The ATTENTION trial, a collaborative effort between Korea and Taiwan, is exploring new possibilities for early treatment strategies for hepatitis B. Interim analysis presented at the European Association of the Study of the Liver Annual Congress (EASL 2024) indicates that Vemlidy (tenofovir alafenamide) could significantly reduce the risk of liver-related events, even in patients with non-cirrhotic hepatitis B who have normal ALT (Alanine transaminase) levels. The study involved 734 patients recruited from 2019 to 2023.
Reduced Risk of Liver-Related Events
The primary endpoint of the ATTENTION trial was the occurrence of liver-related events, including hepatocellular carcinoma (HCC), death, liver transplantation, and non-targeted cirrhosis. At a median follow-up of 1.5 years, the primary analysis revealed that only 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 translates to a 79 percent lower risk of liver disease-related events in the Vemlidy group compared to the observation group (HR=0.21, 99.997 percent CI 0.01-5.45).
The ATTENTION Study: Design and Objectives
Professor Lim Young-suk of the Department of Gastroenterology at Asan Medical Center, who is leading the ATTENTION study, explained the motivation behind the trial: "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 design involved randomizing patients to a treatment arm, receiving Vemlidy (tenofovir alafenamide), or an observation arm, monitored without the drug. The trial targeted patients who are not typically prescribed TAF under current reimbursement guidelines.
Collaboration with Taiwan
The decision to collaborate with Taiwan was driven by the need to enhance patient recruitment and ensure the generalizability of the results. Taiwan's stricter reimbursement standards for hepatitis B drugs, compared to Korea, make the study's findings particularly relevant for improving treatment environments in both countries.
Statistical Considerations and Interim Analysis
Recognizing the difficulty in demonstrating survival improvements with hepatitis B drugs due to the low incidence of liver cancer, the researchers designed a statistically robust calculation, enrolling 780 patients and planning for an eight-year follow-up. To allow for early assessment, the design included two interim analyses. The presented results are from the first interim analysis, conducted four years into the study.
Implications for Treatment Standards
Professor Lim suggests that the current reliance on ALT levels as a marker for treatment eligibility is suboptimal due to its low sensitivity and specificity. He advocates for the use of viral titers as a more reliable predictor of liver cancer risk. "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."
Economic Benefits of Early Treatment
Early treatment of hepatitis B is not only clinically beneficial but also economically sound. While expanding treatment eligibility will increase healthcare spending, the cost savings from preventing liver cancer and associated deaths outweigh the initial investment. Liver cancer treatment costs are estimated at over 10 million won per year, while hepatitis B drugs cost approximately 1.1 million won per year. Furthermore, preventing deaths from liver cancer reduces productivity losses and lowers societal costs.
Addressing Concerns about Resistance and Side Effects
Vemlidy has demonstrated a strong safety profile with no known cases of resistance reported worldwide. Its minimal long-term side effects and proven efficacy make it a favorable option for early treatment, especially considering the significant reduction in liver cancer risk.
Future Directions
Professor Lim hopes that the ATTENTION study results will be reflected in revised international guidelines from organizations such as the AASLD, EASL, APASL, and WHO. He envisions Korea taking a leading role in developing guidelines for treating hepatitis B based on viral load and age, potentially becoming the world's most successful country in reducing liver cancer incidence.
