Saudi Journal of Gastroenterology
Home About us Instructions Submission Subscribe Advertise Contact Login    Print this page  Email this page Small font sizeDefault font sizeIncrease font size 
Users Online: 1628 


 
Table of Contents   
EDITORIAL  
Year : 2019  |  Volume : 25  |  Issue : 5  |  Page : 269-271
Quantitative HBsAg: Not helpful to evaluate fibrosis in HBeAg-negative chronic hepatitis B patients


Department of Hepatology, Universite Paris Diderot, Sorbonne Paris Cite, CRI, UMR 1149, Inserm, F-75018 Paris; Department of Hepatology, AP-HP Hopital Beaujon, Clichy, France

Click here for correspondence address and email

Date of Web Publication26-Sep-2019
 

How to cite this article:
Loureiro D, Mansouri A, Asselah T. Quantitative HBsAg: Not helpful to evaluate fibrosis in HBeAg-negative chronic hepatitis B patients. Saudi J Gastroenterol 2019;25:269-71

How to cite this URL:
Loureiro D, Mansouri A, Asselah T. Quantitative HBsAg: Not helpful to evaluate fibrosis in HBeAg-negative chronic hepatitis B patients. Saudi J Gastroenterol [serial online] 2019 [cited 2019 Dec 10];25:269-71. Available from: http://www.saudijgastro.com/text.asp?2019/25/5/269/267751






Around 257 million people worldwide have chronic hepatitis B virus (HBV) infection, which leads to almost 1 million deaths per year from complications, mainly decompensated cirrhosis and hepatocellular carcinoma. Current treatments for HBV infection include pegylated interferon-alfa (Peg-IFNα) for a limited duration (48 weeks), which is associated with mild efficacy and poor tolerability, or nucleoside analogues (NA), which require lifelong administration and rarely achieve hepatitis B surface antigen (HBsAg) loss.[1]

Fibrosis is the most important prognosis predictor of survival. Therefore, fibrosis evaluation is mandatory and subjects at risk of fibrosis progression may be prioritized for treatment. According to the guidelines, all patients with HBeAg positive or negative chronic hepatitis B, and active disease defined by HBV DNA more than 2000 IU/mL, alanine aminotransferase (ALT) above the upper limit of normal, or at least moderate liver necroinflammation or fibrosis, are candidates for treatment. [2,3] The patients with extrahepatic HBV-related manifestations are also candidates for therapy.[1]

Several new markers have been developed to assess the fibrosis.[4] For instance, the expression of 13 fibrosis-related microRNAs was analyzed in 194 serums and 177 liver biopsies of patients with either chronic hepatitis B (CHB) or chronic hepatitis C (CHC) to develop models to diagnose advanced fibrosis and cirrhosis.[5]

Quantifying HBsAg (qHBsAg) is certainly an important new tool for predicting the severity of disease and response to therapy in CHB. [6,7] Quantifying HBsAg has been proposed as a surrogate marker of cccDNA. In this way, HBsAg measurement helps tailor follow-up and treatment management. To distinguish active from inactive hepatitis B, a qHBsAg of 1000 IU/mL has been suggested as an appropriate cutoff.[8] Prediction of disease reactivation in patients with asymptomatic HBeAg-vee CHB has been proposed using baseline serum measurements of HBsAg and HBV-DNA.[9] Regarding treatment, in a study of 48 patients with HBeAg-ve receiving Peg-IFNα-2a, a decrease of 0.5 and 1 log10 IU/mL of serum HBsAg levels at weeks 12 and 24 of therapy had a 90% negative predicting value and a 89% positive predicting value for week 12 and 97% negative predicting value and a 92% positive predicting value for week 24 sustained response, respectively.[10] This was the first study to suggest early kinetics (week 12) of HBsAg to differentiate sustained responders from non-responders to Peg-IFN.

In an interesting study published in this issue of the Saudi Journal of Gastroenterology, an important question was raised: whether qHBsAg, in HBeAg-ve chronic HBV, could be a non-invasive biomarker of liver inflammation and fibrosis.[11] Untreated chronic adult HBV (HBsAg detection >6 months) HBeAg-ve patients (n = 75) with mean HBV DNA <2000, 2,000–20,000 and >20,000 IU/mL were included. These well-phenotyped patients were the part of a cohort of 366 HBeAg-ve carriers previously reported by the authors.[12] The methodology was adequate: the qHBsAg levels (Abbott ARCHITECT® Assay, Abbott Diagnostics) were measured at baseline as single-point quantification. Furthermore, all specimens were centrally assessed and scored according to the METAVIR system by a hepatopathologist who was blinded to all clinical information.

