Pathways to Poor Adherence to Antiretroviral Therapy Among People Living with HIV: The Role of Food Insecurity and Alcohol Misuse.

Daily adherence to antiretroviral therapy (ART) increases the length and quality of life of people living with HIV (PLHIV). We explored whether socioeconomic status directly impacts ART adherence and whether part of the effect is mediated by pathways through alcohol misuse or food insecurity. A cross-sectional study was conducted in Rio de Janeiro/Brazil (November/2019 to March/2020) with PLHIV aged ≥ 18 years. Validated instruments were used to measure alcohol use, food insecurity, and ART adherence. Using structural equation modeling we assessed the direct and indirect effects of variables on ART adherence. Participants reported significant challenges: hunger: 12%, alcohol use: 64%, and missing ART doses: 24%. Results showed that lower socioeconomic status increased poor adherence and that this effect was mediated through higher food insecurity. Alcohol misuse also increased poor adherence through a strong direct effect. Providing socio-economic support coupled with interventions to mitigate alcohol's harmful impact can aid HIV care.

RESUMEN: La adherencia diaria a la terapia antirretroviral (TAR) aumenta la duración y calidad de vida de las personas que viven con el VIH (PVVIH). Exploramos si el estatus socioeconómico afecta directamente la adherencia al TAR y si parte del efecto está mediado por vías a través del abuso del alcohol o la inseguridad alimentaria. Se realizó un estudio en Río de Janeiro/Brasil (noviembre/2019 a marzo/2020) con PVVIH con edad ≥ 18 años. Utilizando modelos de ecuaciones estructurales evaluamos los efectos directos e indirectos. Los participantes informaron desafíos significativos: hambre: 12%, consumo de alcohol: 64%, mala adherencia: 24%. Los resultados mostraron que un nivel socioeconómico más bajo aumentaba la mala adherencia por un efecto mediado por mayor inseguridad alimentaria. Abuso de alcohol también aumentó la mala adherencia por un fuerte efecto directo. Brindar apoyo socioeconómico con intervenciones para mitigar el impacto nocivo del alcohol puede ayudar la atención clínica.

Immunogenicity and Safety of Hepatitis B Virus (HBV) Vaccine With a Toll-Like Receptor 9 Agonist Adjuvant in HBV Vaccine-Naïve People With Human Immunodeficiency Virus.

In this international, multicenter open-label study (ACTG A5379) of HepB-CpG vaccine in people with human immunodeficiency virus (HIV) without prior hepatitis B virus (HBV) vaccination, all 68 participants achieved HBV seroprotective titers after the 3-dose series in the primary analysis. No unexpected safety issues were observed.

Acceptability and usability of oral fluid HCV self-testing for hepatitis C diagnosis: A systematic review and meta-analysis.

Data on the acceptability and usability of hepatitis C virus self-testing (HCVST) remain scarce. We estimated the pooled rates of acceptability/feasibility and re-reading/re-testing agreement of HCVST using oral fluid tests (PROSPERO-CRD42022349874). We searched online databases for studies that evaluated acceptability, usability and inter-reader/operator variability for HCVST using oral fluid tests. Pooled estimates of feasibility, agreement and post-testing perspectives were analysed. Sensitivity analyses were performed in men who have sex with men (MSM) and people who inject drugs (PWID). Heterogeneity was assessed using the I2 statistics. A total of six studies comprising 870 participants were identified: USA (n = 95 with liver disease), Kenya (n = 150 PWID), Egypt (n = 116 from the general population), Vietnam (n = 104 MSM and n = 105 PWID), China (n = 100 MSM) and Georgia (n = 100 MSM and n = 100 PWID)]. All studies used OraQuick® HCV Rapid Antibody Test. The pooled overall estimates for correct sample collection and for people who performed HCVST without needing assistance in any step (95% confidence interval [CI]) were 87.2% [76.0-95.3] (n = 755; I2 = 93.7%) and 62.6% [37.2-84.8] (n = 755; I2 = 98.0%), respectively. The pooled estimate of agreement for re-reading was 95.0% [95% CI 91.5-97.6] (n = 831; I2 = 74.0%) and for re-testing was 94.4% [90.3-97.5] (n = 726; I2 = 77.1%). The pooled estimate of those who would recommend HCVST was 94.4% [84.7-99.6] (n = 625; I2 = 93.7%). Pooled estimates (95% CI) of correct sample collection (72.8% [63.3-81.5] vs. 90.8% [85.9-94.8]) and performance of HCVST without needing assistance (44.1% [14.1-76.7] vs. 78.1% [53.4-95.3]) was lower in PWID compared to MSM. In summary, HCV testing with oral fluid HCVST was feasible and well-accepted. Oral fluid HCVST should be considered in key populations for uptake HCV testing.

