Objective
To compare the diagnostic accuracy of TE and MRE and establish cutoff levels and diagnostic strategies for both techniques, enabling selection of patients for liver biopsy.
Methods
One ...hundred three patients with chronic hepatitis B or C and liver biopsy were prospectively included. Areas under curves (AUROC) were compared for TE and MRE for METAVIR fibrosis grade ≥ F2 and ≥F3. We defined cutoff values for selection of patients with F0–F1 (sensitivity >95 %) and for significant fibrosis F2–F4 (specificity >95 %).
Results
Following exclusions, 85 patients were analysed (65 CHB, 19 CHC, 1 co-infected). Fibrosis stages were F0 (
n
= 3), F1 (
n
= 53), F2 (
n
= 15), F3 (
n
= 8) and F4 (
n
= 6). TE and MRE accuracy were comparable AUROC
TE
≥ F2: 0.914 (95 % CI: 0.857–0.972) vs. AUROC
MRE
≥ F2: 0.909 (0.840–0.977),
P
= 0.89; AUROC
TE
≥ F3: 0.895 (0.816–0.974) vs. AUROC
MRE
≥ F3: 0.928 (0.874–0.982),
P
= 0.42. Cutoff values of <5.2 and ≥8.9 kPa (TE) and <1.66 and ≥2.18 kPa (MRE) diagnosed 64 % and 66 % of patients correctly as F0–F1 or F2–F4. A conditional strategy in inconclusive test results increased diagnostic yield to 80 %.
Conclusion
TE and MRE have comparable accuracy for detecting significant fibrosis, which was reliably detected or excluded in two-thirds of patients. A conditional strategy further increased diagnostic yield to 80 %.
Key Points
•
Both ultrasound-based transient elastography and magnetic resonance elastography can assess hepatic fibrosis.
•
Both have comparable accuracy for detecting liver fibrosis in viral hepatitis.
•
The individual techniques reliably detect or exclude significant liver fibrosis in 66 %.
•
A conditional strategy for inconclusive findings increases the number of correct diagnoses.
Sub-Saharan African (SSA) ethnicity has been associated with a higher risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis B in cross-sectional studies. However, the ...incidence of HCC and performance of HCC risk scores in this population are unknown.
We conducted an international multicenter retrospective cohort study of all consecutive HBV-monoinfected individuals of SSA or Afro-Surinamese (AS) ethnicity managed at sites in the Netherlands, the United Kingdom and Spain. We assessed the 5- and 10-year cumulative incidences of HCC in the overall study population, among different clinically relevant subgroups and across (m)PAGE-B subgroups. Next, we explored the different risk factors for HCC.
During a median follow-up of 8 years, we analyzed 1,473 individuals of whom 34 developed HCC. The 5- and 10-year cumulative incidences of HCC were 1% and 2.4%. The 10-year cumulative incidence of HCC was 0.7% among individuals without advanced fibrosis at baseline, compared to 12.1% among individuals with advanced fibrosis (p <0.001). Higher age (adjusted hazard ratio aHR 1.05), lower platelet count (aHR 0.98), lower albumin level (aHR 0.90) and higher HBV DNA log10 (aHR 1.21) were significantly associated with HCC development. The 10-year cumulative incidence of HCC was 0.5% among individuals with a low PAGE-B score, compared to 2.9% in the intermediate- and 15.9% in the high-risk groups (p <0.001).
In this unique international multicenter cohort of SSA and AS individuals with chronic hepatitis B, we observed 5- and 10-year cumulative HCC risks of 1% and 2.4%, respectively. The risk of HCC was negligible for individuals without advanced fibrosis at baseline, and among individuals with low baseline (m)PAGE-B scores. These findings can be used to guide HCC surveillance strategies.
Sub-Saharan African ethnicity has been associated with a higher risk of hepatocellular carcinoma among individuals with chronic hepatitis B. In this international multicenter cohort study of sub-Saharan African and Afro-Surinamese individuals living with chronic hepatitis B in Europe, we observed 5- and 10-year cumulative incidences of hepatocellular carcinoma of 1% and 2.4%, respectively. The risk was negligible among individuals without advanced fibrosis and a low baseline (m)PAGE-B score. These findings can be used to guide HCC surveillance strategies in this population.
