Real-World Treatment and Care Patterns in Patients With Rheumatoid Arthritis Initiating First-Line Tumor Necrosis Factor Inhibitor Therapy in the United States.

OBJECTIVE: Treatment guidelines for rheumatoid arthritis (RA) recommend targeting low disease activity or remission and switching therapies for patients not reaching those targets. We evaluated real-world use of disease activity measures, treatment discontinuation, and switching patterns among patients with RA initiating a first-line tumor necrosis factor inhibitor (TNFi). METHODS: Data from adult patients with RA initiating a first-line TNFi were collected from the American Rheumatology Network (January 2014-August 2021). The proportion of patients with recorded disease activity scores (Clinical Disease Activity Index [CDAI] or Routine Assessment of Patient Index Data 3 [RAPID3]) at TNFi initiation was assessed. Among patients with moderate or severe RA at TNFi initiation, reasons for discontinuation and subsequent advanced therapy were evaluated. RESULTS: Among TNFi initiators (n = 15,182), 44.8% recorded a CDAI/RAPID3 score at treatment initiation; of those who did not, 47.0% had recorded a tender and/or swollen joint count or pain score. Among patients with moderate or severe RA (n = 1,651), 52% discontinued their initial TNFi during follow-up, of which 15%, 46%, 28%, and 12% initiated the same TNFi, another TNFi, a non-TNFi biologic, or a Janus kinase inhibitor, respectively. The proportion of patients restarting the same TNFi or initiating another TNFi varied according to TNFi discontinuation reason. CONCLUSION: In clinical practice, over half of patients with RA initiating a first-line TNFi did not have baseline disease activity assessments. Many patients cycled through TNFi despite citing lack of efficacy as the most common reason for discontinuation. Consistent, objective monitoring of treatment response and timely switch to effective therapy is needed in patients with RA.

Effects of PK-guided prophylaxis on clinical outcomes and FVIII consumption for patients with moderate to severe Haemophilia A.

INTRODUCTION: In recent years, there has been increased focus on individualizing treatment for persons with hemophilia including pharmacokinetic-guided (PK) dosing. AIMS: In this retrospective study clinical outcomes before and after PK-guided prophylaxis were examined. MATERIALS AND METHODS: Eight Haemophilia Treatment Centres from the United States participated in the study and included 132 patients classified into two cohorts: those undergoing a PK-assessment for product switch (switchers) or to optimize treatment (non-switchers). Subset analyses for the two most common products and patients with dosing per prescription label were included for annual bleeding rates (ABR), mean weekly consumption outcomes, and annualized cost of prophylaxis. RESULTS: The most common products before and after index date were octocog alfa, rurioctocog alfa pegol, and efmoroctocog alfa. Seventy-four (56%) patients were identified as switchers and 58 (44%) patients were classified as non-switchers. The majority of patients (78.0%) experienced either a decrease in ABR post-index or maintained 0 ABR during pre- and post-index time periods, with similar proportions identified in both switchers (77.0%) and non-switchers (79.3%) populations. Non-switchers were identified as having no significant change in cost of therapy, while switchers experienced increased cost of therapy driven by higher price of extended half-life products. Within subset analyses, patients receiving rurioctocog alfa pegol and efmoroctocog alfa had mean ABR under 1 after index date. CONCLUSION: PK-guided prophylaxis has the potential to improve clinical outcomes without increase in cost of therapy for patients maintaining product and can aid in maintaining effective protection against bleeds in those switching product.

Characteristics of patients with pulmonary arterial hypertension from an innovative, comprehensive real-world patient data repository.

