Natural Killer Cell Characteristics in Patients With Chronic Hepatitis B Virus (HBV) Infection Are Associated With HBV Surface Antigen Clearance After Combination Treatment With Pegylated Interferon Alfa-2a and Adefovir

J Infect Dis. 2015 Oct 1;212(7):1042-51. doi: 10.1093/infdis/jiv180. Epub 2015 Mar 19.


Background: The role of natural killer (NK) cells in the process of hepatitis B virus (HBV) surface antigen (HBsAg) clearance and whether their phenotype is related to treatment outcome in patients with chronic hepatitis B are currently unknown.

Methods: Patients with chronic hepatitis B (HBV DNA load, >17 000 IU/mL) were treated with pegylated interferon alfa-2a and adefovir for 48 weeks. NK cell phenotype and function were analyzed in 7 responders (defined as individuals with HBsAg clearance by week 72; 3 HBV e antigen [HBeAg]-positive and 4 HBeAg-negative), 7 matched nonresponders, and 7 healthy controls. Subsequently, 34 baseline samples from HBeAg-positive patients with chronic hepatitis B were analyzed.

Results: During treatment, the percentage and absolute number of CD56(bright) NK cells increased significantly, whereas the percentage and absolute number of CD56(dim) NK cells decreased. At baseline, responders had a significantly lower expression of chemokine receptor CX3CR1 on CD56(bright) NK cells and inhibitory receptor NKG2A on CD56(dim) NK cells, compared with nonresponders. In addition, responders had higher CD56(bright) TRAIL expression and interferon γ production at end of treatment. These baseline differences were not found in HBeAg-positive patients who had HBeAg seroconversion without HBsAg clearance.

Conclusions: Combination therapy significantly influences NK cell phenotype and function. Differences between patients with chronic hepatitis B with HBsAg clearance and nonresponders suggest that NK cells play a role in the clearance of HBsAg during interferon-based combination therapy.

Keywords: Hepatitis B; NK cells; TRAIL; combination therapy; innate immunity; interferon alfa.

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / therapeutic use
  • Adult
  • Aged
  • Antigens, Surface / immunology
  • Antiviral Agents / therapeutic use*
  • DNA, Viral / immunology
  • Drug Therapy, Combination
  • Female
  • Hepatitis B Surface Antigens / immunology
  • Hepatitis B e Antigens / immunology
  • Hepatitis B virus / immunology*
  • Hepatitis B, Chronic / drug therapy
  • Hepatitis B, Chronic / immunology*
  • Hepatitis B, Chronic / prevention & control
  • Humans
  • Interferon-alpha / therapeutic use*
  • Killer Cells, Natural / immunology*
  • Male
  • Middle Aged
  • Organophosphonates / therapeutic use*
  • Polyethylene Glycols / therapeutic use*
  • Recombinant Proteins / therapeutic use
  • Treatment Outcome
  • Young Adult


  • Antigens, Surface
  • Antiviral Agents
  • DNA, Viral
  • Hepatitis B Surface Antigens
  • Hepatitis B e Antigens
  • Interferon-alpha
  • Organophosphonates
  • Recombinant Proteins
  • Polyethylene Glycols
  • adefovir
  • Adenine
  • peginterferon alfa-2a