Riociguat real-world use in patients with chronic thromboembolic pulmonary hypertension: A retrospective, observational cohort study in France.

BACKGROUND: Riociguat is the first approved treatment for inoperable and persistent/recurrent post-surgery chronic thromboembolic pulmonary hypertension (CTEPH). The RetrospectIve Adempas® stuDy (RiAD) aimed to describe the real-world utilization of riociguat in France. METHODS: In this retrospective multicentric study in patients initiating riociguat, dosing regimen, co-treatments and clinical characteristics were collected over a 2-year follow-up period. RESULTS: A total of 173 patients (mean age, 71.4 years; female, 63.0%; NYHA II-III, 80.3%) were included from January 2015 to December 2016 in 18 centers. All patients were diagnosed with CTEPH (75.7% inoperable and 20.8% with persistent/recurrent pulmonary hypertension [pH] after surgery) with mean (SD) right atrial pressure 7.6 (4.2) mmHg, mean pulmonary artery pressure 43.0 (11.4) mmHg and mean cardiac output 4.1 (1.1) L/min. Before riociguat initiation, 32.4% of patients previously received at least one pH-specific therapy. At initiation, 93.1% of patients were receiving anticoagulants and 83.2% were not receiving pH-specific co-treatments. Riociguat was initiated at 1 mg three times daily (t.i.d.) in 85.5% of patients and 82.1% were receiving 2.5 mg dose t.i.d. at 24 months. The maximal daily dose of 7.5 mg was never exceeded. At 24 months, the estimated rate of patients still taking riociguat was 78.8% with an estimated mean (SD) time on treatment of 20.1 (0.5) months per patient. No new safety signals were recorded. CONCLUSIONS: The results of this real-world study show that riociguat is used in France in accordance with its therapeutic indication in patients with inoperable or persistent/recurrent post-operative CTEPH and confirm its long-term safety.

Effective Letermovir Prophylaxis of CMV infection post allogeneic hematopoietic cell transplantation: Results from the French temporary authorization of use compassionate program.

We report the results of the French Temporary Authorization of Use (ATU) compassionate program of letermovir for primary prophylaxis conducted in 21 transplant centers. Patients were CMV seropositive allogeneic hematopoietic cell transplantation recipients and at high risk for CMV infection. Primary prophylaxis was defined as initiation of letermovir between day 0 and day +28 post-transplant. Between November 2017 and January 2019, 96 patients with a median age of 56 years received letermovir and follow-up data were available for 78 patients. The median time from transplant to letermovir initiation was 4 days, and the median duration of exposure to letermovir was 78 days, with 57 patients still on treatment at the cutoff date. Letermovir was temporarily discontinued in 4 patients (5.1%) and stopped in 39 patients (50.0%), in most cases due to planned end of treatment (n = 16, 20.5%). Fifteen patients (19.2%) each presented one positive CMV PCR, in median 13 days after letermovir initiation. Clinically significant CMV infection was reported in 5 patients (6.4%). No CMV disease was reported. At least one adverse drug reaction was reported for 12 patients (15.4%). In this early access program, letermovir was effective with comparable results of the phase 3 study with a low rate of clinically significant CMV infection, including in patients who were at high-risk for CMV infection.

Letermovir for Secondary Prophylaxis of Cytomegalovirus Infection and Disease after Allogeneic Hematopoietic Cell Transplantation: Results from the French Compassionate Program.