Increased Body Mass Index and Type 2 Diabetes Are the Main Predictors of Nonalcoholic Fatty Liver Disease and Advanced Fibrosis in Liver Biopsies of Patients With Human Immunodeficiency Virus Monoinfection.

BACKGROUND: Liver disease is an important cause of morbidity and mortality in people living with human immunodeficiency virus (PLWH), of which nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized cause. There are limited data investigating NAFLD in HIV monoinfection and histologically defined disease. We aimed to identify who is at risk of fibrosis, NAFLD, and nonalcoholic steatohepatitis (NASH) among PLWH and explore the diagnostic accuracy of noninvasive markers of fibrosis. METHODS: This was a retrospective, cross-sectional, international, multicenter study including patients with HIV monoinfection, without chronic viral hepatitis or other known causes of chronic liver disease, who underwent liver biopsy for abnormal liver biochemistry and/or clinical suspicion of liver fibrosis. RESULTS: A total of 116 patients from 5 centers were included. Sixty-three (54%) had NAFLD, of whom 57 (92%) had NASH. Overall, 36 (31%) had advanced fibrosis (≥F3) and 3 (3%) had cirrhosis. Of the 53 cases without NAFLD, 15 (28%) had advanced fibrosis. Collagen proportionate area was similar between cases with and without NAFLD (3% vs 2%). Body mass index was independently associated with NAFLD (aOR, 1.2; 95% CI, 1.08-1.34), and type 2 diabetes was independently associated with advanced fibrosis (aOR, 3.42; 95% CI, 1.00-11.71). The area under the curve for advanced fibrosis was 0.65 and 0.66 for both NAFLD Fibrosis Score (NFS) and FIB-4. Cutoff values of -1.455 (NFS) and 1.3 (FIB-4) have negative-predictive values of 0.80 and 0.82, respectively. CONCLUSIONS: Advanced fibrosis is strongly associated with type 2 diabetes in PLWH. Serological markers require further optimization.

Brazilian Society of Hepatology and Brazilian College of Radiology practice guidance for the use of elastography in liver diseases.

In 2015 the European Association for the Study of Liver Diseases (EASL) and the Asociación Latinoamericana para el Estudio del Hígado (ALEH) published a guideline for the use of non-invasive markers of liver disease. At that time, this guideline focused on the available data regarding ultrasonic-related elastography methods. Since then, much has been published, including new data about XL probe use in transient elastography, magnetic resonance elastography, and non-invasive liver steatosis evaluation. In order to draw evidence-based guidance concerning the use of elastography for non-invasive assessment of fibrosis and steatosis in different chronic liver diseases, the Brazilian Society of Hepatology (SBH) and the Brazilian College of Radiology (CBR) sponsored a single-topic meeting on October 4th, 2019, at São Paulo, Brazil. The aim was to establish specific recommendations regarding the use of imaging-related non-invasive technology to diagnose liver fibrosis and steatosis based on the discussion of evidence-based topics by an organizing committee of experts. It was submitted online to all SBH and CBR members. The present document is the final version of the manuscript that supports the use of this new technology as an alternative to liver biopsy.

Prediction of Esophageal Varices by Liver Stiffness and Platelets in Persons With Human Immunodeficiency Virus Infection and Compensated Advanced Chronic Liver Disease.

