Individual ingredients of NP-101 (Thymoquinone formula) inhibit SARS-CoV-2 pseudovirus infection.

Thymoquinone TQ, an active ingredient of Nigella Sativa, has been shown to inhibit COVID-19 symptoms in clinical trials. Thymoquinone Formulation (TQF or NP-101) is developed as a novel enteric-coated medication derivative from Nigella Sativa. TQF consists of TQ with a favorable concentration and fatty acids, including palmitic, oleic, and linoleic acids. In this study, we aimed to investigate the roles of individual ingredients of TQF on infection of SARS-CoV-2 variants in-vitro, by utilizing Murine Leukemia Virus (MLV) based pseudovirus particles. We demonstrated that NP-101, TQ, and other individual ingredients, including oleic, linoleic, and palmitic acids inhibited SARS-CoV-2 infection in the MLV-based pseudovirus model. A large, randomized phase 2 study of NP-101 is planned in outpatient COVID-19 patients.

Spontaneous Rupture of Hepatocellular Carcinoma With Fatal Outcome in a Patient Taking Direct-Acting Antivirals.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors globally. Many complications are attributed to it, including spontaneous rupture, which is a serious and rare complication that can be life-threatening. Managing and detecting this condition might pose challenges, especially when there is no prior history of liver cirrhosis or tumor. We report on a 57-year-old man followed as an outpatient for chronic hepatitis C who presented to the emergency department for abdominal pain with abdominal distention and jaundice, occurring two months after treatment by direct-acting antiviral (DAA). He was not known to have a liver tumor on the ultrasound performed before the start of treatment. Therefore, the diagnosis of tumor rupture was not very clear. The evolution was fatal, and death occurred quickly. Although the association between DAA treatment and hepatocarcinogenesis and its possible complications is unknown, close monitoring by high-performance imaging is probably required in patients under DAA.

Tracing down the updates on Ebola virus surges: An update on anti-ebola therapeutic strategies.

Ebola virus (EBOV) related health complications have presented a great threat to the healthcare system in the endemic regions. The outbreaks of 2013-2016 and 2018-2020 brought along a huge healthcare burden for the afected communities. Knowing the seriousness of the matter, a series of research experiments have been actively carried out to devise efective therapeutics, drugs, and vaccination protocols against the Ebola virus disease (EVD) in the past decade. The purpose of this piece of literature is to shed light on vaccination protocols being clinically evaluated for EVD. A methodological approach has been adopted to gather relevant data from the latest publications. The compiled data include the molecular mechanistic insights into Ebola infection and a brief overview of diferent vaccination strategies: inactivated and DNA vaccines, virus-like particles and replicons, reverse genetic and recombinant approaches, entry, ion, and gene expression inhibitors, and some repurposed drugs. This data will help the scientific community to get a comprehensive overview of therapeutic interventions against Ebola that could be related to modifying EBOV vaccines and designing other antiviral vaccinations. Having said that, further work in modern therapeutic design is pertinent to tackle and lessen the healthcare burden expected from such outbreaks in the future.

A Systematic Review of Second-Line Treatments in Antiviral Resistant Strains of HSV-1, HSV-2, and VZV.

