Simeprevir in combination with sofosbuvir in treatment-naïve and -experienced patients with hepatitis C virus genotype 4 infection: a Phase III, open-label, single-arm study (PLUTO).

BACKGROUND: Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and subsequent hepatocellular carcinoma. HCV genotype 4 is found widely in the Middle East, Egypt and Africa, and has also spread into Europe. There are limited data available regarding the use of direct-acting antiviral agents in HCV genotype 4-infected patients with cirrhosis. AIM: To evaluate in the phase III, open-label, single-arm PLUTO study the efficacy and safety of 12 weeks of simeprevir (HCV NS3/4A protease inhibitor) plus sofosbuvir (HCV nucleotide-analogue NS5B polymerase inhibitor) in treatment-naïve and (peg)interferon ± ribavirin-experienced HCV genotype 4-infected patients, with or without compensated cirrhosis. METHODS: Adult patients with chronic HCV genotype 4 infection received simeprevir 150 mg once-daily and sofosbuvir 400 mg once-daily for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety was also assessed. RESULTS: Forty patients received treatment; the majority were male (73%) and treatment-experienced (68%). Overall, 7/40 (18%) patients had compensated cirrhosis. All patients achieved SVR12 [100% (Clopper-Pearson 95% confidence interval: 91-100%)]. Adverse events, all Grade 1 or 2, were reported in 20/40 (50%) patients. No serious adverse events were reported and no patients discontinued study treatment. Grade 3 treatment-emergent laboratory abnormalities were noted in 2/40 (5%) patients. CONCLUSIONS: Treatment with simeprevir plus sofosbuvir for 12 weeks resulted in SVR12 rates of 100% in treatment-naïve and -experienced patients with HCV genotype 4 infection with or without compensated cirrhosis, and was well tolerated. [NCT02250807].

The effects of hydrogen peroxide on DNA repair activities.

Oxygen free radicals generated by H2O2 are involved in the multistage carcinogenic process; mechanisms include carcinogen activation, oxidative DNA damage, and tumor promotion. In this study, we have evaluated another potential mechanism of H2O2 in carcinogenesis--modulation of DNA repair activities. Preexposure of human peripheral mononuclear leukocytes to H2O2 significantly inhibited DNA repair activities in response to damage induced by N-methyl-N'-nitro-N-nitrosoguanidine, measured as unscheduled DNA synthesis. The responses to H2O2 were compared in four healthy human subjects with two sample preparations on different days. Results from multivariate general linear models showed that H2O2 significantly inhibited DNA repair in a dose-dependent manner after adjustment for between- and within-subject variabilities. There was an estimate of 5.0 units (dpm/5 x 10(5) cells) decrease in induced unscheduled DNA synthesis per unit (microM) increase of H2O2 treatment. Furthermore, there was substantial variability in DNA repair activities for the same individual sampled on different days regardless of H2O2 dose level. Results from this study suggest that H2O2 not only can induce DNA damage, but also have suppressive effects on DNA repair.

A review of quality evaluation systems for mental health services.

Mental health quality of care evaluation systems found in an extensive search are reviewed. The quality measures are differentiated from other seemingly similar types of scales and instruments. The quality systems are reviewed in reference to 1) reliability and validity of data, type, and source of data, allowance for patient variables, standards of quality, and other parameters and 2) range and comprehensiveness, particularly with regard to coverage of the range of disorders and conditions, of age groups, care needs, care settings, treatment modalities, and of types of provider performance. Most measures were reliable and valid. Some gave consideration to patient variables and case mix, to timing, and to treatment intensity. There were no measures of providers' interpersonal performance. With regard to range and comprehensiveness, there was a substantial imbalance toward the medical model and pharmacotherapy and away from systems orientation, from psychotherapy, and from other modalities, interventions, and types of programs.