Assisted Reproduction

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Parenting and HIV Strategies for reducing risk
Dr Carole Gilling-Smith Assisted Conception
Unit, Chelsea Westminster Hospital,
London Agora Clinic, Brighton Grand Round
Columbia University 30th October 2008
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Lecture Objectives

• HIV in 2008 - update
• Ethical concerns
• Reducing transmission risk
• To uninfected partner and unborn child
• Impact of HIV on fertility reproductive outcome
• Safety of staff and non-infected patients
• Laboratory adaptations
• The way forward

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HIV The Global Situation

• gt 42 million infected with HIV-1 worldwide
• 95 of new infections in subsaharan Africa
• majority of transmissions heterosexual
• limited resources and access to antiretrovirals

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HIV Is parenting an option?

• In developed countries HIV defined as a chronic
  disease
• ARV treatment available
• Life expectancy 30 years
• 80 of infected patients of reproductive age
• MCT lt 1
• Increased prevalence of subfertility in HIV
  patients

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HIV- the stigma

• KEY QUESTIONS
• Should HIV patients have children?
• Should they receive fertility care?
• Should they receive funding?
• Are they putting others at risk?

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Ethical concerns welfare of the child (Frodsham
et al. Hum Reproduction 2005 192420)

• Life expectancy of the infected parent
• co-infection with HCV
• Viral transmission risk to -ve partner and child
• Associated high risk behaviour
• drug abuse
• prostitution

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UK Law who should receive ART ?

• HFEA Act 1990 Clause 3.8 - Welfare of the Child
• a woman shall not be provided with treatment
  services (ART) unless account has been taken of
  the welfare of any child who may be born as a
  result of the treatment (including the need of
  that child for a father, and of any other child
  who may be affected by the birth).

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European Law the right to have a family?

• Article 12, European Court of Human Rights
• Men and women of marriageable age have the
  right to marry and found a family, according to
  the national laws governing the exercise of this
  right

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HFEA directive Jan 2004

• All patients undergoing licensed treatment should
  be screened for HIV, hep B hep C
• IVF, ICSI, DI, OD
• immediate without quarantine period
• separate storage facilities for infected samples
• separate storage tank for infection/ infection
  combination

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Legal Ethical views in the USA

• Changes in policy by
• ACOG (2001 Committee opinion 255)
• ASRM (Fert Stert 2002 , 77218-22)
• advocating policies of non-discrimination and
  equal access to fertility care
• Wide variation between states in treatments
  offered
• lt 5 of clinics offering any form of treatment
• Sperm washing regarded as criminal action in some

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Suggested criteria for treatment

• CD4 count gt 200
• Undetectable / low viral load
• stable disease
• Reproductive counselling identifies no issues
• F
• Effective safe antiretroviral medication can be
  used during pregnancy

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Reproductive Counselling

• Assess stability of relationship and wish for a
  family
• Explore the risks
• Current health (VL, CD4, Liver disease, CA)
• Lifestyle
• Discuss treatment options
• Ensure there is emotional and practical support

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Reproductive options forHIV ve ? and HIV
negative ?

• Unprotected timed intercourse (natural conception
• Donor insemination
• Adoption
• Sperm washing and insemination

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HIV contamination of semen
L Kim et al, AIDS 1999, 13 645-51

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SPERM WASHING PROTOCOL
semen
semen
semen
NASBA check for HIV-1 RNA (detection limit gt
50copies/ml)
density gradient
density gradient
density gradient
seminal plasma
seminal plasma
seminal plasma
dead sperm non-sperm cells
dead sperm non-sperm cells
live sperm
live sperm
2
4
4
medium
medium
NASBA check for HIV-1 RNA (detection limit gt
50copies/ml)
live sperm
live sperm
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Management of HIVve men
Initial referral info sent out
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Pre-treatment work-up

• ? ? sexual health screen
• ? pelvic scan endocrine profile (day 2 - 5)
• mid-luteal progesterone
• tubal assessment
• ? ? counselling
• ? IVF laboratory semen analysis

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Reproductive Counselling information
implications

• understanding risks and benefits of each Rx
• SPERM WASHING
• investigations needed and why
• how is it done
• viral testing before insemination
• the female cycle and timed insemination
• viral testing after insemination
• risks to partner and future child

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Consent / legal issues

• Method is risk reduction not risk elimination
• Consent form
• Suggest freeze a washed -ve sample
• Better identify quality of sperm post wash
• Back up if failed wash on day of treatment
• Back up problems producing a sample