BACKGROUND: People living with human immunodeficiency virus (PLWH) are at increased risk of cirrhosis and esophageal varices. Baveno VI criteria, based on liver stiffness measurement (LSM) and platelet count, have been proposed to avoid unnecessary esophagogastroduodenoscopy (EGD) screening for esophageal varices needing treatment (EVNT). This approach has not been validated in PLWH. METHODS: PLWH from 8 prospective cohorts were included if they fulfilled the following criteria: (1) compensated advanced chronic liver disease (LSM >10 kPa); (2) availability of EGD within 6 months of reliable LSM. Baveno VI (LSM <20 kPa and platelets >150 000/µL), expanded Baveno VI (LSM <25 kPa and platelets >110 000/µL), and Estudio de las Hepatitis Víricas (HEPAVIR) criteria (LSM <21 kPa) were applied to identify patients not requiring EGD screening. Criteria optimization was based on the percentage of EGDs spared, while keeping the risk of missing EVNT <5%. RESULTS: Five hundred seven PLWH were divided into a training (n = 318) and a validation set (n = 189). EVNT were found in 7.5%. In the training set, Baveno VI, expanded Baveno VI, and HEPAVIR criteria spared 10.1%, 25.5%, and 28% of EGDs, while missing 0%, 1.2%, and 2.2% of EVNT, respectively. The best thresholds to rule out EVNT were platelets >110 000/µL and LSM <30 kPa (HIV cirrhosis criteria), with 34.6% of EGDs spared and 0% EVNT missed. In the validation set, HEPAVIR and HIV cirrhosis criteria spared 54% and 48.7% of EGDs, while missing 4.9% and 2.2% EVNT, respectively. CONCLUSIONS: Baveno VI criteria can be extended to HEPAVIR and HIV cirrhosis criteria while sparing a significant number of EGDs, thus improving resource utilization for PLWH with compensated advanced chronic liver disease.

Effectiveness of direct-acting agents for chronic hepatitis C treatment in South America: A systematic review and meta-analysis.

The effectiveness of direct-acting agents (DAAs) for hepatitis C treatment in limited-resource settings remains unclear. We estimated the pooled sustained virological response rates of DAA therapy in South America. We searched online databases for studies that reported 12-week sustained virological response (SVR12) to hepatitis C virus (HCV) treatment in individuals living in South America. Pooled SVR12 in intention-to-treat (ITT) and per-protocol were estimated. Additionally, using all studies with available data, the pooled relative risk (RR) of SVR12 using a random-effects model (DerSimonian-Laird) was estimated to compare effectiveness of DAAs in patients with or without cirrhosis, HIV co-infection or previous HCV therapy. Heterogeneity was assessed using the I2 statistics. We identified 20 studies [14 manuscripts and 6 conference abstracts] comprising 7393 individuals from five countries [Brazil (n = 11), Argentina (n = 4), Chile (n = 1), Colombia (n = 1) and Peru (n = 1)] and two South-American collaborations. The pooled overall SVR12 rates [95% confidence interval (CI)] were 92.6% [90.2-94.7] and 95.5% [94.3-96.6] by ITT (11 studies; n = 4,153; I2  = 84.2%) and per-protocol analysis (15 studies; n = 4,833; I2  = 64.5%), respectively. The RR of SVR12 was similar in patients with or without HIV co-infection [4 studies; RR = 1.03 (0.99-1.07)] and those naive compared with treatment experimented-individuals [9 studies; RR = 1.01 (1.00-1.03)], but significantly higher in patients without cirrhosis compared with those with cirrhosis [11 studies; RR = 1.04 (1.02-1.05), P < .001]. DAAs are highly effective for HCV treatment in South America. The use of DAAs should be considered in limited-resource settings to decrease the burden of liver disease in HCV-infected patients. PROSPERO[CRD 42019134603].

Effectiveness of generic direct-acting agents for the treatment of hepatitis C: systematic review and meta-analysis.

