Occult HBV Infection in Patients Infected by HIV or HCV: Comparison between HBV-DNA and Two Assays for HBsAg.

We investigated the frequency and serological correlates of occult hepatitis B virus infection (OBI) and the potential impact of a highly sensitive assay for HBsAg in subjects infected by human immunodeficiency virus (HIV) or hepatitis C virus (HCV), who are also at risk for hepatitis B virus (HBV) infection, often in an occult form. Samples from 499 patients with HIV, all HBsAg negative and anti-HBc positive, and 137 patients with HCV were tested for HBV-DNA, anti-HBc, anti-HBs, and HBsAg by a conventional and highly sensitive assay. HBV biomarkers were detected in 71.5% of HCV-RNA-positive, with a higher prevalence of cases positive only for anti-HBc in patients with HCV than in those with HIV. HBV-DNA was detectable in 0.6% of HIV-positive and 7.3% of HCV-RNA-positive patients. Among patients with HCV, four were positive for HBsAg and negative for HBV-DNA, bringing the rate of HBV-active infection in this group to 10.2%. Active HBV infection was not related to gender or specific patterns of HBV biomarkers but was higher in HCV patients coinfected by HIV compared to those infected only by HCV. Monitoring patients at high risk for HBV infection and reactivation may require testing for both HBV-DNA and HBsAg.

Serological and Molecular Characterization of Occult HBV Infection in Blood Donors from South Italy.

Despite good vaccine coverage and careful blood donor selection policies, hepatitis B virus (HBV) is still the most frequent viral infection among blood donors (BDs) in Italy, mostly in the occult form (OBI). We studied the virological features of OBI in BDs from South Italy by serology, molecular testing for HBV-DNA, and sequencing for HBV genotypes and mutations. One hundred and two samples from 95 BDs (22.1% first time, 87.9% regular, median age 57 years) positive for HBV-DNA and negative for HBsAg were retrospectively analyzed. HBV biomarkers were detected in 96.9% (anti-HBc in 44.2%, anti-HBc plus anti-HBs in 49.5%, anti-HBs alone in 3.2%). No risk factor was declared by 45.3% of donors. HBV-DNA levels were very low (median: 7 IU/mL). All samples harbored HBV genotype D and single or multiple mutations in the S gene were found in 28/36 sequences analyzed and in 75% of donors. Mutations were unrelated to gender, donor group or serological patterns. An HBsAg assay with enhanced sensitivity was positive in samples from seven donors (7.4%), two of which negative for HBV-DNA by real-time PCR. OBI still represents a risk for HBV transmission from blood donations; screening by highly sensitive serological and molecular assays is warranted.

Tierra Del Fuego: What Is Left from the Precolonial Male Lineages?

Similar to other South American regions, Tierra del Fuego has an admixed population characterized by distinct ancestors: Native Americans who first occupied the continent, European settlers who arrived from the late 15th century onwards, and Sub-Saharan Africans who were brought to the Americas for slave labor. To disclose the paternal lineages in the current population from Tierra del Fuego, 196 unrelated males were genotyped for 23 Y-STRs and 52 Y-SNPs. Haplotype and haplogroup diversities were high, indicating the absence of strong founder or drift events. A high frequency of Eurasian haplogroups was detected (94.4%), followed by Native American (5.1%) and African (0.5%) ones. The haplogroup R was the most abundant (48.5%), with the sub-haplogroup R-S116* taking up a quarter of the total dataset. Comparative analyses with other Latin American populations showed similarities with other admixed populations from Argentina. Regarding Eurasian populations, Tierra del Fuego presented similarities with Italian and Iberian populations. In an in-depth analysis of the haplogroup R-M269 and its subtypes, Tierra del Fuego displayed a close proximity to the Iberian Peninsula. The results from this study are in line with the historical records and reflect the severe demographic change led mainly by male newcomers with paternal European origin.

Optimizing diagnostic algorithms to advance Hepatitis C elimination in Italy: A cost effectiveness evaluation.

