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Is viral breakthrough during treatment unusual?
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Is viral breakthrough during treatment unusual?

Does anyone know the answer to this?  I'd like to know if there are any studies on this and/or anyone's perception of how often this happens. I've read of it happening to a few posters on this board but, for the most part, don't know a lot about it.  

Thanks in advance for any info or ideas anyone can provide.
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Avatar_n_tn
what do you mean?
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131817_tn?1209532911
I think a viral breakthough is rare, but not unheard of. I have heard a least one member had a viral breakthrough...
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131817_tn?1209532911
Viral breakthrough is when you are UND and you get a positive result from PCR after UND.
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Avatar_n_tn
sorry whats und and pcr?
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Avatar_n_tn
Thanks for replying.  It's my perception too that it's rare.  I just wanted to know if others thought that as well.

Nitramog, und means undedected and pcr is the viral load test
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Avatar_n_tn
I had what was called a viral break through although I don't know if that was what it really was. I was und at week 12 but around week 22 the virus was back kept treating for 8 more weeks to see if i could get back to und but didn't. Not clear if that really would  be considered a break through. From what I understand my count could have just been und at the time i tested.
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Avatar_n_tn
If you were und at wk 12 and it was back at 22, I thought that was the definition of a viral breakthrough?  No?
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151263_tn?1243377877
You ain't gonna have a viral breakthrough, you're a VX baby who's on full riba and peg now!! It's in the bag man, relax!! lol

Just kidding, but I do think your odds are unprecendently good...is unprecedently a word? Maybe I should ask George, he's the decider on these matters. ;-) Hope you're doing good char, hang in there.

Oh yeah did you see what APK said about what his study nurse said? He's definitely getting the 20 week unblinding including VL results, which is what I was told in the beginning as well. Gonna raise hell on this one and demand to get what we were promised in the beginning. I want those VL's as promised, and aren't waiting another month to get them.
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131817_tn?1209532911
My understanding is someone who does not get to UND at any point in tx is a non responder or slow responder. Someone who has had an UND at 12 and 24 and then has a VL then has a viral breakthrough.
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148987_tn?1287809526
My doc tells me he considers any increase in VL during treatment a breakthrough, not just post PCR.
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Avatar_m_tn
I wanted to ask a similar question. See:
http://www.natap.org/2006/AASLD/AASLD_32.htm

* All patients had undetectable HCV RNA at 24 weeks of therapy.
* The end-of-treatment response rates were significantly higher in the 72-week group compared to those in the 48-week group (54% vs 33%).
* Overall, the rate of SVR was superior in patients treated for 72 weeks vs 48 weeks (39% vs 18%)

So 100% UND at 24 wk, but ONLY 33% UND at 48 wk (!?)
Does it mean that 67% had viral breakthrough during treatment between 24 and 48 wk?
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Avatar_f_tn
I don't know how rare it is.   I thought viral breakthrough was any increase in the viral activity  (viral load) at any time during treatment.  I've always thought that to lower the incidence of "viral breakthrough" was the goal of therapy and future therapies (and that that was the reason VX-950 needs help with Peg/Rib). Wasn't it the addition of Ribavirin that helped reduced the incidence of viral breakthrough and that without Ribavirin there is "breakthrough"?  
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Avatar_n_tn
yes i think you are right except it is not clear if i was really und. the virus level goes on swings up and down and it could have been at a very low level when tested at week 12 which would have read as und.
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Avatar_m_tn
In the VX case, the pathway gets the VX molecule locked onto the viron during replication. Virus with the VX inhibitor cannot replicate [or so the theory goes]. VX is a finely pointed spear.

If/when mutations lead to virons that are resistant to the VX molecule, the Inf and Riba are there to sweep them up. Seems that the current expectation is that VX will need to be given in a combo with Inf and maybe Riba to provide the broad sweep up of mutations.

The Prove 2 trial is without Riba. If that shows strong results, then maybe a combo VX & Inf is possible. Its conjecture until the data is available, but a combo without Riba would be a life changer for many treaters.
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131817_tn?1209532911
Does anyone see my post above? I posted a while ago and I see my name, but not the post. Weird?

I guess I will say it again...My understanding is that if you have an UND at say 12 weeks, and 24 weeks and then a positive VL at 36 weeks you have had a viral breakthough. When you never have an UND you are a non responder.
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Avatar_f_tn
Thanks APK.  Yeah that's it!  In a nutshell, or at least how I've understood it (just couldn't remember how to say all of that :)  And on the polymerase end (the poly inhibitors like HCV 796), I think I'm understanding it's doing somewhat the same thing as the protease inhibitors (VX) except it's interfering with the polyermase ...something or another...with the replication, and ... (I'll leave it at that since beyond that point it's too easy to tell I flunked molecular science.)  But yeah, that's it!  Thanks for the explanation.  

