Costs and outcomes of treating chronic hepatitis C patients in routine care - results from a nationwide multicenter trial.

Viral hepatitis is a major public health problem affecting millions of people worldwide. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. The aim of the study was to assess outcomes and costs of treating patients with chronic hepatitis C in clinical practice in Germany. We carried out a prospective noninterventional study. Information on treatment outcomes, resource utilization and quality of life was provided by 281 physicians throughout Germany. Data of 3708 monoinfected HCV-patients treated between 2008 and 2011 were analysed. Therapy consisted of peginterferon/ribavirin. Mean age of patients was 43.7 years, 60.3% were male and estimated duration of infection was 13.6 years. Predominantly genotype 1 (61.3%) or 3 (28.5%) infections were observed. Sustained viral response (SVR)-rates in most frequently observed genotypes were 49.2% in GT-1 and 61.9% in GT-3 treatment-naive patients (Relapser: GT-1: 35.3% and GT-3: 57.3%; Nonresponder: GT-1: 25.0% and GT-3: 33.3%). Average treatment costs were lowest in treatment-naive patients (€18 965) and higher in patients who failed previous treatments (relapsers: €24 753; nonresponders: €19 511). Differences according to genotype were observed. Average costs per SVR in treatment-naive patients were €44 744 for GT-1 and €22 218 for GT-3. Treatment was associated with a decrease in quality of life; post-treatment quality of life was higher in patients achieving SVR. Our insight on real-life treatment outcomes and costs can serve as a reference for a comparison with other treatments. There is high need for short-term and long-term cost-effectiveness analysis in real-life settings as newly introduced treatment strategies with direct acting antivirals result in high SVR-rates but are more costly.

[Costs of a guideline-based treatment of patients with chronic hepatitis C in the era of interferon-free treatment]. / Kosten einer leitliniengerechten Versorgung von Hepatitis-C-Patienten im Zeitalter Interferon-freier Therapien.

The treatment of chronic hepatitis C has considerably changed with the introduction of recent direct acting antivirals. These antivirals have sustained virologic response (SVR) rates above 90 % as well as reduced toxicity and treatment duration. Therefore, current German guidelines recommend these interferon-free regimens as first-choice treatment. Nevertheless, recent developments were accompanied by a significant increase in treatment costs, which led to extensive discussions on reasonable pharmaceutical prices. The aim of the current study was to analyze the average treatment costs and costs per patient cured for guideline treatment recommendations. Analyses were stratified according to genotype, treatment status (naive/experienced), and presence/absence of cirrhosis. Costs were separated in (1.) basic diagnostic procedures, (2.) monitoring, and (3.) pharmaceuticals. The calculation is based on a remuneration scheme in the statutory health insurance system. In treatment-naïve non-cirrhotic patients, the average cost is 41 766 €/SVR for the treatment with SOF/LDV calculated (PTV/r/OMV+DSV: 53 129 €/SVR). In treatment-naive cirrhotic patients, costs were 60 323 €/SVR (SOF/LDV+RBV) and 80 604 €/SVR (PTV/r/OMV+DSV+RBV). Treatment-experienced genotype 1 patients had average costs of 60 366 €/SVR for SOF/LDV treatment as well as 53 134 €/SVR for PTV/r/OMV+DSV±RBV treatment (cirrhotic patients: 62 208 €/SVR for SOF/LDV+RBV; 80 824 €/SVR for PTV/r/OMV+DSV+RBV). The average treatment costs per SVR in treatment-naive genotype 1 patients are comparable to previous standard of care treatments and lower in treatment-experienced patients. In other genotypes, treatment costs and costs per cure are significantly higher compared to previous standard of care. However, long-term modelling studies show that new regimens are cost-effective.

[Costs of a guideline-based treatment of patients with chronic hepatitis C in Germany]. / Kosten einer leitliniengerechten Versorgung von Hepatitis-C-Patienten in Deutschland.

