Publications by authors named "Maria Buti"

294 Publications

Impact of HBeAg on Hepatocellular Carcinoma Risk During Oral Antiviral Treatment in Patients with Chronic Hepatitis B.

Clin Gastroenterol Hepatol 2021 Sep 6. Epub 2021 Sep 6.

Hospital U Puerta de Hierro, IDIPHIM CIBERehd, Madrid, Spain.

Background & Aims: Antiviral treatment from hepatitis B envelope antigen (HBeAg)-positive status may attenuate the integration of hepatitis B virus DNA into the host genome causing hepatocellular carcinoma (HCC). We investigated the impact of HBeAg status at the onset of antiviral treatment on the risk of HCC.

Methods: The incidence of HCC was evaluated in Korean chronic hepatitis B (CHB) patients who started entecavir or tenofovir in either HBeAg-positive or HBeAg-negative phase. The results in the Korean cohort were validated in a Caucasian PAGE-B cohort.

Results: A total of 9,143 Korean patients (mean age=49.2 years) were included: 49.1% were HBeAg-positive and 49.2% had cirrhosis. During follow-up (median=5.1 years), 916 patients (10.0%) developed HCC. Baseline HBeAg-positivity was not associated with the risk of HCC in the entire cohort or cirrhotic subcohort. However, in the non-cirrhotic subcohort, HBeAg-positivity was independently associated with a lower risk of HCC in multivariable (adjusted hazard ratio [aHR]=0.41, 95% confidence interval [CI]=0.26-0.66), propensity score matching (aHR=0.46, 95% CI=0.28-0.76), and inverse probability weighting analyses (aHR=0.44, 95% CI=0.28-0.70). In the Caucasian cohort (n=719, mean age=51.8 years, HBeAg-positive=20.3%, cirrhosis=34.8%), HBeAg-positivity was not associated with the risk of HCC either in the entire cohort or cirrhotic subcohort. In the non-cirrhotic subcohort, none of the HBeAg-positive group developed HCC, although the difference failed to reach statistical significance (aHR=0.21, 95% CI=0.00-1.67).

Conclusions: This multinational cohort study implies that HBeAg-positivity at the onset of antiviral treatment seems to be an independent factor associated with a lower risk of HCC in CHB patients without cirrhosis, but not in those with cirrhosis.
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http://dx.doi.org/10.1016/j.cgh.2021.09.001DOI Listing
September 2021

Naïve hepatitis B e antigen-negative chronic hepatitis B patients are at risk of carotid atherosclerosis: A prospective study.

World J Gastroenterol 2021 Aug;27(30):5112-5125

Department of Medicine of the UAB, Hospital Universitari Vall d'Hebron, Barcelona 08035, Spain.

Background: There is an increased risk of atherosclerosis in patients with chronic hepatitis C or human immunodeficiency virus, but there is scarce data on hepatitis B virus infection. The hypothesis of this study is that hepatitis B virus infection increases the risk of carotid plaques and subclinical atherosclerosis in naïve hepatitis B e antigen (HBeAg) negative subjects.

Aim: To assess the rate of carotid plaques and subclinical atherosclerosis in naïve HBeAg negative subjects in comparison with a cohort of healthy controls.

Methods: Prospective case-control collaborative study conducted in two tertiary hospitals. Four hundred and two subjects prospectively recruited at the outpatient clinic were included from May 2016 to April 2017: 201 naïve HBeAg-negative hepatitis B virus-infected [49 chronic hepatitis B (CHB) and 152 inactive carriers(ICs)] and 201 healthy controls. Anthropomorphic and metabolic measures, liver stiffness and carotid Doppler ultrasound were performed. Subclinical atherosclerosis was established on an intima-media thickness increase of ≥1.2 mm and/or the presence of carotid plaques. Normally distributed quantitative variables were compared with the Student test and those with a non-normal distribution with the Mann-Whitney test. Categorical variables were compared between groups using the or Fisher exact test.

Results: Carotid plaques were found more often in CHB (32.7%) than ICs (17.1%) or controls (18.4%) ( = 0.048). Subclinical atherosclerosis was also increased in CHB (40.8%) ICs (19.1%) or controls (19.4%) ( = 0.003). No differences in the risk of atherosclerosis were observed between controls and ICs. The factors independently associated with the presence of carotid plaques were age [odds ratio(OR) 1.43, < 0.001] and CHB (OR 1.18, = 0.004) and for subclinical atherosclerosis, age (OR 1.45, < 0.001), CHB (OR 1.23, < 0.001) and diabetes (OR 1.13, = 0.028). In the subset of young subjects (< 50 years), carotid plaques (12.5% 1.1%, = 0.027) and subclinical atherosclerosis (12.5% 2.2%, = 0.058) were more frequent among CHB than ICs.

Conclusion: Untreated HBeAg-negative CHB is an independent risk factor for carotid plaques and subclinical atherosclerosis, while ICs present a similar risk to controls.
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http://dx.doi.org/10.3748/wjg.v27.i30.5112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384736PMC
August 2021

Barriers to linkage to care in hepatitis C patients with substance use disorders and dual diagnoses, despite centralized management.

Therap Adv Gastroenterol 2021 27;14:17562848211016563. Epub 2021 Aug 27.

Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Passeig Vall Hebron 119-129, Barcelona, 08035, Spain.

Background: Hepatitis C virus (HCV) management is a challenge in patients with substance use disorder (SUD). This study aimed to describe an HCV screening and linkage to care program in SUD patients, and analyze the characteristics of this population in relation to HCV infection, particularly the impact of psychiatric comorbidities (dual diagnosis).

Methods: This study was a prospective clinical cohort study using a collaborative, multidisciplinary model to offer HCV care (screening, diagnosis, and therapy) to individuals with SUD attending a dedicated hospital clinic. The characteristics of the participants, prevalence of HCV infection, percentage who started therapy, and adherence to treatment were compared according to the patients' consumption characteristics and presence of dual diagnosis. HCV screening, diagnosis, treatment initiation, and sustained virologic response were analyzed.

Results: 528 individuals attended the center (November 2018-June 2019) and 401 (76%) accepted screening. In total, 112 (28%) were anti-HCV-positive and 42 (10%) had detectable HCV RNA, but only 20 of the latter started HCV therapy. Among the 253 (63%) patients with a dual diagnosis, there were no differences in HCV infection prevalence patients with SUD alone ( = 0.28). Dual diagnosis did not lead to a higher risk of HCV infection or interfere with linkage to care or treatment.

