Is the goal of antiviral Hepatitis B (HBV) therapy a cure?

Is the Goal of Antiviral Hepatitis B Therapy a Cure?

No, the goal of current antiviral therapy for chronic hepatitis B is not a cure—it is to improve survival and quality of life by preventing disease progression, cirrhosis, and hepatocellular carcinoma through long-term viral suppression. 1

Primary Treatment Goals

The main therapeutic objectives prioritize clinical outcomes over viral eradication:

• Improve survival and quality of life by preventing progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC) 1
• Achieve long-term HBV DNA suppression as the cornerstone endpoint of all current treatment strategies 1, 2
• Normalize ALT levels and reduce hepatic inflammation in most patients with sustained viral suppression 1
• Prevent HBV-related complications including mother-to-child transmission, reactivation during immunosuppression, and extrahepatic manifestations 1

Why Current Therapy Cannot Achieve True Cure

Current antiviral agents have fundamental limitations that prevent viral eradication:

• Covalently closed circular DNA (cccDNA) persists indefinitely in the hepatocyte nucleus and cannot be eliminated by nucleos(t)ide analogues or interferons 1, 3
• HBV DNA integrates into the host genome, making true viral eradication impossible even with optimal therapy 1
• HBsAg loss (functional cure) is rare, occurring in only 0-4% of patients at one year and 1-12% even after years of therapy with current agents 1, 2, 4
• Long-term or indefinite treatment is required in most patients to maintain clinical benefit, as stopping therapy frequently leads to viral rebound 1, 5

Hierarchy of Achievable Treatment Endpoints

Since cure is not feasible with current therapy, guidelines define a hierarchy of realistic endpoints:

Optimal Endpoint (Rarely Achieved)

• HBsAg loss with or without anti-HBs seroconversion represents the closest approximation to a "functional cure" and is associated with profound viral suppression, improved long-term outcomes, reduced HCC risk, and decreased mortality 1, 2

Satisfactory Endpoints for HBeAg-Positive Patients

• Sustained off-therapy HBeAg seroconversion combined with HBV DNA <2000 IU/mL and ALT normalization represents partial immune control and improved prognosis 1, 2

Satisfactory Endpoints for HBeAg-Negative Patients

• Sustained off-therapy virological response with HBV DNA <2000 IU/mL (ideally undetectable) and ALT normalization 2

Realistic On-Therapy Endpoint (Most Common)

• Maintained virological remission with undetectable HBV DNA by sensitive PCR assay (<10-15 IU/mL) under long-term antiviral therapy when off-therapy endpoints cannot be achieved 1, 2

Clinical Implications of Current Treatment Limitations

The inability to cure HBV has important practical consequences:

• Most patients require indefinite therapy with nucleos(t)ide analogues until the rare event of HBsAg loss occurs 2, 4
• Stopping therapy carries significant risk of hepatitis flare and disease progression, typically within 6 months of discontinuation 1, 5
• Lifelong HCC surveillance remains necessary even in patients achieving viral suppression, particularly those with cirrhosis or significant fibrosis at baseline 2, 6
• Treatment prevents but does not eliminate HCC risk, as oncogenic mechanisms including viral integration and chromosomal alterations occur early in infection 1

Future Directions Toward Cure

Guidelines acknowledge that achieving cure will require fundamentally different therapeutic approaches:

• Novel direct-acting antivirals targeting HBV entry, cccDNA destruction/silencing, nucleocapsid assembly, and HBsAg release are in early clinical development 1, 7
• Immunotherapeutic agents including checkpoint inhibitors, therapeutic vaccines, and innate immunity modulators aim to restore anti-HBV immune responses 1, 7
• Combination strategies using multiple mechanisms will likely be necessary to achieve functional cure in the majority of patients 1, 8
• These curative therapies may become available in 5-10 years, at which point treatment indications could be expanded more liberally 1, 8

Common Pitfalls to Avoid

• Do not tell patients current therapy will cure their infection—this creates false expectations and misunderstands treatment goals 5, 9
• Do not stop antiviral therapy without close monitoring—viral rebound with hepatitis flare can occur rapidly and requires regular blood tests for at least 6 months 1, 5
• Do not discontinue HCC surveillance after achieving viral suppression—HCC risk persists, particularly in patients with advanced fibrosis or cirrhosis 2, 6
• Do not delay treatment in cirrhotic patients waiting for higher ALT or HBV DNA thresholds—any detectable HBV DNA warrants immediate treatment to prevent decompensation 6