Direct Antiviral Treatment Research Articles

Cardiac effects of direct anti-viral treatment in type II diabetic patients with hepatitis C infection

BackgroundThe link between diabetes mellitus and chronic hepatitis C infection remains well established. It is estimated that up to one third of chronic hepatitis C patients have type II diabetes mellitus. Hepatitis C virus infection is one of the main global health burdens. Sofosbuvir and Daclatasvir are used as effective antiviral inhibitors of hepatitis C virus. The cardiovascular effects of those drugs are not well studied. We used electrocardiography and echocardiography with global longitudinal strain assessment by speckle tracking to detect their effect on cardiac function.Methods and resultsOne hundred diabetic patients with hepatitis C infection were included in the study. Abdominal ultrasound and laboratory work up were carried out for all participants. Left ventricular systolic and diastolic function were assessed by 2D-echocardiography and global longitudinal strain, before and 3 months after treatment. Results showed significant decrease in global longitudinal strain 3 months after therapy (-21 ± 4 vs. -18 ± 7; P < 0.001) but other echocardiographic findings showed no significant changes.ConclusionsSofosbuvir and Daclatasvir were associated with early left ventricular systolic dysfunction as assessed by global longitudinal strain in diabetic patients. More deterioration in left ventricular systolic function was detected among those with Child-Pough class B. Further long-term follow-up may be required.

The safety and efficacy of imatinib a tyrosine kinase inhibitor for the treatment of SARS-COV-2 induced pneumonia: a pilot study

Introduction Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in a wide spectrum of disease, approximately 15–20% of affected patients present with severe phenotype that require supplemental oxygen, including up to 5% who may develop critical illness. The main therapeutic strategies proposed for the management of COVID-19 pneumonia are direct antiviral and immunomodulatory treatments aiming to prevent disease progression. In this pilot study we are testing the hypothesis of using imatinib a tyrosine kinase inhibitor (TKI) as an immunomodulatory treatment to prevent disease progression, based on encouraging data from cellular, animal models and clinical trials, showing a beneficial role of TKI in the regulation of inflammation and endothelial barrier integrity, as well as their antiviral properties. Aim The primary end point is to assess the effect of the imatinib treatment, in terms of safety and efficacy, to prevent the progression of patients with moderate to severe COVID-19 pneumonia into critical illness and need for invasive mechanical ventilation. The secondary end point is a composite of change in clinical, laboratory and radiological parameters, including: clinical parameters − the percentage of patients reaching normal hypoxic index (HI) at time of hospital discharge, hospital length of stay and days on mechanical ventilation (MV) in patient intubated and mechanically ventilated, the changes in the levels of laboratory inflammatory markers: serum ferritin, serum C reactive protein (CRP), serum interleukin 6 (IL6), viral clearance presented by the delta time till negative SARS-CoV-2 PCR results, as well as the change in the chest radiological parameters (Computed tomography chest or radiography). Methods Thirty SARS-COV-2 positive patients with moderate to severe respiratory symptoms, were enrolled and randomized into three groups: group 1 Control, group 2 Low dose Imatinib (receiving 200 mg Imatinib/day) and group 3 Standard dose Imatinib (receiving 400 mg Imatinib/day). Results There was no significant difference between the three groups regarding the severity of the disease at baseline, as assessed by clinical, laboratory and radiological parameters. There was a nonstatistically significant difference in the primary end point of the study, regarding the number of patients in need for invasive mechanical ventilation, between the control group and the intervention groups receiving imatinib. Conclusion Despite the negative results regarding the efficacy of imatinib to flatten the curve of the illness and the prevention of more severe phenotype of the disease, our study showed positive findings regarding the medication’s safety and patients’ tolerability. These finding would pave the way for further studies to assess the concept of immunomodulation in the treatment of immunity derived disease, like sepsis and acute respiratory distress syndrome (ARDS).

Healing Treatments in COVID-19 Patients: A Narrative Review.