OBJECTIVES: Optimized diagnostic algorithms to detect active infections are crucial to achieving HCV elimination. We evaluated the cost effectiveness and sustainability of different algorithms for HCV active infection diagnosis, in a context of a high endemic country for HCV infection. METHODS: A Markov disease progression model, simulating six diagnostic algorithms in the birth cohort 1969-1989 over a 10-year horizon from a healthcare perspective was used. Conventionally diagnosis of active HCV infection is through detection of antibodies (HCV-Ab) detection followed by HCV-RNA or HCV core antigen (HCV-Ag) confirmatory testing either on a second sample or by same sample reflex testing. The undiagnosed and unconfirmed rates were evaluated by assays false negative estimates and each algorithm patients' drop-off. Age, liver disease stages distribution, liver disease stage costs, treatment effectiveness and costs were used to evaluate the quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratios (ICER). RESULTS: The reference option was Rapid HCV-Ab followed by second sample HCV-Ag testing which produced the lowest QALYs (866,835 QALYs). The highest gains in health (QALYs=974,458) was obtained by HCV-RNA reflex testing which produced a high cost-effective ICER (€891/QALY). Reflex testing (same sample-single visit) vs two patients' visits algorithms, yielded the highest QALYs and high cost-effective ICERs (€566 and €635/QALY for HCV-Ag and HCV-RNA, respectively), confirmed in 99.9% of the 5,000 probabilistic simulations. CONCLUSIONS: Our data confirm, by a cost effectiveness point of view, the EASL and WHO clinical practice guidelines recommending HCV reflex testing as most cost effective diagnostic option vs other diagnostic pathways.

Predicting the protective humoral response to a SARS-CoV-2 mRNA vaccine.

OBJECTIVES: Simple and standardized methods to establish correlates to vaccine-elicited SARS-CoV-2 protection are needed. METHODS: An observational study on antibody response to a mRNA vaccine (Comirnaty) was performed on health care workers (V, n=120). Recovered COVID-19 patients (N, n=94) were used for comparison. Antibody response was evaluated by a quantitative anti-receptor binding domain IgG (anti-RBD) commercial assay and by virus microneutralization test (MNT), in order to establish a threshold of anti-RBD binding antibody units (BAU) able to predict a robust (≥1:80) MNT titer. RESULTS: Significant correlation between BAU and MNT titers was found in both V and N, being stronger in V (rs=0.91 and 0.57 respectively, p<0.001); a higher incremental trend starting from MNT titer 1:80 was observed in the V group. The 99% probability of high MNT titer (≥1:80) was reached at 1,814 and 3,564 BAU/mL, and the area under the receiver operating characteristic (ROC) curve was 0.99 (CI: 0.99-1.00) and 0.78 (CI: 0.67-0.86) in V and N, respectively. CONCLUSIONS: A threshold of 2,000 BAU/mL is highly predictive of strong MNT response in vaccinated individuals and may represent a good surrogate marker of protective response. It remains to be established whether the present results can be extended to BAU titers obtained with other assays.

Hepatitis C Virus Core Antigen (HCVAg): an affordable assay to monitor the efficacy of treatment in DAAs era.

Hepatitis C virus (HCV) Core Antigen (HCVAg) and HCV-RNA were tested in 962 plasma/serum samples from 180 patients during Direct Antiviral Agents (DAAs) treatment and at follow-up. One hundred and eighty individuals were included: 71% carried advanced fibrosis and 43% were treatment-experienced. A Sustained Virological Response (SVR) was achieved in 166/180 (92%) individuals: 96/102 (94.1%) na ve and 70/78 (89.7%) treatment-experienced (p=0.20). The baseline median levels of HCV-RNA and HCVAg were not significantly different between individuals achieving SVR (5.92 x 105 IU/mL, IQR 5.4-6.4, and 3,417 fmol/L, 2,900-3,795) and those without SVR (6.06 x 105 IU/mL, 5.63-6.57, and 3,391 fmol/L, 2,828-4,077). The HCV-RNA vs. HCVAg assays results showed a fair correlation with an overall moderate qualitative agreement (kappa=0.52). Among treatment-failed individuals, at failure 100% of the assays results were positive for both techniques, with HCV-RNA median value 3.09 x 105 IU/mL (2.10-29.09) and HCVAg median value 1570.28 fmol/L (360.15-9317.67). Undetectable HCV-RNA at EOT showed sensitivity 54%, specificity 100%, negative predictive value (NPV) 93% and positive predictive value (PPV) 100%. Undetectable HCVAg at EOT showed sensitivity 74%, specificity 100%, NPV 97% and PPV 100%. The operative and economic advantages of the HCVAg support the alternative use of HCVAg to monitor DAAs treatment outcome.

