Impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes of liver disease

Chronic infections with the hepatitis B and C viruses have significant worldwide health and economic impacts. Previous treatments for hepatitis C such as interferon and ribavirin therapy were ineffective and poorly tolerated by patients. The introduction of directly acting curative antiviral therapy for hepatitis C and the wider use of nucleos(t)ide analogues for suppression of chronic Hepatitis B infection have resulted in many positive developments. Decreasing the prevalence of hepatitis B and C have concurrently reduced transmission rates and hence, the number of new infections. Antiviral treatments have decreased the rates of liver decompensation and as a result, lowered hospitalisation and mortality rates for both chronic hepatitis B and C infection. The quality of life of chronically infected patients has also been improved significantly by modern treatment. Antiviral therapy has stopped the progression of liver disease to cirrhosis in certain patient cohorts and prevented ongoing hepatocellular damage in patients with existing cirrhosis. Longer term benefits of antiviral therapy include a reduced risk of developing hepatocellular carcinoma and decreased number of patients requiring liver transplantation. This review article assesses the literature and summarises the impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes from liver disease.     

Influence of atazanavir 200 mg on the intracellular and plasma pharmacokinetics of saquinavir and ritonavir 1600/100 mg administered once daily in HIV-infected patients

OBJECTIVES: To examine cellular and plasma concentrations of atazanavir when given in combination with saquinavir/ritonavir in HIV+ patients. METHODS: Twelve HIV+ patients were receiving saquinavir/atazanavir/ritonavir 1600/200/100 mg once daily and venous blood samples were taken to determine cellular and plasma concentrations of each protease inhibitor at 2, 6, 12 and 24 h. Peripheral blood mononuclear cells were separated by density gradient centrifugation. The ratio of the cellular AUC0-24/plasma AUC0-24 was calculated to determine cellular drug accumulation. Lymphocyte P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated protein (MRP1) expression was determined by flow cytometry. Nine of the patients had previously received a regimen of saquinavir/ritonavir 1600/100 mg; therefore the effect of atazanavir on the cellular and plasma pharmacokinetics of saquinavir and ritonavir was examined. RESULTS: In vivo cellular and plasma determinations of saquinavir, atazanavir and ritonavir gave accumulation ratios of 4.9, 1.2 and 1.7, respectively. There was no relationship between saquinavir, atazanavir or ritonavir accumulation and P-gp, MRP1 or BCRP expression. When comparing pharmacokinetic values in the nine patients receiving saquinavir/ritonavir with and without atazanavir, the median cellular saquinavir AUC0-24 was significantly increased (34.9-117.2 mg.h/L) on addition of atazanavir (P=0.004). The C24 of saquinavir in plasma and cells was significantly higher with atazanavir (plasma C24 0.05 versus 0.14 mg/L with atazanavir; cellular C24 0.61 versus 2.03 mg/L with atazanavir, P=0.02). CONCLUSIONS: The mechanism of differential intracellular protease inhibitor accumulation is unclear. Co-administration of atazanavir caused an increase in both the plasma and cellular exposure (AUC0-24) and C24 of saquinavir but not ritonavir.     

Continuous template collection and updating for electrogram morphology discrimination in implantable cardioverter defibrillators

