Nina Weis

Circulating levels of TNF-alpha and IL-6-relation to truncal fat mass and muscle mass in healthy elderly individuals and in patients with type-2 diabetes

The purpose of the current study was to test the hypothesis that an altered fat distribution in elderly healthy subjects and in patients with type-2 diabetes contributes to high circulating levels of interleukin (IL)-6 and tumor necrotic factor (TNF)-alpha, which secondly is related to lower muscle mass. Twenty young controls, (20-35 yr), 20 healthy elderly subjects (65-80 yr) and 16 elderly patients with type 2 diabetes (65-80 yr) were included in a cross sectional study. Plasma levels of TNF-alpha and IL-6 were measured after an overnight fast. Dual-energy X-ray absorptiometry and total body potassium counting measured truncal fat, appendicular skeletal muscle mass (ASM) and body cell mass (BCM), respectively. TNF-alpha, IL-6 and the relative truncal fat mass were higher in elderly compared with young controls. ASM was lower in diabetic men than in young controls and BCM was lower in elderly men compared with young men. TNF-alpha and IL-6 were correlated with the absolute as well as the relative truncal fat mass in univariate regression analyses. Similar results were found in multivariate linear regression analyses after adjusting for the effect of age and gender. TNF-alpha was related to lower ASM and BCM in elderly men both in a univariate regression analysis and a multivariate regression analysis. In conclusion, high plasma levels of TNF-alpha and IL-6 in elderly healthy people and in patients with type 2 diabetes are associated with increased truncal fat mass, suggesting that cytokines are partly derived from this adipose tissue bed. Furthermore, TNF-alpha was related to lower ASM and BCM, suggesting that TNF-alpha contributes to sarcopenia in ageing.

Historical epidemiology of hepatitis C virus (HCV) in selected countries

Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6 358 000 cases in 2008 and Brazil with 2 106 000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV‐infected populations are critical for addressing HCV‐related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.

Strategies to manage hepatitis C virus (HCV) disease burden

The number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. The largest reduction in HCV‐related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3–5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical.

High Levels of Chronic Immune Activation in the T-Cell Compartments of Patients Coinfected with Hepatitis C Virus and Human Immunodeficiency Virus Type 1 and on Highly Active Antiretroviral Therapy Are Reverted by Alpha Interferon and Ribavirin Treatment

ABSTRACT Chronic immune activation is a driver of human immunodeficiency virus type 1 (HIV-1) disease progression. Here, we describe that subjects with chronic hepatitis C virus (HCV)/HIV-1 coinfection display sharply elevated immune activation as determined by CD38 expression in T cells. This occurs, despite effective antiretroviral therapy, in both CD8 and CD4 T cells and is more pronounced than in the appropriate monoinfected control groups. Interestingly, the suppression of HCV by pegylated alpha interferon and ribavirin treatment reduces activation. High HCV loads and elevated levels of chronic immune activation may contribute to the high rates of viral disease progression observed in HCV/HIV-1-coinfected patients.

Macrophage serum markers in pneumococcal bacteremia: Prediction of survival by soluble CD163*

Objective:Soluble CD163 (sCD163) is a new macrophage-specific serum marker. This study investigated sCD163 and other markers of macrophage activation (neopterin, ferritin, transcobalamin, and soluble urokinase plasminogen activator receptor [suPAR]) as prognostic factors in patients with pneumococcal bacteremia. Design:Observational cohort study. Setting:Five university hospitals in Denmark. Patients:A total of 133 patients with Streptococcus pneumoniae bacteremia (positive blood culture) and 133 age- and gender-matched controls. Interventions:Samples were collected for biochemical analyses at the time of first positive blood culture. Measurements and Main Results:sCD163 was highly correlated with other macrophage markers and was significantly elevated (median [25–75 percentiles], 4.6 mg/L [2.8–8.9]) compared with healthy controls (2.7 mg/L [2.1–3.3], p < .0001). Increased levels were observed in patients who needed intensive care (hemodialysis, p = .0011; hypotension, p = .0014; mechanical ventilation, p = .0019). Significantly lower levels of sCD163, ferritin, transcobalamin, and suPAR (but not C-reactive protein) were measured in patients ≥75 yrs. In patients <75 yrs, all macrophage markers were increased in patients who died from their infection compared with survivors, whereas no change was observed in any of the markers in the very old age. At cutoff levels of 9.5 mg/L (sCD163) and 1650 nmol/L (C-reactive protein), the relative risk for fatal outcome in patients <75 yrs was 10.1 (95% confidence interval 3.4–31.0) and 7.0 (95% confidence interval 2.4–21.6) for sCD163 and C-reactive protein, respectively. In a multivariate logistic regression model for patients <75 yrs, ferritin, transcobalamin, neopterin, and suPAR contained no significant information on the probability of survival when sCD163 and CRP were known (p = .25). Conclusions:Macrophage marker response in pneumococcal bacteremia was compromised in old age. In patients <75 yrs old, sCD163 was superior to other markers, including C-reactive protein, in predicting fatal disease outcome.

Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study

Objective To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. Design In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA<lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa-2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients. Results Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups. Conclusions The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4. Trial registration number NCT01125189.

Efficient Culture Adaptation of Hepatitis C Virus Recombinants with Genotype-Specific Core-NS2 by Using Previously Identified Mutations†

ABSTRACT Hepatitis C virus (HCV) is an important cause of chronic liver disease, and interferon-based therapy cures only 40 to 80% of patients, depending on HCV genotype. Research was accelerated by genotype 2a (strain JFH1) infectious cell culture systems. We previously developed viable JFH1-based recombinants encoding the structural proteins (core, E1, E2), p7, and NS2 of prototype isolates of the seven major HCV genotypes; most recombinants required adaptive mutations. To enable genotype-, subtype-, and isolate-specific studies, we developed efficient core-NS2 recombinants from additional genotype 1a (HC-TN and DH6), 1b (DH1 and DH5), and 3a (DBN) isolates, using previously identified adaptive mutations. Introduction of mutations from isolates of the same subtype either led to immediate efficient virus production or accelerated culture adaptation. The DH6 and DH5 recombinants without introduced mutations did not adapt to culture. Universal adaptive effects of mutations in NS3 (Q1247L, I1312V, K1398Q, R1408W, and Q1496L) and NS5A (V2418L) were investigated for JFH1-based genotype 1 to 5 core-NS2 recombinants; several mutations conferred adaptation to H77C (1a), J4 (1b), S52 (3a), and SA13 (5a) but not to ED43 (4a). The mutations permitting robust virus production in Huh7.5 cells had no apparent effect on viral replication but allowed efficient assembly of intracellular infectious HCV for adapted novel or previously developed recombinants. In conclusion, previously identified mutations permitted development of novel HCV core-NS2 genotype recombinants. Mutations adapting several recombinants to culture were identified, but no mutations were universally adaptive across genotypes. This work provides tools for analysis of HCV genotype specificity and may promote the understanding of genotype-specific patterns in HCV disease and control.

Daclatasvir Plus Peginterferon and Ribavirin Is Noninferior to Peginterferon and Ribavirin Alone, and Reduces the Duration of Treatment for HCV Genotype 2 or 3 Infection

BACKGROUND & AIMS Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy. METHODS Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24). RESULTS Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those expected from peginterferon alfa and ribavirin therapy. CONCLUSIONS Twelve or 16 weeks of treatment with daclatasvir, in combination with peginterferon alfa-2a and ribavirin, is a well tolerated and effective therapy for patients with HCV genotype 2 or 3 infections. Daclatasvir-containing regimens could reduce the duration of therapy for these patients. Clinicaltrials.gov number: NCT01257204.

Stereological estimation of mean nuclear volume in prostatic cancer, the reproducibility and the possible value of estimations on repeated biopsies in the course of disease

The reproducibility of stereological estimates of mean nuclear volume by using the principle of volume estimation of particles of arbitrary shape is investigated together with the possible prognostic value of the estimates in the course of advanced prostatic cancer.

Interleukin‐28B polymorphisms are associated with hepatitis C virus clearance and viral load in a HIV‐1‐infected cohort

Summary.  Twenty‐five per cent of individuals infected with hepatitis C virus (HCV) are able to clear HCV spontaneously. Differences in host genetics are believed to affect the outcome of HCV infection. We analysed an exonic, a promoter and an intronic single nucleotide polymorphism (SNP) of the interferon‐λ3 coding interleukin (IL)‐28B gene to study the relationship between IL28B SNPs and outcome of HCV infection. Among 206 HIV‐1‐infected Europeans with evidence of HCV infection, 47 (23%) individuals had cleared HCV and 159 (77%) had developed chronic infection. The exonic rs8103142 CT, the promoter rs12979860 CT and the intronic rs11881222 AG genotypes were associated with a decreased HCV clearance rate with adjusted odds ratios (aOR) of 0.3 (95% CI, 0.1–0.7), 0.4 (95% CI, 0.2–0.8) and 0.4 (95% CI, 0.2–0.8), respectively. The haplotype block TCG CTA was associated with a decreased HCV clearance rate (aOR 0.4, 95% CI, 0.2–0.8). Further, we found significant differences in HCV RNA levels among individuals chronically infected with HCV genotype 1 for rs8103142 and rs12979860 (P ≤ 0.05). Chronically infected individuals with HCV genotype 3 and with the favourable haplotype block CTA CTA had higher median HCV RNA levels than individuals with unfavourable haplotype blocks (P ≤ 0.05). Our findings suggest that IL28B may account for some differences in HCV outcome but that other factors including the viral genotype, host genetics and the host–virus interaction are likely to influence the outcome of HCV infection.