High real-world effectiveness of 12-week elbasvir/grazoprevir without resistance testing in the treatment of patients with HCV genotype 1a infection in Norway.

BACKGROUND AND AIMS: The recommended treatment duration of hepatitis C virus (HCV) genotype 1a (GT1a) infection with elbasvir/grazoprevir (EBR/GZR) in the presence of a high baseline viral load and resistance associated substitutions (RAS) is 16 weeks with ribavirin added. The objective of this study was to evaluate the real-world effectiveness of 12 weeks of EBR/GZR without ribavirin and regardless of baseline viral load and RAS testing. METHOD: This retrospective, observational cohort study was performed at five Norwegian hospitals that did not systematically utilize RAS testing. All adult patients with chronic HCV GT1a and compensated liver disease who had received 12 weeks of EBR/GZR without ribavirin and baseline RAS testing, were included. The primary endpoint was sustained virologic response at week 12 (SVR12), or if not available, at week 4 (SVR4). RESULTS: We included 433 patients and attained SVR data on 388. The mean age was 45.7 years (22-73 years). 67.2% were male. HIV co-infection was present in 3.8% (16/424) and cirrhosis in 4% (17/424). The viral load was >800 000 IU/mL in 55.0% (235/427) of patients. Overall SVR was achieved in 97.2% (377/388). SVR was achieved in 98.3% (169/172) of those with viral load ≤800 000 IU/mL and in 96.2% (202/210) of those with viral load >800 000 IU/mL. CONCLUSION: We observed high SVR rates among patients with HCV GT1a infection treated with EBR/GZR for 12 weeks without ribavirin, with no regard to baseline viral load and no RAS testing.

Efficacy and safety of elbasvir/grazoprevir for 8 or 12 weeks for hepatitis C virus genotype 4 infection: A randomized study.

BACKGROUND & AIMS: Hepatitis C virus (HCV) genotype (GT) 4 infection is prevalent in sub-Saharan Africa and the Middle East, particularly in Egypt. This study evaluated the safety and efficacy of elbasvir/grazoprevir administered for 8 and 12 weeks in participants with HCV GT4 infection. METHODS: In this partially randomized, open-label multicentre study conducted in France (NCT03111108; Protocol MK5172-096), treatment-naive participants with GT4 infection and F0-F2 fibrosis were randomized 2:1 to elbasvir (50 mg)/grazoprevir (100 mg) for 8 or 12 weeks. Treatment-naive participants with F3-F4 fibrosis and all treatment-experienced participants (F0-F4) were assigned to elbasvir/grazoprevir for 12 weeks. The primary endpoint was sustained virologic response (SVR) 12 weeks after the end of therapy. RESULTS: One hundred and seventeen participants were enrolled. Among treatment-naive participants with F0-F2 fibrosis, SVR was achieved by 94% (50/53) and 96% (26/27) of those receiving elbasvir/grazoprevir for 8 or 12 weeks, respectively, and four participants relapsed. In the 12-week arm, 95% (35/37) achieved SVR and two participants relapsed. NS5A resistance-associated substitutions were present at baseline and virologic failure in five of the participants with relapse. Drug-related adverse events occurred in 42% (n = 22) and 50% (n = 32) of participants receiving 8 and 12 weeks of treatment, respectively. No participant discontinued treatment owing to an adverse event. CONCLUSION: These data confirm the efficacy of elbasvir/grazoprevir administered for 12 weeks in treatment-experienced individuals with HCV GT4 infection and those with advanced fibrosis. Treatment-naive individuals with mild fibrosis can be treated effectively with an 8-week regimen.

Online Self-Help as an Add-On to Inpatient Psychotherapy: Efficacy of a New Blended Treatment Approach.

BACKGROUND: Depression is one of the most frequent and costly mental disorders. While there is increasing evidence for the efficacy of online self-help to improve depression or prevent relapse, there is little evidence in blended care settings, especially combined with inpatient face-to-face psychotherapy. Therefore, we evaluated whether an evidence-based online self-help program improves the efficacy of inpatient psychotherapy. METHODS: A total of 229 depressed patients were randomly allocated either to an online self-help program (intervention group [IG]; Deprexis) or an active control group (CG; weekly online information on depression) in addition to inpatient psychodynamic psychotherapy. Both groups had access to their respective experimental intervention for 12 weeks, regardless of inpatient treatment duration. Reduction of depressive symptoms, as measured with the Beck Depression Inventory-II, was the primary outcome at the end of the intervention (T2). RESULTS: Depressive symptoms were statistically significantly lower in the IG compared to the active CG at T2 with a moderate between-group effect size of d = 0.44. The same applied to anxiety (d = 0.33), quality of life (d = 0.34), and self-esteem (d = 0.38) at discharge from inpatient treatment (T1). No statistically significant differences were found regarding dysfunctional attitudes (d = 0.14) and work ability (d = 0.08) at T1. CONCLUSIONS: This is the first evidence for blended treatment combining online self-help with inpatient psychotherapy. The study opens new and promising avenues for increasing the efficacy of inpatient psychotherapy. Future studies should determine how integration of online self-help into the therapeutic process can be developed further.

