All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study.

UNLABELLED: Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all-oral regimens requiring 24-week treatment and the addition of ribavirin (RBV). This phase III study (ALLY-3; ClinicalTrials.gov: NCT02032901) evaluated the 12-week regimen of daclatasvir (DCV; pangenotypic nonstructural protein [NS]5A inhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment naïve (n = 101) or treatment experienced (n = 51) and received DCV 60 mg plus SOF 400 mg once-daily for 12 weeks. Coprimary endpoints were the proportions of treatment-naïve and treatment-experienced patients achieving a sustained virological response (SVR) at post-treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment-naïve and treatment-experienced patients, respectively; no virological breakthrough was observed, and ≥99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF-containing regimen and 2 of 2 who previously failed treatment with an alisporivir-containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV-RNA levels, and interleukin-28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on-treatment, which was unrelated to study medications. The few treatment-emergent grade 3/4 laboratory abnormalities that were observed were transient. CONCLUSION: A 12-week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3-infected patients with cirrhosis is underway.

On-treatment HCV RNA as a predictor of sustained virological response in HCV genotype 3-infected patients treated with daclatasvir and sofosbuvir.

BACKGROUND AND AIMS: Many currently available direct-acting antiviral (DAA) regimens are less effective against HCV genotype 3 than against other HCV genotypes. The all-oral, pangenotypic DAA combination of daclatasvir (NS5A inhibitor) + sofosbuvir (nucleotide NS5B inhibitor) was studied in genotype 3-infected treatment-naive and -experienced patients (ALLY-3) who achieved rates of sustained virological response at post-treatment Week 12 (SVR12) of 90 and 86% respectively. In this analysis, we assessed whether on-treatment responses to daclatasvir + sofosbuvir in genotype 3-infected patients could predict treatment outcome. METHODS: In ALLY-3, treatment-naive and -experienced patients, with or without cirrhosis, were treated with daclatasvir + sofosbuvir for 12 weeks. HCV RNA kinetics and categorical virological responses on treatment were assessed. The proportions of responders and nonresponders by study week, and time to first undetectable HCV RNA, were analysed for utility in predicting treatment outcome. RESULTS: Overall, HCV RNA levels declined rapidly during Week 1 of treatment in both treatment-naive and -experienced cohorts. Although patients with cirrhosis had a slower initial virological response as measured by the proportion of patients with HCV RNA below the lower limit of quantification at Week 1, responses converged thereafter. Positive and negative predictive values calculated for on-treatment responses were generally comparable with the overall SVR12 rate and were therefore limited indicators of outcome. SVR12 rates were not impacted by time to first undetectable HCV RNA. CONCLUSIONS: On-treatment responses are not useful predictors of ultimate virological response to the daclatasvir + sofosbuvir regimen.

Clinical Outcomes for Patients With Monomicrobial vs Polymicrobial Acinetobacter baumannii-calcoaceticus Complex Infections Treated With Sulbactam-Durlobactam or Colistin: A Subset Analysis From a Phase 3 Clinical Trial.

Background: In a previous study, the efficacy and safety of sulbactam-durlobactam vs colistin for the treatment of patients with carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRABC) infections were evaluated in a randomized controlled phase 3 trial. Both arms were dosed on a background of imipenem-cilastatin to treat coinfecting gram-negative pathogens. Thirty-six percent of infections in the primary efficacy population were polymicrobial. Methods: A subset analysis was performed to compare clinical and microbiological outcomes at test of cure (7 ± 2 days after the last dose) for patients with monomicrobial and polymicrobial CRABC infections. Minimal inhibitory concentrations of antibiotics against baseline isolates were determined by broth microdilution according to Clinical and Laboratory Standards Institute methodology. Results: Clinical cure, 28-day all-cause mortality, and microbiological outcomes were similar for patients in the sulbactam-durlobactam treatment arm with monomicrobial or polymicrobial A baumannii-calcoaceticus infections. Patients in the colistin arm with monomicrobial CRABC infections had higher mortality rates with worse clinical and microbiological outcomes as compared with those with polymicrobial infections. For patients who received sulbactam-durlobactam, imipenem susceptibility of coinfecting gram-negative pathogens trended with clinical benefit for patients with polymicrobial A baumannii-calcoaceticus infections. When tested in vitro, durlobactam restored imipenem susceptibility to the majority of coinfecting gram-negative pathogens from the sulbactam-durlobactam arm. This phenotype appeared to be related to the clinical outcome in 13 of 15 evaluable cases. Conclusions: These results suggest that the use of sulbactam-durlobactam plus a carbapenem could be an effective approach to treat polymicrobial infections that include CRABC, but additional clinical data are needed to demonstrate efficacy.

Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK).

BACKGROUND: An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC). Sulbactam-durlobactam is a ß-lactam-ß-lactamase inhibitor combination with activity against Acinetobacter, including multidrug-resistant strains. In a phase 3, pathogen-specific, randomised controlled trial, we compared the efficacy and safety of sulbactam-durlobactam versus colistin, both in combination with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. METHODS: The ATTACK trial was done at 59 clinical sites in 16 countries. Adults aged 18 years or older with ABC-confirmed hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia, or bloodstream infections were randomised 1:1 using a block size of four to sulbactam-durlobactam (1·0 g of each drug in combination over 3 h every 6 h) or colistin (2·5 mg/kg over 30 min every 12 h) for 7-14 days. All patients received imipenem-cilastatin (1·0 g of each drug in combination over 1 h every 6 h) as background therapy. The primary efficacy endpoint was 28-day all-cause mortality in patients with laboratory-confirmed carbapenem-resistant ABC (the carbapenem-resistant ABC microbiologically modified intention-to-treat population). Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference was less than +20%. The primary safety endpoint was incidence of nephrotoxicity assessed using modified Risk, Injury, Failure, Loss, End-stage renal disease criteria measured by creatinine level or glomerular filtration rate through day 42. This trial is registered at ClinicalTrials.gov, NCT03894046. FINDINGS: Between Sep 5, 2019, and July 26, 2021, 181 patients were randomly assigned to sulbactam-durlobactam or colistin (176 hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, or ventilated pneumonia; and five bloodstream infections); 125 patients with laboratory-confirmed carbapenem-resistant ABC isolates were included in the primary efficacy analysis. 28-day all-cause mortality was 12 (19%) of 63 in the sulbactam-durlobactam group and 20 (32%) of 62 in the colistin group, a difference of -13·2% (95% CI -30·0 to 3·5), which met criteria for non-inferiority. Incidence of nephrotoxicity was significantly (p<0·001) lower with sulbactam-durlobactam than colistin (12 [13%] of 91 vs 32 [38%] of 85). Serious adverse events were reported in 36 (40%) of 91 patients in the sulbactam-durlobactam group and 42 (49%) of 86 patients in the colistin group. Treatment-related adverse events leading to study drug discontinuation were reported in ten (11%) of 91 patients in the sulbactam-durlobactam group and 14 (16%) of 86 patients in the colistin group. INTERPRETATION: Our data show that sulbactam-durlobactam was non-inferior to colistin, both agents given in combination with imipenem-cilastatin, for the primary endpoint of 28-day all-cause mortality. Sulbactam-durlobactam was well tolerated and could be an effective intervention to reduce mortality from serious infections caused by carbapenem-resistant ABC, including multidrug-resistant strains. FUNDING: Entasis Therapeutics and Zai Lab.

Acute Adverse Effects of Vaccines Against SARS-COV-2.

