hbsag quant in etv mono and etv+tdf

[stef2011]

http://viral-hep.org/images_content/O224%20Griffin.pdf

Quantification of HBsAg in
nucleos(t)ide-naïve patients treated for
chronic hepatitis B (CHB) with entecavir
(ETV) monotherapy or ETV plus tenofovir
(TDF) in the BE-LOW study

[4est]

I read and agree that reduction of the vitrion effect will be translated into a low intensity of hepatitis / fibrosis.
And yes, my question was that if the people with low vl will start nucs treatment will be a chance that the surface antigen to be different (to have a bigger decrease) then the one presented in the article.  

I suspect that the decrees of the surface antigen is do to the immune response and not directly related to the nucs. Taking nucs will reduce the pressure putit on the immune sistem and alow to the immune sistem to react over the surface antigen. Supposing that the people with low vl and no nucshas a better immune resonse I will expect that going to nucs will reduce the pressure under immune system and alow him to go against surface antigen.
So base on this mechanism and supposition I will expect a bigger decrees in surface antigen if the treatment will be in people with vl, but on the other hand I don't know if this will be a real gain in the end.

[studyforhope]

Are you asking if the nucs single or in combo will increase the immune response in already low vl patients?
As the surface antigen curves show, there is little effect of antiviral treatments on the surface antigen level, thus no real increase in immune control can be seen here. The reduction in viral load decreases the stimulatory effect of virions as i explained elsewhere which reduces the intensity of hepatitis and fibrogenesis.

[4est]

will this result apply also to the people that had the infection under control by the immune response?
Most of the HBe negative people had a very low viral load (<2000 UI), so adding a NUC or a NUC Combo will some how help to increase the immune response in term of effects.  

[StephenCastlecrag]

As I said before, your points are fair. Following through your reasoning, even Tenofovir or combo are at risk of developing resistance over a long period of time. I agree most of us are often guilty of oversimplification and even errors when representing research findings. That is why an open forum is valuable as others can always point out the errors or disagree. In the case of Professor Lok's paper, the review quoted directly from the paper and public press statements:

"At week 96, both treatment arms (entecavir monotherapy and entecavir + [tenofovir] combination therapy) showed comparable antiviral efficacy in a mixed population (70% HBeAg positive) of nucleoside analog-naive chronic hepatitis B patients," the researchers concluded. "Both treatments were well tolerated with comparable safety profiles."

However, they added, the combination of entecavir plus tenofovir "may provide incremental benefit in HBeAg positive patients with baseline viral load ≥ 108 IU/mL."

"In these 96-week data comparing entecavir monotherapy to combination of entecavir plus tenofovir, we found that combination therapy did not result in statistically significant difference in virologic response compared to entecavir monotherapy," Lok said in a press release issued by entecavir manufacturer Bristol-Myers Squibb. "The BE-LOW study data confirmed the results of previous studies showing limited or no benefit of combination therapy compared to monotherapy for treatment-naive patients with chronic hepatitis B."

As for the explanation for the low % of ETV drug resistance, I would not have a clue. I copy the following from a paper by Zoulim:
Typically, the development of NA resistance depends on six factors [14, 15]: (i) magnitude and rate of virus replication; (ii) fidelity of the viral polymerase; (iii) selective pressure exerted by the NA (potency); (iv) amount of available replication space in the liver; (v) replication fitness of the emerging NA resistant HBV; and (vi) genetic barrier to resistance of the NA.

[studyforhope]

The effects on surface antigen levels were very small, no matter which drug was used. this is of course the really sad point, the equilibrium between infected cell elimination and de novo reinfection is just minimally sifted downwards with the use of antivirals.

But the potential long term resistance protection by initial combo use is no small issue to patients that indeed develop late resistance by the slow accumulation of additional fitness loss compensating mutations.

If resistance can still develop at a hugely reduced viral synthesis rate like in the und status for Entecavir long term is not entirely clear, but the statistical chance for this to happen is obviously extremely low. Thus we have to ask ourself the question if the observed low% Entecavir patients resistance after 5years was seeded in the initial ramp down phase or was the mutants grandfather already present in the cccDNA pool at the start of therapy.

[studyforhope]

It takes many years to evaluate resistance development in low resistance prone drug as we know from adefovir and now Entecavir.Thus the study design was unable to test the question of mutant protection with the combo.