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•We found a 5- and 10-year cumulative HCC incidence of 1% and 2.4%.•Older age, higher HBV DNA levels, lower platelet count, and lower albumin levels increased the risk of HCC.•The 10-year HCC risk was negligible for individuals without advanced fibrosis at baseline.•The 10-year HCC risk was negligible for individuals with low baseline (m)PAGE-B scores.•These findings suggest opportunities for individualized HCC surveillance strategies.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Patients with chronic hepatitis B (CHB) are at increased risk of hepatocellular carcinoma and (liver-related) mortality. In addition to hepatitis B–related factors, metabolic comorbidities may ...contribute to the progression of fibrosis. Therefore, we studied the association between metabolic comorbidities and adverse clinical outcomes in patients with CHB.
We conducted a retrospective cohort study of CHB patients attending the Erasmus MC University Medical Center (Rotterdam, The Netherlands) and CHB patients who underwent liver biopsy at the Toronto General Hospital (Toronto, Canada). The presence of metabolic comorbidities (ie, overweight, diabetes mellitus, hypertension, and dyslipidemia) was assessed based on chart review. The primary end point was liver-related events, defined as the first composite of hepatocellular carcinoma, liver transplantation, or liver-related mortality.
We analyzed 1850 patients, of whom 926 (50.1%) were overweight, 161 (8.7%) had hypertension, 116 (6.3%) had dyslipidemia, and 82 (4.4%) had diabetes. During a median follow-up period of 7.3 years (interquartile range, 2.9–11.5 y), a total of 111 first events were recorded. Hypertension (hazard ratio HR, 8.3; 95% CI, 5.5–12.7), diabetes (HR, 5.4; 95% CI, 3.2–9.1), dyslipidemia (HR, 2.8; 95% CI, 1.6–4.8), and overweight (HR, 1.7; 95% CI, 1.1–2.5) were associated with an increased risk for liver-related events. The presence of multiple comorbidities further increased the risk. Findings were consistent for patients with and without cirrhosis, among noncirrhotic hepatitis B e antigen–negative patients with hepatitis B virus DNA less than 2000 IU/mL and in multivariable analysis adjusting for age, sex, ethnicity, hepatitis B e antigen status, hepatitis B virus DNA, use of antiviral therapy, and the presence of cirrhosis.
Metabolic comorbidities in CHB patients are associated with an increased risk for liver-related events, with the highest risk observed in patients with multiple comorbidities. Findings were consistent in various clinically relevant subgroups, underscoring the need for thorough metabolic assessment in patients with CHB.
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The Rotterdam Study is a population-based cohort study, started in 1990 in the district of Ommoord in the city of Rotterdam, the Netherlands, with the aim to describe the prevalence and incidence, ...unravel the etiology, and identify targets for prediction, prevention or intervention of multifactorial diseases in mid-life and elderly. The study currently includes 17,931 participants (overall response rate 65%), aged 40 years and over, who are examined in-person every 3 to 5 years in a dedicated research facility, and who are followed-up continuously through automated linkage with health care providers, both regionally and nationally. Research within the Rotterdam Study is carried out along two axes. First, research lines are oriented around diseases and clinical conditions, which are reflective of medical specializations. Second, cross-cutting research lines transverse these clinical demarcations allowing for inter- and multidisciplinary research. These research lines generally reflect subdomains within epidemiology. This paper describes recent methodological updates and main findings from each of these research lines. Also, future perspective for coming years highlighted.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Current standard-of-care treatment of chronically infected hepatitis C virus (HCV) patients involves direct-acting antivirals (DAA). However, concerns exist regarding the emergence of drug -resistant ...variants and subsequent treatment failure. In this study, we investigate potential natural drug-resistance mutations in the NS5B gene of HCV genotype 1b from treatment-naïve patients. Population-based sequencing and 454 deep sequencing of NS5B gene were performed on plasma and liver samples obtained from 18 treatment- naïve patients. The quasispecies distribution in plasma and liver samples showed a remarkable overlap in each patient. Although unique sequences in plasma or liver were observed, in the majority of cases the most dominant sequences were shown to be identical in both compartments. Neither in plasma nor in the liver codon changes were detected at position 282 that cause resistance to nucleos(t)ide analogues. However, in 10 patients the V321I change conferring resistance to nucleos(t)ide NS5B polymerase inhibitors and in 16 patients the C316N/Y/H non-nucleoside inhibitors were found mainly in liver samples. In conclusion, 454-deep sequencing of liver and plasma compartments in treatment naïve patients provides insight into viral quasispecies and the pre-existence of some drug-resistant variants in the liver, which are not necessarily present in plasma.