The costs of a guideline-based treatment in chronic hepatitis C infected people are unknown. The goal of HCV therapy is to achieve a sustained viral response and thereby to reduce morbidity and mortality due to complications of liver cirrhosis and hepatocellular carcinoma. This study analyses the costs of a guideline-based treatment based on the German guideline on the management of HCV infection. In addition, costs of newly introduced protease inhibitors were calculated. Costs for baseline diagnostics, monitoring and medical treatment were calculated according to the stage of the disease, the HCV genotype and viral response. Costs for baseline diagnostics account for €â€Š302.75 and monitoring accounts for €â€Š596 to €â€Š1173. Dual therapy with pegylated interferon and ribavirin results in average costs of €â€Š7709 to €â€Š34 692. Total costs of a guideline-based treatment range between €â€Š8,608 and €â€Š36 167 depending on HCV genotype and length of therapy. With the introduction of protease inhibitors for HCV genotype 1 patients, costs of pharmaceuticals have increased further. Triple-therapy with telaprevir accounts for €â€Š43 280 respectively €â€Š54 844. Costs for Boceprevir treatment range from €â€Š34 143 to €â€Š60 990. Due to increasing costs, health-economic evaluations gain significant relevance and should be considered when implementing new treatment strategies.

Interleukin-12 induction of Th1 cytokines is important for viral clearance in chronic hepatitis B.

Interleukin-12, a cytokine with an important role against intracellular pathogens, promotes Th1 cell development, cellmediated cytotoxicity, and interferon-gamma production. We investigated the immunoregulatory role of IL-12 in 72 chronic hepatitis B virus (HBV) carriers, 33 of whom were monitored longitudinally during interferon-alpha treatment. Serum levels of IL-12 heterodimer, IL-12 p40 subunit, IL-4, and Th1 cytokines were determined by specific ELISAs, and hepatitis B core antigen-specific T cell response by a proliferation assay. Chronic HBV carriers had higher serum levels of IL-12 and IL-12 p40 in comparison with controls (P < 0.01), suggesting that IL-12 production is not impaired. The longitudinal analysis revealed a further substantial increase (> 2.5x baseline level) of bioactive IL-12 and Th1 cytokines in patients who cleared HBV and seroconverted to anti- hepatitis B e, unlike the 23 nonresponders with persistent HBV replication (P < 0.01). The IL-12 peak followed the peak of hepatocytolysis by 9.8+/-2.8 wk and occurred either before or simultaneously with hepatitis B e seroconversion. Hepatitis B core antigen-specific T cell proliferation closely correlated with hepatocytolysis and increased significantly in all patients (8 responders and 15 nonresponders) who developed hepatitis flare, irrespective of the virological outcome. These results provide in vivo evidence that IL-12 may have an important role for viral clearance in chronic HBV infection.

[Chronic HCV infections. A model disease for therapy, economics and social-medical aspects]. / Chronische HCV-Infektion. Modellerkrankung für Therapie, Okonomie und sozialmedizinische Aspekte.

In Germany up to 800,000 persons are chronically infected with the hepatis C virus. This chronic disease is correlated with a significant morbidity and mortality. This is a consequence of the development of liver cirrhosis and hepatocellular carcinoma in a substantial proportion of the patients. Health quality of life is also affected by the infection. There are reliable standards available for diagnosis and treatment. Antiviral treatment is highly effective and the combination of pegylated interferon alpha with ribavirin leads to a sustained viral eradication in about 60% of the cases. The treatment is also cost-effective and results in an increased life expectancy. Costs for HCV treatment are favourable in comparison to other well accepted therapies and interventions and a reduction of future costs can be expected.Thus, active screening for HCV infected persons should be intensified to improve the quality of medical care. Early and broad treatment is potentially able to reduce the future burden of HCV-related diseases.

[Chronic hepatitis C virus infection]. / Bei jeder Transaminasen-Erhöhung plus spezifischem Hepatitis-Risiko. Schliessen Sie Hepatitis B und C aus!

The only way to prevent the late sequelae of chronic HCV infection--liver cirrhosis or HCC--is by early and specific antiviral therapy. A prerequisite is the identification of HCV-infected persons in the general population. To accomplish this a screening concept that includes all patients with exposure risks or elevated serum transaminases is needed.

