L.C. Mendes

Transient elastography and APRI score: looking at false positives and false negatives. Diagnostic performance and association to fibrosis staging in chronic hepatitis C

Although long regarded as the gold standard for liver fibrosis staging in chronic hepatitis C (CHC), liver biopsy (LB) implies both the risk of an invasive procedure and significant variability. The aim of this study was to evaluate the diagnostic performance for transient elastography (TE) and aspartate aminotransferase to platelet index (APRI) used alone and in combination compared to liver biopsy and to analyze false positive/negative results. Patients with CHC, and no previous clinical diagnosis of cirrhosis were enrolled to undergo liver biopsy, TE and APRI. A total of 182 adult patients with a median age of 55 years and median body mass index of 26.71 kg/m2 were analyzed. On LB, 56% of patients had significant levels of fibrosis (METAVIR F≥2) and 28% had advanced fibrosis (F3/F4). The strongest performance for both tests was observed for exclusion of advanced fibrosis with good negative predictive values (89 and 86%, respectively). Low necroinflammatory activity on LB was associated with false negative TE. False positives were associated with NASH and smaller LB fragments. Correlation between APRI and Fibroscan for F≥2 was 100% and 84% for F≥3 and remained high in both false negative and false positive instances, correctly identifying F<2 in 71% of cases and F<3 in 78% (and potentially foregoing up to 84% of LB). We concluded that low individual performance indicators could be attributable to limitations of LB. Poorer differentiation of lower levels of fibrosis is a known issue for LB and remains so for noninvasive tests. Good predictability is possible, however, for advanced fibrosis.

A Universidade colaborando na construção de um projeto de promoção da saúde: relato de experiência de um grupo de alunos de Medicina da Unicamp, Campinas, SP, Brasil

The goal of this project was to promote eye health and provide eye care to children from 0 to 7 years of age and to offer to medical students of Unicamp the possibility of participating in practice in a public health action carried out according to the principles of the Brazilian Unified Health System (SUS - Sistema Unico de Saude). In 2003, a questionnaire was applied to a sample of users of the Jardim Santa Monica Health Care Center in Campinas, SP. Analysis of the data there obtained revealed some deficiencies in the promotion of eye health such as lack of information about basic eye care, lack of resources for treatment, lack of information about the right to care by the Unified Health System and the absence of any preventive measures, mainly for children. Thus, a project was developed offering workshops for students, teachers, community health agents and personnel from a neighborhood nurser y-school to enable them to act as multipliers of the obtained knowledge and to initiate a process of awareness building. A spectacle bank was created in order to grant the sustainability of the project, offering the confection of eye glasses with frames donated by the population and lenses offered by the city government and some optic stores to needed persons. Through this experience the medical students could obtain some practical knowledge about the organization of health services and the dynamics of the health system, enabling them to understand some limitations and to suggest public eye health policies meeting the needs of the population. A closer study of this project shows not only how important this kind of action is for the most needed segments of society but also the role a doctor can play as someone able to convince people to go for their rights.

Predictors of early discontinuation of interferon-free direct antiviral agents in patients with hepatitis C virus and advanced liver fibrosis: results of a real-life cohort

Aim The aim of this study was to determine risk factors for premature treatment discontinuation among patients with hepatitis C and advanced fibrosis with advanced fibrosis treated with interferon (IFN)-free direct antiviral agents (DAA)-based therapy. Patients and methods We included all patients with chronic hepatitis C virus infection and advanced liver fibrosis in whom treatment was initiated with IFN-free DAA therapy at a university hospital from December 2015 through June 2016. We prospectively collected data from medical records using standardized questionnaires and evaluated them using Epi Info 7.1.2.0. The primary outcome was treatment interruption and associated factors. Results In total, 214 patients were included in this study; 180 patients were treated with sofosbuvir (SOF)+daclatasvir±ribavirin (RBV), 31 received SOF+simeprevir±RBV, and three were treated with SOF+RBV. Treatment discontinuation rate was 8.9% (19 patients) and cirrhotic decompensation was the main reason [8 (42.1%)]. Among patients with Child B or C cirrhosis (31), 10 (32.2%) prematurely interrupted treatment. The risk factors for treatment discontinuation in univariate analysis were older age (P=0.0252), higher comorbidity index (P=0.0078), higher model for end-stage liver disease (P<0.0001), higher fibrosis index based on the 4 factores (P=0.0122), and lower hemoglobin (P=0.0185) at baseline. Multivariate analysis showed that older age (odds ratio: 1.1, 95% confidence interval: 1.02–1.19) and higher model for end-stage liver disease (odds ratio: 1.27, 95% confidence interval: 1.03–1.56) were associated with premature treatment interruption. Conclusion Older age and advanced liver disease were related to treatment interruption. Identification of risk factors associated with treatment discontinuation is important to recognize patients who should be followed up closely during treatment, ando those whom possibly may not benefit from immediate DAA treatment or should be followed up closely during treatment.

