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HR : HepB combo treatment question
HR, firstly thanks for taking question on this forum. When I was diagnosed with chronic HepB, I learned a lot from your responses to the HepB post, since we are in the minority, but no less concern for our health.
I would appreciate it if you could offer some feedback so I could have a more engaging discussion with my GI during my next visit.
I was diagnosed with chronic HepB (eAg +, eAb -, with about 3 million VL, ALT in the 50’s) about 1.5 years ago. I am Asian and probably infected as infant. I am also one of those that is positive for both the surface antibody and antigen.
My MD started me on Hepsera after being diagnosed, after 10 months; VL went down to about 1,000 copies, ALT in 30’s. Then it went back up slightly to about 4,000 the next month.
Genotyping was done. And there was no indicator of antiviral resistance, but it detected the BCP mutation (and I am still eAg + and eAb-). So on the 11th month, MD added Baraclude as a precaution. What are your thoughts on being BCP and still eAg+ ?
At 12 month, with combo Hepsera and Baraclude, my VL became UND. Also at 12 months, eAb became +, stayed + for a1 month, then “borderline”, then return to -. eAg didn’t change and always + since I was diagnosed. What happened here? I thought I was seroconverting…was disappointed.
VL remains UND today (at 16 months), ALT in high 20’s. AFPs and annual sonogram were in range and normal.
At this point in my treatment, should any changes to antiviral meds be considered? To PEG-INF, or change one of the anti-viral to Tenofovir?
Any feedback is much appreciated.
I would appreciate it if you could offer some feedback so I could have a more engaging discussion with my GI during my next visit.
I was diagnosed with chronic HepB (eAg +, eAb -, with about 3 million VL, ALT in the 50’s) about 1.5 years ago. I am Asian and probably infected as infant. I am also one of those that is positive for both the surface antibody and antigen.
My MD started me on Hepsera after being diagnosed, after 10 months; VL went down to about 1,000 copies, ALT in 30’s. Then it went back up slightly to about 4,000 the next month.
Genotyping was done. And there was no indicator of antiviral resistance, but it detected the BCP mutation (and I am still eAg + and eAb-). So on the 11th month, MD added Baraclude as a precaution. What are your thoughts on being BCP and still eAg+ ?
At 12 month, with combo Hepsera and Baraclude, my VL became UND. Also at 12 months, eAb became +, stayed + for a1 month, then “borderline”, then return to -. eAg didn’t change and always + since I was diagnosed. What happened here? I thought I was seroconverting…was disappointed.
VL remains UND today (at 16 months), ALT in high 20’s. AFPs and annual sonogram were in range and normal.
At this point in my treatment, should any changes to antiviral meds be considered? To PEG-INF, or change one of the anti-viral to Tenofovir?
Any feedback is much appreciated.
MEDICAL PROFESSIONAL
we all had great expectations for telbivudine ( LdT) For your info, clevudine/LFMAU, the new Korean HBV drug is totally identical to LdT, just with a fluor atom attached to the ring.. LdT is substantially more potent than lamuvidine, but still has an unacceptable high rate of resistance, similar type as LAM. LdT also suffers from some unexplained muscle toxicity (10% of patients had CPK elevations).
Resistance to Adefovir does not come like LAM resistance off/on, it creeps up slowly. So let us hope that you do not have a mildy resistant cccDNA subset in your - overall low quantity - quasispecies distribution . If you add/change to the tenofovir now, you should have literally nothing to fear in terms of resistance, even in the long run - and that is extremely important, since, realistically considered, no new wonder HBV drug is waiting on the horizon anymore.. There are many one way roads in HBV therapy.
There is no question that Tenofovir will be approved for HBV. It was, as expected, a blasting success at the AASLD. I recommended its use for HBV to hepatologists since 2001. The first patients that received it here in CA a week after its approval in the fall of 2001 did not have HIV. They had HBV.
LAM resistance also fosters at least some increased risk of Adefovir/Tenofovir resistance in the long run.
Tenofovir is normally able to overcome , by its huge comparative dose ( 30 times the dose for Adefovir), certain forms of Adefovir resistance, but von Boemmels presentation at this AASLD already showed that those patients are having a very hard time to get UND on tenofovir. And what in 5 years from now? 1o years?
I want to mention that the truly multiresistant HBV patients is also not doing too well on/after transplant, because the drugs then wont work after transplant either and he has to a large degree rely on HBIGshots. Thats could be 80,000 dollars/year.
Interestingly, NTZ seems to have fairly potent anti HBV effects as well. Time will tell if it will ever be developed for this indication, like in a multiresistant patient.
Resistance to Adefovir does not come like LAM resistance off/on, it creeps up slowly. So let us hope that you do not have a mildy resistant cccDNA subset in your - overall low quantity - quasispecies distribution . If you add/change to the tenofovir now, you should have literally nothing to fear in terms of resistance, even in the long run - and that is extremely important, since, realistically considered, no new wonder HBV drug is waiting on the horizon anymore.. There are many one way roads in HBV therapy.
There is no question that Tenofovir will be approved for HBV. It was, as expected, a blasting success at the AASLD. I recommended its use for HBV to hepatologists since 2001. The first patients that received it here in CA a week after its approval in the fall of 2001 did not have HIV. They had HBV.
LAM resistance also fosters at least some increased risk of Adefovir/Tenofovir resistance in the long run.
Tenofovir is normally able to overcome , by its huge comparative dose ( 30 times the dose for Adefovir), certain forms of Adefovir resistance, but von Boemmels presentation at this AASLD already showed that those patients are having a very hard time to get UND on tenofovir. And what in 5 years from now? 1o years?
I want to mention that the truly multiresistant HBV patients is also not doing too well on/after transplant, because the drugs then wont work after transplant either and he has to a large degree rely on HBIGshots. Thats could be 80,000 dollars/year.
Interestingly, NTZ seems to have fairly potent anti HBV effects as well. Time will tell if it will ever be developed for this indication, like in a multiresistant patient.
I actually expected worse. I thought I had no shot at full sero-conversion, given the BCP is detected. I had thought that it was already written in stone that I would need a lifetime of meds. To know that I have a shot to become "a healthy carrier" (heavy on the sarcasm) is welcome news. If, in time I have to decide to change to mono-therapy or come off meds, that would be a great day. Hope is good.
Re: meds and resistance. I know resistance to lamivudine promotes resistance to entecavir, adefovir to tenofovir. What is a person takes adefovir for some months and before developing resistance, switches to tenofovir (hopefully in my case), does it still increase the risk for resistance to tenofovir. I guess the same analogy for lamivudine and entecavir.
How about Telbivudine, which I don't hear much about?
I think these are my last questions. And with that I think I should have enough to have an interesting session with my GI.
I THANK YOU again for taking the time. I know you are very busy.
Re: meds and resistance. I know resistance to lamivudine promotes resistance to entecavir, adefovir to tenofovir. What is a person takes adefovir for some months and before developing resistance, switches to tenofovir (hopefully in my case), does it still increase the risk for resistance to tenofovir. I guess the same analogy for lamivudine and entecavir.
How about Telbivudine, which I don't hear much about?
I think these are my last questions. And with that I think I should have enough to have an interesting session with my GI.
I THANK YOU again for taking the time. I know you are very busy.
MEDICAL PROFESSIONAL
BCPs do change the sequence of the x protein, as briefly mentioned, that leads to the speculation that the "new' x is even more pro HCC as the x is already accused of being. This is a difficult shady area of HBv molecular biology and every year at the annual meetings we have a section just devoted to x and HCC. But IMO it is much more the enhanced inflammation (see above why) and mutagenic effects, that the prooxidative stress has on the hepatocyte genomes that cause the higher propensity for HCC in the untreated BCP cases.