Conclusion: This study found a high prevalence of dual diagnosis and HCV infection in SUD patients, but dual diagnosis was not associated with an increased risk of acquiring HCV or more complex access to care. Despite use of a multidisciplinary management approach, considerable barriers to HCV care remain in this population that would need more specific focus.
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http://dx.doi.org/10.1177/17562848211016563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404622PMC
August 2021

A novel model of care for simplified testing of HBV in African communities during the COVID-19 pandemic in Spain.

Sci Rep 2021 08 25;11(1):17063. Epub 2021 Aug 25.

Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona, Spain.

Chronic hepatitis B virus (HBV) infection is a major public health threat for migrant populations in Spain and efforts to scale up testing are needed to reach the WHO elimination targets. The Hepatitis B Virus Community Screening and Vaccination in Africans (HBV-COMSAVA) study aims to use point-of-care testing and simplified diagnostic tools to identify, link to care, or vaccinate African migrants in Barcelona during the COVID-19 pandemic. From 21/11/20 to 03/07/2021, 314 study participants were offered HBV screening in a community clinic. Rapid tests for HBsAg screening were used and blood samples were collected with plasma separation cards. Patients received results and were offered: linkage to specialist care; post-test counselling; or HBV vaccination in situ. Sociodemographic and clinical history were collected and descriptive statistics were utilized. 274 patients were included and 210 (76.6%) returned to receive results. The HBsAg prevalence was 9.9% and 33.2% of people had evidence of past resolved infection. Overall, 133 required vaccination, followed by post-test counselling (n = 114), and linkage to a specialist (n = 27). Despite the COVID-19 pandemic, by employing a community-based model of care utilizing novel simplified diagnostic tools, HBV-COMSAVA demonstrated that it was possible to diagnose, link to care, and vaccinate African migrants in community-based settings.
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http://dx.doi.org/10.1038/s41598-021-96350-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387363PMC
August 2021

2020 position statement and recommendations of the European Liver and Intestine Transplantation Association (ELITA): management of hepatitis B virus-related infection before and after liver transplantation.

Aliment Pharmacol Ther 2021 09 19;54(5):583-605. Epub 2021 Jul 19.

Valencia, Spain.

Background: Prophylaxis of HBV recurrence is critical after liver transplantation in HBV patients. Despite new prophylactic schemes, most European LT centres persist on a conservative approach combining hepatitis B immunoglobulin (HBIG) and nucleos(t)ides analogues (NA).

Aim: This setting prompted the European Liver Intestine Transplantation Association (ELITA) to look for a consensus on the prevention of HBV recurrence.

Methods: Based on a 4-round Delphi process, ELITA investigated 16 research questions and established 50 recommendations.

Results: Prophylaxis should be driven according to 3 simplified risk groups: Low and high virological risk patients, with undetectable and detectable HBV DNA pre-LT, respectively, and special populations (HDV, HCC, poorly adherent patients). In low-risk patients, short-term (4 weeks) combination of third-generation NA+ HBIG, or third generation NA monotherapy can be considered as prophylactic options. In high-risk patients, HBIG can be discontinued once HBV DNA undetectable. Combined therapy for 1 year is advised. HBV-HCC patients should be treated according to their virological risk. In HDV/HBV patients, indefinite dual prophylaxis remains the gold standard. Full withdrawal of HBV prophylaxis following or not HBV vaccination should only be attempted in the setting of clinical trials. Organs from HBsAg+ve donors may be considered after assessment of risks, benefits, and patient consent. They should not be used if HDV is present. In poorly adherent patients, dual long-term prophylaxis is recommended. Budget impact analysis should be taken into account to drive prophylactic regimen.

Conclusions: These ELITA recommendations should stimulate a more rational and homogeneous approach to HBV prophylaxis across LT programs.
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http://dx.doi.org/10.1111/apt.16374DOI Listing
September 2021

A Global Survey of Physicians Knowledge About Non-alcoholic Fatty Liver Disease.

Clin Gastroenterol Hepatol 2021 Jul 3. Epub 2021 Jul 3.

Center for Liver Disease, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, Virginia; Inova Medicine, Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia.

Background & Aims: Despite rapidly increasing nonalcoholic fatty liver disease (NAFLD) prevalence, providers' knowledge may be limited. We assessed NAFLD knowledge and associated factors among physicians of different specialties globally.

Methods: NAFLD knowledge surveys containing 54 and 59 questions covering 3 domains (epidemiology/pathogenesis, diagnostics, and treatment) were completed electronically by hepatologists, gastroenterologists (GEs), endocrinologists (ENDOs), and primary care physicians (PCPs) from 40 countries comprising 5 Global Burden of Disease super-regions. Over 24 months, 2202 surveys were completed (488 hepatologists, 758 GEs, 148 ENDOs, and 808 PCPs; 50% high-income Global Burden of Disease super-region, 27% from North Africa and Middle East, 12% Southeast Asia, and 5% South Asian and Latin America).

Results: Hepatologists saw the greatest number of NAFLD patients annually: median 150 (interquartile range, 60-300) vs 100 (interquartile range, 35-200) for GEs, 100 (interquartile range, 30-200) for ENDOs, and 10 (interquartile range, 4-50) for PCPs (all P < .0001). The primary sources of NAFLD knowledge acquisition for hepatologists were international conferences (33% vs 8%-26%) and practice guidelines for others (39%-44%). The Internet was the second most common source of NAFLD knowledge for PCPs (28%). NAFLD knowledge scores were higher for hepatologists than GEs: epidemiology, 62% vs 53%; diagnostics, 80% vs 73%; and treatment, 61% vs 58% (P < .0001), and ENDOs scores were higher than PCPs: epidemiology, 70% vs 60%; diagnostics, 71% vs 64%; and treatment, 79% vs 68% (P < .0001). Being a hepatologist or ENDO was associated with higher knowledge scores than a GE or PCP, respectively (P < .05). Higher NAFLD knowledge scores were associated independently with a greater number of NAFLD patients seen (P < .05).

Conclusions: Despite the growing burden of NAFLD, a significant knowledge gap remains for the identification, diagnosis, and management of NAFLD.
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http://dx.doi.org/10.1016/j.cgh.2021.06.048DOI Listing
July 2021

One-quarter of chronic hepatitis D patients reach HDV-RNA decline or undetectability during the natural course of the disease.

Aliment Pharmacol Ther 2021 08 28;54(4):462-469. Epub 2021 Jun 28.

Liver Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

Background: Spontaneous HDV-RNA fluctuations, assessed by nonstandardised in-house assays, have been reported during the course of chronic hepatitis delta (CHD).

Aims: To evaluate changes in serum HDV-RNA concentrations in untreated CHD patients and correlate these changes with other HBV markers.

