Defining the natural history of rare genetic liver diseases:Lessons learned from the NAPPED initiative

While rare diseases collectively affect similar to 300 million people worldwide, the prevalence of each disease concerns a relatively small number of patients. Usually, only limited data with regard to natural history are available. Multicenter initiatives are needed to aggregate data and answer clinically relevant research questions. In 2017, we launched the NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) consortium. In three years, NAPPED created a global network focused on rare genetic liver diseases in the Progressive Familial Intrahepatic Cholestasis (PFIC) spectrum. During these years, we have learned important lessons which we feel should be taken into account when initiating and leading a global consortium.First, it is essential to 'keep it simple' from the start. Research questions, case report forms (CRFs) and data acquisition should be limited and clear to stay focused and keep the workload low for new participants. Secondly, early rewards and research output are needed to keep momentum and motivation. Quick output can only follow a clean and simple design. Thirdly, the leading team should be in touch and accessible. Ideally, an involved PhD-candidate is appointed as primary contact person. Lastly, be inclusive and actively involve all participants the consortium's course.Global consortia are critical for personalized medicine in rare diseases. Also, they are essential for setting up trials to investigate generic drugs and personalized therapies. We hope to herewith stimulate others that are starting (or are planning to start) a global consortium, ultimately to help improve the care for patients with a rare disease.</p

Risk of hepatocellular carcinoma in chronic hepatitis B: Assessment and modification with current antiviral therapy

SummaryIn 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

Analysis of Time to Treatment and Survival Among Adults Younger Than 50 Years of Age With Colorectal Cancer in Canada

Importance: Colorectal cancer (CRC) is uncommon in adults younger than 50 years of age, so this population may experience delays to treatment that contribute to advanced stage and poor survival. Objective: To investigate whether there is an association between time from presentation to treatment and survival in younger adults with CRC. Design, Setting, and Participants: This retrospective cohort study used linked population-based data in Ontario, Canada. Participants included patients with CRC aged younger than 50 years who were diagnosed in Ontario between 2007 and 2018. Analysis was performed between December 2019 and December 2022. Exposure: Administrative and billing codes were used to identify the number of days between the date of first presentation and treatment initiation (overall interval). Main Outcomes and Measures: The associations between increasing overall interval, overall survival (OS), and cause-specific survival (CSS) were explored with restricted cubic spline regression. Multivariable Cox proportional hazards models were also fit for OS and CSS, adjusted for confounders. Analyses were repeated in a subset of patients with lower urgency, defined as those who did not present emergently, did not have metastatic disease, did not have cross-sectional imaging or endoscopy within 14 days of first presentation, and had an overall interval of at least 28 days duration. Results: Among 5026 patients included, the median (IQR) age was 44.0 years (40.0-47.0 years); 2412 (48.0%) were female; 1266 (25.2%) had metastatic disease and 1570 (31.2%) had rectal cancer. The lower-urgency subset consisted of 2548 patients. The median (IQR) overall interval was 108 days (55-214 days) (15.4 weeks [7.9-30.6 weeks]). Patients with metastatic CRC had shorter median (IQR) overall intervals (83 days [39-183 days]) compared with those with less advanced disease. Five-year overall survival was 69.8% (95% CI, 68.4%-71.1%). Spline regression showed younger patients with shorter overall intervals (&lt;108 days) had worse OS and CSS with no significant adverse outcomes of longer overall intervals. In adjusted Cox models, overall intervals longer than 18 weeks were not associated with significantly worse OS or CSS compared with those waiting 12 to 18 weeks (OS: HR, 0.83 [95% CI, 0.67-1.03]; CSS: HR, 0.90 [95% CI, 0.69-1.18]). Results were similar in the subset of lower-urgency patients, and when stratified by stage. Conclusions and relevance: In this cohort study of 5026 patients with CRC aged younger than 50 years of age in Ontario, time from presentation to treatment was not associated with advanced disease or poor survival. These results suggest that targeting postpresentation intervals may not translate to improved outcomes on a population level.</p

Blood Cell Salvage and Autotransfusion Does Not Worsen Oncologic Outcomes Following Liver Transplantation with Incidental Hepatocellular Carcinoma: A Propensity Score-Matched Analysis

