Precore & BCP mutations Question

[NashPred]

My lab results say the following:

HBV Genotype                       A
Polymerase Mutations            Not Detected
Precore Mutation         Detected
BCP mutations         Detected
It also gives precore and BCP tag numbers. Not sure if these are useful or not.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>

At the bottom of the sheet, it says:

Polymerase                          Not Detected
Precore                                Not Detected
BCP                                     Not Detected
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>

I guess this means I have a double mutation? What does this mean as far as treatment? Greater resistance to anti-virals?
Are these 2 mutations fighting for dominance and 1 will win out over the other?
Trying to understand how these 2 mutations interact w/ each other and what role (if any) genotype plays in it.

[NashPred]

I'll need to let all this soak in for a while. It takes me alot longer to understand due to the HCV treatment induced brain fog I'm in right now.....but I'm trying.

I'm sure I am putting the cart before the horse (so to speak) as there is alot of variables yet to be determined i.e. when/if I get rid of HCV and it is no longer providing supression of the HBV virus. I'll keep my fingers crossed.

Thanks for you help

[cajim]

I am not sure if it is right.  I remember the original article talking about certain treatments being more effective against some species.

[NashPred]

Thanks cajim,

If I’m reading this correctly, the non dominate species is actually helping to keep the dominant species from being able to replicate as fast. Is this right?

I guess I’ll need to wait and see what happens when I come off IFN as far as anti-viral resistance is concerned, but it looks like anti viral resistance is more closely related to a polymerase mutation.

My gosh!  HBV is hard to understand. HCV is so much more straight forward.

[cajim]

Does this help?

"Viral Replication and Selection of Resistant Strains

The genome of HBV consists of partially double-stranded, 3.2-kb, covalently closed, circular DNA (ccc DNA) comprising 4 overlapping open reading frames.11 The viral genome is transcribed into 4 major subgenomic viral messenger RNAs, under the control of specific enhancers,12 and is the template for the pregenomic RNA. The virus is encapsidated after binding of the polymerase and core to the pregenomic RNA in the cytoplasm. Nucleocapsids are enveloped by budding into the endoplasmic reticulum, after which they are secreted from the cell or return to the nucleus to amplify the cccDNA reservoir.13

Viral mutations occur spontaneously during HBV replication. Viral reverse transcriptases intrinsically are error prone and lack a proofreading function, allowing for replication errors to occur. These replication errors result in the emergence of multiple HBV variant quasispecies that coexist and reach population densities in direct proportion to their relative replication fitness.11 This phenomenon is responsible for the generation of significant diversity; it has been shown that HBV genomes in one given patient displayed a rate of 1.4 to 3.2 × 10−5 nucleoside substitutions per year, a value approximately 104 times greater than DNA genomes and about 10−2 less than that for HIV.14 A chronic HBV carrier can produce up to 1013 virions per day, and, as a result, every nucleotide of the 3.2-kb HBV genome theoretically can be substituted within one patient every day.2

The dominant quasispecies is by definition the best adapted to its host environment, and, as expected, random mutations generally will impair its fitness to a degree. Thus, the emergence of successful HBV variants resistant to an antiviral drug is affected by the mutation rate and viral load and is determined eventually by the replication fitness of the mutant virus in relation to the antiviral potency of the drug and the number of mutations required to confer resistance (ie, the genetic barrier to resistance).15
Mutations Associated With Resistance to Nucleoside/Nucleotide Analogues
return to Article Outline
Defining the Consequences of Resistance

Treatment failure can be defined as primary or secondary. Primary treatment failure is the failure of a drug to reduce HBV DNA levels by 1 × log10 IU/mL or greater within 3 months of initiation of therapy, and secondary failure is defined as a rebound of HBV replication by 1 × log10 IU/mL or greater from nadir in patients in whom treatment initially produced a decrease in serum HBV DNA of 1 × log10 IU/mL or greater.16

Secondary treatment failure due to resistance to antiviral therapy can result in a decreased rate of hepatitis B e antigen (HBeAg) seroconversion17; reversion of virologic, biochemical, and histologic improvement18, 19; increased rate of disease progression5; severe exacerbations in the presence of cirrhosis20, 21; and risk for graft loss and death after liver transplantation.22
Mutations in the Polymerase Gene and Antiviral Resistance

Mutations resulting in resistance to nucleoside/nucleotide analogues mainly involve the viral polymerase gene (Figure 1).11, 23, 24, 25 This gene contains 7 functional domains (A–G), and mutations that give rise to nucleoside/nucleotide resistance are located essentially in domains A through E.23."

From "Chronic Hepatitis B: Preventing, Detecting, and Managing Viral Resistance" by Keeffe, Emmet B., Dieterich, Douglas T., Pawlotsky, Jean-Michael, and Benhamou, Yves in Clinical Gastroenterology and Hepatology 2008;6:268-274.

Full paper in:

http://www.cghjournal.org/article/S1542-3565(07)01246-3/fulltext#sec1