Hepatitis E

Why does Hepatitis E become chronic in some patients, and why do medications not work? To find out, an international research team led by scientists from Bochum observed a patient with chronic Hepatitis E infection over a year. Repeated sequencing of the virus RNA showed that the virus incorporated various parts of the host's messenger RNA into its genome. This resulted in a replication advantage, which may have contributed to the infection becoming chronic. Why does Hepatitis E become chronic in some patients, and why do medications not work? To find out, an international research team led by scientists from Bochum observed a patient with chronic Hepatitis E infection over a year. Repeated sequencing of the virus RNA showed that the virus incorporated various parts of the host's messenger RNA into its genome. This resulted in a replication advantage, which may have contributed to the infection becoming chronic. "The so-called insertion of host RNA can possibly predict the transition of an acute infection to a chronic condition," says Dr Daniel Todt, head of the Computational Virology research group in the Department of Medical and Molecular Virology at Ruhr University Bochum, Germany. The researchers report in the journal Nature Communications on June 6, 2024. Sequencing of the virus population Around 20 million people worldwide contract Hepatitis E every year. Normally, the infection heals without consequences, but it can be life-threatening for pregnant women or people with suppressed immune systems. In some cases, it becomes chronic. There are no specific effective medications. The broad-spectrum antiviral drug Ribavirin is also used against Hepatitis E, but it does not always work. How can the virus evade the immune system? Why does the infection become chronic and not heal? The researchers wanted to find out and analyzed for the first time all virus populations of a chronically infected patient over a period of more than a year. They examined more than 180 individual sequences from blood samples in detail. Replication in Cell Culture Benefits from Host RNA "The Hepatitis E virus has a so-called hypervariable region in its genetic information, into which it can incorporate various RNA sequences from host cells," describes Daniel Todt. His team was able to show that the composition of this region changed massively during the observation period. Additionally, many different compositions occurred simultaneously. In cell culture experiments, it was shown that incorporating host RNA provided a replication advantage: The altered viruses could replicate better than others. "We assume that this is partly responsible for the infection becoming chronic and the therapy failing," says Daniel Todt. The researchers examined the composition of the host RNA incorporated into the virus to determine if there were any common features characterizing the gene segments. "However, we could not detect any meaningful similarities," says Todt. The incorporated gene sequences are predominantly those that are very common in host cells, indicating a random selection. "Possibly, during Hepatitis E infection, a race between the virus and the immune system occurs in the body," speculates Daniel Todt. If the virus manages to incorporate host RNA before the immune system successfully combats the infection, it may lead to a chronic course. "Host RNA in the viral genome could, in any case, serve as a biomarker in the acute phase of an infection, indicating early on that it is likely to become chronic." The researchers plan to expand their studies to larger cohorts of patients.

