Reproductive Technologies & Counseling Patricia Kloser, MD, MPH, FACP Professor of Medicine Professor of Public Health June 2006 UMDNJ, a Local Performance Site of the NY/NJ AETC

Objectives  Transmission risks  Pregnancy options  Infertility  Treatment options

Transmission Risks  Heterosexual  Vertical

Risk of Transmission  Unprotected vaginal intercourse –Male to female = 3% to.01% per contact –Female to male = 10% to 17% less efficient

HIV in Body Fluids  Blood  Semen  Cervical secretions  Breast milk  Spinal fluid

HIV in Semen  Higher in acute HIV infection in men  Correlation between viral levels of HIV in blood and semen  Men hyperinfectious before symptoms of HIV infection occur (lasts 6 weeks)  Could infect 7 to 24% of partners during first 2 months of infection  STD would increase this rate (in either partner) JID 2004; 189:

U.S.  HIV-1 RNA in Cervical Secretions –Varies in menstrual cycle (due to hormone variation) –Highest just before menses start –Risk of transmission riskiest as menses approach –Lowest level at mid-cycle –Explains increase of HIV in cervical secretions in women on oral contraceptives –No increase of cervical shedding in menses –Less variation in serum than genital secretions –Less virus in vaginal than cervical in secretions

Heterosexual Transmission Risks Increase With  Genital ulcer or STD  Cervical ectopy  Male partner not circumcised  Sex during menses  Bleeding during intercourse  Receptive anal intercourse  Partner with high viral load

Risk of Vertical-Transmission  Mother - cigarette smoking - older maternal age - high viral load - low CD4 - vaginal delivery - prolonged rupture of membranes >4hrs - acute HIV infection  Baby- prematurity - breastfeeding

Vertical Transmission  In utero - <10%  Peripartum – 40 – 70%  Breastfeeding – 0.5% per month risk  Most important factor is viral load

Vertical Transmission Rate  Total rate – 13% to 60%  U.S. – 25% to 30%  Europe – as low as 13%  Africa – 50% to 60%

MTCT with ARV (U.S.)  Treatment –None –AZT –HAART  Transmission –24.5% (WITS 1993) –7.6% (ACTG ) –<1% (2006) –7 cases NJ (2004)

Viral load and MTCT (U.S.)  Mother’s viral load –<1000 –1000 to 10,000 –10,000 to 50,000 –50,000 to 100,000 –More than 100,000 –Garcia, et al NEJM 1990;341:394  Transmission rate –0% –16.5% –21.3% –30.9% –40.6%

Vertical Transmission with Treatment  U.S. – with HAART <1%  Developing Countries –PMTCT reduces transmission by 50%  Nevirapine – 200mg to mother - 6ml to baby  Or equivalent AZT dose

Viral load in Genital Secretions & MTCT (Thailand) Plasma VLHIV in CVLTransmission rate >10,000Yes28.7% >10,000No1.5% <10,000Yes15.0% <10,000 Chuachoowong et al JID 2000: No1.0%

Cesarean Delivery AZTC/STransmission rate No Yes International Perinatal HIV Group NEJM 1999: No Yes No Yes 18% 10.4% 7% 2%

Cesarean Section  Elective cesarean section before rupture of membranes or onset of labor usually at weeks may further decrease vertical transmission  Not routinely done unless mother requests or if the viral load is high

Pregnancy Options

Pregnancy  Does not affect disease progression  Lowers CD4 count  Should not use Stavudine and ddi together  No Efavirenz in the first trimester

 In unprotected vaginal intercourse leading to pregnancy the risks are twofold: –Partner’s risk of infection –Baby’s risk of infection

Risk to Partners  Expense (depending on method)  Possibility of HIV infection (depending on method used)  Possibility of passing “resistant” HIV to infected partner  Time consuming (depending on method used)

Negative Female Positive Male  Timed unprotected intercourse (as above) not recommended  Intrauterine insemination (IUI) after “sperm washing”  Intracytoplasmic sperm injection (ICSI) one sperm-one egg with zygote implanted in uterus (aliquots tested for cell free virus) via laser manipulation

Negative Male Positive Female  Timed unprotected intercourse (using basal body temperature monitoring)  “Turkey baster” method self insemination  Ovarian stimulation with artificial insemination (partner/donor)  In vitro fertilization (ova harvested and fertilized outside of body and then implanted in hormonally stimulated uterus)

Positive Male Positive Female  Remember undetectable viral load in serum does not mean undetectable genital viral load  It may be possible to impart resistant virus from one partner to the other

Superinfection  Controversial  5 published verified cases  Appears to occur but difficult to verify  Usually occurs shortly after initial infection less likely later on  Positive partners study on-going  HIV positive people prefer other HIV positive people

Reproductive Decisions  Artificial insemination  Invitro fertilization  Intracytoplasmic sperm injection – most expensive  Self insemination  Timed intercourse  Transmission rates MTCT <1% in women with VL <1000 copies in U.S.

