Abstract Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).
Therapeutic options for patients with HCV-related liver disease have increased over the last two decades. In fact, the old standard of care based on the combination of pegylated interferon and ribavirin did not result in satisfactory eradication rates, particularly in patients with liver cirrhosis. With the advent of direct-acting antivirals (DAAs), higher rates of viral clearance became possible and, patients with contraindications to interferon obtained access to treatment. However, several concerns have been raised regarding first-generation DAAs, namely their high costs, and the emergence of resistant-associated variants with low susceptibility to these drugs.In this review, the authors discuss the data about the efficacy and safety of the main anti-HCV direct-acting antivirals currently in the pipeline. Furthermore, they evaluate the impact of these drugs on the therapeutic options currently available for HCV patients.The results of trials evaluating the effectiveness of new DAAs are encouraging. These new antivirals lead to high rates of viral eradication without relevant adverse reactions and seem to be effective regardless of viral genotypes, presence of resistant-associated variants or advanced liver disease. Consequently, with the advent of this new family of drugs, chronic HCV-related hepatitis may become a curable disease.
About 240 million people worldwide are chronically infected with hepatitis B virus (HBV). Vertical transmission is the most important mechanism of infection persistence in endemic areas. About 150 million people worldwide are chronically infected with hepatitis C virus (HCV). Mother-to-child transmission of HCV, which occurs in 3–10% of cases, is the leading route of infection in childhood. This review focuses on strategies to reduce the vertical transmission of HBV and HCV. The at-birth prophylaxis of newborns of HBV-infected mothers with specific immunoglobulin and vaccine plus administration of antivirals (tenofovir or telbivudine) in the third trimester of pregnancy (in case of high maternal viral load) greatly reduces the risk of transmission. In contrast, currently there is no drug able to reduce the vertical transmission of HCV infection. We discuss the possibility of reducing mother-to-child HCV transmission using newly available antivirals or antivirals in the pipeline for the treatment of hepatitis C.
Introduction: About 185,000,000 people worldwide are chronically infected with hepatitis C virus (HCV). Currently, the most successful HCV infection antiviral therapies reduce the chance of progression towards the advanced phases of the hepatopathy (liver cirrhosis, hepatocellular carcinoma and death). Recently, however, several new direct-acting antivirals against HCV are available or are in an advanced phase of clinical development.Areas covered: This review focuses on beclabuvir, an allosteric non-nucleotide inhibitor of HCV polymerase. The article covers its pharmacokinetics, mechanism of action, in addition to its tolerability and safety profile as well as its resistance pattern.Expert opinion: The pharmacokinetic, efficacy and tolerability profile of beclabuvir, as well as its barrier to resistance, are very favorable. In particular, the combination of beclabuvir with asunaprevir and daclatasvir achieves very high rates of viral eradication (about 90%) in patients infected with HCV genotype 1, which is the most common genotype worldwide. Therefore, beclabuvir represents a powerful weapon against HCV infection and has to be considered an optimal option in tailored IFN-free combinations.
Autism spectrum disorder (ASD) is a group of central nervous system disorders lacking a definite etiology. The aim of the present study was to compare the exposure rate and titer of antibodies to Varicella Zoster Virus (VZV) in children with ASD and in healthy controls.We enrolled 54 children with ASD and 46 control individuals.The exposure rate and titer of anti-VZV antibodies were significantly higher in children with ASD compared to controls (59% vs. 39% and 694 mIU/ml vs. 94 mIU/ml, respectively).In the present case-control study, exposure to VZV was found to be independently associated with ASD.
Clostridium difficile infection is a disease with increasing incidence, particularly in high‑riskpatients such as the elderly, immunocompromised patients, etc.We report an unexpected decrease of International Normalized Ratio (INR) response to warfarin during a first recurrence of Clostridium difficile infection (CDI) treated with fidaxomicin. The patient, an old man who has prosthetic heart valves on anticoagulation therapy with warfarin, was treated with an association of vancomycin plus metronidazole for a first episode of CDI. Patient remained symptom‑free for few days and then he presented with recurrent diarrhea. A retreatment with vancomycin and metronidazole didn’t resolve symptoms of CDI, therefore he underwent fidaxomicin treatment for 10 days, with rapid resolution of diarrhea. In the meantime, warfarin effects diminished, and only with increases of dosage INR therapeutic range was achieved few days after discontinuing fidaxomicin. According to product information, fidaxomicin doesn’t interfere with warfarin. The authors highlight the different plausible mechanisms to explain the association between the unexpected decreased effect of warfarin and factors that could have influenced such event. The frequent update of product information through good pharmacovigilance practices could help clinicians in the management of unexpected events.