Since December 2019, many drugs have been evaluated or advocated as potential treatments of SARS-CoV-2 induced disease (COVID-19), including many repositioned drugs and some others specifically developed for these diseases. They can be roughly classified into three categories according to their main mechanism of action (passive immunization, direct antivirals, and anti-inflammatory treatments), and their use depends on the stage of the disease. Despite often promising preclinical data, most of the treatments evaluated failed to show a significant clinical benefit. In addition, a few others have seen their effectiveness affected by the occurrence of SARS-CoV-2 variants and sub-variants. Herein, the aim of this article is to take stock of the data available as of the 14th of July 2022, concerning the specific healing options evaluated for patients suffering from COVID-19. We focus particularly on healing treatments of COVID-19 and do not deal with preventive treatments such as vaccine. Associated therapies such as venous thromboembolism prophylaxis are not detailed since they are covered in a specific chapter of this issue. Passive immunization, especially through monoclonal antibodies, showed a positive impact on the clinical evolution, whether in outpatients or inpatients without oxygen supply. However, their effectiveness strongly depends on the type of SARS-CoV-2 variant, and often decreases or even vanishes with the most recent variants. Among direct antiviral treatments, ritonavir-boosted nirmatrelvir appears to currently be the cornerstone in the management of early infections, but its use may be limited by drug interactions. Remdesivir remains as an alternative in this situation, even though it is potentially less convenient. Anti-inflammatory treatments have often been shown to be the most effective in inpatients with oxygen supply. Dexamethasone is now a cornerstone of management of these patients. Added tocilizumab seems beneficial in the case of hyper inflammation. JAK inhibitors and anakinra have also gained an interest in some studies. As a conclusion of this narrative review, the best treatment strategy has yet to be defined and is likely to evolve in the future, not only because many other drugs are still under development and evaluation, but also because of the viral epidemics and epidemiology evolution.

#3928 NEPHROTIC SYNDROME IN LIVER DISEASES: PRESENTATION OF TWO UNUSUAL AND INSTRUCTIVE CASES

Abstract Background and Aims However, there are known associations between chronic liver diseases and glomerulopathies, here we report two rare cases, where diagnostic and therapeutic challenges influenced the patients’ care. Method The patients’ medical parameters were obtained from the electronical charts of the hospital. Kidney biopsy samples were examined with immunofluorescence (frozen samples), light microscopy (paraffin embedded tissue, 2-3 um sections) and electron microscopy (1 um, toluidine blue). The follow-up time was 24 months for case 1 and 23 months for case 2. Both patients gave written consent to the presentation of the reports. Results Case 1: A 42-year-old man with recent pulmonary embolism was presented in our hospital with nephrotic syndrome and reduced kidney function (estimated glomerular filtration rate (eGFR): 43 ml/min/1.73 m2, urinary protein/creatinine ratio (UPCR): 2124 mg/mmol, serum albumin: 24 g/L). Kidney biopsy confirmed primary membranous nephropathy (MN). The anti-phospholipase-A-2 receptor (aPLA2R) was positive in high titer, and PLA2R positivity was also seen in the renal sample. Additionally, an active hepatitis C (HCV) infection with viremia was confirmed. The nephrotic syndrome was worsened with severe edema requiring ultrafiltration; therefore, after one-week direct anti-HCV therapy, methylprednisolone was started. Immunosuppressive therapy had to be determined soon due to severe infections. With combined direct antiviral treatment, HCV PCR test became negative, which was followed by the disappearance of the aPLA2R antibodies. The patient's kidney function stabilized and there are no symptoms of nephrotic syndrome (eGFR: 52 ml/min/1.73 m2, serum albumin: 37 g/L, UPCR: 321 mg/mmol). Case 2: A 66-year-old woman was admitted to the hospital with coronavirus disease (COVID)- associated pneumonia. At admission, nephrotic syndrome was diagnosed (eGFR: 29 ml/min/1.73 m2, serum albumin: 22 g/L, proteinuria: 8 g/day). Additionally, elevated gamma glutamyl transferase was registered. Immune serology was negative for aPLA2R, but antinuclear antibodies (anti-cytoplasm, chromatin, Ro), and anti-mitochondrial antibodies (AMA-M2) were positive. Biopsies were performed after the COVID infection. Liver biopsy confirmed primary biliary cholangitis (stage 1-2), while the kidney biopsy showed secondary membranous nephropathy with signs of potential monoclonal gammopathy (monoclonal immunoglobulin-G1-kappa deposits). After the exclusion of malignancies, monoclonal gammopathy, and potential other causes of the secondary MN, PBC-associated MN was diagnosed. Based on case reports in the literature, cyclosporine A treatment was started. The patient reached complete remission in 5 months (no significant proteinuria, stable eGFR around 34 ml/min/1.73 m2). Conclusion The association of an active HCV infection and an aPLA2R positive MN has not been reported in the literature. Nephrotic syndrome and the aPLA2R positivity disappeared related to the direct antiviral treatment, which may indicate a diagnosis of secondary MN. PBC-associated secondary MN is a known but rare entity, where calcineurin inhibitor treatment may reduce the symptoms of nephrotic syndrome.