At present, there is no specific active substance against hepatitis E. As the disease kills 70,000 people every year, researchers are actively searching for one. A team may have found what they're looking for. The researchers showed that the compound K11777 prevents host cells from helping the virus out of its shell by cleaving the viral capsid. This means it can no longer infect cells. At present, there is no specific active substance against hepatitis E. As the disease kills 70,000 people every year, researchers are actively searching for one. The team from the Department of Molecular and Medical Virology at Ruhr University Bochum, Germany, may have found what they're looking for. The researchers showed that the compound K11777 prevents host cells from helping the virus out of its shell by cleaving the viral capsid. This means it can no longer infect cells. "The compound is already being tested in clinical trials against other viruses such as Sars-Cov-2," says lead author Mara Klöhn. "There's still a lot of work to be done to find out whether it can be used as an active substance against hepatitis E, but it's a first step." The researchers published their findings on May, 11, 2024 in the journal Hepatology. In order to infect an organ, viruses need the help of the host cells. "An effective approach is therefore to identify targets in the host that can be manipulated by drugs so that they no longer perform this helper function," explains Mara Klöhn. The researchers became aware of the compound K11777 in a roundabout way: During a control study conducted as part of cell culture studies on the hepatitis C virus with a known active ingredient, they discovered that this active ingredient was also effective against hepatitis E. "However, the drug wasn't using the same pathway as with the hepatitis C virus, because the hepatitis E virus doesn't have the target structure that this active substance attacks," explains Mara Klöhn. This suggested that the drug may have an effect on host cells instead. The research team narrowed down the possible target structures and turned their attention to cathepsins, which can process proteins, i.e. cleave them. K11777 inhibits many cathepsin types, i.e. blocks their function. Tests in cell culture with human liver cells showed that the compound actually prevents infection with hepatitis E viruses. "In follow-up experiments, we proved our hypothesis that the compound prevents cathepsin L from cleaving and opening up the viral capsid," says Mara Klöhn. "This means that the virus can no longer infect host cells." Hepatitis E The hepatitis E virus (HEV) is the main cause of acute viral hepatitis. Approximately 70,000 people die from the disease every year. After the first documented epidemic outbreak between 1955 and 1956, more than 50 years passed before researchers began to address the issue in depth. Acute infections usually clear up spontaneously in patients with an intact immune system. In patients with a reduced or suppressed immune system, such as organ transplant recipients or people infected with HIV, HEV can become chronic. HEV also poses a serious threat to pregnant women. There aren't any vaccines nor specific active substances against the virus.

The launch of the quantitative and qualitative hepatitis B test comes shortly after Roche’s last addition to its hepatitis diagnostics slate. Earlier this month the company launched two immunoassays for detecting hepatitis E. For the second time this month, Roche is launching a new immunoassay to help diagnose cases of hepatitis. This time around, the newly unveiled test is one designed to identify the hepatitis B e antigen (HBeAg) in samples of human serum and plasma. The test, launched in Europe, not only detects the presence of the antigen, but also measures its quantity, meaning it can help measure the extent of a patient’s condition and their response to therapy. The Elecsys HBeAg quant test runs on Roche’s Cobas e-series analyzers and is available in all countries that recognize CE mark approval, according to the company’s announcement Monday. The test is meant to be used even after helping with the initial hepatitis B diagnosis. For one, because it quantifies the presence of the antigen, it can be administered to help monitor the effects of various treatments. For another, according to Roche, it can be used alongside other hepatitis B diagnostics to determine the phase of the disease, as well as how the virus is affecting the liver and the chances it may progress into liver cancer or other conditions. Roche noted that the immunoassay’s potential impact could be particularly large, since hepatitis B is the most common type of viral hepatitis around the world. “Hepatitis B affects millions of people each year and is a major global health burden. An accurate diagnosis is critical to ensuring timely treatment options,” Matt Sause, CEO of Roche Diagnostics, said in the announcement. “If hepatitis B is left untreated, it can cause chronic infections, putting people at high risk of death from cirrhosis and liver cancer.” He continued, “The addition of the Elecsys HBeAg quant immunoassay to our viral hepatitis testing portfolio underlines Roche’s commitment to tackle healthcare’s biggest challenges to support clinicians and their patients.” The launch of the quantitative and qualitative hepatitis B test comes shortly after Roche’s last addition to hepatitis diagnostics slate. Earlier this month the company announced the launch of two immunoassays for catching cases of hepatitis E. One of the Elecsys Anti-HEV tests looks for IgM antibodies to the hepatitis E virus, while the other focuses on IgG antibodies. The former can be used to detect both acute and recently acquired cases of the virus, while the latter broadens the scope to identify either recent or past infections. Roche’s debut comes as the World Health Organization has added hepatitis E diagnostics to its annual Essential Diagnostics List for the first time, and as estimates suggest that one-third of the world’s population could be at risk of infection, according to data cited by Roche. As with the hepatitis B test, the HEV tests are meant to run on certain Cobas e-series analyzers and modules. They return results in about 18 minutes, per their maker, and round out Roche’s panel of tests to differentiate between different forms of acute hepatitis.