HLA-C/KIR genotype linked to HBeAg-positive HBV interferon response

By Shreeya Nanda

The human leucocyte antigen (HLA)-C and killer immunoglobin-like receptor (KIR) genotypes are associated with response to interferon-based therapy in patients with chronic hepatitis B virus (HBV) infection positive for hepatitis B e antigen (HBeAg), say researchers.

Although acknowledging the need for validation in further studies, they believe that "[i]n combination with other known response markers, HLA-C/KIR genotype could enable the selection of patients more likely to respond to interferon-based therapy."

The study included 86 patients treated with combination pegylated interferon alfa-2a and adefovir for 48 weeks and followed up until week 72. At this timepoint, 35% of 41 HBeAg-positive patients and 35% of 45 HBeAg-negative participants demonstrated a combined response, defined as persistently low HBV DNA levels (<2000 IU/mL), normalisation of alanine aminotransferase (ALT) levels and HBeAg loss in those positive for the antigen.

Of 12 single nucleotide polymorphisms (SNPs) located in or near the HLA-C gene, the rs2308557 SNP was the only one significantly associated with response in HBeAg-positive (p=0.003), but not -negative, patients.

This SNP is in almost complete linkage disequilibrium (ie, closely linked to one another) with another that classifies individuals into either the HLA-C1 or HLA-C2 ligand group, whereby each ligand is recognised by a different set of KIRs, explains the team led by Femke Stelma (Academic Medical Center, Amsterdam, the Netherlands).

Among patients positive for HBeAg, the combination of the heterozygous HLA-C2 allele with KIR2DL1, which encodes the KIR receptor that binds to the HLA-C2 ligand, was observed in 13 of 14 responders compared with 11 of 27 nonresponders, a significant difference (p=0.002). By contrast, the homozygous HLA-C2C2 allele together with KIR2DL1 was not associated with response.

Furthermore, multivariable analysis adjusting for HBV genotype and ALT levels showed that the combined KIR2DL1-HLA-C2 genotype was an independent predictor of response in HBeAg-positive individuals.

"HLA-C and KIR genotype is strongly associated with response in HBeAg-positive [chronic HBV] patients treated with interferon-based therapy", the researchers reiterate in the Journal of Viral Hepatitis, adding that the combination could be a "novel marker" in this patient population.

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