Hepatocyte-derived DPP4 regulates portal GLP-1 bioactivity, glucose production, and its absence alters liver disease progression.

Elevated circulating dipeptidyl-peptidase 4 is a biomarker for liver disease, but its involvement in gluconeogenesis and in metabolic-associated fatty liver disease (MAFLD) progression remains unclear. Here we identified that DPP4 in hepatocytes but not Tie2+ endothelial cells regulates the local bioactivity of incretin hormones and gluconeogenesis. However, the complete absence of DPP4 (Dpp4-/-) in aged mice with metabolic syndrome accelerates liver fibrosis without altering dyslipidemia and steatosis. Analysis of transcripts from the livers of whole body Dpp4-/- displayed enrichment for inflammasome, p53, and senescence programs compared to littermate controls. High-fat high-cholesterol (HFHC)-feeding decreased Dpp4 expression in F4/80+ cells, with only minor changes in immune signaling. Moreover, in a lean mouse model of severe non-alcoholic fatty liver disease (NAFLD), phosphatidylethanolamine N-methyltransferase (Pemt -/-) mice fed with HFHC diet, we observed a 4-fold increase in circulating DPP4, disassociating its release from obesity. Lastly, we evaluated DPP4 levels in patients with hepatitis C infection with dysglycemia (HOMA-IR > 2) who underwent direct antiviral treatment (with or without ribavirin). DPP4 protein levels decreased with viral clearance, and DPP4 activity levels were reduced at longer-term follow-up in ribavirin-treated patients, although metabolic factors did not improve. These data suggest elevations in DPP4 during HCV infection are not primarily regulated by metabolic disturbances.

Codivir suppresses SARS-Cov-2 viral replication and stabilizes clinical outcome: In vitro and Phase I clinical trial results.

Treatment of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) remains a significant challenge in the face of increased worldwide morbidity and mortality. The acute illness caused by SARS-CoV-2 is initiated by a viral phase, followed by an inflammatory phase. Numerous anti-inflammatory and anti-viral therapies, with a relatively minor clinical effect, have been applied. Developing a safe and efficient direct anti-viral treatment is essential as it can block disease progression before significant complications ensue and potentially prevent transmission. The present phase 1 study aimed to determine the safety of Codivir, a newly developed anti-viral agent, and to preliminarily assess its anti-viral activity in patients infected by COVID-19. In vitro studies were conducted to determine the direct anti-viral effect of Codivir using an immunofluorescence-based assay and to assess its cytotoxic effect by tetrazolium assay (MTT). In a phase I clinical trial, Codivir was administered for ten days in 12 patients who were followed for its safety. Patients were followed for clinical manifestations during administration. Sequential nasal viral PCR titers (Cycle Threshold, CT) were determined preceding and during treatment. In vitro, Codivir showed activity against SARS-CoV-2 with 90% viral replication suppression and minimal cytotoxicity. The anti-viral activity was demonstrated at the early stages of infection, post-entry of the virus in the cell. Codivir was safe in all 12 patients in phase I clinical trial and significantly suppressed viral replication in 5/7 fully assessed patients, with an anti-viral effect noted as early as three days. The present study's data support the safety of Codivir administration in humans and suggest its significant anti-COVID-19 effect. These results support the testing of the drug in more extensive controlled trials in patients with SARS-CoV-2.

European College of Equine Internal Medicine consensus statement on equine flaviviridae infections in Europe.

Horses and other equids can be infected with several viruses of the family Flaviviridae, belonging to the genus Flavivirus and Hepacivirus. This consensus statement focuses on viruses with known occurrence in Europe, with the objective to summarize the current literature and formulate clinically relevant evidence-based recommendations regarding clinical disease, diagnosis, treatment, and prevention. The viruses circulating in Europe include West Nile virus, tick-borne encephalitis virus, Usutu virus, Louping ill virus and the equine hepacivirus. West Nile virus and Usutu virus are mosquito-borne, while tick-borne encephalitis virus and Louping ill virus are tick-borne. The natural route of transmission for equine hepacivirus remains speculative. West Nile virus and tick-borne encephalitis virus can induce encephalitis in infected horses. In the British Isle, rare equine cases of encephalitis associated with Louping ill virus are reported. In contrast, equine hepacivirus infections are associated with mild acute hepatitis and possibly chronic hepatitis. Diagnosis of flavivirus infections is made primarily by serology, although cross-reactivity occurs. Virus neutralization testing is considered the gold standard to differentiate between flavivirus infections in horses. Hepacivirus infection is detected by serum or liver RT-PCR. No direct antiviral treatment against flavi- or hepacivirus infections in horses is currently available and thus, treatment is supportive. Three vaccines against West Nile virus are licensed in the European Union. Geographic expansion of flaviviruses pathogenic for equids should always be considered a realistic threat, and it would be beneficial if their detection was included in surveillance programs.

Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease Mpro and Papain-like Protease PLpro of SARS-CoV-2.

The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. The main protease (Mpro) and papain-like protease (PLpro) are attractive drug targets among coronaviruses due to their essential role in processing the polyproteins translated from the viral RNA. In this study, we virtually screened 688 naphthoquinoidal compounds and derivatives against Mpro of SARS-CoV-2. Twenty-four derivatives were selected and evaluated in biochemical assays against Mpro using a novel fluorogenic substrate. In parallel, these compounds were also assayed with SARS-CoV-2 PLpro. Four compounds inhibited Mpro with half-maximal inhibitory concentration (IC50) values between 0.41 μM and 9.0 μM. In addition, three compounds inhibited PLpro with IC50 ranging from 1.9 μM to 3.3 μM. To verify the specificity of Mpro and PLpro inhibitors, our experiments included an assessment of common causes of false positives such as aggregation, high compound fluorescence, and inhibition by enzyme oxidation. Altogether, we confirmed novel classes of specific Mpro and PLpro inhibitors. Molecular dynamics simulations suggest stable binding modes for Mpro inhibitors with frequent interactions with residues in the S1 and S2 pockets of the active site. For two PLpro inhibitors, interactions occur in the S3 and S4 pockets. In summary, our structure-based computational and biochemical approach identified novel naphthoquinonal scaffolds that can be further explored as SARS-CoV-2 antivirals.

Persistence of African swine fever virus on porous and non-porous fomites at environmental temperatures

BackgroundAfrican swine fever (ASF) is a lethal contagious disease affecting both domestic pigs and wild boars. Even though it is a non-zoonotic disease, ASF causes economic loss in swine industries across continents. ASF control and eradication are almost impossible since effective vaccines and direct antiviral treatment are not available. The persistence of ASFV on fomites plays an important role in the indirect transmission of ASFV to pigs encountering ASFV-contaminated fomites. ASFV persistence on porous and non-porous fomites (glass, metal, rubber, and cellulose paper) at different environmental temperatures was determined. The persistence of ASFV of fomites was determined by the rate of ASFV inactivation in terms of DT, or the time required to reduce ASFV per 1 log at each selected environmental temperature (T). DT is used to compare the persistence of ASFV on the fomites.ResultsThe mean D25, D33, and D42, of dried infectious ASFV on glass, metal, rubber, and paper were in the ranges 1.42–2.42, 0.72–1.94, and 0.07–0.23 days, respectively. The multiple DT were used to develop a DT model to predict the DT for some other environmental temperatures. The DT models to predict the persistence of dried infectious ASFV on glass, metal, rubber, and paper are log DT = (− T/21.51) + 1.34, log DT = (− T/20.42) + 1.47, log DT = (− T/14.91) + 2.03, and log DT = (− T/10.91) + 2.84, respectively. A spreadsheet as a quick and handy tool predicting the persistence time of dried infectious ASFV on fomites at various environmental temperatures based on these DT models is available for public to download.ConclusionPersistence of dried infectious ASFV on paper are significantly the longest at lower environmental temperatures whereas that of dried infectious ASFV on paper is significantly the shortest at higher environmental temperature.

Occult Hepatitis (B) Infection in Hepatitis (C) Virus Infection Patients after the Treatment with Direct Acting Antiviral Drugs

Background: The prevalence of occult hepatitis B ranges widely in patients with hepatitis C. This may have an impact on treatment of hepatitis C.&#x0D; Aims: The current study aimed to evaluate the prevalence of occult hepatitis B infection in chronic hepatitis C patients who finished the course of treatment with direct acting antiviral drugs and it’s correlation with treatment failure.&#x0D; Setting: Outpatient Clinic of Internal Medicine Department, Faculty of Medicine, Menoufia University, Egypt.&#x0D; Patients and methods: This study was conducted on 900 Egyptian patients chronically infected with HCV. All patients tested positive for serum real time polymerase chain reaction for HCV- RNA and received DAAs therapy for 12 weeks. Patients were categorized to: Group I: 450 patients with chronic hepatitis C after direct antiviral treatment who responded to treatment. Group II: 450 patients with chronic hepatitis C after direct antiviral treatment who didn’t respond to treatment. All patients were submitted to clinical examination, laboratory investigations and abdominal ultrasonography. Detection of HBV- DNA and HCV- RNA was performed by PCR.&#x0D; Results: The prevalence of OBI detected in sera of HCV patients was 10.6 % (96/900). The present study showed no significant correlation between prevalence of OBI and virologic failure (p-value: 0.084). There was no statistically significant difference (p-value &gt; 0.05) between the studied groups as regard prevalence of OBI.&#x0D; Conclusion: The prevalence of OBI was 10.6% in patients chronically infected with HCV. OBI doesn't affect the anti-HCV DAAs outcomes.

