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.

Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D.

BACKGROUND: In a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear. METHODS: In this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 µg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 µg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group. RESULTS: A total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity. CONCLUSIONS: The combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.).

Infective Endocarditis of a Rare Etiology of Streptococcus alactolyticus: A Case Report and Literature Review.

Streptococcus alactolyticus is a non-motile Gram-positive, catalase-negative cocci, a part of group D Streptococci. In the literature, S. alactolyticus is documented as a causative agent of infective endocarditis, demonstrated by blood cultures in only four other cases, representing an extremely rare circumstance. Here, we describe a case of infective endocarditis due to S. alactolyticus in a young patient known with a bicuspid aortic valve and associated with a sigmoid precancerous polyp. The patient was also known to have blood hypertension and type II diabetes. Symptoms at the debut appeared insidiously and were non-specific: fatigue, loss of appetite, weight loss, night sweats, and fever. They lasted for the entire period of the illness with transient improvement during the courses of antibiotics. He followed more antibiotic courses prescribed for various clinical diagnoses. Each round of antibiotic treatment transitorily alleviated the symptoms, which reappeared each time after the cessation. The correct diagnosis was made only about three months after the appearance of the first clinical manifestations. This was based on ultrasound criteria (presence of vegetation and lesions of aortic cusps) and microbiological criteria (isolation of S. alactolyticus in blood cultures). A course of six weeks of ceftriaxone was considered the opportune antibiotic therapy. Similar to all other cases described in the literature, our patient presented important damage to the valvular tissue and required cardiac surgery to re-establish the normal function of the valve. The surgery consisted of the excision of the severely affected natural aortic valve and her replacement with a mechanical prosthetic valve. Following medical and surgical treatment, the patient is completely healed and has a normal life. Our case is noteworthy because of the scarcity of the involvement of S. alactolyticus in the pathogeny of infective endocarditis. This is the fifth published case with this etiology, and an overview of all five cases is provided in the article.

Results of Response-Guided Therapy with Pegylated Interferon Alpha 2a in Chronic Hepatitis B and D.

Pegylated interferon alpha 2a continues to be used for the treatment of chronic hepatitis D. The reported on-treatment virologic response varies between 17 and 47%, with relapses in more than 50% of these patients. No stopping rules have been defined, and the duration of the treatment is not clearly established, but it should be between 48 and 96 weeks. In total, 76 patients with compensated liver disease treated with peg-interferon according to the Romanian National protocol for the treatment of hepatitis D were retrospectively included. The duration of treatment was up to 96 weeks, with the following stopping rules: less than a 2 log HDV RNA decrease by week 24 and less than a 1 log decrease every 6 months afterwards. Six months after stopping the treatment, it can be restarted for unlimited cycles. The inclusion criteria were aged above 18, HBs Ag-positive, HDV RNA detectable, ALT above ULN and/or liver fibrosis at least F1 at liver biopsy, or Fibrotest and/or Fibroscan higher than 7 KPa and/or inflammation at least A1 at liver biopsy or Fibrotest. We monitored our patients for a total period of 4 years (including those that repeated the cycle). After the first 6 months of treatment, 27 patients (35.5%) had a greater than 2 log HDV RNA decrease, 19 of them achieving undetectable HDV RNA. Seventeen patients (22.3%) had undetectable HDV RNA 24 weeks after stopping 96 weeks of treatment, and none relapsed in the following 2 years. Of these 17 patients, 6 were cirrhotic, and 4 had F3. Undetectable HDV RNA at 24 weeks was the only parameter that predicted a long-term suppression of HDV RNA. In 49 patients, the treatment was stopped after 6 months according to protocol, but it was restarted 6 months later. Five of these patients finished a 48-week course of treatment; none achieved undetectable HDV RNA. During the first course of therapy, 45 patients had at least one moderate adverse reaction to treatment. In one patient, the treatment was stopped due to a serious adverse event (osteomyelitis). Treatment doses had to be reduced in 29 patients. The virologic response at week 24 can select the patients who will benefit from continuing the treatment from those who should be changed to another type of medication when available.

Acute severe hepatitis outbreak in children: A perfect storm. What do we know, and what questions remain?

During the first half of 2022, the World Health Organization reported an outbreak of acute severe hepatitis of unknown aetiology (AS-Hep-UA) in children, following initial alerts from the United Kingdom (UK) where a cluster of cases was first observed in previously well children aged <6 years. Sporadic cases were then reported across Europe and worldwide, although in most countries incidence did not increase above the expected baseline. There were no consistent epidemiological links between cases, and microbiological investigations ruled out known infectious causes of hepatitis. In this review, we explore the evidence for the role of viral infection, superimposed on a specific host genetic background, as a trigger for liver pathology. This hypothesis is based on a high prevalence of Human Adenovirus (HAdV) 41F in affected children, together with metagenomic evidence of adeno-associated virus (Adeno-associated viruses)-2, which is a putative trigger for an immune-mediated liver injury. Roles for superantigen-mediated pathology have also been explored, with a focus on the potential contribution of SARS-CoV-2 infection. Affected children also had a high frequency of the MHC allele HLA-DRB1*04:01, supporting an immunological predisposition, and may have been vulnerable to viral coinfections due to disruption in normal patterns of exposure and immunity as a result of population lockdowns during the COVID-19 pandemic. We discuss areas of ongoing uncertainty, and highlight the need for ongoing scrutiny to inform clinical and public health interventions for this outbreak and for others that may evolve in future.