Drug-resistant variants of herpes simplex viruses (HSV) have been reported that are not effectively treated with first-line antiviral agents. The objective of this study was to evaluate available literature on the possible efficacy of second-line treatments in HSV and the use of second-line treatments in HSV strains that are resistant to first-line treatments. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a final search was conducted in six databases on November 5, 2021 for all relevant literature using terms related to antiviral resistance, herpes, and HSV. Eligible manuscripts were required to report the presence of an existing or proposed second-line treatment for HSV-1, HSV-2, or varicella zoster virus (VZV); have full-text English-language access; and potentially reduce the rate of antiviral resistance. Following screening, 137 articles were included in qualitative synthesis. Of the included studies, articles that examined the relationship between viral resistance to first-line treatments and potential second-line treatments in HSV were included. The Cochrane risk-of-bias tool for randomized trials was used to assess risk of bias. Due to the heterogeneity of study designs, a meta-analysis of the studies was not performed. The dates in which accepted studies were published spanned from 2015-2021. In terms of sample characteristics, the majority (72.26%) of studies used Vero cells. When looking at the viruses on which the interventions were tested, the majority (84.67%) used HSV-1, with (34.31%) of these studies reporting testing on resistant HSV strains. Regarding the effectiveness of the proposed interventions, 91.97% were effective as potential managements for resistant strains of HSV. Of the papers reviewed, nectin in 2.19% of the reviews had efficacy as a second-line treatments in HSV, amenamevir in 2.19%, methanol extract in 2.19%, monoclonal antibodies in 1.46%, arbidol in 1.46%, siRNA swarms in 1.46%, Cucumis melo sulfated pectin in 1.46%, and components from Olea europeae in 1.46%. In addition to this griffithsin in 1.46% was effective, Morus alba L. in 1.46%, using nucleosides in 1.46%, botryosphaeran in 1.46%, monoterpenes in 1.46%, almond skin extracts in 1.46%, bortezomib in 1.46%, flavonoid compounds in 1.46%, andessential oils were effective in 1.46%, but not effective in 0.73%. The available literature reviewed consistently supports the existence and potentiality of second-line treatments for HSV strains that are resistant to first-line treatments. Immunocompromised patients have been noted to be the population most often affected by drug-resistant variants of HSV. Subsequently, we found that HSV infections in this patient population are challenging to manage clinically effectively. The goal of this systematic review is to provide additional information to patients on the potentiality of second-line treatment in HSV strains resistant to first-line treatments, especially those who are immunocompromised. All patients, whether they are immunocompromised or not, deserve to have their infections clinically managed in a manner supported by comprehensive research. This review provides necessary information about treatment options for patients with resistant HSV infections and their providers.

Plant Extracts and SARS-CoV-2: Research and Applications.

The recent pandemic of COVID-19 caused by the SARS-CoV-2 virus has brought upon the world an unprecedented challenge. During its acute dissemination, a rush for vaccines started, making the scientific community come together and contribute to the development of efficient therapeutic agents and vaccines. Natural products have been used as sources of individual molecules and extracts capable of inhibiting/neutralizing several microorganisms, including viruses. Natural extracts have shown effective results against the coronavirus family, when first tested in the outbreak of SARS-CoV-1, back in 2002. In this review, the relationship between natural extracts and SARS-CoV is discussed, while also providing insight into misinformation regarding the use of plants as possible therapeutic agents. Studies with plant extracts on coronaviruses are presented, as well as the main inhibition assays and trends for the future regarding the yet unknown long-lasting effects post-infection with SARS-CoV-2.

Recent advances to overcome the burden of Japanese encephalitis: A zoonotic infection with problematic early detection.

Japanese encephalitis (JE) is a vector-borne neurotropic disease caused by Japanese encephalitis virus (JEV) associated with high mortality rate distributed from Eastern and Southern Asia to Northern Queensland (Australia). The challenges in early detection and lack of point-of-care biomarkers make it the most important Flavivirus causing encephalitis. There is no specific treatment for the disease, although vaccines are licenced. In this review, we focussed on point-of-care biomarkers as early detection tools and developing the effective therapeutic agents that could halt JE. We have also provided molecular details of JEV, disease progression, and its pathogenesis with recent findings which might bring insights to overcome the disease burden.

Revolution in the diagnosis and management of hepatitis C virus infection in current era.

Chronic hepatitis C virus (HCV) infection is a major global public health problem, particularly in developing part of the world. Significant advances have been made in the early diagnosis and treatment of the disease. Its management has been particularly revolutionized during the past two decades. In this review, we summarize the major advances in the diagnostic and management armamentarium for chronic HCV infection. The focus of the present review is on the newer directly acting anti-viral agents, which have revolutionized the management of chronic HCV infection. Management of uncomplicated chronic HCV infection and of specific complications and special at-risk populations of patients will be covered in detail. Despite the advent and approval of highly effective and well tolerable oral agents, still many challenges remain, particularly the affordability, the equitable distribution and access to later drugs. The World Health Organization aims to eliminate viral hepatitis including HCV by 2030 since its poses a major public health threat. There is an urgent need to ensure uniform and early access to diagnostic and therapeutic facilities throughout the world if the later goal has to be realized.

COVID-19 in Kidney Transplant Recipients: A Multicenter Experience from the First Two Waves of Pandemic.