BACKGROUND: Intraoperative blood cell salvage and autotransfusion (IBSA) during liver transplantation (LT) for hepatocellular carcinoma (HCC) is controversial for concern regarding adversely impacting oncologic outcomes. OBJECTIVE: We aimed to evaluate the long-term oncologic outcomes of patients who underwent LT with incidentally discovered HCC who received IBSA compared with those who did not receive IBSA. METHODS: Patients undergoing LT (January 2001-October 2018) with incidental HCC on explant pathology were retrospectively identified. A 1:1 propensity score matching (PSM) was performed. HCC recurrence and patient survival were compared. Kaplan-Meier survival analyses were performed, and univariable Cox proportional hazard analyses were performed for risks of recurrence and death. RESULTS: Overall, 110 patients were identified (IBSA, n = 76 [69.1%]; non-IBSA, n = 34 [30.9%]). Before matching, the groups were similar in terms of demographics, transplant, and tumor characteristics. Overall survival was similar for IBSA and non-IBSA at 1, 3, and 5 years (96.0%, 88.4%, 83.0% vs. 97.1%, 91.1%, 87.8%, respectively; p = 0.79). Similarly, the recurrence rate at 1, 3, and 5 years was not statistically different (IBSA 0%, 1.8%, 1.8% vs. non-IBSA 0%, 3.2%, 3.2%, respectively; p = 0.55). After 1:1 matching (26 IBSA, 26 non-IBSA), Cox proportional hazard analysis demonstrated similar risk of death and recurrence between the groups (IBSA hazard ratio [HR] of death 1.26, 95% confidence interval [CI] 0.52-3.05, p = 0.61; and HR of recurrence 2.64, 95% CI 0.28-25.30, p = 0.40). CONCLUSIONS: IBSA does not appear to adversely impact oncologic outcomes in patients undergoing LT with incidental HCC. This evidence further supports the need for randomized trials evaluating the impact of IBSA use in LT for HCC

Increased Hepatitis E Virus Seroprevalence Correlates with Lower CD4+Cell Counts in HIV-Infected Persons in Argentina

Hepatitis E virus (HEV) is a single-stranded RNA virus that can cause hepatitis in an epidemic fashion. HEV usually causes asymptomatic or limited acute infections in immunocompetent individuals, whereas in immunosuppressed individuals such as transplant recipients, HEV can cause chronic infections. The risks and outcomes of HEV co-infection in patients infected with human immunodeficiency virus (HIV) are poorly characterized. We used a third generation immunoassay to measure serum IgG antibodies specific for HEV in 204 HIV-infected individuals from Argentina and a control group of 433 HIV-negative individuals. We found 15 of 204 (7.3%, 95% CI 3.74-10.96%) individuals in the HIV-positive group to have positive HEV IgG levels suggestive of previous infection, compared to 19 of 433 (4.4%, 95% CI 2.5-6.3%) individuals in the HIV-negative control group (p = 0.12). Among HIV-positive individuals, those with HEV seropositivity had lower CD4 counts compared to those that were HEV seronegative (average CD4 count of 234 vs 422 mm(3), p = 0.01), indicating that patients with lower CD4 counts were more likely to be HEV IgG positive. Moreover, HEV seropositivity in patients with CD4 counts &lt;200 mm(3) was 16%, compared to 4.5% in those with CD4 counts &gt;200 mm(3) (p = 0.012). We found a positive PCR result for HEV in one individual. Our study found that increased seroprevalence of HEV IgG correlated with lower CD4 counts in HIV-infected patients in Argentina

Factors associated with knowledge and awareness of Hepatitis B in individuals of Chinese descent:Results from a mass point of care testing and outreach campaign in Toronto, Canada

BACKGROUND: Migrants from hepatitis B virus (HBV) endemic regions are at high risk of having chronic infection. Despite this, HBV knowledge and awareness programming, and low-barrier screening methods such as point of care (POC) testing, among this group have yet to become routine. METHODS: We conducted a mass HBV POC screening and knowledge and awareness campaign for individuals of Chinese descent in Toronto, Canada. POC screening was administered, then participants completed a knowledge questionnaire. Logistic regression identified associations between demographic factors and participants’ level of HBV knowledge. RESULTS: From 2015 to 2018, 33 outreach events resulted in 891 individuals completing testing and the knowledge questionnaire. Individuals averaged 64.4 years old. Most, 62% (N = 552), were female, and 73.6% (N = 656) have been in Canada for &lt;30 years. The average questionnaire score was 70.7% correct, with 65.2% (N = 581) demonstrating a high level of HBV knowledge. Post-secondary education (OR: 2.19, 95% CI: 1.41, 3.39), income of 50,000 to <75,000 (OR: 2.74, 95% CI: 1.39, 5.43), and having familial history of HBV (OR: 1.72, 95% CI: 1.06, 2.78) were associated with high knowledge. The observed prevalence of HBV was 1.5%, with 13 individuals testing positive on the POC test and confirmatory laboratory testing. CONCLUSIONS: Improving knowledge and awareness of HBV is critical to empowering people, especially migrants who experience barriers to care, to pursue vaccination, testing, and treatment. Combining knowledge outreach and POC test campaigns, enabled discussion and screening for HBV with large numbers of people, and can be tailored for optimal effectiveness for specific groups.</p

