Long-term survival and clinical outcomes following direct-acting antiviral (DAA) treatment in HCV decompensated cirrhosis in Brazil: a real-world study.

INTRODUCTION: The outcomes regarding portal hypertension-related complications and infections after HCV cure in decompensated cirrhosis are scarcely reported. We aimed to identify the predictors of survival and to evaluate the frequency of decompensation events of cirrhosis, including hepatocellular carcinoma (HCC), portal hypertension complications and infections in a cohort of decompensated cirrhotic with sustained virological response (SVR) in a real-world scenario. PATIENTS AND METHODS: This was a prospective study in consecutive HCV-infected patients with decompensated cirrhosis who achieved SVR after direct-acting antiviral (DAA) treatment. At baseline, clinical and laboratory data were recorded. Patients were followed until development of outcomes regarding further decompensation, death, or liver transplant. A Cox-regression analysis was performed and survival curves were constructed using the Kaplan Mayer method. RESULTS: One hundred and thirty patients (age 60 ± 9 years, 64% female, 70% genotype 1) were included and followed-up through three years. SVR was associated with a lower prevalence of ascites and an improvement in Child-Pugh and MELD scores. One and three-year probability of transplant-free survival was 93% and 66%, respectively. Variables related to three-years survival were MELD < 11 (HR 1.24, 95% CI 1.13-1.37) and absence of ascites (HR 2.03, 95% CI 0.99-4.13) after the end of treatment (91% versus 37% in patients with ascites and a higher MELD, p < 0.001). CONCLUSIONS: Decompensated cirrhotics with SVR and a low MELD without ascites have an excellent long-term prognosis. On the contrary, those with higher MELD and ascites have a low probability of survival even in the short term and might be evaluated for liver transplantation.

Long-term survival and clinical outcomes following direct-acting antiviral (DAA) treatment in HCV decompensated cirrhosis in Brazil: a real-world study

Abstract Introduction The outcomes regarding portal hypertension-related complications and infections after HCV cure in decompensated cirrhosis are scarcely reported. We aimed to identify the predictors of survival and to evaluate the frequency of decompensation events of cirrhosis, including hepatocellular carcinoma (HCC), portal hypertension complications and infections in a cohort of decompensated cirrhotic with sustained virological response (SVR) in a real-world scenario. Patients and methods This was a prospective study in consecutive HCV-infected patients with decompensated cirrhosis who achieved SVR after direct-acting antiviral (DAA) treatment. At baseline, clinical and laboratory data were recorded. Patients were followed until development of outcomes regarding further decompensation, death, or liver transplant. A Cox-regression analysis was performed and survival curves were constructed using the Kaplan Mayer method. Results One hundred and thirty patients (age 60 ± 9 years, 64% female, 70% genotype 1) were included and followed-up through three years. SVR was associated with a lower prevalence of ascites and an improvement in Child-Pugh and MELD scores. One and three-year probability of transplant-free survival was 93% and 66%, respectively. Variables related to three-years survival were MELD < 11 (HR 1.24, 95% CI 1.13-1.37) and absence of ascites (HR 2.03, 95% CI 0.99-4.13) after the end of treatment (91% versus 37% in patients with ascites and a higher MELD, p< 0.001). Conclusions Decompensated cirrhotics with SVR and a low MELD without ascites have an excellent long-term prognosis. On the contrary, those with higher MELD and ascites have a low probability of survival even in the short term and might be evaluated for liver transplantation.

Chemoinformatics Studies on a Series of Imidazoles as Cruzain Inhibitors.

Natural products based on imidazole scaffolds have inspired the discovery of a wide variety of bioactive compounds. Herein, a series of imidazoles that act as competitive and potent cruzain inhibitors was investigated using a combination of ligand- and structure-based drug design strategies. Quantitative structure-activity relationships (QSARs) were generated along with the investigation of enzyme-inhibitor molecular interactions. Predictive hologram QSAR (HQSAR, r2pred = 0.80) and AutoQSAR (q2 = 0.90) models were built, and key structural properties that underpin cruzain inhibition were identified. Moreover, comparative molecular field analysis (CoMFA, r2pred = 0.81) and comparative molecular similarity indices analysis (CoMSIA, r2pred = 0.73) revealed 3D molecular features that strongly affect the activity of the inhibitors. These findings were examined along with molecular docking studies and were highly compatible with the intermolecular contacts that take place between cruzain and the inhibitors. The results gathered herein revealed the main factors that determine the activity of the imidazoles studied and provide novel knowledge for the design of improved cruzain inhibitors.

