Fertility options for HIV discordant couples

Amy Criniti MDFellow Reproductive Endocrinology and Infertility

University of Washington Medical Centerarcrinit@yahoo.com

“We hope to have a vaccine ready for testing in about 2 years. Yet another terrible disease is about to yield to patience, persistence, and outright genius.”

Margaret Heclker, US Health & Human Services, April 23, 1984Margaret Heclker, US Health & Human Services, April 23, 1984

HIV statistics

• Nearly 42 million persons affected worldwide

• 75% of those affected are between the ages of 20 and 40

• Antiretroviral treatment has significantly changed prognosis

Antiretrovirals

• AZT approved in 1987• Saquinavir approved in 1995

• 1996 AIDS deaths in U.S. ↓ by 42%• Mortality Rate: Mortality Rate per

100 Patient Years — Not on therapy 65— HAART therapy 3.4

Desire to conceive

• 28% of HIV infected adults desire to have biologic children

• High priority for many HIV positive women

Chen et al, Family Planning Perspectives, 2001

HIV Discordant Couples

• 20% had engaged in unprotected intercourse to achieve pregnancy

• 50% did not consider donor sperm a reasonable option

• Many would consider unprotected intercourse if fertility treatment was not an option

• More than 50% feel that their reproductive options have not been addressed sufficiently

Previous Recommendations

• 1985: CDC encourages HIV infected women to avoid pregnancy

• 1987: ACOG encourages HIV infected women to avoid pregnancy

• 1994: ASRM presents donor sperm or adoption as options

New Recommendations

• ACOG states that ART should not be denied to HIV infected couples solely on the basis of HIV status

• CDC recommends that HIV positive women receive nondirective counseling about all options

HIV positive female partner

• Risk to child

• Risk to unaffected partner

Preconception Counseling

• Discussion of risk of vertical transmission

• Assessment of status of HIV infection CD4 count and viral load

• History of prior or current antiretroviral therapy

• Hepatitis C status

• Discussion about breast feeding

Perinatal HIV Transmission

15% Breastfeeding

<2% HAART and viral load <1000

< 2% AZT + scheduled C/S

5-8% AZT

25-40% No intervention

Risk Vertical Transmission Delivery Mode/Factors

Antiretrovirals in Pregnancy

• Perinatal transmission ↑ with viral load

• Transmission <2% in women on HAART

• If already on meds, continue

• If not on meds, defer to after 1st trimester

Antiretrovirals in pregnancy

• Combination therapy recommended when viral load > 1000

• Always include AZT

• Avoid Efavirenz ddI +d4T Nevirapine Amprenavir

• Risks

ACOG Recommendations

• Elective C/S if viral load>1000 copies/mL

• C/S should be performed at 38 weeks

• Intrapartum AZT prophylaxis

• If viral load <1000 and receiving HAART, vaginal delivery may be considered

• AROM, scalp electrodes and other invasive procedures to be avoided

Reducing Risk to Male Partner

• Timed intercourse

• Self insemination

• Intrauterine Insemination

HIV positive male partner

• Risk to female partner

• Effect of HIV infection and treatment on sperm function

• Ability to detect virus in semen

• Semen washing techniques

• “ART” (Assisted Reproductive Technologies)

Risks of HIV transmission

• Male to female 1/1000

• Female to male <1/1000

• Increased risk with advanced disease, genital infection, STD

Semen vs Blood

• Genital tract thought to act as a distinct reservoir for HIV

• 4-10% of men with undetectable viral loads still have viral shedding in semen

Vernazza et al, AIDS 2000Bujan et al, AIDS 2004

Impact of viral load on seminal viral excretion

• Estimated risk of infection per act of unprotected intercourse not known

• Longitudinal Ugandan study in 415 discordant couples

- no seroconversions when VL<1500 - probability of transmission rose to .0023 per act at VL >38,500

Gray et al, Lancet 2001

HIV and Semen Parameters

• Majority of HIV+ men have normal parameters

• However all parameters impaired compared to HIV-

• Parameters correlate with CD4 count

Nicopoullos et al, Human Reprod 2004

Sperm Washing

• Based on theory that HIV virus exists in seminal fluid and not within sperm cells

