1. 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

3. 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

4. HIV – The Global Situation
> 42 million infected with HIV-1 worldwide
95% of new infections in subsaharan Africa
majority of transmissions heterosexual
limited resources and access to antiretrovirals
Majority of those infected will die of AIDS
Protected Intercourse encouraged

5. 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 < 1%
Increased prevalence of subfertility in HIV patients
Demand for reproductive care increasing

6. Need to understand the risks and
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?
Need to understand the risks and
put aside prejudice

9. Ethical concerns: welfare of the child (Frodsham et al
Ethical concerns: welfare of the child (Frodsham et al. Hum Reproduction 2005; 19:2420)
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

10. UK Law: who should receive ART ?
HFEA Act 1990 Clause 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).”

11. 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”

12. 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

13. Legal & Ethical views in the USA
Changes in policy by:
ACOG (2001 Committee opinion 255)
ASRM (Fert Stert 2002 , 77;218-22)
advocating policies of non-discrimination and equal access to fertility care
Wide variation between states in treatments offered
< 5% of clinics offering any form of treatment
Sperm washing regarded as criminal action in some

14. Suggested criteria for treatment
CD4 count > 200
Undetectable / low viral load
‘stable’ disease
Reproductive counselling identifies no issues F+
Effective ‘safe’ antiretroviral medication can be used during pregnancy

15. 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

16. Reproductive options for HIV +ve ♂ and HIV negative ♀
Unprotected timed intercourse (natural conception
Donor insemination
Adoption
Sperm washing and insemination

17. HIV contamination of semen
seminal fluid
NSC
sperm
L Kim et al, AIDS 1999, 13:

20. SPERM WASHING PROTOCOL1
semen
density gradient
semen
semen
semen
NASBA check for HIV-1 RNA
(detection limit > 50copies/ml)
density gradient
density gradient
density gradient 2
dead sperm & non-sperm cells
seminal plasma
live sperm
dead sperm & non-sperm cells
seminal plasma
live sperm
seminal plasma
seminal plasma
seminal plasma
dead sperm & non-sperm cells
dead sperm & non-sperm cells
swim-up 3
live sperm
medium
live sperm
live sperm 2 4 4
medium
medium
NASBA check for HIV-1 RNA
(detection limit > 50copies/ml)
live sperm
live sperm

21. Management of HIV+ve men
LOCAL HOSPITAL
Fertility Screen
Sexual Health Screen
Initial referral
info sent out
Pre-conceptual
Counselling
1st appointment ACU
History/Results reviewed
Semen analysis
2nd appointment ACU
Sperm sample
washed and frozen
IVF or ICSI
IUI

22. Pre-treatment work-up
♂ & ♀ : sexual health screen
♀: pelvic scan & endocrine profile (day 2 - 5)
mid-luteal progesterone
tubal assessment
♂ & ♀ : counselling
♂: IVF laboratory semen analysis

23. 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

24. 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

25. Ultrasound monitoring of the ovary: follicle tracking
18mm
Day Day Day 13

26. Intrauterine Insemination (IUI)
uterus
cervix
prepared
sperm

27. Egg collection

28. Insemination (3 hours)

29. ICSI (3 hours)

30. Eight Cell Embryo (72 hours)

31. Embryo transfer (ET)

32. Results : C & W SWP 238 couples
IUI
IVF/ICSI
415 cycles
LB 39
CPR / cycle: 13.3%
LB rate/cycle:9.4%
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

33. Source of HIV infection (n=110)
Patients (% of total)
Sexual
49 (44.5%)
Haematological
18 (16.4%)
IVDA
8 (7.3%)
Unknown
35 (31.8%)

34. HIV and IUI outcome (Nicopoullos et al. Hum Reproduction 2004;19:2289)
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 < 1000 copies/ml
Use of ARV
CD4 count has no impact
If we summarise our results.
Although sperm parameters, and most consistently TMC inseminated, have been shown to successfully predict the outcome of IUI in reports of HIV-ve men none had a significant impact following sperm-washing in our cohort of patients.
Although there is a trend towards improved CPR with controlled ovarian stimulation, at our present sample size this does not achieve statistical significance. This supports our current practice of initially offering couples natural cycle IUI.
However, in view of the trend towards impaired outcome with increasing age, it may also be reasonable to proceed with controlled ovarian stimulation and IUI immediately at advanced maternal ages. This option may also be sensible in view of the cost involved per cycle, minimal funding available for the fertility treatment of HIV-infected couples and the low incomes of many couples seeking treatment.
Only markers of HIV-infection significantly affected IUI outcome in our cohort of cycles. CPR was significantly higher in those cycles from men with low VL (<1000copies/ml) and in those from men on anti-retroviral therapy.