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Ultrasound monitoring of the ovaryfollicle
tracking
Day 8 Day 11
Day 13
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Intrauterine Insemination (IUI)
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Egg collection
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Insemination (3 hours)
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ICSI (3 hours)
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Eight Cell Embryo (72 hours)
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Embryo transfer (ET)
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Results C W SWP 238 couples
IUI
IVF/ICSI

• 415 cycles
• LB 39
• CPR / cycle 13.3
• LB rate/cycle9.4
• Cancellation rate 1.8

• IVF 104 cycles
• LB 27
• LB rate/cycle 25
• ICSI 103 cycles
• LB 24
• LB rate/cycle 23.3

90 healthy children born following 622 cycles (3
twins) 38 successful no seroconversions in
either partner or child
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Source of HIV infection (n110)
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HIV and IUI outcome(Nicopoullos et al. Hum
Reproduction 2004192289)

• HIV significantly impairs all sperm parameters
• Parameters correlate with CD4 count
• No correlation with use of ARV
• But IUI outcome (CPR) improved with
• Low VL lt 1000 copies/ml
• Use of ARV
• CD4 count has no impact

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Severe OATS Azospermia

• SSR, sperm washing and ICSI
• Nicopoullos et al, Fert Steril, 2004 81 670
  (CBAVD)
• Bujan et al, Human Reproduction, 2007 22 2377
  (OA)
• In many cases insufficient viable sperm for
  density gradient and HIV testing (gt 5.106/ml)
• Can testicular sperm be used without washing
  and/or testing?

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• Centres for Reproductive Assistance Techniques in
  HIV in Europe
• 17 centres in 9 countries to pool data to assess
• safety efficacy
• epidemiology
• behavioural and psychosocial aspects
• draw up guidelines for counselling and treatment

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Literature Review Risks of sperm washing

• Bujan et al, AIDS 2007 Multicentre Retrospective
  study
• 8 European centres
• 1036 serodiscordant couples
• 3396 treatment cycles
• 2840 IUIs
• 107 IVF
• 394 ICSI
• 49 FET

NO SEROCONVERSIONS Probability of infection zero
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North American Experience(Sauer et al, Fert
Steril 2008)

• Sauer et al (AJOG 2002, 186627-33)
• Advocate ICSI as safer than IUI or IVF
• 10 years experience no seroconversion of mother
  or child 420 cycles in 181 couples
• Problems
• Multiple pregnancy rate
• Invasive nature of treatment
• Higher cost

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Swiss National AIDS CommissionSwiss Medical
Bulletin Jan 2008

• HIV-positive individuals
• without additional sexually transmitted diseases
  (STD) and on effective antiretroviral (HAART)
  therapy
• are sexually non-infectious
• Caveat No STDs , VL fully suppressed for 6
  months

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Literature Review Risks of unprotected vaginal
intercourse

• Quinn et al, 2000 Uganda prospective study
• 453 HIV ve ? HIV -ve ?
• risk of transmission correlated with VL
• No transmission if VL lt 1000 copies/ml
• Castilla et al, 2005 prospective study over 14
  years
• 393 HIV ve ? HIV -ve ? (1991-2003)
• No transmission if ? on HAART
• 8.6 risk of transmission if not

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Literature Review Risks of natural conception

• Mandelbrot et al, 1997 Prospective study 92 HIV
  ve ? HIV -ve ? timed unprotected intercourse
  to conceive
• 4 seroconversions
• Barreiro et al, 2000 retrospective study of 62
  discordant couples . HIV ve ? had undetectable
  VL through HAART for 6 months
• No seroconversions
• Vernazza et al, 2007 prospective study 22 HIV
  ve ? natural conception PREP (License to Love)
• No seroconversions

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Can HAART reduce risk to Zero ?

• In men on HAART fully suppressed with -ve VL
• Mathematical models give risk of HIV transmission
  during intercourse lt 0.0001
• Problems
• HIV in serum and semen are not correlated
• Delay in achieving undetectable VL in semen
• STDs increase genital viral load (asymptomatic)
• Some patients get occasional spikes in VL

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Seminal viral shedding on HAART(Gilling-Smith et
al. Hum Reproduction 2008)

• Retrospective analysis of 551 consecutive cycles
  of sperm washing (1999 2007) at C W
• Detectable HIV in ejaculated semen in men with
  undetectable VL through HAART (74 of cases)
• 3.7 (15 / 407)
• Median viral load 1100 copies/ml (range 360
  18,000 cp/ml)
• Median CD4 400 cells / mm3 (range 165-812 cells
  / mm3)
• No correlation with type of HAART (2 cases on
  Tenofovir)

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Seminal viral shedding on HAART(Gilling-Smith et
al. Hum Reproduction 2008)

• Detectable HIV-1 in men on HAART with VLlt 50 post
  sperm washing
• 2 / 15 cases (2 / 407 or 0.005 of cycles)
• No consistent pattern between type of HAART and
  risk of viral shedding in semen
• In 2 men HAART included Tenofovir
• (used in PREP)

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Seminal viral shedding on HAART(Gilling-Smith et
al. Hum Reproduction 2008)

• appreciable viral shedding in 3. 7 of men fully
  suppressed on HAART in the absence of STDs
• These men cannot therefore be regarded as
  sexually non-infectious
• Natural conception cannot be advised as a safe
  option

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Reproductive options forHIV ve ? and HIV
negative ?