BACKGROUND: Kidney transplant recipients have an increased risk of complications from COVID-19. However, data on the risk of allograft damage or death in kidney transplant recipients recovering from COVID-19 is limited. In addition, the first and second waves of the pandemic occurred at different times all over the world. In Turkey, the Health Minister confirmed the first case in March 2020; after that, the first wave occurred between March and August 2020; afterward, the second wave began in September 2020. This study aims to demonstrate the clinical presentations of kidney transplant recipients in the first two waves of the pandemic in Turkey and explore the impact of COVID-19 on clinical outcomes after the initial episode. METHODS: Patients with COVID-19 from seven centers were included in this retrospective cohort study. Initially, four hundred and eighty-eight kidney transplant recipients diagnosed with COVID-19 between 1 March 2020 to 28 February 2021 were enrolled. The endpoints were the occurrence of all-cause mortality, acute kidney injury, cytokine storm, and acute respiratory distress syndrome. In addition, longer-term outcomes such as mortality, need for dialysis, and allograft function of the surviving patients was analyzed. RESULTS: Four hundred seventy-five patients were followed up for a median of 132 days after COVID-19. Forty-seven patients (9.9%) died after a median length of hospitalization of 15 days. Although the mortality rate (10.1% vs. 9.8%) and intensive care unit admission (14.5% vs. 14.5%) were similar in the first two waves, hospitalization (68.8% vs. 29.7%; p < 0.001), acute kidney injury (44.2% vs. 31.8%; p = 0.009), acute respiratory distress syndrome (18.8% vs. 16%; p = 0.456), and cytokine storm rate (15.9% vs. 10.1%; p = 0.072) were higher in first wave compared to the second wave. These 47 patients died within the first month of COVID-19. Six (1.4%) of the surviving patients lost allografts during treatment. There was no difference in the median serum creatinine clearance of the surviving patients at baseline (52 mL/min [IQR, 47-66]), first- (56 mL/min [IQR, 51-68]), third- (51 mL/min [IQR,48-67]) and sixth-months (52 mL/min [IQR, 48-81]). Development of cytokine storm and posttransplant diabetes mellitus were independent predictors for mortality. CONCLUSIONS: Mortality remains a problem in COVID-19. All the deaths occur in the first month of COVID-19. Also, acute kidney injury is common in hospitalized patients, and some of the patients suffer from graft loss after the initial episode.

Thymoquinone's Antiviral Effects: It is Time to be Proven in the Covid-19 Pandemic Era and its Omicron Variant Surge.

The COVID-19 pandemic has impacted every country in the world. With more than 400 million cases and more than 5.5 million deaths. The FDA either approved or authorized the emergency use for three vaccines against COVID-19. The treatment options of COVID-19 are very limited. Multiple complementary and alternative medicine modalities were suggested to be efficacious in the treatment of COVID-19 such as Thymoquinone. The effects of Thymoquinone have been examined and multiple studies indicate a promising beneficial effect. However, the current body of research is limited in terms of its scope, quality, and quantity. While higher-quality studies are required, physicians do not routinely recommend the use of marketed supplements of natural products, including Thymoquinone for COVID-19. Given the numerous suggested positive effects of Thymoquinone, including anti-inflammatory and antimicrobial properties, additional research is required to confirm or refute these promising benefits. Complementary and alternative medicine is an area that requires additional evidence-based practice and research to confirm effects observed in clinical practice.

Drug Repurposing: An Alternative Strategy to Treat COVID-19.

In order to curve the ongoing trend of the COVID-19 pandemic and save more lives, effective treatments against COVID-19 are urgently needed. Compared to developing new drugs, which may take too much time, it's more efficient and cost-effective to repurpose existing drugs in the treatment of COVID-19. Fortunately, some of the shared features of COVID-19 and other wellknown diseases make it possible to use old strategies to combat this new challenge. In this paper, we reviewed various possible strategies of drug repurposing in the treatment of COVID-19 and explored the possible scientific mechanisms behind each strategy.

Expanding the Deceased Donor Pool in Manitoba Using Hepatitis C-Viremic Donors: Program Report.

