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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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2.
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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3.
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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4.
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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5.
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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6.
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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7.
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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8.
The current treatment of Hepatitis C.
Arleo, A, Mangia, A
Minerva gastroenterologica e dietologica. 2016;(2):167-82
Abstract
The development of potent antivirals able to directly block multiple step of viral lifecycle (DAAs) led to a revolution in HCV treatment. These compounds are associated with unprecedent high rates of SVR and can be administered orally, regardless of the severity of the associated liver disease, allowing treatment of large number of HCV infected patients. Three main classes of DAAs are currently available, NS3/4 inhibitors, NS5A inhibitors and NS5B inhibitors. They can be combined according to 2 different strategies, the use of a backbone drug with high barrier of resistance as the NS5B inhibitor sofosbuvir, with the addition of a second drug either NS3/4 or NS5A, or the use of more than 1 drug from different classes to simultaneously attack the virus at different sequence sites. DAAs can be administered for 12 or 24 weeks in the majority of patients, although attempts to reduce to 6-8 weeks the treatment duration in patients with baseline favorable characteristics are ongoing. Overall, SVR rates ensured by the currently approved combinations, are 90% or higher. Although cirrhotic patients and in particular patients with decompensated disease may represent a difficult to cure group, data from real life confirm evidence derived from phase III studies, showing improvement in biochemical parameters, even in such a special populations. We can expect, the number of patients with unmet medical needs will decline over time in the next 4 years. This review aims to discuss updated regimens by HCV genotype and to provide a brief summary of the coming strategies.
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9.
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.
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10.
Efficacy of Second Generation Direct-Acting Antiviral Agents for Treatment Naïve Hepatitis C Genotype 1: A Systematic Review and Network Meta-Analysis.
Suwanthawornkul, T, Anothaisintawee, T, Sobhonslidsuk, A, Thakkinstian, A, Teerawattananon, Y
PloS one. 2015;(12):e0145953
Abstract
BACKGROUND The treatment of hepatitis C (HCV) infections has significantly changed in the past few years due to the introduction of direct-acting antiviral agents (DAAs). DAAs could improve the sustained virological response compared to pegylated interferon with ribavirin (PR). However, there has been no evidence from randomized controlled trials (RCTs) that directly compare the efficacy among the different regimens of DAAs. AIM: Therefore, we performed a systematic review and network meta-analysis aiming to compare the treatment efficacy between different DAA regimens for treatment naïve HCV genotype 1. METHODS Medline and Scopus were searched up to 25th May 2015. RCTs investigating the efficacy of second generation DAA regimens for treatment naïve HCV genotype 1 were eligible for the review. Due to the lower efficacy and more side effects of first generation DAAs, this review included only second generation DAAs approved by the US or EU Food and Drug Administration, that comprised of simeprevir (SMV), sofosbuvir (SOF), daclatasvir (DCV), ledipasvir (LDV), and paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD). Primary outcomes were sustained virological response at weeks 12 (SVR12) and 24 (SVR24) after the end of treatment and adverse drug events (i.e. serious adverse events, anemia, and fatigue). Efficacy of all treatment regimens were compared by applying a multivariate random effect meta-analysis. Incidence rates of SVR12 and SVR24, and adverse drug events of each treatment regimen were pooled using 'pmeta' command in STATA program. RESULTS Overall, 869 studies were reviewed and 16 studies were eligible for this study. Compared with the PR regimen, SOF plus PR, SMV plus PR, and DVC plus PR regimens yielded significantly higher probability of having SVR24 with pooled risk ratios (RR) of 1.98 (95% CI 1.24, 3.14), 1.46 (95% CI: 1.22, 1.75), and 1.68 (95% CI: 1.14, 2.46), respectively. Pooled incidence rates of SVR12 and SVR24 in all treatment regimens without PR, i.e. SOF plus LDV with/without ribavirin, SOF plus SMV with/without ribavirin, SOF plus DCV with/without ribavirin, and PrOD with/without ribavirin, (pooled incidence of SVR12 ranging from 93% to 100%, and pooled incidence of SVR24 ranging from 89% to 96%) were much higher than the pooled incidence rates of SVR12 (51%) and SVR24 (48%) in PR alone. In comparing SOF plus LDV with ribavirin and SOF plus LDV without ribavirin, the chance of having SVR12 was not significantly different between these two regimens, with the pooled RR of 0.99 (95% CI: 0.97, 1.01). Regarding adverse drug events, risk of serious adverse drug events, anemia and fatigue were relatively higher in treatment regimens with PR than the treatment regimens without PR. The main limitation of our study is that a subgroup analysis according to dosages and duration of treatment could not be performed. Therefore, the dose and duration of recommended treatment have been suggested in range and not in definite value. CONCLUSIONS Both DAA plus PR and dual DAA regimens should be included in the first line drug for treatment naïve HCV genotype 1 because of the significant clinical benefits over PR alone. However, due to high drug costs, an economic evaluation should be conducted in order to assess the value of the investment when making coverage decisions.