Influence of age on force and re-lengthening dynamics after tetanic stimulation withdrawal in the tibialis anterior muscle.

PURPOSE: During alternate movements across a joint, the changeover from one direction of rotation to the opposite may be influenced by the delay and rate of tension reduction and the compliance to re-lengthening of the previously active muscle group. Given the aging process may affect the above-mentioned factors, this work aimed to compare the dynamics of both the ankle torque decline and muscle re-lengthening, mirrored by mechanomyogram (MMG), in the tibialis anterior because of its important role in gait. METHODS: During the relaxation phase, after a supramaximal 35 Hz stimulation applied at the superficial motor point, in 20 young (Y) and 20 old (O) subjects, the torque (T) and MMG dynamics characteristics were measured. RESULTS: The T and MMG analysis provided: (I) the beginning of the decay after cessation of stimulation (T: 22.51 ± 5.92 ms [Y] and 51.35 ± 15.21 ms [O]; MMG: 27.38 ± 6.93 ms [Y] and 61.41 ± 18.42 ms [O]); (II) the maximum rate of reduction (T: - 110.4 ± 45.56 Nm/s [Y] and - 52.72 ± 32.12 Nm/s [O]; MMG: - 24.47 ± 10.95 mm/s [Y] and - 13.76 ± 6.54 mm/s [O]); (III) the muscle compliance, measuring the MMG reduction of every 10% reduction of torque (bin 20-10%: 15.69 ± 7.5[Y] and 10.8 ± 3.3 [O]; bin 10-0%: 22.12 ± 10.3 [Y] and 17.58 ± 5.6 [O]). CONCLUSION: Muscle relaxation results are different in Y and O and can be monitored by a non-invasive method measuring physiological variables of torque and re-lengthening dynamics at the end of the electromechanical coupling previously induced by the neuromuscular stimulation.

Influence of age on motor control accuracy during static ramp contractions.

We investigated the influence of the ageing process on the performance of the motor control system accuracy during a challenging motor task throughout the analysis of force output oscillations. The force signal of the first dorsal interosseous during linearly varying static contraction, 0-100-0% of the maximal volitional abduction in 15 s, was studied in 11 young and older adults. The relative error between the target and the actual force as well as several parameters of the force oscillations (corrections) were estimated. To understand the experimental results, we analyzed the force output generated by a set of computational simulations of a pool of motor units controlled by a proportional-integral-derivative system. Compared to young adults the older subjects presented larger errors and a lower number of corrections with longer duration and larger relative amplitude. The motor control system modelling varied the error update frequency (UF) of the controller (from 1 to 2.5 Hz) as well as the range of contraction time (CT) of the recruited motor unit (30-90 ms and 60-120 ms reflecting young and old ranges, respectively). The simulation generated force profiles with parameters similar to experimental recordings in young (UF = 1.5; CT 30-90 ms) and older (UF = 1; CT 60-120 ms) adults. Interestingly, the results of the simulations suggested that the improvement in the error update frequency of the controller was not able to compensate for the contractile changes in the motor unit twitches. In conclusion, the peripheral contractile changes with age can influence motor unit control strategies and represent a crucial phenomenon in the generation of larger force oscillations in older adults.

Trends in hepatitis C-related mortality in Switzerland.

