Ombitasvir,paritaprevir, ritonavir,dasabuvir and ribavirin in cirrhosis after complete destruction of hepatocellular carcinoma

We observed a sustained viral response(SVR) of ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin therapy, for 12 wk, in two cases with compensated liver cirrhosis and fully destroyed early hepatocellular carcinoma(HCC). Patients were infected with hepatitis C virus(HCV) genotype 1b and were previous null responders/relapsers to interferon-alpha/ribavirin(IFN/RBV). There was a rapid suppression of HCV RNA to undetectable levels within the first two treatment weeks. SVR was achieved even after marked reduction of the RBV dose. The treatment was well tolerated. Both subjects experienced worsening of liver disease during therapy, in different patterns: severe, transient, predominantly direct hyperbilirubinemia without cytolysis(case 1) or progressive increase of aminotransferases(grade 4) without severe hyperbilirubinemia(case 2).Adverse events spontaneously resolved. The patients remained in a good clinical condition without hepatic decompensation. There was no re-occurrence of HCC. This is the first report for treatment of HCV cirrhosis after complete HCC destruction.     

Ombitasvir/paritaprevir/ritonavir + dasabuvir +/-ribavirin in real world hepatitis C patients

BACKGROUND The hepatitis C virus(HCV) NS5A inhibitor ABT-267(ombitasvir, OBV), the HCV NS4/4A protease inhibitor ABT-450(paritaprevir, PTV), the CYP3A inhibitor ritonavir(r) and the non-nucleoside NS5B polymerase inhibitor ABT-333(dasabuvir, DSV)(OBV/PTV/r + DSV) with or without ribavirin(RBV) is a direct-acting antiviral regimen approved in the United States and other major countries for the treatment of HCV in genotype 1(GT1) infected patients. Patients with HCV who are considered "hard-to-cure" have generally been excluded from registration trials due to rigorous study inclusion criteria, presence of comorbidities and previous treatment failures.AIM To investigate the efficacy of this regimen in HCV G1-infected patients historically excluded from clinical trials.METHODS Patients were ≥ 18 years old and chronically infected with HCV GT1(GT1a, GT1b or GT1a/1b). Patients were treatment-na?ve or previously failed a regimen including pegylated interferon/RBV +/-telaprevir, boceprevir, or simeprevir.One hundred patients were treated with the study drug regimen, which was administered for 12 or 24 wk +/-RBV according to GT1 subtype and presence/absence of cirrhosis. Patients were evaluated every 4 wk from treatment day 1 and at 4 and 12 wk after end-of-treatment.RESULTS Many of the patients studied had comorbidities(44.2% hypertensive, 33.7%obese, 20.2% cirrhotic) and 16% previously failed HCV treatment. Ninety-six patients completed study follow-up and 99% achieved 12-wk sustained virologic response. The majority(88.4%) of patients had undetectable HCV RNA by week 4. The most common adverse events were fatigue(12%), headache(10%),insomnia(9%) and diarrhea(8%); none led to treatment discontinuation. Physical and mental patient reported outcomes scores significantly improved after treatment. Almost all(98%) patients were treatment compliant.CONCLUSION In an all-comers HCV GT1 population, 12 or 24-wk of OBV/PTV/r + DSV +/-RBV is highly effective and tolerable and results in better mental and physical health following treatment.     

3D方案治疗基因1b型低病毒载量慢性丙型肝炎患者应答疗效研究

目的 观察3D方案(帕里瑞韦/利托那韦/奥比他韦)联合达塞布韦治疗基因1b型低血清病毒载量的慢性丙型肝炎(CHC)患者的疗效及其血浆γ-干扰素(IFN-γ)和干扰素诱导蛋白10(IP-10)水平的变化.方法 2019年5月～2020年5月在我院接受治疗的基因1b型低血清病毒载量的CHC患者77例(初始治疗者62例,复治...     

All-oral interferon-free treatments:The end of hepatitis C virus story,the dream and the reality

The year 2014 marked the beginning of the end of the interferon era and the triumph of the all-oral interferon-free regimens for treatment of hepatitis C virus(HCV) infection. These innovative therapies are safe and yield a cure rate of over 90%. The scientifichepatology community is euphoric about the possibility of elimination and even eradication of HCV infection. However,the current high cost of the new all-oral regimens allows access to treatment only for a restricted number of HCV-infected patients. In addition,many other conditions such as modality of access and delivery of care,inadequate knowledge of HCV epidemiology and political commitments to be undertaken,hamper the fulfillment of the dream to eliminate the virus. Since,such conditions are not impossible to overcome,a global urgent effort must be made to allow a widespread access to the new treatments which will permit in the next years to avoid million of HCV-related deaths.     