35. 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 (> 5.106/ml)
Can testicular sperm be used without washing and/or testing?

36. 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

37. 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

38. North American Experience (Sauer et al, Fert Steril 2008)
Sauer et al (AJOG 2002, 186;627-33)
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

39. Swiss National AIDS Commission Swiss 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 STD’s , VL fully suppressed for 6 months

40. 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 < 1000 copies/ml
Castilla et al, 2005: prospective study over 14 years
393 HIV +ve ♂ + HIV -ve ♀ ( )
No transmission if ♂ on HAART
8.6% risk of transmission if not

41. 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)

42. Can HAART reduce risk to Zero ?
In men on HAART fully suppressed with -ve VL
Mathematical models give risk of HIV transmission during intercourse < %
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

43. Seminal viral shedding on HAART (Gilling-Smith et al
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 cells / mm3)
No correlation with type of HAART (2 cases on Tenofovir)

44. Seminal viral shedding on HAART (Gilling-Smith et al
Seminal viral shedding on HAART (Gilling-Smith et al. Hum Reproduction 2008)
Detectable HIV-1 in men on HAART with VL< 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)

45. Seminal viral shedding on HAART (Gilling-Smith et al
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

47. Reproductive options for HIV +ve ♂ and HIV negative ♀
Unprotected timed intercourse (natural conception)
Transmission risk 0.3% %
Donor insemination
Adoption
Sperm washing and insemination
No reported transmissions to child or partner

48. 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)
The most dramatic results were seen in the tests of tubal patency. 41% of the patients seen had tubal factor infertility. 16 of the 21 patients with abnormal HSG/laparoscopy had bilateral tubal blockage with the other 5 having 1 patent tube (2 with irregular outlines to the patent tube). In comparison, Hull’s population study of the aetiology of subfertility in the BMJ of 1985 found only a 14% rate of tubal factor infertility. Our patients all have a full sexual health screen prior to review and no co existing sexually transmitted infections were found. Only 1 patient has a history of identified sexually transmitted infection.
The patients who had unknown tubal status were either lost to follow up or their partners had very suboptimal semenalysis that would necessitate IVF/ICSI.
Demand for IVF is rising

49. HIV +ve women & MCT risk equal or greater risks to offspring in:
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 ( %)

50. Fertility Rx for HIV +ve females
LOCAL HOSPITAL
Fertility Screen
Sexual Health Screen
Initial referral
info pack sent out
Pre-conceptual
Counseling
1st appointment ACU
History/Results reviewed
Semenanalysis
IVF or ICSI
IUI
Obstetric Monitoring
(HAART, no breast feeding)

51. 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

52. 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
Emphasises need for:
Separate laboratory/laboratory area
Ongoing monitoring of safety
Fractions are the number of follicles with HIV found in them/total number of follicles-no obvious pattern to aspirate v. flush1 v. flush 2

53. Reproductive outcome :HIV +ve women (Coll et al
Reproductive outcome :HIV +ve women (Coll et al. Hum Reproduction 2005;O-022)
HIV +ve ♂
lower IVF CPR than HIV –ve women
No difference in ovum donation CPR
suggests effect of HIV on ovarian reserve

54. 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

55. Lab Risk Assessment HIV & HCV detectable in
follicular fluid
endometrial samples
even when patient has –ve VL
(Frodsham et al. Hum Reproduction 2004)

56. 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

57. VEC / ET Room
Low Risk Lab
High Risk Lab

58. 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

60. ACU Infectious cases / year

61. 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

62. 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

63. Acknowledgements Gynaecology Immunology James Nicopoullos
Leila Frodsham
Rebecca Wood
Richard Smith
Urology
Jonathan 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