Seroprevalence of hepatitis E virus in Argentinean blood donors.

BACKGROUND: Hepatitis E virus (HEV) is the main cause of enteric acute viral hepatitis worldwide. In this epidemiological framework, it has become a threat to blood safety and a relevant issue for blood transfusions. However, there is a paucity of data regarding prevalence of HEV infection. The aim of this study was to determine HEV seroprevalence in blood donors from different regions from Argentina. MATERIAL AND METHODS: Serum samples from 391 individuals attending five blood donor centers located in different regions from Argentina were analyzed for anti-HEV IgG and anti-HEV IgM. RESULTS: Overall, anti-HEV IgG was detected in 44 out of 391 (11.3%) samples. HEV prevalence ranged from 5.1 to 20.0% among different country regions. A significant difference in blood donors' age was observed between anti-HEV IgG positive and negative individuals [44 (37-51) vs. 35 (27-43), P < 0.001, respectively]. Anti-HEV IgM was detected in 8 out of 44 (18.2%) anti-HEV IgG positive cases. CONCLUSION: Anti-HEV IgG was detected in blood donor samples from five analyzed Argentinean regions, highlighting the wide distribution of the virus in the country. HEV prevalence was variable among different regions and significantly higher in older donors. Given the evidence of anti-HEV IgM presence in blood donors, suggesting a potential risk of transfusion-transmitted HEV, screening for HEV in blood units to be used in vulnerable population would be desirable. Molecular studies for detection of viremic donors and donor-recipients follow-up are necessary to certainly determine the risk of transfusion-transmitted HEV in Argentina.

The combination of PIVKA-II and AFP improves the detection accuracy for HCC in HBV caucasian cirrhotics on long-term oral therapy.

BACKGROUND & AIMS: Protein induced by vitamin K absence or antagonist-II (PIVKA-II) has been suggested as a serum biomarker for hepatocellular carcinoma (HCC) in Asian hepatitis B virus (HBV)-treated subjects but no studies tested it in Caucasian cirrhotics long-term nucleos(t)ide analogues (NUCs)-treated. We assessed the detection accuracy of PIVKA-II alone or in combination with alpha-foetoprotein (AFP) in patients under surveillance. METHODS: This cross-sectional, single centre case-control study was conducted in 212 NUC-treated cirrhotics: 64 HCC and 148 HCC-free controls for 84 (60-107) months. PIVKA-II was determined by a CMIA immunoassay (Abbott; limit of quantification: 8.2 mAU/mL). RESULTS: Protein induced by vitamin K absence or agonist II (PIVKA-II) and AFP levels were significantly higher in HCC patients [Barcelona Clinic Liver Cancer staging system stage 0/A in 91%, diameter 20 (6-50) mm] compared to controls: 109 (17-12 157) vs 31 (13-82) mAU/mL and 5 (1-1163) vs 2 (1-7) ng/mL (P < .001 for both markers), with a cut-off of 48 mAU/mL and 4.2 ng/mL by AUROC analysis. The PIVKA-II 82 mAU/mL and AFP 7 ng/mL cut-offs showed 100% specificity, with the former more sensitive (54% vs 42%), accurate (86% vs 83%), with higher negative predictive value (80% vs 76%) compared to AFP for HCC detection. PIVKA-II more frequently than AFP levels exceeded the cut-off 6-18 months before HCC diagnosis. Combining PIVKA-II with AFP increased sensitivity, accuracy and negative predictive values to 67%, 90% and 85%, preserving 100% specificity. PIVKA-II was associated with lesions >20 mm or neoplastic thrombosis. CONCLUSIONS: Combination of PIVKA-II and AFP increases the detection rate for HCC in NUC-treated HBV Caucasian cirrhotics, a potential new approach for surveillance.

