Hepatitis B: Controlling the virus does not mean a cure

Having a vaccine available is essential for preventing hepatitis B, but it is not enough when part of the population cannot access it. In Brazil this challenge is particularly significant in large areas of the Amazon and the North Region of the country, where long distances, limited transportation and low health service availability can hinder vaccination, diagnosis and medical follow-up. The hepatitis B vaccine is provided free of charge by Brazil’s Unified Health System and since 2016 has been available to people of all ages. Even so, people born before the vaccination schedule was expanded or who did not have access to health services may remain at risk. In 2025 approximately 4,600 confirmed cases were recorded in Brazil, according to the Ministry of Health. These figures represent detected and reported cases, not necessarily all infections acquired in the same year. Since hepatitis B can remain asymptomatic for long periods, many people discover the infection only during routine exams, blood donations, prenatal visits or investigations into other health conditions. When the infection becomes chronic Some patients experience worsening of the infection and develop signs and symptoms similar to acute hepatitis. If patients with chronic hepatitis B progress to cirrhosis, when the liver becomes severely scarred, they will develop signs and symptoms of liver failure, including jaundice, enlarged spleen, fluid retention in the abdomen, swelling of extremities, especially in the legs and feet, and liver cancer. The age at which hepatitis B infection occurs also influences its progression. Most adults are able to clear the virus spontaneously and develop lasting immunity. When infection occurs in the first years of life, however, the risk of it becoming chronic is much higher. A baby receives the hepatitis B vaccine. The age at which infection occurs influences its progression. When it occurs in the first years of life, the risk of it becoming chronic is much higher. eskymaks_1/Ulimphotos Hepatitis B becomes chronic when the body is unable to clear the virus, which remains in the liver. The virus does not usually destroy cells directly: Much of the damage results from the immune system’s attempt to recognize and eliminate cells carrying viral components. If this response persists for many years, it can contribute to liver damage and failure, as well as liver cancer. Global estimates indicate that hundreds of millions of people live with chronic hepatitis B. In Brazil, the Unified Health System offers free treatment to patients who need it. Medications such as tenofovir and entecavir block a key step in replication of the hepatitis B virus. As a result, they reduce the amount of virus in the blood and the risk of complications. But controlling the virus’s replication is not the same as eliminating it. Even when treatment reduces the virus to very low levels in the blood, persistent forms of viral DNA may remain inside liver cells. Reservoirs inside the cells After entering liver cells, the viral DNA can be converted into a stable, circular molecule called covalently closed circular DNA, or cccDNA. Its function can be understood simply: cccDNA acts as a viral reservoir within the cell nucleus. From there, the cell can continue to produce viral proteins. In addition, portions of viral DNA can integrate into the host cell’s genetic material. As long as cccDNA remains active, the virus can resume replication if treatment is discontinued. The integrated sequences, in turn, are not necessarily capable of supporting all stages of the viral cycle, but they can contribute to the continued production of viral proteins, especially the virus’s surface antigen, known as HBsAg. An antigen is a marker that tells your immune system whether something in your body is harmful. In the case of hepatitis B, it may trigger the chronic immune response that causes liver damage. After entering liver cells, hepatitis B viral DNA can be converted into a stable molecule called covalently closed circular DNA that acts as a viral reservoir within the cell nucleus. put3d/Unlimphotos Therefore, effectively and sustainably reducing HBsAg is one of the main goals in developing strategies to achieve what is known as a functional cure for hepatitis B. In this context, a functional cure means keeping the virus under control, with no detectable hepatitis B virus in the blood after treatment. A strategy based on RNA interference This is where RNA interference, or RNAi, comes into play. This strategy uses small RNA molecules that recognize RNA molecules produced from the virus’s genetic material. When RNAi recognizes one of these molecules, it can selectively intercept and destroy messenger RNA before it delivers its instructions, which can be used to produce viral proteins. In the case of the hepatitis B virus, RNAi can be engineered to recognize RNA molecules responsible for the production of viral proteins, including HBsAg. By eliminating these molecules, the strategy reduces the amount of viral proteins produced by the cell. RNAi technology is already used in approved medications for various diseases, including some that affect the liver. In the case of the hepatitis B virus, different RNAi molecules can be designed to recognize specific regions of the viral genetic material, allowing them to target different viral proteins. There are multiple RNAi therapies for hepatitis B virus in early phase clinical trials. It was in this context that we conducted our research. In the laboratory we introduced the hepatitis B virus RNA into cultured liver cells and tested various RNAi-based candidates. Among the candidates evaluated, one showed the most promising results, with a reduction in HBsAg levels in the cell cultures. This result is still preliminary. The model used allows us to assess viral protein production, but it does not replicate all the steps of a natural infection. Therefore, we still need to verify whether the effect persists over longer periods and whether it also occurs in cellular models that better reproduce hepatitis B infection. The next challenge The research is now moving forward in collaboration with KU Leuven in Belgium. Through this partnership, we can test RNAi in cellular models that more closely mimic natural infection from the hepatitis B virus and in hamsters, allowing us to assess whether the observed silencing persists in more complex systems and in the organism as a whole. Another challenge will be ensuring that RNAi reaches liver cells safely and effectively. The goal is not necessarily to replace available medications but to act in a complementary manner, reducing the production of viral antigens while these drugs control the virus’s replication. On its own, RNAi will likely not eliminate all viral reservoirs, but it may contribute to more effective and long-lasting control of the disease. Years of research will still be needed before this approach can be tested in patients. For now, the goal is to verify whether the results obtained in cultured cells hold true in more complex models, with sufficient efficacy, specificity and safety. The research discussed in this article was funded by the Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (FAPERJ).