Viral kinetics analysis and virological characterization of treatment failures in patients with chronic hepatitis C treated with sofosbuvir and an NS5A inhibitor.

BACKGROUND: The combination of sofosbuvir (SOF) plus an NS5A inhibitor for 12 weeks is highly efficacious in patients with chronic hepatitis C. As the costs of generic production of sofosbuvir and NS5A inhibitor are rapidly decreasing, the combination of these DAAs will be the standard treatment in most low- to middle-income countries in the future. AIM: To identify key predictors of response that can be used to tailor treatment decisions. METHODS: A cohort of 216 consecutive patients infected with HCV genotype 1 (1a: n = 57; 1b: n = 77), 2 (n = 4), 3 (n = 33) or 4 (n = 44) were treated with sofosbuvir (SOF) + daclatasvir (n = 176) or SOF + ledipasvir (n = 40) for 12 weeks. The viral kinetics was analysed using the biphasic model and the cure boundary was used to predict time to clear HCV. RESULTS: The overall SVR rate was high (94.4%; n = 204), regardless of the time to viral suppression or low-level viraemia at the end of treatment. The model-based predicted HCV RNA levels at the end of treatment could not differentiate patients who did from those who did not achieve SVR. The presence of NS5A resistance-associated substitutions [position 28 (OR = 70.3, P<.001) and/or 31 (OR = 61.6, P = .002)] at baseline was predictive of virological failure in cirrhotic patients but was not associated with on-treatment viral kinetics. CONCLUSION: This real-world study confirms the excellent results of clinical trials with therapies based on a combination of SOF plus an NS5A inhibitor. It suggests that a personalized approach including baseline NS5A inhibitor resistance testing may inform treatment decisions in cirrhotic patients.

Cost-effectiveness and budget impact of interferon-free direct-acting antiviral-based regimens for hepatitis C treatment: the French case.

We evaluated the cost-effectiveness and the budget impact of new DAA-based regimen use in France. A Markov model simulated chronic hepatitis C (CHC) treatment interventions with IFN-based and IFN-free regimens at stage of fibrosis ≥F3, ≥F2 or regardless of fibrosis stage, and treatment either with the least or the most expensive combination. It estimated quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). It also assessed the budget impact over 5 years of treating all CHC-screened patients, regardless of fibrosis, assuming ≤20 000 patients treated/year and priority to ≥F3. Sensitivity analyses were also conducted. For genotypes (G) 1-4, the initiation of IFN-free regardless of fibrosis was a cost-effective strategy compared to prior standard of care (SOC) initiated at stage F2: €40 400-88 300/QALY gained in G1; similar results were obtained for patients infected with G4. Considering G2-3, the most cost-effective strategy was IFN-based regimens regardless of fibrosis compared to prior SOC initiated at stage F2: €21 300 and €19 400/QALY gained, respectively; the strategy with IFN-free regimens being more effective but not cost-effective at current costs. The budget impact of treating all CHC-screened patients over 5 years would range between 3.5 and 7.2 billion €, depending on whether one considers the least or the most expensive combination of new DAAs and whether one treats G2-3 with IFN-based or IFN-free new DAAs. In France, treatment initiation with new DDAs regardless of fibrosis stage is cost-effective, but would add 3.5-7.2 billion € to an already overburdened medical care system.

Performance of rapid diagnostic tests for the detection of antibodies to hepatitis C virus in whole blood collected on dried blood spots.

Rapid diagnostic tests (RDTs) represent an attractive alternative to enzyme immunoassays. A total of 207 individuals, including 68 HCV-seronegative subjects, 10 patients with resolved infection and 129 patients with chronic HCV infection, were studied. The specificity of RDT detection of anti-HCV antibodies in whole blood was 100% with the four RDTs tested: OraQuick(®) HCV Rapid Antibody Test, First Response HCV Card Test, ASSURE HCV Rapid Test and MultiSure HCV Antibody Assay. Their diagnostic sensitivity varied between 98.6% and 100%. RDT detection of anti-HCV antibody in whole blood collected on dried blood spots appears to be a promising new tool for broadscale screening of HCV infection in high- to medium-risk populations.

Effects 4.5 years after an interactive GP educational seminar on antibiotic therapy for respiratory tract infections: a randomized controlled trial.

