESOLVE-sponsored AB 441 (1997) • “A recipient of sperm may consent to… insemination of sperm or use of sperm in other advanced reproductive technologies even if the sperm donor is found reactive for hepatitis B, hepatitis C, or syphilis if the sperm donor is the spouse of, partner of, or designated donor for that recipient” • ACOG: CA only state to prohibit such sperm • Sperm from HTLV-I & HIV-infected donors remains prohibited Assembly Bill 441, 1997

39. California Law, HIV and Assisted Reproduction • “Felony punishable by imprisonment for any person to donate blood, body organs or other tissue, semen…for purposes of artificial insemination.” California Health & Safety Code 1621.5 Chapter 6, 1988

40. Bragdon vs. Abbott, 1998 • U.S. Supreme Court decision • AIDS considered a disability & protected under the 1990 ADA • Bragdon vs. Abbott decision changed ADA to include asymptomatic HIV infection

41. Bragdon vs. Abbott, 1998 • “Respondent’s HIV infection is a physical impairment which substantially limits a major life activity, as the ADA defines it.” • “Respondent’s infection substantially limited her ability to reproduce in two independent ways”: • Risk of HIV transmission to her partner • Risk of HIV transmission to her offspring. • May be the basis of ensuring access to infertility treatment in the future

43. Case Presentation • 32yo HIV+ man & 29yo HIV- woman present for preconception counseling • Consistent condom use over the past 2 yrs but now want to get pregnant. He was adopted, & they feel strongly about having “their own kid.” • His CD4=525 & VL=2500 on HAART. He was dx’d with HIV 6 yrs ago & has been on HAART for 5 yrs. His lipids are elevated, so his doctor has talked to him about stopping his HAART • They heard something about “sperm washing” from a friend & want to do everything possible to reduce the chance of her acquiring HIV & passing it on to a baby

44. Case Presentation • 40 yo G1P1 HIV+ woman, recently married to 32 y/o HIV- man • She had an uncomplicated SVD with post-partum tubal ligation in 1994. She was HIV+ at the time & did not transmit HIV to her infant • She is currently on HAART with CD4=520 and undetectable VL • She wants either a reversal of tubal ligation or IVF

45. Case Presentation • 42 yo woman L&D nurse, who gave birth 10 months ago to a child who died at age 4 months of PCP and other AIDS conditions. Neither parent was screened for HIV infection during pregnancy • The couple has been trying and so far failed to achieve pregnancy again. The patient now asks to have fertility treatment (stimulation of ovulation and intrauterine insemination) • The woman feels this is the only way she will recover from the death of her child