Predictors of early treatment discontinuation and severe anemia in a Brazilian cohort of hepatitis C patients treated with first-generation protease inhibitors

The aim of this study was to determine risk factors for adverse events (AE)-related treatment discontinuation and severe anemia among patients with chronic hepatitis C virus (HCV) genotype 1 infection, treated with first-generation protease inhibitor (PI)-based therapy. We included all patients who initiated treatment with PI-based therapy at a Brazilian university hospital between November 2013 and December 2014. We prospectively collected data from medical records using standardized questionnaires and used Epi Info 6.0 for analysis. Severe anemia was defined as hemoglobin ≤8.5 mg/dL. We included 203 patients: 132 treated with telaprevir (TVR) and 71 treated with boceprevir (BOC). AE-related treatment discontinuation rate was 19.2% and anemia was the main reason (38.5%). Risk factors for treatment discontinuation were higher comorbidity index (OR=1.85, CI=1.05-3.25) for BOC, and higher bilirubin count (OR=1.02, CI=1.01-1.04) and lower BMI (OR=0.98, CI=0.96-0.99) for TVR. Severe anemia occurred in 35 (17.2%) patients. Risk factors for this outcome were lower estimated glomerular filtration rate (eGFR; OR=0.95, CI=0.91-0.98) for patients treated with TVR, and higher comorbidity index (OR=2.21, CI=1.04-4.67) and ribavirin dosage (OR=0.84, CI=0.72-0.99) for those treated with BOC. Fifty-five (57.3%) patients treated with TVR and 15 (27.3%) patients treated with BOC achieved sustained virological response (SVR). Among patients who received TVR and interrupted treatment due to AE (n=19), only 26.3% (n=5) achieved SVR (P=0.003). Higher number of comorbidities, lower eGFR and advanced liver disease are associated with severe anemia and early treatment cessation, which may compromise SVR achievement.

Treatment of hepatitis C virus genotype 3 infection with direct-acting antiviral agents

Hepatitis C virus (HCV) genotype 3 is responsible for 30.1% of chronic hepatitis C infection cases worldwide. In the era of direct-acting antivirals, these patients have become one of the most challenging to treat, due to fewer effective drug options, higher risk of developing cirrhosis and hepatocellular carcinoma and lower sustained virological response (SVR) rates. Currently there are 4 recommended drugs for the treatment of HCV genotype 3: pegylated interferon (PegIFN), sofosbuvir (SOF), daclatasvir (DCV) and ribavirin (RBV). Treatment with PegIFN, SOF and RBV for 12 weeks has an overall SVR rate of 83–100%, without significant differences among cirrhotic and non-cirrhotic patients. However, this therapeutic regimen has several contraindications and can cause significant adverse events, which can reduce adherence and impair SVR rates. SOF plus RBV for 24 weeks is another treatment option, with SVR rates of 82–96% among patients without cirrhosis and 62–92% among those with cirrhosis. Finally, SOF plus DCV provides 94–97% SVR rates in non-cirrhotic patients, but 59–69% in those with cirrhosis. The addition of RBV to the regimen of SOF plus DCV increases the SVR rates in cirrhotic patients above 80%, and extending treatment to 24 weeks raises SVR to 90%. The ideal duration of therapy is still under investigation. For cirrhotic patients, the optimal duration, or even the best regimen, is still uncertain. Further studies are necessary to clarify the best regimen to treat HCV genotype 3 infection.

Loss to follow-up in anti-HCV-positive patients in a Brazilian regional outpatient clinic.

