Low-Level Viremia in Nucleoside Analog-Treated Chronic Hepatitis B Patients

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Low-Level Viremia in Nucleoside Analog-Treated Chronic Hepatitis B Patients

Introduction

Hepatitis B virus (HBV) infection remains a global health challenge, affecting over 257 million people worldwide. Chronic hepatitis B (CHB) can lead to severe liver complications, including cirrhosis and hepatocellular carcinoma (HCC). Nucleoside/nucleotide analog (NUC) therapies, such as entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF), are first-line treatments that suppress viral replication and reduce disease progression. However, a significant subset of patients continues to exhibit low-level viremia (LLV)—persistent or intermittent HBV DNA levels below 2,000 IU/mL after 48 weeks of therapy. This phenomenon raises concerns about its clinical implications, management, and underlying mechanisms.

Definition of LLV

LLV is defined as detectable HBV DNA levels (10–2,000 IU/mL) in patients undergoing antiviral therapy for ≥48 weeks. It is further categorized into persistent LLV (continuously detectable HBV DNA without achieving complete virological response [CVR, HBV DNA <10–20 IU/mL]) and intermittent LLV (episodic viral detection after temporary CVR). Current guidelines lack consensus on LLV definitions, though the American Association for the Study of Liver Diseases (AASLD) recognizes HBV DNA <2,000 IU/mL as LLV. Improved nucleic acid testing has enabled the stratification of LLV into two subgroups: "LLV" (20–2,000 IU/mL) and "very low-level viremia" (10–19 IU/mL). Importantly, factors like poor adherence, drug interactions, and resistance mutations must be excluded before diagnosing LLV.

Viral Replication and Disease Progression

HBV replicates via covalently closed circular DNA (cccDNA), a stable episomal form in hepatocyte nuclei. NUCs inhibit viral reverse transcriptase but do not directly target cccDNA, allowing residual replication. Studies demonstrate that even low-level HBV DNA (2,000 IU/mL had a 2.7-fold higher HCC risk than those with lower levels. Liver biopsy data reveal that 62% of HBeAg-negative patients with HBV DNA ≤2,000 IU/mL exhibit significant histologic changes (Ishak fibrosis score ≥2). These findings underscore that incomplete viral suppression, even at low levels, perpetuates liver injury.

Epidemiology and Risk Factors

Real-world studies indicate that 20–40% of CHB patients develop LLV despite NUC therapy. In China, a nationwide survey of 21,614 patients reported LLV in 20% of cases. Risk factors include:

  • Baseline characteristics: Higher pretreatment HBV DNA levels, HBeAg positivity, and cirrhosis.
  • Treatment-related factors: Delayed virological response (HBV DNA ≥20 IU/mL at 6 months) and non-first-line NUC use.
  • Host factors: Lower ALT levels (<100 U/L), reduced hepatocyte proliferation, and impaired immune clearance.

For instance, a Korean cohort study of ETV-treated patients identified HBeAg positivity and cirrhosis as independent predictors of LLV. Similarly, baseline HBsAg levels >1,000 IU/mL and HBV DNA >6 log 10 IU/mL correlate with reduced CVR rates.

Clinical Consequences of LLV

Persistent LLV is linked to adverse outcomes, particularly in cirrhotic patients. Key findings include:

  • Liver fibrosis progression: Patients with LLV (20–200 IU/mL) after 78 weeks of ETV therapy had a 4.84-fold higher risk of fibrosis progression than those with CVR.
  • HCC risk: In ETV-treated cirrhotic patients, 5-year cumulative HCC incidence was 23.4% in LLV vs. 10.3% in those with maintained virological response (MVR).
  • Cirrhosis reversal: Among 200 compensated cirrhotics, reversal rates at 5 years were 39.8% in MVR vs. 10.6% in LLV.
  • Mortality: HCC patients with LLV and HBV relapse had a 1.71-fold higher mortality risk than those with sustained viral suppression.

These data highlight that LLV negates the benefits of antiviral therapy, perpetuating liver damage and increasing long-term morbidity.

Mechanisms Underlying LLV

The persistence of cccDNA is central to LLV. NUCs block reverse transcription but cannot eliminate cccDNA, allowing low-level HBV replication. Key mechanisms include:

  1. cccDNA stability: cccDNA survives in quiescent hepatocytes, evading immune detection and NUC activity.
  2. Impaired hepatocyte proliferation: Compensatory liver regeneration during inflammation reduces cccDNA via mitotic dilution. However, LLV patients often exhibit lower ALT levels, suggesting reduced hepatocyte turnover and cccDNA retention.
  3. Drug resistance: While rare in first-line NUC therapy, preexisting resistance mutations (e.g., lamivudine resistance) may contribute to LLV.
  4. NTCP downregulation: Proliferating hepatocytes downregulate the HBV entry receptor NTCP, limiting de novo infections but failing to clear cccDNA reservoirs.

Management Strategies

Current guidelines offer limited guidance on LLV management. Key approaches include:

  1. Adherence monitoring: Ensure patient compliance before altering therapy.
  2. Therapy intensification:
    • Switch to TAF: In ETV-treated LLV patients, switching to TAF achieved CVR in 62.7% vs. 9.3% with continued ETV.
    • Combination therapy: ETV + TDF improved CVR rates in HBeAg-positive patients with high baseline HBV DNA (8 log 10 IU/mL).
  3. Risk stratification: Use HCC prediction models (e.g., PAGE-B, CU-HCC) to identify high-risk patients requiring aggressive monitoring.

Notably, AASLD recommends continuing first-line NUCs for LLV, while EASL suggests switching to TAF/ETV combination if HBV DNA plateaus (69–2,000 IU/mL).

Conclusion

LLV represents a critical gap in CHB management, affecting 20–40% of NUC-treated patients. Its association with fibrosis, cirrhosis, and HCC underscores the need for complete viral suppression. Mechanisms like cccDNA persistence and low hepatocyte proliferation explain LLV’s refractoriness to current therapies. Emerging strategies, including switching to TAF and combination regimens, show promise in achieving CVR. Future research must clarify LLV’s molecular drivers and optimize therapies to eradicate cccDNA, ultimately improving long-term outcomes.

doi.org/10.1097/CM9.0000000000001793

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