The BCPmutations occur in an attempt of the virus to curb e-Ag expression ( but note that it does not turn it off completely, maybe only 90% or so, not like the precore mutation does!) once the anticore Tcell pressure mounts, like under a reduced virus production (by antivirals) with concomitant eAg production/reduction towards the borderline. If the antiviral pressure falls and the eAg conversion has not fully occcured, it tends to snap back to wild type in some cases , as you said, sometimes causing a new flare of hepatitis. Flipflops are not a good thing, if they are accompanied by successive bouts of semiacute hepatitis a rapid progression to cirrhosis often occurs.
BCPs work towards seroconverting PROVIDED that the hepatic viral burden and remaining eAg production falls further, so that the e-antibody can overwhelm the remaining circulating eAg. The true true eAb, always there but normally invisible below the sea of antigen, also can be present in considerable varying amounts. So it is the relative amount of the two that finally determines the e-seroconversion, and in your case I am pretty sure if you use the entecavir/tenofovir combo that you will fully seroconvert with time. The question is what to do then. Most hepatologists will want to continue for at least 6 month with the antivirals. If you had advanced fibrosis or cirrhosis the general recommendation by the expert panel would be to NEVER come off the antivirals, so that you do not risk a potentially deadly flare. You might reduce the combo to a mono at this time and watch carefully with a super sensitive test if the virus creeps up. I have developed a PCR test that can measure the HBV virus levels to well below one single copy per ml - it uses 10mls of serum for full work up and it is quantitative - hard to believe but true. But it is only for research purposes and uses a total of 90 individual PCRs for one single ultra low HBV VL determination. It will always find the virus, even the vast majority of "cleared acute HBV" patients have measurable levels with that assay. But there is also an HBV PCR assay that will catch down to 2 or 3 virions of HBV per mL., that one is commercially available.(NFI)
The BCPmutations occur in an attempt of the virus to curb e-Ag expression ( but note that it does not turn it off completely, maybe only 90% or so, not like the precore mutation does!) once the anticore Tcell pressure mounts, like under a reduced virus production (by antivirals) with concomitant eAg production/reduction towards the borderline. If the antiviral pressure falls and the eAg conversion has not fully occcured, it tends to snap back to wild type in some cases , as you said, sometimes causing a new flare of hepatitis. Flipflops are not a good thing, if they are accompanied by successive bouts of semiacute hepatitis a rapid progression to cirrhosis often occurs.
BCPs work towards seroconverting PROVIDED that the hepatic viral burden and remaining eAg production falls further, so that the e-antibody can overwhelm the remaining circulating eAg. The true true eAb, always there but normally invisible below the sea of antigen, also can be present in considerable varying amounts. So it is the relative amount of the two that finally determines the e-seroconversion, and in your case I am pretty sure if you use the entecavir/tenofovir combo that you will fully seroconvert with time. The question is what to do then. Most hepatologists will want to continue for at least 6 month with the antivirals. If you had advanced fibrosis or cirrhosis the general recommendation by the expert panel would be to NEVER come off the antivirals, so that you do not risk a potentially deadly flare. You might reduce the combo to a mono at this time and watch carefully with a super sensitive test if the virus creeps up. I have developed a PCR test that can measure the HBV virus levels to well below one single copy per ml - it uses 10mls of serum for full work up and it is quantitative - hard to believe but true. But it is only for research purposes and uses a total of 90 individual PCRs for one single ultra low HBV VL determination. It will always find the virus, even the vast majority of "cleared acute HBV" patients have measurable levels with that assay. But there is also an HBV PCR assay that will catch down to 2 or 3 virions of HBV per mL., that one is commercially available.(NFI)
Whoa, will have to read that a few more times. My understanding is already enhanced.
Here are the questions that I've been avoiding to ask re: "BCP mutations are therefore, untreated, often leading to accelerated progression in liver damage, inflammation and fibrosis/cirrhosis, compared with patients having the wild type, ie no BCPs"
I read back then, a study on the BCP and they found that the incidents of HCC is much higher in those with BCP because the x-protein affects liver cell or DNA repair. Is it a direct relationship or is it because of the untreated risk of the BCP. What's your take on this?
I also read that in some antiviral studies, under antiviral pressure, the wild-type mutates to the BCP and once antiviral is stopped some BCP reverts back to wild-type. Any significant to these flip-flops, if they occur?
In my case, You think I may have a mix of the BCP and wild-type since I'm still eAg +? And what effects does BCP have on the common understand of e-seroconverting?
Here are the questions that I've been avoiding to ask re: "BCP mutations are therefore, untreated, often leading to accelerated progression in liver damage, inflammation and fibrosis/cirrhosis, compared with patients having the wild type, ie no BCPs"
I read back then, a study on the BCP and they found that the incidents of HCC is much higher in those with BCP because the x-protein affects liver cell or DNA repair. Is it a direct relationship or is it because of the untreated risk of the BCP. What's your take on this?
I also read that in some antiviral studies, under antiviral pressure, the wild-type mutates to the BCP and once antiviral is stopped some BCP reverts back to wild-type. Any significant to these flip-flops, if they occur?
In my case, You think I may have a mix of the BCP and wild-type since I'm still eAg +? And what effects does BCP have on the common understand of e-seroconverting?
MEDICAL PROFESSIONAL
Here is the HBV Polymerase that we can now block with our antivirals, as long as it does not succesful mutates: Note the huge size of this protein and that it overlaps most other proteins of HBV , just with a different genetic reading frame. the number on the right side are the amino acid numbers in the polymerase, the inner numbers the systematic position numbers of the nucleotides in the HBV DNA genome.