Flux of amino acids and energy substrates across the leg in weight-stable HIV-infected patients with acute opportunistic infections: indication of a slow protein wasting process.

Increased whole-body proteolysis with muscle protein net degradation has been suggested as one of the causes of weight loss in patients infected with human immunodeficiency virus (HIV). We studied the exchange rates of amino acids and energy substrates across the lower extremity in 16 HIV patients and 16 age-matched controls with similar body cell mass. The patients had either opportunistic infections or chronic diarrhea but no signs of clinical malnutrition. The following findings were obtained in the HIV patients: an augmented peripheral net release of arginine and lysine; an increase in both the negative arterial-venous difference and the efflux of the nitrogen contained in nonmetabolized amino acids; diminished export of 3-methylhistidine; lowered plasma and erythrocyte amino acid concentrations; reduced output of glycerol and furthermore; and neither a net release nor a net uptake of free fatty acids. The findings concerning nitrogen metabolism support the hypothesis that, in the presence of a reduction in protein breakdown, peripheral protein synthesis is severely depressed, making a slow protein wasting process likely to occur. The balances of glycerol and free fatty acids are due not only to the leg tissues but perhaps also in part to increased net retention of these substrates by skeletal muscle.

Endothelin-1 in subarachnoid hemorrhage: An acute-phase reactant produced by cerebrospinal fluid leukocytes.

BACKGROUND AND PURPOSE: The most potent vasoconstrictor known, endothelin-1, is currently considered to mediate cerebral vasospasm in subarachnoid hemorrhage (SAH), which can cause delayed cerebral ischemia. In our study, we performed clinical and in vitro experiments to investigate the origin and the mechanisms of the secretion of endothelin-1 in SAH. METHODS: Endothelin-1 and markers of inflammatory host response (interleukin [IL]-1ss, IL-6, and tumor necrosis factor-alpha) were comparatively quantified in the cerebrospinal fluid (CSF) of SAH patients and control subjects, and concentrations were related to clinical characteristics. Furthermore, mononuclear leukocytes isolated from the CSF of SAH patients and control subjects were analyzed regarding their mRNA expression of endothelin-1 and inflammatory cytokines. Finally, complementary in vitro experiments were performed to investigate whether coincubation of blood and CSF can trigger leukocytic mRNA expression and release of these factors. RESULTS: Activated mononuclear leukocytes in the CSF of SAH patients synthesize and release endothelin-1 in parallel with known acute-phase reactants (IL-1ss, IL-6, and tumor necrosis factor-alpha). Complementary in vitro experiments not only further confirmed this leukocytic origin of endothelin-1 but also showed that aging and subsequent hemolysis of blood is sufficient to induce such endothelin-1 production. CONCLUSIONS: The demonstration that endothelin-1 is produced by activated CSF mononuclear leukocytes suggests that subarachnoid inflammation may represent a therapeutic target to prevent vasospasm and delayed cerebral ischemia after SAH.

Interferon-gamma-inducing factor (IL-18) and interferon-gamma in inflammatory CNS diseases.

OBJECTIVE: To examine the intrathecal production of a newly identified cytokine, interferon-gamma-inducing factor (IL-18), together with interferon-gamma itself, in inflammatory diseases of the CNS (i.e., bacterial meningitis, viral meningoencephalitis, and MS). RESULTS: IL-18 concentrations in CSF were significantly increased in bacterial meningitis and tended toward increased levels in viral meningoencephalitis. In contrast, IL-18 was detectable only in a few patients with MS and healthy controls. Interestingly, interferon-gamma was significantly increased selectively in CSF of patients with viral meningoencephalitis. CONCLUSION: The observation of an intrathecal release of IL-18 in patients with meningitis argues for a pathophysiologic role of this novel cytokine in immunity against invading microorganisms the CNS.

Increased release of interleukin-12p40 in MS: association with intracerebral inflammation.