Potential CYP2C9‐mediated drug–drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide,glimepiride or glipizide

Abstract. Tirkkonen T, Heikkilä P, Huupponen R, Laine K (University of Turku; Turku University Hospital; and StatFinn Ltd; Turku, Finland). Potential CYP2C9‐mediated drug–drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide, glimepiride or glipizide. J Intern Med 2010; 268 : 359–366. Objectives. Sulphonylureas are widely used in the treatment of type 2 diabetes mellitus (T2DM). Based on laboratory findings, we determined the clinical significance of potential CYP2C9‐mediated drug–drug interactions in hospitalized patients receiving glibenclamide, glimepiride or glipizide, all of which are metabolized by CYP2C9, together with a CYP2C9 inhibitor. Design, setting and subjects. An observational pharmaco‐epidemiological database study was performed in a university hospital setting with 3884 patients with T2DM. Main outcome measures. Efficacy and safety of sulphonylurea therapy during the potential interaction (sulphonylurea treatment with a CYP2C9 inhibitor) vs. control periods (sulphonylurea treatment without a CYP2C9 inhibitor) were estimated using laboratory parameters. Results. Almost 20% of patients were exposed to a potential drug–drug interaction with a CYP2C9 inhibitor during sulphonylurea treatment. More than 75% of the potential interactions occurred with trimethoprim, metronidazole and fluconazole. When all sulphonylureas were pooled and adjusted for age, gender, ward and sulphonylurea dose, mean and maximum fasting plasma glucose concentrations as well as maximum values of glycosylated haemoglobin were significantly lower during the interaction periods compared with control periods, whereas mean and minimum activities of alanine amino transferase and gamma‐glutamyl transferase were higher. The minimum fasting plasma glucose values were more often below the target range in patients with potential interactions. The sulphonylurea dose did not differ significantly between patients who were or were not concomitantly treated with a potentially interacting drug. Conclusions. Concomitant use of a CYP2C9 inhibitor results in exaggerated pharmacodynamic effects of sulphonylureas and increases the risk of hypoglycaemia in T2DM patients receiving glibenclamide, glimepiride or glipizide.     

Analysis of drug-drug interactions (DDIs) in nursing homes in Central Taiwan

With the progressive aging of the population, the long-term nursing care and drug safety for the elderly are gradually gaining attention. In Taiwan, nursing homes are the main institutes helping society or families take care of elderly people suffering from diseases. The aim of this study was to assess the prescribed medications of nursing home residents, the occurrence of DDIs and the association between the number of drugs and DDIs with a view to reinforce drug safety for the elderly. The findings of this study showed that the mean number of medications per resident was 5.74+/-2.4. Of the 323 samples, 81 (25.1%) had experienced DDIs, 63 (64.95%) were of moderate and 7 (7.2%) of major severity. The findings also showed that the number of potential DDIs increased as the number of medications used per residents increased. The residents with nine or more medications tended to have more DDIs, in comparison to those with one or two medications. The odds ratio (OR) was 11.389, which had reached statistical significance in difference. Therefore, to reduce potential DDIs, the number of medications for the senior people with chronic diseases should be properly controlled.     

Prevalence of drug-drug interactions at hospital entry and during hospital stay of patients in internal medicine

OBJECTIVE: The aim of this study was to assess potential drug-drug interactions (pDDIs) at hospital admission, during hospitalization and at discharge and to evaluate the number of pDDIs created during hospitalization. METHODS: The medication of 851 patients was screened for pDDIs (major and moderate severity) using the screening program Pharmavista. The frequency of pDDIs per patient, per number of drugs and drug pairs was estimated. RESULTS: During hospitalization, the frequency of major and moderate pDDIs per patient was 1.11, which was higher compared to hospital admission (0.59) or to hospital discharge (0.60). The frequency of major and moderate pDDIs per drug prescribed (13.7% vs. 9.1%) or per drug pairs analyzed (4.5% vs. 2.3%) was higher at hospital admission compared to hospital discharge. 47% of all major and moderate pDDIs at discharge were due to a medication change during hospitalization. CONCLUSIONS: Although the number of major and moderate pDDIs per patient did not increase from hospital admission to discharge, it is important to realize that 47% of all major and moderate DDIs at hospital discharge were created during hospitalization. Prescribing drugs with a low risk for pDDIs as well as careful monitoring for adverse drug reactions are important measures to minimize harm associated with DDIs.     