306 1 F H C L P P N S A G S Q S Q G S V S S C
326 61 W W L Q F R N S K P C S E Y C L S H L V
346 121 N L R E D W G P C D E H G E H H I R I P
366 181 R T P A R V T G G V F L V D K N P H N T
386 241 A E S R L V V D F S Q F S R G I S R V S
406 301 W P K F A V P N L Q S L T N L L S S N L
426 361 S W L S L D V S A A F Y H I P L H P A A
446 421 M P H L L I G S S G L S R Y V A R L S S
466 481 N S R I N N N Q Y G T M Q N L H D S C S
486 541 R Q L Y V S L M L L Y K T Y G W K L H L
506 601 Y S H P I V L G F R K I P M G V G L S P
526 661 F L L A Q F T S A I C S V V R R A F P H
546 721 C L A F S Y M D D V V L G A K S V Q H R
566 781 E S L Y T A V T N F L L S L G I H L N P
586 841 N K T K R W G Y S L N F M G Y I I G S W
606 901 G T L P Q D H I V Q K I K H C F R K L P
626 961 V N R P I D W K V C Q R I V G L L G F A
646 1021 A P F T Q C G Y P A L M P L Y A C I Q A
666 1081 K Q A F T F S P T Y K A F L S K Q Y M N
686 1141 L Y P V A R Q R P G L C Q V F A D A T P
706 1201 T G W G L A I G H Q R M R G T F V A P L
726 1261 P I H T A E L L A A C F A R S R S G A K
746 1321 L I G T D N S V V L S R K Y T S F P W L
766 1381 L G C T A N W I L R G T S F V Y V P S A
786 1441 L N P A D D P S R G R L G L S R P L L R
806 1501 L P F Q P T T G R T S L Y A V S P S V P
826 1561 S H L P V R V H F A S P L H V A W R P P
1621 end
1681 tgtcaacgac cgaccttgag gcctacttca aagactgtgt gtttaaggac tgggaggagc
1741 tgggggagga gattaggtta aaggtctttg tattaggagg ctgtaggcac aaattggtct
1801 gcgcaccagc accatgcaac tttttcacct ctgcctaatc atctcttgta catgtcccac
1861 tgttcaagcc tccaagctgt gccttgggtg gctttggggc atggacattg acccttataa
1921 agaatttgga gctactgtgg agttactctc gtttttgcct tctgacttct ttccttccgt
1981 cagagatctc ctagacaccg cctcagctct gtatcgagaa gccttagagt ctcctgagca
2041 ttgctcacct caccatactg cactcaggca agccattctc tgctgggggg aattgatgac
2101 tctagctacc tgggtgggta ataatttgga agatccagca tctagggatc ttgtagtaaa
2161 ttatgttaat actaacgtgg gtttaaagat caggcaacta ttgtggtttc atatatcttg
2221 ccttactttt ggaagagaga ctgtacttga atatttggtc tctttcggag tgtggattcg
2281 cactcctcca gcctatagac caccaa M P L S Y Q H F R K L
12 2341 L L L D D G T E A G P L E E E L P R L A D A
34 2401 D L H R R V A E D L N L G N L N V S I P
54 2461 W T H K V G N F T G L Y S S T V P I F N
74 2521 P E W Q T P S F P K I H L Q E D I I N R
94 2581 C Q Q F V G P L T V N E K R R L K L I M
114 2641 P A R F Y P T H T K Y L P L D K G I K P
134 2701 Y Y P D Q V V N H Y F Q T R H Y L H T L
154 2761 W K A G I L Y K R E T T R S A S F C G S
174 2821 P Y S W E Q E L Q H G R L V I K T S Q R
194 2881 H G D E S F C S Q S S G I L S R S S V G
214 2941 P C I R S Q L K Q S R L G L Q P R Q G R
234 3001 L A S S Q P S R S G S I R A K A H P S T
254 3061 R R Y F G V E P S G S G H I D H S V N N
274 3121 S S S C L H Q S A V R K A A Y S H L S T
294 3181 S K R Q S S S G H A V E VALENZUELA GenotypeA adw2
306 1 F H C L P P N S A G S Q S Q G S V S S C
326 61 W W L Q F R N S K P C S E Y C L S H L V
346 121 N L R E D W G P C D E H G E H H I R I P
366 181 R T P A R V T G G V F L V D K N P H N T
386 241 A E S R L V V D F S Q F S R G I S R V S
406 301 W P K F A V P N L Q S L T N L L S S N L
426 361 S W L S L D V S A A F Y H I P L H P A A
446 421 M P H L L I G S S G L S R Y V A R L S S
466 481 N S R I N N N Q Y G T M Q N L H D S C S
486 541 R Q L Y V S L M L L Y K T Y G W K L H L
506 601 Y S H P I V L G F R K I P M G V G L S P
526 661 F L L A Q F T S A I C S V V R R A F P H
546 721 C L A F S Y M D D V V L G A K S V Q H R
566 781 E S L Y T A V T N F L L S L G I H L N P
586 841 N K T K R W G Y S L N F M G Y I I G S W
606 901 G T L P Q D H I V Q K I K H C F R K L P
626 961 V N R P I D W K V C Q R I V G L L G F A
646 1021 A P F T Q C G Y P A L M P L Y A C I Q A
666 1081 K Q A F T F S P T Y K A F L S K Q Y M N
686 1141 L Y P V A R Q R P G L C Q V F A D A T P
706 1201 T G W G L A I G H Q R M R G T F V A P L
726 1261 P I H T A E L L A A C F A R S R S G A K
746 1321 L I G T D N S V V L S R K Y T S F P W L
766 1381 L G C T A N W I L R G T S F V Y V P S A
786 1441 L N P A D D P S R G R L G L S R P L L R
806 1501 L P F Q P T T G R T S L Y A V S P S V P
826 1561 S H L P V R V H F A S P L H V A W R P P
1621 end
1681 tgtcaacgac cgaccttgag gcctacttca aagactgtgt gtttaaggac tgggaggagc
1741 tgggggagga gattaggtta aaggtctttg tattaggagg ctgtaggcac aaattggtct
1801 gcgcaccagc accatgcaac tttttcacct ctgcctaatc atctcttgta catgtcccac
1861 tgttcaagcc tccaagctgt gccttgggtg gctttggggc atggacattg acccttataa
1921 agaatttgga gctactgtgg agttactctc gtttttgcct tctgacttct ttccttccgt
1981 cagagatctc ctagacaccg cctcagctct gtatcgagaa gccttagagt ctcctgagca
2041 ttgctcacct caccatactg cactcaggca agccattctc tgctgggggg aattgatgac
2101 tctagctacc tgggtgggta ataatttgga agatccagca tctagggatc ttgtagtaaa
2161 ttatgttaat actaacgtgg gtttaaagat caggcaacta ttgtggtttc atatatcttg
2221 ccttactttt ggaagagaga ctgtacttga atatttggtc tctttcggag tgtggattcg
2281 cactcctcca gcctatagac caccaa M P L S Y Q H F R K L
12 2341 L L L D D G T E A G P L E E E L P R L A D A
34 2401 D L H R R V A E D L N L G N L N V S I P
54 2461 W T H K V G N F T G L Y S S T V P I F N
74 2521 P E W Q T P S F P K I H L Q E D I I N R
94 2581 C Q Q F V G P L T V N E K R R L K L I M
114 2641 P A R F Y P T H T K Y L P L D K G I K P
134 2701 Y Y P D Q V V N H Y F Q T R H Y L H T L
154 2761 W K A G I L Y K R E T T R S A S F C G S
174 2821 P Y S W E Q E L Q H G R L V I K T S Q R
194 2881 H G D E S F C S Q S S G I L S R S S V G
214 2941 P C I R S Q L K Q S R L G L Q P R Q G R
234 3001 L A S S Q P S R S G S I R A K A H P S T
254 3061 R R Y F G V E P S G S G H I D H S V N N
274 3121 S S S C L H Q S A V R K A A Y S H L S T
294 3181 S K R Q S S S G H A V E VALENZUELA GenotypeA adw2
MEDICAL PROFESSIONAL
The previous page also shows the total "precore protein, not just the core protein. It is from its precore protein, that the eAntigen is modeled by further cutting/processing on both sides. Note that the aa numbers on the left start again with 8 .This means this is the number 8aa of the actual core protein, the amino acids before are part of the precore protein, that is processed into the soluble e-Antigen. So for the 18-27 epitope you have to start from the left#8 ,the sequence is:
F L P S D F F P S V : This is the majestic core class I epitope to which the 95% of acute HBV patient owe their recovery. Note this is written in single letter aa code.
F L P S D F F P S V : This is the majestic core class I epitope to which the 95% of acute HBV patient owe their recovery. Note this is written in single letter aa code.
MEDICAL PROFESSIONAL
Here is a smaple page from the HBV "Atlas " that I invented and use to show all of HBVs sequencs on one page, with transparent overlays. This particular page shows you the core amino acid sequences embedded into the genomic context, with the aa numbers on the left. So you can actually see the 18-27 epitope. You can also find your BCP mutation/ positions, if you look carefully.