PURPOSE OF PROGRAM: The ongoing shortage of organs for transplant combined with Manitoba having the highest prevalence of end-stage renal disease (ESRD) in Canada has resulted in long wait times on the deceased donor waitlist. Therefore, the Transplant Manitoba Adult Kidney Program has ongoing quality improvement initiatives to expand the deceased donor pool. This clinical transplant protocol describes the use of prophylactic pan-genotypic direct-acting anti-viral agents (DAA) for transplanting hepatitis C (HCV)-viremic kidneys (HCV antibody positive/nucleic acid [nucleic acid amplification testing, NAT] positive) to HCV-naïve recipients as routine standard of care. We will evaluate the provincial implementation of this protocol as a prospective observational cohort study. SOURCES OF INFORMATION: Scoping literature review and key stakeholder engagement with interdisciplinary health care providers and health system leaders/decision markers. METHODS: Patients will be screened pre-transplant for eligibility and undergo a multilevel education and consent process to participate in this expanded donor program. Incident adult HCV-naïve recipients of an HCV-viremic kidney transplant will be treated prophylactically with glecaprevir-pibrentasvir with the first dose administered on call to the operation. Glecaprevir-pibrentasvir will be used for 8 weeks with viral monitoring and hepatology follow-up. Primary outcomes are sustained virologic response (SVR) at 12 weeks and the tolerability of DAA therapy. Secondary outcomes within the first year post-transplant are patient and graft survival, graft function, biopsy-proven rejection, HCV transmission to recipient (HCV NAT positive), and HCV nonstructural protein 5A (NS5A) resistance. Safety outcomes within the first year post-transplant include fibrosing cholestatic hepatitis, acute liver failure, primary and secondary DAA treatment failure, HCV transmission to a recipient's partner, elevated liver enzymes ≥2-fold, abnormal international normalized ratio (INR), angioedema, anaphylaxis, cirrhosis, and hepatocellular carcinoma. KEY FINDINGS: This program successfully advocated for and obtained hospital formulary, provincial Exceptional Drug Status (EDS), and Non-Insured Health Benefits (NIHB) to provide prophylactic DAA therapy for this indication, and this information may be useful to other provincial transplant organizations seeking to establish an HCV-viremic kidney transplant program with prophylactic DAA drug coverage. LIMITATIONS: (1) Patient engagement was not undertaken during the program design phase, but patient-reported experience measures will be obtained for continuous quality improvement. (2) Only standard criteria donors (optimal kidney donor profile index [KDPI] ≤60) will be used. If this approach is safe and feasible, then higher KDPI donors may be included. IMPLICATIONS: The goal of this quality improvement project is to improve access to kidney transplantation for Manitobans. This program will provide prophylactic DAA therapy for HCV-viremic kidney transplant to HCV-naïve recipients as routine standard of care outside a clinical trial protocol. We anticipate this program will be a safe and effective way to expand kidney transplantation from a previously unutilized donor pool.