OBJECTIVE: To compare the efficacy of generic direct-acting agents and brand-name medicines for treating hepatitis C virus (HCV) infection by conducting a systematic review and meta-analysis. METHODS: We searched online databases for studies that reported sustained virological responses 12 weeks after the end of HCV treatment with generic direct-acting agents. We derived pooled proportions of treated patients with a sustained virological response from intention-to-treat and per-protocol analyses. In addition, we calculated the pooled relative risk (RR) of a sustained virological response brand-name versus generic direct-acting agents using a random-effects model (DerSimonian-Laird) from the data available. Between-study heterogeneity was assessed using the I2 statistic. FINDINGS: We identified 19 studies involving a total of 57 433 individuals from eight territories or regions. The pooled overall proportions of patients with a sustained virological response were 98% (95% confidence interval, CI: 97-99; 18 studies; I2 = 94.1%) in per-protocol analyses and 96% (95% CI: 93-98; 8 studies; I2 = 68.1%) in intention-to-treat analyses. The likelihood of a sustained virological response with brand-name medicines was similar to that with generic direct-acting agents (RR: 1.00; 95% CI: 0.98-1.02; I2 = 0.0%). The likelihood of a sustained virological response was significantly higher in patients without than with cirrhosis (RR:1.03; 95% CI: 1.01-1.06; 7 studies) but was not significantly affected by either previous treatment (3 studies) or human immunodeficiency virus coinfection (3 studies). CONCLUSION: Generic direct-acting agents are highly effective for treating hepatitis C. Generic agents should be considered in resource-constrained settings for decreasing the burden of liver disease in HCV-infected patients.

Prediction of Liver Steatosis Applying a New Score in Subjects from the Brazilian Longitudinal Study of Adult Health.

GOALS: To develop a noninvasive algorithm for diagnosis of liver steatosis and to compare its diagnostic value with available predictive models. BACKGROUND: Liver steatosis represents the most frequent liver disease worldwide. STUDY: This cross-sectional study analyzed data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Patients were randomly divided into training (n=6571) and validation (n=3286) cohort. Abdominal ultrasound (US), used to grade steatosis, and overnight fasting blood tests were performed at the same day. Fatty Liver Index (FLI), Hepatic Steatosis Index, and Nonalcoholic Fatty Liver Disease-Liver Fat Score were calculated. A backward stepwise multivariate logistic regression analysis was used to develop the new predictive model, Steato-ELSA. RESULTS: In total, 9857 subjects [58% female, age=51 (interquartile range, 45 to 58) years, body mass index=26.4 (23.9 to 29.6) Kg/m] were included. Body mass index, waist circumference, homeostasis model of assessment of insulin resistance, transaminases, and triglycerides were independently associated with steatosis in the multivariate model (Hosmer-Lemeshow P=0.279). In the validation cohort, the area under the receiver-operator characteristics (95% confidence interval) for prediction of mild and moderate steatosis were: (i) 0.768 (0.751-0.784) and 0.829 (0.810-0.848) for Steato-ELSA; (ii) 0.762 (0.745-0.779) and 0.819 (0.799-0.838) for Fatty Liver Index; (iii) 0.743 (0.727-0.761) and 0.800 (0.779-0.822) for Hepatic Steatosis Index; and (iv) 0.719 (0.701-0.737) and 0.769 (0.747-0.791) for Nonalcoholic Fatty Liver Disease-Liver Fat Score. Steato-ELSA performed significantly better than other models and yielded sensitivity (Se)/specificity (Sp) (95% confidence interval): (i) for mild steatosis (score ≥0.386): Se=65.6% (63.0-68.3) and Sp=73.7% (71.8-75.6); (ii) for moderate steatosis (score ≥0.403): Se=83.5% (80.0-86.9) and Sp=68.7% (67.0-70.4). CONCLUSIONS: Steato-ELSA is an accurate and inexpensive tool that uses simple parameters to identify individuals at high risk of liver steatosis.

Development of algorithms to estimate EQ-5D and derive health utilities from WHOQOL-HIV Bref: a mapping study.