OBJECTIVE: The p40 subunit of interleukin (IL)-12 was recently demonstrated in active lesions in MS. We tested whether the p40 subunit of IL-12 can also be detected in CSF and serum of patients with this disease and, if so, whether release is associated with inflammatory disease activity. RESULTS: This study demonstrates an increased (up to 1,000-fold) compartmentalized release of the p40 subunit but not of the heterodimer p70 in MS. Release of IL-12p40 correlated with classic markers of CNS inflammation (CSF cell counts, immunoglobulin G index) and was significantly increased in patients with gadolinium-enhancing plaques on MRI. Moreover, release of IL-12p40 was associated with CSF levels of myelin basic protein as a measure of myelin degradation. CONCLUSION: These results suggest a role of IL-12p40 in the pathophysiology of MS.

Immunopathogenesis of hepatitis B virus recurrence after liver transplantation.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation is associated with inflammatory graft changes, despite immunosuppression and donor/recipient HLA mismatch. We investigated whether immune mechanisms are involved in the pathogenesis of hepatitis B after liver transplantation. METHODS: The virus-specific T helper (Th) cell response, activation of Th1/Th2 subpopulations, donor/recipient HLA, and expression of tumor necrosis factor (TNF)-alpha/TNF receptors were determined in 28 patients who underwent transplantation for HBV-related cirrhosis (17 with HBV recurrence and 11 without recurrence) in comparison to 30 nontransplant patients with chronic hepatitis B. RESULTS: Orthotopic liver transplantation recipients with HBV recurrence showed significant hepatitis B core antigen-specific T-cell proliferation, comparable to nontransplant patients, which was not present in transplant recipients without recurrence. In addition, hepatic and serum interleukin (IL)-2, interferon-gamma, and TNF-alpha were enhanced, without changes in IL-4 and IL-10. Phenotypically, hepatic infiltrates in allografts with HBV recurrence were comprised of CD4+ lymphocytes and macrophages with a correlation between interferon-gamma- and TNF-alpha-producing cells and the degree of necroinflammatory activity. There was a marked up-regulation of both TNF-alpha receptors, significantly greater than in nontransplant patients. CONCLUSIONS: These findings suggest that despite immunosuppression, HLA class I-independent immune mechanisms have a significant pathogenic role in liver damage associated with HBV recurrence after liver transplantation.

CD14+ peripheral blood mononuclear cells from chronic myeloid leukemia and normal donors are inhibitory to short- and long-term cultured colony-forming cells.

Monocyte-induced cell-cytotoxicity has been implicated in the mechanism of suppression of normal haematopoietic progenitors in chronic myeloid leukemia (CML). We examined here the in vitro effect of CML-derived and normal peripheral blood (PB) monocytes on short- and long-term cultured haematopoietic progenitor cells. Short-term coculture (5 days) of CML or normal monocytes with CML or normal peripheral blood mononuclear cells (PBMNC)/CD34+ cells as targets resulted in a significant inhibition of colony-forming cell (CFC) growth. Coculture conditioned medium (CCM) from 5-days cocultures of normal or CML CD14+ monocytes with CD34+ cells were likewise inhibitory to CFC. In 5-week long-term cocultures of monocytes in direct contact with normal bone marrow (BM) progenitors, CML monocytes reduced the proportion of long-term cultured CFC (LTC-CFC) significantly to 52% of the controls, while normal monocytes had a less pronounced inhibitory effect (89% of the controls) on LTC-CFC. Reduction of LTC-CFC was great when CML monocytes and target cells were separated by a transwell membrane as compared to control cultures in the absence of CD14+ cells (53.5 vs. 9%). CCM from 5-week cocultures of normal or CML CD14+ monocytes with CD34+ progenitors from bone marrow (BM) cells were also inhibitory to CFC. No difference in cytokine levels for TNF-alpha, IFN-gamma, G-CSF, IL-10, IL-6 was detectable between CML CD14+ CCM and control CCM derived from short- and long-term cocultures. Our results suggest that CML monocytes may play a role in the inhibition of normal haematopoiesis through a yet not defined soluble factor supporting the expansion of the malignant clone in CML.

Dual biological activity of apurinic acid on human lymphocytes: induction of interferon-gamma and protection from human immunodeficiency virus infection in vitro.

