‘Early treatment of hepatitis B is key to preventing liver cancer and reducing healthcare costs’ < Hospital < Article

Hepatitis B is caused by the hepatitis B virus (HBV), a leading cause of chronic liver disease and a condition that significantly increases the risk of developing cirrhosis and hepatocellular carcinoma (HCC).

It is a crucial risk factor for liver cancer, with about 60 percent of liver cancers being attributed to HBV. However, even for patients with chronic hepatitis B, starting treatment at an early stage (immune tolerance) can significantly reduce the risk of HCC and the need for liver transplantation, so early treatment is becoming increasingly important.

The ATTENTION trial, conducted in Korea and Taiwan, has garnered attention by offering new possibilities for early treatment strategies for hepatitis B.

The first interim analysis, presented at the European Association of the Study of the Liver Annual Congress (EASL 2024) in June, suggested that the hepatitis B treatment Vemlidy (tenofovir alafenamide) could significantly reduce the risk of liver-related events, even in patients with non-cirrhotic hepatitis B who had normal ALT (Alanine transaminase) levels.

The study involved 734 patients recruited in Korea and Taiwan from 2019 to 2023, and the primary endpoint was “liver-related events,” which included hepatocellular carcinoma, death, liver transplantation, and non-targeted cirrhosis.

At a median follow-up of 1.5 years, the primary analysis showed that two liver disease-related events, both HCC, occurred in the Vemlidy arm (369 patients), compared to nine events in the observation arm (seven HCC, one death, and one non-targeted cirrhosis). This confirmed that the risk of liver disease-related events in the Vemlidy group was 79 percent lower than in the observation group (HR=0.21, 99.997 percent CI 0.01-5.45).

Korea Biomedical Review spoke to Professor Lim Young-suk of the Department of Gastroenterology at Asan Medical Center, who is leading the ATTENTION study, to learn about the significance of the interim analysis, the potential for new treatment standards and indicators, and the clinical and economic benefits of early treatment of hepatitis B to prevent liver cancer.

Question: How did you develop the idea for the ATTENTION study?

Answer: Hepatitis B is a viral disease, and effective control of viral proliferation can reduce the incidence of liver cancer by up to 50 percent. However, the diagnosis rate in Korea is very high at about 75 percent, while only 2.6 percent of patients receive treatment. This is because the criteria for treatment are too strict. For example, patients must meet certain conditions, such as viral load or ALT levels, to be eligible for medication. Compared to other viral diseases, including hepatitis C or AIDS, where treatment is recommended immediately upon diagnosis, the Korean standards are unrealistic.

In the past, the concept was to treat only those patients who needed it due to the risk of drug resistance and side effects. Now, however, with the introduction of drugs that have no resistance and are proven safe for long-term use, the need to expand the indications for drug administration has been greatly emphasized. It is against this backdrop that we conducted the ATTENTION study.

Q: Describe the design and objectives of the ATTENTION study.

A: The ATTENTION study was motivated by two problems. First, the indications were too strict, and many patients who needed treatment were not receiving it. Second, there were no clinical trials showing that the drug could reduce the incidence of liver cancer in these patients. We needed to confirm this with reliable clinical trial data, not observational studies.

The study used tenofovir alafenamide (TAF), the most efficacious and safest worldwide drug. Patients were randomized to a treatment and observation arm, targeting patients who cannot be prescribed TAF under current reimbursement guidelines. The treatment arm was prescribed Vemlidy, while the observation arm was monitored without the drug, using the same reimbursement guidelines.

The reality is that such a large-scale study requires a large budget. Until then, we could not conduct clinical trials due to lack of funding, but a donation of 1 billion won ($714,285) from a patient who unfortunately passed away while undergoing treatment for liver cancer made it possible to start the study. Since then, we have received various additional funding, including national projects.

Q: Interestingly, you collaborated with Taiwan. Was there a particular reason for this?

A: The main reason was the difficulty of recruiting patients, and the generalizability of the results was also an important consideration. If we only studied patients in Korea, there would be questions about whether the results could be applied to other countries. A multi-country study was necessary to ensure reliability and universality.

