Background. Chronic hepatitis C virus (HCV) infection is a global health problem, resulting in liver failure, hepatocellular carcinoma, and liver-related death. Natural killer (NK) cells are innate ...immune cells, and their activity is known to correlate to viral treatment response of HCV. In this study, we investigate the immune effects of viral load decline with direct-acting antivirals (DAAs) in blood. Methods. Twelve patients with chronic HCV were treated with asunaprevir and daclatasvir, and peripheral blood was analyzed at various time points during therapy. Results. In line with previous studies, we confirmed restoration of HCV-specific T-cell frequency upon viral load decline. In addition, we show that serum interferon (IFN)-γ inducible-protein 10, interleukin (IL)–12p40, and IL-18 levels decreased early after start of therapy. Surface expression of activation receptors NKp30, NKp46, and inhibitory receptor NKG2A on blood NK cells reduced during therapy. In addition, the expression of TRAIL on NK cells was reduced during IFN-free therapy, suggesting a decrease in TRAIL-mediated killing by NK cells. Conclusions. We show that viral load decline as a consequence of treatment with novel DAAs in chronic HCV patients reduces serum levels of NK cell–stimulating cytokines and causes correction of the altered NK cell phenotype observed in chronic HCV patients. Clinical Trials Registration. NCT02282709.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
A beneficial effect of bezafibrate (BZF) on symptoms and biochemical features of primary biliary cholangitis (PBC) has been reported in patients with an incomplete response to ursodeoxycholic acid ...(UDCA), but long-term effects on survival remain unknown. In Japan, BZF has been used as a de facto second-line therapy for PBC since 2000. Herein, we compared the survival rates between patients treated with and those without BZF in a large nationwide Japanese PBC cohort.
All consecutively registered patients of this cohort who started UDCA therapy from 2000 onwards and had a follow-up ≥1 year were included. Association between BZF exposure and mortality or need for liver transplantation (LT) was assessed using time-dependent, multivariable-and propensity score-adjusted Cox proportional hazards models. Clinical benefit was quantified using the number needed to treat (NNT).
Of 3,908 eligible patients, 3,162 (81%) received UDCA only and 746 (19%) UDCA and BZF over 17,360 and 3,932 patient-years, respectively. During follow-up, 183 deaths (89 liver-related) and 21 LT were registered. Exposure to combination therapy was associated with a significant decrease in all-cause and liver-related mortality or need for LT (adjusted hazard ratios: 0.3253, 95% CI 0.1936–0.5466 and 0.2748, 95% CI 0.1336–0.5655, respectively; p <0.001 for both). This association was consistent across various risk groups at baseline. The NNTs with combination therapy to prevent 1 additional death or LT over 5, 10, and 15 years were 29 (95% CI 22–46), 14 (10–22), and 8 (6–15), respectively.
In a large retrospective cohort study of treatment effects in patients with PBC, the addition of BZF to UDCA was associated with improved prognosis.
The long-term efficacy of bezafibrate (BZF) on liver transplantation (LT) – free survival in patients with PBC and an incomplete response to ursodeoxycholic acid (UDCA) remains to be determined. In this Japanese nationwide retrospective cohort study, the use of UDCA-BZF combination therapy, compared to UDCA alone, was associated with a lower risk of all-cause and liver-related mortality or need for LT. These results indicate that BZF is so far the only drug in PBC to have demonstrated efficacy in improving symptoms, biochemical markers, and long-term outcomes.
