Gene Therapy in Hemophilia A: Achievements, Challenges, and Perspectives.

Strides in advancements of care of persons with hemophilia include development of long-acting factor replacement therapies, novel substitution and hemostatic rebalancing agents, and most recently approved gene therapy. Several decades of preclinical and clinical trials have led to development of adeno-associated viral (AAV) vector-mediated gene transfer for endogenous production of factor VIII (FVIII) in hemophilia A (HA). Only one gene therapy product for HA (valoctocogene roxaparvovec) has been approved by regulatory authorities. Results of valoctocogene roxaparvovec trial show significant improvement in bleeding rates and use of factor replacement therapy; however, sustainability and duration of response show variability with overall decline in FVIII expression over time. Further challenges include untoward adverse effects involving liver toxicity requiring immunosuppression and development of neutralizing antibodies to AAV vector rendering future doses ineffective. Real-life applicability of gene therapy for HA will require appropriate patient screening, infrastructure setup, long-term monitoring including data collection of patient-reported outcomes and innovative payment schemes. This review article highlights the success and development of HA gene therapy trials, challenges including adverse outcomes and variability of response, and perspectives on approach to gene therapy including shared decision-making and need for future strategies to overcome the several unmet needs.

Mobile Application Measurement of Menstrual Cycle Characteristics and Their Association with Dysmenorrhea and Activity Limitation in Early Adolescents.

OBJECTIVE: Real-time tracking of menstrual bleeding is a barrier to research due to limitations with traditional data collection tools. This prospective cohort study utilized a mobile application (TDot app) in young adolescents aged 10-14 years to assess the relationship between heavy menstrual bleeding (HMB), dysmenorrhea, and activity limitation. METHODS: Menstrual cycles were captured over six months in real-time using the Pictorial Blood loss Assessment Chart (PBAC). A median PBAC score of >100 was used to identify participants with HMB. Participants also completed a modified WaLIDD (Working ability, Location, Intensity, Days of pain, Dysmenorrhea) scale. Impact of menses on daily activities was collected for each cycle. RESULTS: A total of 160 participants enrolled and 100 (63%) participants with ≥3 cycles recorded in the mobile app were analyzed. HMB was noted in 41% of participants. Median modified WaLIDD score was significantly higher in participants with HMB than those without HMB (p=0.01). No significant differences were found in activity limitations between participants with and without HMB (p=0.34). Median modified WaLIDD score for participants with activity limitation was significantly higher than those without activity limitation (p=0.01). CONCLUSION: Utilizing mobile app technology, we were able to gather real-time menstrual outcome data from young adolescents on heaviness of flow, dysmenorrhea and activity limitations. While we did not find that patients with HMB were more likely to have activity limitations, we did find that those with limitations had modestly higher dysmenorrhea scores. Future studies should focus on identifying additional variables that impact activity limitation during menstruation.

Comparison of thromboembolism outcomes in patients with sickle cell disease prescribed hormonal contraception.

Patients with sickle cell disease (SCD) are at a risk of thromboembolism (TE), and use of hormonal contraception can further increase that risk. This study aims to assess patterns of hormonal contraceptive use and compare risk of contraception-related TE between combined hormonal contraceptives (CHCs) and progestin-only contraceptives (POCs). Patients with SCD aged between 12 and 44 years with a new prescription of a hormonal contraceptive in the Centers for Medicare and Medicaid Services Medicaid Analytic eXtract database (2006-2018) were followed up to 1 year. We identified 7173 new users: 44.6% initiated CHC and 55.4% initiated POC. Combined oral contraceptive pills (OCPs; 36.5%) and progestin-only depot medroxyprogesterone acetate (33.9%) were the most frequently prescribed agents. A total of 1.8% of contraception users had a new diagnosis of TE within 1 year of the first identified contraception prescription. There were no significant differences in TE event rates between CHC and POC users (17.2 and 24.7 events per 1000 person-years, respectively). In patients prescribed OCP, there were no differences in TE event rates based on estrogen dose or progestin generation. Transdermal patch had a 2.4-fold increased risk of TE as compared with that of OCP. Although limited by the retrospective study design and use of administrative claims data, this study found no significant differences in TE rates between new users of CHC and POC in patients with SCD. Careful evaluation of underlying TE risk factors should be considered for each patient with SCD before initiation of hormonal contraception.