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.

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.