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•Long-term efficacy of second-line therapies for PBC (obeticholic acid, bezafibrate) remains to be established.•In Japan, bezafibrate has been used since 2000 as a de facto second-line treatment for UDCA-resistant PBC.•In this large Japanese retrospective cohort study (n = 3,908), addition of bezafibrate to UDCA was associated with improved transplant-free survival.•Bezafibrate is currently the only drug in PBC demonstrating efficacy in improving symptoms, biochemical markers, and prognosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary In the treatment of chronic hepatitis B (CHB), the ultimate goal is preventing hepatitis B virus (HBV)-associated liver disease, including hepatocellular carcinoma (HCC). Recently published ...studies show that in CHB patients treated with the currently recommended first-line nucleos(t)ide analogs (NAs) entecavir or tenofovir, annual HCC incidences range from 0.01% to 1.4% in non-cirrhotic patients, and from 0.9% to 5.4% in those with cirrhosis. In Asian studies including matched untreated controls, current NA therapy consistently resulted in a significantly lower HCC incidence in patients with cirrhosis, amounting to an overall HCC risk reduction of ∼30%; in non-cirrhotic patients, HCC risk reduction was overall ∼80%, but this was only observed in some studies. For patients of Caucasian origin, no appropriate comparative studies are available to date to evaluate the impact of NA treatment on HCC. Achievement of a virologic response under current NA therapy was associated with a lower HCC risk in Asian, but not Caucasian studies. Studies comparing entecavir or tenofovir with older NAs generally found no difference in HCC risk reduction between agents, except for one study which used no rescue therapy in patients developing lamivudine resistance. Overall, these data indicate that with the current, potent NAs, HCC risk can be reduced but not eliminated, probably due to risk factors that are not amenable to change by antiviral therapy, or events that may have taken place before treatment initiation. Validated pre- and on-therapy HCC risk calculators that inform the best practice for HCC surveillance and facilitate patient counseling would be of great practical value.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background & Aims We aimed to validate the fatty liver index (FLI), an algorithm that is based on waist circumference, body mass index, and levels of triglyceride and γ-glutamyltransferase. We ...calculated its ability to identify fatty liver disease from any cause or nonalcoholic fatty liver disease (NAFLD) in a large population of white elderly persons. Methods We collected ultrasonography and FLI data from participants of the Rotterdam Study from February 2009 to February 2012; 2652 subjects (mean age, 76.3 ± 6.0 years) were interviewed and received a clinical examination that included abdominal ultrasound, analysis of blood samples during fasting, and anthropometric assessment. The ability of the FLI to detect (nonalcoholic) fatty liver was assessed by using area under the receiver operator characteristic (AUROC) curve analysis. Results FLI score was associated with NAFLD in multivariable analysis (odds ratio, 1.05; 95% confidence interval CI, 1.04–1.05; P < .001). FLI identified patients with NAFLD with an AUROC curve of 0.813 (95% CI, 0.797–0.830) and those with fatty liver from any cause with an AUROC curve of 0.807 (95% CI, 0.792–0.823). Conclusions The FLI (an algorithm that is based on waist circumference, body mass index, and levels of triglyceride and γ-glutamyltransferase) accurately identifies NAFLD, confirmed via ultrasonography, in a large, white, elderly population.
The incidence of colorectal cancer is rising in adults <50 years of age. As a primarily unscreened population, they may have clinically important delays to diagnosis and treatment. This study aimed ...to review the literature on delay intervals in patients <50 years with colorectal cancer (CRC), and explore associations between longer intervals and outcomes.
MEDLINE, Embase, and LILACS were searched until December 2, 2021. We included studies published after 1990 reporting any delay interval in adults <50 with CRC. Interval measures and associations with stage at presentation or survival were synthesized and described in a narrative fashion. Risk of bias was assessed using the Newcastle-Ottawa Scale, Institute of Health Economics Case Series Quality Appraisal Checklist, and the Aarhus Checklist for cancer delay studies.
55 studies representing 188,530 younger CRC patients were included. Most studies used primary data collection (64%), and 47% reported a single center. Sixteen unique intervals were measured. The most common interval was symptom onset to diagnosis (21 studies; N = 2,107). By sample size, diagnosis to treatment start was the most reported interval (12 studies; N = 170,463). Four studies examined symptoms onset to treatment start (total interval). The shortest was a mean of 99.5 days and the longest was a median of 217 days. There was substantial heterogeneity in the measurement of intervals, and quality of reporting. Higher-quality studies were more likely to use cancer registries, and be population-based. In four studies reporting the relationship between intervals and cancer stage or survival, there were no clear associations between longer intervals and adverse outcomes.