OBJECTIF DU PROGRAMME: La pénurie actuelle d'organes à transplanter, combinée au fait que le Manitoba est la province qui présente la plus forte prévalence d'insuffisance rénale terminale au Canada, entraîne de longs délais sur la liste d'attente d'un organe provenant d'un donneur décédé. Le programme de transplantation rénale pour les adultes du Manitoba (Transplant Manitoba Adult Kidney Program) a mis en place des initiatives d'amélioration continue de la qualité afin d'élargir le bassin de donneurs décédés. Ce protocole clinique de transplantation décrit l'emploi, comme traitement habituel, d'agents antiviraux directs (AAD) pan-génotypiques prophylactiques pour la transplantation de reins provenant de donneurs infectés par le virus de l'hépatite C (VHC) (individus positifs pour les anticorps VHC et acides nucléiques [NAT]) à des receveurs naïfs pour VHC. La mise en œuvre provinciale de ce protocole sera évaluée en tant qu'étude de cohorte prospective et observationnelle. SOURCES: Examen de la documentation et évaluation de l'engagement des principaux intervenants avec les fournisseurs de soins de santé interdisciplinaires et les dirigeants/décideurs du système de santé. MÉTHODOLOGIE: L'admissibilité au programme sera évaluée avant la greffe. Pour participer à ce programme élargi de donneurs, les patients devront se soumettre à un processus d'information et de consentement à plusieurs niveaux. Les adultes incidents naïfs pour VHC devant recevoir un rein virémique-VHC seront traités de façon prophylactique par glécaprévir+pibrentasvir; la première dose administrée au moment de l'appel pour l'opération. Le traitement par glécaprévir+pibrentasvir sera administré pendant 8 semaines avec surveillance virale et suivi hépatologique. Les principaux résultats évalués seront une réponse virologique prolongée (RVP) à 12 semaines et la tolérance au traitement par AAD. Les résultats secondaires mesurés dans la première année suivant la greffe seront la survie du patient et du greffon; la fonction du greffon; le rejet avéré par biopsie; la transmission du VHC au receveur (positif pour VHC et NAT) et la résistance aux protéines non structurelles 5A (NS5A) du VHC. Les résultats relatifs à l'innocuité dans la première année suivant la greffe comprennent la cholestase hépatique fibrosante; l'insuffisance hépatique aiguë; l'échec primaire et secondaire du traitement par AAD; la transmission du VHC au partenaire d'un receveur; une élévation supérieure à 2 fois du taux d'enzymes hépatiques; un INR anormal; un angio-œdème; l'anaphylaxie; une cirrhose ou un carcinome hépatocellulaire. PRINCIPAUX RÉSULTATS: Le programme a recommandé et obtenu l'inscription du traitement prophylactique par AAD sur la liste de médicaments des hôpitaux pour cette indication, en plus du statut de médicament d'exception provincial et de son ajout au Programme des services de santé non assurés (SSNA). Ces renseignements pourraient être utiles à d'autres organismes provinciaux de transplantation qui cherchent à mettre en œuvre un programme de transplantation rénale virémique-VHC avec un traitement prophylactique par AAD. LIMITES: (1) La participation des patients n'a pas été entreprise pendant la phase de conception du programme, mais des mesures de l'expérience des patients seront obtenues pour l'amélioration continue de la qualité. (2) Seuls les donneurs satisfaisant aux critères standards (Kidney Donor Profile Index [KDPI] ≤ 60) seront inclus. Si cette approche est sécuritaire et faisable, des donneurs de KDPI plus élevés pourront être inclus. CONCLUSION: L'objectif de ce projet d'amélioration de la qualité est d'améliorer l'accès aux transplantations rénales pour les Manitobains. Ce programme offrira un traitement prophylactique aux AAD pour les greffes de reins virémiques-VHC à des receveurs naïfs pour VHC comme traitement de référence habituel en dehors d'un protocole d'essai clinique. Nous pensons que ce programme sera un moyen sûr et efficace d'étendre la transplantation rénale à partir d'un bassin de donneurs auparavant non utilisés.

Transcriptomic and Functional Analyses Indicate Novel Anti-viral Mode of Actions on Tobacco Mosaic Virus of a Microbial Natural Product ε-Poly-l-lysine.

Novel anti-viral natural product ε-poly-l-lysine (ε-PL) produced by Streptomyces is a homopolymer of l-lysine, of which the underlying molecular mode of action remains to be further elucidated. In this study, ε-PL induced significant fragmentation of tobacco mosaic virus (TMV) virions and delayed the systemic infection of TMV-GFP as well as wild-type TMV in plants. ε-PL treatment also markedly inhibited RNA accumulation of TMV in tobacco BY-2 protoplasts. The results of RNA-seq indicated that the agent induced significantly differential expression of genes that are associated with defense response, stress response, autophagy, and ubiquitination. Among them, 15 critical differential expressed genes were selected for real-time quantitative PCR validation. We further demonstrated that ε-PL can induce host defense responses by assessing the activity of several defense-related enzymes in plants. Our results provided valuable insights into molecular anti-viral mode of action for ε-PL, which is expected to be applied as a novel microbial natural product against plant virus diseases.

Hepatitis C and Treatment in Patients with Chronic Kidney Disease.

Hepatitis C virus (HCV) is associated with increased mortality and morbidity in patients with chronic kidney disease (CKD). The early detection and treatment of Hepatitis C associated with kidney disease is paramount to preventing the progressive loss of kidney function. HCV treatment until the advent of direct acting anti-viral agents (DAAs) was limited to interferon and ribavirin. Interferon and ribavirin treatment resulted in only modest success but with frequent adverse events and poor tolerability. Furthermore, interferon and ribavirin could not be used in certain patient populations including those with advanced CKD, were on dialysis, or those who have received a kidney transplant. DAAs have now made treatment possible in these sub-groups with a sustained viral response (SVR) of 90-100% and minimal side effects. DAAs have helped increase transplant rates by allowing for the use of HCV positive kidneys in recipients who are HCV negative. Although the choice of DAAs should be carefully considered and based on patient characteristics, concomitant medications, and HCV genotype.