Occult hepatitis B - the result of the host immune response interaction with different genomic expressions of the virus.

With over 40 years of history, occult hepatitis B infection (OBI) continues to remain an important and challenging public health problem. Defined as the presence of replication-competent hepatitis B virus (HBV) DNA (i.e., episomal HBV covalently closed circular DNA) in the liver and/or HBV DNA in the blood of people who test negative for hepatitis B surface antigen (HBsAg) in currently available assays, OBI is currently diagnosed using polymerase chain reaction (PCR) and real-time PCR assays. However, all efforts should be made to exclude a false negative HBsAg in order to completely follow the definition of OBI. In recent years, significant advances have been made in understanding the HBV lifecycle and the molecular mechanisms that lead to the persistence of the virus in the occult form. These factors are mainly related to the host immune system and, to a smaller proportion, to the virus. Both innate and adaptive immune responses are important in HBV infection management, and epigenetic changes driven by host mechanisms (acetylation, methylation, and microRNA implication) are added to such actions. Although greater genetic variability in the S gene of HBV isolated from OBIs was found compared with overt infection, the mechanisms of OBI are not mainly viral mutations.

Histopathologically Confirmed Pulmonary Mucormycosis as a Complication of COVID-19: a Case Report from Romania and Insight into Pathology.

COVID-19 has proven to be an independent risk factor for secondary infectious complications. Amongst them, mucormycosis has recently been noticed more frequently than in the past. Caused by molds belonging to the Mucorales order, this is a rare, but potentially fatal infection unless adequately treated. Ear, nose and throat involvement is prevalent with often expansion to the orbit, sinuses or brain. Pulmonary, cutaneous and gastrointestinal infections are also recognized. Classical risk factors for progression to angioinvasive disease include poorly controlled diabetes mellitus, defects in phagocytic function (prolonged neutropenia, glucocorticoid treatment), immunosuppressive therapy associated with transplantation, malignancy, elevated levels of free iron as well as iron chelators (deferoxamine). In addition, immune dysregulation rendered by COVID-19 itself may contribute or solely lead to invasive mold disease. The largest experience comes from India, which has dealt with a challenging epidemic of COVID-19-associated mucormycosis (CAM). To our knowledge, no previous studies have reported CAM in Romania. We therefore present a case of severe COVID-19 pneumonia initially complicated by bacterial superinfection and secondary sepsis at admission in an unvaccinated 61-year-old male who presented in our clinic with respiratory failure and digestive symptoms. Although improvement occurred rapidly following antiviral, empiric large spectrum Intraantibiotics and pathogenic medication, unfavorable clinical course ensued later on. Biological and imaging investigations were consistent with pulmonary superinfection in the form of multiple different-sized upper right field opacities, which eventually evolved to form cavities. Differential diagnosis was thoroughly performed. Since unable to sterilize the lung by means of medication alone, the patient underwent major thoracic surgery with removal of the entire right lung. Microscopic study of the damaged tissue was able to determine the presence of broad, aseptate hyphae which morphologically belong to Mucorales. A diagnosis of pulmonary mucormycosis was established and proper antifungal treatment was initiated, with full recovery of the patient.

Primary Hepatic Marginal Zone Lymphoma in a Patient with Chronic Hepatitis C.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is a low-grade malignant lymphoma that appears frequently in the stomach, but other sites can also be involved: the intestinal tract, lungs, head, neck, skin, thyroid, breasts and liver. Recently, epidemiological evidences support the idea that there is an association between hepatitis C and B-cell non-Hodgkin lymphomas (that include MALT as a subtype). Primary non-Hodgkin lymphomas confi ned only to the liver are very rare (only 0.016% of all cases of all non-Hodgkin's lymphomas) and MALT is not the most frequent type. We present the case of a male patient, age 62, known with chronic hepatitis C, previously relapser a" er a 72 week treatment with peg-interferon alfa and ribavirin that was diagnosed at three years a" er the relapse with multiple focal liver lesions. One of the tumors was surgically removed and the histological exam performed demonstrated an extranodal marginal zone lymphoma with small B-cell with plasmacytoid diff erentiation confi ned only to the liver. Direct acting antiviral (DAA) therapy was started, but the virologic clearance was not obtained by week 10, leading to a change of DAA regimen at week 12. The antiviral therapy was continued until week 24. Imaging showed an increase in number and size of the focal lesions until week 12. At week 12 chemo- and immune-therapy was started with bendamustine and rituximab. A" erwards the evolution was favorable, the patient being now in complete remission and with undetectable viral load.

Liver ultrasound elastography: More than staging the disease.

Ultrasound elastography is perhaps the most important breakthrough in the evolution of ultrasonography in the last 15 years. Since transient elastography was introduced, many other methods have been developed and became more and more widely available. The value of ultrasound elastography in staging a chronic liver disease has been established by numerous studies. There have been many studies that have shown that using liver elastography it is possible to predict the presence of the complications of cirrhosis: portal hypertension, presence of esophageal varices (and even their risk of bleeding) and hepatocellular carcinoma. It has been shown that liver elastography can predict the progression of liver fibrosis and also the survival (hepatic events - free) of the patients with chronic liver diseases. These are the real quests of the clinicians, this is the ultimate scope of any medical investigation - to predict the outcome of a patient and to help making therapeutic decisions. I brought together only a small amount of the data that has already been written on this subject to support my affirmation that liver ultrasound elastography is more than a tool for staging the liver disease, but it is also comparable to a crystal ball which in the hands of a skilled clinician can reveal the future of the patient and can help to improve this future.