PURPOSE: This study aimed to develop and evaluate different families of applicable models available for utility mapping between World Health Organization Quality of Life for HIV-abbreviated version (WHOQOL-HIV Bref) and EQ-5D-3L and to propose an optimised algorithm to estimate health utilities of people living with HIV. METHODS: Estimation dataset was collected between July 2014 and September 2016 in a cross-sectional study including 1526 people living with HIV/Aids (PLWH) under care at the Instituto Nacional de Infectologia Evandro Chagas-FIOCRUZ, in Brazil. Data of WHOQOL-HIV Bref and EQ-5D-3L questionnaires were collected. Fisher's exact tests were used for testing WHOQOL-HIV Bref response frequencies among groups of responses to each of the five EQ-5D-3L domains. Multiple correspondence analyses (MCA) were used to inspect the relationships between both instrument responses. Different families of applicable models available for utility mapping between WHOQOL-HIV Bref and EQ-5D-3L were adjusted for the prediction of disutility. RESULTS: Candidate models' performances using mean absolute error (MAE), mean squared error (MSE), and root mean squared error (RMSE) were similarly good, which was evidenced by the overlapping of its 95% confidence intervals of the mean tenfold cross-validation or estimated generalisation errors. However, the Hurdle Logistic-Log-Normal model was better on average according to generalisation errors both in the prediction of Brazilian utility values (MAE = 0.1037, MSE = 0.0178, and RMSE = 0.1332) and for those of the UK (MAE = 0.1476, MSE = 0.0443, and RMSE = 0.2099). CONCLUSIONS: Mapping EQ-5D-3L responses or deriving health utilities directly from WHOQOL-HIV Bref responses can be a valid alternative for settings with no preference-based health utility data.

Effectiveness of direct-acting agents for hepatitis C and liver stiffness changing after sustained virological response.

BACKGROUND AND AIM: Few studies have evaluated sustained virological response (SVR) rates by direct-acting agents (DAAs) and liver stiffness measurement (LSM) changing post-SVR in limited-resource settings. We aimed to describe the effectiveness of DAAs for hepatitis C virus treatment and to assess the changing of LSM post-SVR. METHODS: This retrospective study analyzed data of consecutive hepatitis C virus-infected patients treated by DAAs from 2015 to 2017 in two tertiary centers in Brazil. SVR rates were reported by intention-to-treat and per-protocol analyses. LSM by transient elastography performed before treatment and post-SVR was compared, and logistic regression models were performed. RESULTS: Six hundred seventy-one patients (63% female, 62 years [55-68], 89% genotype 1, 8% HIV co-infected, and 64% with cirrhosis) were included. Most patients were treated by sofosbuvir/daclatasvir ± ribavirin (74%) and sofosbuvir/simeprevir ± ribavirin (21%). SVR rates (95% confidence interval [CI]) were 94.6% (92.7-96.1) and 97.8% (96.4-98.7) for intention-to-treat and per-protocol analyses, respectively. The leading adverse event was anemia (9.6% [95% CI 7.6-12.1]). Pretreatment and post-SVR12 LSM were available in 400 patients. LSM had significantly decreased after SVR (13.6 kPa [interquartile range, 10.0-21.6] vs 10.2 kPa [7.0-17.6], P < 0.001). A total of 167 patients (42%) decreased at least 30% of LSM post-SVR. The absence of type 2 diabetes (odds ratio = 1.52 [95% CI 1.05-2.21], P = 0.028) and presence of platelet count ≥ 150 × 109 /mm3 (odds ratio = 1.75 [1.23-2.50], P = 0.002) were independently associated with a significant LSM regression (≥ 30%) post-SVR. CONCLUSION: DAAs were highly effective and safe, and LSM significantly decreased after SVR in a real-life cohort in Brazil. The absence of type 2 diabetes and presence of high platelet count were independently associated with LSM decrease post-SVR.

Reliability and safety of transnasal compared to conventional endoscopy for detecting oesophageal varices in cirrhotic patients.