1 ttccactgcc ttccaccaaa ctctgcagga tcccagagtc aggggtctgt atcttcctgc
61 tggtggctcc agttcaggaa cagtaaaccc tgctccgaat attgcctctc acatctcgtc
121 aatctccgcg aggactgggg accctgtgac gaacatggag aacatcacat caggattcct
181 aggacccctg ctcgtgttac aggcggggtt tttcttgttg acaagaatcc tcacaatacc
241 gcagagtcta gactcgtggt ggacttctct caattttcta gggggatctc ccgtgtgtct
301 tggccaaaat tcgcagtccc caatctccaa tcactcacca acctcctgtc ctccaatttg
361 tcctggttat cgctggatgt gtctgcggcg ttttatcata ttcctcttca tcctgctgct
421 atgcctcatc ttcttattgg ttcttctgga ttatcaaggt atgttgcccg tttgtcctct
481 aattccagga tcaacaacaa ccagtacggg accatgcaaa acctgcacga ctcctgctca
541 aggcaactct atgtttccct catgttgctg tacaaaacct acggatggaa attgcacctg
601 tattcccatc ccatcgtcct gggctttcgc aaaataccta tgggagtggg cctcagtccg
661 tttctcttgg ctcagtttac tagtgccatt tgttcagtgg ttcgtagggc tttcccccac
721 tgtttggctt tcagctatat ggatgatgtg gtattggggg ccaagtctgt acagcatcgt
781 gagtcccttt ataccgctgt taccaatttt cttttgtctt tgggtataca tttaaaccct
841 aacaaaacaa aaagatgggg ttattcccta aacttcatgg gctacataat tggaagttgg
901 ggaactttgc cacaggatca tattgtacaa aagatcaaac actgttttag aaaacttcct
961 gttaacaggc ctattgattg gaaagtatgt caaagaattg tgggtctttt gggctttgct
1021 gctccattta cacaatgtgg atatcctgcc ttaatgcctt tgtatgcatg tatacaagct
1081 aaacaggctt tcactttctc gccaacttac aaggcctttc taagtaaaca gtacatgaac
1141 ctttaccccg ttgctcggca acggcctggt ctgtgccaag tgtttgctga cgcaaccccc
1201 actggctggg gcttggccat aggccatcag cgcatgcgtg gaacctttgt ggctcctctg
1261 ccgatccata ctgcggaact cctagccgct tgttttgctc gcagccggtc tggagcaaag
1321 ctcatcggaa ctgacaattc tgtcgtcctc tcgcggaaat atacatcgtt tccatggctg
1381 ctaggctgta ctgccaactg gatccttcgc gggacgtcct ttgtttacgt cccgtcggcg
1441 ctgaatcccg cggacgaccc ctctcggggc cgcttgggac tctctcgtcc ccttctccgt
1501 ctgccgttcc agccgaccac ggggcgcacc tctctttacg cggtctcccc gtctgtgcct
1561 tctcatctgc cggtccgtgt gcacttcgct tcacctctgc acgttgcatg gagaccaccg
1621 tgaacgccca tcagatcctg cccaaggtct tacataagag gactcttgga ctcccagcaa
1681 tgtcaacgac cgaccttgag gcctacttca aagactgtgt gtttaaggac tgggaggagc
1741 tgggggagga gattaggtta aaggtctttg tattaggagg ctgtaggcac aaattggtct
1 1801 gcgcaccagc acc M Q L F H L C L I I S C T C P T
17 1861 V Q A S K L C L G W L W G M D I D P Y K #1
8 1921 E F G A T V E L L S F L P S D F F P S V
28 1981 R D L L D T A S A L Y R E A L E S P E H #2
48 2041 C S P H H T A L R Q A I L C W G E L M T #3
68 2101 L A T W V G N N L E D P A S R D L V V N
88 2161 Y V N T N V G L K I R Q L L W F H I S C
108 2221 L T F G R E T V L E Y L V S F G V W I R #4 #5
128 2281 T P P A Y R P P N A P I L S T L P E T T #6
148 2341 V V R R R D R G R S P R R R T P S P R R R R
168 2401 S P S P R R R R S Q S R E S Q C E NDtattcctt
2461 ggactcataa ggtgggaaac tttacggggc tttattcctc tacagtacct atctttaatc
2521 ctgaatggca aactccttcc tttcctaaga ttcatttaca agaggacatt attaataggt
2581 gtcaacaatt tgtgggccct ctcactgtaa atgaaaagag aagattgaaa ttaattatgc
2641 ctgctagatt ctatcctacc cacactaaat atttgccctt agacaaagga attaaacctt
2701 attatccaga tcaggtagtt aatcattact tccaaaccag acattattta catactcttt
2761 ggaaggctgg tattctatat aagcgggaaa ccacacgtag cgcatcattt tgcgggtcac
2821 catattcttg ggaacaagag ctacagcatg ggaggttggt catcaaaacc tcgcaaaggc
2881 atggggacga atctttctgt tcccaatcct ctgggattct ttcccgatca tcagttggac
2941 cctgcattcg gagccaactc aaacaatcca gattgggact tcaaccccgt caaggacgac
3001 tggccagcag ccaaccaagt aggagtggga gcattcgggc caaggctcac ccctccacac
3061 ggcggtattt tggggtggag ccctcaggct cagggcatat tgaccacagt gtcaacaatt
3121 cctcctcctg cctccaccaa tcggcagtca ggaaggcagc ctactcccat ctctccacct
3181 ctaagagaca gtcatcctca ggccatgcag tggaa VALENZUELA GenotypeA adw2
1 ttccactgcc ttccaccaaa ctctgcagga tcccagagtc aggggtctgt atcttcctgc
61 tggtggctcc agttcaggaa cagtaaaccc tgctccgaat attgcctctc acatctcgtc
121 aatctccgcg aggactgggg accctgtgac gaacatggag aacatcacat caggattcct
181 aggacccctg ctcgtgttac aggcggggtt tttcttgttg acaagaatcc tcacaatacc
241 gcagagtcta gactcgtggt ggacttctct caattttcta gggggatctc ccgtgtgtct
301 tggccaaaat tcgcagtccc caatctccaa tcactcacca acctcctgtc ctccaatttg
361 tcctggttat cgctggatgt gtctgcggcg ttttatcata ttcctcttca tcctgctgct
421 atgcctcatc ttcttattgg ttcttctgga ttatcaaggt atgttgcccg tttgtcctct
481 aattccagga tcaacaacaa ccagtacggg accatgcaaa acctgcacga ctcctgctca
541 aggcaactct atgtttccct catgttgctg tacaaaacct acggatggaa attgcacctg
601 tattcccatc ccatcgtcct gggctttcgc aaaataccta tgggagtggg cctcagtccg
661 tttctcttgg ctcagtttac tagtgccatt tgttcagtgg ttcgtagggc tttcccccac
721 tgtttggctt tcagctatat ggatgatgtg gtattggggg ccaagtctgt acagcatcgt
781 gagtcccttt ataccgctgt taccaatttt cttttgtctt tgggtataca tttaaaccct
841 aacaaaacaa aaagatgggg ttattcccta aacttcatgg gctacataat tggaagttgg
901 ggaactttgc cacaggatca tattgtacaa aagatcaaac actgttttag aaaacttcct
961 gttaacaggc ctattgattg gaaagtatgt caaagaattg tgggtctttt gggctttgct
1021 gctccattta cacaatgtgg atatcctgcc ttaatgcctt tgtatgcatg tatacaagct
1081 aaacaggctt tcactttctc gccaacttac aaggcctttc taagtaaaca gtacatgaac
1141 ctttaccccg ttgctcggca acggcctggt ctgtgccaag tgtttgctga cgcaaccccc
1201 actggctggg gcttggccat aggccatcag cgcatgcgtg gaacctttgt ggctcctctg
1261 ccgatccata ctgcggaact cctagccgct tgttttgctc gcagccggtc tggagcaaag
1321 ctcatcggaa ctgacaattc tgtcgtcctc tcgcggaaat atacatcgtt tccatggctg
1381 ctaggctgta ctgccaactg gatccttcgc gggacgtcct ttgtttacgt cccgtcggcg
1441 ctgaatcccg cggacgaccc ctctcggggc cgcttgggac tctctcgtcc ccttctccgt
1501 ctgccgttcc agccgaccac ggggcgcacc tctctttacg cggtctcccc gtctgtgcct
1561 tctcatctgc cggtccgtgt gcacttcgct tcacctctgc acgttgcatg gagaccaccg
1621 tgaacgccca tcagatcctg cccaaggtct tacataagag gactcttgga ctcccagcaa
1681 tgtcaacgac cgaccttgag gcctacttca aagactgtgt gtttaaggac tgggaggagc
1741 tgggggagga gattaggtta aaggtctttg tattaggagg ctgtaggcac aaattggtct
1 1801 gcgcaccagc acc M Q L F H L C L I I S C T C P T
17 1861 V Q A S K L C L G W L W G M D I D P Y K #1
8 1921 E F G A T V E L L S F L P S D F F P S V
28 1981 R D L L D T A S A L Y R E A L E S P E H #2
48 2041 C S P H H T A L R Q A I L C W G E L M T #3
68 2101 L A T W V G N N L E D P A S R D L V V N
88 2161 Y V N T N V G L K I R Q L L W F H I S C
108 2221 L T F G R E T V L E Y L V S F G V W I R #4 #5
128 2281 T P P A Y R P P N A P I L S T L P E T T #6
148 2341 V V R R R D R G R S P R R R T P S P R R R R
168 2401 S P S P R R R R S Q S R E S Q C E NDtattcctt
2461 ggactcataa ggtgggaaac tttacggggc tttattcctc tacagtacct atctttaatc