Hepatitis B surface antibodies seroprevalence among people born before and after implementation of universal HBV vaccination.

Universal vaccination is the most effective strategy to control hepatitis B virus (HBV) infection. In Argentina, vaccination against HBV was incorporated in year 2000 for newborns and in 2003 for 11 years old children. However, there is a paucity of data about protection levels against HBV infection. The aim of this work was to determine the prevalence of seroprotective anti-HBs antibodies (aHBs) in Argentina. Serum samples negative for HBsAg and anti-HBc from 132 children born after year 2000 and 762 blood donors, older than 18 years, from five centers across the country, were analyzed for aHBs. Titers ≥10 mIU/mL were observed in 74/132 children (56.1%) and 336/762 (44.1%) in blood donors. The median age for blood donors was 33.9 (23-43); from them, 210 (27.6%) were born after 1992 and, therefore, were catch-up by vaccine implementation at 11 years old age. Donors born in 1992 or before showed a significantly lower frequency of protection (32.2%) compared to donors born after 1992 (75.2%), p < 0.0001. In addition, significant differences were observed in the status of seroprotection between different participating centers (p = 0.024). Implementation of HBV vaccine in 2000 and 2003 implied an overall increase of the aHBs seroprotective rates, with a particularly adequate response in children vaccinated at 11 years old age. The observed results suggest that population born in 1992 or before is currently the most susceptible. Consequently, it would be advisable to become aware of the risk of transmission in this age group and to stress this population vaccination campaigns.

Community screening for hepatitis C virus infection in a low-prevalence population.

BACKGROUND: Age cohort screening for hepatitis C virus (HCV) might be an effective strategy if the majority of undiagnosed cases are concentrated in a particular age group. The objective of this study was to determine HCV prevalence in different age cohorts of the general population in the Central European part of Russia and second, to assess feasibility of HCV antigen testing for community screening programs. METHODS: Sera from 2027 volunteers were tested for anti-HCV (Architect Anti-HCV, Abbott Laboratories). All anti-HCV reactive samples were confirmed in an immunoblot and tested for HCV Ag (ARCHITECT HCV Ag, Abbott Laboratories), HCV RNA and HCV viral load. RESULTS: Out of 31 individuals with anti-HCV reactive result, 22 (71%) were confirmed by immunoblot, six were false positives and three were indeterminate. Active infection was observed in 73% of anti-HCV confirmed positives. Five out of 16 individuals had low HCV-RNA levels (< 10,000 IU/mL) and one of those had a very low level (594 IU/mL). Agreement between HCV Ag and HCV RNA was 100%. Total anti-HCV and active HCV infection rates were 1.09% (22/2027) and 0.79% (16/2027), respectively. The peak rates were observed in people 60 years or older (anti-HCV: 2.84% [95% CI: 1.66-4.74%], 13/319; HCV RNA/HCV Ag: 2.23% [95% CI: 1.20-4.00%], 10/319). CONCLUSIONS: Overall HCV prevalence is low, except in people 60 years or older. The latter should be considered as a target group for HCV screening. The high agreement between HCV RNA and HCV Ag suggests the utility of HCV Ag testing to confirm active infection in screening programs.

Streamlining the screening cascade for active Hepatitis C in Russia: A cost-effectiveness analysis.

