Curing Hepatitis B: Hope, Challenges, and Breakthroughs

Curing Hepatitis B: Hope, Challenges, and Breakthroughs

Summary of Medical Lecture by Anna Suk-Fong Lok, MD, DSc (Hon), FAASLD

1. Main Clinical Topics Discussed

• Current limitations of approved hepatitis B (HBV) therapies
• Strategies to improve HBsAg (surface antigen) loss rates, including nucleos(t)ide analogue (NUC) cessation and pegylated interferon (PEG-IFN) add-on therapy
• Evolving definitions of HBV "cure" (sterilizing vs. functional vs. partial)
• Novel antiviral and immunomodulatory agents in clinical development
• Capsid assembly modulators (CAMs) as a promising emerging drug class

2. Key Learning Points, Guidelines, and Recommendations

Current Approved Therapies:

• Entecavir (ETV) and tenofovir (TDF/TAF) are the cornerstone NUC therapies, highly potent at suppressing HBV DNA
• Pegylated interferon (PEG-IFN) offers higher HBsAg loss rates but is limited by tolerability and is most effective in genotype A patients
• HBsAg loss rates with long-term NUC therapy remain very low (~3% at 8–10 years with entecavir)
• Current therapies reduce but do not eliminate hepatocellular carcinoma (HCC) risk, particularly in HBsAg-positive patients

NUC Cessation Strategy:

• Stopping NUC after ≥4 years of suppressed HBV DNA may improve HBsAg loss rates in select Caucasian patients
• This strategy shows significantly less benefit in Asian patients, likely related to HBV genotype differences and longer duration of infection
• Clinicians must weigh the risk of virologic flares and hepatic decompensation against potential benefit

PEG-IFN Add-On Strategy (China Studies):

• Adding PEG-IFN to NUC in patients with low baseline HBsAg (<1,500 IU/mL) and suppressed HBV DNA yielded improved HBsAg loss rates
• Treatment durations extended up to 3 years; results applicable only to a carefully selected minority of patients
• Not broadly generalizable due to side effect burden and strict selection criteria

Definitions of Cure (Evolving):

• *Sterilizing cure*: Complete viral eradication — considered unachievable at present
• *Functional cure*: HBsAg loss with or without HBsAb seroconversion — the primary target goal
• *Partial cure*: Sustained HBsAg reduction without loss; clinical benefit remains uncertain
• As of 2022, functional cure rates from combination novel regimens remain modest, prompting reassessment of intermediate endpoints

3. Specific Clinical Data and Study Results Cited

• Tenofovir Phase 3 Trial (liver biopsy data): By year 5, ~75% of patients with baseline cirrhosis no longer had cirrhosis on repeat biopsy, demonstrating significant fibrosis reversal
• NUC Cessation RCTs:

- Two German trials (predominantly Caucasian): Stopping NUC after >4 years led to meaningfully higher HBsAg loss rates vs. continuing NUC

- Toronto trial (97% Asian patients): No significant improvement in HBsAg loss after NUC cessation

• Retrospective Analysis (Har Yansen et al., ~1,200+ patients):

- Caucasians with HBsAg <1,000 IU/mL at NUC stop: 41% HBsAg loss at 4 years

- Asians with HBsAg <100 IU/mL at NUC stop: 33% HBsAg loss at 4 years

- Overall HBsAg loss in Asian cohort: only ~5%; ~50% required resumption of NUC therapy

• First-Generation CAM + siRNA + NUC Combination: HBsAg loss observed in only ~1% of patients on treatment; benefit not sustained post-treatment

-