The Goal of Antiviral Therapy for Chronic Hepatitis B
Chronic hepatitis B (CHB) is a persistent viral infection that can lead to serious liver complications, including cirrhosis and liver cancer [1.4.2]. The primary goal of antiviral treatment, typically using nucleos(t)ide analogues (NAs) like entecavir or tenofovir, is to suppress the replication of the hepatitis B virus (HBV) [1.2.2]. By keeping HBV DNA levels low or undetectable, these medications reduce liver inflammation and damage, thereby preventing the progression of liver disease [1.2.2].
For many years, treatment was considered indefinite for most patients [1.7.3]. However, the paradigm is shifting towards a finite duration of therapy for select individuals who achieve stable virological remission [1.2.1]. The ultimate goal is to achieve a "functional cure," defined as the sustained loss of the hepatitis B surface antigen (HBsAg) from the blood, with or without developing protective surface antibodies (anti-HBs) [1.5.2, 1.5.4]. While a sterilizing cure—the complete elimination of all HBV DNA, including the persistent cccDNA form in liver cells—is not currently achievable, a functional cure signifies a deep and lasting immune control over the virus [1.5.1, 1.5.2].
Criteria for Stopping Antivirals: HBeAg-Positive vs. HBeAg-Negative
The decision to discontinue NA therapy is not taken lightly and depends heavily on a patient's specific virological markers, particularly their hepatitis B e-antigen (HBeAg) status [1.7.5]. International guidelines from bodies like the American Association for the Study of the Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the Asian Pacific Association for the Study of the Liver (APASL) provide frameworks, though they have some differences [1.3.3].
HBeAg-Positive Patients
For patients who are HBeAg-positive at the start of treatment, the path to discontinuation is more clearly defined. The key milestone is achieving HBeAg seroconversion. This means the patient stops producing the HBeAg and develops antibodies against it (anti-HBe) [1.3.3]. Most guidelines agree that therapy can be considered for discontinuation in non-cirrhotic patients who meet these criteria [1.7.3]:
- Achieve HBeAg seroconversion (HBeAg loss and appearance of anti-HBe).
- Have undetectable HBV DNA levels.
- Complete a period of consolidation therapy for at least 12 months after seroconversion to ensure the response is stable [1.2.1, 1.3.2]. APASL guidelines sometimes recommend a longer consolidation period of up to three years [1.2.1].
HBeAg-Negative Patients
For the majority of patients, who are HBeAg-negative, the criteria for stopping treatment are more stringent and controversial [1.3.6]. Since they lack the HBeAg marker, the primary endpoint shifts to long-term viral suppression or the much rarer event of HBsAg loss [1.3.3].
- HBsAg Loss (Functional Cure): The ideal and universally accepted endpoint for stopping therapy in all patients, including those with compensated cirrhosis, is sustained HBsAg loss for at least one year [1.2.1]. Unfortunately, this is a rare outcome with current NA therapy [1.2.1].
- Prolonged Viral Suppression: In the absence of HBsAg loss, some guidelines (like EASL and APASL) allow for consideration of stopping NAs in non-cirrhotic HBeAg-negative patients who have maintained undetectable HBV DNA for a long period, typically 2 to 3 years [1.3.1, 1.7.3]. The AASLD has traditionally been more cautious, recommending indefinite therapy unless HBsAg is lost, though it acknowledges discontinuation can be considered if there's a compelling reason and careful monitoring is guaranteed [1.2.1, 1.7.6].
Comparison of Stopping Criteria
| Patient Group | Primary Endpoint for Stopping | Consolidation/Duration Requirement | Status in Cirrhosis |
|---|---|---|---|
| HBeAg-Positive | HBeAg seroconversion with undetectable HBV DNA [1.3.3] | At least 12 months of consolidation therapy after seroconversion [1.2.2] | Lifelong therapy generally recommended [1.4.6] |
| HBeAg-Negative | Sustained HBsAg loss (functional cure) [1.2.1] | If stopping without HBsAg loss, requires ≥3 years (EASL) or ≥2 years (APASL) of undetectable HBV DNA [1.3.3, 1.3.4] | Indefinite/lifelong therapy is the standard recommendation from most guidelines [1.2.1, 1.2.5] |
Risks and Rigorous Monitoring After Discontinuation
Stopping antiviral medication is not without significant risks and must never be done without a doctor's instruction [1.2.8]. The most serious risk is viral reactivation or relapse, which can lead to a sudden spike in HBV DNA and a flare in liver enzymes (ALT) [1.4.6]. In some cases, these flares can be severe, causing acute liver injury or even acute-on-chronic liver failure, although this is rare, particularly in non-cirrhotic patients [1.4.1, 1.4.7].
Because of these risks, a strict monitoring protocol is mandatory for anyone who stops therapy [1.2.1].
- Initial Phase (First 3-6 months): This is the period of highest risk for relapse [1.7.5]. Monitoring is most intense, often involving monthly blood tests for HBV DNA and ALT levels [1.6.6].
- First Year: After the initial phase, monitoring typically continues every three months for at least the first year [1.6.3, 1.7.6].
- Long-Term Follow-up: If the patient remains stable, follow-up may be extended to every 6-12 months, similar to monitoring for an inactive carrier state [1.4.8]. This lifelong surveillance is crucial to detect late relapses or the development of liver cancer [1.4.8].
Conclusion
The decision on when hepatitis B patients can stop taking antivirals is complex and highly individualized. While the goal is moving from indefinite treatment to a finite course, this is only possible for select patients who meet stringent criteria under the guidance of a hepatologist [1.2.2]. For HBeAg-positive patients, HBeAg seroconversion is a key milestone. For HBeAg-negative patients, the ideal goal is HBsAg loss (a functional cure), though stopping after several years of deep viral suppression is an option in some cases [1.2.1]. In all scenarios, stopping treatment mandates a commitment to lifelong, rigorous monitoring to ensure patient safety and promptly manage any potential relapse [1.4.6].
For more information, consult authoritative sources such as the Hepatitis B Foundation.