In order to accurately assess the burden of hepatitis C (HCV) and develop effective interventions, we must understand the magnitude and trends of mortality related to the disease. In the United States, HCV-related mortality is continuously increasing. We have no comparable data for Switzerland and other European countries, although a modelling study predicted a similar increase. We analysed time trends (1 January 1995-31 December 2014) in HCV-specific mortality rates in the Swiss general population using the death registry of the Swiss Federal Statistical Office (SFSO). We compared HCV-related mortality to HIV-related and hepatitis B (HBV)-related mortality. To determine potential under-reporting in HCV-related mortality, we probabilistically linked the SFSO data to persons who died in the Swiss Hepatitis C Cohort Study (SCCS). SFSO data showed that HCV-related mortality more than doubled between 1995 and 2003, but has since stabilized at ~2.5/100 000 person-years. Since 2000, HCV-related mortality has been higher than HIV-related mortality and was about fivefold higher in 2014. HBV-related mortality remained low at ~0.5/100 000 person-years. Of 4556 persons in the SCCS, 421 have died and 86.2% could be linked to the death registry. According to the SCCS, 133 deaths were HCV-related. HCV was not mentioned on the SFSO death certificate of 45% of these (n = 60/133). In conclusion, HCV-related mortality remained constant, possibly because quality of care was high, or because of under-reporting or because mortality has not yet increased. However, HCV-related mortality is now much higher than HIV- and HBV-related mortality, and under-reporting was common.

Effect of hepatitis B virus on steatosis in hepatitis C virus co-infected subjects: A multi-centre study and systematic review.

It remains unclear whether hepatitis B virus (HBV) infection may modify the severity of viral steatosis in patients coinfected with chronic hepatitis C virus (HCV). We examined the influence of coinfection with HBV on prevalence of steatosis in chronic hepatitis C in a multi-centre cohort of HBV-HCV subjects, and by performing a systematic review and meta-analysis of the literature. We centrally and blindly assessed steatosis prevalence and severity in a cohort of HBV-HCV coinfected subjects compared to HCV and HBV monoinfected controls and we performed a systematic review of studies addressing the prevalence of steatosis in HBV-HCV subjects compared to HCV controls. In the clinical cohort, we included 85 HBV-HCV, 69 HBV and 112 HCV subjects from 16 international centres. There was no significant difference in steatosis prevalence between the HBV-HCV and the HCV groups (33% vs 45%, P = .11). In subgroup analysis, lean HBV-HCV subjects with detectable HBV DNA had less steatosis than lean HCV subjects matched for HCV viremia (15% vs 45%, P = .02). Our literature search identified 5 additional studies included in a systematic review. Overall, prevalence of steatosis > 5% was similar in HBV-HCV infection compared to HCV (pooled odds ratio [OR] 0.91, 95% CI 0.53-1.6) although there was significant heterogeneity (I2 69%, P = .007). In conclusion, although the prevalence of steatosis is similar in HBV-HCV compared to HCV subjects, our analysis suggests that there may be an inhibitory effect of HCV-induced steatogenesis by HBV in certain subgroups of patients.

Tracking motor units longitudinally across experimental sessions with high-density surface electromyography.

KEY POINTS: Classic motor unit (MU) recording and analysis methods do not allow the same MUs to be tracked across different experimental sessions, and therefore, there is limited experimental evidence on the adjustments in MU properties following training or during the progression of neuromuscular disorders. We propose a new processing method to track the same MUs across experimental sessions (separated by weeks) by using high-density surface electromyography. The application of the proposed method in two experiments showed that individual MUs can be identified reliably in measurements separated by weeks and that changes in properties of the tracked MUs across experimental sessions can be identified with high sensitivity. These results indicate that the behaviour and properties of the same MUs can be monitored across multiple testing sessions. The proposed method opens new possibilities in the understanding of adjustments in motor unit properties due to training interventions or the progression of pathologies. ABSTRACT: A new method is proposed for tracking individual motor units (MUs) across multiple experimental sessions on different days. The technique is based on a novel decomposition approach for high-density surface electromyography and was tested with two experimental studies for reliability and sensitivity. Experiment I (reliability): ten participants performed isometric knee extensions at 10, 30, 50 and 70% of their maximum voluntary contraction (MVC) force in three sessions, each separated by 1 week. Experiment II (sensitivity): seven participants performed 2 weeks of endurance training (cycling) and were tested pre-post intervention during isometric knee extensions at 10 and 30% MVC. The reliability (Experiment I) and sensitivity (Experiment II) of the measured MU properties were compared for the MUs tracked across sessions, with respect to all MUs identified in each session. In Experiment I, on average 38.3% and 40.1% of the identified MUs could be tracked across two sessions (1 and 2 weeks apart), for the vastus medialis and vastus lateralis, respectively. Moreover, the properties of the tracked MUs were more reliable across sessions than those of the full set of identified MUs (intra-class correlation coefficients ranged between 0.63-0.99 and 0.39-0.95, respectively). In Experiment II, ∼40% of the MUs could be tracked before and after the training intervention and training-induced changes in MU conduction velocity had an effect size of 2.1 (tracked MUs) and 1.5 (group of all identified motor units). These results show the possibility of monitoring MU properties longitudinally to document the effect of interventions or the progression of neuromuscular disorders.