• Cell associated form in the seminal leukocytes

• Cell free form in seminal plasma

Semen Washing

• Gradient Centrifugation

• Washing

• Spontaneous Migration (aka Swim Up)

Detection of virus in semen

• RT-PCR of seminal plasma has limitations

• Inhibitors in semen reduce the sensitivity of the assay

• Nested PCR improves sensitivity

Timed Intercourse

• 1997 Lancet study followed 96 HIV discordant couples attempting pregnancy

• 104 pregnancies with 2 seroconversions

• Infection rate significantly higher than expected

Intrauterine Insemination (IUI)

• Sperm is collected, washed, and motile fraction separated

• Sample placed into uterine cavity around the time of the LH surge

• Success rate approx 8% per cycle

Intrauterine Insemination

• Used extensively in Europe

• 10 clinics have used this method

• 3166 inseminations performed in 1263 women

• 571 pregnancies w/o seroconversion

• Pregnancy rates per cycle 10-20%

Is Intrauterine Insemination Safe?

• Unclear whether it is safer than intercourse

• Places millions of sperm above the immunological barrier of the cervix

• Need more cases to demonstrate safety

• CDC does not currently support IUI

Assisted Reproductive Technology

State of the ART

• Includes IVF and ICSI

• Involves extensive screening

• May be cost prohibitive for many couples

• Involves risk

Cycle Specifics

• Patient stimulated with gonadotropins

• Eggs aspirated from ovary by ultrasound guided procedure

• Eggs fertilized with sperm from partner

IVF Monitoring

Sonographic Egg Recovery

•

ICSI

Embryo Development

• Fertilization and early embryo development occurs in the lab

• Embryos transferred into uterus of on day 3 or 5 of development

Embryo Transfer

• Done under ultrasound guidance

• Soft catheter used

• No anesthesia needed

• Full bladder helps

Extensive Screening

• Ovarian reserve testing (antral follicle count and Day 3 FSH)

• Uterine evaluation (HSG, SHG, OH)

• Semen analysis

• Genetic history

IVF/ICSI Trial Discordant Couples N=61

Cycles = 113

HIV testing 3 and 6 mosAfter Embryo Transfer

Infants and mothers testedat delivery and 3 mos

No seroconversions !

IVF and ICSI

Sauer et al, Fert Stert 2003

Cycle Outcome

0 20 40 60 80 100

Multiple

Delivery

Pregnancy

Advantages of IVF/ICSI

• Reduces exposure from millions to a single sperm cell

• Only motile spermatozoa used

• Routine laboratory testing of semen for HIV virus is relatively experimental

• Higher success rates than with IUI (fewer exposures)

• Can be used even if sperm parameters are poor

Disadvantages of IVF/ICSI

• Invasive

• Expensive

• Risk of Ovarian Hyperstimulation

• Risk of Multiple Pregnancy

• Questions about the safety of IVF and ICSI

Cost of IVF/ICSI

• Pre Cycle Evaluation $2000

• Medications $3500

• IVF Procedures $8000

• ICSI $1500________

$15,000

Ovarian Hyperstimulation Syndrome

• Severe cases are rare

• Can cause fluid shifts, hemoconcentration, and ARDS

• Can require ICU admission

Multiple Pregnancy

Number of Embryos Transferred

CDC Assisted Reproductive Technology Success Rates, 2001

6.2%

27.3%

34.5%

20.6%

11.4%

Embryo Transfer GuidelinesASRM/SART (11/99)

Female RecommendedAge Transfer No.

<35 1–235–38 2–338–40 3–4>40 4–6

Twins are not an ideal ART outcome

• Fetal and maternal complications

• 12 fold increase in cerebral palsy

• 5-10 fold increase in perinatal mortality

• $600 million excess cost in year 2000

Kinzler et al, 2000

Conclusions

• Fertility counseling and treatment options should be presented to HIV discordant couples

• IUI and ICSI both appear to be safe options, although numbers are still relatively small

• Neither are yet the standard of care and prevention can not be guaranteed.

• IUI is not widely available in the United States

Ethical Issues

• Risk of transmission to the seronegative partner

• Risk of transmission to the infant

• Early death of one or both parents

• Possible need for third party parenting

• Posthumous reproduction