OBJECTIVE: Screening for hepatitis C in Russia is a complex process that involves several visits and stepwise testing, limiting adherence and substantially reducing the yield in the identification of active infections. We aimed to evaluate the cost-effectiveness of different screening algorithms from a health system perspective. METHODS: A decision analytic model was applied to a hypothetical adult population eligible to participate in a general screening program for hepatitis C in Russia. The standard pathway (I: Screen for anti-HCV antibodies followed by a nucleic acid test for HCV RNA on antibody positives) was compared to three alternatives (II: Screen for antibodies, a reflexed test for HCV antigen on antibody positives, and RNA on antigen negatives; III: Screen for antibodies, a reflexed test for HCV antigen on antibody positives; IV: Screen for antigen). Each strategy considered a cascade of events (referral, adherence, testing, diagnosis) that must occur for screening to be effective. The primary measure of effectiveness was the number of diagnosed active infections. Calculations followed a health system perspective with costs derived from 2017 reimbursement rates and a willingness-to-pay of 2,000RUB ($82) per diagnosed active infection. Model was tested with deterministic and probabilistic sensitivity analyses. RESULTS: Non-adherence to screening stages reduced the capture rate of active infections in Strategy I from 79.0% to 40.6%. Strategies II, III, and IV were less affected and identified 69%, 67%, and 104% more infections. Average costs per diagnosed infection were decreased by 41% from 89,599RUB ($3,681) for I to 53,072RUB ($2,180), 53,004RUB ($2,177), and 59,633RUB ($2,450) for II, III, and IV, respectively. With a probability of 97%, Strategy III was most cost-effective with an incremental cost-effectiveness ratio vs. I of -1,373RUB (CI: -5,011RUB to -2,033RUB; $-56; CI: -$206 to -$84). Below a willingness-to-pay of 91,000RUB ($3,738), Strategy IV was not cost-effective. Sensitivity analyses confirmed the robustness of results. CONCLUSIONS: Testing strategies for hepatitis C with HCV antigen on HCV antibody positive cases offer a streamlining opportunity for population screening programs. Those shall increase the chances for detecting active infections and are cost-effective over current practice in Russia.

HCV core antigen comes of age: a new opportunity for the diagnosis of hepatitis C virus infection.

The diagnosis of hepatitis C virus (HCV) infection has been traditionally based on the detection of the host antibody response. Although antibody assays are available in different formats and are fairly accurate, they cannot distinguish between an ongoing infection with HCV replicative activity and a past infection where HCV has been cleared, spontaneously or after a successful therapy. As a chronic infection is mostly asymptomatic until the late clinical stages, there is a compelling need to detect active HCV infection by simple and reproducible methods. On this purpose, the clinical guidelines have suggested to search for the HCV ribonucleic acid (HCV-RNA) after anti-HCV has been detected, but this second step carries several limitations especially for population screening. The availability of fast and automated serological assays for the hepatitis C core antigen (HCVAg) has prompted an update of the guidelines that now encompass the use of HCVAg as a practical alternative to HCV-RNA, both for screening and monitoring purposes. In this paper, we summarize the features, benefits and limitations of HCVAg testing and provide an updated compendium of the evidences on its clinical utility and on the indications for use.

An infant formula containing dairy lipids increased red blood cell membrane Omega 3 fatty acids in 4 month-old healthy newborns: a randomized controlled trial.

BACKGROUND: When breastfeeding is not possible, infants are fed formulas (IF) in which lipids are usually of plant origin. However, the use of dairy fat in combination with plant oils enables a lipid profile closer to breast milk in terms of fatty acid (FA) composition, triglyceride structure, polar lipids and cholesterol contents. The objective of this study was to determine the effect of an IF containing a mix of dairy fat and plant oils on Omega-3 FA content in red blood cells (RBC). METHODS: This study was a monocentric, double-blind, controlled, randomized trial. Healthy term infants were fed formulas containing a mix of dairy fat and plant oils (D), plant oils (P) or plant oils supplemented with ARA and DHA (PDHA). Breastfed infants were enrolled as a reference group (BF). FA in RBC phosphatidylethanolamine was evaluated after 4 months and FA in whole blood were evaluated at enrollment and after 4 months by gas chromatography. Differences between groups were assessed using an analysis of covariance with sex and gestational age as covariates. RESULTS: Seventy IF-fed and nineteen BF infants completed the protocol. At 4 months, RBC total Omega-3 FA levels in infants fed formula D were significantly higher than in group P and similar to those in groups PDHA and BF. RBC DHA levels in group D were also higher than in group P but lower than in groups PDHA and BF. RBC n-3 DPA levels in group D were higher than in groups P, PDHA and BF. A decrease in proportions of Omega-3 FA in whole blood was observed in all groups. CONCLUSIONS: A formula containing a mix of dairy lipids and plant oils increased the endogenous conversion of Omega-3 long-chain FA from precursor, leading to higher total Omega-3, DPA and DHA status in RBC than a plant oil-based formula. Modifying lipid quality in IF by adding dairy lipids should be considered as an interesting method to improve Omega-3 FA status. TRIAL REGISTRATION: Identifier NCT01611649 , retrospectively registered on May 25, 2012.

