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European clinical experience with assisted reproductive technology in HIV-discordant couples

European clinical experience with assisted reproductive technology in HIV-discordant couples. Augusto Enrico Semprini Research Fellow – University of Milan Medical School Honorary Research Fellow – University College of London Honorary Consultant – Chelsea and Westminster Hospital of London.

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European clinical experience with assisted reproductive technology in HIV-discordant couples

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  1. European clinical experiencewith assisted reproductive technology in HIV-discordant couples Augusto Enrico SempriniResearch Fellow – University of Milan Medical SchoolHonorary Research Fellow – University College of LondonHonorary Consultant – Chelsea and Westminster Hospital of London

  2. HIV/AIDS epidemic in Europe WHO/UNAIDS estimates, end of 2004: PLWHA: 2,010,000 (1.40 – 2.86m) Estimated prevalence: 0.4% (range: 0.2-0.6%)

  3. <20% 20-40% 40-60% 60-80% >80% 71% 74% 77% 68% 72% 75% 76% 82% 61% 71% 78% 62.5% 79% 79.5% 81% 66% 85% 61.2% 84% 83% 85% 73% 72% 97% 80% 80.3% 77% 70.9% 80% 72% 79% 70% 80% 64% 79% 62% 75% 75% 78% 77% 81% 80% 63% 90% 74% N/A 68% 82% Males as % of all HIV/AIDS reported cases NOTE: % of AIDS cases in countries not reporting HIV Sources: EuroHIV; national reports; 82,8%

  4. Historical scenario of the HIV epidemic in Italy • From the eighties on there was an epidemy of HIV and HCV infections among drug users with 75% acquiring both infections • In the drug addicted population there is a four to one ratio of males to females • Less than 5% of drug addicted males admits also homosexual behaviour • A large reservoir of HIV-infected young heterosexual males was formed • Couples formed by HIV-infected male and uninfected female adamant to conceive • The sperm washing method was developed as a “harm reduction” measure to avoid sexual transmission of HIV to healthy females “we do not help them have babies… … we help preventing sexual transmission to their healthy female partners and possibily to the child”

  5. REMOVAL OF p18 IMMUNOREACTIVE CELLS FROM THE SEMEN HTLV-III/LAV SEROPOSITIVE MENAugusto E Semprini, A Vucetich, E Morandi, CL Parravicini, G Pardi and AE Beer. Colloque INSERM, Vol. 154, 1987, pp 462 A cytospin preparation of washed spermatozoa, supernatant and the second fraction of the ejaculate were tested against a monoclonal anti-p18 antibody by immunoperoxidase technique. Washed sperm of seropositive and seronegative men were non-reactive, while many mononuclear cells and those in the second fraction of seropositive males were strongly reactive. Experiments are under way to test the possibility of safe intrauterine insemination with processed semen of HIV-positive men desiring a child.

  6. Gradient Sperm-migration Wash Test for residual HIV 45% 90% SPERM WASHINGSemprini et al. – Lancet 1992 Total dilution: 4 x 106

  7. INSEMINATION OF HIV-NEGATIVE WOMEN WITH PROCESSED SEMEN OF HIV-POSITIVE PARTNERS 85 HIV-discordant couples were screened for fertility; 29 women were found suitable for a timed insemination course with the processed semen of their HIV-positive partner. None of the inseminated women seroconverted and 17 pregnancies were achieved in 15 women. All 10 infants born to these mothers remain HIV seronegative. The eldest child is now three years old, healthy and uninfected. (Semprini et al. - Lancet 1992; 340: 1317-19)

  8. AMOUNT OF HIV-1 IN SPERM FRACTION AFTER SPERM PROCESSING TECHNIQUES(normal semen spiked with 106 pg as by Abbot HIV-Ag ELISA)Anderson and Semprini, Fertil Steril 1993, abstract

  9. SPERM WASHING AND REPRODUCTIVE ASSISTANCE IN ITALY (1989 -2005) • 2506 cycles of assisted conception • 732 women treated • 2210 IUI • 73 IVFET • 173 ICSI • 41 ET • 6 ICSI with donor egg

  10. KEY ISSUES FOR ASSISTED CONCEPTION IN HIV-DISCORDANT COUPLES LESS RISKY THAN NATURAL CONCEPTION CLINICAL SELECTION OF ADEQUATE AND FEASIBLE REPRODUCTIVE TECHNOLOGY TO ACHIEVE PREGNANCY

  11. Natural conception in HIV-negative women with HIV-infected partnersL Mandelbrot, I Heard, E Henrion-Geant, R Henrion (Lancet 1997; 349: 850) We followed 104 consecutive pregnancies in 92 HIV-negative women with HIV-positive partners. Couples were advised to pinpoint ovulation in order to reduce possible exposure. Seroconversion was observed in two women at 7 months of pregnancy and in two others post partum. Some authors advocate intrauterine insemination with semen from the HIV-infected males, but the risk of this must be measured against the low background risk of natural conception. Stringent standard of safety must be required before inseminating potentially infected semen.