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Progressive dilation of the infrarenal aortic diameter is a consequence of the ageing process and is considered the main determinant of abdominal aortic aneurysm (AAA). We aimed to investigate the ...genetic and clinical determinants of abdominal aortic diameter (AAD). We conducted a meta-analysis of genome-wide association studies in 10 cohorts (n = 13 542) imputed to the 1000 Genome Project reference panel including 12 815 subjects in the discovery phase and 727 subjects Partners Biobank cohort 1 (PBIO) as replication. Maximum anterior-posterior diameter of the infrarenal aorta was used as AAD. We also included exome array data (n = 14 480) from seven epidemiologic studies. Single-variant and gene-based associations were done using SeqMeta package. A Mendelian randomization analysis was applied to investigate the causal effect of a number of clinical risk factors on AAD. In genome-wide association study (GWAS) on AAD, rs74448815 in the intronic region of LDLRAD4 reached genome-wide significance (beta = -0.02, SE = 0.004, P-value = 2.10 × 10-8). The association replicated in the PBIO1 cohort (P-value = 8.19 × 10-4). In exome-array single-variant analysis (P-value threshold = 9 × 10-7), the lowest P-value was found for rs239259 located in SLC22A20 (beta = 0.007, P-value = 1.2 × 10-5). In the gene-based analysis (P-value threshold = 1.85 × 10-6), PCSK5 showed an association with AAD (P-value = 8.03 × 10-7). Furthermore, in Mendelian randomization analyses, we found evidence for genetic association of pulse pressure (beta = -0.003, P-value = 0.02), triglycerides (beta = -0.16, P-value = 0.008) and height (beta = 0.03, P-value < 0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases.
Background
The discovery of novel biomarkers that predict treatment response in advanced cancer patients requires acquisition of high‐quality tumor samples. As cancer evolves over time, tissue is ...ideally obtained before the start of each treatment. Preferably, samples are freshly frozen to allow analysis by next‐generation DNA/RNA sequencing (NGS) but also for making other emerging systematic techniques such as proteomics and metabolomics possible. Here, we describe the first 469 image‐guided biopsies collected in a large collaboration in The Netherlands (Center for Personalized Cancer Treatment) and show the utility of these specimens for NGS analysis.
Patients and Methods
Image‐guided tumor biopsies were performed in advanced cancer patients. Samples were fresh frozen, vital tumor cellularity was estimated, and DNA was isolated after macrodissection of tumor‐rich areas. Safety of the image‐guided biopsy procedures was assessed by reporting of serious adverse events within 14 days after the biopsy procedure.
Results
Biopsy procedures were generally well tolerated. Major complications occurred in 2.1%, most frequently consisting of pain. In 7.3% of the percutaneous lung biopsies, pneumothorax requiring drainage occurred. The majority of samples (81%) contained a vital tumor percentage of at least 30%, from which at least 500 ng DNA could be isolated in 91%. Given our preset criteria, 74% of samples were of sufficient quality for biomarker discovery. The NGS results in this cohort were in line with those in other groups.
Conclusion
Image‐guided biopsy procedures for biomarker discovery to enable personalized cancer treatment are safe and feasible and yield a highly valuable biobank.
Implications for Practice
This study shows that it is safe to perform image‐guided biopsy procedures to obtain fresh frozen tumor samples and that it is feasible to use these biopsies for biomarker discovery purposes in a Dutch multicenter collaboration. From the majority of the samples, sufficient DNA could be yielded to perform next‐generation sequencing. These results indicate that the way is paved for consortia to prospectively collect fresh frozen tumor tissue.
Here are described the first 469 image‐guided biopsies collected in a large collaboration in The Netherlands (Center for Personalized Cancer Treatment).The utility of these specimens for next‐generation sequencing analysis is shown, revealing that image‐guided biopsy procedures for biomarker discovery to enable personalized cancer treatment are safe and feasible and yield a highly valuable biobank.