Pulmonary arterial hypertension (PAH) is a rare, life-limiting disease. PAH registries provide real-world data that complement clinical trial data and inform treatment decisions. The TRIO comprehensive, integrated patient data repository (TRIO CIPDR), is an innovative US repository capturing data on contemporary patients diagnosed with pulmonary hypertension and receiving US Food and Drug Administration-approved PAH therapies. This repository uniquely combines clinical data from electronic medical records with the ability to track drug-prescription and drug-dispensing characteristics, and includes 946 adult patients with PAH (data collected January 2019 to December 2020) enrolled from nine representative US specialist tertiary care centers. Potentially eligible patients were identified based on dispensing data from specialty pharmacies. Hemodynamic and clinical data, as well as dispensing information on prescribed PAH medications, were provided by tertiary centers. At enrollment, 75% of patients were female, 67% were White, median age at PAH diagnosis was 53 years (median time from diagnosis to enrollment was 5 years), and 37% were obese. Comorbidity profiles were as expected for a PAH population, although the proportion with atrial fibrillation (34%) was higher than expected. Overall, 38% of patients had idiopathic PAH and 30% had connective tissue disease-related PAH. Among 917 patients receiving PAH-specific therapy, 40% were on monotherapy, 43% on dual therapy, and 17% on triple therapy. Longitudinal data from this repository will allow tracking of the PAH treatment journey in relation to clinical characteristics and outcomes.

Real-world study of rurioctocog alfa pegol and emicizumab in US clinical practice among patients with hemophilia A.

BACKGROUND: FVIII replacement is standard treatment for hemophilia A without inhibitors, but non-factor therapies, such as emicizumab, are changing the treatment landscape. We explore the ramifications of switching treatment. METHODS: Pharmacy database data (July 2017-May 2020) from patients with hemophilia A without inhibitors who switched to rurioctocog alfa pegol or emicizumab prophylaxis after ≥6 months' prophylaxis with another FVIII product were analyzed for total mean weekly consumption, dosing frequency, product wastage, and ABR. RESULTS: Post-switch mean weekly consumption of prophylactic rurioctocog alfa pegol and emicizumab were 6224 IU/kg and 109 mg, respectively. Dosing schedules for emicizumab were primarily weekly (48.2%) and every 2 weeks (40.0%). Most patients in the rurioctocog alfa pegol cohort received treatment twice-weekly (83.3%). Mean product wastage of emicizumab (8.4%) was significantly higher versus rurioctocog alfa pegol (-0.3%; P < 0.001). Mean annualized emicizumab and rurioctocog alfa pegol wastage during prophylaxis was 330.82 mg and -974.80 IU, respectively. ABR change was not significantly different (P = 0.527) for patients switching to emicizumab (-1.05) or rurioctocog alfa pegol (-1.53). CONCLUSIONS: Bleed rates were similar for patients receiving prophylaxis with emicizumab or rurioctocog alfa pegol after switching from prophylaxis with another FVIII. However, wastage associated with dispensing inaccuracies was greater with emicizumab.

First-line therapies for hepatitis B in the United States: A 3-year prospective and multicenter real-world study after approval of tenofovir alefenamide.

Real-world data are limited on tenofovir alafenamide (TAF). We aimed to study TAF real-world outcomes with other first-line regimens for chronic hepatitis B (CHB). We enrolled patients with CHB from 10 centers retrospectively and followed them for 36 months prospectively. We analyzed switching patterns of antiviral therapy and treatment outcomes of TAF, tenofovir disoproxil fumarate (TDF), and entecavir therapy. For efficacy and safety, we analyzed a subset of patients with complete data at 24 months after switching to TAF or remaining on TDF or entecavir. Among 1037 enrollees, 889 patients were analyzed. The mean age was 52%, and 72% were hepatitis B e antigen-negative. After enrollment, shifts in therapies were mostly in reduced use of TDF from 63% to 30% due to switching to TAF. Clinical parameters were compared at enrollment or initiation to measures at 24 months for patients remaining on TAF (187), TDF (229), or entecavir (181). At 24 months, a significantly higher portion of patients on TAF achieved hepatitis B virus (HBV) DNA ≤ 20 IU/ml (93% vs. 86%; p = 0.012) and normalized alanine aminotransferase (ALT) (66% vs. 56%; p = 0.031) with stable estimated glomerular filtration rates (eGFRs). However, a higher percentage of the patient with eGFR < 60 ml/mi/1.7 m2 was observed in the TDF-treated group (9% vs. 4%; p = 0.010). In patients who remained on entecavir or TDF for 24 months, ALT and HBV-DNA results did not differ significantly from baseline. Treatment of CHB in the United States has significantly shifted from TDF to TAF. Our data suggest that switching from TDF or entecavir to TAF may result in increased frequency of ALT normalization and potential clearance of viremia at the 24-month time point.