  12. NATURAL CONCEPTION AND HIV • In 56 HIV-discordant couples trying for a pregnancy on their own after failing to achieve gestation trough sperm washing and ART there was one documented case of HIV transmission to the uninfected woman

  13. CAVEATS ABOUT NATURAL CONCEPTION • Presence of infertility factors in the couple • Assessment of transmissibility of HIV in the couple • Ruling out gential infections • 10% of males without detectable blood viraemia have significant concentration of HIV in their semen • Availability of infertility services if pregnancy does not occur • Long-term effect of discontinuing the use of condoms

  14. TESTING SEMEN FOR THE PRESENCE OF HIV DNA AND RNA

  15. HIV-1 RNA IN SEMEN AND BLOOD PLASMA AS DETECTED BY PCR(LOWER DETECTION LIMIT 100 COPIES/ML)

  16. HIV-1 DNA IN SEMEN AND PBMC BY PCR ASSAY(LOWER DETECTION LIMIT 50 COPIES/ML)

  17. CONRAD Main study – quantitative analysis • 811 couples in original clinical dataset • 243 excluded, 80 lost to follow up • 488 contacted • 369 women and 293 men consented to phone survey • 646 conducted (365 and 281)

  18. CONRAD - findings • 223 (46%) couples achieved pregnancy. • Of the 264 couples who failed to conceive 67 (26%) attempted spontaneous conception. • In these couples we had reports of pregnancy in 56 women and one documented HIV infection. • Survey findings corroborated pilot results.

  19. ART IN COUPLES WITH HIV to avoid sexual transmission of HIV to overcome an infertility problem

  20. INFERTILITY IN COUPLES WITH HIV Couples with HIV suffer an increased prevalence of infertility factors: GENITAL INFECTIONS (up to 50%) TUBAL DAMAGE (up to 10%) ANOVULATION (up to 10%) DYSPERMIA?

  21. PSICHOLOGICAL ASPECTS OF ACHIEVING PREGNANCY BY ASSISTED CONCEPTION IN HIV-DISCORDANT COUPLES

  22. CONRAD - findings • Desire for children • desire for a biological child described as a normal instinct. • Women: renouncing parenthood is a difficult aspect of relationship with an HIV-positive man. • Having a child gives a sense of ‘normalcy’. • Stigma deriving from childlessness. • Child as a continuation of the family and love relationship once the man was gone. • Men and women described learning about assisted conception as opening a door that was closed to them before.

  23. CONRAD - findings Decision making process • No woman was pressured by her partner to have children • Men were more concerned about avoiding the risk of transmission • Physicians had recommended unprotected sex to conceive Experience with program • Very intense • Access was difficult: no info, treatment centers • Failure or interruption of a cycle and loss of pregnancy were the most sensitive moments • Information and psychological suppport - key issues for retaining couples in the program

  24. CONRAD - findings Effect on quality of life • Families are stable (28 separated of 488) • Notwithstanding the tension, the experience highlighted mutual solidarity • Successful outcome had a significant positive impact on quality of life • Men who became fathers: enhanced motivation to follow treatment and remain healthy • Treatment enhanced attention to safe sex behavior • Independent of the outcome, participants felt very strongly that reproductive assistance should be offered. • Participants strongly argued that it was unethical to withhold assisted reproductive services from couples who wanted them

  25. CREAThE CENTRES FOR REPRODUCTIVE ASSISTANCE TECHNIQUES IN hiv-INFECTED INDIVIDUALS IN EUROPE

  26. CREAThE

  27. creathe A non profit organization founded by all European centres providing reproductive assistance to couples with HIV aiming at: • Establishing a forum for collaboration • Establishing a common database • Standardisation of protocols of assistance • Training and support for new centers

  28. Creathe network for assisted conception in couples with HIV • 9 European centres 1. Italy, Milano, San Paolo 2. Italy, Milano, Esman 3. UK, London, C&WS 4. France, Toulouse 5. France, Strasbourg 6. France, Paris, Cochin 7. Switzerland, St. Gallen, KSSG 8. Germany, Mannheim 9. Belgium, Brussels, Free University

  29. IN SIXTEEN YEARS NOT A SINGLE CASE OF SEXUAL TRANSMISSION OF HIV HAS BEEN REPORTED BY ANY CENTER IN EUROPE USING SPERM WASHING WITH SEROLOGIC FOLLOW-UP RATES 75 -100%

  30. “I am glad I had a chance to have my child this way, but I would have gone on and had it anyway…because in our case, what keeps you from having children is fear. And what pushes you to have them is life itself…… and life is always stronger than fear”

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