Long-term outcome of hepatitis delta in different regions world-wide: Results of the Hepatitis Delta International Network.

BACKGROUND AND AIMS: Chronic hepatitis delta represents a major global health burden. Clinical features of hepatitis D virus (HDV) infection vary largely between different regions worldwide. Treatment approaches are dependent on the approval status of distinct drugs and financial resources. METHODS: The Hepatitis Delta International Network (HDIN) registry involves researchers from all continents (Wranke, Liver International 2018). We here report long-term follow-up data of 648 hepatitis D patients recruited by 14 centres in 11 countries. Liver-related clinical endpoints were defined as hepatic decompensation (ascites, encephalopathy and variceal bleeding), liver transplantation, hepatocellular carcinoma or liver-related death. RESULTS: Patient data were available from all continents but Africa: 22% from Eastern Mediterranean, 32% from Eastern Europe and Central Asia, 13% from Central and Southern Europe, 14% from South Asia (mainly Pakistan) and 19% from South America (mainly Brazil). The mean follow-up was 6.4 (.6-28) years. During follow-up, 195 patients (32%) developed a liver-related clinical event after 3.5 (±3.3) years. Liver cirrhosis at baseline and a detectable HDV RNA test during follow-up were associated with a worse clinical outcome in multivariate regression analysis while patients receiving interferon alfa-based therapies developed clinical endpoints less frequently. Patients from South Asia developed endpoints earlier and had the highest mortality. CONCLUSIONS: The HDIN registry confirms the severity of hepatitis D and provides further evidence for HDV viraemia as a main risk factor for disease progression. Hepatitis D seems to take a particularly severe course in patients born in Pakistan. There is an urgent need to extend access to antiviral therapies and to provide appropriate education about HDV infection.

Hepatitis delta virus: From infection to new therapeutic strategies.

The hepatitis delta virus (HDV) is a small RNA virus that encodes a single protein and which requires the hepatitis B virus (HBV)-encoded hepatitis B surface antigen (HBsAg) for its assembly and transmission. HBV/HDV co-infections exist worldwide and show a higher prevalence among selected groups of HBV-infected populations, specifically intravenous drug users, practitioners of high-risk sexual behaviours, and patients with cirrhosis and hepatocellular carcinoma. The chronic form of HDV-related hepatitis is usually severe and rapidly progressive. Patterns of the viral infection itself, including the status of co-infection or super-infection, virus genotypes (both for HBV and HDV), and persistence of the virus' replication, influence the outcome of the accompanying and manifested liver disease. Unfortunately, disease severity is burdened by the lack of an effective cure for either virus type. For decades, the main treatment option has been interferon, administered as mono-therapy or in combination with nucleos(t)ide analogues. While its efficacy has been reported for different doses, durations and courses, only a minority of patients achieve a sustained response, which is the foundation of eventual improvement in related liver fibrosis. The need for an efficient therapeutic alternative remains. Research efforts towards this end have led to new treatment options that target specific steps in the HDV life cycle; the most promising among these are myrcludex B, which inhibits virus entry into hepatocytes, lonafarnib, which inhibits farnesylation of the viral-encoded L-HDAg large hepatitis D antigen, and REP-2139, which interferes with HBsAg release and assembly.

False-positive results of SARS-CoV-2 IgM/IgG antibody tests in sera stored before the 2020 pandemic in Italy.

OBJECTIVES: Aside from the outbreak of the coronavirus disease 2019 (COVID-19), serological tests are not well known for their diagnostic value. We assessed the performance of serological tests using stored sera from patients with a variety of pathologic conditions, collected before the 2020 pandemic in Italy. METHODS: Rapid lateral flow tests and Enzyme-Linked Immunosorbent Assays (ELISA) that detect Immunoglobulin M (IgM) and Immunoglobulin G (IgG) antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were carried out using 1150 stored human serum samples that had been collected in 2018 and 2019. The tests were also run using samples from 15 control patients who had positive or negative oral swab test results, as assessed using real-time reverse transcription-polymerase chain reaction (rRT-PCR). The urea dissociation test was employed to rule out false-positive reactivity in the two antibody detection methods. RESULTS: The lateral flow tests revealed 21 positive samples from the stored sera: 12 for IgM, four for IgG, and five for IgM/IgG. Among the nine rRT-PCR- positive controls, six individuals presented IgG and three IgM/IgG positivity. Using the urea (6 mol/L) dissociation test, two of the twelve stored samples that had shown IgM positivity were confirmed to be positive. The ELISA test detected four IgM-positive and three IgG-positive specimens. After treatment with 4 mol/L urea, the IgM-positive samples became negative, whereas the IgG positivity persisted. All of the rRT-PCR-positive controls were found to retain IgM or IgG positivity following the urea treatment. CONCLUSIONS: Our findings highlight the limited utility of serological testing for the SARS-CoV-2 virus based on the results of specimens collected before the outbreak of the infection.

Low influenza vaccination coverage in subjects with liver cirrhosis. An alert waiting for winter season 2020-2021 during the COVID-19 pandemic.