Effects of Laropiprant,a Selective Prostaglandin D2 Receptor 1 Antagonist,on the Pharmacokinetics of Rosiglitazone

Laropiprant (LRPT), a prostaglandin D₂ receptor‐1 antagonist shown to reduce niacin‐induced flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open‐label, randomized, 2‐period crossover study assessed the pharmacokinetics of single‐dose rosiglitazone in the presence and absence of multiple‐dose LRPT. Twelve healthy male and female subjects, 34–64 years of age, received two, once‐daily oral treatments in random sequence separated by ≥3‐day washout: (1) multiple‐dose LRPT 40 mg/day for 7 days (Days 1 to 7) coadministered with single‐dose rosiglitazone 4 mg on Day 6; (2) single‐dose rosiglitazone 4 mg on Day 1. Comparability was declared because the 90% confidence interval (CI) for the AUC_0‐∞ geometric mean ratio (GMR; rosiglitazone + LRPT/rosiglitazone alone) [0.92 (0.86, 0.99)], was contained within prespecified bounds (0.70, 1.43). The C_max GMR (90% CI) for rosiglitazone was 0.98 (0.95, 1.02). There was no evidence of clinically meaningful alterations in the pharmacokinetics of rosiglitazone, a probe CYP2C8 substrate, following coadministration of multiple‐dose LRPT in healthy subjects. Therefore, findings suggest that LRPT does not inhibit CYP2C8‐mediated metabolism.     

Life‐threatening drug interactions: what the physician needs to know

Adverse drug–drug interactions are a significant cause of adverse events and outcomes. Their incidence is rising, with more patients taking more drugs, and newer, more precise but often more hazardous drugs becoming available. Despite considerable information, including computerised alerts about potential adverse drug–drug interactions, prescribers increasingly override alerts, possibly symptomatic of the immense problem of evaluating the risk of an interaction in a particular patient. Many reports emanate from small studies often of normal and young volunteers, entirely different from the real world where, more often, older patients with multiple health conditions are receiving many more than the two drugs identified in the drug interaction report. Focusing on those drug–drug interactions that are clinically relevant is necessary, and increasingly, tools and reliable sources of this information are easily accessible.     

The optimal dose of ribavirin for chronic hepatitis C: From literature evidence to clinical practice: The optimal dose of ribavirin for chronic hepatitis C

Approximately 170 million people worldwide are chronically infected by hepatitis C virus (HCV), which can result in progressive hepatic injury and fibrosis, culminating in cirrhosis and end-stage liver disease. The benchmark therapy for untreated HCV patients is a combination of pegylated interferon-alpha (PEG-IFN) and ribavirin (RBV). Several studies have suggested several potential new approaches to improve HCV therapy-optimization of the dose and duration of RBV therapy, accompanied by careful clinical management, is crucial in ensuring the greatest likelihood of a long response to therapy. RBV causes serious side effects, but in clinical practice, there are no alternatives for the treatment of HCV infection. Based on our results, weight-based doses of RBV are advantageous for genotype 1-infected patients, but its success in genotype 2- and 3-infected patients is unknown, particularly for shorter treatment durations.     

Potential food‐drug interactions in patients with rheumatoid arthritis

Various medications are used for the treatment of rheumatoid arthritis (RA). Food–drug interactions may occur with concomitant ingestion of particular food. For example, methotrexate (MTX), the anchor drug in the therapeutic strategy against RA, is an antifolate agent. Excessive presence or absence of dietary folic acid may regulate MTX metabolism, possibly leading to unexpected adverse reactions. In this review, we focus on MTX, isoniazide and calcineurin inhibitors, and the implications of potential food–drug reactions in rheumatology, suggesting the important role of nutritional evaluations in RA patients.     