Methods: A total of 323 consecutive serum samples from 56 CHD patients (detectable HDV-RNA) followed for >3 years were retested for HDV-RNA levels by a sensitive technique using the first WHO international HDV-RNA standard. Quantitative HBsAg, HBV-DNA, and HBV-RNA were also determined.

Results: Most participants were male, middle-aged, white European, and HBeAg-negative (82%). Almost half had liver cirrhosis and 64% were receiving nucleos(t)ide analogues. At inclusion, median-HDV-RNA was 5.3 (4.2-6.5) log IU/mL, HBsAg 4.0 (3.5-4.3) log IU/mL, and HBV-DNA 1.6 (1.0-2.6) log IU/mL; ALT values were normal in 13 (23%). During a mean follow-up of 5.6 (3-16) years, 14 (25%) showed ≥2log HDV-RNA decline, including 11 (20%) who spontaneously achieved undetectable HDV-RNA. Four patients (7%) lost HBsAg, with undetectable HDV-RNA. The remaining 42 (75%) had persistently detectable HDV-RNA. During follow-up, patients with a ≥2log HDV-RNA decline showed a greater HBsAg drop (-0.7 ± 1.1 vs -0.09 ± 0.9 log IU/mL; P = 0.039) than those with a <2 log HDV-RNA decline. Overall, ALT and HBV-DNA levels decreased over time. There were no differences in clinical outcomes between groups.

Conclusions: One-quarter of untreated CHD patients showed a ≥2log decline in HDV-RNA and 20% reached HDV-RNA undetectability during a mean follow-up of 5.6 years. The decline was associated with ALT decrease. These findings have implications for designing new therapies for CHD.
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http://dx.doi.org/10.1111/apt.16485DOI Listing
August 2021

Nucleos(t)ide analogue therapy: The role of tenofovir alafenamide.

Liver Int 2021 06;41 Suppl 1:9-14

Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

Chronic hepatitis B virus (HBV) infection remains an important global health problem, and may be difficult to manage in clinical practice. Nucleos(t)ide analogues (NAs) with a high barrier to resistance (entecavir [ETV], tenofovir disoproxil fumarate [TDF] and tenofovir alafenamide [TAF]) are the most frequently used HBV treatments because of their long-term effectiveness and tolerability. ETV may be less effective in patients with lamivudine-resistant strains, and TDF is associated with impaired renal function and reductions in bone mineral density. TAF, a new tenofovir prodrug, has been developed to overcome the less favourable safety profile of TDF. TAF is more stable in plasma, and higher tenofovir levels are achieved within cells at lower doses than with TDF. Several registration and real-life studies, performed up to week 144 of treatment, have shown that TAF is at least as effective as TDF, with higher rates of ALT normalization and significantly fewer kidney disturbances and changes in bone mineral density. No emergence of drug resistance has been found with TAF use. The main limitation to prescribing TAF is its price. The European Association for the Study of the Liver has suggested selecting TAF or ETV instead of TDF in patients >65 years old and in those with a risk of osteoporosis or renal abnormalities, and to prescribe TAF rather than ETV in patients previously exposed to NAs.
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http://dx.doi.org/10.1111/liv.14848DOI Listing
June 2021

Anti-epileptic drugs and hepatitis C therapy: Real-world experience.

J Hepatol 2021 Jun 11. Epub 2021 Jun 11.

Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.05.040DOI Listing
June 2021

Predictive performance of newer Asian hepatocellular carcinoma risk scores in treated Caucasians with chronic hepatitis B.

JHEP Rep 2021 Jun 20;3(3):100290. Epub 2021 Apr 20.

Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background & Aims: Recently, several risk scores for prediction of hepatocellular carcinoma (HCC) were developed in cohorts of treated Asian patients with chronic hepatitis B (CHB), but they have not been assessed in non-Asian patients. We evaluated the predictability and comparative utility of our PAGE-B and recent Asian HCC risk scores in nucleos(t)ide analogue (NA)-treated adult Caucasian patients with CHB, with or without well-documented compensated cirrhosis but not previous diagnosis of HCC.

Methods: We included 1,951 patients treated with entecavir/tenofovir and followed up for a median of 7.6 years. The c-statistic was used to estimate the predictability of PAGE-B, HCC-Rescue, CAMD, mPAGE-B, and AASL score for HCC development within 5 or 10 years. The low- and high-risk group cut-offs were used for estimation of negative (NPV) and positive predictive values (PPV), respectively.

Results: HCC developed in 103/1,951 (5.3%) patients during the first 5 years and in another 39/1,428 (2.7%) patients between years 5 and 10. The 3-, 5-, and 10-year cumulative HCC rates were 3.3%, 5.9%, and 9.6%, respectively. All scores offered good 5- and 10-year HCC prediction (c-statistic: 0.78-0.82). NPVs were always >99% (99.3-100%), whereas PPV ranged between 13% and 24%.

Conclusions: In NA-treated Caucasian patients with CHB including compensated cirrhosis, HCC risk scores developed in NA-treated Asian patients offer good 5- and 10-year HCC predictability, similar to that of PAGE-B. PAGE-B and mPAGE-B scores are simpler in clinical practice, as they do not require an accurate diagnosis of cirrhosis, but the addition of albumin in mPAGE-B score does not seem to offer an advantage in patients with well compensated liver disease.

Lay Summary: Several risk scores for prediction of hepatocellular carcinoma (HCC) were recently developed in cohorts of treated Asian patients with chronic hepatitis B (CHB). In Caucasian patients with CHB treated with oral antivirals, newer Asian HCC risk scores offer good 5- and 10-year HCC predictability, similar to that of PAGE-B. For clinical practice, PAGE-B and mPAGE-B scores are simpler, as they do not require an accurate diagnosis of cirrhosis.
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http://dx.doi.org/10.1016/j.jhepr.2021.100290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144729PMC
June 2021

Chronic hepatitis D associated with worse patient-reported outcomes than chronic hepatitis B.

JHEP Rep 2021 Jun 17;3(3):100280. Epub 2021 Mar 17.

Department of Medicine, Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA, USA.

Background & Aims: Health-related quality of life (HRQoL) determined by patient-reported outcomes (PROs) is impaired in chronic hepatitis B (CHB) and C patients, but there are no data regarding patients with chronic hepatitis D (CHD). The aim of this study was to assess PRO scores in untreated patients with CHD and compare them with those obtained for patients with CHB.

Methods: Patients with CHD completed 3 PRO instruments (Chronic Liver Disease Questionnaire [CLDQ], Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F], and Work Productivity and Activity Impairment [WPAI]), and the results were compared with those of patients mono-infected with CHB.

