Effectiveness and Experiences of Gene Therapy in Haemophilia Patients

Introduction

Haemophilia is referred to as the genetic disorder inherited through genetic information passed from the parents to be offspring that results the blood of the individuals lose their clotting ability. It results people getting bruised or cuts to bleed for long hours leading to create increased risk of bleeding in the brain or inside the joints (Peters & Harris, 2018). The extensive bleeding in haemophilia patients may lead them to face permanent brain damage, seizure and lower level of consciousness (Ghosh & Ghosh, 2016). Haemophilia A is caused due to reduced amount of clotting factor VIII and haemophilia B is caused due to reduced level of clotting factor IX (Ljung et al., 2019). Haemophilia mainly affects men and is rare. In the UK, 1 in 10,000 are affected by Haemophilia A and 1 in 40,000 are affected by Haemophilia B (NHS, 2021). The use of gene therapy is seen to be effective in the treatment of haemophilia because it helps in introducing a modified virus to implement a copy of the gene which encode for the missing clotting factor allowing the missing factors to be included in the blood (Batty & Lillicrap, 2019). Thus, to understand the extent to which gene therapy in haemophilia is effective as well as experiences regarding it among haemophilia patients, the current study is been executed. The five articles by Miesbach & Klamroth (2020), Vasquez-Loarte et al. (2020), Machin, Ragni & Smith (2018), Pasi et al. (2020) and Cook et al. (2020) are specifically included as they contain information on the common theme of gene therapy experience and impact in haemophilia patients. Moreover, the mentioned articles are chosen as they contain most updated information regarding gene therapy for haemophilia patients.

Annotated Bibliography

Article 1: Vasquez-Loarte, T. C., Lucas, T. L., Harris-Wai, J., & Bowen, D. J. (2020). Beliefs and Values About Gene Therapy and In-Utero Gene Editing in Patients with Hemophilia and Their Relatives. The Patient-Patient-Centered Outcomes Research, 13(5), 633-642

Vasquez-Loarte et al. (2020) aims to determine the beliefs and values regarding gene therapy compared to In-utero gene editing in patients with haemophilia. The study used qualitative study design and semi-structured interviews is gathering information. This acts as strength for the study because it allowed developing in-depth experiences, feeling, beliefs and attitude of patients with haemophilia to consider gene therapy or In-utero gene editing for their heath improvement (Kallio et al., 2016). However, one of the key limitations faced is selection bias as the participants of the study are contacted by the researchers based on their understanding of haemophilia genetic disorder and not on their perception or understanding regarding gene therapy or In-utero gene editing. It led to hinder achieving the generalisation of the results as the selected participants do not represent entire population of haemophilia. Further, the 21 participants selected were not informed about different between somatic and germline gene editing which create confusion regarding In-utero gene editing in the participants and that may have negatively influenced the results. This is because though results mentioned most of the participants preferred gene therapy as better treatment for haemophilia than In-utero gene editing, but few of them replied to the fact in spontaneous manner. This indicates they may have not replied with effective understanding of the two methods to appropriately determine their choices.

Article 2: Miesbach, W., & Klamroth, R. (2020). The patient experience of gene therapy for hemophilia: qualitative interviews with trial patients. Patient preference and adherence, 14, 767.

The study by Miesbach & Klamroth (2020) aimed to identify the views of haemophilia patients regarding gene therapy. The study included 3 participants who are interviewed through telephone in gathering information. The small sample size acted as limitation for the study because it caused data saturation and lowered power of the study while increasing chances of margin of error in data collection (Van de Schoot & Miocević, 2020). The results mention that all three of the participants with haemophilia after gene therapy expressed greater activity in sports with lower bleeds and no negative consequence of the therapy, but they expressed anxiety for not knowing the viability of the therapy in avoiding relapse of the condition. The study used retrospective case study design in executing the research. The use of the design acted as strength for the study because it allowed cheaper and faster gathering of information regarding the rare exposure of haemophilia on managed with gene therapy (Lee et al., 2016). However, limitation faced with the use of the study design is that it created gathering of inferior level of evidence that is prone to cause misclassification bias and error in results.