Similarities,differences, and possible interactions between hepatitis E and hepatitis C viruses: Relevance for research and clinical practice

Hepatitis E virus (HEV) and hepatitis C virus (HCV) are both RNA viruses with a tropism for liver parenchyma but are also capable of extrahepatic manifestations. Hepatitis E is usually a viral acute fecal-oral transmitted and self-limiting disease presenting with malaise, jaundice, nausea and vomiting. Rarely, HEV causes a chronic infection in immunocompromised persons and severe fulminant hepatitis in pregnant women. Parenteral HCV infection is typically asymptomatic for decades until chronic complications, such as cirrhosis and cancer, occur. Despite being two very different viruses in terms of phylogenetic and clinical presentations, HEV and HCV show many similarities regarding possible transmission through organ transplantation and blood transfusion, pathogenesis (production of antinuclear antibodies and cryoglobulins) and response to treatment with some direct-acting antiviral drugs. Although both HEV and HCV are well studied individually, there is a lack of knowledge about coinfection and its consequences. The aim of this review is to analyze current literature by evaluating original articles and case reports and to hypothesize some interactions that can be useful for research and clinical practice.     

Effectiveness and safety of ombitasvir,paritaprevir, ritonavir ± dasabuvir ± ribavirin: An early access programme for Spanish patients with genotype 1/4 chronic hepatitis C virus infection

Over the last 5 years, therapies for hepatitis C virus (HCV) infection have improved significantly, achieving sustained virologic response (SVR) rates of up to 100% in clinical trials in patients with HCV genotype 1. We investigated the effectiveness and safety of ombitasvir/paritaprevir/ritonavir±dasabuvir in an early access programme. This was a retrospective, multicentre, national study that included 291 treatment‐naïve and treatment‐experienced patients with genotype 1 or 4 HCV infection. Most patients (65.3%) were male, and the mean age was 57.5 years. The mean baseline viral load was 6.1 log, 69.8% had HCV 1b genotype, 72.9% had cirrhosis and 34.7% were treatment‐naïve. SVR at 12 weeks posttreatment was 96.2%. Four patients had virological failure (1.4%), one leading to discontinuation. There were no statistical differences in virological response according to genotype or liver fibrosis. Thirty patients experienced serious adverse events (SAEs) (10.3%), leading to discontinuation in six cases. Hepatic decompensation was observed in five patients. Four patients died during treatment or follow‐up, three of them directly related to liver failure. Multivariate analyses showed a decreased probability of achieving SVR associated with baseline albumin, bilirubin and Child‐Pugh score B, and a greater probability of developing SAEs related to age and albumin. This combined therapy was highly effective in clinical practice with an acceptable safety profile and low rates of treatment discontinuation.     

Real‐world safety and effectiveness of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin in hepatitis C virus genotype 1‐ and 4‐infected patients with diverse comorbidities and comedications: A pooled analysis of post‐marketing observational studies from 13 countries

Ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) regimens show high efficacy and good tolerability in clinical trials for chronic hepatitis C virus (HCV) genotypes (GT) 1 or 4. To evaluate whether these results translate to clinical practice, data were pooled from observational studies across 13 countries. Treatment‐naïve or ‐experienced patients, with or without cirrhosis, received OBV/PTV/r ± DSV ± RBV according to approved local labels and clinical practice. Sustained virologic response at post‐treatment Week 12 (SVR12), adverse events (AEs) and comedication management were assessed for patients initiating treatment before 1 June 2017. The safety population included 3850 patients who received ≥1 dose of study drug. The core population (N = 3808) further excluded patients with unknown GT or cirrhosis status, or who received off‐label treatment. Patients had HCV GT1a (n = 732; 19%), GT1b (n = 2619; 69%) or GT4 (n = 457; 12%). In 3546 patients with sufficient follow‐up data at post‐treatment Week 12, the SVR12 rate was 96% (n/N = 3401/3546 [95% CI 95.2‐96.5]). In patients with or without cirrhosis, SVR12 was comparable (96%). In patients with HCV GT1a, GT1b or GT4, SVR12 rates were 93%, 97% and 94%. In GT1b‐infected patients with planned treatment for 8 weeks, SVR12 was 96%. In patients with ≥1 comorbidity (67%), SVR12 was 95%. 58% of patients received ≥1 comedication, and there was minimal impact on SVR12 rates using comedications for peptic ulcers and gastro‐esophageal reflux disease, statins, antipsychotics or antiepileptics. Most comedications were maintained during treatment although 58% of patients changed their statin medication. AEs and serious AEs occurred in 26% and 3% of patients. Post‐baseline Grade 3‐4 laboratory abnormalities were rare (<3%), and discontinuation rates were low (<4%). Real‐world evidence confirms the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with HCV GT1 or GT4, regardless of common comorbidities or comedications, and is consistent with clinical trial results. Adverse safety outcomes may be limited by underreporting in the real‐world setting.