COVID-19 drug repurposing: Summary statistics on current clinical trials and promising untested candidates.

Repurposing of existing anti-viral drugs, immunological modulators and supportive therapies represents a promising path towards rapidly developing new control strategies to mitigate the devastating public health consequences of the COVID-19 pandemic. A comprehensive text-mining and manual curation approach was used to comb and summarize the most pertinent information from existing clinical trials and previous efforts to develop therapies against related betacoronaviruses, particularly SARS and MERS. In contrast to drugs in current trials, which have been derived overwhelmingly from studies on taxonomically unrelated RNA viruses, a number of untested small molecule anti-virals had previously demonstrated remarkable in vitro specificity for SARS-CoV or MERS-CoV, with high selectivity indices, EC50 and/or IC50 . Due to the rapid containment of the prior epidemics, however, these were generally not followed up with in vivo animal studies or clinical investigations and thus largely overlooked as treatment prospects in the current COVID-19 trials. This brief review summarizes and tabulates core information on recent or ongoing drug repurposing-focused clinical trials, while detailing the most promising untested candidates with prior documented success against the aetiologic agents of SARS and/or MERS.

Trends of Liver Stiffness in Inflammatory Bowel Disease with Chronic Hepatitis C.

Concomitant inflammatory bowel disease (IBD) and hepatitis C virus (HCV) infection is a relevant comorbidity since IBD itself exposes to a high risk of liver damage. We aimed to evaluate liver stiffness (LS) in IBD-HCV after antiviral treatment. We enrolled IBD patients with HCV. All patients at baseline underwent LS measurement by elastography. Patients who were eligible for antiviral therapy received direct antiviral agents (DAAs) and sustained viral response was evaluated at the 12th week. A control group was selected within IBD patients without HCV. One year later, all IBD-HCV patients and controls repeated LS measurement. Twenty-four IBD-HCV patients and 24 IBD controls entered the study. Only twelve out of 24 received DAAs and all achieved sustained viral response (SVR). All IBD subjects were in remission at enrollment and maintained remission for one year. After one year, IBD patients who eradicated HCV passed from a liver stiffness of 8.5 ± 6.2 kPa to 7.1 ± 3.9, p = 0.13. IBD patients who did not eradicate HCV worsened liver stiffness: from 7.6 ± 4.4 to 8.6 ± 4.6, p = 0.01. In the IBD control group, stiffness decreased from 7.8 ± 4.4 to 6.0 ± 3.1, p < 0.001. In conclusion, HCV eradication is able to stop the evolution of liver fibrosis in IBD, while failure to treat may lead to its progression. A stable IBD remission may improve LS even in non-infected subjects.

Patterns of Hepatocellular Carcinoma After Direct Antiviral Agents and Pegylated-Interferon Therapy.

INTRODUCTION:  The impact of direct-acting antiviral agents (DAAs) on the development of hepatocellular carcinoma (HCC) is controversial and a part of the scientific community believes it as a biased interpretation of data. Many studies have reported an aggressive pattern of HCC after DAA use. In this study, we attempted to assess the changes in the pattern of HCC after treatment with DAAs or PI (PEG, pegylated-interferon). METHODS:  A total of 37 HCC patients after DAA treatment and 21 HCC patients after PI treatment were included. The diagnosis of HCC was made and information about demographics, HCC infiltrative pattern, portal vein thrombosis (PVT), time at initial presentation, Child-Turcotte-Pugh (CTP) score, and Barcelona Clinic Liver Cancer (BCLC) stage were compared in the two groups. RESULTS:  The total number of male patients in the DAA group was 62% while either gender was almost equal in PI. The age group of 40-60 was more prevalent in the DAA group while the PI group comprised more patients who were above 60 years. Patients in the DAA group presented after 3.35 years on average while patients in the PI group presented after about seven years. Most of the patients presented with the CTP stage of A. That is true for both groups. For BCLC staging, most of the patients had stage C, which means multiple lesions. At the initial presentation, most of the patients presented with multifocal lesions. CONCLUSION:  Our study found no significant difference in the initial presentation between both groups. However, HCC patients with prior DAA therapy presented early than those with PI therapy.