Fibrosis-4 Index Can Independently Predict Major Adverse Cardiovascular Events in Nonalcoholic Fatty Liver Disease.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is closely associated with an increased risk of cardiovascular disease. We aimed to determine whether the fibrosis-4 index (FIB-4) can identify patients with NAFLD at highest risk of cardiovascular events. METHODS: We analyzed data from 81,108 patients with (i) a diagnosis of NAFLD, (ii) nonalcoholic steatohepatitis (NASH), or (iii) at risk (RISK) of NASH. The outcome of interest was major adverse cardiovascular events (MACE) defined by myocardial infarction, hospitalization for unstable angina or heart failure, and coronary revascularization. RESULTS: The mean age was 62 years, and 49.6% were men. Among 67,273 patients without previous cardiovascular disease, 9,112 (13.5%) experienced MACE over median follow-up of 3 years. In univariate analysis, a FIB-4 ≥2.67 was a significant predictor of MACE overall (hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.63-2.04, P < 0.001) and across all baseline groups. After adjusting for established cardiovascular risk factors, FIB-4 ≥2.67 remained the strongest predictor of MACE overall (adjusted HR [aHR] 1.80, 95% CI 1.61-2.02, P < 0.001) and was consistently associated with myocardial infarction (aHR 1.46, 95% CI 1.25-1.70, P < 0.001), hospitalization for unstable angina (aHR 1.24, 95% CI 1.03-1.49, P = 0.025), hospitalization for heart failure (aHR 2.09, 95% CI 1.86-2.35, P < 0.001), coronary artery bypass graft (aHR 1.65, 95% CI 1.26-2.17, P < 0.001), and percutaneous coronary intervention (aHR 1.72, 95% CI 1.21-2.45, P = 0.003). DISCUSSION: In a large, real-world cohort of patients with NAFLD, NASH, or at RISK of NASH, the FIB-4 score was the strongest independent predictor of MACE, beyond established cardiovascular risk factors and baseline liver diagnosis.

Fibrosis-4 Index as an Independent Predictor of Mortality and Liver-Related Outcomes in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and its prevalence continues to rise. Fibrosis-4 index (FIB-4) has been shown to be a prognostic marker of liver-related outcomes in patients with NAFLD. We analyzed data from TriNetX global federated research network, combining data on 30 million patients. Patients were categorized into three diagnostic groups: NAFLD, nonalcoholic steatohepatitis (NASH), and at risk of NASH. Primary outcome was all-cause mortality, and secondary outcomes included progression to NASH, development of cirrhosis, end-stage liver disease, hepatocellular carcinoma (HCC), and liver transplantation. A total of 442,277 subjects (1.5% of the cohort) were assessed, and 81,108 were retained for analysis. Median follow-up was 34.8 months (interquartile range 12.2). FIB-4 was < 1.3 in 52.3% patients and ≥ 2.67 in 11.4% patients. In multivariate analysis, FIB-4 ≥ 2.67 was significantly and independently associated with all-cause mortality (hazard ratio [HR] 2.49, 95% confidence interval [CI] 2.20-2.82, P < 0.001) as well as with progression to NASH (HR 5.78, 95% CI 4.72-7.07, P < 0.001), cirrhosis (HR 2.04, 95% CI 1.86-2.24, P < 0.001), end-stage liver disease (HR 1.86, 95% CI 1.68-2.05, P < 0.001), HCC (HR 3.66, 95% CI 2.71-4.94, P < 0.001), and liver transplantation (HR 7.98, 95% CI 4.62-13.79, P < 0.001). Conclusion: In a real-world nationwide database, FIB-4 ≥ 2.67 was a strong predictor of both all-cause mortality and liver-related adverse outcomes independently of the baseline diagnostic group and common risk factors. Our findings indicate that FIB-4 could play a role as a risk-stratification tool for a population health approach. Significant underdiagnosis of both NAFLD/NASH and NASH cirrhosis in electronic medical records was observed.

Cytokine Network and Sexual Human Immunodeficiency Virus Transmission in Men Who Have Sex With Men.