2521 ctgaatggca aactccttcc tttcctaaga ttcatttaca agaggacatt attaataggt
2581 gtcaacaatt tgtgggccct ctcactgtaa atgaaaagag aagattgaaa ttaattatgc
2641 ctgctagatt ctatcctacc cacactaaat atttgccctt agacaaagga attaaacctt
2701 attatccaga tcaggtagtt aatcattact tccaaaccag acattattta catactcttt
2761 ggaaggctgg tattctatat aagcgggaaa ccacacgtag cgcatcattt tgcgggtcac
2821 catattcttg ggaacaagag ctacagcatg ggaggttggt catcaaaacc tcgcaaaggc
2881 atggggacga atctttctgt tcccaatcct ctgggattct ttcccgatca tcagttggac
2941 cctgcattcg gagccaactc aaacaatcca gattgggact tcaaccccgt caaggacgac
3001 tggccagcag ccaaccaagt aggagtggga gcattcgggc caaggctcac ccctccacac
3061 ggcggtattt tggggtggag ccctcaggct cagggcatat tgaccacagt gtcaacaatt
3121 cctcctcctg cctccaccaa tcggcagtca ggaaggcagc ctactcccat ctctccacct
3181 ctaagagaca gtcatcctca ggccatgcag tggaa VALENZUELA GenotypeA adw2
MEDICAL PROFESSIONAL
Steven;
"18-27 cytotoxic epitope is very likely to be of no effect in your case, since the virus will have immune escape-mutated that epitope a long time ago", is this immune escape-mutation the same as the BCP? "
No it is not. It is the one class I (cytotoxic) epitope against the core that patients with the HLA2 (most common) MHCtype are able to present with high efficacy and that will bind to a high affinity T-cell receptor specific for it. It is the actual reason that most acute HBV clears, because it is so potent. All other core epitopes are of minor strength/antiviral efficiency. HBV has indeed eliminated, as much as it could, all "grippy"/ sticky epitopes from its core protein. This one (aa18-27)core it had a very hard time changing, since it has delicate core assembly functions in its aa sequence. But, over time, it still manages then to change one aa or the other, like the anchor (into the MHCgroove) aa in it, rendering it a weak epitope.
The Basic Core Promotor is a region in front of the e-antigen and core HBV DNA, that serves mainly as promotor region for the efficient expression/transcription of the e antigen. Its ( the BCPs) sequence is, due to the double reading frame of the HBV genome also part of the HBV X-protein. It so happens that the x-protein also contains an important antiviral epitope at the same place where the PCPmutations sit on the DNA.
The PCPmutations sharply reduce the expression of the e-Antigen AND eliminate this important X-epitope at the same time. Smart move again, on part of the virus to defend against immune attacks by smooth adaptive moves. You might want to read "Impact of Hepatitis B Virus Basic Core Promotor mutations on T cell response to an immunodominant Hbx-derived epitope" by Marie-Loise Michel, in Hepatology 2007;45:1199-1209. It talks exactly about your mutation A1762T/G1764A , which is by far the most common encountered, for the reasons above.
It must be made fundamentally clear, that HBV constantly tries to adapt itself against the attacks of the immune system just as it will adapt itself against chemicals/antivirals.
the BCP mutations are also a sign that there is immune pressure mounting against the core.But that immune pressure is often not sufficient to reduce the virus enough, so there is a constant enhanced battle. BCP mutations are therefore, untreated, often leading to accelerated progression in liver damage, inflammation and fibrosis/cirrhosis, compared with patients having the wild type, ie no BCPs.
"18-27 cytotoxic epitope is very likely to be of no effect in your case, since the virus will have immune escape-mutated that epitope a long time ago", is this immune escape-mutation the same as the BCP? "
No it is not. It is the one class I (cytotoxic) epitope against the core that patients with the HLA2 (most common) MHCtype are able to present with high efficacy and that will bind to a high affinity T-cell receptor specific for it. It is the actual reason that most acute HBV clears, because it is so potent. All other core epitopes are of minor strength/antiviral efficiency. HBV has indeed eliminated, as much as it could, all "grippy"/ sticky epitopes from its core protein. This one (aa18-27)core it had a very hard time changing, since it has delicate core assembly functions in its aa sequence. But, over time, it still manages then to change one aa or the other, like the anchor (into the MHCgroove) aa in it, rendering it a weak epitope.
The Basic Core Promotor is a region in front of the e-antigen and core HBV DNA, that serves mainly as promotor region for the efficient expression/transcription of the e antigen. Its ( the BCPs) sequence is, due to the double reading frame of the HBV genome also part of the HBV X-protein. It so happens that the x-protein also contains an important antiviral epitope at the same place where the PCPmutations sit on the DNA.
The PCPmutations sharply reduce the expression of the e-Antigen AND eliminate this important X-epitope at the same time. Smart move again, on part of the virus to defend against immune attacks by smooth adaptive moves. You might want to read "Impact of Hepatitis B Virus Basic Core Promotor mutations on T cell response to an immunodominant Hbx-derived epitope" by Marie-Loise Michel, in Hepatology 2007;45:1199-1209. It talks exactly about your mutation A1762T/G1764A , which is by far the most common encountered, for the reasons above.
It must be made fundamentally clear, that HBV constantly tries to adapt itself against the attacks of the immune system just as it will adapt itself against chemicals/antivirals.
the BCP mutations are also a sign that there is immune pressure mounting against the core.But that immune pressure is often not sufficient to reduce the virus enough, so there is a constant enhanced battle. BCP mutations are therefore, untreated, often leading to accelerated progression in liver damage, inflammation and fibrosis/cirrhosis, compared with patients having the wild type, ie no BCPs.
I read all your HepB posts, including the one to zellyf, and even some of the HepC posts. That is why I want to learn as much as I can to make informed decisions, that the one part that I have control over. Thanks for educating us all.
And without saying, your post are quite a read, can't wait for the chapter on BCP.
-Steven
And without saying, your post are quite a read, can't wait for the chapter on BCP.