Estimating HCV disease burden-volume 4 (editorial).

Hepatitis C virus (HCV) is a major global public health issue, with an estimated 71 million people living with HCV infection and a rising burden of cirrhosis, hepatocellular carcinoma (HCC) and liver-related mortality. The advent of interferon-free, direct acting antiviral-based (DAA) therapies, with short duration (8-12 weeks), high efficacy, excellent tolerability and ease of delivery (once daily oral dosing), is one of the major advances in clinical medicine in recent decades, and provides the opportunity to address this growing global HCV burden. In May 2014, January 2015 and December 2015, three supplements were published in the Journal of Viral Hepatitis presenting data from 47 countries on the historical epidemiology of HCV, the current HCV-related morbidity and mortality and potential strategies to manage the HCV disease burden in the future. The countries included in those manuscripts were from multiple regions including North and South America, Europe, Asia, the Middle East, Africa and Oceania. In this supplement, data from an additional 17 countries are presented, following a similar pattern as in the previous manuscripts. These countries represent a mixture of high-, middle- and low-income countries that hail from five geographical regions: Africa, Asia, Europe, Middle East and South America. Expert advisory panels were convened in each country to identify the best data sources to use and to review the assumptions and outputs from the model. In the countries considered in the current analyses, there is a wide variance in the availability of robust data.

Access to therapy and therapy outcomes in the Swiss Hepatitis C Cohort Study: a person-centred approach.

Socio-demographic and behavioural characteristics are associated with delayed diagnosis and disease progression in HCV-infected persons. However, many analyses focused on single variables rather than groups defined by several variables. We used latent class analysis to study all 4488 persons enrolled in the Swiss Hepatitis C Cohort Study. Groups were identified using predefined variables at enrolment. The number of groups was selected using the Bayesian information criterion. Mortality, loss to follow-up, cirrhosis, treatment status and response to antivirals were analysed using Laplace and logistic regressions. We identified five groups and named them according to their characteristics: persons who inject drugs, male drinkers, Swiss employees, foreign employees and retirees. Two groups did not conform to common assumptions about persons with chronic hepatitis C and were already in an advanced stage of the disease at enrolment: 'male drinkers' and 'retirees' had a high proportion of cirrhosis at enrolment (15% and 16% vs <10.3%), and the shortest time to death (adjusted median time 8.7 years and 8.8 years vs >9.0). 'Male drinkers' also had high substance use, but they were well educated and were likely to be employed. This analysis may help identifying high-risk groups which may benefit from targeted interventions.

Impact of common risk factors of fibrosis progression in chronic hepatitis C.