Results: In total, 125 patients were included: 43 with CHD and 82 with CHB. Overall, baseline PROs showed differences between both groups. Several assessments, such as the worry score from CLDQ ( = 0.0118), functional well-being from FACIT-F ( = 0.0281), and activity impairment from WPAI ( = 0.0029) showed a significant trend to worse scores in patients with CHD than with CHB. In addition, the linear regression model supports the finding that having CHD as opposed to having CHB was a predictor of a higher worry score (CLDQ) and a higher activity impairment (WPAI).

Conclusions: In this first assessment in CHD, PROs recorded in patients with CHD showed a significant impairment in some domains of HRQoL questionnaires in comparison with those with CHB. Studies in larger cohorts with lengthier follow-up are needed to fully assess patient-reported quality of life over the course of CHD.

Lay Summary: Chronic hepatitis D (CHD) is a viral disease that causes rapid evolution to liver cirrhosis, amongst other severe complications, when compared to patients with chronic hepatitis B (CHB). Health-related quality of life in chronic hepatitis C and CHB has been reported widely, but no studies have been performed on patient-reported outcomes in patients with CHD. Results showed that CHD patients reported worse outcomes in psychological domains such as worry and emotional well-being, as well as in physical domains such as abdominal symptoms, physical well-being, and activity impairment in comparison with patients with CHB.
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http://dx.doi.org/10.1016/j.jhepr.2021.100280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141931PMC
June 2021

Estimating the attributable fraction of cirrhosis and hepatocellular carcinoma due to hepatitis B and C.

J Viral Hepat 2021 Aug 8;28(8):1177-1189. Epub 2021 Jun 8.

European Centre for Disease Prevention and Control, Stockholm, Sweden.

A goal of the WHO strategy on the elimination of hepatitis as a public threat is a 65% reduction in the attributable mortality. Deaths related to hepatitis B and C infections are mostly due to decompensated cirrhosis and hepatocellular carcinoma (HCC) but accurately measuring mortality is challenging as death certificates often do not capture the underlying disease. The aim of this collaborative study between European Centre for Disease Prevention and Control (ECDC) and the European Association for the Study of the Liver (EASL) was to assess a WHO-developed protocol to support countries in implementing studies to collect data on the fraction of cirrhosis and hepatocellular carcinoma attributable to hepatitis B and C. Three sentinel sites (in Bulgaria, Norway and Portugal) collected data for patients first admitted or seen in their centres during 2016. Patients with cirrhosis or HCC were identified through patient files or healthcare databases using ICD-10 codes. The proportion of patients with cirrhosis and HCC who tested positive for HBV and HCV were calculated to estimate the aetiological fractions. After the pilot study was completed, each site was asked about the feasibility and acceptability of the protocol. A total of 1249 patients presenting with cirrhosis and/or HCC were evaluated across the three sites. The prevalence of HBV and HCV among cases of cirrhosis showed that in Norway and Portugal, HCV was responsible for about one-quarter of the cases, whereas in Bulgaria, HBV was more common. For HCC, HCV was responsible for more than one-third of cases in Norway and Portugal, while in Bulgaria HBV was more frequent as the underlying cause. Results obtained during the pilot study were comparable to published estimates obtained through statistical modelling or meta-analyses. Several challenges were reported from the sites involved in the pilot including the considerable time needed for reviewing the hospital records and extracting patient data. The pilot demonstrated the feasibility of collecting data on the prevalence of HBV and HCV infection among patients with cirrhosis and HCC in sentinel sites. This method can be used to estimate mortality attributable to HBV and HCV for elimination monitoring. Where easily implementable, sentinel studies are the best way to empower countries, get up-to date data and closely monitor the changes in the attributable fraction at a country level.
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http://dx.doi.org/10.1111/jvh.13545DOI Listing
August 2021

Incidences and Determinants of Functional Cure during Entecavir or Tenofovir Disoproxil Fumarate for Chronic Hepatitis B.

J Infect Dis 2021 May 17. Epub 2021 May 17.

Department of Medicine, Stanford University Medical Center, Palo Alto, California, United States of America.

Background: Long-term incidences and baseline determinants of functional cure (HBsAg seroclearance) during entecavir (ETV) or tenofovir disoproxil fumarate (TDF) treatment are incompletely understood.

Methods: This is an international multicenter cohort study of treatment-naïve chronic hepatitis B (CHB) patients who initiated on ETV or TDF without baseline malignancy. Patients were observed for HBsAg seroclearance until death or loss to follow-up. We calculated the incidences and explored the baseline determinants of HBsAg seroclearance using competing risk regression.

Results: The analysis included 4,769 patients (median age, 50 years; 69.05% male), with a median follow-up of 5.16 years (26,614.47 person-years). HBsAg clearance occurred in 58 patients, yielding a 10-year cumulative incidence of 2.11% (95% CI, 1.54 -- 2.88%) and an annual rate of 0.22% (95% CI, 0.17--0.28%). Baseline predictors included low-level viremia with HBV DNA <2,000 IU/mL (adjusted sub-distribution HR [aSHR], 3.14; 95% CI, 1.80--5.49), elevated serum alanine aminotransferase (ALT) >200 U/L (aSHR, 3.68; 95% CI, 2.07--6.53), serum bilirubin (aSHR, 1.11 per mg/dL; 95% CI, 1.06--1.17), and fatty liver (aSHR, 1.84; 95% CI, 1.03--3.29).

Conclusion: HBsAg seroclearance rarely occurs in CHB patients treated with ETV or TDF and is associated with low-level viremia, ALT flare, bilirubin level, and fatty liver.
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http://dx.doi.org/10.1093/infdis/jiab241DOI Listing
May 2021

Next-generation sequencing for the diagnosis of hepatitis B: current status and future prospects.

Expert Rev Mol Diagn 2021 Apr 21;21(4):381-396. Epub 2021 Apr 21.

Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma De Barcelona, Barcelona Spain.

Introduction: Hepatitis B virus (HBV) causes a complex and persistent infection with a major impact on patients health. Viral-genome sequencing can provide valuable information for characterizing virus genotype, infection dynamics and drug and vaccine resistance.

Areas Covered: This article reviews the current literature to describe the next-generation sequencing progress that facilitated a more comprehensive study of HBV quasispecies in diagnosis and clinical monitoring.

Expert Opinion: HBV variability plays a key role in liver disease progression and treatment efficacy. Second-generation sequencing improved the sensitivity for detecting and quantifying mutations, mixed genotypes and viral recombination. Third-generation sequencing enables the analysis of the entire HBV genome, although the high error rate limits its use in clinical practice.
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http://dx.doi.org/10.1080/14737159.2021.1913055DOI Listing
April 2021

Utility of the Cobas Plasma Separation Card as a Sample Collection Device for Serological and Virological Diagnosis of Hepatitis C Virus Infection.