-Steven
MEDICAL PROFESSIONAL
You wrote:
Under title HBV Genotype: No sequence data was obtained from codons 96-250 of the pol gene. The presence or absence of mutations at codons 169, 173, 180, 181, 184, 194, 202, 204, 207, 236, and 250 could not be determined. The genotype could not be determined.
Polymerase Mutations: Same as above, but with additional "Associated resistance is to be interpreted with caution.
As I suspected, they could not analyze the adefovir critical mutation sites codon 181 and 236. So we know nothing about them.
The Inno Lipa assay would have been better. But ok now you have no virus that can be analyzed. Sounds even better.
Steve:
And I don't quite understand the "functional effects of the eAg circulating on the anticore response are". Please explain"
HBV is a very smart molecular machine, the result of quintillion rounds of evolution. It has evolved two soluble antigens, the surface and the e-Antigen, to be able to persist in the population. Soluble means that these are, aside of the virions itself, proteins the virus produces inside the infected hepatocytes in very large quantities, orders of magnitude higher than the virion numbers, and releases them into the circulating blood, for the following virus protecting purposes:
1. The huge amount of surface antigen renders any attempt of the Bcell system to produce neutralizing antibodies against an established viral infection useless. Thus circulating virions cannot be coated and hindered from reinfection by covering the virion surface with antibodies.
2. The large amount of circulating surface antigen induces tolerance to all potential surface antigen protein Tcell epitopes, regardless of class, that are potentially present in the surface antigen protein. There are many of those, but with this mechanism the virus eliminates this defense system.
3. The surface antigen is frequently integrated/incorporated/translocated in the human genome of infected hepatocytes itself, often without the rest of the viral genome remaining. Now some of your hepatocytes produce just the surface antigen, no other viral protein. If the immune system attacks other viral proteins/aspects and eliminates almost al cells harboring the virus, these cells remain -AND STILL PRODUCE -surface antigen. This prevents the anti HbS to achieve functional titers against the minute remnants of true virus even after successful 99.9999% "clearance" in many cases, THUS REINFECTION is not hindered and the virus slowly grows back from minute remnants. This happens mostly in long standing infections. An ingenious idea.
4. THE E-ANTIGEN STORY:In evolution, the virus still had to deal with the problem, that the viral core ( in contrast to the surface antigen) is a very immunogenic structure, in particular when a partially denuded (dacaying peripheral virion) HBV virion shows the numerous spikes of its core particle to the dendritic cells. The resulting strong T cell response against core epitopes, with an army of sharp shooting well core epitope trained specific T cells entering and patroling the liver often leads to an early elimination of all virus containing hepatocytes.
So the worlwide HBV community ( of virions, in this case) called a board meeting and pondered a second invention, to prevent the effect. And the chief evolutionary designer had a radically ingenious idea: He said: "My dear fellow HBV virions, we have already invented the soluble surface antigen, to protect against neutralizing antibodies etc. We are still wiped out most of the time! Why not invent a second soluble antigen, by making a few changes to the core protein, that, instead of being spiky and large and core particle like appears just as a smooth innocent looking ball of a protein, that introduces tolerance just like all the autoantigens of our host? You know we can make a 1000 times more of these soluble antigens than our main precious virions.
And then he presented the details of his invention : " By just cutting off the ends of the core protein, it will not fold up in this spiky football, but instead curl up into relatively tiny smooth spheres, BUT it will have almost all of the darn epitopes of our real core protein right inside of it. Then we flood the peripheral immune system with it, all the possible core epitope reactive T cells will be pseudoactivated and destroyed by apoptosis, so only few of them will ever come to this liver, where we live and thrive and will attack us. And as an additional bonus, we will give it some extra immune calming features, that will deactivate the immune cells that have eaten it."
The HBV board was stunned with excitement and voted to release the necessary 50 trillion evolutionary rounds to build this new feature. So now we have the eAntigern pos hepatitis with all the protective effects that the eAg has against the anticore directed immunity- the one that still had the punch to work.
s you can see successful dealing with this ultra smart HBV devil requires the understanding and mastery of all its tricks and then some.
The practical management of an HBV patient depends, in current practice, very much on the advancement of his liver disease, similar as in HCV management. You should get a biopsy and/or at least a fibroscan and a fibrosure.
Current practice of HBV hepatitis is way suboptimal and does not consider the long term outcome of the disease, in particular after resistance has developed. This is in part due to the complexity of the individual presentation and the hesitance of the insurance companies to pay for antiviral therapies, particular combos. Also the potential toxicity of long term combos is not yet known in full, although it looks promising at this point.
I also assume you read my explanation to zellyf re the future development of HBV drugs.
We still need to cover the relevance of the BCP mutations in your case.
Under title HBV Genotype: No sequence data was obtained from codons 96-250 of the pol gene. The presence or absence of mutations at codons 169, 173, 180, 181, 184, 194, 202, 204, 207, 236, and 250 could not be determined. The genotype could not be determined.
Polymerase Mutations: Same as above, but with additional "Associated resistance is to be interpreted with caution.
As I suspected, they could not analyze the adefovir critical mutation sites codon 181 and 236. So we know nothing about them.
The Inno Lipa assay would have been better. But ok now you have no virus that can be analyzed. Sounds even better.
Steve:
And I don't quite understand the "functional effects of the eAg circulating on the anticore response are". Please explain"
HBV is a very smart molecular machine, the result of quintillion rounds of evolution. It has evolved two soluble antigens, the surface and the e-Antigen, to be able to persist in the population. Soluble means that these are, aside of the virions itself, proteins the virus produces inside the infected hepatocytes in very large quantities, orders of magnitude higher than the virion numbers, and releases them into the circulating blood, for the following virus protecting purposes:
1. The huge amount of surface antigen renders any attempt of the Bcell system to produce neutralizing antibodies against an established viral infection useless. Thus circulating virions cannot be coated and hindered from reinfection by covering the virion surface with antibodies.
2. The large amount of circulating surface antigen induces tolerance to all potential surface antigen protein Tcell epitopes, regardless of class, that are potentially present in the surface antigen protein. There are many of those, but with this mechanism the virus eliminates this defense system.
3. The surface antigen is frequently integrated/incorporated/translocated in the human genome of infected hepatocytes itself, often without the rest of the viral genome remaining. Now some of your hepatocytes produce just the surface antigen, no other viral protein. If the immune system attacks other viral proteins/aspects and eliminates almost al cells harboring the virus, these cells remain -AND STILL PRODUCE -surface antigen. This prevents the anti HbS to achieve functional titers against the minute remnants of true virus even after successful 99.9999% "clearance" in many cases, THUS REINFECTION is not hindered and the virus slowly grows back from minute remnants. This happens mostly in long standing infections. An ingenious idea.
4. THE E-ANTIGEN STORY:In evolution, the virus still had to deal with the problem, that the viral core ( in contrast to the surface antigen) is a very immunogenic structure, in particular when a partially denuded (dacaying peripheral virion) HBV virion shows the numerous spikes of its core particle to the dendritic cells. The resulting strong T cell response against core epitopes, with an army of sharp shooting well core epitope trained specific T cells entering and patroling the liver often leads to an early elimination of all virus containing hepatocytes.
So the worlwide HBV community ( of virions, in this case) called a board meeting and pondered a second invention, to prevent the effect. And the chief evolutionary designer had a radically ingenious idea: He said: "My dear fellow HBV virions, we have already invented the soluble surface antigen, to protect against neutralizing antibodies etc. We are still wiped out most of the time! Why not invent a second soluble antigen, by making a few changes to the core protein, that, instead of being spiky and large and core particle like appears just as a smooth innocent looking ball of a protein, that introduces tolerance just like all the autoantigens of our host? You know we can make a 1000 times more of these soluble antigens than our main precious virions.