BACKGROUND: Seminal human immunodeficiency virus (HIV) transmission from men to their partners remains the main driver of HIV epidemics worldwide. Semen is not merely a carrier of the virus, but also provides an immunological milieu that affects HIV transmission. METHODS: We collected blood and semen from people with HIV whose epidemiologically linked sexual partners either did or did not acquire HIV. Viral transmission was confirmed by phylogenetic linkage (HIV pol). We measured the concentration of 34 cytokines/chemokines by Luminex in the blood and semen of 21 source partners who transmitted HIV (transmitters) and 22 who did not transmit HIV (nontransmitters) to their sexual partners. Differences between cytokine profiles in transmitters versus nontransmitters were analyzed using the multivariate statistical technique of partial least square discriminant analysis. RESULTS: The cytokine profile in seminal fluid, but not in peripheral blood, was significantly different between men who have sex with men (MSM) who transmitted HIV and those who did not transmit HIV to their sexual partners (E = 19.77; P < .01). This difference persisted after excluding people with undetectable HIV RNA levels in nontransmitters. CONCLUSIONS: Seminal cytokine profiles correlated with transmission or nontransmission of HIV from the infected MSM to their partners, independently from seminal viral load. Seminal cytokine spectra might be a contributing determinant of sexual HIV transmission, thus providing new directions for the development of strategies aimed at preventing HIV transmission.

Subclinical Cytomegalovirus DNA Is Associated with CD4 T Cell Activation and Impaired CD8 T Cell CD107a Expression in People Living with HIV despite Early Antiretroviral Therapy.

Most people living with HIV (PLWH) are coinfected with cytomegalovirus (CMV). Subclinical CMV replication is associated with immune dysfunction and with increased HIV DNA in antiretroviral therapy (ART)-naive and -suppressed PLWH. To identify immunological mechanisms by which CMV could favor HIV persistence, we analyzed 181 peripheral blood mononuclear cell (PBMC) samples from 64 PLWH starting ART during early HIV infection with subsequent virologic suppression up to 58 months. In each sample, we measured levels of CMV and Epstein-Barr virus (EBV) DNA by droplet digital PCR (ddPCR). We also measured expression of immunological markers for activation (HLA-DR+ CD38+), cycling (Ki-67+), degranulation (CD107a+), and the immune checkpoint protein PD-1 on CD4+ and CD8+ T cell memory subsets. Significant differences in percentages of lymphocyte markers by CMV/EBV shedding were identified using generalized linear mixed-effects models. Overall, CMV DNA was detected at 60/181 time points. At the time of ART initiation, the presence of detectable CMV DNA was associated with increased CD4+ T cell activation and CD107a expression and with increased CD8+ T cellular cycling and reduced CD107a expression on CD8+ T cells. While some effects disappeared during ART, greater CD4+ T cell activation and reduced CD107a expression on CD8+ T cells persisted when CMV was present (P < 0.01). In contrast, EBV was not associated with any immunological differences. Among the covariates, peak HIV RNA and CD4/CD8 ratio had the most significant effect on the immune system. In conclusion, our study identified immune differences in PLWH with detectable CMV starting early ART, which may represent an additional hurdle for HIV cure efforts.IMPORTANCE Chronic viral infections such as with HIV and CMV last a lifetime and can continually antagonize the immune system. Both viruses are associated with higher expression of inflammation markers, and recent evidence suggests that CMV may complicate efforts to deplete HIV reservoirs. Our group and others have shown that CMV shedding is associated with a larger HIV reservoir. Subclinical CMV replication could favor HIV persistence via bystander effects on our immune system. In this study, we collected longitudinal PBMC samples from people starting ART and measured immune changes associated with detectable CMV. We found that when CMV was detectable, CD4+ T cell activation was higher and CD8+ T cell degranulation was lower. Both results may contribute to the slower decay of the size of the reservoir during CMV replication, since activated CD4+ T cells are more vulnerable to HIV infection, while the loss of CD8+ T cell degranulation may impede the proper killing of infected cells.

Herd Immunity Likely Protected the Men Who Have Sex With Men in the Recent Hepatitis A Outbreak in San Diego, California.

A high seroprevalence of hepatitis A virus (81%) among human immunodeficiency virus-negative high-risk men who have sex with men is likely why this community was largely spared from a recent hepatitis A virus outbreak in San Diego, California.