Adults <50 with CRC may have intervals between symptom onset to treatment start greater than 6 months. Studies reporting intervals among younger patients are limited by inconsistent results and heterogeneous reporting. There is insufficient evidence to determine if longer intervals are associated with advanced stage or worse survival.
This study's protocol was registered with the Prospective Register of Systematic Reviews (PROSPERO; registration number CRD42020179707).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although most patients with chronic hepatitis B (CHB) reach effective virological suppression with long-term nucleos(t)ide analogues (NA) therapy, some might not need to continue treatment for life. ...In this randomised, controlled, phase IV trial, we evaluated off-therapy outcomes in patients after discontinuing long-term NA therapy.
Patients who had received NA therapy for ≥1 year and achieved virological suppression (hepatitis B e antigen (HBeAg) seroconversion combined with undetectable hepatitis B virus (HBV) DNA ≥12 months in HBeAg-positive patients or undetectable HBV DNA ≥36 months in HBeAg-negative patients) were randomised 2:1 to stop or continue NA therapy for 72 weeks. Sustained disease remission (HBeAg negative, HBV DNA <2000 IU/mL and normal alanine aminotransferase (ALT)) was evaluated at 72 weeks after stopping NA therapy.
Among 67 enrolled patients, sustained disease remission was observed in 13/45 (29%) stop versus 18/22 (82%) continue patients. Hepatitis B surface antigen (HBsAg) loss occurred in two patients (one in each group). The median HBsAg decline from randomisation to week 72 was similar in both groups (0.2 (0.0-0.4) vs 0.1 (0.0-0.2) log IU/mL in stop vs continue patients). Among patients who stopped, 15/45 (33%) had virological or biochemical relapse and 17/45 (38%) were retreated according to predefined criteria. A total of 11/18 (61%) pretreatment HBeAg-positive versus 6/27 (22%) HBeAg-negative patients required retreatment (p=0.01). Fourteen (31%) patients developed ALT >10× upper limit of normal (ULN) and another 7 (16%) had ALT >5× ULN. No patients experienced liver decompensation or died.
The findings of this prospective study suggest limited benefit of stopping NA therapy in chronic hepatitis B.
NCT01911156.
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Risk scores for hepatocellular carcinoma (HCC) developed in Asians offer poor-moderate predictability in Caucasian patients with chronic hepatitis B (CHB). This nine center cohort ...study aimed to develop and validate an accurate HCC risk score in Caucasian CHB patients treated with the current oral antivirals, entecavir/tenofovir.
We included 1815 adult Caucasians with CHB and no HCC at baseline who received entecavir/tenofovir for ⩾12months. Using data from eight centers (derivation dataset, n=1325), a HCC risk score was developed based on multivariable Cox models and points system for simplification. Harrell’s c-index was used as discrimination, bootstrap for internal validation and the data from the 9th and largest center (validation dataset, n=490) for external validation.
The 5-year cumulative HCC incidence rates were 5.7% and 8.4% in the derivation and validation dataset, respectively. In the derivation dataset, age, gender, platelets and cirrhosis were independently associated with HCC. The PAGE-B score was developed based on age, gender and platelets (c-index=0.82, 0.81 after bootstrap validation). The addition of cirrhosis did not substantially improve the discrimination (c-index=0.84). The predictability of PAGE-B score was similar (c-index=0.82) in the validation dataset. Patients with PAGE-B ⩽9, 10–17, ⩾18 had 5-year cumulative HCC incidence rates of 0%, 3%, 17% in the derivation and 0%, 4%, 16% in the validation dataset.