• Unprotected timed intercourse (natural
  conception)
• Transmission risk 0.3 - 0.001
• Donor insemination
• Adoption
• Sperm washing and insemination
• No reported transmissions to child or partner

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HIV ve women Increased subfertility

• No signif difference in endocrine profile / cycle
  Hx
• (D2-5 FSH, LH)
• Increased prevalence of tubal blockage
• 41 versus 14
• Reduced ovarian reserve (Coll et al, 2007)

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HIV ve women MCT risk

• equal or greater risks to offspring in
• women gt 40
• trisomy 21 and other chromosome abnormalities
• women with cardiac disease or cystic fibrosis
  (20)
• Insulin dependant diabetes (2)
• multiple pregnancy following ART
• severe oligoasthenospermia ICSI (3.5)
• previous cancer
• known genetic disease (25 - 50)

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Fertility Rx for HIV ve females
Initial referral info pack sent out
Obstetric Monitoring (HAART, no breast feeding)
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Results C W FP
IUI
IVF/ICSI

• 38 cycles
• 2 EPL
• LB rate/cycle 0

• IVF 46 cycles
• LB 11 (5 EPL)
• LB rate/cycle 24
• ICSI 24 cycles
• LB 7
• LB rate/cycle 29

18 healthy children born following 108 cycles (4
twins) no seroconversions in either partner or
child
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Risks of IVF in ve women(Frodsham et al. Hum
Reproduction 2004)

• 9 HIV ve women IVF/ ICSI
• Detectable virus was found in follicular fluid
• Irrespective of serum viral load
• Detectable virus in some endometrial samples
• Irrespective of serum viral load
• Emphasises need for
• Separate laboratory/laboratory area
• Ongoing monitoring of safety

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Reproductive outcome HIV ve women (Coll et al.
Hum Reproduction 2005O-022)

• HIV ve ?
• lower IVF CPR than HIV ve women
• No difference in ovum donation CPR
• suggests effect of HIV on ovarian reserve

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Lab Risk Assessment Cross Contamination

• Nocosomal (between patients) REPORTED
• Between samples in storage tanks REPORTED
• Between fluids / gametes handled in ACU
• NOT REPORTED BUT POSSIBLE

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Lab Risk Assessment

• HIV HCV detectable in
• follicular fluid
• endometrial samples
• even when patient has ve VL
• (Frodsham et al. Hum Reproduction 2004)

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Laboratory Planning
(Gilling-Smith et al. Hum Reproduction 2005)

• Risk of cross contamination to uninfected gametes
  and embryos can occur
• incubator
• micromanipulation
• cryopreservation
• Risk to laboratory staff

separate laboratory
separate incubators
heat-sealed straws
universal precautions
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The high risk laboratory (Gilling-Smith et al.
Human Reproduction 2005)

• Zero risk does not exist
• Aim to minimise risk and human error
• Segregate low and high risk patients
• Separate laboratory or laboratory area
• Dedicated equipment
• heat sealed straws leakproof for HIV in
  liquid N2
• ? Vapour phase storage

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ACU Infectious cases / year
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Conclusions

• Increased demand for fertility care in HIV
• Risk reduction treatments are available for HIV
• HIV ve men and women have reduced fertility
• Sperm washing is preferable to timed intercourse
• Positive women must be able to access fertility
  treatment

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Future Developments

• Prospective studies analysing safety of timed
  intercourse in men on HAART /- PREP
• Continued multicentre analysis of outcome and
  follow-up data postive men and women
• Extension of methods into third world countries
  as part of a global public health strategy

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Gynaecology James Nicopoullos Leila
Frodsham Rebecca Wood Richard Smith Urology Jonat
han Ramsay Embryology Paula Almeida Maria
Vourlioutis Funding Elton John
Foundation Serono
Immunology Frances Gotch Jill Gilmour Alison
Cox George Rozis Genitourinary Medicine Simon
Barton Fiona Boag CREAThE Enrico Semprini
Acknowledgements
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