Factors associated with knowledge and awareness of Hepatitis B in individuals of Chinese descent:Results from a mass point of care testing and outreach campaign in Toronto, Canada

BACKGROUND: Migrants from hepatitis B virus (HBV) endemic regions are at high risk of having chronic infection. Despite this, HBV knowledge and awareness programming, and low-barrier screening methods such as point of care (POC) testing, among this group have yet to become routine. METHODS: We conducted a mass HBV POC screening and knowledge and awareness campaign for individuals of Chinese descent in Toronto, Canada. POC screening was administered, then participants completed a knowledge questionnaire. Logistic regression identified associations between demographic factors and participants’ level of HBV knowledge. RESULTS: From 2015 to 2018, 33 outreach events resulted in 891 individuals completing testing and the knowledge questionnaire. Individuals averaged 64.4 years old. Most, 62% (N = 552), were female, and 73.6% (N = 656) have been in Canada for &lt;30 years. The average questionnaire score was 70.7% correct, with 65.2% (N = 581) demonstrating a high level of HBV knowledge. Post-secondary education (OR: 2.19, 95% CI: 1.41, 3.39), income of 50,000 to <75,000 (OR: 2.74, 95% CI: 1.39, 5.43), and having familial history of HBV (OR: 1.72, 95% CI: 1.06, 2.78) were associated with high knowledge. The observed prevalence of HBV was 1.5%, with 13 individuals testing positive on the POC test and confirmatory laboratory testing. CONCLUSIONS: Improving knowledge and awareness of HBV is critical to empowering people, especially migrants who experience barriers to care, to pursue vaccination, testing, and treatment. Combining knowledge outreach and POC test campaigns, enabled discussion and screening for HBV with large numbers of people, and can be tailored for optimal effectiveness for specific groups.</p

No Superiority of Tacrolimus Suppositories vs Beclomethasone Suppositories in a Randomized Trial of Patients With Refractory Ulcerative Proctitis

Background &amp; Aims: Ulcerative proctitis (UP) refractory to 5-aminosalicylic acid (5-ASA) suppositories is a challenge to treat, often requiring step up to immunomodulator or biological therapy. Topical tacrolimus is effective and safe in patients with refractory UP. However, it is not clear how tacrolimus suppositories fit into in the treatment algorithm of UP. Methods: We performed a randomized controlled, double-blind study at 8 hospitals in the Netherlands and Belgium from 2014 through 2017. Eighty-five patients with refractory UP (65% women) were randomly assigned to groups given once daily tacrolimus suppositories (2 mg; n = 43) or beclomethasone (3 mg; n = 42) for 4 weeks. The primary outcome was clinical response (decrease in Mayo score of 3 or more). Secondary outcomes included clinical remission, endoscopic response and remission, adverse events and quality of life. Outcomes were compared using Fisher's exact test and Mann-Whitney U test. Results: Proportions of patients with clinical responses were 63% in the tacrolimus group and 59% in the beclomethasone group (P =.812); proportions of patients in clinical remission were 46% and 38%, respectively (P =.638). Proportions of patients with an endoscopic response were 68% and 60% in the tacrolimus group and in the beclomethasone group (P =.636); proportions in endoscopic remission rates were 30% and 13%, respectively (P =.092) Median increases in the inflammatory bowel disease questionnaire score were 18.0 in the tacrolimus group and 20.5 in the beclomethasone group (P =.395). Adverse event rates did not differ significantly between groups. Conclusions: In a 4-week randomized controlled trial, tacrolimus and beclomethasone suppositories induce comparable clinical and endoscopic responses in patients with UP refractory to 5-ASA. There were no significant differences in adverse events rates. Tacrolimus and beclomethasone suppositories are therefore each safe and effective treatment options for 5-ASA refractory disease. EUDRACT 2013-001259-11; Netherlands Trial Register NL4205/NTR4416.</p