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

Ultrasound monitoring of the ovary:follicle tracking

Day 8 Day 11 Day 13

18mm

Intrauterine Insemination (IUI)

uterus

cervixprepared sperm

Egg collection

Insemination (3 hours)

ICSI (3 hours)

Eight Cell Embryo (72 hours)

Embryo transfer (ET)

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)

VEC / ET Room

Low Risk Lab

High Risk Lab

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

www.justgiving.com/carolegs