BACKGROUND: The few studies assessing long-term effects of educational interventions on antibiotic prescription have produced conflicting results. OBJECTIVES: Our aim was to assess the effects after 4.5 years of an interactive educational seminar designed for GPs and focused on antibiotic therapy in respiratory tract infections (RTIs). The seminar was expected to decrease antibiotic prescriptions for any diagnosis. METHODS: We conducted a randomized controlled parallel-group trial in a Paris suburb (France), with GPs as the randomization unit and prescriptions as the analysis unit. The intervention occurred in September 2004 and the final assessment in March 2009. Among 203 randomized GPs, 168 completed the study, 70 in the intervention group and 98 in the control group. Intervention GPs were randomized to attending only a 2-day interactive educational seminar on evidence-based guidelines about managing RTIs or also 1 day of problem-solving training. The primary outcome was the percentage of change in the proportion of prescriptions containing an antibiotic for any diagnosis in 2009 versus 2004. An intention-to-treat sensitivity analysis was performed using multiple imputation. RESULTS: After 4.5 years, absolute changes in the primary outcome measure were -1.1% (95% confidence interval: -2.2 to 0.0) in the intervention group and +1.4% (0.3-2.6) in the control group, yielding an adjusted between-group difference of -2.2% (-2.7 to -1.7; P < 0.001). Both intervention modalities had significant effects, and multiple imputation produced similar results. CONCLUSIONS: A single, standardized and interactive educational seminar targeting GPs significantly decreased antibiotic use for RTIs after 4.5 years.

Prospective assessment of rapid diagnostic tests for the detection of antibodies to hepatitis C virus, a tool for improving access to care.

Large-scale hepatitis C screening is required to prevent further spread of the infection, improve access to care in the context of new hepatitis C virus (HCV) drug regimens without interferon-alpha and subsequently reduce the risk of long-term complications of chronic liver disease. Rapid diagnostic tests (RDTs) represent an attractive alternative to enzyme immunoassay using blood from venepuncture. The aim of the present study was to prospectively assess the clinical performance of CE-marked RDTs detecting anti-HCV antibodies in fingerstick capillary whole blood and/or oral fluid. A total of 513 individuals, including 318 patients with chronic HCV infection, 25 patients with resolved HCV infection and 170 HCV-seronegative individuals, were prospectively enrolled. The specificity of RDTs with fingerstick whole blood varied from 98.8% to 100%. The clinical sensitivity was high for the OraQuick(®) and Toyo(®) tests (99.4% and 95.8%, respectively), but low for the Labmen(®) test (63.1%). The specificity and clinical sensitivity in crevicular fluid were both satisfactory for the OraQuick(®) test (100% and 97.6%, respectively). HCV antibody RDTs were easy and rapid to perform in the context of patient care. They were highly specific. Both the OraQuick(®) and Toyo(®) tests reached the expected level of performance for wide-scale use, with a performance advantage for the OraQuick(®) HCV test. RDTs appear to be a promising new tool for wide-scale screening of HCV infection in high-risk to medium-risk populations. Hence, careful assessment of the performance of HCV RDTs must be recommended before they can be implemented in clinical practice.

Historical epidemiology of hepatitis C virus (HCV) in selected countries.

Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6,358,000 cases in 2008 and Brazil with 2,106,000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV-infected populations are critical for addressing HCV-related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.

The state of hepatitis B and C in the Mediterranean and Balkan countries: report from a summit conference.

The burden of disease due to chronic viral hepatitis constitutes a global threat. In many Balkan and Mediterranean countries, the disease burden due to viral hepatitis remains largely unrecognized, including in high-risk groups and migrants, because of a lack of reliable epidemiological data, suggesting the need for better and targeted surveillance for public health gains. In many countries, the burden of chronic liver disease due to hepatitis B and C is increasing due to ageing of unvaccinated populations and migration, and a probable increase in drug injecting. Targeted vaccination strategies for hepatitis B virus (HBV) among risk groups and harm reduction interventions at adequate scale and coverage for injecting drug users are needed. Transmission of HBV and hepatitis C virus (HCV) in healthcare settings and a higher prevalence of HBV and HCV among recipients of blood and blood products in the Balkan and North African countries highlight the need to implement and monitor universal precautions in these settings and use voluntary, nonremunerated, repeat donors. Progress in drug discovery has improved outcomes of treatment for both HBV and HCV, although access is limited by the high costs of these drugs and resources available for health care. Egypt, with the highest burden of hepatitis C in the world, provides treatment through its National Control Strategy. Addressing the burden of viral hepatitis in the Balkan and Mediterranean regions will require national commitments in the form of strategic plans, financial and human resources, normative guidance and technical support from regional agencies and research.

[French survey on perioperative nutrition in cirrhotic adult patients waiting for liver transplantation]. / Enquête sur l'évaluation et la prise en charge nutritionnelle des patients adultes cirrhotiques candidats à une transplantation hépatique.