Occurrence and recurrence of hepatitis C-related hepatocellular carcinoma after direct antiviral treatment

Hepatitis C virus (HCV) RNA can be cleared from the blood circulation by direct antiviral treatment to achieve sustained virologic response (SVR). Studies have shown that SVR after direct antiviral therapy can reduce the incidence of hepatocellular carcinoma; however, monitoring for hepatocellular carcinoma is still needed. This review briefly summarizes and discusses the existing studies on the possible causes of hepatitis C secondary to HCC after antiviral therapy, which is mainly divided into epigenetic alterations and abnormal DNA methylation, HCV-related cirrhosis and abnormal DNA amplification, HBV reactivation, several aspects of occult HCV infection, and the effect of direct antiviral treatment on hepatocellular carcinoma recurrence. In few cases, direct antiviral treatment cannot completely prevent the occurrence and recurrence of hepatitis C-related hepatocellular carcinoma. Therefore, its mechanism needs to be studied and explored, and clinicians should also approach it with caution.

Entry Inhibitors of Hepatitis B and D Viruses.

Human hepatitis B virus (HBV) and hepatitis D virus (HDV) cause acute and chronic infections. The latter poses a serious public health threat as it is the major cause of chronic hepatitis, liver failure, cirrhosis, and hepatocellular carcinoma (HCC). In nature, HBV and HDV have a narrow host range and highly hepatotropic, only infecting the hepatocytes of humans and a few primates. The elucidation of cell entry mechanism by HBV has made great progress in recent years, which strongly promotes the establishment of new HBV infection models and the development of viral entry inhibitors. The study of HBV entry inhibitors has culminated in the first direct antiviral treatment for HDV. This review provides a concise introduction on the progress of HBV/HDV entry inhibitors in the recent years.

Post-exposure Lopinavir-Ritonavir Prophylaxis versus Surveillance for Individuals Exposed to SARS-CoV-2: The COPEP Pragmatic Open-Label, Cluster Randomized Trial.

BackgroundSince the beginning of the COVID-19 pandemic, no direct antiviral treatment is effective as post-exposure prophylaxis (PEP). Lopinavir/ritonavir (LPV/r) was repurposed as a potential PEP agent against COVID-19.MethodsWe conducted a pragmatic open-label, parallel, cluster-randomised superiority trial in four sites in Switzerland and Brazil between March 2020 to March 2021. Clusters were randomised to receive LPV/r PEP (400/100 mg) twice daily for 5 days or no PEP (surveillance). Exposure to SARS-CoV-2 was defined as a close contact of >15 minutes in <2 metres distance or having shared a closed space for ≥2 hours with a person with confirmed SARS-CoV-2 infection. The primary outcome is the occurrence of COVID-19 defined by a SARS-CoV-2 infection (positive oropharyngeal SARS-CoV-2 PCR and/or a seroconversion) and ≥1 compatible symptom within 21 days post-enrolment. ClinicalTrials.gov (Identifier: NCT04364022); Swiss National Clinical Trial Portal: SNCTP 000003732.FindingsOf 318 participants, 157 (49.4%) were women; median age was 39 (interquartile range, 28-50) years. A total of 209 (179 clusters) participants were randomised to LPV/r PEP and 109 (95 clusters) to surveillance. Baseline characteristics were similar, with the exception of baseline SARS-CoV-2 PCR positivity, which was 3-fold more frequent in the LPV/r arm (34/209 [16.3%] vs 6/109 [5.5%], respectively). During 21-day follow-up, 48/318 (15.1%) participants developed COVID-19: 35/209 (16.7%) in the LPV/r group and 13/109 (11.9%) in the surveillance group (unadjusted hazard ratio 1.44; 95% CI, 0.76-2.73). In the primary endpoint analysis, which was adjuted for baseline imbalance, the hazard ratio for developing COVID-19 in the LPV/r group vs surveillance was 0.60 (95% CI, 0.29-1.26; p =0.18).InterpretationThe role of LPV/r as PEP for COVID-19 remains unanswered. Although LPV/r over 5 days did not significantly reduce the incidence of COVID-19 in exposed individuals, we observed a change in the directionality of the effect in favour of LPV/r after adjusting for baseline imbalance. LPV/r for this indication merits further testing against SARS-CoV-2 in clinical trials.FundingSwiss National Science Foundation (project no.: 33IC30_166819) and the Private Foundation of Geneva University Hospitals (Edmond Rothschild (Suisse) SA, Union Bancaire Privée and the Fondation pour la recherche et le traitement médical).