OBJECTIVE: The natural course of chronic hepatitis C varies widely. To improve the profiling of patients at risk of developing advanced liver disease, we assessed the relative contribution of factors for liver fibrosis progression in hepatitis C. DESIGN: We analysed 1461 patients with chronic hepatitis C with an estimated date of infection and at least one liver biopsy. Risk factors for accelerated fibrosis progression rate (FPR), defined as ≥ 0.13 Metavir fibrosis units per year, were identified by logistic regression. Examined factors included age at infection, sex, route of infection, HCV genotype, body mass index (BMI), significant alcohol drinking (≥ 20 g/day for ≥ 5 years), HIV coinfection and diabetes. In a subgroup of 575 patients, we assessed the impact of single nucleotide polymorphisms previously associated with fibrosis progression in genome-wide association studies. Results were expressed as attributable fraction (AF) of risk for accelerated FPR. RESULTS: Age at infection (AF 28.7%), sex (AF 8.2%), route of infection (AF 16.5%) and HCV genotype (AF 7.9%) contributed to accelerated FPR in the Swiss Hepatitis C Cohort Study, whereas significant alcohol drinking, anti-HIV, diabetes and BMI did not. In genotyped patients, variants at rs9380516 (TULP1), rs738409 (PNPLA3), rs4374383 (MERTK) (AF 19.2%) and rs910049 (major histocompatibility complex region) significantly added to the risk of accelerated FPR. Results were replicated in three additional independent cohorts, and a meta-analysis confirmed the role of age at infection, sex, route of infection, HCV genotype, rs738409, rs4374383 and rs910049 in accelerating FPR. CONCLUSIONS: Most factors accelerating liver fibrosis progression in chronic hepatitis C are unmodifiable.

HCV genotype 3 and squamous cell carcinoma antigen (SCCA)-IgM are independently associated with histological features of NASH in HCV-infected patients.

Nonalcoholic steatohepatitis (NASH) enhances the risk of progressive liver disease. In chronic hepatitis C (CHC), liver steatosis is frequent, especially in genotype 3, but its clinical significance is debated. As squamous cell carcinoma antigen (SCCA)-IgM has been associated with advanced liver disease and risk of tumour development, we evaluated its occurrence in CHC and the possible relation with NASH at liver biopsy. Using a validated ELISA, serum SCCA-IgM was measured in 91 patients with CHC at the time of liver biopsy performed before antiviral treatment, at the end of treatment and 6 months thereafter, and in 93 HCV-negative patients with histological diagnosis of nonalcoholic fatty liver disease, as controls. SCCA-IgM was detected in 33% of CHC patients and in 4% of controls. This biomarker was found more elevated in CHC patients with histological NASH, and at multivariate analysis, SCCA-IgM and HCV genotype 3 were independently associated with NASH [OR (95% CI): 6.94 (1.21-40) and 27.02 (4.44-166.6)]. As predictors of NASH, HCV genotype 3 and SCCA-IgM had a specificity and a sensitivity of 97% and 44%, and of 95% and 27%, respectively. PPV and NPV were 80% and 86% for HCV genotype 3 vs 73% and 72% for SCCA-IgM. In patients with sustained virologic response to therapy, SCCA-IgM levels decreased significantly, while these remained unchanged in nonresponders. In conclusion, SCCA-IgM is detectable in one-third of patients with CHC and significantly correlates with histological NASH.

Extrahepatic manifestations of HCV.

The hepatic consequences of an infection with the hepatitis C virus (HCV) are well recognised, but extrahepatic manifestations of HCV may be just as severe. Here we have reviewed various extrahepatic manifestations of HCV such as mixed cryoglobulinemia, lymphoma, metabolic features and neurologic consequences and we discuss pathogenesis and management of these clinical problems. We concluded with important aspects of therapy with novel anti-HCV agents and its effects on extrahepatic manifestations.

[Rethinking the reimbursement policy of direct acting antivirals against chronic hepatitis C]. / Repenser la politique de remboursement des agents antiviraux directs contre l'hépatite C chronique.

New direct-acting antivirals (DAA) against hepatitis C virus (HCV) have led to a therapeutic revolution in HCV management and virological cure rates approaching 100% while potentially avoiding significant complications of HCV (first cause of liver transplantation). We estimated the price of sustained virological response (SVR) depending on treatment strategy and patient profile. Costs of treatment with recent DAAs being so high, the accessibility to those drugs for the majority of subjects is hitherto limited to advanced stages of hepatitis C. This current situation increases the inequity and strengthens the dominant position of insurers and pharmaceutical companies with a rationing of care. We suggest herein global approaches from a population-level and health-care perspective aiming to reduce the prevalence, morbidity, and mortality related to HCV.