Diagnostics (Basel) 2021 Mar 8;11(3). Epub 2021 Mar 8.

Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.

Diagnosis and clinical management of people infected with hepatitis C virus (HCV) relies on results from a combination of serological and virological tests. The aim of this study was to compare the performance of dried plasma spots (DPS), prepared using the cobas Plasma Separation Card (PSC), to plasma and serum from venipuncture, for HCV diagnosis. We carried out a prospective study using DPS and paired plasma or serum samples. Serum and DPS samples were analyzed by immunoassay using Elecsys Anti-HCV II (Roche). Plasma and DPS samples were analyzed using the cobas HCV viral load and cobas HCV genotyping tests (Roche). All DPS samples that had high anti-HCV antibody titers in serum were also antibody-positive, as were five of eight samples with moderate titers. Eight samples with low titers in serum were negative with DPS. Among 80 samples with plasma HCV viral loads between 61.5 and 2.2 × 10 IU/mL, 74 were RNA-positive in DPS. The mean viral load difference between plasma and DPS was 2.65 log IU/mL. The performance of DPS for detection of serological and virological markers of hepatitis C virus infection was comparable to that of the conventional specimen types. However, the limits of detection were higher for DPS.
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http://dx.doi.org/10.3390/diagnostics11030473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998864PMC
March 2021

Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality.

medRxiv 2021 Mar 12. Epub 2021 Mar 12.

Background: There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium.

Method: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors.

Findings: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2-1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3-1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors.

Interpretation: The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality-and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management.

Funding: Funding was obtained by each of the participating cohorts individually.
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http://dx.doi.org/10.1101/2021.03.07.21252875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987046PMC
March 2021

Resistance-associated substitutions after sofosbuvir/velpatasvir/voxilaprevir triple therapy failure.

J Viral Hepat 2021 Sep 22;28(9):1319-1324. Epub 2021 Mar 22.

Liver Diseases-Viral Hepatitis, Liver Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.

Direct-acting antivirals (DAAs) resolve chronic HCV infection in >95% of patients, but a small percentage do not respond to DAA-based therapy. These may be difficult to treat because of resistance-associated substitutions (RAS) emerging after treatment failure. Triple therapy with sofosbuvir (SOF)/velpatasvir (VEL)/voxilaprevir (VOX) is the recommended retreatment after DAA-based failure. However, in rare cases, failure to triple therapy occurs, and there is little information characterizing the viruses that relapse. To determine the RAS profile after failing SOF/VEL/VOX, and seek suitable alternatives for retreatment, samples from 5 patients were analysed using MiSeq Illumina deep sequencing before and after triple therapy. All patients were men, aged 59-78 years, 2 HCV genotype (G) 1b and 3 G3a. The most prevalent NS3 substitutions after SOF/VEL/VOX failure were Y56F and A166T. Four patients had the NS5A RAS, Y93H, after triple failure, and Y93H was observed in both G1b patients before retreatment and after SOF/ledipasvir failure. In 2 G3a patients, Y93H appeared at triple failure, and on the other G3a, A30K persisted in 100% of viral genomes. Finally, G1b patients showed C316N in NS5B, associated with SOF failure, but G3a patients had no known NS5B substitutions. HCV RAS analysis identified the following substitutions present at higher rates after triple failure: Y56F in NS3 (G1b), A166T in NS3 (G3a), A30K or Y93H in NS5A, and C316N in NS5B (G1b). A RAS-based salvage treatment (SOF + glecaprevir/pibrentasvir + RBV) was successfully used in one G3a patient.
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http://dx.doi.org/10.1111/jvh.13497DOI Listing
September 2021

Differential characteristics and outcomes of Asian and non-Asian patients with HBV-related hepatocellular carcinoma.

Liver Int 2021 08 1;41(8):1922-1932. Epub 2021 Apr 1.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA.

Background & Aims: The epidemiology of hepatitis B virus (HBV) infection differs between Asians and non-Asians, but little is known regarding the effect of ethnicity on outcomes of HBV-related hepatocellular carcinoma (HCC). We aim to characterize the presentation and survival outcomes in Asian and non-Asian patients with HBV-related HCC.

Methods: We analyzed the baseline characteristics and long-term survival of 613 Asian and 410 non-Asian patients with HBV-related HCC from three US and one Spanish centre.

Results: Overall, non-Asian patients were more likely to have HIV or hepatitis C co-infection, cirrhosis, decompensated liver disease and advanced BCLC stage (all P ≤ .04). Compared with Asians, non-Asians were more likely to be listed for transplantation (P < .0001) and undergo HCC treatment with curative intent (P = .003). Propensity-score matching on HCC diagnosis year, gender and age was performed to balance the two groups for survival analysis and yielded 370 pairs of patients. There was no significant difference in survival overall (P = .43) and among patients with cirrhosis (P = .57). Among patients without cirrhosis, non-Asians had poorer 5-year survival compared with Asians (37.6% vs 53.7%, P = .01), and was associated with poorer survival after adjusting for age, gender, diabetes, alcohol, co-infections, diagnosis date, antiviral therapy, BCLC stage and HCC treatment (adjusted HR 2.01 [95% CI 1.07-3.74], P = .03).

Conclusion: Among HBV-related HCC patients, non-Asians presented with more advanced BCLC stage compared to Asians. Non-Asian ethnicity was independently associated with twice the risk of mortality among patients without cirrhosis, but not among those with cirrhosis. Additional studies are needed to clarify this disparity.
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http://dx.doi.org/10.1111/liv.14877DOI Listing
August 2021

COVID-19 and hepatitis B infection.

Antivir Ther 2020 ;25(8):389-397

Liver Unit, Vall d'Hebron University Hospital, Barcelona, Spain.

The 2019 coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a major burden worldwide, resulting in serious public health challenges. HBV infection is another widely spread virus that chronically affects about 257 million people. The management of patients with HBV infection has gained attention in the context of the COVID-19 pandemic. Patients with COVID-19 have varying levels of liver involvements, resulting from direct viral effects on the liver as well as hepatotoxic drugs. This was demonstrated by elevated levels of liver enzymes, particularly evident in those patients with severe SARS-CoV-2 infection. However, scarce information is available on the management of COVID-19 patients having an underlying chronic liver disease, including HBV infection. Studies have shown reactivation of HBV infection following treatment with tocilizumab and corticosteroids, emphasizing the need for caution when using these agents to treat COVID-19 patients with HBV infection. HBV screening and prophylaxis should be considered in patients with elevated transaminase levels and also in high prevalence populations. In patients with advanced liver disease, attention must be given to minimize the risk of liver decompensation. Nevertheless, further investigation is needed to enable an evidence-based approach for the care of these patients.
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http://dx.doi.org/10.3851/IMP3382DOI Listing
May 2021

Long-term efficacy and safety of nucleos(t)ides analogues in patients with chronic hepatitis B.