OBJECTIVE: The European Society for Clinical Nutrition and Metabolism (EPSEN) guidelines on nutrition for liver disease patients has been recently updated. The aim of our study was to evaluate perioperative nutrition in cirrhotic patients waiting for liver transplantation (LT). STUDY DESIGN: Prospective electronic survey. A standardized questionnaire was sent to the anaesthesiologist of the 18 French adult LT centers. The questionnaire had closed-ended questions to evaluate nutritional practices in cirrhotic patients waiting for a LT. RESULTS: The response rate was 100%. Nutritional status of the cirrhotic patients waiting for LT was assessed by anaesthesiologists (12 centres) and/or hepatologists (11 centres) and more rarely by nutrition physician, dietetics or liver surgeons. Body mass index (13 centres), weight loss (10 centres), albuminemia (10 centres) were the most frequent items used to assess the nutritional status. Before LT, preoperative oral intakes were administered in undernourished patients in only 55% of the cases. Postoperatively, nutritional support was administered between day 1 and 3 after LT. CONCLUSION: Perioperative nutritional practices in cirrhotic patients waiting for LT are heterogeneous between centers, especially about nutrition assessment. Most of the centres did not follow the actual guidelines.

[Postoperative pain management on surgical wards; impact of using a validated reference tool in a short, medium and long term]. / Évaluation des pratiques professionnelles de la prise en charge de la douleur postopératoire à court, moyen et long terme.

OBJECTIVES: To evaluate the short medium and long-term impact of a quality-improvement program (QIP) in a university hospital using a validated reference tool. METHODS: Seven surgical departments were audited before and after implementation of a QIP in postoperative pain management. Audits were conducted in 2005, 2007, 2009 and 2012. In each audit, 10 medical charts from each surgical department were analyzed for 9 quality criteria. A surgical department score (SDS) was calculated for each department (maximum score=90). The surgical departments with a SDS<45 received targeted training sessions. RESULTS: In 2005, three surgical departments had a SDS<45. After the first audit, a targeted training sessions was conducted in the three surgical departments, all seven departments improved their scores with a SDS>45 in 2007. Between 2007 and 2009, all seven departments improved their scores. Conversely, between 2009 and 2012, the SDS diminished in six of the seven surgical departments and four of the nine evaluated quality criteria decreased significantly: right detailed order for postoperative pain analgesia (prescriber identifier, agent used, unit doses, mode of administration; 100% versus 53; P=0.027), appropriate dosing of steps I and II analgesics (96% versus 80%; P=0.041), morphine (90% versus 76%; P=0.039), based on corresponding physician orders and monitor morphine side effects (87% versus 29; P=0.027). CONCLUSION: Audits should be performed regularly (at least every two years) for detecting postoperative pain management degradation. Lack of targeted training sessions can explain partially this degradation.

The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference*.

Worldwide, the hepatitis B virus (HBV) and the hepatitis C virus (HCV) cause, respectively, 600,000 and 350,000 deaths each year. Viral hepatitis is the leading cause of cirrhosis and liver cancer, which in turn ranks as the third cause of cancer death worldwide. Within the WHO European region, approximately 14 million people are chronically infected with HBV, and nine million people are chronically infected with HCV. Lack of reliable epidemiological data on HBV and HCV is one of the biggest hurdles to advancing policy. Risk groups such as migrants and injecting drug users (IDU) tend to be under-represented in existing prevalence studies; thus, targeted surveillance is urgently needed to correctly estimate the burden of HBV and HCV. The most effective means of prevention against HBV is vaccination, and most European Union (EU) countries have universal vaccination programmes. For both HBV and HCV, screening of individuals who present a high risk of contracting the virus is critical given the asymptomatic, and thereby silent, nature of disease. Screening of migrants and IDUs has been shown to be effective and potentially cost-effective. There have been significant advances in the treatment of HCV and HBV in recent years, but health care professionals remain poorly aware of treatment options. Greater professional training is needed on the management of hepatitis including the treatment of liver cancer to encourage adherence to guidelines and offer patients the best possible outcomes. Viral hepatitis knows no borders. EU Member States, guided by the EU, need to work in a concerted manner to implement lasting, effective policies and programmes and make tackling viral hepatitis a public health priority.

Liver stiffness diminishes with antiviral response in chronic hepatitis C.