[Cell transplantation: current treatments and future prospects]. / Transplantation cellulaire: traitements actuels et perspectives d'avenir.

Regenerative medicine aims to replace a body function or specific cell loss. It includes therapies at the forefront of modem medicine, issuing from translational biomedical research. Transplantation of organs and cells has revolutionized the management of patients for whom medical treatment is a failure. Unfortunately, organ shortage is limiting treatment possibility. As an example, among the 15,000 patients with type I diabetes in Switzerland, only approximately 30 can receive a pancreas or an islet transplant per year. Second example, 500 patients die each year in Switzerland from alcoholic cirrhosis because no treatment is available. Transplantation of islet cells, hepatocytes, mesenchymal stem cells or dopaminergic neurons represents hope fora therapy available for large populations of patients.

The weekend factor: the effect on healthcare quality. A medico-legal, retrospective study.

Background: In the healthcare system, in the last 30 years, the prognostically negative value of the so-called Weekend Effect (WE) has been internationally recognized. The WE is regarded as the increased risk a patient might incur when hospitalized during non-working days, of enduring severe complications in comparison to the same hospitalization that occur on working days. The aim of this study was to retrospectively verify whether, once a mistake was made during weekends or on holidays, in comparison to a mistake occurred on workdays, it subsequently implied a higher risk of complications, death included, in a statistical and medico-legal way. Methods: Three different evaluators independently examined a total of 378 medico-legal cases over a more than 20-year period. Eventual medical actions and omissions were labelled as 'mistake' when the AJ claimed that at least one occurred; 'alleged mistake' included the cases where the EW's report disagreed with the AJ's one; finally, 'no mistake' when both the AJ and the EW agreed in their evaluations. During weekends there is a higher risk that a mistake occurs (OR=3.3, 95% CI=1.6;7.4; p-value<0.001) compared to weekdays. When death occurs, delayed diagnosis is the main cause (p=0.02), whereas a damaging action is more frequently claimed in general. Conclusions: We verified as actual the impact of the WE on patients' outcome from a medico-legal point of view. The implications for an improvement of the several settings of the Italian NHS are various, and many are the consequences in the healthcare management.

IL28B polymorphisms predict response to therapy among chronic hepatitis C patients with HCV genotype 4.

Genetic polymorphisms near IL28B are associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV). Our objective was to assess the predictive value of IL28B polymorphisms in the treatment of chronic hepatitis C of patients with HCV genotypes 4, for which data are currently limited. We analysed the association of IL28B polymorphisms with the virological response to treatment among 182 naïve chronic hepatitis C patients with HCV genotype 4, all from Syria. Associations of alleles with the response patterns were evaluated by univariate analysis and multivariate logistic regression, accounting for all relevant covariates. Sustained virological response (SVR) was achieved in 26% of rs8099917 TG/GG carriers compared with 60% of TT carriers (P < 0.0001) and 35% of rs12979860 CT/TT carriers compared with 62% of CC carriers (P = 0.0011). By multivariate analysis, the association between rs8099917 and SVR remained significant (OR = 0.19, 95% CI 0.07-0.50, for TG/GG vs TT, P = 0.0007), with the only significant covariate being advanced fibrosis (OR = 0.13, 95% CI 0.04-0.37, P = 0.0002). In conclusion, IL28B polymorphisms are the strongest predictors of response to therapy among chronic hepatitis C patients with HCV genotype 4.

[Reactivation of hepatitis B associated with immunosuppression]. / Réactivation de l'hépatite B au cours de l'immunosuppression.