INTRODUCTION: Electrogram morphology analysis improves discrimination of supraventricular tachycardias (SVTs) from ventricular tachycardias (VTs) in implantable cardioverter defibrillators (ICDs), but electrogram morphology may change with lead maturation, drugs, or disease progression. We report the clinical performance of an automatic algorithm that creates and updates templates from non-paced, slow rhythm and continuously checks the quality of the template used for arrhythmia discrimination. METHODS AND RESULTS: We studied this algorithm in 193 patients with single-chamber ICDs (Marquis VR, Medtronic Inc., Minneapolis, MN, USA). Of the 112 patients who completed 6-month follow-up, 99.1% of the patients had > or =1 automatic template created. Match scores between template and ongoing rhythm are computed using Haar Wavelets. Of the 435 automatic templates evaluated at follow-up, 423 (97.2%) had a median match score > or =70%. Intrinsic rhythm at 1 month had significantly higher match scores (P < 0.001) with automatic templates (90.3 +/- 7.0%) than with manual templates (85.7 +/- 10.9%) generated at pre-hospital discharge (PHD). The percentage of appropriately rejected SVTs was slightly higher with the automatic template (280/339 episodes) than with the manual template at PHD (272/339 episodes) while the Wavelet detection of VT was the same (218/220 episodes). CONCLUSIONS: In patients receiving ICDs, the automatic templates were successfully created during a 6-month follow-up period, and consistently matched the patients' intrinsic rhythm at the nominal match threshold. Both early (<1 month postimplant) and late (1- to 3-month follow-up period) changes in electrogram morphology were identified, confirming the need for automatic template updating.     

Ropinirole in the treatment of patients with restless legs syndrome: a US-based randomized, double-blind, placebo-controlled clinical trial

OBJECTIVE: To assess the efficacy, safety, and tolerability of the dopamine agonist ropinirole in the treatment of patients with moderate to severe primary restless legs syndrome (RLS). PATIENTS AND METHODS: This multicenter, 12-week, double-blind, placebo-controlled, flexible-dose study enrolled US patients and was conducted between September 2003 and May 2004. Patients were randomized to ropinirole or placebo, 0.25-4.0 mg as needed and tolerated, once daily, 1 to 3 hours before bedtime. The primary end point was mean change from baseline to week 12 in International Restless Legs Scale (IRLS) total score. Key secondary efficacy measures included the Clinical Global Impression-Improvement scale. RESULTS: A total of 381 patients were enrolled; 164 (87.7%) of 187 patients randomized to ropinirole and 167 (86.1%) of 194 randomized to placebo completed the study. Significant treatment differences favoring ropinirole, compared with placebo, were observed for change in IRLS total score at week 12 (adjusted mean treatment difference, -3.7; 95% confidence interval, -5.4 to -2.0; P < .001) and for all 3 key secondary end points: mean change from baseline in IRLS total score at week 1 and proportion of patients who were much/very much improved on the Clinical Global Impression Improvement scale at weeks 1 and 12. Ropinirole was associated with significantly greater Improvements in subjective measures of sleep disturbance, quantity, and adequacy; quality of life; and anxiety. Although treatment differences favoring ropinirole in daytime somnolence were observed, they were not statistically significant (P = .10). Ropinirole was generally well tolerated, with an adverse-event profile consistent with other dopamine agonists. CONCLUSION: This study confirms that ropinirole improves RLS symptoms and subjective measures of sleep, quality of life, and anxiety and that it is generally well tolerated.     

Radiotherapy Quality Assurance for the CHHiP Trial: Conventional Versus Hypofractionated High-Dose Intensity-Modulated Radiotherapy in Prostate Cancer

