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New treatments for cytomegalovirus in transplant patients.
Coppock, GM, Blumberg, E
Current opinion in nephrology and hypertension. 2019;(6):587-592
Abstract
PURPOSE OF REVIEW The purpose of this review is to highlight novel advances in prophylaxis against and treatment of CMV in kidney transplant recipients. Current options include intravenous ganciclovir and oral valganciclovir, but use of these agents is limited by side effects, such as myelosuppression as well as evolving resistance in CMV strains. RECENT FINDINGS Advances in the field include novel drugs that have shown promise in preliminary studies and are now being tested in large-scale clinical trials. Moreover, there is a developing focus in enhancing host immune responses to better protect against viral infection using anti-CMV vaccines. Studying host immune responses to CMV has also led to improved monitoring strategies, such as the QuantiFERON assay, which will allow for improved risk stratification and targeted therapies in transplant recipients. SUMMARY In summary, although options for prophylaxis and treatment against CMV have been somewhat limited to date, a number of new strategies are currently under development with several drugs in phase 3 trials. Therefore, the landscape of CMV management in kidney transplant recipients will be changing significantly in the coming years with the ultimate goal of safer and more effective therapies to combat CMV.
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Current Strategies for Elimination of HIV-1 Latent Reservoirs Using Chemical Compounds Targeting Host and Viral Factors.
Jean, MJ, Fiches, G, Hayashi, T, Zhu, J
AIDS research and human retroviruses. 2019;(1):1-24
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Abstract
Since the implementation of combination antiretroviral therapy (cART), rates of HIV type 1 (HIV-1) mortality, morbidity, and newly acquired infections have decreased dramatically. In fact, HIV-1-infected individuals under effective suppressive cART approach normal life span and quality of life. However, long-term therapy is required because the virus establish a reversible state of latency in memory CD4+ T cells. Two principle strategies, namely "shock and kill" approach and "block and lock" approach, are currently being investigated for the eradication of these HIV-1 latent reservoirs. Actually, both of these contrasting approaches are based on the use of small-molecule compounds to achieve the cure for HIV-1. In this review, we discuss the recent progress that has been made in designing and developing small-molecule compounds for both strategies.
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Successful treatment of chronic hepatitis C virus infection with crushed glecaprevir/pibrentasvir administered via a percutaneous endoscopic gastrostomy tube: case report and review of the literature.
Tanaka, Y, Tateishi, R, Koike, K
Clinical journal of gastroenterology. 2019;(6):588-591
Abstract
Glecaprevir (GLE)/pibrentasvir (PIB) is a direct-acting antiviral regimen approved for patients infected with hepatitis C virus. No data are available on the safety and efficacy of this regimen when crushed and administered through a percutaneous endoscopic gastrostomy (PEG) tube. Here, we report a patient who successfully achieved a sustained viral response after treatment with GLE/PIB administered via a PEG tube. A 41-year-old female with chronic hepatitis C viral infection was referred to our department for treatment. She had a history of spina bifida and hydrocephalus, and she received a PEG tube for nutrition and medication due to an aftereffect of hydrocephalus. She received crushed GLE/PIB treatment through a PEG tube for 8 weeks and achieved a sustained viral response 12, without any treatment-related severe adverse events. This is the first documented case treated with GLE/PIB administered through a PEG tube. Based on this case report and a review of the literature, we discuss the safety and efficacy of direct-acting antiviral treatment via a PEG tube.
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Viral Infections and Interferons in the Development of Obesity.
Tian, Y, Jennings, J, Gong, Y, Sang, Y
Biomolecules. 2019;(11)
Abstract
Obesity is now a prevalent disease worldwide and has a multi-factorial etiology. Several viruses or virus-like agents including members of adenoviridae, herpesviridae, slow virus (prion), and hepatitides, have been associated with obesity; meanwhile obese patients are shown to be more susceptible to viral infections such as during influenza and dengue epidemics. We examined the co-factorial role of viral infections, particularly of the persistent cases, in synergy with high-fat diet in induction of obesity. Antiviral interferons (IFNs), as key immune regulators against viral infections and in autoimmunity, emerge to be a pivotal player in the regulation of adipogenesis. In this review, we examine the recent evidence indicating that gut microbiota uphold intrinsic IFN signaling, which is extensively involved in the regulation of lipid metabolism. However, the prolonged IFN responses during persistent viral infections and obesogenesis comprise reciprocal causality between virus susceptibility and obesity. Furthermore, some IFN subtypes have shown therapeutic potency in their anti-inflammation and anti-obesity activity.
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Chrysin: Pharmacological and therapeutic properties.
