Reproductive care in human immunodeficiency virus serodiscordant couples with haemophilia.

Dear Editor, Haemophilia is the most common hereditary bleeding disorder: it is spread worldwide, without ethnic or geographical limitations, and remains a life-threatening and often disabling condition. A typical patient with severe haemophilia develops spontaneous haemorrhages into joints, muscles or soft tissues. Until 1985, the mainstay of the treatment of haemophilia was repeated infusions of plasma-derived products. Prior to the development of viral inactivation procedures in the mid-1980s, virtually all haemophiliac patients who had previously received large pool plasma-derived factor concentrates were infected with hepatitis C virus. Moreover, 15% of haemophiliacs were also infected with human immunodeficiency virus (HIV)1. The development and introduction of highly active anti-retroviral therapy (HAART) have transformed the lives of haemophiliacs infected with HIV and redefined this as a chronic, as opposed to fatal, infection. Haemophilic patients infected with HIV lead relatively normal lives and, as a consequence of this improvement in wellbeing, an increasing number of couples consider the possibility of having a child. Reproductive assistance to HIV serodiscordant couples, in which the male partner is HIV-positive and the female partner is negative, could give a significant contribution to the prevention of viral transmission. In such couples, it has been estimated that the HIV-negative female partner has a 0.1–0.5% risk of acquiring HIV per act of unprotected intercourse, considering couples in stable monogamous relationship, not abusing intravenous drugs or participating in any other high-risk activities2. HIV-positive subjects who wish to avoid the risk of transmitting HIV to their uninfected partners, have various possibilities when considering having a family. They may decide to remain childless or to use non-biological methods, such as insemination using donor sperm or adoption. These couples may also opt for techniques of assisted conception using specialised semen preparations, such as sperm washing. The use of this procedure is based on the observation that HIV is present as free virus in seminal plasma and as cell-associated virus in leucocytes, but does not infect spermatozoa3. An HIV-negative female partner can be inseminated with her HIV-positive partner’s sperm, after this virus elimination procedure. We report our experience on 17 HIV-discordant couples referred to the Haemophilia Centre of Milan for reproductive assistance, for whom the sperm washing method was used to remove HIV DNA and RNA from the ejaculate. All couples underwent complete fertility screening to define the optimal reproductive technique to achieve pregnancy after sperm washing. Both members of the couple were informed of a minimal residual risk of HIV transmission and signed written informed consent. All haemophilic patients were on anti-retroviral therapy at the time of semen analysis. The male patients had undetectable concentrations of HIV RNA in their blood plasma (range 50–200 copies/mL) and stable CD4+ T-cell counts for the preceding 6 months. Female partners were tested for HIV and were seronegative. The semen samples were processed by centrifuging in a 40–80% density gradient to separate motile spermatozoa from non-sperm cells. After centrifugation, the supernatant was removed and the sperm pellet was recovered and re-suspended in fresh medium and centrifuged twice before preparation of a final swim-up. As a procedure quality control, an aliquot of washed sperm (approximately 100 μL) was tested for detectable HIV RNA. The assay detection limit was 50 RNA copies/mL. The remaining washed sperm was stored at 4 °C for 22 hours and used, if the HIV test was negative, for reproductive procedures. In the absence of infertility factors in the female partner and with good seminal quality after sperm washing, couples underwent up to three cycles of intrauterine insemination (IUI) with washed spermatozoa. Extracorporeal fertilisation, with standard in vitro fertilisation (IVF) procedures or by direct intracytoplasmic sperm injection (ICSI) into the oocyte, was selected forthwith when required by the couple’s fertility parameters or used when three cycles of IUI failed to achieve a pregnancy. Results for IUI, IVF and ICSI using washed sperm in our series of 17 treated patients are shown in Table I. Table I Assisted reproductive techniques and pregnancy outcomes in HIV-discordant couples. Four couples (23.5%) underwent IUI. The mean age of the female partners was 32.5 years (range, 30 to 34 years). Three singleton pregnancies were achieved and were carried to term (75%). The mean age of the 13 women (76.5%) who underwent IVF/ICSI treatment was 34.6 years (range, 27 to 42 years). One of the two women treated with IVF became pregnant; her pregnancy is currently ongoing. Among the 11 women treated with ICSI, 6 clinical pregnancies were achieved (54%): three singletons, one twin and one triplet. Only one singleton was miscarried at the eighth week. All the women who underwent these reproductive procedures were monitored for HIV infection in the third and sixth months after the treatment with washed sperm and they were all negative. The women were tested again after delivery and the results were negative in all cases. All the neonates delivered were healthy and uninfected. Sperm washing coupled with IUI/ICSI offers haemophiliacs infected with HIV the possibility of becoming fathers without the risk of transmitting the HIV infection to their partners and offspring, showing that providing information on reproductive possibilities should be part of the management of haemophiliacs, enabling them to make the optimal reproductive choice. Recently an alternative method, based on the potential role of oral pre-exposure prophylaxis (PrEP) with antiretroviral therapy, has been developed to achieve safe conception in HIV-discordant couples. Research in animal models has provided evidence for the efficacy of PrEP drugs, and has formed the basis for design of human clinical trials4,5. On-going trials will answer many of the outstanding questions about the effects of PrEP drugs, including optimal dosing schedule, route of administration, and efficacy for different types of HIV exposure.