A phase 3, randomized,double-blind,parallel-group study to evaluate tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for F508del-CFTR and a gating mutation

BackgroundTezacaftor (TEZ)/ivacaftor (IVA) is an approved CFTR modulator shown to be efficacious and generally safe and well tolerated in people ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous for the F508del-CFTR mutation and a residual function mutation. Although previous studies with IVA alone showed clinical benefits in people with CFTR gating mutations, TEZ/IVA has not yet been evaluated in a Phase 3 study of participants heterozygous for F508del-CFTR and a gating mutation (F/gating genotypes). Here, we present results from a randomized, double-blind, IVA-controlled, parallel-group, Phase 3 study assessing the efficacy, safety, and pharmacokinetics (PK) of TEZ/IVA in participants ≥12 years of age with F/gating genotypes.MethodsEnrolled participants entered a 4-week IVA run-in period to create a stable IVA baseline. Participants were then randomized to receive IVA or TEZ/IVA for 8 weeks in an active comparator treatment period (ACTP). The primary endpoint was absolute change in percent predicted forced expiratory volume in 1 second (ppFEV₁). Key secondary endpoints were relative change in ppFEV₁ and absolute change in CF Questionnaire–Revised respiratory domain score. Secondary endpoints included absolute change in sweat chloride (SwCl) concentration, PK parameters, and safety. All endpoints except PK parameters and safety were assessed from baseline through Week 8.ResultsSixty-nine participants (92.0%) in the IVA group and 75 participants (98.7%) in the TEZ/IVA group completed treatment. No improvements were seen in efficacy endpoints from baseline at the end of the IVA run-in period through the end of the ACTP in the IVA group. No significant differences in ppFEV₁ or any key secondary endpoint were observed between the IVA and TEZ/IVA groups. SwCl concentrations decreased more in the TEZ/IVA versus IVA group during the ACTP. The safety profile and PK parameters of TEZ/IVA were consistent with those of previous studies in participants ≥12 years of age with CF.ConclusionsThis Phase 3 study showed that the dual-combination regimen of TEZ/IVA demonstrated clinical efficacy but did not have significantly greater clinical efficacy than IVA alone in participants ≥12 years of age with F/gating genotypes. However, as reported in other studies, TEZ/IVA was generally safe and well tolerated (NCT02412111).     

Biliary disease and cholecystectomy after initiation of elexacaftor/ivacaftor/tezacaftor in adults with cystic fibrosis

Individuals with cystic fibrosis (CF) have an increased risk for gallbladder abnormalities and biliary tract disease, but the reported incidence of these manifestations of CF varies widely in the literature. With the approval of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), increasing numbers of CF patients have been initiated on highly effective cystic fibrosis transmembrane regulator (CFTR) modulator therapy. While elevations in hepatic panel are known potential side effects of CFTR modulators, there have been no published cases of biliary disease or acute cholecystitis attributed to these medications. In this case series, we describe seven patients at two adult CF centers with biliary colic shortly after initiation with ELX/TEZ/IVA, six of whom required cholecystectomy.     

Retrospective-prospective study of safety and efficacy of sofosbuvir-based direct-acting antivirals in HIV/HCV-coinfected participants with decompensated liver disease pre– or post–liver transplant

Direct-acting antiviral (DAA) therapy has transformed the management of human immunodeficiency virus (HIV) and hepatitis C (HCV) coinfected patients with advanced liver disease. STOP-Coinfection was a multicenter prospective and retrospective, open-label study using sofosbuvir-based DAA therapy to treat HIV/HCV-coinfected participants pre– or post–liver transplant (LT). Sixty-eight participants with end-stage liver disease (Child-Turcotte-Pugh score ≥7 and Model for End-Stage Liver Disease score 6–29) were enrolled, 26 had hepatocellular carcinoma. Forty-two participants were treated pre–LT and 26 post–LT. All participants completed therapy without need for dose reduction or transfusion; eight required two or more courses of therapy. Ninety-three percent achieved a sustained virologic response and DAA therapy was well tolerated. Despite HCV cure, 12 end-stage liver disease participants required subsequent LT, 7 for decompensated liver disease. Thirteen participants died, 10 with decompensated liver disease pre–LT and three post–LT. Overall, transplant free survival was 42.8% at 4 years and post–LT survival was 87.9% at 5 years. We conclude that sofosbuvir-based DAA therapy is safe and highly effective in HCV-HIV patients with decompensated liver disease and post–LT, with post–LT survival rates comparable to other indications. This removes one of the last barriers to liver transplantation in this challenging cohort of recipients.     

COVID-19 in solid organ transplant recipients: A national cohort study from Sweden

Solid organ transplant (SOT) recipients run a high risk for adverse outcomes from COVID-19, with reported mortality around 19%. We retrospectively reviewed all known Swedish SOT recipients with RT-PCR confirmed COVID-19 between March 1 and November 20, 2020 and analyzed patient characteristics, management, and outcome. We identified 230 patients with a median age of 54.0 years (13.2), who were predominantly male (64%). Most patients were hospitalized (64%), but 36% remained outpatients. Age >50 and male sex were among predictors of transition from outpatient to inpatient status. National early warning Score 2 (NEWS2) at presentation was higher in non-survivors. Thirty-day all-cause mortality was 9.6% (15.0% for inpatients), increased with age and BMI, and was higher in men. Renal function decreased during COVID-19 but recovered in most patients. SARS-CoV-2 antibodies were identified in 78% of patients at 1–2 months post-infection. Nucleocapsid-specific antibodies decreased to 38% after 6–7 months, while spike-specific antibody responses were more durable. Seroprevalence in 559 asymptomatic patients was 1.4%. Many patients can be managed on an outpatient basis aided by risk stratification with age, sex, and NEWS2 score. Factors associated with adverse outcomes include older age, male sex, greater BMI, and a higher NEWS2 score.     

Perceptual Accuracy for Sexual Rejection in Romantic Relationships

In the current research, we investigated perceptual accuracy in romantic partners’ detection of sexual rejection. In two daily diary studies of predominantly cisgender heterosexual couples, we examined patterns of accuracy and bias concerning both the degree of sexual disinterest (Study 1; N?=?98 couples) and occurrence of sexual rejection (Study 2; N?=?115 couples), as well as how these perceptions were associated with satisfaction. Using a multi-method approach to capture both continuous and categorical operationalizations of sexual rejection (Study 1: truth and bias; Study 2: quasi-signal detection), we found that people were both accurate and biased in their perceptions of partner rejection. Across studies, results showed that people demonstrated general tracking accuracy in detecting a partner’s sexual rejection, but they also overestimated the degree and occurrence of this rejection. Additionally, this overestimation bias was associated with lower daily relationship and sexual satisfaction. Overall, our findings highlight the importance of dyadic perceptions of sexual rejection in shaping daily relationship and sexual functioning.

     

A Scoping Review of Empirical Asexuality Research in Social Science Literature

Archives of Sexual Behavior - Research on asexuality as a part of the experience of human sexuality has increased over the last two decades. However, there has not yet been a systematic review of...