Article 3: Machin, N., Ragni, M. V., & Smith, K. J. (2018). Gene therapy in hemophilia A: a cost-effectiveness analysis. Blood advances, 2(14), 1792-1798

In the study by Machin, Ragni and Smith (2018), the aim is to create cost-effectiveness analysis of gene therapy use in treatment for haemophilia. In the study, Markov state–transition model is developed to determine the cost-effectiveness of gene therapy in haemophilia treatment. In determining information for the study, the 30-year-old hypothetical cohort of haemophilia patients are gathered, and their quality-adjusted-life-years are measured. The results revealed that gene therapy is cost-effective in treatment of haemophilia as $1.6M and were <$100 000 per 1 QALY was gained in people with the therapy whereas those initiated prophylaxis treatments required spending <$1.7M as initial cost. One of the limitations in gathering information for the study is that lack of commercial availability of gene therapy for haemophilia treatment is ignored while framing the model for cost analysis which may have created bias in the study results in calculating cost-effectiveness. The other limitation faced is that no long-term information was available that ensured gene therapy to be effective for long in treatment and control of haemophilia in patients. However, the strength of the study is that the results gathered could be generalised as the utilities, clinical probability and cost-effectiveness o gene therapy identified are different among various age groups indicating wide applicability of the results.

Article 4: Cook, K., Forbes, S. P., Adamski, K., Ma, J. J., Chawla, A., & Garrison Jr, L. P. (2020). Assessing the potential cost-effectiveness of a gene therapy for the treatment of hemophilia A. Journal of medical economics, 23(5), 501-512.

The study by Cook et al. (2020) aimed to examine the cost-effectiveness of prophylactic FVIII as gene therapy compared to valoctocogene roxaparvovec use for therapy. The study used information from 10,000 patients to determine the experiences regarding use of different gene therapy. The sample size acts as strength for the study as it ensures high generalisation of the results to be reached with increased powerful research to be executed as the sample represented real-world haemophilia patients (Van de Schoot & Miocević, 2020). The limitation of the study is that it includes individual-based, state-transition microsimulation model for analysis of data which works on evidence-based assumptions due to limited availability of data regarding cost-effectiveness of gene therapy in haemophilia. However, the uncertainty is resolved through heterogenous inclusion of data among varied populations regarding lifetime bleeding rate, gene therapy durability and others. The use of cohort study design also created limited opportunity in capturing the heterogenous response of individuals regarding duration and variation of response regarding prophylactic FVIII. The study concludes that valoctocogene roxaparvovec on average allows saving cost for haemophilia management by nearly $6.8 million per patient. The use of valoctocogene roxaparvovec also expressed lesser bleeding and reduced accumulated joint bleeds in patients with haemophilia compared to those who used prophylactic FVIII.

Article 5: Pasi, K. J., Rangarajan, S., Mitchell, N., Lester, W., Symington, E., Madan, B., ... & Wong, W. Y. (2020). Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. New England Journal of Medicine, 382(1), 29-40.

Pasi et al. (2020) aimed to determine the impact of Adeno-associated virus (AAV)–mediated gene therapy in haemophilia A patients through multi follow-up year process. For this purpose, the study included 15 adults who are biologically and clinically classified as being severe haemophilic. The small sample size created limitation of lack of gathering specific information of variables from the gene therapy which contributed to manage individual VIII levels in patients. However, the strength of the study is that follow-up action for multiple years helped in determine the long-term efficiency of Adeno-associated virus (AAV)–mediated gene therapy to control haemophilia in patients. The results conclude that the use of AAV gene therapy was effective in lowering joint bleeds of five participants out of six showing its increased efficiency is managing symptoms of haemophilia that are fatal in condition. Moreover, it is determined that gene therapy of 4×1013 vg per kilogram or 6×1013 vg per kilogram in patients are effective in cessation of annualised bleeding and use of prophylactic factor VIII. Thus, the strength of the study is that it specifies the amount of gen therapy required on an average in haemophilia patients to control their diseases which was not mentioned in previous studies. Therefore, it allows the study to be used for executing evidence-based practice in determining gene therapy level for haemophilia patients.

