In this issue of Hepatology, Lampertico et al.1 present a study of mostly hepatitis B virus (HBV) genotype D hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients treated with peginterferon (PEG-)IFN and show that hepatitis B s antigen (HBsAg) loss was significantly associated with IL28B genotype. Our group recently published a study on the association of IL28B genotype with response to PEG-IFN in HBeAg-positive CHB patients. Favorable IL28B genotypes, CC for rs12979860 and AA for rs12980275, were associated with higher rates of HBeAg seroconversion and HBsAg loss.2 Taken together, these findings provide mounting evidence for the importance of the IL28B genotype for prediction of response to PEG-IFN in CHB, although these findings require further confirmation.
There is, however, an important pitfall that should be taken into consideration. In our study, IL28B genotype distribution varied across ethnicity: 90% of Asian patients were genotyped CC, compared to 50% of non-Asians.2 Response to PEG-IFN in CHB also depends on the HBV genotype: patients with HBV genotype A achieve higher rates of response than those with HBV genotypes B, C, or D.3 Importantly, HBV genotypes A and D predominate in Caucasians, and nearly all south east Asian patients are infected with HBV genotypes B or C. Because IL28B genotype is associated with ethnicity, it is also associated with HBV genotype. In our study of HBeAg-positive patients, the favorable IL28B genotype was present in 42% of HBV genotype A patients, in 88%-90% of patients with HBV genotypes B or C, and in 52% of HBV genotype D patients.2 If differences in HBV genotype distribution are ignored, analyses of the association between IL28B genotype and HBsAg loss in a cohort of patients with mixed ethnicities could result in an overrepresentation of Asian patients (with “poor response” HBV genotypes B or C) in the favorable CC group, and an overrepresentation of Caucasians and black Africans (with “good response” HBV genotype A) in the unfavorable CT/TT groups. This could result in a biased estimate of association, or failure to detect one. This issue is particularly relevant for studies conducted in countries with mixed ethnicities, such as those in Western Europe and the United States, where the HBV-infected population comprises Caucasians, Asians, and black Africans.
In conclusion, the study by Lampertico et al. provides fascinating new data and urges further studies of IL28B genotype and response to PEG-IFN in CHB. However, the association of IL28B genotype distribution with that of HBV genotype may introduce an important pitfall. Therefore, we strongly recommend that future studies of IL28B in CHB be stratified by, or adjusted for, HBV genotype.