Prospective associations between dietary patterns and high sensitivity C-reactive protein in European children: the IDEFICS study.

PURPOSE: This prospective study explores high sensitivity C-reactive protein (hs-CRP) levels in relation to dietary patterns at two time points in European children. METHODS: Out of the baseline sample of the IDEFICS study (n = 16,228), 4020 children, aged 2-9 years at baseline, with available hs-CRP levels and valid data from a food frequency questionnaire (FFQ) at baseline (T0) and 2 years later (T1) were included. K-means clustering algorithm based on the similarities between relative food consumption frequencies of the FFQ was applied. hs-CRP was dichotomized according to sex-specific cutoff points. Multilevel logistic regression was performed to assess the relationship between dietary patterns and hs-CRP adjusting for covariates. RESULTS: Three consistent dietary patterns were found at T0 and T1: 'animal protein and refined carbohydrate', 'sweet and processed' and 'healthy'. Children allocated to the 'protein' and 'sweet and processed' clusters at both time points had significantly higher odds of being in the highest category of hs-CRP (OR 1.47; 95% CI 1.03-2.09 for 'animal protein and refined carbohydrate' and OR 1.44; 95% CI 1.08-1.92 for 'sweet and processed') compared to the 'healthy' cluster. The odds remained significantly higher for the 'sweet and processed' pattern (OR 1.39; 95% CI 1.05-1.84) when covariates were included. CONCLUSIONS: A dietary pattern characterized by frequent consumption of sugar and processed products and infrequent consumption of vegetables and fruits over time was independently related with inflammation in European children. Efforts to improve the quality of the diet in childhood may prevent future diseases related with chronic inflammation.

Identifying cost-effective screening algorithms for active hepatitis C virus infections in a high prevalence setting.

OBJECTIVE: To evaluate the cost-effectiveness of different screening patterns for active chronic hepatitis C virus (HCV) infections utilizing the hepatitis C core antigen test compared to standard care in the context of a general screening program in a high-prevalence country. METHODS: This study developed a decision analytic model to estimate the cost-effectiveness of four screening algorithms for the detection of active HCV infections among asymptomatic individuals with an unknown HCV status in a context of high (>5%) HCV prevalence. Three algorithms started with a serological test for antibodies (AB) followed by a nucleic acid test for HCV-RNA (RNA), the HCVAg (AG) assay, or both. An additional single marker screening strategy with AG was added to the analysis. By the example of the Republic of Georgia, strategies were compared in terms of total costs for screening and diagnosis of an active infection from a health system perspective. RESULTS: Replacing RNA with AG for confirmation of positive AB identified fewer active infections (-110 per 100,000 screened subjects) at significantly reduced total costs (-$2.74 per screened) and costs per diagnosed infection (-$44). Adding a subsequent RNA confirmatory test on AG negative results captured at least the same rate compared to the standard (AB followed by RNA) at still reduced costs (-$1.16 per subject screened, -$22 per case detected). Utilizing AG as the frontline test revealed the highest detection rate (97.9%) at the highest costs (+$3.80 per subject, +$323 per case detected vs standard). CONCLUSION: A combined pattern of HCV AB screening followed by sequential confirmation with AG and RNA on AG negatives would provide equal or better diagnostic performance at lower cost over a broad range of scenarios. Potential long-term consequences of screening strategies to patients and society have to be considered, since the latency period for HCV to develop into severe liver disease is long.