Characteristics of De novo Hepatocellular carcinoma (HCC) in Chronic HCV Egyptian patients received Direct Acting Antivirals (DAAs) therapy: A pilot study

Abstract Background Direct-acting antiviral agents for chronic hepatitis C have initiated a revolution in the management and control of this important liver disease with cure rates over 90%. However, it has been suggested that HCC may occur or recur in patients with chronic HCV infection who received DAAs therapy. Aim To compare characteristics and behavior of de novo Hepatocellular carcinoma (HCC) in chronic HCV patients who received direct acting antiviral treatment with those who didn't receive DAAs . Patients and methods The current study was conducted on patients with de novo HCC presented at HCC clinic, Tropical medicine department Ain Shams University Hospitals between December 2017 and December 2018, aged (18-70 years old) . Total number of HCC cases visited the clinic during the study period was 416 patients. 160 patients with de novo HCC were enrolled in the study fullfiling the inclusion criteria and divided to two groups, 80 patients with HCC who received Direct antiviral treatment, the other 80 patients who didn't receive Direct antiviral treatment. Results Unlike some previous concerns about increased biologic aggressiveness of HCC after DAA treatment, resulting in infiltrative pattern and multinodular HCC outside Milan criteria, our results on de novo HCC after DAAs were mostly single, small, and diagnosed in early stages, resulting in BCLC stage 0-B in the majority of patients. There were no statistical differences regarding total size of tumor,or vascular invasion or AFP, but there’s a statistical difference in largest size of HFLs that was more significant in group (A) P = 0.04 The mean Child score was 5.75 in group A, with 61 patients (76.3%) were Child class A,19 patients (23.8%) were Child class B and 0 patients were child C. For the patients in group (B) the mean Child score was 6.15, with 50 patients (62.5%) were Child class A, 26 patients (32.5%) were Child class B and 4 patients (5%) were child C. Conclusion The current study shows no differences between the 2 studied groups as regard tumor aggressiveness, but data on risk of HCC and behaviour after DAAs is still conflicting and further studies are needed

GALAD Score Detects Early-Stage Hepatocellular Carcinoma in a European Cohort of Chronic Hepatitis B and C Patients.

Despite vaccination programs and direct antiviral treatments, the incidence of virus-related hepatocellular carcinoma (HCC) remains high, while ultrasound-based detection rates for early-stage HCC is continuously low. To address this insufficiency, we set out to characterize whether the GALAD score, which incorporates gender, age, and serum levels of AFP, AFP isoform L3 (AFP-L3), and des-gamma-carboxy-prothrombin (DCP), can improve early-stage HCC detection in a Caucasian HBV/HCV cohort. In a retrospective German single-center study, 182 patients with HBV, 223 with HCV and 168 with other etiology (OE) of chronic liver disease (CLD) were enrolled. HCC was confirmed in 52 HBV, 84 HCV and 60 OE CLD patients. The diagnostic performance of the single biomarkers in HCC detection was compared to the GALAD model. At initial diagnosis, most patients were at (very) early BCLC 0 (n = 14/7%) or A (n = 56/29%) or intermediate stage BCLC B (n = 93/47%) HCC in all three subgroups. In the BCLC 0/A cohort, GALAD exhibited an AUC of 0.94 discriminating HCC from non-HCC, surpassing AFP (AUC 0.86), AFP-L3 (AUC 0.83) and DCP (AUC 0.83). In the HBV population, GALAD achieved an AUC of 0.96, in HCV an AUC of 0.98 and in OE an AUC of 0.99, clearly superior to the biomarkers alone. Furthermore, in HCV patients GALAD showed a significantly higher specificity (89%) versus AFP (64%) alone. In chronic viral hepatitis, the GALAD model showed superior performance in detection of early-stage HCC, while exhibiting higher specificity in HCV patients compared to AFP alone. We conclude that the GALAD score shows potential for HCC surveillance in Caucasian HBV/HCV patients.