And then he presented the details of his invention : " By just cutting off the ends of the core protein, it will not fold up in this spiky football, but instead curl up into relatively tiny smooth spheres, BUT it will have almost all of the darn epitopes of our real core protein right inside of it. Then we flood the peripheral immune system with it, all the possible core epitope reactive T cells will be pseudoactivated and destroyed by apoptosis, so only few of them will ever come to this liver, where we live and thrive and will attack us. And as an additional bonus, we will give it some extra immune calming features, that will deactivate the immune cells that have eaten it."
The HBV board was stunned with excitement and voted to release the necessary 50 trillion evolutionary rounds to build this new feature. So now we have the eAntigern pos hepatitis with all the protective effects that the eAg has against the anticore directed immunity- the one that still had the punch to work.
s you can see successful dealing with this ultra smart HBV devil requires the understanding and mastery of all its tricks and then some.
The practical management of an HBV patient depends, in current practice, very much on the advancement of his liver disease, similar as in HCV management. You should get a biopsy and/or at least a fibroscan and a fibrosure.
Current practice of HBV hepatitis is way suboptimal and does not consider the long term outcome of the disease, in particular after resistance has developed. This is in part due to the complexity of the individual presentation and the hesitance of the insurance companies to pay for antiviral therapies, particular combos. Also the potential toxicity of long term combos is not yet known in full, although it looks promising at this point.
I also assume you read my explanation to zellyf re the future development of HBV drugs.
We still need to cover the relevance of the BCP mutations in your case.
One more thing that I don't understand:
You wrote, "18-27 cytotoxic epitope is very likely to be of no effect in your case, since the virus will have immune escape-mutated that epitope a long time ago", is this immune escape-mutation the same as the BCP?
Should I ask my GI for specific test (ie, specific genotyping) to further clarify my situation?
You wrote, "18-27 cytotoxic epitope is very likely to be of no effect in your case, since the virus will have immune escape-mutated that epitope a long time ago", is this immune escape-mutation the same as the BCP?
Should I ask my GI for specific test (ie, specific genotyping) to further clarify my situation?
I should also mention that after the 10 months of Hepsera and the VL went up to about 4000 (from 1000), my GI re-did the HBV DNA again. The VL went back down to about 1000 and that was BEFROE I started Baraclude. In case this is important to issues relating to mutations.
THANK YOU so much for your time and explanation.
Most of what I learned was from reading you past post and from Hepb.org. I starting to read into the BCP mutations in reputable online research sites a while back, but decided to take a break, because what I read from various research article wasn't very good news. And because I don't have the chance to discuss the information with a knowlegeable person.
To answer some of your questions:
My GI is an Asian MD who treats a large HepB pt population and said to be in HepB research. I actually found him when the NY Times when he was interviewed about the HepB in the community. My PCP initially gave me a LAM prescirption. I insisted on consulting at least a GI. My GI said no to LAM and went with Hepsera. My GI didn't order a liver biopsy, just started me on treatment after reading my HepB related labs.
My initial viral load was 1250000 IU/mL ; 3942324 copies / mL. The reference range is <100 IU/mL ; <160 copies / mL respectively.
As for the genotyping, I don't know what method was used. It was performed by Quest Diagnostics. I got a copy of the result:
Under title HBV Genotype: No sequence data was obtained from codons 96-250 of the pol gene. The presence or absence of mutations at codons 169, 173, 180, 181, 184, 194, 202, 204, 207, 236, and 250 could not be determined. The genotype could not be determined.
Polymerase Mutations: Same as above, but with additional "Associated resistance is to be interpreted with caution.
Precore Mutation: Not detected
BCP Mutations: Detected A1762T, G1764A
And I don't quite understand the "functional effects of the eAg circulating on the anticore response are". Please explain.
I really appreciate your time. I chose this time to write after I have gather a still basic understand of this complex disease. I understand your explanations, but I did read your post 3 times. Not because I don't understand the words, but trying to really grasp the concepts.
I look forward to your additional feedback.
-Steven
Most of what I learned was from reading you past post and from Hepb.org. I starting to read into the BCP mutations in reputable online research sites a while back, but decided to take a break, because what I read from various research article wasn't very good news. And because I don't have the chance to discuss the information with a knowlegeable person.
To answer some of your questions:
My GI is an Asian MD who treats a large HepB pt population and said to be in HepB research. I actually found him when the NY Times when he was interviewed about the HepB in the community. My PCP initially gave me a LAM prescirption. I insisted on consulting at least a GI. My GI said no to LAM and went with Hepsera. My GI didn't order a liver biopsy, just started me on treatment after reading my HepB related labs.
My initial viral load was 1250000 IU/mL ; 3942324 copies / mL. The reference range is <100 IU/mL ; <160 copies / mL respectively.
As for the genotyping, I don't know what method was used. It was performed by Quest Diagnostics. I got a copy of the result:
Under title HBV Genotype: No sequence data was obtained from codons 96-250 of the pol gene. The presence or absence of mutations at codons 169, 173, 180, 181, 184, 194, 202, 204, 207, 236, and 250 could not be determined. The genotype could not be determined.
Polymerase Mutations: Same as above, but with additional "Associated resistance is to be interpreted with caution.
Precore Mutation: Not detected
BCP Mutations: Detected A1762T, G1764A
And I don't quite understand the "functional effects of the eAg circulating on the anticore response are". Please explain.
I really appreciate your time. I chose this time to write after I have gather a still basic understand of this complex disease. I understand your explanations, but I did read your post 3 times. Not because I don't understand the words, but trying to really grasp the concepts.
I look forward to your additional feedback.
-Steven
MEDICAL PROFESSIONAL
Your HBV history contains many important and complex aspects. When discussing HBV meds, i prefer to use generic names, so no company gets upset.
The untreated VL of 3Million is surprisingly low for an e Ag pos Asian. Are you certain of that VL and it was not some >than sign involved?
When you started treatment, Entecavir was already approved for HBV in the USA. Using Adefovir dipivoxil to start your treatment was unfortunately a mistake. Specifically, because the most potent and future standard drug against HBV, tenofovir, shares almost the same chemical structure with Adefovir, there is just one additional Methyl group added. This little methyl group meant the difference in renal toxicity that made tenofovir a blockbuster in HIV and now also coming up in HBV, while poor Adefovir was dying in HIV development and was schlepped to an underdosed ( because of the renal toxicity) semipale existence in HBV teatment.
Any beginning resistance to Adefovir ( which has about 30% breakthrough after 5 years of use, as you probably know) prepares for a future resistance to Tenofovir, becouse of its chemical similarity.
Why all the fuss about future resistance, when we have now Entecavir and you are UND?
You are in your 30ties and it is entirely possible that you can never let go of these HBV antivirals without the danger of reactiation of your hepatitis. You might need 45 years of antiviral treatment, with no resistance.That is a tough goal to achieve.
Your GI was wise to add the Entecavir at month 11. You need to be HBV UND with those standard tests, to prevent slow creeping up of resistant strains, always think of the long term future.
You wrote 'Genotyping was done", but not the result??
What was used to check for resistance mutations, sequencing or the Inno Lipa strips? What generation Inno Lipas?What resistance mutations, specifically against Adefovir was checked against?