Dynamic gadoxetate-enhanced MRI for the assessment of total and segmental liver function and volume in primary sclerosing cholangitis.

PURPOSE: To evaluate dynamic hepatocyte-specific contrast-enhanced MRI (DHCE-MRI) for the assessment of global and segmental liver volume and function in patients with primary sclerosing cholangitis (PSC), and to explore the heterogeneous distribution of liver function in this patient group. MATERIALS AND METHODS: Twelve patients with primary sclerosing cholangitis (PSC) and 20 healthy volunteers were examined using DHCE-MRI with Gd-EOB-DTPA. Segmental and total liver volume were calculated, and functional parameters (hepatic extraction fraction [HEF], input relative blood-flow [irBF], and mean transit time [MTT]) were calculated in each liver voxel using deconvolutional analysis. In each study subject, and incongruence score (IS) was constructed to describe the mismatch between segmental function and volume. Among patients, the liver function parameters were correlated to bile duct obstruction and to established scoring models for liver disease. RESULTS: Liver function was significantly more heterogeneously distributed in the patient group (IS 1.0 versus 0.4). There were significant correlations between biliary obstruction and segmental functional parameters (HEF rho -0.24; irBF rho -0.45), and the Mayo risk score correlated significantly with the total liver extraction capacity of Gd-EOB-DTPA (rho -0.85). CONCLUSION: The study demonstrates a new method to quantify total and segmental liver function using DHCE-MRI in patients with PSC.

Parental acceptance and knowledge of varicella vaccination in relation to socioeconomics in Sweden: A cross-sectional study.

Varicella infection is a highly contagious disease which, whilst mild in most cases, can cause severe complications. Varicella vaccination is available privately in Sweden and is currently being reviewed for inclusion in the Swedish Public Health Agency's national immunisation program (NIP). A cross-sectional study of parents of Swedish children aged 1-8 years (n = 2212) was conducted to understand parental acceptance, beliefs and knowledge around varicella infection and vaccination. Respondents generally viewed varicella infection as a mild disease, with only a small proportion aware of potential severe complications. While 65% of respondents were aware of the vaccine, only 15% had started the course of vaccination as of February 2019. Further, 43% of parents did not intend to vaccinate, most commonly due to lack of inclusion in the NIP, but also due to perception of mild disease. Nevertheless, if offered within the NIP, 85% of parents would be highly likely to vaccinate their child. A number of statistically significant differences in awareness and behaviours were observed between sociodemographic subgroups. In general, women were more aware of vaccination (72%) compared to men (58%). Among unemployed or respondents with elementary school education, awareness was below 43%, and among respondents with high income the awareness was above 75%. Similarly, among unemployed or respondents with a low income the vaccination rate was as low as 30% compared with at least 57% among respondents with a high income. Respondents from metropolitan areas, those with university degrees and respondents with a higher income were more likely to be aware of the varicella vaccine and to have vaccinated their child. Whilst inclusion in the NIP is clearly the main driver for uptake, these identified knowledge gaps should inform educational efforts to ensure that all parents are informed of the availability and benefits of the varicella vaccine independent of socioeconomic status.

Pegylated interferon and ribavirin combination therapy for chronic hepatitis C virus infection in patients with Child-Pugh Class A liver cirrhosis.

OBJECTIVE: Pegylated interferon (peg-IFN) and ribavirin (RBV) treatment is less effective in patients with hepatitis C virus (HCV) and liver cirrhosis than in non-cirrhotic patients. Many patients with advanced liver disease have been excluded from the pivotal randomized controlled studies. The aim of this study was to investigate the efficacy and tolerability of combination therapy in unselected patients with Child-Pugh Class A liver cirrhosis at a Swedish university clinic. MATERIAL AND METHODS: The virologic response and adverse events were retrospectively analyzed in 104 patients with HCV-associated Child-Pugh Class A liver cirrhosis who had been treated with peg-IFN and RBV. RESULTS: Overall sustained virologic response (SVR) was achieved in 13% genotype 1-, 60% genotype 2-, and 31% genotype 3-infected patients. In treatment-naive patients, the corresponding rates were 13%, 82%, and 38%, respectively. In 46% of patients, treatment was discontinued prematurely owing to lack of virologic response in the majority. CONCLUSIONS: SVR rates found in our study, in particular for genotype 1 patients (13%), were lower than those generally found in randomized controlled studies. For cirrhotic patients, new treatment alternatives are urgently needed to improve treatment outcome.