The hepatitis B virus is an important cause of viral reactivation and flares in immunosuppressed patients. Factors associated with viral reactivation include positive HBs antigen, rituximab treatment, onco-haematological pathology and bone marrow transplantation. In situations at high risk of viral reactivation prophylactic antiviral therapy is indicated and reduces morbidity and mortality related to viral hepatitis flares.

Sex-related differences and chronobiology of ST-elevation myocardial infarction: findings from a single hub center in Italy.

OBJECTIVE: Type I acute myocardial infarction (AMI) is a life-threatening condition. Time of event and rescue procedures, and sex-specific differences may play a crucial role. We aimed to investigate chronobiological patterns and sex-specific differences in a cohort of AMI patients referred to a single hub center in Italy. PATIENTS AND METHODS: We considered all patients consecutively admitted for AMI (STEMI) to the Hospital of the Heart, in Massa, Tuscany (a region of Italy), between 2006 to 2018, who underwent interventional procedures. Sex, age, time of hospital admission, outcome (discharged alive/deceased), main comorbidities, and time between symptom onset and emergency medical service (EMS) activation, were analyzed. Chronobiologic analysis was applied according to hour of day, month, and season of the year. RESULTS: Overall 2,522 patients (mean age 64.6±13.1 years, 73% males) were considered. In-hospital death (IHM) occurred in 96 subjects (3.8%). At univariate analysis, deceased subjects were more likely to be female, older, with longer wait for EMS activation and with interventional procedures during night-time. The multivariate analysis identified female sex, age, history of ischemic heart disease, and night-time interventional procedure as independently associated factors to IHM. Chronobiologic analysis showed a pattern with a main morning peak for total sample, males, and females (p=0.00027; p=0.0006); p=0.0121, respectively). Events showed a higher peak in summer, with no differences by sex, but IHM was higher in winter. Females showed a higher delay for EMS activation, compared to males (p<0.001), but with no effects on prognosis. On the contrary, males with a delay showed higher mortality. CONCLUSIONS: Great effort should be spent to reduce patient-related delays in interventional procedures, being this issue crucial in both sexes.

Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity.

OBJECTIVE: NADPH oxidase 4 (NOX4) is a reactive oxygen species (ROS) producing NADPH oxidase that regulates redox homeostasis in diverse insulin-sensitive cell types. In particular, NOX4-derived ROS is a key modulator of adipocyte differentiation and mediates insulin receptor signaling in mature adipocytes in vitro. Our study was aimed at investigating the role of NOX4 in adipose tissue differentiation, whole body metabolic homeostasis and insulin sensitivity in vivo. DESIGN: Mice with genetic ablation of NOX4 (NOX4-deficient mice) were subjected to chow or high-fat-containing diet for 12 weeks. Body weight gain, adiposity, insulin sensitivity, and adipose tissue and liver gene and protein expression were analyzed and compared with similarly treated wild-type mice. RESULTS: Here, we report that NOX4-deficient mice display latent adipose tissue accumulation and are susceptible to diet-induced obesity and early onset insulin resistance. Obesity results from accelerated adipocyte differentiation and hypertrophy, and an increase in whole body energy efficiency. Insulin resistance is associated with increased adipose tissue hypoxia, inflammation and adipocyte apoptosis. In the liver, more severe diet-induced steatosis was observed due to the lack of proper upregulation of mitochondrial fatty acid ß-oxidation. CONCLUSION: These findings identify NOX4 as a regulator of metabolic homeostasis. Moreover, they indicate an anti-adipogenic role for NOX4 in vivo and reveal its function as a protector against the development of diet-induced obesity, insulin resistance and hepatosteatosis.

Steatosis and insulin resistance in response to treatment of chronic hepatitis C.