Seasonality of distinct respiratory viruses in a tropical city: implications for prophylaxis.

OBJECTIVE: The frequency and seasonality of viruses in tropical regions are scarcely reported. We estimated the frequency of seven respiratory viruses and assessed seasonality of respiratory syncytial virus (RSV) and influenza viruses in a tropical city. METHODS: Children (age ≤ 18 years) with acute respiratory infection were investigated in Salvador, Brazil, between July 2014 and June 2017. Respiratory viruses were searched by direct immunofluorescence and real-time polymerase chain reaction for detection of RSV, influenza A virus, influenza B virus, adenovirus (ADV) and parainfluenza viruses (PIV) 1, 2 and 3. Seasonal distribution was evaluated by Prais-Winsten regression. Due to similar distribution, influenza A and influenza B viruses were grouped to analyse seasonality. RESULTS: The study group comprised 387 cases whose median (IQR) age was 26.4 (10.5-50.1) months. Respiratory viruses were detected in 106 (27.4%) cases. RSV (n = 76; 19.6%), influenza A virus (n = 11; 2.8%), influenza B virus (n = 7; 1.8%), ADV (n = 5; 1.3%), PIV 1 (n = 5; 1.3%), PIV 3 (n = 3; 0.8%) and PIV 2 (n = 1; 0.3%) were identified. Monthly count of RSV cases demonstrated seasonal distribution (b3 = 0.626; P = 0.003). More than half (42/76 [55.3%]) of all RSV cases were detected from April to June. Monthly count of influenza cases also showed seasonal distribution (b3 = -0.264; P = 0.032). Influenza cases peaked from November to January with 44.4% (8/18) of all influenza cases. CONCLUSIONS: RSV was the most frequently detected virus. RSV and influenza viruses showed seasonal distribution. These data may be useful to plan the best time to carry out prophylaxis and to increase the number of hospital beds.

Multiparameter Optimization of Trypanocidal Cruzain Inhibitors With In Vivo Activity and Favorable Pharmacokinetics.

Cruzain, the main cysteine protease of Trypanosoma cruzi, plays key roles in all stages of the parasite's life cycle, including nutrition acquisition, differentiation, evasion of the host immune system, and invasion of host cells. Thus, inhibition of this validated target may lead to the development of novel drugs for the treatment of Chagas disease. In this study, a multiparameter optimization (MPO) approach, molecular modeling, and structure-activity relationships (SARs) were employed for the identification of new benzimidazole derivatives as potent competitive inhibitors of cruzain with trypanocidal activity and suitable pharmacokinetics. Extensive pharmacokinetic studies enabled the identification of metabolically stable and permeable compounds with high selectivity indices. CYP3A4 was found to be involved in the main metabolic pathway, and the identification of metabolic soft spots provided insights into molecular optimization. Compound 28, which showed a promising trade-off between pharmacodynamics and pharmacokinetics, caused no acute toxicity and reduced parasite burden both in vitro and in vivo.

Discovery of Potent, Reversible, and Competitive Cruzain Inhibitors with Trypanocidal Activity: A Structure-Based Drug Design Approach.