Naz, S, Imran, M, Rauf, A, Orhan, IE, Shariati, MA, Iahtisham-Ul-Haq, , IqraYasmin, , Shahbaz, M, Qaisrani, TB, Shah, ZA, et al
Life sciences. 2019;:116797
Abstract
Chrysin is a promising phytochemical that is categorized under the class of flavonoids based on its chemical structure. Naturally, it is widely present in propolis, honey, passion fruit, and even in mushrooms and other plant sources, whereas its synthetic counterparts are also being employed for pharmacological purposes. It has widely been employed in treatment of various degenerative disorders and provides cytotoxic and anti-inflammatory functions. Its antioxidant and disease preventing abilities are attributed to its structural diversity arising in ring-A and absence of oxygenation in B and C ring. In this review, the scientific studies are being reported emphasizing benefits and its allied health claims on chrysin in numerous metabolic malfunctions.
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Concept of Viral Inhibitors via NTCP.
Fukano, K, Tsukuda, S, Watashi, K, Wakita, T
Seminars in liver disease. 2019;(1):78-85
Abstract
Identification of sodium taurocholate cotransporting polypeptide (NTCP) as an entry receptor for hepatitis B and D viruses (HBV and HDV) has not only promoted our understanding of the mechanism underlying the viral entry process, but also provided cell culture models supporting viral infection. These models have greatly facilitated cell-based chemical screening for the discovery of entry inhibitors, and mode of action studies using such inhibitors have shown the advantages of NTCP as a drug target. Furthermore, in vitro chemical screening by application of high-throughput affinity-based technologies that target NTCP has identified a variety of unique small molecules that interfere with viral entry. This review summarizes this hot topic in the development of HBV/HDV entry inhibitors, with special focus on the use of NTCP as a drug target.
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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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Current state-of-the-art pharmacotherapy for the management of hepatitis B infection.
Tillmann, HL, Samuel, G
Expert opinion on pharmacotherapy. 2019;(7):873-885
Abstract
INTRODUCTION Hepatitis B virus (HBV) infection remains a global challenge with several hundred million infected individuals. Disease activity can be controlled, and adverse outcomes prevented when treatment can be provided. Frequently life-long therapy is required instead of defined treatment periods such as with the case of Hepatitis C Virus (HCV) infection. AREAS COVERED In this review, the authors provide an overview of current start of the art therapy for HBV and indicate where variation from the current guidelines could be considered. Certain patients may be eligible for treatment with suboptimal therapies when their baseline viral load is low. Identifying ideal candidates for interferon therapy will result in good sustained responses for some patients. EXPERT OPINION The biggest challenge remains linking patients to care and therapy. Patients can nowadays be sufficiently treated before the disease advances to a more progressed phase. However, future therapies must be extremely safe and ideally limit the required treatment period. Given Hepatitis D Virus's dependence on HBV and being a disease with an unmet clinical need, HDV may be the best target group for the development of a functional cure for hepatitis B.
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Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants.
Jensen, SB, Fahnøe, U, Pham, LV, Serre, SBN, Tang, Q, Ghanem, L, Pedersen, MS, Ramirez, S, Humes, D, Pihl, AF, et al
Hepatology (Baltimore, Md.). 2019;(3):771-787
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Abstract
Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance-associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as a RAS hotspot for genotype 1-4, but not 5 and 6, escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156-RASs were not maintained. For genotypes 1 and 2, persistence of 156-RASs depended on genome-wide substitution networks, co-selected under continued PI treatment and identified by next-generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156-RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir, and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre-existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156-RASs, we observed genome-wide selection of substitutions under treatment. Conclusion: Comprehensive PI resistance profiling for HCV genotypes 1-6 revealed 156-RASs as key determinants of high-level resistance across clinically relevant PIs. We obtained in vitro proof of concept for persistence of highly fit genotype 1-3 156-variants, which might pose a threat to clinically relevant combination treatments.
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Management of Hepatitis C Infection in children in the era of Direct-acting Antiviral Agents.
Karnsakul, W, Schwarz, KB
Journal of viral hepatitis. 2019;(9):1034-1039
Abstract
Chronic hepatitis C certainly is a global health burden in children as well as in adults. Spontaneous viral clearance can occur in early childhood but is uncommon thereafter. Although the majority of cases are asymptomatic during childhood and young adulthood, without an effective treatment, children who acquire HCV via vertical transmission can develop chronic liver disease and other complications including end-stage liver disease and hepatocellular carcinoma in adulthood. Efforts from worldwide health organizations, the pharmaceutical industry, and clinical and research institutions have resulted in very effective interferon-free therapy with direct-acting antiviral agents (DAAs) for HCV-infected children. In this manuscript, we will briefly review the epidemiology of HCV in children, historic treatment, current published data on DAAs in children and conclude with suggestions for management of the child with HCV in the era of DAAs.