The chemically modified DNA, apurinic acid (APA), is cytotoxic for human lymphocytes at concentrations above 100 micrograms/ml. At low concentrations (0.05-1 micrograms/ml) APA acts as an inducer interferon gamma (IFN-gamma) in lymphocytes in vitro; the maximum interferon titer of 50 units/ml was reached at 0.4 micrograms/ml. When added to the cells in combination with phytohemagglutinin A (PHA), APA displays a significant synergistic interferon-inducing ability; the maximum titer of 940 units/ml was obtained with 10 micrograms/ml of APA and 6.25 micrograms/ml of PHA. APA also proved to be an effective inhibitor of human immunodeficiency virus (HIV-1) replication in H9 cells. At a concentration of 10 micrograms/ml, APA causes a 49% inhibition of virus growth, while 20 micrograms/ml of APA are required to inhibit expression of HIV-1 p17 and p24 gag proteins by 60%. The mechanism of anti HIV-1 activity of APA likely occurs at the level of viral reverse transcriptase. This enzyme is inhibited by APA in a noncompetitive way with a Ki of 0.39 microM, while the cellular DNA polymerases alpha, beta and gamma are 140- to 300-fold less sensitive to APA.

Proinflammatory cytokines in serum of patients with acute cerebral ischemia: kinetics of secretion and relation to the extent of brain damage and outcome of disease.

The release of the proinflammatory cytokines IL-1 beta, IL-6, TNF-alpha and soluble TNF-receptors p55 and p75 in peripheral blood was serially determined in 19 patients with acute cerebral ischemia. Only patients admitted within 4 h following onset of symptoms were studied. In contrast to serum levels of IL-1 beta, TNF-alpha and TNF-receptors, which did not exhibit a significant response, IL-6 showed a significant increase of serum levels already within the first hours following onset of disease and reached a plateau at 10 h until day 3 and returned to baseline by day 7. The increase of levels of this cytokine was significantly (P < 0.05) correlated with increasing volumes of brain lesion and was also significantly (P < 0.005) associated with poor functional and neurological outcome. The increase of levels of IL-6 despite a considerable dilution in peripheral blood shown in this preliminary study suggests an early inflammatory response in ischemic brain lesion.

Regulation of Staphylococcus aureus-mediated activation of interleukin-18 in peripheral blood mononuclear cells.

Bacteria and bacterial antigens strongly induce cytokine secretion by peripheral blood leukocytes and thereby initiate an inflammatory cascade with potentially deleterious consequences for the host. The present study focussed on receptors and signal transduction pathways involved in activation of interleukin (IL)-18 by heat-inactivated Gram-positive Staphylococcus aureus Cowan strain I (SAC). Similarly to IL-12/IL-12p40, IL-10 and IFN-gamma, SAC dose-dependently activated IL-18. Secretion of IL-18 was independent of functional activity of IL-10, IL-12 or IFN-gamma. Lipoteichoic acid (LTA), a structural component of SAC, was not sufficient for activation of IL-18, while it dose-dependently induced IL-10. In contrast to IL-12, blockade of CD14 only partially diminished secretion of IL-18 and did not affect secretion of IL-10, suggesting involvement of other receptors (e.g., Toll-like receptors) in SAC responses. Further down-stream however, secretion of IL-10, IL-12 and IL-18 was uniformly inhibited by blockade of G-protein-mediated kinase activation by mastoparan. Secretion of IL-18 required phosphatidylinositol-3'-kinase, and secretion of IL-12 phosphotyrosine kinase activity. The data demonstrate that SAC potently activates secretion of IL-18 by peripheral blood mononuclear cells with differential involvement of cell-surface receptors and signal transduction pathways as compared to other natural killer- and T cell-promoting cytokines.

[Lymphographic findings in AIDS patients]. / Lymphographische Befunde bei AIDS-Patienten.

The lymphographic findings in 20 patients with AIDS-most in clinical stage IV-can be divided into four categories. In six there were no specific changes and in a further six the storage pattern was that of sinus histiocytosis. One patient showed transition to malignant lymphoma and another patient had atypical mycobacterial infection of the retroperitoneal lymph nodes. Six patients showed a lymphographic pattern of scarring. The results of this study show that lymphography is a sensitive method that can provide important additional information.

