Methodological considerations in studying natural history of HBeAg‐negative and ‐positive chronic hepatitis B

To the editor:We read with great interest the report of Croaghet al. (1), which confirmed a positive correlationbetween high HBV-DNA levels and the presence ofsignificant liver fibrosis in HBeAg-negative, but not inHBeAg-positive disease. This study differed fromREVEAL(2) in that all patients had histological quanti-fication of fibrosis rather than ultrasound and overhalf the patients had HBeAg-positive disease.We offer the following comments. Firstly, it may notbe suitable to identify the predictors of disease pro-gression in a chronic progressive disease through across-sectional study. Many studies have shown that thenatural history of chronic HBV infection varies signifi-cantly at an individual level (3). The risk of liver inflam-mation and fibrosis in chronic hepatitis B is the complexresult of many interacting factors and HBV-DNA level isonly one of them (1). As so many other variables affectthe natural history, just examining viral load in a cross-sectional study produces an oversimplified and poten-tially incorrect conclusion about disease progression.In addition, this study of an Australian clinicalcohort was a heterogeneous one, with all major geno-types (A–D) being represented. It is well known(3)that Genotype D infection prevails in the Mediterra-nean region (>90%) and its associated HBeAg-negativeprecore mutations can lead to cirrhosis and hepatocel-lular carcinoma. Contrary to Southeast Asia, HBVvertical transmission is rare in the Mediterraneanregion where horizontal transmission in early child-hood is the predominant mode of HBV transmission,accounting for the vast majority of chronic HBV infec-tions (>90%). Moreover, the natural history of chronicHBV infection varies with age of infection (4).Although Croagh et al. pointed out that “the ethnicmakeup of these groups did not differ significantly(P = 0.189), with the majority (>74%) of the patientsbeing of Asian ethnicity in all the groups”, we thinkthat the possible impact of the complex ethnic makeupof the patients on the findings cannot be ignored.In summary, we contend that the use of a cross-sec-tional study method and the ethnic heterogeneity oftheir cohort may reduce the validity of their conclu-sions.