A Review of Treatment of Coronavirus Disease 2019 (COVID-19): Therapeutic Repurposing and Unmet Clinical Needs.

For the initial phase of pandemic of coronavirus disease 2019 (COVID-19), repurposing drugs that in vitro inhibit severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been attempted with overlooked or overestimated efficacy owing to limited clinical evidence. Most early clinical trials have the defects of study design, small sample size, non-randomized design, or different timings of treatment initiation. However, well-designed studies on asymptomatic or mild, or pediatric cases of COVID-19 are scarce and desperately needed to meet the clinical need. However, a trend could be observed based on current clinical evidence. Remdesivir and favipiravir may shorten the recovery time; lopinavir/ritonavir does not demonstrate treatment efficacy in severe patients. Triple therapy of ribavirin, lopinavir, and interferon ß-1b showed early viral negative conversion, and the major effect may be related to interferon. Some small sample-size studies showed that interleukin-6 inhibitors may demonstrate clinical improvement; non-critical patients may benefit from convalescent plasma infusion in small sample-size studies; and the role of hydroxychloroquine or chloroquine in the treatment and prophylaxis of COVID-19 remains unclear. Combination therapy of traditional Chinese medicine with antiviral agents (ex. interferon, lopinavir, or arbidol) may alleviate inflammation in severe COVID-19 patients based on small sample-sized observational studies and experts' opinion. Most of the published studies included severe or critical patients with COVID-19. Combination therapy of antiviral agents and immune-modulating drugs is reasonable especially for those critical COVID-19 patients with cytokine release syndrome. Drugs to blunt cytokine release might not benefit for patients in the early stage with mild disease or the late stage with critical illness. Traditional Chinese medicine with antiviral effects on SARS-CoV-2 and immune-modulation is widely used for COVID-19 patients in China, and is worthy of further studies. In this review, we aim to highlight the available therapeutic options for COVID-19 based on current clinical evidence and encourage clinical trials specific for children and for patients with mild disease or at the early stage of COVID-19.

Functional Profile of Human Cytomegalovirus Genes and Their Associated Diseases: A Review.

The human cytomegalovirus (HCMV), whose genome is 235 ± 1.9 kbp long, is a common herpesvirus. However, the functions of many of its genes are still unknown. HCMV is closely associated with various human diseases and infects 60-90% of the global population. It can infect various human cells, including fibroblasts, epithelial cells, endothelial cells, smooth muscle cells, and monocytes. Although HCMV infection is generally asymptomatic and causes subtle clinical symptoms, it can generate a robust immune response and establish a latent infection in immunocompromised individuals, including those with AIDS, transplant recipients, and developing fetuses. Currently available antivirals approved for the treatment of HCMV-associated diseases are limited by dose-limiting toxicity and the emergence of resistance; however, vaccines and immunoglobulins are unavailable. In this review, we have summarized the recent literature on 43 newly identified HCMV genes. We have described their novel functions on the viral replication cycle, latency, and host immune evasion. Further, we have discussed HCMV-associated diseases and current therapeutic targets. Our review may provide a foundational basis for studies aiming to prevent and develop targeted therapies for HCMV-associated diseases.

Ombitasvir/paritaprevir/ritonavir & dasabuvir ± ribavirin following protease inhibitors failure - a prospective multi-centre trial.

BACKGROUND: Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virologic response (SVR) rates of 65-75% but was associated with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs. METHODS: An investigator-initiated, open-label, multi-centre clinical trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 weeks according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance associated variants. RESULTS: Thirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m2). Thirty-seven (94.9%) completed the study. Thirty-five patients had genotype 1b (9 cirrhotics) and 4 had genotype 1a (2 cirrhotics). Intention-to-treat SVR12 was 92.3% and per-protocol SVR12 was 97.3%. The rate of advanced fibrosis (FibroScan® score F3-4) declined from 46.2 to 25.7% (P = 0.045). Abnormal ALT levels declined from 84.6 to 8.6% (P < 0.001). Seven patients (17.9%) experienced serious adverse events (3 Psychiatric admissions, 1 pneumonia, 1 ankle fracture, 2 palpitations), and 12 patients (30.8%) experienced self-reported adverse events, mostly weakness. CONCLUSION: 3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment. TRIAL REGISTRATION: NCT02646111 (submitted to ClinicalTrials.gov, December 28, 2015).