Efficacy of Lopinavir-Ritonavir Prophylaxis for Individuals Exposed to SARS-CoV-2: The COPEP Pragmatic Open-Label, Cluster Randomized Trial

Background: Since the beginning of the COVID-19 pandemic, no direct antiviral treatment is effective as post-exposure prophylaxis (PEP). Lopinavir/ritonavir (LPV/r) was repurposed as a potential PEP agent against COVID-19.Methods: We conducted a pragmatic open-label, parallel, cluster-randomized superiority trial in four sites in Switzerland and Brazil. Clusters were randomized to receive LPV/r PEP (400/100 mg) twice daily for 5 days or no PEP (surveillance). The primary outcome is the occurrence of COVID-19 within 21 days post-enrollment.Findings: Of 318 participants, 157 (49.4%) were women, median age was 39 (interquartile range, 28-50) years. A total of 209 (179 clusters) participants were randomized to LPV/r PEP and 109 (95 clusters) to surveillance. Baseline characteristics were similar, with the exception of baseline SARS-CoV-2 PCR positivity, which was 3-fold more frequent in the LPV/r arm (34/209 [16.3%] vs 6/109 [5.5%], respectively). During 21-day follow-up, 48/318 (15.1%) participants developed COVID-19: 35/209 (16.7%) in the LPV/r group and 13/109 (11.9%) in the surveillance group (unadjusted hazard ratio 1.44; 95% CI, 0.76 to 2.73). In the primary endpoint analysis adjusted for propensity score to receive LPV/r, the hazard ratio for developing COVID-19 in the LPV/r group vs surveillance was 0.53 (95% CI, 0.23 to 1.23, respectively; P =.14).Interpretation: LPV/r role as PEP for COVID-19 remains unanswered. In this trial, LPV/r over 5 days did not significantly reduce incidence of COVID-19 in exposed individuals. We observed a change in directionality of the effect in favor of LPV/r after adjusting for baseline SARS-CoV-2 PCR results, indicating a potential role of antivirals in COVID-19 prevention.Clinical Trial Registration Details: ClinicalTrials.gov (Identifier: NCT04364022); Swiss National Clinical Trial Portal: SNCTP 000003732.Funding Information: Fondation privée des HUG and Swiss National Fund (project number: 33IC30_166819).Declaration of Interests: None reported.Ethics Approval Statement: The protocol and amendments were approved by Swissmedic and local ethics committees in Switzerland and Brazil. Participants provided written informed consent before study entry.

Impact of Interleukin 28B and ICAM-1 Genetic Polymorphisms on Response to Direct Antiviral Treatment Among HCV Infected Patients.

Single nucleotide polymorphisms (SNPs) of IL-28B and/or ICAM-1 could have a role in expecting a response from HCV infected patients to direct antiviral agents (DAAs). The aim of the current study was to investigate the impact of IL-28B rs12979860 and rs8099917, and, ICAM-1 rs281437 SNPs on response to treatment with sofosbuvir + Daclatsvir ± Ribavirin, among HCV-infected Egyptian patients. Whole blood genomic DNA was extracted from 120 participants (80 HCV-infected patients and 40 healthy volunteers). HCV-infected patients were subdivided into responders and nonresponders to DAAs. Liver function testing, anti-HCV antibodies, HCV-RNA viral load and HCV genotyping were performed. IL-28B and ICAM-1 SNPs were evaluated by real-time PCR. ALT and AST levels were significantly higher among non-responder HCV infected patients (P = 0.001*). 90% of the patients had HCV genotype 4a and the remaining 10% had 4l genotype. Allelic discrimination revealed that IL-28B rs12979860 T, IL-28B rs809917 T and ICAM-1 rs281437 C alleles were more frequent among HCV-infected patients (responders or non-responders) than controls. However, IL-28B rs8099917 G allele was more frequent among healthy controls. Regarding the response to DAAs treatment, HCV-infected patients with IL-28B rs8099917 GG genotype showed a significantly earlier viral response compared to those carrying TT alleles. ICAM-1 rs281437 CT alleles were non significantly more frequent among responders. However, IL-28B rs12979860 alleles did not show any difference. Genotyping of IL-28B rs8099917 is a useful independent tool for expecting a response of Egyptian HCV-infected patients to DAAs.