Enhancing inpatient psychotherapeutic treatment with online self-help: study protocol for a randomized controlled trial.

BACKGROUND: Depression is one of the most debilitating and costly mental disorders. There is increasing evidence for the efficacy of online self-help in alleviating depression. Knowledge regarding the options of combining online self-help with inpatient psychotherapy is still limited. Therefore, we plan to evaluate an evidence-based self-help program (deprexis®; Gaia AG, Hamburg, Germany) to improve the efficacy of inpatient psychotherapy and to maintain treatment effects in the aftercare period. METHODS/DESIGN: Depressed patients (n = 240) with private internet access aged between 18 and 65 are recruited during psychosomatic inpatient treatment. Participants are randomized to an intervention or control group at the beginning of inpatient treatment. The intervention group (n = 120) is offered an online self-help program with 12 weekly tasks, beginning during the inpatient treatment. The control group (n = 120) obtains access to an online platform with weekly updated information on depression for the same duration. Assessments are conducted at the beginning (T0) and the end of inpatient treatment (T1), at the end of intervention (T2) and 6 months after randomization (T3). The primary outcome is the depression score measured by the Beck Depression Inventory-II at T2. Secondary outcome measures include anxiety, self-esteem, quality of life, dysfunctional cognitions and work ability. DISCUSSION: We expect the intervention group to benefit from additional online self-help during inpatient psychotherapy and to maintain the benefits during follow-up. This could be an important approach to develop future concepts of inpatient psychotherapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02196896 (registered on 16 July 2014).

Regulatory effects of tumor necrosis factor-alpha and interleukin-6 on HAMP expression in iron loaded rat hepatocytes.

BACKGROUND/AIMS: To study the effect of iron and proinflammatory cytokines on the expression of HAMP and other iron regulatory genes in primary rat hepatocytes. METHODS: Primary hepatocytes from rats fed a control or iron-enriched diet were plated on extracellular matrix and incubated with inflammatory stimuli in the presence or absence of serum. Cells were also incubated with desferrioxamine or ferric ammonium citrate. mRNA levels were determined by Real-Time PCR. RESULTS: Hepatocytes from control rats increased their HAMP expression during culturing, whereas the opposite was seen in hepatocytes from carbonyl-iron loaded animals. In the presence of serum, tumor necrosis factor-alpha, lipopolysaccharide and interleukin-6 increased HAMP expression in hepatocytes from both control and iron-loaded rats. Under serum-free conditions only tumor necrosis factor-alpha increased HAMP mRNA levels. Desferrioxamine and ferric ammonium citrate decreased HAMP gene expression. Tumor necrosis factor-alpha significantly increased mRNA levels of TfR2 and decreased those of DMT1 and IREG1. CONCLUSIONS: HAMP expression differs in cultured as compared with freshly isolated hepatocytes, and decreases in iron-loaded hepatocytes in serum free-media, suggesting that additional serum factors influence HAMP expression. Tumor necrosis factor-alpha regulates the mRNA levels of HAMP, IREG1, DMT1 and TfR2 in cultured hepatocytes from both iron-loaded and control animals.

A role for CD28 in lymphopenia-induced proliferation of CD4 T cells.

The peripheral mechanisms that regulate the size and the repertoire of the T cell compartment during recovery from a lymphopenic state are incompletely understood. In particular, the role of costimulatory signals, such as those provided by CD28, which have a critical importance for the immune response toward foreign Ags in nonlymphopenic animals, has been unclear in lymphopenia-induced proliferation (LIP). In this study, we show that accumulation of highly divided CD4 T cells characterized by great potential to make IFN-gamma is significantly delayed in the absence of B7:CD28 costimulation during LIP. Furthermore, CD28-sufficient CD4 T cells show great competitive advantage over CD28-deficient CD4 T cells when transferred together into the same lymphopenic hosts. Administration of CTLA-4-Ig removed this competitive advantage. Interestingly, CTLA-4-Ig treatment resulted in modest inhibition of LIP by CD28-deficient responders, suggesting that some of its effects may be independent of mere B7 blockade.