Taiwan was also a good choice as a collaborating country because of its environmental similarities to Korea. Hepatitis B has a high prevalence in China, Mongolia, some countries in Southeast Asia, and less developed countries on the African continent, and a low prevalence in North America and Japan. While recruiting patients in high prevalence countries is relatively easy, it can be challenging to ensure study’s quality in collaborations with less developed countries. Taiwan and Hong Kong were considered possible collaborators because of their high research quality and similar environmental conditions, and Taiwan was ultimately selected.

Taiwan has stricter reimbursement standards for hepatitis B drugs than Korea. In this respect, the study’s results are expected to substantially improve the treatment environment for patients in both countries.

Q: What were the key factors considered in the design of the ATTENTION study?

A: It is very difficult to demonstrate an improvement in survival with hepatitis B drugs. This is because the incidence of liver cancer is low, making it difficult to generate statistically significant results in a short period. To address this, we designed a statistically sophisticated calculation, enrolling 780 patients and following them for eight years. Assuming a liver cancer incidence rate of 1 percent per year, the researchers calculated that they would need about 50 cases throughout the study to identify differences between the two groups.

However, the patient recruitment process took longer than expected. Initially, we anticipated enrolling patients for two years, but it took four years, bringing the total study duration to 12 years (four years of enrollment + eight years of follow-up). We also adjusted the design to include two interim analyses to allow us to check the primary outcome at the end of the long-term study. The results presented here are from the first interim analysis, which took place four years into the study.

Q: What are the implications of the first interim analysis?

A: The ATTENTION study was a well-designed prospective clinical trial based on numerous observational studies and was designed with sufficient data at the design stage. The results of the first interim analysis of the study are positive, supporting the effectiveness of early therapy.

According to the interim analysis, only two patients developed liver cancer in the treatment arm, compared to nine cases of liver cancer, death, or liver failure in the observation arm. While the 9:2 statistical result is interpreted as significant, the small sample size is open to further debate. Therefore, we are not taking this result as a conclusion and will continue the study as planned to determine the results.

While we cannot completely rule out the possibility that the results could be reversed, this is very unlikely, with a probability of around 2 percent. The data to date suggests that early treatment is likely to be effective.

Q: In addition to confirming the benefits of early treatment, we wonder if this study will produce any major outcomes, such as new treatment standards or metrics.

A: Currently, medications are only available when hepatitis is active, and ALT is used as a marker to determine activity. However, ALT has low sensitivity and specificity, making it an ineffective marker. Therefore, the possibility of using viral titers as an alternative to ALT has been discussed. Viral titers are more sensitive and reliable in predicting the risk of developing liver cancer.

A large cohort study of 4,600 people in Taiwan demonstrated a strong association between viral titers and the risk of developing liver cancer. The results showed that higher viral titers tended to increase the risk of liver cancer, but there was also a perception that immune tolerant individuals with extremely high viral titers had a lower risk of liver cancer. A decade ago, Asan Medical Center analyzed large-scale data and found a non-linear relationship between viral titers and liver cancer incidence. That was difficult to accept at first because it differed from the linear relationship perception of the existing academic community. Still, the academic community has gradually accepted it through multiple validations and repeated publications.

Even with normal ALT, patients with viral titers near 1 million units are eight times more likely to develop liver cancer than those with lower viral titers. These patients need immediate treatment, but currently, there is a lack of evidence for treatment until ALT levels rise.

Q: Would you like to see the removal of the ALT criterion reflected in reimbursement criteria or guidelines?

A: Yes. We are working to create level A1 evidence through the ATTENTION study. Once the A1 guidelines are in place, they will likely be reflected in reimbursement criteria, which could reduce the number of patients who develop liver cancer by 4,000 to 5,000 per year.

Liver cancer is a disease with a very poor prognosis, with a five-year survival rate of only about 25 percent, so reducing the incidence of liver cancer in the first place is of utmost importance. If the results of our research are reflected in policy, thousands of productive people can be saved every year. Especially in Korea, if the guidelines are revised first and all patients diagnosed with hepatitis B are treated, many lives will be saved.

