Sustained virological response with intravenous silibinin: individualized IFN-free therapy via real-time modelling of HCV kinetics.

BACKGROUND & AIMS: Intravenous silibinin (SIL) is a potent antiviral agent against hepatitis C virus (HCV) genotype-1. In this proof of concept case-study we tested: (i) whether interferon-alfa (IFN)-free treatment with SIL plus ribavirin (RBV) can achieve sustained virological response (SVR); (ii) whether SIL is safe and feasible for prolonged duration of treatment and (iii) whether mathematical modelling of early on-treatment HCV kinetics can guide duration of therapy to achieve SVR. METHODS: A 44 year-old female HCV-(genotype-1)-infected patient who developed severe psychiatric adverse events to a previous course of pegIFN+RBV, initiated combination treatment with 1200 mg/day of SIL, 1200 mg/day of RBV and 6000 u/day vitamin D. Blood samples were collected frequently till week 4, thereafter every 1-12 weeks until the end of therapy. The standard biphasic mathematical model with time-varying SIL effectiveness was used to predict the duration of therapy to achieve SVR. RESULTS: Based on modelling the observed viral kinetics during the first 3 weeks of treatment, SVR was predicted to be achieved within 34 weeks of therapy. Provided with this information, the patient agreed to complete 34 weeks of treatment. IFN-free treatment with SIL+RBV was feasible, safe and achieved SVR (week-33). CONCLUSIONS: We report, for the first time, the use of real-time mathematical modelling of HCV kinetics to individualize duration of IFN-free therapy and to empower a patient to participate in shared decision making regarding length of treatment. SIL-based individualized therapy provides a treatment option for patients who do not respond to or cannot receive other HCV agents and should be further validated.

Correction: Modeling suggests that microliter volumes of contaminated blood caused an outbreak of hepatitis C during computerized tomography.

[This corrects the article DOI: 10.1371/journal.pone.0210173.].

Modeling suggests that microliter volumes of contaminated blood caused an outbreak of hepatitis C during computerized tomography.

BACKGROUND & AIMS: Acute hepatitis C (AHC) is not frequently identified because patients are usually asymptomatic, although may be recognized after iatrogenic exposures such as needle stick injuries, medical injection, and acupuncture. We describe an outbreak of AHC among 12 patients who received IV saline flush from a single multi-dose vial after intravenous contrast administration for a computerized tomography (CT) scan. The last patient to receive IV contrast with saline flush from a multi-dose vial at the clinic on the previous day was known to have chronic HCV genotype 1b (termed potential source, PS). Here we sought to confirm (via genetic analysis) the source of infection and to predict the minimal contaminating level of IV saline flush needed to transmit infectious virus to all patients. METHODS: In order to confirm the source of infection, we sequenced the HCV E1E2 region in 7 CT patients, in PS, and in 2 control samples from unrelated patients also infected with HCV genotype 1b. A transmission probabilistic model was developed to predict the contamination volume of blood that would have been sufficient to transmit infectious virus to all patients. RESULTS: Viral sequencing showed close clustering of the cases with the PS. The transmission probabilistic model predicted that contamination of the multi-dose saline vial with 0.6-8.7 microliters of blood would have been sufficient to transmit infectious virus to all patients. CONCLUSION: Analysis of this unique cohort provides a new understanding of HCV transmission with respect to contaminating volumes and viral titers.

A novel purgative protocol for capsule endoscopy of the small bowel produces better quality of visibility than 2 l of PEG: Timing is of the essence.