The mean age of the patients was 39.4 ± 11.4 years and 58 were male (77.3%). ALT levels were normal in 30 (40%) with the median ALT of the overall cohort being 1.2 ULN (IQR 0.6–1.6). The log10 qHBsAg level of the overall cohort was 3.4 ± 0.9 IU/mL. Significant fibrosis (F2-4) was seen in 31 (41.3%) and these patients were more likely to have higher Log10 HBV DNA, elevated ALT and AST, and lower platelets. In patients with HBV DNA >2000 IU/mL, when qHBsAg levels were >1000 IU/mL (n = 56, 74.7%), F2-4 fibrosis was more frequently seen (50.0%) as opposed to those with qHBsAg <1000 IU/mL (7.1%, P = 0.005). However, in one-half of the patients who fulfilled these criteria of HBV DNA >2000 IU/mL and qHBsAg >1000 IU/mL non-significant (F0-1) fibrosis was found.

Finally, the results show that qHBsAg do not distinguish patients with F2-4 fibrosis. Mean levels were similar in patients with significant and non-significant fibrosis, and in those with levels >1000 IU/mL less than half had significant fibrosis. More than half the patients with non-significant fibrosis were also found to have a qHBsAg level >1000 IU/mL. More importantly, patients with qHBsAg <1000 IU/mL had a presence of significant fibrosis similar to those with levels >1000 IU/mL. The authors concluded that disease stratification is not feasible with qHBsAg levels, with results being in conformity with other studies in patients with HBeAg-ve where higher qHBsAg levels did not identify significant fibrosis. [13,14]

In conclusion, this interesting study demonstrates that the fibrosis evaluation is not precise with qHBsAg levels in patients with HBeAg-ve. Although this study has few limitations: mainly for the less number of patients and with a limited HBV genotype distribution, the results are in agreement with the previous reports. Future studies will have to address the reproducibility of the correlation in larger, patient cohorts of different origins, with a large HBV genotype distribution, and over time with liver biopsies performed to correlate HBsAg quantification, inflammation, fibrosis, cccDNA, and antiviral therapy in patients with CHB.

Finally, what are the clinical implications of HBs quantification? HBs quantification appears to have a better correlation with fibrosis stage in patients with HBe+ve CHB. [7,15] Monitoring serum HBsAg concentrations in patients with HBV infection could provide substantial complementary information to HBV DNA measurements when predicting treatment response, although this is complicated because it has recently been demonstrated that HBsAg could also be produced by integrated HBV-DNA.[16] Recent studies in chimpanzees suggest a dramatic increase of the integration in the HBeAg-ve phase with more than 90% of the mRNAs deriving from integrated HBV-DNA. A significant proportion of HBsAg in patients with HBeAg-ve could derive from integrated HBV sequences. Immune response (reflected by necroinflammation) with mitochondrial antiviral response has also an important role during HBV infection and might interact with HBs production.[17]



 
   References Top

1.
Asselah T, Loureiro D, Boyer N, Mansouri A. Targets and future direct-acting antiviral approaches to achieve hepatitis B virus cure. Lancet Gastroenterol Heparol 2019. [In press].  Back to cited text no. 1
    
2.
EASL. Clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370-98.  Back to cited text no. 2
    
3.
Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67:1560-99.  Back to cited text no. 3
    
4.
Martinot-Peignoux M, Lapalus M, Maylin S, Boyer N, Castelnau C, Giuily N, et al. Baseline HBsAg and HBcrAg titres allow peginterferon-based 'precision medicine' in HBeAg-negative chronic hepatitis B patients. J Viral Hepat 2016;23:905-11.  Back to cited text no. 4
    
5.
Appourchaux K, Dokmak S, Resche-Rigon M, Treton X, Lapalus M, Gattolliat CH, et al. MicroRNA-based diagnostic tools for advanced fibrosis and cirrhosis in patients with chronic hepatitis B and C. Sci Rep 2016;6:34935.  Back to cited text no. 5
    
