Fertility options for HIV discordant couples

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Fertility options for HIV discordant couples

• Amy Criniti MD
• Fellow Reproductive Endocrinology and Infertility
• University of Washington Medical Center
• arcrinit_at_yahoo.com

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• 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, 1984
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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

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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

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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
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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

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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

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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

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HIV positive female partner

• Risk to child
• Risk to unaffected partner

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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

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Perinatal HIV Transmission
Delivery Mode/Factors
Risk Vertical Transmission
25-40
No intervention
5-8
AZT
lt 2
AZT scheduled C/S
lt2
HAART and viral load lt1000
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Breastfeeding
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Antiretrovirals in Pregnancy

• Perinatal transmission ? with viral load
• Transmission lt2 in women on HAART
• If already on meds, continue
• If not on meds, defer to after 1st trimester

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Antiretrovirals in pregnancy

• Combination therapy recommended when viral load gt
  1000
• Always include AZT
• Avoid Efavirenz
• ddI d4T
• Nevirapine
• Amprenavir
• Risks

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ACOG Recommendations

• Elective C/S if viral loadgt1000 copies/mL
• C/S should be performed at 38 weeks
• Intrapartum AZT prophylaxis
• If viral load lt1000 and receiving HAART, vaginal
  delivery may be considered
• AROM, scalp electrodes and other invasive
  procedures to be avoided

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Reducing Risk to Male Partner

• Timed intercourse
• Self insemination
• Intrauterine Insemination

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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)

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Risks of HIV transmission

• Male to female 1/1000
• Female to male lt1/1000
• Increased risk with advanced disease, genital
  infection, STD

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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 2000 Bujan et al, AIDS 2004
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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 VLlt1500
• - probability of transmission rose to
• .0023 per act at VL gt38,500

Gray et al, Lancet 2001
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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
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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

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Semen Washing

• Gradient Centrifugation
• Washing
• Spontaneous Migration (aka Swim Up)

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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

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Timed Intercourse

• 1997 Lancet study followed 96 HIV discordant
  couples attempting pregnancy
• 104 pregnancies with 2 seroconversions
• Infection rate significantly higher than expected

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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

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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

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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

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Assisted Reproductive Technology
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State of the ART

• Includes IVF and ICSI
• Involves extensive screening
• May be cost prohibitive for many couples
• Involves risk

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Cycle Specifics

• Patient stimulated with gonadotropins
• Eggs aspirated from ovary by ultrasound guided
  procedure
• Eggs fertilized with sperm from partner

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IVF Monitoring
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Sonographic Egg Recovery

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ICSI
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Embryo Development

• Fertilization and early embryo development occurs
  in the lab
• Embryos transferred into uterus of on day 3 or 5
  of development

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Embryo Transfer

• Done under ultrasound guidance
• Soft catheter used
• No anesthesia needed
• Full bladder helps

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Extensive Screening

• Ovarian reserve testing (antral follicle count
  and Day 3 FSH)
• Uterine evaluation (HSG, SHG, OH)
• Semen analysis
• Genetic history

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IVF/ICSI Trial
Discordant Couples N61 Cycles 113
IVF and ICSI
HIV testing 3 and 6 mos After Embryo Transfer
Infants and mothers tested at delivery and 3 mos
No seroconversions !
Sauer et al, Fert Stert 2003
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Cycle Outcome
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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

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Disadvantages of IVF/ICSI

• Invasive
• Expensive
• Risk of Ovarian Hyperstimulation
• Risk of Multiple Pregnancy
• Questions about the safety of IVF and ICSI

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Cost of IVF/ICSI

• Pre Cycle Evaluation 2000
• Medications 3500
• IVF Procedures 8000
• ICSI 1500
• ________
• 
  15,000

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Ovarian Hyperstimulation Syndrome

• Severe cases are rare
• Can cause fluid shifts, hemoconcentration, and
  ARDS
• Can require ICU admission

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Multiple Pregnancy
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Number of Embryos Transferred
6.2
11.4
27.3
20.6
34.5
CDC Assisted Reproductive Technology Success
Rates, 2001
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Embryo Transfer GuidelinesASRM/SART (11/99)
Female Recommended Age Transfer
No. lt35 12 3538 23 3840 34 gt40 46

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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
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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

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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