A virtual screening conducted with nearly 4 000 000 compounds from lead-like and fragment-like subsets enabled the identification of a small-molecule inhibitor (1) of the Trypanosoma cruzi cruzain enzyme, a validated drug target for Chagas disease. Subsequent comprehensive structure-based drug design and structure-activity relationship studies led to the discovery of carbamoyl imidazoles as potent, reversible, and competitive cruzain inhibitors. The most potent carbamoyl imidazole inhibitor (45) exhibited high affinity with a Ki value of 20 nM, presenting both in vitro and in vivo activity against T. cruzi. Furthermore, the most promising compounds reduced parasite burden in vivo and showed no toxicity at a dose of 100 mg/kg. These carbamoyl imidazoles are structurally attractive, nonpeptidic, and easy to prepare and synthetically modify. Finally, these results further advance our understanding of the noncovalent mode of inhibition of this pharmaceutically relevant enzyme, building strong foundations for drug discovery efforts.

Structure-Based and Molecular Modeling Studies for the Discovery of Cyclic Imides as Reversible Cruzain Inhibitors With Potent Anti-Trypanosoma cruzi Activity.

Chagas disease causes ~10,000 deaths each year, mainly in Latin America, where it is endemic. The currently available chemotherapeutic agents are ineffective in the chronic stage of the disease, and the lack of pharmaceutical innovation for Chagas disease highlights the urgent need for the development of new drugs. The enzyme cruzain, the main cysteine protease of Trypanosoma cruzi, has been explored as a validated molecular target for drug discovery. Herein, the design, molecular modeling studies, synthesis, and biological evaluation of cyclic imides as cruzain inhibitors are described. Starting with a micromolar-range cruzain inhibitor (3a, IC50 = 2.2 µM), this molecular optimization strategy resulted in the nanomolar-range inhibitor 10j (IC50 = 0.6 µM), which is highly active against T. cruzi intracellular amastigotes (IC50 = 1.0 µM). Moreover, most compounds were selective toward T. cruzi over human fibroblasts, which were used as host cells, and are less toxic to hepatic cells than the marketed drug benznidazole. This study enabled the discovery of novel chemical diversity and established robust structure-activity relationships to guide the design of optimized cruzain inhibitors as new trypanocidal agents.

Molecular modeling and structure-activity relationships for a series of benzimidazole derivatives as cruzain inhibitors.

AIM: Chagas disease is endemic in Latin America and no effective treatment is available. Efforts in drug research have focused on several enzymes from Trypanosoma cruzi, among which cruzain is a validated pharmacological target. METHODOLOGY: Chemometric analyses were performed on the data set using the hologram quantitative structure-activity relationship, comparative molecular field analysis and comparative molecular similarity index analysis methods. Docking simulations were executed using the crystallographic structure of cruzain in complex with a benzimidazole inhibitor. The top-scoring enzyme-inhibitor complexes were selected for the development of the 3D quantitative structure-activity relationship (QSAR) models and to assess the inhibitor binding modes and intermolecular interactions. RESULTS: Benzimidazole derivatives as cruzain inhibitors were used in molecular docking and QSAR studies. Significant statistical indicators were obtained, and the best models demonstrated high predictive ability for an external test set (r 2pred = 0.65, 0.94 and 0.82 for hologram QSAR, comparative molecular field analysis and comparative molecular similarity index analysis, respectively). Additionally, the graphical information of the chemometric analyses demonstrated substantial complementarity with the enzyme-binding site. CONCLUSION: These results demonstrate the relevance of the QSAR models to guide the design of structurally related benzimidazole derivatives with improved potency.

Synthesis, biological evaluation, and structure-activity relationships of potent noncovalent and nonpeptidic cruzain inhibitors as anti-Trypanosoma cruzi agents.

The development of cruzain inhibitors has been driven by the urgent need to develop novel and more effective drugs for the treatment of Chagas' disease. Herein, we report the lead optimization of a class of noncovalent cruzain inhibitors, starting from an inhibitor previously cocrystallized with the enzyme (K(i) = 0.8 µM). With the goal of achieving a better understanding of the structure-activity relationships, we have synthesized and evaluated a series of over 40 analogues, leading to the development of a very promising competitive inhibitor (8r, IC50 = 200 nM, K(i) = 82 nM). Investigation of the in vitro trypanocidal activity and preliminary cytotoxicity revealed the potential of the most potent cruzain inhibitors in guiding further medicinal chemistry efforts to develop drug candidates for Chagas' disease.