6.
Martinot-Peignoux M, Lapalus M, Asselah T, Marcellin P. HBsAg quantification: Useful for monitoring natural history and treatment outcome. Liver Int 2014;34(Suppl 1):97-107.  Back to cited text no. 6
    
7.
Martinot-Peignoux M, Carvalho-Filho R, Lapalus M, Netto-Cardoso AC, Lada O, Batrla R, et al. Hepatitis B surface antigen serum level is associated with fibrosis severity in treatment-naive, e antigen-positive patients. J Hepatol 2013;58:1089-95.  Back to cited text no. 7
    
8.
Brunetto M, Oliveri F, Colombatto P, Moriconi F, Ciccorossi P, Coco B, et al. Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers. Gastroenterology 2010;139:483-90.  Back to cited text no. 8
    
9.
Martinot-Peignoux M, Lapalus M, Laouénan C, Lada O, Netto-Cardoso AC, Boyer N, et al. Prediction of disease reactivation in asymptomatic hepatitis B e antigen-negative chronic hepatitis B patients using baseline serum measurements of HBsAg and HBV-DNA. J Clin Virol 2013;58:401-7.  Back to cited text no. 9
    
10.
Moucari R, Mackiewicz V, Lada O, Ripault MP, Castelnau C, Martinot-Peignoux M, et al. Early serum HBsAg drop: A strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology 2009;49:1151-7.  Back to cited text no. 10
    
11.
Ahmed FA, Bajaifar MS, Ahmed MA, Alalwan A, Sanai FA, Albeladi K, et al. Quantitative HBsAg levels do not identify hepatic fibrosis in HBeAg-negative chronic hepatitis B patients. Saudi J Gastroenterol 2019;25:286-92.  Back to cited text no. 11
[PUBMED]  [Full text]  
12.
Sanai FM, Alghamdi H, Alswat KA, Babatin MA, Ismail MH, Alhamoudi WK, et al. Greater prevalence of comorbidities with increasing age: Cross-sectional analysis of chronic hepatitis B patients in Saudi Arabia. Saudi J Gastroenterol 2019;25:194-200.  Back to cited text no. 12
[PUBMED]  [Full text]  
13.
Chakrabarty G, Bruce M, Horner M, Wang B, Agarwal K, Carey I. Can quantitative hepatitis B surface antigen levels predict the severity of liver disease in genotype E Patients? J Viral Hepat 2018;25:80-7.  Back to cited text no. 13
    
14.
Balkan A, Namiduru M, Balkan Y, Mete AO, Karaoglan I, Bosnak VK. Are serum quantitative hepatitis B surface antigen levels, liver histopathology and viral loads related in chronic hepatitis B-infected patients? Saudi J Gastroenterol 2016;22:208-14.  Back to cited text no. 14
[PUBMED]  [Full text]  
15.
Marcellin P, Martinot-Peignoux M, Asselah T, Batrla R, Messinger D, Rothe V, et al. Serum levels of hepatitis B surface antigen predict severity of fibrosis in patients with E antigen-positive chronic hepatitis B. Clin Gastroenterol Hepatol 2015;13:1532-9.  Back to cited text no. 15
    
16.
Wooddell CI, Yuen MF, Chan HL, Gish RG, Locarnini SA, Chavez D, et al. RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci Transl Med 2017;9. doi: 10.1126/scitranslmed.aan0241.  Back to cited text no. 16
    
17.
Mansouri A, Gattolliat CH, Asselah T. Mitochondrial dysfunction and signaling in chronic liver diseases. Gastroenterology 2018;155:629-47.  Back to cited text no. 17
    

Top
Correspondence Address:
Dr. Tarik Asselah
Viral Hepatitis INSERM UMR 1149, Hopital Beaujon, 100 Boulevard Du General Leclerc, Clichy - 92110
France
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjg.SJG_445_19

Rights and Permissions




 

Top
  
 
  Search
 
  
  
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Email Alert *
    Add to My List *
* Registration required (free)  


    References

 Article Access Statistics
    Viewed4411    
    Printed57    
    Emailed0    
    PDF Downloaded181    
    Comments [Add]    

Recommend this journal