A randomized, double-blind study of certoparin vs. unfractionated heparin to prevent venous thromboembolic events in acutely ill, non-surgical patients: CERTIFY Study.

BACKGROUND: In medically ill patients, no contemporary double-blind head-to-head evaluation of low molecular weight heparin vs. unfractionated heparin (UFH) for the prevention of venous thromboembolic events is available. OBJECTIVES: To compare the efficacy and safety of certoparin with those of UFH. PATIENTS/METHODS: In this double-blind, randomized, controlled trial, acutely ill, non-surgical patients aged > or = 70 years were randomized to certoparin (3000 U of anti-factor Xa once daily) or to UFH (5000 IU t.i.d.). The primary endpoint was the composite of proximal deep vein thrombosis as assessed by bilateral compression ultrasonography, symptomatic non-fatal pulmonary embolism and venous thromboembolism-related death, and was assessed by a blinded central adjudication committee. Non-inferiority margins were set at 1.8 for the odds ratio (OR) and 3.45% for the absolute difference. RESULTS: Three thousand two hundred and thirty-nine patients aged 78.8 + or - 6.3 years were treated for 9.1 + or - 3.4 days. The incidence of the primary endpoint was 3.94% in the certoparin group and 4.52% in the UFH group, with a difference in proportions of - 0.59% [95% confidence interval (CI) -2.09 to 0.92; P < 0.0001 for non-inferiority], and an OR of 0.87 (95% CI 0.60-1.26; P = 0.0001 for non-inferiority). Major bleeding occurred in 0.43% of certoparin-treated patients and 0.62% of UFH-treated patients (OR 0.69; 95% CI 0.26-1.83). Any bleeding occurred at 3.20% in certoparin-treated patients vs. 4.58% in UFH-treated patients (OR 0.69; 95% CI 0.48-0.99; P < 0.05), and 5.73% of certoparin-treated patients and 6.63% of UFH-treated patients experienced serious adverse events. All-cause mortality was 1.27% in certoparin-treated patients and 1.36% in UFH-treated patients. CONCLUSIONS: In acutely ill, non-surgical elderly patients, thromboprophylaxis with certoparin (3000 U of anti-FXa once daily) was non-inferior to 5000 IU of UFH t.i.d., with a favorable safety profile.

[Health economics of chronic infectious diseases: the example of hepatitis C]. / Gesundheitsökonomische Aspekte chronischer Infektionskrankheiten am Beispiel der chronischen Hepatitis C.

Based on the German Hepatitis C Model (GEHMO) we developed a Hepatitis C Policy Model and applied it to the heterogeneous German hepatitis C population within the German health care context. We used Markov cohort simulation to predict absolute clinical and economic outcomes for a 20-year time horizon. For the cost-effectiveness analysis, a lifelong time horizon was used. Four different strategies were compared: (1) no antiviral treatment, (2) interferon monotherapy, (3) combination therapy with interferon plus ribavirin, and (4) combination therapy with pegylated interferon plus ribavirin. Based on our model, antiviral therapy with pegylated interferon and ribavirin could prevent about 17,000 cases of cirrhosis, 580 liver transplants, and 7,600 HCV-related deaths and is expected to save about 53,000 life years at total costs of 1.3 billion Euros within the next 20 years. Pegylated interferon plus ribavirin was the most effective treatment with an incremental cost-utility ratio of 23,000 Euros per quality-adjusted life year saved.

Studies of interleukin-12 in chronic hepatitis B virus infection.

Interleukin-12 is produced by antigen-presenting cells and regulates the balance between TH1/TH2 lymphocyte subsets, promoting cell-mediated immune reactions. Amongst patients with chronic hepatitis B undergoing interferon-alpha treatment, only those who clear hepatitis B virus show a substantial increase in the production of biologically active IL-12 and an inverse ratio between serum levels of IL-12p40 subunit and IL-12. The peak of serum IL-12 occurs after the hepatitis flare and precedes or coincides with the time of HBe seroconversion. These data indicate that IL-12 is an important element for establishing the host immune control on hepatitis B virus replication in patients with chronic hepatitis B virus infection.