Letermovir potently inhibits the cytomegalovirus (CMV)-terminase complex. Letermovir primary prophylaxis given for the first 3 months after allogeneic hematopoietic cell transplantation (HCT) has been shown to reduce clinically significant CMV infection and is well tolerated. Until now, only case reports or small retrospective series have been published on the use of letermovir for a secondary prophylaxis (SP) of CMV infection or diseases after HCT. Here we report the outcome of 80 consecutive CMV-seropositive adult patients included in the French compassionate program and who received letermovir as a SP after at least 1 CMV episode (infection or disease) since HCT. Letermovir was initiated at a median of 170 (49 to 1829) days after transplant and given orally for a median of 118 (26 to 396) days at the usual daily dose of 480 mg once daily and adjusted to 240 mg once daily when coadministered with cyclosporine. The donors were seronegative in 53% of the cases. Fifty patients had a current or previous graft-versus-host disease (GVHD) and 14 had experienced CMV disease since transplant. Four (5.5%) patients developed CMV breakthrough infections (n = 1) or diseases (n = 3) after the initiation of letermovir. In 3 of these 4 patients, further investigation of virologic resistance showed a CMV UL56 mutation C325Y or W, conferring the high-level letermovir resistance. One or more adverse reactions were declared by the local investigator in 15 (19%) patients. Only 2 patients stopped letermovir SP because of an adverse reaction (pruritus, 1; cytopenia, 1). In our experience, letermovir given as a SP may prevent a new CMV reactivation in a high-risk patient population and can be administered for several weeks, providing a bridge between the pre-emptive or therapeutic treatment of a CMV episode and CMV-specific immune reconstitution, giving time for tapering immunosuppressants. Prospective studies are required to confirm these results.

Patient perceptions and understanding of treatment instructions for ovarian stimulation during infertility treatment.

The impact of patient-physician communication and levels of understanding of treatment on patient knowledge and compliance has been studied in patients undergoing their first cycle of infertility treatment. This observational, real-life, longitudinal study involved 488 patients from 28 infertility centres in France. Data on communication quality, understanding of treatment instructions, patient knowledge and compliance to treatment protocol were collected through questionnaires administered before treatment initiation (V1) and at oocyte retrieval (V2). At V1, patients were very satisfied with their levels of understanding of the injection and monitoring schedules, the information given by the medical team, and the way of receiving instructions, with average ratings on a scale of 0-100% of > 75%. They rated their understanding of possible treatment side-effects as satisfactory (average score 71.1%). Gaps in patient knowledge about their treatment, revealed by discrepancies between physician and patient reports, were observed in 20.5% of patients (n = 79/386), and most commonly resulted from confusion about the units and dose of gonadotropin. Anxiety about performing self-injections and a lack of confidence in their ability to self-inject correctly were each observed in approximately one-third of patients. Patient self-assessment of compliance at V2 revealed that 27% of patients (n = 83/305) did not comply with or had doubts about the injection schedule or dose injected. Meanwhile physicians reported high levels of patient compliance (94.3%; n = 350/371). In conclusion, even when patient-physician relationships appear to be satisfactory, patient miscomprehension and non-compliance during infertility treatment may be underestimated. Further interventions are required to improve these outcomes.

A fruit-specific phospho enolpyruvate carboxylase is related to rapid growth of tomato fruit.

Malic and citric acids accumulate in cherry tomato (Lycopersicon esculentum Mill.) fruit during the period of rapid growth, from the end of cell division to the onset of ripening. The involvement of phospho enolpyruvate carboxylase (PEPCase, EC 4.1.1.31) in organic acid accumulation and tomato fruit development was investigated. Two PEPCases, named LYCes;Ppc1 and LYCes;Ppc2 and mapped to chromosomes 12 and 7, respectively, were shown to be differentially expressed during tomato fruit development. LYCes;Ppc1 mRNA was present in all fruit tissues and in all other plant organs examined. In contrast, LYCes;Ppc2 was strongly and specifically expressed in fruit from the end of cell division to ripening. No LYCes;Ppc2 expression was detected by northern blot in other plant tissues. In fruit, the increase in LYCes;Ppc2 mRNA was closely followed by an increase in fruit PEPCase protein and activity, and was coincident with the increased accumulation of malate and citrate during the initial period of rapid growth rate, from 8 to 20 days post anthesis. Localization of LYCes;Ppc2 mRNA in young tomato fruit by in situ hybridization revealed that LYCes;Ppc2 is preferentially expressed in large cells of the pericarp and in enlarging cells of the gel surrounding the seeds. Examination of the kinetic and regulatory properties of the PEPCases of growing and ripening fruit further showed that PEPCase in growing fruit is less sensitive to low pH and malate inhibition, indicating a high phosphorylation state and/or the presence of a PEPCase isoform with these characteristics. Taken together, these results indicate that in developing tomato fruit PEPCase is probably important in permitting the synthesis of organic acids to provide the turgor pressure necessary for cell expansion.