Ther Adv Infect Dis 2021 Jan-Dec;8:2049936120985954. Epub 2021 Feb 5.

Liver Unit, Internal Medicine Department, Hospital Universitario Vall d'Hebrón, Vall d'Hebron Barcelona Hospital Campus, Barcelona, 119-129, Spain. Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Carlos III, Madrid, Spain.

Nucleos(t)ide analogues with high barrier to resistance are regarded as the principal therapeutic option for chronic hepatitis B (CHB). Treatment with entecavir (ETV), tenofovir disoproxil (TDF) and the later released tenofovir alafenamide (TAF) is highly effective at controlling hepatitis B virus (HBV) infection and, in the vast majority of patients, is well tolerated. No significant differences in viral suppression have been described among the different regimens, although an earlier achievement in biochemical response has been suggested first under TDF and recently under TAF. High barrier to resistance NAs rarely achieve hepatitis B surface antigen sero-clearance, and therefore should be maintained life-long in most cases. This has increased concerns about treatment-related toxicity, especially in patients under TDF with additional risk factors for kidney and bone impairment. TAF has shown a better bone and kidney safety profile than TDF, although it is not yet available worldwide due to its higher cost. Emergence of adverse events should be monitored since treatment-switch to ETV/TAF seems to be effective and safe in HBV mono-infected subjects. Finally, although an effective antiviral treatment leads to a clear improvement in clinical outcome of CHB patients; the risk of developing hepatocellular carcinoma (HCC) is not completely avoided with viral suppression. Whether tenofovir-based regimens provide any additional benefit over ETV in HCC prevention remains unclear and requires further investigation.
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http://dx.doi.org/10.1177/2049936120985954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871062PMC
February 2021

Sophisticated viral quasispecies with a genotype-related pattern of mutations in the hepatitis B X gene of HBeAg-ve chronically infected patients.

Sci Rep 2021 Feb 18;11(1):4215. Epub 2021 Feb 18.

Liver Pathology Unit, Departments of Biochemistry and Microbiology, Vall d'Hebron University Hospital and Universitat Autònoma de Barcelona, Barcelona, Spain.

Patients with HBeAg-negative chronic infection (CI) have not been extensively studied because of low viremia. The HBx protein, encoded by HBX, has a key role in viral replication. Here, we analyzed the viral quasispecies at the 5' end of HBX in CI patients and compared it with that of patients in other clinical stages. Fifty-eight HBeAg-negative patients were included: 16 CI, 19 chronic hepatitis B, 16 hepatocellular carcinoma and 6 liver cirrhosis. Quasispecies complexity and conservation were determined in the region between nucleotides 1255 and 1611. Amino acid changes detected were tested in vitro. CI patients showed higher complexity in terms of mutation frequency and nucleotide diversity and higher quasispecies conservation (p < 0.05). A genotype D-specific pattern of mutations (A12S/P33S/P46S/T36D-G) was identified in CI (median frequency, 81.7%), which determined a reduction in HBV DNA release of up to 1.5 log in vitro. CI patients showed a more complex and conserved viral quasispecies than the other groups. The genotype-specific pattern of mutations could partially explain the low viremia observed in these patients.
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http://dx.doi.org/10.1038/s41598-021-83762-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892877PMC
February 2021

EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients.

J Hepatol 2021 04 6;74(4):944-951. Epub 2021 Feb 6.

Liver Unit, Department of Medicine, Hadassah-Hebrew University Hospital, Jerusalem, Israel.

According to a recent World Health Organization estimate, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, which originated in China in 2019, has spread globally, infecting nearly 100 million people worldwide by January 2021. Patients with chronic liver diseases (CLD), particularly cirrhosis, hepatobiliary malignancies, candidates for liver transplantation, and immunosuppressed individuals after liver transplantation appear to be at increased risk of infections in general, which in turn translates into increased mortality. This is also the case for SARS-CoV-2 infection, where patients with cirrhosis, in particular, are at high risk of a severe COVID-19 course. Therefore, vaccination against various pathogens including SARS-CoV-2, administered as early as possible in patients with CLD, is an important protective measure. However, due to impaired immune responses in these patients, the immediate and long-term protective response through immunisation may be incomplete. The current SARS-CoV-2 pandemic has led to the exceptionally fast development of several vaccine candidates. A small number of these SARS-CoV-2 vaccine candidates have already undergone phase III, placebo-controlled, clinical trials in healthy individuals with proof of short-term safety, immunogenicity and efficacy. However, although regulatory agencies in the US and Europe have already approved some of these vaccines for clinical use, information on immunogenicity, duration of protection and long-term safety in patients with CLD, cirrhosis, hepatobiliary cancer and liver transplant recipients has yet to be generated. This review summarises the data on vaccine safety, immunogenicity, and efficacy in this patient population in general and discusses the implications of this knowledge on the introduction of the new SARS-CoV-2 vaccines.
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http://dx.doi.org/10.1016/j.jhep.2021.01.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867401PMC
April 2021

The impact of direct acting antivirals on hepatitis C virus disease burden and associated costs in four european countries.

Liver Int 2021 05 24;41(5):934-948. Epub 2021 Feb 24.

Center for Global Health, Istituto Superiore di Sanità, Rome, Italy.

Background And Aims: We assessed the clinical and economic impact of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) in England, Italy, Romania and Spain.

Methods: An HCV progression Markov model was developed considering DAA eligibility and population data during the years 2015-2019. The period of time to recover the investment in DAAs was calculated as the cost saved by avoiding estimated clinical events for 1000 standardized treated patients. A delayed treatment scenario because of coronavirus disease (COVID-19) was also developed.

Results: The estimated number of avoided hepatocellular carcinoma, decompensated cirrhosis and liver transplantations over a 20-year time horizon was: 1,057 in England; 1,221 in Italy; 1,211 in Romania; and 1,103 in Spain for patients treated during 2015-2016 and 640 in England; 626 in Italy; 739 in Romania; and 643 in Spain for patients treated during 2017-2019. The cost-savings ranged from € 45 to € 275 million. The investment needed to expand access to DAAs in 2015-2019 is estimated to be recovered in 6.5 years in England; 5.4 years in Italy; 6.7 years in Romania; and 4.5 years in Spain. A delay in treatment because of COVID-19 will increase liver mortality in all countries.