Loss to follow-up (LF), which refers to patients who started care but voluntary stopped it, is a problem for patients with chronic disease. We aimed to estimate the rate of LF among patients seropositive for hepatitis C virus (HCV) and identify possible demographic and lifestyle risk factors associated with LF. From January 2009 through December 2012, 1010 anti-HCV-positive patients were included in the study. Among participants, 223 (22.1%) met the case definition for LF (more than 1-year elapsed since the last clinical appointment). Among 787 patients who remained in follow-up, 372 (47.2%) were discharged after undetectable HCV RNA, 88 (11.1%) were transferred (and remained on regular follow-up at the destination), and 25 (3.1%) died. According to univariate analysis, male gender, absence of a life partner, black race, psychiatric illness, previous alcohol abuse, previous or current recreational drug use, and previous or current smoking were significantly associated with LF. In multivariate analysis, absence of a life partner (adjusted odds ratio (AOR)=1.44; 95% confidence interval (95%CI)=1.03–2.02), black race (AOR=1.81, 95%CI=1.12–2.89), psychiatric illness (AOR=1.77, 95%CI=1.14–2.73), and the presence of at least one lifestyle risk factor (pertaining to substance abuse) (AOR=1.95, 95%CI=1.29–2.94) were independently associated with LF. Our study provides an estimate of the incidence of LF among anti-HCV-positive patients and identifies risk factors associated with this outcome. In addition, these results can help clinicians recognize patients at risk for LF, who require additional support for the continuity of care.

All-oral direct antiviral treatment for hepatitis C chronic infection in a real-life cohort: The role of cirrhosis and comorbidities in treatment response

Background Hepatitis C virus (HCV) infection is the major cause of end-stage liver disease (LD) worldwide. The aim of this study was to assess sustained virological response (SVR) rates in a real-world cohort of patients with HCV infection treated with interferon-free direct antiviral agents (DAA). Patients and methods All patients with genotypes 1, 2 or 3 HCV infection who started interferon-free treatment at a university hospital from December 2015 through July 2017 were included. The primary outcome was SVR at post-treatment week 12 by intention-to-treat (ITT) and modified ITT (mITT) analysis. Results Five hundred twenty seven patients were enrolled, 51.6% with cirrhosis. Most patients received sofosbuvir + daclatasvir + ribavirin (60.7%) and sofosbuvir + simeprevir (25.6%). Overall SVR rates were 90.5% for ITT and 96% for mITT. SVR rates were higher in non-cirrhotic (94.2% in ITT and 96.8% in mITT) versus cirrhotic patients (87.1% in ITT and 95.2% in mITT). In ITT and mITT assessments, SVR rates were higher in patients with Child-Pugh A (n = 222, 88.7% and 95.7%, respectively) versus Child-Pugh B or C (n = 40, 80% and 90%, respectively); SVR rates were higher in patients with genotype 1 (n = 405, 92.1% and 98.2%), followed by genotype 2 (n = 13, 84.6% and 92.7%) and genotype 3 (n = 109, 84.4% and 88.4%). Lower comorbidity index (p = 0.0014) and absence of cirrhosis (p = 0.0071) were associated with SVR. Among cirrhotic patients, lower Model for End-Stage Liver Disease (p = 0.0258), higher albumin (p = 0.0015), and higher glomerular filtration rate (p = 0.0366) were related to SVR. Twenty-two cirrhotic patients (8%) had clinical liver decompensation during treatment. Complications of advanced LD were responsible for discontinuation of treatment and death in 12 and 7 patients, respectively. Conclusion Treatment with all-oral DAA achieved high SVR rates, particularly in patients without cirrhosis and few comorbidities. Advanced LD is associated to poor outcome, such as treatment failure and death.