BackgroundThe Netherlands has a low hepatitis C virus (HCV) prevalence, estimated at 0.16%. Previous studies have shown that up to 30% of the diagnosed HCV population in the Netherlands has been lost ...to follow-up (LTFU). Retrieval of these patients could halt progression of liver disease in infected patients, reduce the number of infected individuals and limit HCV transmission. Several regional Dutch retrieval projects have already been executed, which demonstrated that retrieval is feasible. Therefore, we initiated a nationwide retrieval project, aiming to achieve microelimination in previously diagnosed but LTFU patients with chronic HCV through retrieval.MethodsLaboratory records will be used to identify possible patients with chronic hepatitis C, defined as either a positive most recent HCV RNA or positive HCV antibodies without known RNA result. Reviewing patient records and obtaining current contact information from municipality databases will identify LTFU patients who are eligible for retrieval. These patients will be invited for outpatient clinic care. The primary outcome of the study is the total number of LTFU patients who have been successfully linked to care.DiscussionHepatitis C ELimination In the NEtherlands (CELINE) is within the remit of WHO elimination targets and the Dutch National Hepatitis Plan. The methodology of CELINE is based on previously conducted regional retrieval projects and is designed to overcome some of their limitations. After ethical approval was obtained in 2018, the first centre initiated retrieval in 2018 and the project is expected to finish in 2021.Trial registration numberNCT04208035.
Summary
Addition of peginterferon alpha (PEG‐IFN add‐on) to entecavir (ETV) treatment after a short lead‐in phase results in more response than ETV monotherapy in HBeAg‐positive chronic hepatitis B ...infection (CHB). This study is the first to assess long‐term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG‐IFN add‐on in a global trial (ARES study) and completed follow‐up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200 IU/mL) at LTFU. In total, 48 patients treated with PEG‐IFN add‐on and 48 patients treated with ETV monotherapy were included. The median follow‐up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non‐responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P = 0.81), and 1 log10 HBsAg decline in 59% vs 28% (P = 0.02) for PEG‐IFN add‐on and ETV monotherapy, respectively. In 41 initial non‐responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG‐IFN add‐on: 5/22 23%; ETV monotherapy: 4/19 21%). Beyond week 96 of follow‐up, rates of serological response became comparable between PEG‐IFN add‐on and ETV monotherapy. Although in this LTFU study initial non‐responders were overrepresented in the add‐on arm, PEG‐IFN add‐on possibly leads rather to accelerated HBeAg loss than to increased long‐term HBeAg loss rates.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Addition of peginterferon alpha (
PEG
‐
IFN
add‐on) to entecavir (
ETV
) treatment after a short lead‐in phase results in more response than
ETV
monotherapy in
HB
eAg‐positive chronic ...hepatitis B infection (
CHB
). This study is the first to assess long‐term efficacy of this treatment strategy. Patients who received
ETV
± 24 weeks of
PEG
‐
IFN
add‐on in a global trial (
ARES
study) and completed follow‐up were eligible to participate in this observational
LTFU
study if they had at least one combined
HB
eAg and
HBV DNA
measurement beyond week 96 of the
ARES
study. The primary endpoint was combined response (
HB
eAg loss and
HBV DNA
<200
IU
/
mL
) at
LTFU
. In total, 48 patients treated with
PEG
‐
IFN
add‐on and 48 patients treated with
ETV
monotherapy were included. The median follow‐up duration was 226 (
IQR
51) weeks, and 86/96 (90%) patients were initial non‐responders. At
LTFU
, combined response was present in 13 (27%) vs 11 (23%) patients (
P
= 0.81), and 1 log
10
HB
sAg decline in 59% vs 28% (
P
= 0.02) for
PEG
‐
IFN
add‐on and
ETV
monotherapy, respectively. In 41 initial non‐responders who continued
ETV
therapy, combined response at
LTFU
was present in 9 patients (
PEG
‐
IFN
add‐on: 5/22 23%;
ETV
monotherapy: 4/19 21%). Beyond week 96 of follow‐up, rates of serological response became comparable between
PEG
‐
IFN
add‐on and
ETV
monotherapy. Although in this
LTFU
study initial non‐responders were overrepresented in the add‐on arm,
PEG
‐
IFN
add‐on possibly leads rather to accelerated
HB
eAg loss than to increased long‐term
HB
eAg loss rates.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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