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Prophylaxis, diagnosis and therapy of infections in patients undergoing high-dose chemotherapy and autologous haematopoietic stem cell transplantation. 2020 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO).
Christopeit, M, Schmidt-Hieber, M, Sprute, R, Buchheidt, D, Hentrich, M, Karthaus, M, Penack, O, Ruhnke, M, Weissinger, F, Cornely, OA, et al
Annals of hematology. 2021;(2):321-336
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Abstract
To ensure the safety of high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT), evidence-based recommendations on infectious complications after HDC/ASCT are given. This guideline not only focuses on patients with haematological malignancies but also addresses the specifics of HDC/ASCT patients with solid tumours or autoimmune disorders. In addition to HBV and HCV, HEV screening is nowadays mandatory prior to ASCT. For patients with HBs antigen and/or anti-HBc antibody positivity, HBV nucleic acid testing is strongly recommended for 6 months after HDC/ASCT or for the duration of a respective maintenance therapy. Prevention of VZV reactivation by vaccination is strongly recommended. Cotrimoxazole for the prevention of Pneumocystis jirovecii is supported. Invasive fungal diseases are less frequent after HDC/ASCT, therefore, primary systemic antifungal prophylaxis is not recommended. Data do not support a benefit of protective room ventilation e.g. HEPA filtration. Thus, AGIHO only supports this technique with marginal strength. Fluoroquinolone prophylaxis is recommended to prevent bacterial infections, although a survival advantage has not been demonstrated.
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Whole Lotta Lipids-from HCV RNA Replication to the Mature Viral Particle.
Bley, H, Schöbel, A, Herker, E
International journal of molecular sciences. 2020;(8)
Abstract
Replication of the hepatitis C virus (HCV) strongly relies on various lipid metabolic processes in different steps of the viral life cycle. In general, HCV changes the cells' lipidomic profile by differentially regulating key pathways of lipid synthesis, remodeling, and utilization. In this review, we sum up the latest data mainly from the past five years, emphasizing the role of lipids in HCV RNA replication, assembly, and egress. In detail, we highlight changes in the fatty acid content as well as alterations of the membrane lipid composition during replication vesicle formation. We address the role of lipid droplets as a lipid provider during replication and as an essential hub for HCV assembly. Finally, we depict different ideas of HCV maturation and egress including lipoprotein association and potential secretory routes.
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Hepatitis C Virus Downregulates Core Subunits of Oxidative Phosphorylation, Reminiscent of the Warburg Effect in Cancer Cells.
Gerresheim, GK, Roeb, E, Michel, AM, Niepmann, M
Cells. 2019;(11)
Abstract
Hepatitis C Virus (HCV) mainly infects liver hepatocytes and replicates its single-stranded plus strand RNA genome exclusively in the cytoplasm. Viral proteins and RNA interfere with the host cell immune response, allowing the virus to continue replication. Therefore, in about 70% of cases, the viral infection cannot be cleared by the immune system, but a chronic infection is established, often resulting in liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Induction of cancer in the host cells can be regarded to provide further advantages for ongoing virus replication. One adaptation in cancer cells is the enhancement of cellular carbohydrate flux in glycolysis with a reduction of the activity of the citric acid cycle and aerobic oxidative phosphorylation. To this end, HCV downregulates the expression of mitochondrial oxidative phosphorylation complex core subunits quite early after infection. This so-called aerobic glycolysis is known as the "Warburg Effect" and serves to provide more anabolic metabolites upstream of the citric acid cycle, such as amino acids, pentoses and NADPH for cancer cell growth. In addition, HCV deregulates signaling pathways like those of TNF-β and MAPK by direct and indirect mechanisms, which can lead to fibrosis and HCC.
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New insights into the rational use of HCV+ organs worldwide.
Morales, JM, Sawinski, D
Clinical transplantation. 2019;(12):e13739
Abstract
Hepatitis C (HCV) is a worldwide health problem. Effective therapies for HCV infection, coupled with an increase in deceased donors due to the opioid epidemic, have led to the broader availability and the use of HCV-infected donor organs, including HCV nucleic acid test-positive (NAT+) donors in HCV-negative recipients. In this review, we discuss the prevalence of HCV infection, trends in the use of HCV-infected donors, and outcomes for those who receive HCV-seropositive or HCV NAT+ donor organs. We discuss management considerations such as hepatitis B reactivation, selection of the optimal direct-acting antiviral regimen, and potential complications. We also present a framework for the rational use of HCV-infected donor organs in the future.
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Antioxidants benefits in hepatitis C infection in the new DAAs era.
Lozano-Sepúlveda, SA, Rincón-Sanchez, AR, Rivas-Estilla, AM
Annals of hepatology. 2019;(3):410-415
Abstract
Some of the evidence on whether antioxidant supplements are effective in treatment of liver diseases is contradictory. Here we perform a descriptive analysis of the available data in vivo and in vitro of the possible antiviral action and controversy of several antioxidant molecules against HCV.
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Managing HCV treatment failure and the potential of resistance testing in informing second-line therapy options.