You are aware that mutations are only detected if there is - depending on the methodology AND the VL at testing - a good percentage, like 10 to 30% of the quasispecies carrying the mutation. I am pointing at that, because resistance creeps up slowly, because originally most primary resistance mutations are substantially less fit than the wild type and also their degree of resistance is variable, thus a slow complex evolution is in reality happening. Thus beginning mutations might have been missed (re "no indicator of antiviral resistance")
At this point no IFN treatment seems warranted. But the Adefovir should be switched to tenofovir ASAP. You probably know that one tablet of tenofovir holds the same power than swallowing a full month/a complete bottle of hepsera, at one moment, with still less renal toxicity.
This will give you a chance to stably seroconvert the e-Ag. You are balancing on the border of "e- seroconversion" because there are still too many copies of cccDNA in your liver, producing too much eAntigen, so that the always existing e-Antibody cannot neutralize it.
The loss of e-Ag will allow your immune system to regain some effectiveness with your anticore/anti-e class I and classII T cell response. This will increase the immune mediated antiviral milieu ( cytotoxic and noncytotoxic T cell response that actually reaches and operates in your liver) , helping to stabilize the low or UND viral load, or better described the total amount of cccDNA that persists in your liver. You probably know that the critical 18-27 cytotoxic epitope is very likely to be of no effect in your case, since the virus will have immune escape-mutated that epitope a long time ago,.
In that context, to you have the sequencing results from the core region?
Always keep in mind that e-seroconversion achieved with antivirals is not as stable as one achieved naturally or under IFN therapy. This awareness will bear on the question, will you be able to let go of antiviral treatment after a while of such seroconversion, if it happens and appears then ( like with additional tenofovir) stable. Beware of a relapse into a high VL and with a severe bout of clinical hepatitis.
There is a zone in which both eAg and anti e are positive. There is an eqilibirum reaction between the antigen and the antibody and the resulting immunecomplexes. As long as the eAg is not fully removed by prevailing antibody ( in reality it is most often a reduction in eAg production, that makes the preexisting Ab now prevail) the qual eAg test is pos.
I assume you know what the functional effects of the eAg circulating on the anticore response are.
There is also some good news here: Your HBV genome does not contain the precore propensity mutation, so a good deal of eAg is produced in your infected hepatocytes ( hence the difficulty to suppress it even at DNA UND conditions) This means your hepatocytes will be recognizable by circulating cytoxic T-cell ( low vigor core class I epitopes left) since the cell surface classI core epitopes presented are mainly produced from the (proteolytically cleaved) eAg, that is produced in much higher numbers inside the hepatocyte and yields the same epitopes as the core protein as they are almost congruent proteins. This mechanism tends to stabilize the eAg seroconversion/viral supression state in such " healthy chronic carriers".
The surface antibody that you have is found in a decent percentage of chronic HBV and has no functional meaning since it is mostly direcrted against a different genotype or your surface antigen has mutated critical B-cell epitopes so the antibody cannot neutralize or form stable immune complexes. Long standing HBV disease has many immune manifestations of a complex quasispecies, this is one of them.
Was there ever a liver biopsy??
Let us discuss the meaning/ impact of the BCP mutations in your case after your response. Please also tell me as much as you already know abou this topic so that I do not unnecessarily repeat what you already know.
The untreated VL of 3Million is surprisingly low for an e Ag pos Asian. Are you certain of that VL and it was not some >than sign involved?
When you started treatment, Entecavir was already approved for HBV in the USA. Using Adefovir dipivoxil to start your treatment was unfortunately a mistake. Specifically, because the most potent and future standard drug against HBV, tenofovir, shares almost the same chemical structure with Adefovir, there is just one additional Methyl group added. This little methyl group meant the difference in renal toxicity that made tenofovir a blockbuster in HIV and now also coming up in HBV, while poor Adefovir was dying in HIV development and was schlepped to an underdosed ( because of the renal toxicity) semipale existence in HBV teatment.
Any beginning resistance to Adefovir ( which has about 30% breakthrough after 5 years of use, as you probably know) prepares for a future resistance to Tenofovir, becouse of its chemical similarity.
Why all the fuss about future resistance, when we have now Entecavir and you are UND?
You are in your 30ties and it is entirely possible that you can never let go of these HBV antivirals without the danger of reactiation of your hepatitis. You might need 45 years of antiviral treatment, with no resistance.That is a tough goal to achieve.
Your GI was wise to add the Entecavir at month 11. You need to be HBV UND with those standard tests, to prevent slow creeping up of resistant strains, always think of the long term future.
You wrote 'Genotyping was done", but not the result??
What was used to check for resistance mutations, sequencing or the Inno Lipa strips? What generation Inno Lipas?What resistance mutations, specifically against Adefovir was checked against?
You are aware that mutations are only detected if there is - depending on the methodology AND the VL at testing - a good percentage, like 10 to 30% of the quasispecies carrying the mutation. I am pointing at that, because resistance creeps up slowly, because originally most primary resistance mutations are substantially less fit than the wild type and also their degree of resistance is variable, thus a slow complex evolution is in reality happening. Thus beginning mutations might have been missed (re "no indicator of antiviral resistance")
At this point no IFN treatment seems warranted. But the Adefovir should be switched to tenofovir ASAP. You probably know that one tablet of tenofovir holds the same power than swallowing a full month/a complete bottle of hepsera, at one moment, with still less renal toxicity.
This will give you a chance to stably seroconvert the e-Ag. You are balancing on the border of "e- seroconversion" because there are still too many copies of cccDNA in your liver, producing too much eAntigen, so that the always existing e-Antibody cannot neutralize it.
The loss of e-Ag will allow your immune system to regain some effectiveness with your anticore/anti-e class I and classII T cell response. This will increase the immune mediated antiviral milieu ( cytotoxic and noncytotoxic T cell response that actually reaches and operates in your liver) , helping to stabilize the low or UND viral load, or better described the total amount of cccDNA that persists in your liver. You probably know that the critical 18-27 cytotoxic epitope is very likely to be of no effect in your case, since the virus will have immune escape-mutated that epitope a long time ago,.
In that context, to you have the sequencing results from the core region?
Always keep in mind that e-seroconversion achieved with antivirals is not as stable as one achieved naturally or under IFN therapy. This awareness will bear on the question, will you be able to let go of antiviral treatment after a while of such seroconversion, if it happens and appears then ( like with additional tenofovir) stable. Beware of a relapse into a high VL and with a severe bout of clinical hepatitis.
There is a zone in which both eAg and anti e are positive. There is an eqilibirum reaction between the antigen and the antibody and the resulting immunecomplexes. As long as the eAg is not fully removed by prevailing antibody ( in reality it is most often a reduction in eAg production, that makes the preexisting Ab now prevail) the qual eAg test is pos.
I assume you know what the functional effects of the eAg circulating on the anticore response are.
There is also some good news here: Your HBV genome does not contain the precore propensity mutation, so a good deal of eAg is produced in your infected hepatocytes ( hence the difficulty to suppress it even at DNA UND conditions) This means your hepatocytes will be recognizable by circulating cytoxic T-cell ( low vigor core class I epitopes left) since the cell surface classI core epitopes presented are mainly produced from the (proteolytically cleaved) eAg, that is produced in much higher numbers inside the hepatocyte and yields the same epitopes as the core protein as they are almost congruent proteins. This mechanism tends to stabilize the eAg seroconversion/viral supression state in such " healthy chronic carriers".
The surface antibody that you have is found in a decent percentage of chronic HBV and has no functional meaning since it is mostly direcrted against a different genotype or your surface antigen has mutated critical B-cell epitopes so the antibody cannot neutralize or form stable immune complexes. Long standing HBV disease has many immune manifestations of a complex quasispecies, this is one of them.
Was there ever a liver biopsy??
Let us discuss the meaning/ impact of the BCP mutations in your case after your response. Please also tell me as much as you already know abou this topic so that I do not unnecessarily repeat what you already know.
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