The viral breakthrough reported resulted from patient compliance issues.

The conference reporters tend to oversimplify things. I personally was present at Ana Loks presentation of this data and she mentioned that in the subgroup analysis the group with the highest starting viral loads had a better response with the combo. Pooling all the data diminished that advantage by dilution.

[StephenCastlecrag]

You were right, BMS did sponsor the trial, but it was an international effort and the list of researchers is quite impressive. If you look at all the HbsAg curves from the slideset, the differences are small. Does it matter long term if viral loads were the same for both arms at the end of the 3 year period?

[stef2011]

too little time and poor sensitivity tests to detect the difference between etv or etv+tdf, plus tdf mono arm missing.to me it is just marketing pro etv infact etv producer paid for the trial

to see the difference at least very long time trial, ultra deep sequence and cccdna quant tests were needed, without these tests i dont think you can really see any valuable difference

[StephenCastlecrag]

You have a very fair point. Indeed, I believe the BELOW study was undertaken partly to test your point:
"Anna Lok and fellow investigators with the international BE-LOW study evaluated whether combination therapy with entecavir plus tenofovir would have additive antiviral activity or prevent resistance better than entecavir alone.".
Liz Highleyman from hivandhepatitis.com further reported:

HBeAg seroconversion was also less likely in the entecavir/tenofovir arm (22% vs 33%).
Virological breakthrough occurred in 4% of entecavir/tenofovir recipients and 1% of entecavir monotherapy recipients.
However, no entecavir or tenofovir drug resistance mutations were detected in either arm

Maybe Potent A + Potent B is not twice the potency and barrier to resistance. I don't know.

[studyforhope]

When the starting viral load is in the billions, then during the antiviral therapy trillions of de novo virions are formed until the viral load is down to low numbers or undo. Each of these trillion viruses could carry one or multiple mutations that would later make it at least more prone to develop additional compensatory mutations, like for Entecavir. If, during the high vl treatment phase a second drug that has no cross resistance is present, then the mutant has no chance to thrive. Once the vl is low or undo the risk of de novo mutations is dramatically lower and a single drug can be safely used. Thus the use of the combo initially is less to increase the response rate but rather to protect against primary mutations that could pop up years later with compensatory mutations, as it has been seen with Entecavir. It's a bit of a roulette game, but why would you not play it safe while it is available?

[StephenCastlecrag]

I see no evidence or recommendation for first line or first time treatment to use combo. Certainly another drug was added to an existing drug after development of resistance to the first drug. Almost all guidelines would recommend  the use of a single drug with high potency and high genetic barrier to resistance. The cupboard of such drugs is pretty bare. Either the two existing such drugs are meeting all the needs or nothing better than them has been "discovered", I don't know. Some doctors are talking already of a "functional" cure being here, but I think all of us would want a safety net, and a real cure.

[imran4535]

Per HepatitisResearcher's posts a few years ago. It would be wise to combo in the beginning to reduce the chance of a mutation because it would provide a good barrier to resistance.  He also mentioned that in the future combos might be needed for everyone for long term success in case mutations come up with ETV or TDF.

I'm going to look for his post so I can ACCURATELY quote him. Another interesting thing he mentioned was that as far as antivirals go whatever was brought to market by 2009 was pretty much it.

[StephenCastlecrag]

This is the often-cited research by Professor Anna Lok el al that concluded TNF + ETV is not superior to ETV, except perhaps in patients with very high viral load.

[studyforhope]

An extremely useful and clear research presentation that should clarify for many what to expect in terms of long term treatment in regard to surface antigen levels and amount of infected cells in the liver.
It also shows again the slight but noticeable advantage of starting treatment with a combo, that can later be followed by mono therapy.

Unfortunately the overall picture is not very encouraging in terms of loosing the infection. It is a rare event, the virus is stably entrenched in the liver and whatever amount of cells are cleared at any day are replaced by reinfection at the same rate, even in the presence of the combined most powerful antivirals. It confirms again, that the undetectable DNA status in the peripheral blood does not mean a complete stop of de novo virion production, just a strong reduction, leaving enough virions to reinfect locally.

But the immunstimulation by the high virion production is dramatically reduced and that means less inflammation in the liver and less or no fibrosis formation. Thus the liver disease is under full control in most patients. And that is in itself a great achievement.