Interferon stimulated gene 15 promotes Zika virus replication through regulating Jak/STAT and ISGylation pathways

Zika virus is an emergent arbovirus that has caused a public health emergency in South America. Zika virus infection is known to cause microcephaly and other congenital defects and Guillain-Barré syndrome. Unfortunately no direct antiviral treatments are available at present. IFN-stimulated gene 15 (ISG15) is one of the most upregulated host genes following type I interferon treatment or virus infections. ISG15 has been shown to have antiviral effect on a wide variety of viruses although pro-HCV replication was observed. However, the effect of ISG15 on ZIKV infection is not well defined. In this study, we try to clarify the effect of ISG15 on ZIKV replication and to further dissect the underlying mechanism. Our results indicated that ZIKV infection led to the increased expression of ISG15 in A549, 2fTGH, U5A cells. Overexpression of ISG15 stimulated ZIKV replication although ISG15 did not affect the viral entry. Further studies showed that this proviral effect was mediated through Jak/STAT signaling pathway and was ISGylation-dependent. Taken together, our work demonstrates that ISG15 is an important host factor exploited by ZIKV to facilitate its replication and might serve as a potential target for the development of novel antiviral agents.

HCV GENOTYPES AND ITS ASSOCIATION WITH RESPONSE TO TREATMENT

BACKGROUND &amp; OBJECTIVE: primary Hepatitis C is a serious public health problem and is the cause of liver cirrhosis, hepatocellular carcinoma (HCC), and numerous end-stage liver disease manifestations. The management of hepatitis C is to preclude liver cirrhosis, lessen the risk of hepatocellular carcinoma or hepatoma, and curing the extra hepatic diseases. Initially, interferon was the cornerstone for treating hepatitis C, but due to its cumbersome complications, route of administration, and limited treatment access, many patients showed noncompliance. New therapies for chronic hepatitis C have been introduced based on direct antiviral effects. Several genotypes of hepatitis C have been discovered and they are responsive to different antiviral therapies. Our objective was to assess the genotypic distribution of HCV in our local setup and their pattern of response to different combination of anti-viral therapies by assessing the sustained viral response (SVR) after 12 weeks post-treatment. To determine the most prevalent genotype of hepatics C virus in our population and pattern of the response of multiple genotypes to different antiviral regimens.&#x0D; METHODOLOGY: It is a cross-sectional study conducted for duration of six months and recruited those patients whose polymerase chain reaction (PCR) was found positive for hepatitis C virus at Islamabad Diagnostic Center. We analyzed 100 patients, both children and adults. Patients were assessed for different genotypes and then different combinations of antiviral treatments were administered. Their clinical data, hematological parameters and viral load before and after treatment were also analyzed.&#x0D; RESULTS: In a total of 100 positive hepatitis C virus-infected patients, 55% were females and 45% males. The frequencies of genotypes observed were 91 %, 06%, and 03% of genotype 3, 1a, and 1b respectively. 51 out of 91 patients with type 3 genotype, who were on antiviral therapy of sofosbuvir and ribavirin, all of them achieved SVR. 30 out of 91 patients with type 3 genotype were treated with sofosbuvir alone, the percentage of failure to achieve SVR in them was 6.7%. Treatment failure percentage of 10% was observed when a combination of Interferon (INF) alpha and ribavirin was used in type 3 genotype. Remaining six patients with type 1a and three patients of type 1b genotype achieved SVR with different regimens used.&#x0D; CONCLUSION: Although the increased load of HCV in our setup is an alarming situation the prevalence of type 3 genotype is a blessing in disguise. The success of sustained viral response after various combinations of direct antiviral therapy and interferon-free treatment is hope for the ultimate cure of the disease and avoidance of debilitating side effects related to interferon.

Potential utility of melatonin in deadly infectious diseases related to the overreaction of innate immune response and destructive inflammation: focus on COVID-19

The high mortality&#x0D; of deadly virus infectious diseases including SARS, MERS, COVID-19, and avian&#x0D; flu is often caused by the uncontrolled innate immune response and destructive&#x0D; inflammation. The majority of viral diseases are self-limiting under the help&#x0D; of the activated adaptive immune system. This activity is cell proliferation&#x0D; dependent and thus, it requires several weeks to develop. Patients are&#x0D; vulnerable and mortality usually occurs during this window period. To control the&#x0D; innate immune response and reduce the inflammation during this period will&#x0D; increase the tolerance of patients and lowers the mortality in the deadly virus&#x0D; infection. Melatonin is a molecule that displays respective properties, since&#x0D; it downregulates the overreaction of the innate immune response and&#x0D; overshooting inflammation, but also promotes the adaptive immune activity. Many&#x0D; studies have reported the beneficial effects of melatonin on deadly virus&#x0D; infections in different animal models and its therapeutic efficacy in septic&#x0D; shock patients. Furthermore, melatonin has a great safety margin without&#x0D; serious adverse effects. We suggest the use of melatonin as an adjunctive or&#x0D; even regular therapy for deadly viral diseases, especially if no efficient&#x0D; direct anti-viral treatment is available.