If this were to happen, the study could be stopped. The current study, divided into treatment and observation groups, would no longer be necessary. However, this would be a welcome end to the study, as it would have achieved its goal. If the guideline improvements that began in Taiwan can be replicated in other countries, including the United States, they could improve the treatment of hepatitis B globally.

Q: How far along are you convincing the scientific community to treat hepatitis B early?

A: When we first designed the ATTENTION study, there was an 80 percent consensus among experts that early treatment was unnecessary. In response, I have conducted research, held invited international conferences, and personally persuaded experts. Today, the consensus has risen to about 60 percent in favor of early treatment. After the recent publication of the ATTENTION interim results, this percentage is likely to have increased, and we believe it is time to discuss revising the guidelines.

Internationally recognized guidelines from the American Association for the Study of the Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), Asia-Pacific Association for the Study of the Liver (APASL), and the World Health Organization (WHO) are due for revision. We hope that the results of the ATTENTION study will be reflected in these revisions and that we are actively engaging in related activities.

Another point I would like to emphasize is that Korea has many hepatitis B patients and a very high level of medical research. We are well-equipped to conduct world-class observational studies, so I expect to see more important studies start in Korea in the future. While we do not yet have the political power at the international level to take the lead in guideline formulation, we need to be the first country to remove the ALT criteria and develop guidelines for treating hepatitis B based on viral load and age.

If these guidelines are implemented, we could become the world’s most successful country in reducing liver cancer incidence in five years. This would provide tangible benefits to patients and greatly enhance the reputation of medicine in Korea.

Q: Explain the specific benefits of early treatment of hepatitis B, including the social cost savings.

A: Currently, an estimated 1.3 million people are living with hepatitis B in Korea, but only about 20 percent, or 300,000 patients, are receiving treatment. Excluding inactive patients who do not need treatment, the cure rate should be increased to at least 60 percent. While it is true that expanding eligibility will increase healthcare spending as more patients are treated, it is essential to look beyond this simple cost increase and consider the cost savings from liver cancer and deaths prevented by treatment.

It is estimated that liver cancer costs more than 10 million won per year to treat. Hepatitis B drugs, on the other hand, cost a relatively small amount, around 90,000 won per month or 1.1 million won per year, including health insurance financing and out-of-pocket expenses. This comparison alone makes the economic benefits of early treatment clear.

The Health Insurance Review and Assessment Service (HIRA) estimates that the cost of extending a person’s life by an additional year without disability is about $30,000. However, the cost of significantly expanding coverage for hepatitis B is only about $2,000 per patient, less than one-tenth of that amount. Early treatment is, therefore, cost-effective.

In addition to direct cost savings, preventing deaths from liver cancer can also reduce productivity losses and lower societal costs. Simulation analyses show that when these indirect costs are considered, early treatment saves money, meaning that improving the treatment environment does not simply cost money but reduces the economic burden on society in the long run.

Based on these comprehensive findings, we hope to improve access to early treatment for hepatitis B as soon as possible. This will save lives and lead to national benefits through reduced social and economic costs.

Q: There are concerns about resistance or side effects from early treatment.

A: Many patients often say that they want to delay starting treatment as much as possible because once they start taking a drug, they must take it for life. However, Vemlidy is a drug with no known cases of resistance, although millions of people take it worldwide. It has also been shown to have few long-term side effects, and a recent study showed that it can be safely used in pregnant women. It’s also considered a highly effective treatment. More importantly, reducing the risk of progression to liver cancer is a much more important option, even if the drug is taken long-term.

Q: What would you like to emphasize to the government and related officials to improve the treatment environment for chronic hepatitis B?

A: Korean medicine is at the highest level internationally. Therefore, there shouldn’t be a situation where we should doubt or distrust study results because it is a domestic study. In the future, there will be more and more cases where Korea will be the first worldwide to revise guidelines or publish new research results. In this regard, the Korean government and officials will actively recognize and support the quality of medical care in Korea.

Ultimately, I hope an environment will be created where new drugs can be developed and approved in Korea proactively rather than following the approval of the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). This will allow us to provide patients with faster and more effective treatment options.