Higher Relapse Rate After stopping Tenofovir Alafenamide Compared With Entecavir; but not Tenofovir Disoproxil Fumarate in HBeAg-Positive Patients

Chronic hepatitis B is a persistent infection of the liver caused by a virus that hides inside liver cells. For decades, doctors have treated this condition with powerful daily pills that stop the virus from multiplying, allowing the liver to heal and preventing serious damage like cancer or liver failure. However, these medicines do not erase the virus completely; they merely keep it in a deep sleep. Because of this, many patients eventually stop taking the pills once their blood tests show the virus is undetectable and their liver enzymes are normal. The hope is that the body's own immune system will then take over and keep the virus dormant forever. But for many people, the virus wakes up again, leading to a relapse that requires restarting treatment. The question of which medicine leads to the most stable, long-term silence after stopping has become a critical puzzle for doctors trying to guide patients toward a cure.

In a large study involving hundreds of patients in Taiwan, researchers set out to compare three specific medicines used to treat hepatitis B: entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide. These drugs are all potent inhibitors that suppress the virus, but they work slightly differently. The study focused on patients who had a specific marker called HBeAg, which indicates the virus is actively replicating, and who had stopped their medication because they met strict national guidelines for doing so. The researchers followed these patients for years after they stopped taking their pills to see how quickly and how often the virus returned. They tracked not just the reappearance of the virus in the blood, but also whether the liver became inflamed again and whether patients needed to start taking medication a second time.

The results revealed a clear difference in how the body responded after stopping the different drugs. Patients who had been taking tenofovir alafenamide were much more likely to experience a return of the virus compared to those who had taken entecavir. In fact, within the first few months after stopping, the virus reappeared in a significantly larger portion of the tenofovir alafenamide group. These patients also saw their liver enzymes spike and required retreatment much sooner than those who had stopped entecavir. The time it took for the virus to return was notably shorter for the tenofovir alafenamide group, with the median time being just 17 weeks, compared to over 40 weeks for the entecavir group. This suggests that the viral suppression achieved by tenofovir alafenamide might be less durable once the daily pill is removed.

When the researchers compared tenofovir alafenamide with the older version of the tenofovir drug, tenofovir disoproxil fumarate, the picture was different. The rates of the virus returning, the liver becoming inflamed, and the need for retreatment were very similar between these two groups. Both tenofovir drugs performed worse than entecavir in terms of keeping the virus away after treatment stopped, but they did not differ significantly from each other. This finding is important because it challenges the idea that the newer tenofovir alafenamide would offer a better long-term outcome after stopping therapy. Instead, it appears that for patients with active viral markers, the older tenofovir and the newer tenofovir alafenamide share a similar risk of relapse, which is higher than that of entecavir.

The study also looked at what happened when the virus did return. A striking observation was that patients who had stopped tenofovir alafenamide were much more likely to experience HBeAg seroreversion, meaning the HBeAg marker reappeared in their blood after they had previously lost it or achieved seroconversion. This happened in about 73 percent of the tenofovir alafenamide group, compared to roughly 51 to 56 percent in the other groups. This high rate of losing control suggests that the immune system's memory of the virus might be weaker after stopping tenofovir alafenamide, allowing the virus to rebound aggressively. The researchers noted that this rapid return of the virus and the loss of immune control happened even though the patients had met all the standard criteria for stopping treatment safely.

To ensure these findings were not just due to differences in the patients' ages or health conditions, the researchers used a statistical method to match patients in the different groups as closely as possible. Even after this careful adjustment, the pattern remained the same: stopping tenofovir alafenamide led to a faster and more frequent return of the virus compared to entecavir, but not compared to tenofovir disoproxil fumarate. The study also identified that older age, certain genetic types of the virus, and higher levels of viral markers at the time of stopping were factors that increased the risk of relapse for everyone, regardless of which drug they had taken.

The implications of these findings are significant for how doctors manage patients who wish to stop treatment. While the study did not find that stopping tenofovir alafenamide caused more severe liver damage or liver failure than the other drugs, the high rate of relapse means that patients who stop this medication need to be watched very closely. The researchers suggest that for patients who stop tenofovir alafenamide or the older tenofovir, the first three months are a critical window where the virus is most likely to wake up. During this time, frequent blood tests are essential to catch the return of the virus early and restart treatment before the liver is harmed. The study concludes that while stopping treatment is a valid goal for many, the choice of which drug to use before stopping matters, and for HBeAg-positive patients, entecavir appears to offer a more stable path to staying off medication than either of the tenofovir options.