Elastogram quality assessment score in Vibration Controlled Transient Elastography: Diagnostic performance compared to digital morphometric analysis of liver biopsy in chronic hepatitis C

Vibration‐controlled transient elastography (VCTE) is widely used for noninvasive fibrosis staging in chronic hepatitis C. However, internal validation is based solely on variability and success rate and lacks reproducible quality indicators. We analysed the graphic representation of shear wave propagation in comparison with morphometric results of liver biopsy, eliminating observer variability bias. Individual elastograms were classified according to two morphologic criteria: extension of wave propagation (length of the graphic representation) and shear wave dispersal (level of parallelism displayed in the elastogram). Then, a score based on these criteria stratified the elastogram in classes I through III (highest to lowest technical quality). Liver stiffness results of each measurement were compared with collagen contents in liver biopsy by morphometric analysis. A total of 3243 elastograms were studied (316 patients). Digital morphometry in liver biopsy showed significant fibrosis in 66% of samples and advanced fibrosis in 31%. Elastogram quality analysis resulted in 1438 class I measurements (44%), 1070 class II (34%) and 735 class III. Area under the receiver operating curve (AUROC) for severe fibrosis according to class (I, II and III) was 0.941, 0.887 and 0.766, respectively. For advanced fibrosis, AUROCs were 0.977, 0.883 and 0.781, respectively. Spearmans correlation testing for all classes and levels of fibrosis demonstrated significant independent association (r2 = −.95, P < .01). Our study is the first to propose measurable quality criteria for VTCE and to validate them against objective assessment of liver biopsy through digital morphometric imaging analysis. We concluded that VCTE performance is significantly influenced by quality assessment of individual measurements. Considering these criteria in clinical practice may improve accuracy.

Diagnosis and staging of fibrosis in patients with chronic hepatitis C: comparison and critical overview of current strategies

In the past years, what has always been considered undisputed true in liver fibrosis staging has been challenged. Diagnostic performance of histological evaluation has proven to be significantly influenced by sample- and observer-related variabilities. Differentiation between lower levels of fibrosis remains difficult for many, if not all, test modalities, including liver biopsy but, perhaps, such a distinction is not indispensable in light of current therapeutic approaches. Biomarkers and elastography offer, nonetheless, high predictive values for advanced fibrosis and cirrhosis and correlate well with liver-related outcomes. Necroinflammation, steatosis, and hemodynamic changes may significantly interfere with elastography-based techniques, and longitudinal follow-up strategies must be tailored in light of these findings. Knowledge of different test modalities and diagnostic performance indicators can allow for better clinical decision-making and resource allocation.

Chronic hepatitis C virus infection: it is not only about the liver.

Background and aims Although hepatitis B virus (HBV) and hepatitis C virus (HCV) are both hepatotropic and quite similar in terms of clinical manifestations and histopathology, their respective infections are distinct in terms of epidemiology and prognosis. Recognizing the differences between patients with HBV and HCV infection with respect to demographic characteristics, prevalence of comorbidities, and presence of lifestyle factors aids the proper treatment of these patients. We aimed to compare two populations with chronic viral liver disease (chronic HCV and chronic HBV), each of them with resolved hepatitis C. Patients and methods We included patients referred to a municipal reference clinic from March 2009 through May 2012. Patient data were collected using standardized questionnaires at the patients’ first visit to clinic. Questionnaires included epidemiological information, presence of comorbidities, and lifestyle. Results A total of 756 patients were included in the study, 348 (46.0%) with chronic HCV infection, 176 (23.3%) with chronic HBV infection, and 232 (30.7%) with resolved HCV infection. Multivariate analysis including patients with chronic HCV infection and chronic HBV infection indicated that age [adjusted odds ratio (AOR)=1.06; 95% confidence interval (CI): 1.03–1.08], alcohol abuse (AOR=1.58; 95% CI: 1.01–2.49), smoking (AOR=1.64; 95% CI: 1.00–2.17), and illicit drug (AOR=2.92; 95% CI: 1.69–5.02) use were associated independently with chronic HCV infection. Multivariate analyses including patients with chronic HCV infection and those patients with resolved HCV infection, presence of at least one comorbidity (AOR=1.94; 95% CI: 1.12–3.3), illicit drug use (AOR=3.24; 95% CI: 1.90–5.54), and age (AOR=1.03; 95% CI: 1.01–1.05) were independently associated with chronic HCV infection. Age (AOR=0.98; 95% CI: 0.96–0.99) and male sex (AOR=1.93; 95% CI: 1.26–2.95) were the only variables associated significantly with chronic HBV infection in the multivariate analysis between patients with chronic HBV infection and resolved HCV infection. Conclusion Our results highlight that patients with chronic HCV infection are complex and require a multidisciplinary approach during patient follow-up and clinical management.