AimsThe CHHiP trial investigated the use of moderate hypofractionation for the treatment of localised prostate cancer using intensity-modulated radiotherapy (IMRT). A radiotherapy quality assurance programme was developed to assess compliance with treatment protocol and to audit treatment planning and dosimetry of IMRT. This paper considers the outcome and effectiveness of the programme.Materials and methodsQuality assurance exercises included a pre-trial process document and planning benchmark cases, prospective case reviews and a dosimetry site visit on-trial and a post-trial feedback questionnaire.ResultsIn total, 41 centres completed the quality assurance programme (37 UK, four international) between 2005 and 2010. Centres used either forward-planned (field-in-field single phase) or inverse-planned IMRT (25 versus 17). For pre-trial quality assurance exercises, 7/41 (17%) centres had minor deviations in their radiotherapy processes; 45/82 (55%) benchmark plans had minor variations and 17/82 (21%) had major variations. One hundred prospective case reviews were completed for 38 centres. Seventy-one per cent required changes to clinical outlining pre-treatment (primarily prostate apex and base, seminal vesicles and penile bulb). Errors in treatment planning were reduced relative to pre-trial quality assurance results (49% minor and 6% major variations). Dosimetry audits were conducted for 32 centres. Ion chamber dose point measurements were within ±2.5% in the planning target volume and ±8% in the rectum. 28/36 films for combined fields passed gamma criterion 3%/3 mm and 11/15 of IMRT fluence film sets passed gamma criterion 4%/4 mm using a 98% tolerance. Post-trial feedback showed that trial participation was beneficial in evolving clinical practice and that the quality assurance programme helped some centres to implement and audit prostate IMRT.ConclusionOverall, quality assurance results were satisfactory and the CHHiP quality assurance programme contributed to the success of the trial by auditing radiotherapy treatment planning and protocol compliance. Quality assurance supported the introduction of IMRT in UK centres, giving additional confidence and external review of IMRT where it was a newly adopted technique.     

Long-term serial passage and neuronal differentiation capability of human bone marrow mesenchymal stem cells

The development of methods to induce differentiation of human mesenchymal stem cells (hMSCs) has opened the possibility of using these cells in regenerative or reparative therapies. However, the low frequency of hMSCs in tissue means it is often necessary to expand these cells extensively in vitro. In this study, we evaluated the effects of long-term serial passage on the characteristics of bone marrow-derived hMSC populations. In addition, we examined the effect on subsequent hMSC neural differentiation ability, which has not been reported earlier. The hMSC population examined was found to maintain a stable phenotype during the first 6-8 passages of culture as assessed by proliferative ability, morphological appearance, and surface antigen, gene and protein expression, and also expressed pluripotency and neural lineage markers constitutively in the undifferentiated state. Long-term subcultivation neither resulted in spontaneous neural differentiation nor compromised the ability of hMSCs to develop toward an early neuronal fate. In addition, the transformation elicited in hMSC cultures in response to cytokine-based neuronal differentiation was examined by live cell microscopy. We demonstrated, for the first time, that the observed changes result from active and dynamic processes involving outgrowth and motility of cellular extensions, processes entirely distinct from the rapid epiphenomena of cytotoxicity and cytoskeleton disruption generated by chemical induction methods. Cytokine-induced differentiation of hMSCs was also associated with upregulation of early neural gene and protein expression. These findings support the neuronal differentiation capability of hMSCs, although further investigation is required to confirm the ability to attain a mature neuronal phenotype.     

Detection of submicroscopic constitutional chromosome aberrations in clinical diagnostics: a validation of the practical performance of different array platforms

For several decades etiological diagnosis of patients with idiopathic mental retardation (MR) and multiple congenital anomalies (MCA) has relied on chromosome analysis by karyotyping. Conventional karyotyping allows a genome-wide detection of chromosomal abnormalities but has a limited resolution. Recently, array-based comparative genomic hybridization (array CGH) technologies have been developed to evaluate DNA copy-number alterations across the whole-genome at a much higher resolution. It has proven to be an effective tool for detection of submicroscopic chromosome abnormalities causing congenital disorders and has recently been adopted for clinical applications. Here, we investigated four high-density array platforms with a theoretical resolution < or =100 kb: 33K tiling path BAC array, 500K Affymetrix SNP array, 385K NimbleGen oligonucleotide array and 244K Agilent oligonucleotide array for their robustness and implementation in our diagnostic setting. We evaluated the practical performance based on the detection of 10 previously characterized abnormalities whose size ranged from 100 kb to 3 Mb. Furthermore, array data analysis was performed using four computer programs developed for each corresponding platform to test their effective ability of reliable copy-number detection and their user-friendliness. All tested platforms provided sensitive performances, but our experience showed that accurate and user-friendly computer programs are of crucial importance for reliable copy-number detection.