parenting and hiv: strategies for reducing risk dr carole gilling-smith assisted conception unit,...
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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
Lecture Objectives
1. HIV in 2008 - update
2. Ethical concerns
3. Reducing transmission risk To uninfected partner and unborn child
4. Impact of HIV on fertility & reproductive outcome
5. Safety of staff and non-infected patientsLaboratory adaptations
6. The way forward
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 AIDSProtected Intercourse encouraged
HIV : Is parenting an option?
In developed countries HIV defined as a chronic diseaseARV 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
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
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 behaviourdrug abuseprostitution
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).”
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”
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
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 treatmentSperm washing regarded as criminal action in some
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
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
Reproductive options forHIV +ve ♂ and HIV negative ♀
Unprotected timed intercourse (natural conception
Donor insemination
Adoption
Sperm washing and insemination
seminal fluidNSC
sperm
NSCNSC
NSC
NSC
sperm
HIV contamination of semen
L Kim et al, AIDS 1999, 13: 645-51
semen
density gradient
dead sperm & non-sperm cells
seminal plasma
live sperm2
NASBA check for HIV-1 RNA(detection limit > 50copies/ml)
4
live sperm
SPERM WASHING PROTOCOL
medium
semen
density gradient
semen
density gradient
1
semen
density gradient
seminal plasma
dead sperm & non-sperm cells
seminal plasma
live sperm
dead sperm & non-sperm cells
seminal plasma
live sperm2
dead sperm & non-sperm cells
seminal plasma
live sperm
live sperm
medium
swim-up
3
live sperm
medium
4
NASBA check for HIV-1 RNA(detection limit > 50copies/ml)
Management of HIV+ve men
LOCAL HOSPITALFertility Screen
Sexual Health Screen
Initial referralinfo sent out
IUI2nd appointment ACU
Sperm sample washed and frozen
Pre-conceptual Counselling
1st appointment ACUHistory/Results reviewed
Semen analysis
IVF or ICSI
Pre-treatment work-up
♂ & ♀ : sexual health screen
♀: pelvic scan & endocrine profile (day 2 - 5)
mid-luteal progesterone
tubal assessment
♂ & ♀ : counselling
♂: IVF laboratory semen analysis
Reproductive Counselling: information & implications
understanding risks and benefits of each Rx
SPERM WASHING investigations needed and whyhow is it doneviral testing before insemination the female cycle and timed inseminationviral testing after insemination risks to partner and future child
Consent / legal issues
Method is risk reduction not risk eliminationConsent form
Suggest freeze a washed -ve sampleBetter identify quality of sperm post washBack up if failed wash on day of treatmentBack up problems producing a sample
Results : C & W SWP 238 couples
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%
IUI IVF/ICSI
90 healthy children born following 622 cycles (3 twins): 38% successful no seroconversions in either partner or child
Source of HIV infection (n=110)
Source of HIV infection Patients (% of total)
Sexual 49 (44.5%)
Haematological 18 (16.4%)
IVDA 8 (7.3%)
Unknown 35 (31.8%)
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/mlUse of ARV
CD4 count has no impact
Severe OATS & Azospermia
SSR, sperm washing and ICSINicopoullos 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?
Centres for Reproductive Assistance Techniques in HIV in Europe
17 centres in 9 countries to pool data to assess:safety & efficacyepidemiologybehavioural and psychosocial aspects
draw up guidelines for counselling and treatment
Literature Review: Risks of sperm washing
Bujan et al, AIDS 2007: Multicentre Retrospective study8 European centres 1036 serodiscordant couples3396 treatment cycles
o 2840 IUIso 107 IVFo 394 ICSIo 49 FET
NO SEROCONVERSIONSProbability of infection zero
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
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 STD’s , VL fully suppressed for 6 months
Literature Review: Risks of unprotected vaginal intercourse
Quinn et al, 2000 Uganda: prospective study
453 HIV +ve ♂ + HIV -ve ♀ risk of transmission correlated with VLNo transmission if VL < 1000 copies/ml
Castilla et al, 2005: prospective study over 14 years
393 HIV +ve ♂ + HIV -ve ♀ (1991-2003)No transmission if ♂ on HAART8.6% risk of transmission if not
Literature Review: Risks of natural conception
Mandelbrot et al, 1997: Prospective study 92 HIV +ve ♂ + HIV -ve ♀ timed unprotected intercourse to conceive4 seroconversions
Barreiro et al, 2000: retrospective study of 62 discordant couples . HIV +ve ♂ had undetectable VL through HAART for 6 monthsNo seroconversions
Vernazza et al, 2007: prospective study 22 HIV +ve ♂ natural conception + PREP (License to Love)No seroconversions
Can HAART reduce risk to Zero ?
In men on HAART fully suppressed with -ve VL Mathematical models give risk of HIV transmission during intercourse
< 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
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)
Seminal viral shedding on HAART(Gilling-Smith et al. Hum Reproduction 2008)
Detectable HIV-1 in men on HAART with VL< 50 post sperm washing2 / 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)
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
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
HIV +ve women: Increased subfertility
No signif difference in endocrine profile / cycle Hx(D2-5 FSH, LH)
Increased prevalence of tubal blockage41% versus 14%
Reduced ovarian reserve (Coll et al, 2007)
Demand for IVF is rising
equal or greater risks to offspring in:women > 40
trisomy 21 and other chromosome abnormalitieswomen with cardiac disease or cystic fibrosis (20%) Insulin dependant diabetes (2%)multiple pregnancy following ARTsevere oligoasthenospermia & ICSI (3.5%)previous cancerknown genetic disease (25 - 50%)
HIV +ve women & MCT risk
LOCAL HOSPITALFertility Screen
Sexual Health Screen
Fertility Rx for HIV +ve females
Initial referralinfo pack sent out
IUI
Pre-conceptualCounseling
1st appointment ACUHistory/Results reviewed
Semenanalysis IVF or ICSI
Obstetric Monitoring(HAART, no breast feeding)
Results : C & W FP
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%
IUI IVF/ICSI
18 healthy children born following 108 cycles (4 twins) no seroconversions in either partner or child
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 areaOngoing monitoring of safety
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
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
Lab Risk Assessment
HIV & HCV detectable in follicular fluid endometrial samples even when patient has –ve VL
(Frodsham et al. Hum Reproduction 2004)
Laboratory Planning
Risk of cross contamination to uninfected gametes and embryos can occur: incubatormicromanipulationcryopreservation
Risk to laboratory staff
separate laboratory
separate incubators
heat-sealed straws
universal precautions
(Gilling-Smith et al. Hum Reproduction 2005)
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
ACU Infectious cases / year
0
20
40
60
80
100
120
1999 2000 2001 2002 2003 2004 2005 2006 2007
ca
se
s/y
ea
r
HIV
HBV
HCV
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
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
GynaecologyJames NicopoullosLeila FrodshamRebecca WoodRichard Smith
UrologyJonathan Ramsay
EmbryologyPaula AlmeidaMaria Vourlioutis
FundingElton John FoundationSerono
ImmunologyFrances GotchJill GilmourAlison CoxGeorge Rozis
Genitourinary MedicineSimon BartonFiona Boag
CREAThEEnrico Semprini
Acknowledgements