Loggi, E, Vukotic, R, Andreone, P
Expert review of anti-infective therapy. 2018;(11):833-838
Abstract
Direct acting antivirals have completely changed the landscape of the treatment of chronic hepatitis C. The management of the few patients who relapse to direct acting antivirals requires a careful analysis of the chances to achieve therapeutic success with a second antiviral course. In this context, the usefulness of viral resistances testing, able to detect resistance-associated substitutions in the viral sequence, is at present a matter of debate. Areas covered: The role of resistance associated substitutions is examined through the evaluation of the data from clinical trials that have assessed the impact of viral resistances on the treatment outcome. Special attention has been paid on the data from re-treatment studies. Expert commentary: The treatment failure in chronic hepatitis C is still a possible event. Therefore, additional real-world clinical data on relapse rates and on the relapse management are welcome to definitely address the clinical guidelines. At present, the testing of viral resistances is an exquisite tool for the choice of the re-treatment schedule. In the near future, widespread use of the most recently registered direct acting antivirals with high barrier to resistance will probably weaken the need of resistance testing as a support in clinical decisions.
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Liver transplantation from HCV RNA-positive donors in the era of interferon-free HCV therapeutics: a re-examination of the situation.
Willuweit, K, Canbay, A, Gerken, G, Timm, J, Paul, A, Treckmann, J, Herzer, K
Minerva gastroenterologica e dietologica. 2017;(1):55-61
Abstract
Although the availability of donor organs is limited, liver grafts from HCV-positive donors remained yet an obstacle, primarily because of limited therapeutic options for HCV reinfection and lower rates of graft and patient survival. However, new interferon-free regimens containing direct-acting antiviral agents have fewer adverse effects and better effectiveness, making HCV treatment feasible early after transplant. In 2014, we successfully used sofosbuvir and ribavirin to treat a patient with HCV genotype 3 cirrhosis who was listed for liver transplantation. Because the patient's hepatocellular carcinoma score was outside the Milan criteria, an allograft from a donor with HCV genotype 3 was accepted as rescue treatment. Patient characteristics, laboratory results, and the course of disease and treatment were documented from March 2014 to May 2015. HCV reinfection was successfully treated with sofosbuvir and ribavirin early after transplant, with no adverse effects. Viral load was below detectable levels 4 weeks after start of treatment. Liver values returned to normal, and the FibroScan score improved. Sustained virologic response was documented 12 weeks after treatment. With interferon-free regimens for HCV infection, expanding the donor pool by including HCV-positive organs is an interesting option that could substantially decrease waiting times and mortality rates for patients listed for transplant. This review comprehends and discusses available data, challenges and chances for using HCV-positive donor organs in the advent of new HCV therapeutic options.
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Update on hepatitis C treatment: systematic review of clinical trials.
Jhaveri, M, Procaccini, N, Kowdley, KV
Minerva gastroenterologica e dietologica. 2017;(1):62-73
Abstract
Chronic hepatitis C is a major public health problem. The chronicity of the hepatitis C can lead to advanced liver disease, cirrhosis and even hepatocellular carcinoma. Chronic hepatitis C is the leading indication of for liver transplantation in the United States. Since the introduction of directly acting antiviral agents (DAAs), there have been there have been dramatic advances in treatment of hepatitis C in terms of tolerability, duration of therapy with significant increases in the rates of sustained virologic response (SVR). This review summarizes the findings of recently published clinical trials of DAAs in the treatment of hepatitis C by genotype and in patients co-infected with HCV/HIV.
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Role of Raltegravir in patients co-infected with HIV and HCV in the era of direct antiviral agents.
Taramasso, L, Cenderello, G, Riccardi, N, Tunesi, S, Di Biagio, A
The new microbiologica. 2017;(4):227-233
Abstract
Integrase strand transfer inhibitors (INSTIs) are the preferred third agent in first-line antiretroviral therapies. Raltegravir (RAL) was the first INSTI to be approved and used in naïve and experienced patients. Due to its good tolerability and low side effects, RAL has been largely used also in hepatitis coinfected patients. Many years of experience in RAL use now allow literature evidence to be gathered on its safety in HIV/HCV-co-infected patients pre, during and post direct acting agents (DAA) treatment, at all possible stages. In both clinical trials and published case series, RAL has been well tolerated in patients harboring HCV co-infection and also in cirrhotic patients with mild hepatic impairment. Literature data show no major interactions or the need for dose adjustments with any of the DAA currently in use for HCV treatment, or with ribavirine. Hence, RAL can be safely administered during HCV treatment with DAA and may be used as a "temporary" regimen in patients who do not present major integrase-inhibitor mutations. Moreover, its characteristics are also favorable in case of orthotropic liver transplantation, both for the evidence of hepatic safety and for possible co-administration with immunosuppressant agents.
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10.
The importance of resistance to direct antiviral drugs in HCV infection in clinical practice.
Sarrazin, C
Journal of hepatology. 2016;(2):486-504
Abstract
Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antiviral agents (DAA) is associated with high rates of sustained virologic response. Remaining factors associated with treatment failure include advanced stages of liver fibrosis, response to previous antiviral therapy and viral factors such as baseline viral load and suboptimal interaction of the DAA with the target based on viral variants. Heterogeneity within NS3, NS5A, and NS5B areas interacting with DAAs exist between HCV geno- and subtypes as well as HCV isolates of the same geno- and subtype and amino acid polymorphisms associated with suboptimal efficacy of DAAs are termed resistance-associated variants (RAVs). RAVs may be associated with virologic treatment failure. However, virologic treatment failure typically occurs only if other negative predictive host or viral factors are present at the same time, susceptibility to additional antiviral agents is reduced or duration of treatment is suboptimal. In this review geno- and phenotypic resistance testing as well as clinical data on the importance of RAVs for conventional triple therapies with sofosbuvir, simeprevir, and daclatasvir and available interferon-free DAA combinations are discussed.