BACKGROUND: Transient elastography measures liver stiffness, which correlates with the hepatic fibrosis stage and has excellent accuracy for the diagnosis of cirrhosis in patients with chronic hepatitis C. AIM: To assess prospectively the kinetics of liver stiffness in treated patients with chronic hepatitis C and compare them with the viral kinetics on treatment and with the final outcome of therapy. METHODS: 91 patients with chronic hepatitis C with significant fibrosis (>7.0kPa) at baseline were included. They received therapy with pegylated interferon-α and ribavirin. The kinetics of liver stiffness were characterized during therapy and thereafter by means of Fibroscan, and compared with the virological responses at weeks 4, 12, 24, end of treatment and 12 and 24weeks after. RESULTS: A significant liver stiffness decrease was observed during therapy, which continued after treatment only in patients who achieved a sustained virological response. In this group, the median intra-patient decrease relative to baseline at the end of follow-up was -3.4kPa, vs-1.8kPa in the patients who did not achieve an SVR. Similar dynamics were observed in cirrhotic and non-cirrhotic patients. In multivariate analysis, only the SVR was associated with long-term improvement of liver stiffness (odds ratio: 3.10; 95% confidence interval: 1.20-8.02, P=0.019). CONCLUSIONS: In patients with advanced fibrosis at the start of therapy, liver stiffness is significantly reduced during treatment, but improvement continues off treatment only in patients who achieve a sustained virological response. Liver stiffness assessment earlier than 6months after the end of therapy does not appear to be clinically meaningful.

The impact of the prevention programme of hepatitis C over more than a decade: the French experience.

To assess the impact of the French national hepatitis C prevention programme initiated in 1999, we analysed trends in hepatitis C virus (HCV) prevalence, testing and characteristics of HCV-infected patient at first referral from 1994 to 2006. We used four data sources: Two national population-based sero-prevalence surveys carried out in 1994 and 2004; two surveillance networks, one based on public and private laboratories throughout France and the other on hepatology reference centres, which aim to monitor, respectively, trends of anti-HCV screening and of epidemiological-clinical characteristics of HCV patients at first referral. Between 1994 and 2004, the anti-HCV prevalence for adults aged 20-59 years decreased from 1.05 (95% confidence interval 0.75-1.34) to 0.71 (0.52-0.97). During the same period, those anti-HCV positive with detectable HCV RNA decreased from 81 to 57%, whereas, the proportion of anti-HCV positive persons aware of their status evolved from 24 to 56%. Anti-HCV screening activity increased by 45% from 2000 to 2005, but decreased in 2006 (-10%), while HCV positivity among those tested decreased from 4.3 to 2.9%. The proportion of cirrhosis at first referral remains around 10% between 2001 and 2006, with many patients with excessive alcohol consumption (34.7% among males) or viral co-infections (HIV seropositivity for 5.2% patients). Our analysis indicates that the national programme had a positive impact at the population level through improved prevention, screening and management. There is still a need to identify timely those at risk for earlier interventions, to assess co-morbidities better and for a multidisciplinary approach to HCV management.

A 20-year experience of electron microscopy in the diagnosis of primary ciliary dyskinesia.

Transmission electron microscopy (TEM) analysis of ciliary ultrastructure is classically used for the diagnosis of primary ciliary dyskinesia (PCD). We report our extensive experience of TEM analysis in a large series of patients in order to evaluate its feasibility and results. TEM analysis performed in 1,149 patients with suspected PCD was retrospectively reviewed. Biopsies (1,450) were obtained from nasal (44%) or bronchial (56%) mucosa in children (66.5%) and adults (33.5%). TEM analysis was feasible in 71.4% of patients and showed a main defect suggestive of PCD in 29.9%. TEM was more feasible in adults than in children, regardless of the biopsy site. Main defects suggestive of PCD were found in 76.9% of patients with sinopulmonary symptoms and in only 0.4% of patients with isolated upper and 0.4% with isolated lower respiratory tract infections. The defect pattern was similar in children and adults, involving dynein arms (81.2%) or central complex (CC) (18.8%). Situs inversus was never observed in PCD patients with CC defect. Kartagener syndrome with normal ciliary ultrastructure was not an exceptional condition (10.2% of PCD). In conclusion, TEM analysis is feasible in most patients and is particularly useful for PCD diagnosis in cases of sinopulmonary syndrome of unknown origin.

Epidermoid anal cancer prognosis comparison among HIV+ and HIV- patients.