PAGE-B, which is based only on baseline patients’ age, gender and platelets, represents a simple and reliable score for prediction of the 5-year HCC risk in Caucasian CHB patients under entecavir/tenofovir.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
On‐treatment levels of hepatitis B surface antigen (HBsAg) may predict response to peginterferon (PEG‐IFN) therapy in chronic hepatitis B (CHB), but previously proposed prediction rules have shown ...limited external validity. We analyzed 803 HBeAg‐positive patients treated with PEG‐IFN in three global studies with available HBsAg measurements. A stopping‐rule based on absence of a decline from baseline was compared to a prediction‐rule that uses HBsAg levels of <1,500 IU/mL and >20,000 IU/mL to identify patients with high and low probabilities of response. Patients with an HBsAg level <1,500 IU/mL at week 12 achieved response (HBeAg loss with HBV DNA <2,000 IU/mL at 6 months posttreatment) in 45%. At week 12, patients without a decline in HBsAg achieved a response in 14%, compared to only 6% of patients with HBsAg >20,000 IU/mL, but performance varied across HBV genotype. In patients treated with PEG‐IFN monotherapy (n = 465), response rates were low in patients with genotypes A or D if there was no decline of HBsAg by week 12 (negative predictive value NPV: 97%‐100%), and in patients with genotypes B or C if HBsAg at week 12 was >20,000 IU/mL (NPV: 92%‐98%). At week 24, nearly all patients with HBsAg >20,000 IU/mL failed to achieve a response, irrespective of HBV genotype (NPV for response and HBsAg loss 99% and 100%). Conclusion: HBsAg is a strong predictor of response to PEG‐IFN in HBeAg‐positive CHB. HBV genotype‐specific stopping‐rules may be considered at week 12, but treatment discontinuation is indicated in all patients with HBsAg >20,000 IU/mL at week 24, irrespective of HBV genotype. (Hepatology 2013;53:872–880)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background and Aims
Following liver resection (LR) for HCC, the likelihood of survival is dynamic, in that multiple recurrences and/or metastases are possible, each having variable impacts on ...outcomes. We sought to evaluate the natural progression, pattern, and timing of various disease states after LR for HCC using multistate modeling and to create a practical calculator to provide prognostic information for patients and clinicians.
Approach and Results
Adult patients undergoing LR for HCC between January 2000 and December 2018 were retrospectively identified at a single center. Multistate analysis modeled post‐LR tumor progression by describing transitions between distinct disease states. In this model, the states included surgery, intrahepatic recurrence (first, second, third, fourth, fifth), distant metastasis with or without intrahepatic recurrence, and death. Of the 486 patients included, 169 (34.8%) remained recurrence‐free, 205 (42.2%) developed intrahepatic recurrence, 80 (16.5%) developed distant metastasis, and 32 (7%) died. For an average patient having undergone LR, there was a 33.1% chance of remaining disease‐free, a 31.0% chance of at least one intrahepatic recurrence, a 16.3% chance of distant metastasis, and a 19.8% chance of death within the first 60 months post‐LR. The transition probability from surgery to first intrahepatic recurrence, without a subsequent state transition, increased from 3% (3 months) to 17.4% (30 months) and 17.2% (60 months). Factors that could modify these probabilities included tumor size, satellite lesions, and microvascular invasion. The online multistate model calculator can be found on https://multistatehcc.shinyapps.io/home/.
Conclusions
In contrast to standard single time‐to‐event estimates, multistate modeling provides more realistic prognostication of outcomes after LR for HCC by taking into account many postoperative disease states and transitions between them. Our multistate modeling calculator can provide meaningful data to guide the management of patients undergoing postoperative surveillance and therapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Interferons induced early after SARS-CoV-2 infection are crucial for shaping immunity and preventing severe COVID-19. We previously demonstrated that injection of pegylated interferon-lambda ...accelerated viral clearance in COVID-19 patients (NCT04354259). To determine if the viral decline is mediated by enhanced immunity, we assess in vivo responses to interferon-lambda by single cell RNA sequencing and measure SARS-CoV-2-specific T cell and antibody responses between placebo and interferon-lambda-treated patients. Here we show that interferon-lambda treatment induces interferon stimulated genes in peripheral immune cells expressing IFNLR1, including plasmacytoid dendritic cells and B cells. Interferon-lambda does not affect SARS-CoV-2-specific antibody levels or the magnitude of virus-specific T cells. However, we identify delayed T cell responses in older adults, suggesting that interferon-lambda can overcome delays in adaptive immunity to accelerate viral clearance in high-risk patients. Altogether, interferon-lambda offers an early COVID-19 treatment option for outpatients to boost innate antiviral defenses without dampening peripheral adaptive immunity.
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