Hepatitis C Virus Clearance and Diffusing Capacity for Carbon Monoxide in Women With and Without Human Immunodeficiency Virus.

Hepatitis C virus (HCV) infection is associated with extrahepatic effects, including reduced diffusing capacity of the lungs. It is unknown whether clearance of HCV infection is associated with improved diffusing capacity. In this sample of women with and without human immunodeficiency virus, there was no association between HCV clearance and diffusing capacity.

Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A.

BACKGROUND: Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously. METHODS: We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII. RESULTS: At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P<0.001) among the participants. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics; the model-estimated typical half-life of the transgene-derived factor VIII production system was 123 weeks (95% confidence interval, 84 to 232). The risk of joint bleeding was estimated among the trial participants; at a transgene-derived factor VIII level of 5 IU per deciliter measured with chromogenic assay, we expected that participants would have 1.0 episode of joint bleeding per year. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred. CONCLUSIONS: The study data show the durability of factor VIII activity and bleeding reduction and the safety profile of valoctocogene roxaparvovec at least 2 years after the gene transfer. Models of the risk of joint bleeding suggest that the relationship between transgene-derived factor VIII activity and bleeding episodes is similar to that reported with the use of epidemiologic data for persons with mild-to-moderate hemophilia A. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).

Real-World Rates of Bleeding, Factor VIII Use, and Quality of Life in Individuals with Severe Haemophilia A Receiving Prophylaxis in a Prospective, Noninterventional Study.

Regular prophylaxis with exogenous factor VIII (FVIII) is recommended for individuals with severe haemophilia A (HA), but standardised data are scarce. Here, we report real-world data from a global cohort. Participants were men ≥18 years old with severe HA (FVIII ≤ 1 IU/dL) receiving regular prophylaxis with FVIII. Participants provided 6 months of retrospective data and were prospectively followed for up to 12 months. Annualised bleeding rate (ABR) and FVIII utilisation and infusion rates were calculated. Differences between geographic regions were explored. Of 294 enrolled participants, 225 (76.5%) completed ≥6 months of prospective follow-up. Pre-baseline and on-study, the median (range) ABR values for treated bleeds were 2.00 (0-86.0) and 1.85 (0-37.8), respectively; the median (range) annualised FVIII utilisation rates were 3629.0 (1008.5-13541.7) and 3708.0 (1311.0-14633.4) IU/kg/year, respectively; and the median (range) annualised FVIII infusion rates were 120.0 (52.0-364.0) and 122.4 (38.0-363.8) infusions/year, respectively. The median (range) Haemo-QoL-A Total Score was 76.3 (9.4-100.0) (n = 289), ranging from 85.1 in Australia to 67.7 in South America. Physical Functioning was the most impacted Haemo-QoL-A domain in 4/6 geographic regions. Despite differences among sites, participants reported bleeding requiring treatment and impaired physical functioning. These real-world data illustrate shortcomings associated with FVIII prophylaxis for this global cohort of individuals with severe HA.