INTRODUCTION: The ideal way of preparing patients for small-bowel capsule endoscopy has been controversial. Previous studies have shown that ingestion of 2 l of polyethylenglycol (PEG) 12 hours prior to capsule ingestion leads to improved visibility in comparison to no preparation at all. We speculated that using a post-ingestion (PI), booster-based cleansing protocol might provide an alternative to the PEG cleansing protocol. METHODS: This randomized, blinded, prospective study enrolled 45 individuals. Patients were allocated to either of two groups. The PEG group ingested 2 l PEG 12 hours prior to the exam (n = 22) and the PI group ingested one sachet of Picolax® dissolved in 250 ml of water one hour after swallowing the capsule with 500 ml of water (n = 18). Primary endpoints were overall small bowel and distal third of small bowel cleansing levels. Secondary endpoints were average gastric and small-bowel transit time. RESULTS: Forty-five patients participated in this study. Five individuals were excluded because of incomplete study. Percentage of patients with adequate visibility in the distal third of the small bowel in the PEG group was 9% vs 72% in the PI group (p < 0.0001). Average gastric time and total transit time were shorter in the PI group vs the PEG group (p = 0.0065). CONCLUSION: Timing of ingestion of the Picolax® purgative 60 minutes after swallowing the capsule endoscopy delivers better visibility in the distal third of the small bowel than the accepted cleansing protocol of ingesting 2 l PEG 12 hours prior to the capsule endoscopy procedure.

HCV genotype-1 subtypes and resistance-associated substitutions in drug-naive and in direct-acting antiviral treatment failure patients.

BACKGROUND: Direct-acting antiviral (DAA) treatment regimens and response rates of patients with HCV genotype-1 (GT1) are currently considered subtype-dependent. Identification of clinically relevant resistance-associated substitutions (RASs) in the NS3 and NS5A proteins at baseline and in DAA failures, may also impact clinical decisions. METHODS: In a multicentre cohort study (n=308), NS3 or NS5B sequencing (n=248) was used to discriminate between GT1 subtypes. The correlation between baseline NS3 and NS5A RASs on the 12-week sustained virological response (SVR12) rates of 160 of the patients treated with second-generation DAAs was also assessed. Post-treatment resistance analysis was performed on samples from 58 patients exhibiting DAA virological failure. RESULTS: GT1a, GT1b and GT1d subtypes were identified in 23.0%, 75.4% and 1.2% of tested samples. GT1b was most prevalent (97.7%, 128/131) among patients born in the former Soviet Union. The Q80K NS3 RAS was identified in 17.5% (10/57) of the GT1a carriers, most of whom were Israeli-born. NS3 and NS5A baseline RASs showed a negligible correlation with SVR12 rates. Treatment-emergent RASs were observed among 8.9% (4/45) and 76.9% (10/13) of first- and second-generation DAA failures, respectively, with D168V/E (NS3), Y93H and L31M (NS5A) being the most prevalent mutations. CONCLUSIONS: NS3 sequencing analysis can successfully discriminate between GT1 subtypes and identify NS3 amino acid substitutions. While pre-treatment NS3 and NS5A RASs marginally affect second-generation DAA SVR12 rates, post-treatment resistance analysis should be considered prior to re-therapy.

Hepatitis C virus cures after direct acting antiviral-related drug-induced liver injury: Case report.

The United States Food and Drug Administration recently warned that the direct acting antiviral (DAA) combination hepatitis C virus (HCV) treatment of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin (PODr + R) can cause severe liver injury in patients with advanced liver disease. Drug induced liver injury was observed in a small number of patients with decompensated cirrhosis treated with other DAAs, but has not been reported in patients with compensated cirrhosis. We report a case of a 74-year-old woman with chronic HCV and Child-Pugh class A cirrhosis (compensated cirrhosis) treated with PODr + R. The patient presented on day 14 of PODr + R therapy with jaundice and new-onset ascites. Her total bilirubin level increased to 23 mg/dL and international normalized ratio rose to 1.65, while aminotransferase levels remained relatively stable. Hepatitis C treatment was discontinued on day 24 and she gradually recovered. Follow-up testing showed that she achieved a sustained virologic response. In conclusion, hepatic decompensation developed within two weeks of starting treatment with PODr + R in a patient with Child-Pugh class A cirrhosis and was characterized by jaundice and ascites with stable aminotransferase levels. Careful monitoring is warranted in patients with HCV-related cirrhosis treated with PODr + R.