This review will focus on the impact of steatosis and insulin resistance on the response to antiviral therapy for chronic hepatitis C. Hepatitis C virus (HCV) infection is known to have direct and/or indirect effects on lipid and glucose metabolism, leading to, among other disturbances, steatosis and insulin resistance, respectively. Some of these disturbances have a marked HCV genotype distribution. For example, on average, patients with HCV genotype 3 have the highest prevalence and severity of viral fatty liver. On the other hand, the current global spread of the metabolic syndrome represents a formidable cofactor of morbidity in HCV-related chronic liver disease. Thus, the pathogenesis of steatosis and insulin resistance in patients with chronic hepatitis C may often be dual, i.e. viral and metabolic. This distinction is relevant because the effect (if any) of steatosis or insulin resistance on the response to antiviral agents seems to depend on their pathogenesis. Accumulating data suggest that viral fatty liver may not impact on response to therapy, while metabolic steatosis does. Similarly, viral insulin resistance may not reduce the rate of response to therapy to the same extent that metabolic insulin resistance does. Some implications for patient management are discussed.

Critical review of the use of erythropoietin in the treatment of anaemia during therapy for chronic hepatitis C.

Combined pegylated interferon (PegIFN) and ribavirin represents the standard therapy for patients with chronic hepatitis C (CHC), which allows for sustained viral response (SVR) in up to 90% of patients depending on certain viral and host factors. Clinical studies have demonstrated the importance of adherence to therapy, that is, the ability of patients to tolerate and sustain a fully dosed therapy regimen. Adherence is markedly impaired by treatment-related adverse effects. In particular, haemolytic anaemia often requires dose reduction or termination of ribavirin treatment, which compromises treatment efficacy. Recent evidence points to a beneficial role of recombinant erythropoietin (EPO) in alleviating ribavirin-induced anaemia thereby improving quality of life, enabling higher ribavirin dosage and consequently improving SVR. However, no general consensus exists regarding the use of EPO for specific indications: its optimal dosing, treatment benefits and potential risks or cost efficiency. The Swiss Association for the Study of the Liver (SASL) has therefore organized an expert meeting to critically review and discuss the current evidence and to phrase recommendations for clinical practice. A consensus was reached recommending the use of EPO for patients infected with viral genotype 1 developing significant anaemia below 100 g/L haemoglobin and a haematocrit of <30% during standard therapy to improve quality of life and sustain optimal ribavirin dose. However, the evidence supporting its use in patients with pre-existing anaemia, non-1 viral genotypes, a former relapse or nonresponse, liver transplant recipients and cardiovascular or pulmonary disease is considered insufficient.

The impact of fibrosis and steatosis on early viral kinetics in HCV genotype 1-infected patients treated with Peg-IFN-alfa-2a and ribavirin.

Hepatitis C viral (HCV) kinetics after initiation of interferon-based therapy provide valuable insights for understanding virus pathogenesis, evaluating treatment antiviral effectiveness and predicting treatment outcome. Adverse effects of liver fibrosis and steatosis on sustained virological response have been frequently reported, yet their impacts on the early viral kinetics remain unclear. In this study, associations between histology status and early viral kinetics were assessed in 149 HCV genotype 1-infected patients treated with pegylated interferon alfa-2a and ribavirin (DITTO trial). In multivariate analyses adjusted for critical factors such as IL28B genotype and baseline viral load, presence of significant fibrosis (Ishak stage > 2) was found to independently reduce the odds of achieving an initial reduction (calculated from day 0 to day 4) in HCV RNA of ≥2 logIU/mL (adjusted OR 0.03, P = 0.004) but was not associated with the second-phase slope of viral decline (calculated from day 8 to day 29). On the contrary, presence of liver steatosis was an independent risk factor for not having a rapid second-phase slope, that is, ≥0.3 logIU/mL/week (adjusted OR 0.22, P = 0.012) but was not associated with the first-phase decline. Viral kinetic modelling theory suggests that significant fibrosis primarily impairs the treatment antiviral effectiveness in blocking viral production by infected cells, whereas the presence of steatosis is associated with a lower net loss of infected cells. Further studies will be necessary to identify the biological mechanisms underlain by these findings.