BACKGROUND: Previous studies suggest a poor prognosis of epidermoid anal cancer in HIV+ patients. AIM: To investigate the long-term outcome of epidermoid anal cancer in HIV+ and HIV- patients in the highly active antiretroviral treatment (HAART) era. METHODS: We included all patients with epidermoid anal cancer referred to six hospitals from 1998 to 2004. RESULTS: In all, 151 patients (44 HIV+, 107 HIV-) were reviewed retrospectively for 27 (median of 16-44) months. HIV+ patients were male (100% vs. 27%, P < 0.001) and younger (45 vs. 62 years old, P < 0.001) than HIV- patients. No significant differences were observed in the tumour stage, pelvic radiotherapy dose or concomitant chemotherapy, according to the HIV status. After chemoradiotherapy, similar numbers of HIV+ and HIV- patients had grade III-IV toxicity. A complete response was obtained in 82% and 75% (N.S.) of cases, respectively. The disease-free survival rates were 77% and 67% (N.S.) and the overall survival rates were 85% and 84% (N.S.), respectively, after 3 years of follow-up. Duration of HIV infection, viral load and CD4 count had no effect on the survival rate of HIV+ patients with EAC. CONCLUSIONS: The clinical outcome of HIV+ patients with epidermoid anal cancer is similar to that of HIV- patients. Therefore, the same therapeutic guidelines should be applied to both populations.

Impact of written information describing postoperative pain management on patient agreement with proposed treatment.

BACKGROUND AND OBJECTIVES: Because patients who are to undergo surgery must give their consent to planned postoperative care, clear and complete information on postoperative pain management should be given. The aim of this quality-of-care study was to evaluate by inquiry the impact of written information describing postoperative pain management on the quality and type of information retained, and patient participation in discussing and agreeing to the postoperative pain management programme during the presurgical anaesthesiology consultation. METHODS: Prospective before and after interventional surveys, each lasting 3 weeks and conducted at a 6-month interval (time required to prepare the written information), used a standardized anonymous questionnaire given to patients after the anaesthesiology consultation. Questions requiring a 'yes' or 'no' response assessed the quality of information and what information was retained by the patient, the extent of the patient's interaction during the discussion with the anaesthesiologist and his/her agreement with the postoperative pain management programme. RESULTS: Among the 180 before-group patients included, 16.7% reported receiving verbal information during the anaesthesiology consultation, none retained all seven principal side-effects of morphine, 14.4% considered the information to be thorough, 20.6% understood it, 16.7% claimed that it had helped them participate in the discussion and 14.4% concurred with the postoperative pain management programme. Compared to the before inquiry, significantly higher percentages of the 107 after-group patients (given written information before the anaesthesiology consultation) responded as having received verbal information during the anaesthesiology consultation (57.0%), retained morphine's main side-effects (12.1%), deemed the information thorough (58.9%) and understandable (53.3%), had participated in the discussion (47.7%) and agreed with the postoperative pain management programme (51.4%). CONCLUSION: Written information on postoperative pain management distributed before the presurgical anaesthesiology consultation improved the quality of information retained, facilitated discussion with the anaesthesiologist and patient agreement with the postoperative pain management programme.

Assessment of calf muscle contraction by diffusion tensor imaging.

The goal of this study was to assess the changes of water diffusion during contraction and elongation of calf muscles using diffusion tensor (DT) MRI in normal volunteers. Twenty volunteers (mean age, 29+/-4 years) underwent DT MRI examination of the right calf. Echo planar imaging sequence was performed at rest, during dorsal flexion and during plantar flexion. The three eigenvalues (lambda1, lambda2, and lambda3), apparent diffusion coefficient (ADC) and fractional anisotropy (FA) of the diffusion tensor were calculated for medial gastrocnemius (mGM) and tibialis anterior (TA). A fiber tractography was performed on both muscles. Non-parametric Wilcoxon and Mann Whitney tests were used for statistical evaluation. At rest, lambda1, lambda2 and ADC of mGM were higher than their counterparts of TA (P<0.01). During dorsal flexion, the three eigenvalues and ADC of TA significantly increased (P<0.05) as their counterparts of mGM slightly decreased (P=NS). Opposite variations were detected during plantar flexion of the foot. Visual analysis evidenced a relationship between 3D representations of MRI fibers and physiological state of muscles. Contraction of calf muscles produces changes in DT parameters, which are related to the physiological state of the muscle.

Hepatitis G virus: a suitable marker of in vivo efficacy for pathogen inactivation.

Being an orphan virus despite a large number of investigations, hepatitis G virus is a blood-borne agent for which screening is not required in blood donations. The in vivo efficacy of pathogen inactivation methods could be assessed by the absence of hepatitis G virus markers after transfusion of pathogen-inactivated blood products, in recipients susceptible to infection before the transfusion.