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precore and core promoter mutants and esponse to peginterferon in HBeAg-positive


Sonneveld MJ, Rijckborst V, Zeuzem S, Heathcote EJ, Simon K, Senturk H, Pas SD, Hansen BE, Janssen HL.
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Peginterferon (PEG-IFN) treatment of HBeAg-positive chronic hepatitis B (CHB) results in HBeAg loss in 30% of patients, but clearance of HBV DNA and HBsAg from serum is less often achieved. We investigated whether the presence of precore (PC) and basal core promoter (BCP) mutants before PEG-IFN treatment affects serological and virological response. A total of 214 HBeAg-positive CHB patients treated with PEG-IFN±lamivudine for 52 weeks in a global randomized trial were classified at baseline as wildtype (WT) or non-WT (detectable mutants at PC/BCP) by line-probe assay. Response was assessed at 6 months post-treatment and through long-term follow-up(LTFU). Mutants were detected in 64% of patients, in varying frequencies across HBV genotypes A through D. Patients with WT had higher baseline HBV DNA, HBeAg and HBsAg levels than patients with non-WT. Patients with WT were more likely to achieve HBeAg loss with HBV DNA<10,000 copies/mL (response, 34 versus 11%,p<0.001) and HBsAg clearance (18 versus 2%,p<0.001) at week 78 than non-WT patients. Among WT patients who achieved HBeAg clearance at week 78, 78% had undetectable HBV DNA and 61% achieved HBsAg clearance at LTFU (versus 26% and 15% in non-WT patients,p<0.001 for both). Presence of WT virus at baseline was an independent predictor of response (OR 2.90, 95%CI:1.15-7.31,p=0.023) and HBsAg clearance (OR 5.58, 95%CI:1.26-24.63,p=0.013) and patients with non-A genotypes with detectable mutants had a low probability of response. CONCLUSION: Presence of only WT virus at baseline is a strong predictor of response (HBeAg loss with HBV DNA <10,000 copies/mL) to PEG-IFN for HBeAg-positive CHB. Patients with detectable PC and/or BCP mutants have a lower probability of response and are less optimal candidates for PEG-IFN therapy. (HEPATOLOGY 2012.).

6 Responses
Avatar universal
one stupid question:

- i was under the impresion that is you have precore and/or core promoter mutants you are HBeAg negative ... and now I read that is also possible to be HBeAg positive.

what is HBeAg negative ? (is mandatory that in case of HBeAg negative to have a precore and/or core promoter mutant?)
Avatar universal

all these studies are useless because we do know that to have best interferon response all that matter is profund hbvdna undetactable by potent nucs like tenofovir or entecavir for 1-3 years before starting interferon

hbeag pos/neg and mutants have no significance in this sequential treatment for response, i guess that use of most potent nucs like tdf or etv is the most important factor and also hbvdna really undetactable

what is HBeAg negative ? (is mandatory that in case of HBeAg negative to have a precore and/or core promoter mutant?)

these mutants are present in any type and phase of hbv infection and are no longer important
Avatar universal
I think the paper refers to detectable mutants, i.e., you have a mixture of WT and precore/core promoter mutants, not 100% WT and not 100% mutants.

I read somewhere that before spontaneous HBeAg serconversion, we will have detectable presence of mutants. Therefore you will expect a higher SVR for people with detectable mutants. Strange. So what causes spontaneous and drug-induced HBeAg seroconversion?
Avatar universal
so you want to say that all HBeAg spontaneous serconversion have at least some mutants and the one that induce HBeAg can have but not mandatory.


indeed - what causes spontaneous and drug-induced HBeAg seroconversion? and is corect to have the same approach for all HBeAg negative or should be splited in 2 ?

Avatar universal
This is what I used to think (without any scientific evidence)
1.Spontaneous HBeAg seroconversion - some of the viruses have mutated to a form that produce less eAg (this can be the precore/core promoter) and the immune system then no longer tolerates the eAg, eventually exerts control over infected cells that produce the eAg.
2. Drug induced HBeAg seroconversion - drugs interfere with virus replication, causing less eAg to be produced and the immune system then no longer tolerates the eAg, eventually exerts control over infected cells that produce the eAg.
Avatar universal

i think that the only fact to care about bcp and precore mutants is the increased hcc risk and cirrhosis risk because there is no correlation with inactive carrier or active carrier, tht depends only on every person immune response

there is a brunetto study about this on genotype D mostly
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