Introduction The global struggle against the impact of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) on physical and mental health and on economic and social aspects of human life continues even after two and a half years have passed since the emergence of this virus. The development of vaccines was a milestone. By June 2022, billions of people have been vaccinated against the deadly virus. However, like any other vaccine, the various vaccines against coronavirus disease 2019 (COVID-19) also cause a variety of adverse effects. Therefore this study aimed to determine the different acute side effects experienced after receiving the vaccines and correlating them with some socio-demographic and biomedical factors.  Methodology This cross-sectional study has a sample size of 467. Study participants were recruited after fulfilling inclusion and exclusion criteria. After gaining approval from the Ethical Review Board (ERB) of CMH Lahore Medical College and Institute of Dentistry, Lahore, Pakistan, an online questionnaire was distributed via social media. The survey questionnaire had a series of questions regarding the socio-demographic and biomedical characteristics of the participants, as well as the type of vaccine they got, followed by questions about the development of adverse effects after each dose (first and second). Data were statistically analyzed using IBM SPSS Statistics for Windows, Version 25.0 (Released 2017; IBM Corp., Armonk, New York, United States). The analysis was carried out in a confidence range of 95%, and a p-value<0.05 was considered statistically significant.  Results Sinopharm (76.0%) was the most frequently received vaccine. Adverse events were reported more after the first dose (79.7%) than in the second (67.2%) (p value 0.001). The reported adverse events after either dose were of mild intensity (p<0.05). None of the individuals reported serious adverse events or hospitalization after getting the shots. Females, younger age groups, and individuals with BMI in the underweight category were more prone to developing symptoms and experiencing difficulty doing routine work after getting the doses. The associations were statistically significant (p<0.05). Blood group (A,B,0,AB), past COVID-19 history, and smoking status were not positively associated with the appearance of symptoms after either dose or with inconvenience doing daily work post-vaccination. Conclusion The vaccines developed against COVID-19 offer benefits that outweigh the few mild adverse effects experienced. None of these symptoms is severe enough to stop an individual from doing routine work or result in morbidity or mortality. Therefore, people should avoid any hesitancy towards getting vaccinated to get past this pandemic.

COVID-19 pandemic and antimicrobial resistance in developing countries.

A wide range of antimicrobial agents were touted as potential remedies during the COVID-19 pandemic. While both developed and developing countries have recorded an increase in the use of antimicrobial drugs, use and misuse have occurred to a far greater degree in developing countries. This can have deleterious consequences on antimicrobial resistance, especially when various developing countries have already reported the emergence of various drug-resistant organisms even before the pandemic. Telemedicine services, societal and cultural pressures, and bacterial co-infections can predispose to overwhelming antimicrobial prescriptions. The emergence of new multidrug resistance species is a major concern for the developing world especially since health services are already overburdened and lack the diagnostic capabilities and basic amenities for infection prevention and control. This can lead to outbreaks and the rampant spread of such microorganisms. Improper waste management and disposal from hospitals and communities establish freshwater runoffs as hubs of various microorganisms that can predispose to the rise of multidrug-resistant species. Microplastics' ability to act as vectors for antibiotic-resistant organisms is also particularly concerning for lower-middle-income countries. In this review, we aim to study the impact of antimicrobial use during the COVID-19 pandemic and antimicrobial resistance in lower middle-income countries, by understanding various determinants of resistance unique to the developing world and exploring solutions to combat the problem.

Correlation Between Peak Expiratory Flow Rate, Markers of Adiposity, and Anthropometric Measures in Medical Students in Pakistan.

Obesity has been defined as the excessive deposition of fats on the body. It presents a very significant risk to humanity, with debilitating consequences for healthcare systems worldwide. It has multiple effects on the body, including grave consequences on the cardiovascular and respiratory systems. Our project explores the latter. There are multiple studies available in the scientific literature that attempt to explain this phenomenon, all with limited success and conflicting results. This cross-sectional exploration of the topic was done on medical undergraduates to pick up on any correlations between peak expiratory flow rate (PEFR) and the markers of obesity (body mass index (BMI), waist circumference (WC), hip circumference (HC), and waist to hip ratio (WHR)). In general, we found that male participants had sizably higher PEFR values than females (r=0.540, p<0.01). Appropriate BMI is mandatory for the physiologic functioning of the human body. This work also statistically demonstrates a negative overall correlation between lung health and various parameters of obesity. Our work suggests a positive correlation between WHR and PEFR (r=0.325, p<0.01), BMI and PEFR (r=0.573, p=0.02), along with weight and PEFR (r=0.464, p<0.01). Maintaining a BMI and WHR in the normal range is essential for optimal physiological functioning and physical well-being.

Is COVID-19 Fatality Rate Associated with Malaria Endemicity?

COVID-19 (coronavirus disease 2019) is a disease caused by the coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). COVID-19 has yielded many reported complications and unusual observations. In this article, we have reviewed one such observation: an association between malaria endemicity and reduced reported COVID-19 fatality. Malaria-endemic regions have a significantly lower reported COVID-19 fatality rate as compared to regions where malaria is non-endemic. Statistical analyses show that there is a strong negative correlation between the reported SARS-CoV-2 fatality and endemicity of malaria. In this review, we have discussed the potential role of CD-147, and potential malaria-induced immunity and polymorphisms in COVID-19 patients. Noteworthy, the results may also be due to underreported cases or due to the economic, political, and environmental differences between the malaria endemic and non-endemic countries. The study of this potential relationship might be of great help in COVID-19 therapy and prevention.

