The delicate balance between viral control and freedom from medication.
For millions living with chronic hepatitis B (CHB), daily nucleos(t)ide analog (NA) pills are a lifeline—powerful drugs that suppress the virus, protect the liver, and significantly reduce the risk of cirrhosis and liver cancer 1 3 . Yet, these treatments are not a cure. This article explores a critical question in the fight against hepatitis B: what happens when effective antiviral therapy is stopped?
Imagine a powerful dam holding back a relentless river. This is what NAs like entecavir and tenofovir do for hepatitis B patients—they block viral replication, allowing the liver to recover 2 . For many, this treatment must be maintained for life to prevent the virus from rebounding.
However, lifelong therapy presents significant challenges, including costs, potential long-term side effects, and the burden of daily medication 1 . This has led researchers to explore a crucial strategy: finite therapy. The goal is to safely discontinue medication in certain patients, aiming for a state known as "functional cure"—the loss of a specific viral marker called hepatitis B surface antigen (HBsAg) 1 4 . Achieving this cure is rare with NA therapy alone, but stopping treatment might unexpectedly trigger the immune response needed to reach it 1 .
Lifelong therapy ensures viral suppression but comes with burdens. Finite therapy offers freedom but carries risks of viral rebound.
Stopping NA therapy is a calculated risk. On one hand, it can lead to a dangerous viral rebound, causing severe liver inflammation. On the other, it may jumpstart the immune system to finally control the virus on its own. The key is identifying which patients are most likely to benefit.
International guidelines suggest that stopping therapy may be considered for certain patients without cirrhosis, particularly those who have lost the "e" antigen (HBeAg) and have maintained undetectable viral levels for an extended period 1 . The best outcomes are often seen in patients who already have low levels of HBsAg before stopping treatment 1 .
To understand why stopping therapy can sometimes work, it helps to know how NAs function. They are essentially fake building blocks that the virus mistakenly uses when trying to replicate its DNA. By incorporating themselves into the growing viral DNA chain, they prevent the virus from successfully copying itself 2 . Some, like entecavir and tenofovir, are so potent they can also block an essential early step in replication called "protein priming" 2 .
When these drugs are withdrawn, the suppression is lifted. The hope is that the patient's immune system, having had a long "break" during therapy to recover, will now be strong enough to recognize and control the resurging virus on its own.
NAs mimic natural DNA components
Incorporation halts viral DNA synthesis
Therapy break allows immune system to reset
A comprehensive systematic review and meta-analysis published in 2024 directly investigated whether starting with a combination of NAs and pegylated interferon (PEG-IFNα) was superior to interferon alone for achieving a functional cure 4 . This "de novo combination" approach and its outcomes provide critical insights into the dynamics of finite therapy.
The researchers followed a rigorous process:
They systematically searched three major scientific databases (Cochrane Library, PubMed, and Embase) for all relevant studies published up to December 31, 2023.
Only Randomized Controlled Trials (RCTs) were included. These studies compared two groups of CHB patients: one receiving the de novo combination of NAs and PEG-IFNα, and the other receiving PEG-IFNα monotherapy.
The researchers extracted data on primary outcomes—HBsAg loss and HBsAg seroconversion (the functional cure)—and a secondary outcome, undetectable HBV DNA. They then pooled the data from the selected studies to perform a meta-analysis, giving a more powerful and reliable conclusion than any single study could.
The analysis included 10 studies and 2,339 patients. The core findings were revealing 4 :
The researchers concluded that, without first identifying the specific patients most likely to benefit (the "eligible preponderant population"), simply combining NAs and interferon from the start was not superior to interferon monotherapy in achieving a functional cure 4 . This underscores a vital lesson for finite therapy: a one-size-fits-all approach does not work. The success of stopping treatment is highly dependent on the individual patient's profile.
| Time Point | De Novo Combination Therapy | PEG-IFNα Monotherapy | Statistical Significance |
|---|---|---|---|
| End of Treatment (Week 48) | No significant difference | No significant difference | Not Significant |
| Follow-up (Week 24) | Higher rates reported | Lower rates reported | Statistically Significant |
| Follow-up (Week 48) | No significant difference | No significant difference | Not Significant |
| Drug Name | Type | Key Feature |
|---|---|---|
| Entecavir (ETV) | Nucleoside Analog | High barrier to resistance; first-line treatment |
| Tenofovir Disoproxil Fumarate (TDF) | Nucleotide Analog | High barrier to resistance; first-line treatment |
| Tenofovir Alafenamide (TAF) | Nucleotide Analog | Similar efficacy to TDF with improved renal and bone safety |
| Lamivudine (LAM) | Nucleoside Analog | High resistance rate; not recommended as first-line |
Understanding what happens when therapy stops relies on sophisticated tools to measure the virus and the patient's response. Here are some of the essential items in a hepatitis B researcher's toolkit:
A promising new biomarker believed to be a surrogate marker for the stubborn "reservoir" of the virus in the liver (cccDNA). It helps assess the potential for viral relapse 1 .
A standard liver enzyme test. A spike in ALT after stopping drugs signals liver inflammation, which can be a dangerous flare or, in some cases, the immune system actively fighting the virus 1 .
These tests check for the development of anti-HBs antibodies, which indicate a serological response and are part of the definition of a functional cure 4 .
The journey toward a functional cure for hepatitis B is becoming increasingly personalized. The future of finite therapy lies not in randomly stopping medication, but in carefully selecting the right patient at the right time.
Newer biomarkers and sophisticated risk scores are being developed to better predict who can safely attempt treatment cessation 6 .
The ultimate goal is to combine finite NA therapy with new, immune-modulating drugs that can specifically boost the body's defense against the virus.
The decision to stop therapy remains a complex gamble, balancing the hope of a cure against the risk of a severe setback. It is a decision that must be made under the strict guidance of a medical professional, backed by the growing body of evidence that helps tilt the scales in the patient's favor.