Conclusion: Direct-acting antivirals have significant clinical benefits and can bring substantial cost-savings over the next 20 years, reaching a Break-even point in a short period of time. When pursuing an exit strategy from strict lockdown measures for COVID-19, providing DAAs should remain high on the list of priorities in order to maintain HCV elimination efforts.
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http://dx.doi.org/10.1111/liv.14808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248004PMC
May 2021

Long-term Patient-Centered Outcomes in Cirrhotic Patients With Chronic Hepatitis C After Achieving Sustained Virologic Response.

Clin Gastroenterol Hepatol 2021 Jan 22. Epub 2021 Jan 22.

Center for Outcomes Research in Liver Disease, Washington, District of Columbia.

Background & Aims: Achieving sustained virologic response (SVR) among patients with hepatitis C virus (HCV) leads to patient reported outcome (PRO) improvement. We aimed to assess the long-term post-SVR PRO trends in HCV patients with cirrhosis.

Methods: Patients with HCV and cirrhosis treated in clinical trials with direct acting antiviral agents (DAAs) who achieved SVR-12 were prospectively enrolled in a long-term registry (clinicaltrials.gov #NCT02292706). PROs were collected every 24 weeks using the Short Form-36v2 (SF-36), CLDQ-HCV, and WPAI-HCV.

Results: Pre-treatment baseline data were available for 854 cirrhotic patients who achieved SVR after DAAs. Of these, 730 had compensated (CC) and 124 had decompensated cirrhosis (DCC) before treatment- patients with DCC reported severe impairment in their PROs in comparison to CC patients (by mean -5% to -16% of a PRO range size; p < .05 for 16 out of 20 studied PROs]. After achieving SVR and registry enrollment, significant PRO improvements were noted from pre-treatment levels in 11/20 domains for those with DCC (+4% to +21%) and 19/20 PRO domains in patients with CC (+3% to +17%). Patients with baseline DCC had higher rates of hepatocellular carcinoma and mortality (P < .05). In patients with CC, the PRO gains persisted up to 168 weeks (3.5 years) of registry follow-up. In patients with DCC, the improvements lasted for at least 96 weeks but a declining trend after year 2.

Conclusions: Patients with HCV cirrhosis experience severe PRO impairment at baseline with sustainable improvement after SVR. Though those with DCC experience improvement, there is a decline after 2 years.
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http://dx.doi.org/10.1016/j.cgh.2021.01.026DOI Listing
January 2021

Incremental value of HBcrAg to classify 1582 HBeAg-negative individuals in chronic infection without liver disease or hepatitis.

Aliment Pharmacol Ther 2021 03 19;53(6):733-744. Epub 2021 Jan 19.

Barcelona, Spain.

Background: An accurate, single-point differential diagnosis between HBeAg-negative infection (ENI) and chronic hepatitis B (CHB) is an unmet need.

Aims: To assess the diagnostic value of the new hepatitis B core-related antigen (HBcrAg) assay.

Methods: A retrospective anonymised data analysis was performed in a multicentre European (nine centres and six countries) cohort of 1582 consecutive HBsAg-positive/HBeAg-negative subjects classified according to EASL guidelines as: 550-CHB, 710-ENI and 322-GZ (grey-zone, HBV-DNA <20 000 IU/mL).

Results: Mean age was 44 (±13.2 y), 59% were men; HBV genotypes were 15% A, 2% B, 2% C, 45% D, 9% E, 1% F and 26% unknown. Median HBV-DNA serum levels were 2.2 (1.5-2.7), 3.5 (3.2-3.8) and 5.6 (4.8-6.6) logIU/mL in ENI, GZ and CHB, P < 0.0001. HBsAg serum levels (HBsAgsl) were comparable in CHB and GZ, but lower in ENI (2.9 [2.1-3.6] logIU/mL), P < 0.0001. HBcrAg serum levels (HBcrAgsl) were <3 logU/mL in 90.7% (644/710) ENI, 75.2% (242/322) GZ and 4.7% (26/550) CHB (P < 0.0001). Median HBcrAgsl were 4.8 (3.9-5.7), 2.5 (2.0-2.9) and 2.0 (2.0-2.5) logU/mL in CHB, GZ and ENI, (P < 0.0001). ROC-AUCs for HBcrAg and HBsAg were 0.968 (95% CI, 0.958-0.977) and 0.732 (95% CI, 0.704-0.760) respectively. The optimal HBcrAgsl cut-off to distinguish CHB from ENI was 3.14 logU/mL (95% CI, 3.02-3.25, 91% SE, 93% SP and 92.4% DA). HBcrAgsl were associated with HBV genotypes (P < 0.001, one-way ANOVA) but using genotype-specific cut-offs, HBcrAg DA remained unchanged with overlapping 95% CI.

Conclusion: The HBcrAg assay showed high diagnostic performance in the accurate single-point identification of patients with HBeAg-negative CHB, independently of HBV genotype. This should prompt future prospective studies to confirm its diagnostic role in clinical practice.
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http://dx.doi.org/10.1111/apt.16258DOI Listing
March 2021

Impact of the COVID-19 pandemic on HCV elimination in Spain.

J Hepatol 2021 05 20;74(5):1246-1248. Epub 2020 Dec 20.

Pharmacoeconomics & Outcomes Research Iberia (PORIB), Madrid, Spain.

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http://dx.doi.org/10.1016/j.jhep.2020.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749992PMC
May 2021

Reflex viral load testing in dried blood spots generated by plasma separation card allows the screening and diagnosis of chronic viral hepatitis.

J Virol Methods 2021 03 15;289:114039. Epub 2020 Dec 15.