Role of Interleukin-10 and Abdominopelvic Ultrasound as a Potential Predictor of Disease Severity in Dengue Hemorrhagic Fever.

Introduction Dengue viral infections are a major cause of morbidity and mortality in tropical/subtropical countries. Early and prompt detection of dengue hemorrhagic fever (DHF), though challenging, is helpful to identify an individual that would benefit from intensive therapy. Objective The goal of this study was to determine the plasma interleukin-10 (IL-10) levels in DHF patients at four to seven days of disease onset and 24 hours after the first sample. We also aimed to determine the association of plasma IL-10 levels and abdominopelvic ultrasound findings. Methods A total of 50 registered DHF patients aged 15 to 50 years were recruited. Plasma IL-10 concentration measurements and abdominopelvic ultrasounds were performed. Patients were also categorized based on ultrasound grading I to IV (based on severity). Outcomes were described as recovery and shock. Platelet count and hematocrit percentages were also recorded. Results Plasma IL-10 levels were elevated in DHF patients and associated with fatal outcomes (p = 0.00). Binary regression-coefficient showed the direct effect of high levels of plasma IL-10 on the fatal outcome of patients 24 hours after the first sample (p = 0.04). Disease severity was predicted by a positive correlation between ultrasound grades and outcomes (p = 0.00). Spearman's correlation coefficient found a highly significant inverse relationship between plasma IL-10 levels and platelet count after 24 hours (p = 0.01). However, a significant positive relationship was observed between elevated plasma IL-10 levels and hematocrit percentage after 24 hours (p = 0.01). Conclusion Elevated plasma IL-10 levels and abdominopelvic ultrasonography are promising potential predictors of disease progression and fatal outcome in DHF patients.

A Randomized Study of Peginterferon Lambda-1a Compared to Peginterferon Alfa-2a in Combination with Ribavirin and Telaprevir in Patients with Genotype-1 Chronic Hepatitis C.

BACKGROUND: A randomized, double-blind, multinational, phase 3 study was conducted comparing the efficacy and safety of peginterferon lambda-1a (Lambda)/ribavirin (RBV)/telaprevir (TVR) vs. peginterferon alfa-2a (Alfa)/RBV/TVR in patients with chronic hepatitis C virus (HCV) genotype-1 (GT-1) infection. METHODS: Patients (treatment-naïve or relapsers on prior Alfa/RBV treatment) were randomly assigned in a 2:1 ratio to receive Lambda/RBV/TVR or Alfa/RBV/TVR. Total duration of treatment was either 24 or 48 weeks (response-guided treatment), with TVR administered for the first 12 weeks. The primary endpoint was the proportion of patients who achieved a sustained virologic response at post treatment week 12 (SVR12), which was tested for noninferiority of Lambda/RBV/TVR. RESULTS: A total of 838 patients were enrolled, and 617 were treated; 411 and 206 patients received Lambda/RBV/TVR and Alfa/RBV/TVR, respectively. The majority of patients were treatment-naïve, with HCV GT-1b and a high baseline viral load (≥800,000 IU/mL). Less than 10% of patients had cirrhosis (Lambda, 7.5%; Alfa, 6.8%). Lambda/RBV/TVR did not meet the criterion for noninferiority (lower bound of the treatment difference interval was -12.3%); the SVR12 in all patients (modified intent-to-treat) was 76.2% in the Lambda arm and 82.0% in the Alfa arm. Overall, the frequency of adverse events in each arm was comparable (Lambda, 91.7%; Alfa, 97.1%). As expected based on the safety profile of the 2 interferons, there were more hepatobiliary events observed in the Lambda arm and more hematologic events in the Alfa arm. CONCLUSIONS: In this comparison of Lambda/RBV/TVR and Alfa/RBV/TVR in patients who were treatment-naïve or had relapsed on prior Alfa/RBV treatment, Lambda failed to demonstrate noninferiority based on SVR12 results. Treatment with Lambda/RBV/TVR was associated with a higher incidence of relapse. More patients discontinued Lambda/RBV/TVR treatment during the first 4 weeks of study treatment, mainly due to hepatobiliary-related events, and more Lambda patients were lost to follow-up.