We have evaluated flu vaccine coverage and variables associated with the lack of vaccination in cirrhotic subjects with particular attention to the cirrhosis etiology. Cirrhotic subjects consecutively referring to eight Italian centers were prospectively enrolled for a 6-month period in 2019. Subjects were asked if they had received a flu vaccine in the last 12 months. Multiple logistic regression analysis was performed to identify independent predictors of lack of vaccination. A total of 818 cases were recruited. The overall vaccine coverage was 39.6% (26.9% in those younger than 65 years and 51.9% in those older than 64 years; p < 0.001). Age < 65 years (odds ratio [OR] = 2.38; 95% confidence interval [CI] = 1.68-3.36), alcoholic etiology (OR = 2.40; 95% CI = 1.49-3.85), birth abroad (OR = 2.7; 95% CI = 1.10-6.61), and residence in South/Sardinia island (OR = 1.66; 95% CI = 1.14-2.42) all resulted independent predictors of the likelihood of lack of vaccination. The lack of information regarding the vaccine as the reason for no vaccination was reported by 71.4% of foreigners and by 34.7% of natives (p < 0.001). In conclusion, much work still should be done to improve coverage among groups at higher risk of lack of vaccination identified in this survey. The ongoing SARS-CoV-2 pandemic may represent one more alert for improving seasonal flu vaccine coverage to avoid further stress to the National Health System.

Clinical and virological heterogeneity of hepatitis delta in different regions world-wide: The Hepatitis Delta International Network (HDIN).

BACKGROUND & AIMS: Chronic hepatitis D (delta) is a major global health burden. Clinical and virological characteristics of patients with hepatitis D virus (HDV) infection and treatment approaches in different regions world-wide are poorly defined. METHODS: The Hepatitis Delta International Network (HDIN) registry was established in 2011 with centres in Europe, Asia, North- and South America. Here, we report on clinical/ virological characteristics of the first 1576 patients with ongoing or past HDV infection included in the database until October 2016 and performed a retrospective outcome analysis. The primary aim was to investigate if the region of origin was associated with HDV replication and clinical outcome. RESULTS: The majority of patients was male (n = 979, 62%) and the mean age was 36.7 years (range 1-79, with 9% of patients younger than 20 years). Most patients were HBeAg-negative (77%) and HDV-RNA positive (85%). Cirrhosis was reported in 48.7% of cases which included 13% of patients with previous or ongoing liver decompensation. Hepatocellular carcinoma (HCC) developed in 30 patients (2.5%) and 44 (3.6%) underwent liver transplantation. Regions of origin were independently associated with clinical endpoints and detectability of HDV RNA. Antiviral therapy was administered to 356 patients with different treatment uptakes in different regions. Of these, 264 patients were treated with interferon-a and 92 were treated with HBV-Nucs only. CONCLUSIONS: The HDIN registry confirms the severity of hepatitis delta but also highlights the heterogeneity of patient characteristics and clinical outcomes in different regions. There is an urgent need for novel treatment options for HDV infection.

Virological profiles in hepatitis B virus/hepatitis C virus coinfected patients under interferon plus ribavirin therapy.

BACKGROUND: Hepatitis C virus (HCV) is believed to exert a suppressive effect on hepatitis B virus (HBV) in most HBV/HCV-coinfected patients; once HCV is cured by interferon-based therapy, these patients may show HBV reactivation. However, recent evidence revealed that the virological status in HBV/HCV-untreated individuals may vary over time and may show fluctuating profiles. METHODS: To evaluate the behaviour of apparently inactive HBV infection in patients under treatment for a concurrent HCV infection, we performed a prospective study that evaluated nine consecutive patients (eight males with a median age of 45.9 years, and one female aged 62 years) longitudinally followed-up with bi-monthly evaluation of HBV/HCV viraemia levels and liver biochemistry during a 1-year treatment with interferon plus ribavirin. RESULTS: In seven cases the HBV infection maintained its inactive status independently of the HCV response to therapy. By contrast, two non-responder cases with persistently high HCV RNA levels showed HBV DNA flairs during the follow-up, indicating a status of active HBV infection with fluctuating virological profiles. CONCLUSIONS: This study suggests that the HBV behaviour may be independent of the HCV activity during anti-HCV therapy in HBV/HCV-coinfected patients, and that the HBV virological profile should be monitored to recognize possible reactivations that might lead to more proper therapeutic choices or adjustments.

Coarse nodular US pattern in hepatic cirrhosis: risk for hepatocellular carcinoma.

PURPOSE: To determine the prevalence of the coarse nodular ultrasonographic (US) pattern and its prognostic importance in terms of hepatocellular carcinoma (HCC) risk in hepatic cirrhosis caused by hepatitis B virus (HBV); HBV with hepatitis D virus (HDV), formerly known as hepatitis delta virus; hepatitis C virus (HCV); and alcoholic cirrhosis (ALC) or primary biliary disease (primary biliary cirrhosis [PBC]). MATERIALS AND METHODS: Four hundred two cases of hepatic cirrhosis caused by HBV (94 patients), HDV (100 patients), HCV (100 patients), ALC (63 patients), or PBC (45 patients) were retrospectively reviewed to identify the US pattern present at diagnosis and its possible association with the cause of the disease and subsequent development of HCC during a mean follow-up of 43.9 months +/- 29.9 (SD). Data were analyzed with the chi2, Fisher exact, and log-rank tests and with the Kaplan-Meier method (all two-tailed). RESULTS: The coarse nodular pattern was found in a significantly higher percentage of patients with HDV-related cirrhosis (51%) compared with those with HBV (9%), HCV (9%), ALC (11%), or PBC (9%) (P <.001). This pattern was associated with a significantly increased risk for HCC in patients with cirrhosis and HBV-, HCV-, and ALC-related disease but not in those with HDV-related disease and PBC. CONCLUSION: The coarse nodular pattern is more often seen in patients with HDV-related cirrhosis, and, in this setting (in contrast to HBV-, HCV-, and ALC-related cirrhosis, as well as in PBC), it does not represent an added risk factor for HCC.