Sofosbuvir with peginterferon-ribavirin for 12 weeks in previously treated patients with hepatitis C genotype 2 or 3 and cirrhosis.

UNLABELLED: Sofosbuvir (SOF) in combination with ribavirin (RBV) for 12 or 24 weeks is the current standard of care for patients infected with hepatitis C virus (HCV) genotypes 2 and 3, respectively. However, in clinical trials treatment-experienced patients, particularly those with cirrhosis, had suboptimal sustained virological response (SVR) rates. We assessed the efficacy and safety of sofosbuvir plus peginterferon and ribavirin (SOF+Peg-IFN+RBV) administered for 12 weeks to treatment-experienced patients with HCV genotypes 2 and 3, with and without cirrhosis. We enrolled 47 patients in this open-label, nonrandomized, uncontrolled phase 2 study. The primary endpoint was the proportion of patients with SVR at 12 weeks after cessation of study treatment (SVR12). The overall rate of SVR12 was 89% (95% confidence interval [CI]: 77-97). Rates of SVR12 were higher in patients with genotype 2 than in those with genotype 3, 96% (95% CI: 78-100) and 83% (95% CI: 62-95), respectively. Rates of SVR12 were similar in patients with and without cirrhosis: for genotype 2, 93% of patients with cirrhosis and 100% of patients without cirrhosis achieved SVR12, and for genotype 3, the SVR12 rate was 83% in patients both with and without cirrhosis. One patient discontinued study treatment because of an adverse event and four patients experienced serious adverse events. The most common adverse events were influenza-like illness, fatigue, anemia, and neutropenia. CONCLUSION: In treatment-experienced patients with HCV genotypes 2 and 3, 12-week administration of SOF+Peg-IFN+RBV provided high SVR rates, irrespective of cirrhosis status. No safety concerns were identified.

Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial.

BACKGROUND: The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. METHODS: For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800,000 IU/mL vs ≥800,000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978. RESULTS: We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug--anaemia and neutropenia--were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event. INTERPRETATION: Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. FUNDING: Gilead Sciences.

Considerations for age estimation accuracy: Method-derived outcomes and practitioner interpretations.

Recent research observed 92% accuracy for age-at-death estimations by U.S. forensic anthropologists. The present study compares this case report level accuracy to method level accuracy for the most commonly used methods in U.S. casework, drawing from the Forensic Anthropology Database for Assessing Methods Accuracy (FADAMA). Method application rate (i.e., how often a method is used in casework) was analyzed for n = 641 cases and identified 15 methods with an application rate >45 cases, and the present study focused further analyses on these 15 methods. Of the 15, only four yielded accuracies greater than or equal to the 92% documented for case-report level accuracy. The other 11 methods produced accuracy rates ranging from 54% to 91%, with six of these below 70% This disconnect between highly accurate age estimations at the case report level compared to the poor performance at method level suggests that practitioner interpretation and synthesis of the methods' outcomes is a critical step for increasing the accuracy rates of the age estimations as reported on the final case report. This inference was further supported by the study's results which indicated that practitioner interpretations of frequently used method combinations improve accuracy and age range width of age estimation. The study also performed a Fisher's Exact test to assess whether case report-level accuracy differed with the number of aging methods used in a case, and found no significant differences.

A phase 2B study of MK-7009 (vaniprevir) in patients with genotype 1 HCV infection who have failed previous pegylated interferon and ribavirin treatment.

BACKGROUND & AIMS: MK-7009 (vaniprevir) is a non-covalent competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease. This report presents the primary analysis results (safety and sustained viral response) of a phase 2b study of MK-7009 given in combination with peginterferon (PegIFN) alfa2a 180 µg weekly and ribavirin (RBV) 1000-1200 mg/day, for 24-48 weeks to non-cirrhotic patients who have failed previous PegIFN and RBV treatment. METHODS: We present results of a randomized, placebo-controlled, double-blind study of MK-7009 administered for 24-48 weeks in combination with PegIFN and RBV in 4 regimens to at least 40 patients per arm. Stratification by prior response to PegIFN and RBV was as follows: null response, partial response, breakthrough and relapse. HCV RNA was determined by Roche Cobas Taqman with a lower limit of detection (LLoD) of 10 IU/ml and a lower limit of quantification (LLoQ) of 25 IU/ml. RESULTS: SVR24 in patients on MK-7009+PegIFN and ribavirin (P/R) was statistically superior to placebo+P/R in all treatment groups (p<0.001). MK-7009 at 300 mg b.i.d. and 600 mg b.i.d. is generally well tolerated for use for up to 48 weeks of therapy. Patients in MK-7009 regimens had higher rates of gastrointestinal adverse events as compared to control (mostly mild to moderate). There were no significant differences in rates of anemia and rash between the MK-7009 regimens and control. CONCLUSIONS: In conclusion, patients treated with MK-7009 plus P/R experienced significant improvement in SVR compared to P/R control in a population of GT 1 experienced patients.

Detection and evaluation of microbeads and other microplastics in wastewater treatment plant samples.

Microplastics (MPs) are ubiquitously spread in water environment and have raised global concerns due to their adverse effect to biological and ecological systems. Wastewater treatment plants have been reported to be an important route of releasing MPs into the environment. As a great source of MPs in number in wastewater, the characteristics of microbeads have hardly been studied. In this study, the variation of the characteristics of microbeads prior to and after incubating in wastewater samples has been identified. Reported digestion methods of acid, alkaline, enzymatic, and wet preoxidation digestion were subsequently applied to assess their efficacy for digesting microbeads from the wastewater, and enzymatic digestion has shown the optimal efficacy. Finally, enzymatic digestion was applied to evaluate microbeads and other MPs in real wastewater treatment plant samples. It is shown that the sequential treatment of fine screen, grit chamber, and improved sequencing batch reactor activated sludge processes were able to remove 72% pellets in number and 43% MPs in total, while a large portion was still remaining after the secondary treatment. This study set a base for understanding the characteristics and occurrence of MPs, especially microbeads in wastewater samples.

Diffusion Performance of Fertilizer Nutrient through Polymer Latex Film.

Matching the nutrient release rate of coated fertilizer with the nutrient uptake rate of the crop is the best way to increase the utilization efficiency of nutrients and reduce environmental pollution from the fertilizer. The diffusion property and mechanism of nutrients through the film are the theoretical basis for the product pattern design of coated fertilizers. For the coated fertilizer with a single-component nutrient, an extended solution-diffusion model was used to describe the difference of nutrient release rate, and the release rate is proportional to the permeation coefficient and the solubility of the nutrient. For the double- and triple-component fertilizer of N-K, N-P, and N-P-K, because of the interaction among nutrient molecules and ions, the release rates of different nutrients were significantly affected by the components in the composite fertilizer. Coating the single-component fertilizer (i.e., nitrogen fertilizer, phosphate fertilizer, and potash fertilizer) first and subsequently bulk blending is expected to be a promising way to adjust flexibly the nutrient release rate to meet the nutrient uptake rate of the crop.