Haemophilia Foundation Australia is only responding to this question.
BACKGROUND
Haemophilia Foundation Australia (HFA) is the national peak body representing people with bleeding disorders and their partners, families and carers.
Inherited bleeding disorders such as haemophilia, von Willebrand disorder (VWD) and rare clotting factor deficiencies occur when a person inherits a gene mutation/alteration in one of the blood clotting factor genes, such as the gene for factor VIII or IX (haemophilia), for von Willebrand factor (VWD), or for factors I, II, V, V+VIII, X, XI, XIII (rare clotting factor deficiencies). In some cases the individual may have experienced a spontaneous mutation in a clotting factor gene rather than inheriting it, but then may pass the altered gene on to their children.
As a result of the gene alteration, the clotting factor protein may be deficient or missing or not work properly, causing bleeding episodes into muscles, joints, organs or mucous membranes of varying severity, and long-term complications such as joint or muscle damage and arthropathy, pain and disability, and anaemia from menorrhagia. There can also be prolonged bleeding after childbirth or invasive medical or dental procedures/surgery. Bleeding episodes can be life- or limb-threatening. Treatment is required to prevent or stop bleeding, often with infusions of clotting factor replacement therapy.
For the community affected by inherited bleeding disorders, and in particular haemophilia, there are two gene technology applications that are currently prominent:
• IVF with pre-implantation genetic diagnosis (PGD): using IVF technology to test embryos for the family gene alteration, before embryo implantation and pregnancy.
• Gene therapy for haemophilia (factor VIII or IX deficiency): where people with haemophilia receive an infusion of a virus carrying a functioning factor VIII or IX protein so that “normal” factor VIII or IX is reproduced in the liver, overtaking the altered factor VIII or IX that causes haemophilia.
ACCESS AND ETHICAL CONSIDERATIONS
Access to these technologies can be limited for a number of reasons.
IVF with PGD:
• Cost
• Local availability of specialist services
• Affected individuals are unaware of this as an option or are not offered a referral.
Gene therapy for haemophilia
• Currently available in clinical trial only.
IVF with PGD
If a person is affected by a bleeding disorder, family planning decisions can be complex and very personal. In haemophilia, for example, the decision to have children or use gene technology such as IVF with PGD will take into consideration:
• The individual and couple’s personal feelings and cultural and religious beliefs
• Their lifestyle
• How they deal with haemophilia
• Family pressures
• How many children they already have with haemophilia
• Their chance of having another child with haemophilia
• Other family members’ experiences with haemophilia.
Having a child with haemophilia can be a significant burden on a family. For some parents, this is an acceptable proposition. Others decide that they could not manage or would prefer not to take on this situation. These parents may decide to use IVF with PGD to select an embryo that does not have the haemophilia gene alteration.
HFA supports equitable access to IVF with PGD as an option for individual family planning decision-making in haemophilia.
However, the availability of this option creates an uneasy space for this community, where the possibility of selecting out children with haemophilia needs to be balanced with the human rights aspect of, as expressed in the United Nations Charter, “the inherent dignity and worth and the equal and inalienable rights of all members of the human family”, including people with a health condition such as a bleeding disorder.
From a community perspective it is crucial always to maintain careful regulatory control over this practice so that parents feel free to decide to let nature take its course and have the potential that their next pregnancy might produce a child with haemophilia rather than being or feeling obliged to have a medical intervention to prevent this. This ethical issue has a strong impact particularly on young people with haemophilia and their concerns about how they are perceived by the wider community. One young man with severe haemophilia highlighted this issue, saying that a priority for him was “For me personally, making prospective mothers of children with haemophilia aware that it shouldn’t be something to abort over.” (1)
Gene therapy
Gene therapy is commonly described as a “cure” for haemophilia. In reality, for participants in some current gene therapy clinical trials factor activity levels may improve from severe to mild haemophilia, reducing the frequency of bleeding episodes so that they are unusual and more likely related to injury and trauma. (2) Even if the individual’s factor activity levels are sustained in the normal range and they no longer technically have haemophilia (and are "cured"), they may well have residual lifelong complications of a lifetime of bleeding episodes, for example, with joint and muscle damage. Moreover, as this treatment is experimental, there will need to be ongoing monitoring to ensure that factor levels are sustained, to identify and manage further bleeding episodes and to check for other complications, including those related to bleeding. These therapies, like other new prophylactic treatments, also create new problems for people with bleeding disorders, such as being at risk of heart disease and stroke when this was formerly very unusual in someone with a clotting factor deficiency.
HFA believes that it is important to recognise that people who have gene therapy and are “cured” of their haemophilia may still need access to management by their Haemophilia Treatment Centre (HTC) and to be encouraged to continue with their care there. These HTCs are specialist centres in each Australian state and territory and designated by their state/territory government. They provide comprehensive care by a multidisciplinary team with expertise in bleeding disorders and use the national Australian Bleeding Disorders Registry (ABDR) system to record all investigations, treatments, allocation of therapeutic products and adverse reactions. The multidisciplinary team works with both national and international peers to maintain best practice in managing bleeding disorders and their complications (3,4).
Access to ongoing management by their HTC after successful gene therapy, alongside collaborative medical care from the gene therapy team, will be critical to people with bleeding disorders for:
• Short and long-term monitoring and management by a multidisciplinary team with the expertise to recognise, identify and treat problems relating to bleeding
• Access to specialised programs for the health and wellbeing of people with bleeding disorders and their complications, eg physiotherapy, education around ageing well, preventing heart disease and stroke when factor levels improve
• Collection and aggregation of data in the ABDR to investigate the impact of gene therapy in comparison to other treatments.
Where people with bleeding disorders are successfully treated with gene therapy, it will be very important for the National Gene Technology Scheme to take the need for ongoing input by a specialist Haemophilia Treatment Centre into account, and for the Australian health system to be able to accommodate this.
(1) Haemophilia Foundation Australia. Beyond Prophylaxis Project: understanding and addressing the unmet needs of young people with bleeding disorders. Needs assessment report. Melbourne: HFA, 2012.
< https://www.haemophilia.org.au/HFA/media/Documents/Young%20people/Beyond-Prophylaxis-HFA-Youth-Needs-Assessment.pdf >
(2) George, LA, Sullivan, SK, Giermasz, A, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med 2017; 377:2215-222
< http://www.nejm.org/doi/full/10.1056/NEJMoa1708538 >
(3) Australian Bleeding Disorders Registry Annual Report 2015-16. Canberra: National Blood Authority, 2017
< https://www.blood.gov.au/system/files/abdr-annual-report-2015-16-final.pdf >
(4) Australian Haemophilia Centre Directors’ Organisation. Guidelines for the management of haemophilia in Australia. Canberra; National Blood Authority, 2016.
< https://www.blood.gov.au/haemophilia-guidelines >