Conclusion

The studies conclude that gene therapy is intervention for treatment of haemophilia in patients suffering from the condition. The patients with haemophilia and their relatives prefer gene therapy over gene editing as it is considered as a potential cure from the disease where as gene editing involves controversial methods that are not always supported for acceptance. Moreover, gene therapy is mentioned to be cost-effective leading individuals with haemophilia to use less amount of money in accessing care for the disease. The studies further reveal that gene therapy contributes to effective lowering of bleeding from wounds, internal bleeding from joints and other associated symptoms of haemophilia patients ensuring them increased quality of life over the years. It is evident as haemophilia patients after gene therapy expressed increased ability to participate in sports and other strenuous activity without facing any clinical issues. The Adeno-associated virus (AAV)–mediated gene therapy is seen to create long-term management of haemophilia A and B patients compared to the use of prophylaxis with factor VIII (FVIII).

References

Batty, P., & Lillicrap, D. (2019). Advances and challenges for hemophilia gene therapy. Human molecular genetics, 28(R1), R95-R101. https://academic.oup.com/hmg/article/28/R1/R95/5537029

Ghosh, K., & Ghosh, K. (2016). Management of haemophilia in developing countries: challenges and options. Indian Journal of Hematology and Blood Transfusion, 32(3), 347-355. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930749/

Kallio, H., Pietilä, A. M., Johnson, M., & Kangasniemi, M. (2016). Systematic methodological review: developing a framework for a qualitative semi‐structured interview guide. Journal of advanced nursing, 72(12), 2954-2965. https://usir.salford.ac.uk/id/eprint/39197/1/jan13031%20Martin%20Johnson%20June%202016.pdf

Lee, S. Y., Ahn, K., Kim, J., Jang, G. C., Min, T. K., Yang, H. J., ... & Lee, S. (2016). A multicenter retrospective case study of anaphylaxis triggers by age in Korean children. Allergy, asthma & immunology research, 8(6), 535-540. https://synapse.koreamed.org/articles/1052623

Ljung, R., Auerswald, G., Benson, G., Dolan, G., Duffy, A., Hermans, C., ... & Santagostino, E. (2019). Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult‐to‐treat patients. European journal of haematology, 102(2), 111-122. https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/ejh.13193

Miesbach, W., & Klamroth, R. (2020). The patient experience of gene therapy for hemophilia: qualitative interviews with trial patients. Patient preference and adherence, 14, 767. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184858/

Vasquez-Loarte, T. C., Lucas, T. L., Harris-Wai, J., & Bowen, D. J. (2020). Beliefs and Values About Gene Therapy and In-Utero Gene Editing in Patients with Hemophilia and Their Relatives. The

Patient-Patient-Centered Outcomes Research, 13(5), 633-642. https://www.researchgate.net/profile/Tania-Vasquez-4/publication/343652486_Beliefs_and_Values_About_Gene_Therapy_and_In-Utero_Gene_Editing_in_Patients_with_Hemophilia_and_Their_Relatives/links/5fe7f23f299bf140884aad29/Beliefs-and-Values-About-Gene-Therap

y-and-In-Utero-Gene-Editing-in-Patients-with-Hemophilia-and-Their-Relatives.pdf Machin, N., Ragni, M. V., & Smith, K. J. (2018). Gene therapy in hemophilia A: a cost-effectiveness analysis. Blood advances, 2(14), 1792-1798.

Cook, K., Forbes, S. P., Adamski, K., Ma, J. J., Chawla, A., & Garrison Jr, L. P. (2020). Assessing the potential cost-effectiveness of a gene therapy for the treatment of hemophilia A. Journal of medical economics, 23(5), 501-512. https://www.tandfonline.com/doi/pdf/10.1080/13696998.2020.1721508

Pasi, K. J., Rangarajan, S., Mitchell, N., Lester, W., Symington, E., Madan, B., ... & Wong, W. Y. (2020). Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. New England Journal of Medicine, 382(1), 29-40. https://www.nejm.org/doi/full/10.1056/NEJMoa1908490

NHS 2021, Haemophilia, https://www.england.nhs.uk/wp-content/uploads/2013/06/b05-haemophilia.pdf

Peters, R., & Harris, T. (2018). Advances and innovations in haemophilia treatment. Nature Reviews Drug Discovery, 17(7), 493-508. https://www.nature.com/articles/nrd.2018.70

Van de Schoot, R., & Miocević, M. (2020). Small sample size solutions: A guide for applied researchers and practitioners (p. 284). Taylor & Francis. https://library.oapen.org/bitstream/handle/20.500.12657/22385/9780367221898_text%20(1).pdf?sequence=1

Appendix