U.S.  Timed intercourse: –Condoms at all times –No condom during fertile times –4% transmission rate (for female if male HIV+) –Men – semen sample – count motility, progression, morphology –Women – ultrasound during follicular phase and endocrine profile

U.S.  Self insemination –Women inseminate themselves with fresh semen using syringe (without needle) or disposable Pasteur pipette (cheap, safe)

U.S.  IVF – for infected male for uninfected female sperm processed and single sperm used to fertilize egg of HIV infected woman  No seroconversion and no HIV+ infants  (intracytoplasmic sperm injection) $$$$

Sperm Washing  Infected male followed by intrauterine insemination  29% success rate for pregnancy  No seroconversion of females

Sperm Washing  For use in cases where male is HIV+  Ejaculate is processed in laboratory separating semen from sperm cells  These cells are then reinserted into female (in vivo) or inserted into ovum (in vitro) for fertilization  This process will reduce possibility of infecting HIV negative woman  This process will reduce chance of re-infection of HIV positive woman with resistant viral strain  Problems – expense, technical availability, needs cooperative couple and committed obstetrician

Patient Considerations  Healthy  No active OI  CD4 >350  VL <50,000  Woman must have normal PAP or normal colposcopy  If Hepatitis C must have normal liver enzymes and hepatology consult  Been on HAART for 1 year  Male semen sample  No unprotected sex during this time

Laboratory Considerations  Cross contamination is a concern  Must have separate freezers and storage for samples  May be difficult regarding food facilities  Milan, Italy criteria and Columbia University in NYC doing this work

U.S.  Assisted reproductive techniques –Expensive $10,000 to $17,000 per cycle –Many (most) cannot afford this expense –VL undetectable –CD4 >400

Goals of these Reproductive Options  Achieve pregnancy  Avoid transmission of HIV to mother, father or baby  Give woman choice regarding pregnancy

Risk to Fetus  Multiple fetuses  Low birth weight  Pre-term delivery

Infertility

 HIV positive and HIV negative workup is no different

Infertility  One year of unprotected intercourse  History/sexual practices  Sperm evaluation  Urologic evaluation  GYN evaluation  Appropriate treatment

Infertility Treatment  Based on problem  Many have no particular medical issue and diagnosis of etiology can’t be determined

Male Infertility Male causes  Sperm- poor quality - poor quantity - poor motility  Semen - poor quality - poor quantity

Male Infertility  Anatomical- obstruction - hypospadia - varicocele - injury - retrograde ejaculation  Endocrine - low testosterone  Genetic - Klinefelters, etc.  Psychiatric - depression - low libido

Male Infertility Suggestions  Stop smoking  Avoid tight fitting pants (male), bicycle riders  Timing of intercourse  Appropriate weight  Healthy life style

Female Infertility  Endocrine- thyroid, pituitary, adrenal insufficiency  Genetic- polycystic ovaries, Turners  Psychiatric - depression - low libido

Female Infertility Female causes  Ova - poor quantity - poor quality – age, nutrition, injury, illness  Anatomical - obstructed fallopian tubes - poor motility of cilia in fallopian tubes - uterine lining abnormality fibroid - endometriosis - uterine anatomy

Treatment Options

Minimal MTCT Risk  With serum VL <1000  No breastfeeding  Woman on HAART

Factors Associated with Vertical Transmission  High viral load  Acute HIV infection  Older maternal age  Cigarette smoking  Prolonged rupture of membranes

U.S.  Pregnancy –Lopinavir with Ritonavir – levels 50% lower in third trimester –Levels still adequate but study needed –Efavirenz – not in 1 st trimester –Nevirapine – watch liver function –D 4 T/DDI – do not combine – lactic acidosis

Counsel Woman  Importance of adherence to care  Importance to take every pill every day  Seek care of experienced OBS/ID team for the best result  Obtain all laboratory tests on schedule  Follow up immediately for any new symptoms or signs

Conclusion  With appropriate education  With minimal risk it is possible for many HIV positive persons to become the parents of HIV negative babies