CIBERehd, Instituto Carlos II, Spain; Biochemistry Department, Clinical Laboratories Hospital Universitari Vall d'Hebron, Spain; Liver Pathology Unit, Biochemistry and Microbiology Departments, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

Dried blood spots (DBS) have been proposed as an alternative diagnostic technique for chronic viral hepatitis. The aim of this observational study was to correlate serologic HBV, HCV, and HDV status and reflex the respective viral load testing by PSC-DBS samples from capillary blood vs conventional plasma samples in patients with chronic viral hepatitis. Besides, we apply these tests in a prospective study for chronic viral hepatitis diagnosis in a rural region of sub-Saharan Africa. In total, 124 HBsAg-positive patients, 75 anti-HCV positive, 2 with HBV-HCV coinfection, and 13 anti-HDV positive were included. PSC-DBS sensitivity/specificity was 98.4 %/96.2 % for HBsAg detection, 98.7 %/100 % for anti-HCV, and 84.6 %/100 % for anti-HDV. HCV-RNA was quantified in all viremic patients using DBS. Only 42 of 78 (53.8 %) samples with HBV-DNA viremia were quantifiable by DBS. Sensitivity increased to 95.7 % in patients with HBV-DNA levels >2000 IU/mL. There was a high correlation between DBS and venous blood. The prevalence of HBsAg among the 93 individuals tested in Angola was 11 %, and 60 % of cases had detectable HBV-DNA viremia. As a conclusion, PSC-DBS is useful for chronic viral hepatitis screening and reflex molecular diagnosis showing globally high sensitivities and correlation with conventional blood samples.
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http://dx.doi.org/10.1016/j.jviromet.2020.114039DOI Listing
March 2021

Prediction of Sustained Response After Nucleo(s)tide Analogue Cessation Using HBsAg and HBcrAg Levels: A Multicenter Study (CREATE).

Clin Gastroenterol Hepatol 2020 Dec 10. Epub 2020 Dec 10.

Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany.

Background & Aims: Predictors of successful nucleo(s)tide analogue (NA) therapy withdrawal remain elusive. We studied the relationship between end-of-treatment levels of hepatitis B core-related antigen (HBcrAg) and hepatitis B surface antigen (HBsAg) and outcome after therapy cessation.

Methods: Patients who discontinued NA therapy in centers in Asia and Europe were enrolled. HBcrAg and HBsAg were measured at treatment cessation, and associations with off-treatment outcomes were explored. The SCALE-B (Surface antigen, Core-related antigen, Age, ALT, and tenofovir for HBV) score was calculated as previously reported. End points included sustained virologic response (VR; hepatitis B virus DNA level <2000 IU/mL), HBsAg loss, and alanine aminotransferase (ALT) flares (>3× upper limit of normal). Re-treated patients were considered nonresponders.

Results: We analyzed 572 patients, 457 (80%) were Asian and 95 (17%) were hepatitis B e antigen positive at the start of NA therapy. The median treatment duration was 295 weeks. VR was observed in 267 (47%), HBsAg loss was observed in 24 (4.2%), and ALT flare was observed in 92 (16%). VR (67% vs 42%) and HBsAg loss (15% vs 1.5%) was observed more frequently in non-Asian patients when compared to Asian patients (P < .001). Lower HBcrAg levels were associated with higher rates of VR (odds ratio [OR], 0.701; P < .001) and HBsAg loss (OR, 0.476; P < .001), and lower rates of ALT flares (OR, 1.288; P = .005). Similar results were observed with HBsAg (VR: OR, 0.812; P = .011; HBsAg loss: OR, 0.380; P < .001; and ALT flare: OR, 1.833; P < .001). Lower SCALE-B scores were associated with higher rates of VR, HBsAg loss, and lower rates of ALT flares in both Asian and non-Asian patients (P < .001).

Conclusions: In this multicenter study, off-treatment outcomes after NA cessation varied with ethnicity. Lower levels of HBcrAg and HBsAg were associated with favorable outcomes. A risk score comprising both factors can be used for risk stratification.
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http://dx.doi.org/10.1016/j.cgh.2020.12.005DOI Listing
December 2020

Amino Acid Substitutions Associated with Treatment Failure for Hepatitis C Virus Infection.

J Clin Microbiol 2020 11 18;58(12). Epub 2020 Nov 18.

Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, Madrid, Spain

Despite the high virological response rates achieved with current directly acting antiviral agents (DAAs) against hepatitis C virus (HCV), around 2% to 5% of treated patients do not achieve a sustained viral response. The identification of amino acid substitutions associated with treatment failure requires analytical designs, such as subtype-specific ultradeep sequencing (UDS) methods, for HCV characterization and patient management. Using this procedure, we have identified six highly represented amino acid substitutions (HRSs) in NS5A and NS5B of HCV, which are not bona fide resistance-associated substitutions (RAS), from 220 patients who failed therapy. They were present frequently in basal and posttreatment virus of patients who failed different DAA-based therapies. Contrary to several RAS, HRSs belong to the acceptable subset of substitutions according to the PAM250 replacement matrix. Their mutant frequency, measured by the number of deep sequencing reads within the HCV quasispecies that encode the relevant substitutions, ranged between 90% and 100% in most cases. They also have limited predicted disruptive effects on the three-dimensional structures of the proteins harboring them. Possible mechanisms of HRS origin and dominance, as well as their potential predictive value for treatment response, are discussed.
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http://dx.doi.org/10.1128/JCM.01985-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685896PMC
November 2020

Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis.

Aliment Pharmacol Ther 2020 10 4;52(8):1399-1406. Epub 2020 Sep 4.

Rotterdam, The Netherlands.

Background: Guidelines recommend liver biopsy to rule out significant inflammatory activity in chronic hepatitis B (CHB) patients with elevated hepatitis B virus (HBV) DNA but without other indications for treatment.

Aim: To study rates and determinants of clinically significant liver inflammation.

Methods: We selected patients with HBV DNA > 2000 IU/mL from the SONIC-B database. The presence of significant inflammation (METAVIR ≥ A2 or HAI ≥ 9) was assessed by liver biopsy and correlated with alanine aminotransferase (ALT) levels (according to AASLD upper limits of normal [ULN]) and stratified by the presence of significant liver fibrosis (Ishak ≥ 3 or METAVIR ≥ F2).

Results: The cohort included 2991 patients; 1672 were HBeAg-positive. ALT was < ULN in 270 (9%), 1-2 times ULN in 852 (29%) and > 2 times ULN in 1869 (63%). Significant fibrosis was found in 1419 (47%) and significant inflammatory activity in 630 (21%). Significant inflammatory activity was found in 34% of patients with liver fibrosis, compared to 9.5% of those without (P < 0.001). Among patients without fibrosis, significant inflammatory activity was detected in 3.6% of those with normal ALT, 5.0% of those with ALT 1-2 times ULN and in 13% of those with ALT > 2 times ULN (P < 0.001). ALT < 2 times ULN had a negative predictive value of 95% for ruling out significant inflammatory activity among patients without liver fibrosis.

Conclusions: Among patients without significant fibrosis, an ALT level < 2 times ULN is associated with < 5% probability of significant inflammatory activity. If fibrosis can be ruled out using non-invasive methods, liver biopsy solely to assess inflammatory activity should be discouraged.
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http://dx.doi.org/10.1111/apt.16067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540526PMC
October 2020
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