BACKGROUND & AIMS: Unsedated transnasal endoscopy may be used for detecting oesophageal varices. However, few studies evaluated feasibility and accuracy of this technique. We aimed to evaluate accuracy, interobserver agreement and safety of the transnasal ultrathin compared to conventional endoscopy in patients with cirrhosis. METHODS: This cross-sectional study included consecutive patients referred for screening or surveillance of oesophageal varices. Patients underwent unsedated transnasal and sedated conventional endoscopies at the same day, which were recorded in a digital video file and randomly analysed by two double-blinded endoscopists. High-risk varices were defined by the presence of large calibre or red wale marks. Accuracy, interobserver agreement and safety of transnasal were compared to conventional endoscopy. RESULTS: One hundred and thirty-three cirrhotic patients (48% male, aged of 60 ± 5, 34% Child-Pugh B/C and 71% of cases for variceal screening) were included in the study. The prevalence of oesophageal varices and high-risk oesophageal varices were 59% (n = 79) and 29% (n = 39) respectively. For the presence of oesophageal varices, transnasal GIE yielded sensitivity of 94% [95% Confidence Interval, CI 88-99], specificity of 89% [81-97] as well as positive and negative predictive value of 93% and 91% respectively. A satisfactory interobserver agreement was observed for the presence of oesophageal varices (κ = 0.89) and high-risk varices (κ = 0.65). No serious adverse events were recorded; transnasal GIE was safe and significantly associated with lower rates of hypoxaemia (P < .0001) and hypotension (P < .0001) compared to conventional endoscopy. CONCLUSIONS: Unsedated transnasal endoscopy was safe and had an excellent accuracy and high interobserver agreement for detecting oesophageal varices and for identifying high-risk varices in cirrhotic patients.

Cost-effectiveness of diagnostic and therapeutic interventions for chronic hepatitis C: a systematic review of model-based analyses.

BACKGROUND: Decisions about which subgroup of chronic hepatitis C (CHC) patients should be treated with direct acting anti-viral agents (DAAs) have economic importance due to high drug prices. Treat-all DAA strategies for CHC have gained acceptance despite high drug acquisition costs. However, there are also costs associated with the surveillance of CHC to determine a subgroup of patients with significant impairment. The aim of this systematic review was to describe the modelling methods used and summarise results in cost-effectiveness analyses (CEAs) of both CHC treatment with DAAs and surveillance of liver disease. METHODS: Electronic databases including Embase and Medline were searched from inception to May 2015. Eligible studies included models predicting costs and/or outcomes for interventions, surveillance, or management of people with CHC. Narrative and quantitative synthesis were conducted. Quality appraisal was conducted using validated checklists. The review was conducted following principles published by NHS Centre for Research and Dissemination. RESULTS: Forty-one CEAs met the eligibility criteria for the review; 37 evaluated an intervention and four evaluated surveillance strategies for targeting DAA treatment to those likely to gain most benefit. Included studies were of variable quality mostly due to reporting omissions. Of the 37 CEAs, eight models that enabled comparative analysis were fully appraised and synthesized. These models provided non-unique cost-effectiveness estimates in a specific DAA comparison in a specific population defined in terms of genotype, prior treatment status, and presence or absence of cirrhosis. Marked heterogeneity in cost-effectiveness estimates was observed despite this stratification. Approximately half of the estimates suggested that DAAs were cost-effective considering a threshold of US$30,000 and 73% with threshold of US$50,000. Two models evaluating surveillance strategies suggested that treating all CHC patients regardless of the staging of liver disease could be cost-effective. CONCLUSIONS: CEAs of CHC treatments need to better account for variability in their estimates. This analysis suggested that there are still circumstances where DAAs are not cost-effective. Surveillance in place of a treat-all strategy may still need to be considered as an option for deploying DAAs, particularly where acquisition cost is at the limit of affordability for a given health system.

The therapeutic landscape of non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is characterized by lobular inflammation and hepatocellular ballooning, and may be associated with liver fibrosis leading to cirrhosis and its complications. A pharmacological approach is necessary to treat NASH because of failure to change dietary habits and lifestyle in most patients. Insulin resistance with an increased release of free fatty acids, oxidative stress and activation of inflammatory cytokines seem to be key features for disease progression. Thiazolidinediones, such as pioglitazone and antioxidant agents, such as vitamin E, were the first pharmacological options to be evaluated for NASH. In recent years, several new molecules that target different pathways related to NASH pathogenesis, such as liver metabolic homeostasis, inflammation, oxidative stress and fibrosis, have been developed. Obeticholic acid (INT-747) and elafibranor (GFT-505) have provided promising results in phase IIb, randomized, placebo-controlled clinical trials and they are being evaluated in ongoing phase III studies. Most of the potential treatments for NASH are under investigation in phase II studies, with some at phase I. This diversity in possible treatments calls for a better understanding of NASH in order to enrich trial populations with patients more susceptible to progress and to respond. This manuscript aims to review the pharmacological NASH treatment landscape.

Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury.

BACKGROUND & AIMS: The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls. METHODS: An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins. RESULTS: We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated. CONCLUSIONS: These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.

Micro-costing analysis of guideline-based treatment by direct-acting agents: the real-life case of hepatitis C management in Brazil.

BACKGROUND: Eradication of hepatitis C virus (HCV) using direct-acting agents (DAA) has been associated with a financial burden to health authorities worldwide. We aimed to evaluate the guideline-based treatment costs by DAAs from the perspective of the Brazilian Ministry of Health (BMoH). METHODS: The activity based costing method was used to estimate the cost for monitoring/treatment of genotype-1 (GT1) HCV patients by the following strategies: peg-interferon (PEG-IFN)/ribavirin (RBV) for 48 weeks, PEG-IFN/RBV plus boceprevir (BOC) or telaprevir (TEL) for 48 weeks, and sofosbuvir (SOF) plus daclastavir (DCV) or simeprevir (SIM) for 12 weeks. Costs were reported in United States Dollars without (US$) and with adjustment for purchasing power parity (PPP$). Drug costs were collected at the National Database of Health Prices and an overview of the literature was performed to assess effectiveness of SOF/DCV and SOF/SIM regimens in real-world cohorts. RESULTS: Treatment costs of GT1-HCV patients were PPP$ 43,176.28 (US$ 24,020.16) for PEG-IFN/RBV, PPP$ 71,196.03 (US$ 39,578.23) for PEG-IFN/RBV/BOC and PPP$ 86,250.33 (US$ 47,946.92) for PEG-IFN/RBV/TEL. Treatment by all-oral interferon-free regimens were the less expensive approach: PPP$ 19,761.72 (US$ 10,985.90) for SOF/DCV and PPP$ 21,590.91 (US$ 12,002.75) for SOF/SIM. The overview reported HCV eradication in up to 98% for SOF/DCV and 96% for SOF/SIM. CONCLUSION: Strategies with all oral interferon-free might lead to lower costs for management of GT1-HCV patients compared to IFN-based regimens in Brazil. This occurred mainly because of high discounts over international DAA prices due to negotiation between BMoH and pharmaceutical industries.

Age-standardized mortality rates related to viral hepatitis in Brazil.

BACKGROUND: Liver-related mortality has been increasing worldwide. We aimed to estimate the age-standardized mortality rates from viral hepatitis in Brazil. METHODS: The Brazilian National Death Registry was analyzed from 2008 to 2014. Viral hepatitis deaths were defined by the following ICD-10 codes in the death certificate: hepatitis A [B15.0; B15.9]; hepatitis B [B16.2; B16.9; B18.1]; hepatitis C [B17.1; B18.2]; hepatitis Delta [B16.0; B16.1; B18.0; B17.0] and other viral hepatitis [B17.2; B17.8; B18.8; B18.9; B19.0; B19.9]. Crude mortality rates were calculated by the ratio between total number of deaths and estimated population. Mortality rates were age-standardized by the direct method using the WHO standard population. RESULTS: Thirty four thousand ,nine hundred seventy eight deaths had viral hepatitis mentioned in their death certificate [65% male, aged 58 years, 73% associated with hepatitis C]. Age-standardized mortality rate (95% CI) due to viral hepatitis was 2.695 (2.667-2.724) deaths per 100,000 inhabitants: South region had the higher rates [3.997 (3.911-4.085)]. Mortality rates associated with hepatitis A and Delta were 0.032 (0.029-0.035) and 0.028 (0.025-0.031), respectively. Hepatitis C mortality rates were 4-fold higher than those associated with hepatitis B [1.964 (1.940-1.989) vs 0.500 (0.488-0.512)]. South region had the higher rates for hepatitis C [3.163 (3.087-3.241)] and North had the higher rates for hepatitis A [0.066 (0.049-0.087)], B [0.986 (0.918-1.058)] and Delta [0.220 (0.190-0.253)]. CONCLUSION: Viral hepatitis remains a major public health issue in Brazil. Mortality rates were not homogeneous across the country, suggesting that health policies should be customized according to geographical location.