I'd read where there is no riba being given in the study (or in some arms) but I've not understood all the arms or the SOC.  I hope you're fortunate enough to be taking no riba at this point! I knew they were projecting the possible exclusion of Riba, which would be fantastic indeed since it's the riba that seems to be so bad for some.

lol sfbgirl. You aren't dreaming or hallucinating, or - if you are - I am too.  I see notes, and then I don't, or I don't see them and suddenly I do. I think it might have something to do with cookies, but I flunked computer too.  I think we should just eat chocolate chip cookies. Yeah :)  

But what you said about UND and no response, yeah - that's what I understand about it, too.
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131817_tn?1209532911
LOL It's you. The post is NOT there!!! It wasn't...I kept looking and going to another thread and looking again. Then I closed down my browser and restarted and viola there it was.
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131817_tn?1209532911
What's interesting in this study by Perlman, is that they used difficult to treat geno 1's, African Americans, High fibrosis, etc. They all were given weight based Ribavarin, unlike Berg (800). But it is a small study and needs to have a larger group. Quite a big difference in SVR rates with extending to 72 weeks.
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Avatar_m_tn
Berg is referred to in the posted study in part here. I'd love to say I fully understand why the rates are different...maybe after I eat some dinner :) In any event, you often have to spend time with the full-text studies to make full sense of them.
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"...Patients who achieved an EVR with HCV RNA levels <50 IU/mL at week 12 achieved an excellent rate of SVR (80%) with a standard duration of therapy of 48 weeks. This response rate was identical to the response achieved in the Berg study,[9] which showed that a 48-week duration of treatment with peginterferon alfa-2a (40KD) and only 800 mg ribavirin resulted in an SVR rate of 80% in patients with HCV genotype 1 and HCV RNA <50 IU/mL at week 12. The data from the analysis presented here is also consistent with data from an earlier analysis[5] of the phase III study published by Fried et al.,[3] which shows that patients treated with 48 weeks of peginterferon alfa-2a (40KD) plus ribavirin 1000/1200 mg who achieved HCV RNA suppression <50 IU/mL had an SVR rate of 78%.

In contrast, in a subgroup of patients who had an EVR but who had incomplete viral suppression (HCV RNA 350 IU/mL) at week 12, a longer treatment duration of 72 weeks was significantly (p<0.001) beneficial compared with the standard 48-week treatment duration (SVR rates of 37% vs 77%, respectively). These data are consistent with the recently published data by Berg et al,[9] indicating that patients with HCV RNA 350 IU/mL at week 12 benefited from a 24-week treatment extension. In the Berg study, SVR rates of 29% were achieved with 72 weeks of therapy with peginterferon alfa-2a plus ribavirin, compared with 17% achieved with 48 weeks of therapy (p=0.040), in patients who were HCV RNA positive at week 12. It should be noted that the findings of Berg et al. are for the intent-to-treat patient population, while our results refer only to those patients in the per-protocol population with an end-of-treatment response. Patients who do not achieve an EVR are unlikely to respond even with 72 weeks of treatment, which confirms the established EVR-based guidelines..."

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131817_tn?1209532911
Could this be because they were detectable at week 12? This is why the odds are so much better for 72 weeks. Who wrote this?
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Avatar_n_tn
Think what it is they talk of end of TX response rates meaning six months post Tx for the 72 week group  that is 56% SVR 28% relapse +15% discontinued = 99% inferring one breakthrough.Although I must say the entire study is as clear as mud.
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Avatar_m_tn
sfbaygirl, it's from the last AASLD.
http://www.natap.org/2006/AASLD/AASLD_32.htm
http://www.hivandhepatitis.com/2006icr/aasld/docs/110306_f.html

Yes, all of them were slow responders. But all of them were UND at  24 weeks. Then they were full-time on TX in the next 24 weeks. So how is it possible that WHILE on TX, 67% become dectable again?

CitizenSmith, interesting suggestion that 'end of TX' my mean '6 months post TX'. But in all the research I read (and it is a lot) 'end-of-treatment' means exactly as it sounds: the time when you stop taking the treatment drugs. On the other hand, '6 months post TX' is the accepted time period for claiming SVR.

And I agree that this paper is as clear as mud.
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131817_tn?1209532911
I think this is a similar study to BERG. It shows that extending tx to 72 weeks improves chances of SVR in slow responders. I haven't read the whole thing yet, but I know that depending on when how low your VL >6000 by 12 weeks, you have a good chance of SVR within the numbers you stated. 57% at 72 weeks and 32% at 48 weeks. I believe BERG says it's about a 25% increase going 72 weeks. I am grappling with this right now ;(
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131817_tn?1209532911
That second paragraph seems to be confused... The Perlman study above in Valtods post, has different numbers than this one, but are hard to tx... A 40% difference from 37% to 77% makes it really a no brainer to me...YUCK, but good to know. Of course ins. co's aren't up on these studies and neither are most dr's.
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Avatar_m_tn
Here's the link to the abstract I took the quote from:

http://www.natap.org/2006/AASLD/AASLD_34.htm

I got a little lost on the "intent to treat" versus the "per protocol" populations but am too tired to pursue it. Seemed like a big difference from the Berg figures but apparently it's explained for those that can understand. What wasn't said in the abstract however, is that my understanding is that Berg used 800 mg fixed dose riba while here they used weight based (1000 or 1200mg). Often these studies a little better written than a confusing lawyer's brief. Hopefully, the doctors know what the study authors intend to say, but my guess is that a lot don't.

-- Jim
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131817_tn?1209532911
Believe me I read thousands of pages of lawyers briefs and some lawyers write just as confusing as some dr's. sometimes I wonder if they are trying to impress someone with their confusion...

Yeah, I got confused on that point too. One of the studies Valtod posted mentions Berg giving 800 Riba versus their weight based. All this is still hard to take in as far as my decisions.
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Avatar_f_tn
that is what happened to me when reading these studies. like the german and italian short tx studies, the numbers did not make sense.  Somewhere from one page to the other, they seemed to loose some subjects(they did not state any stats for them after the first page)  and no one thought it important.  Some of these studies the numbers don' t add up.
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Avatar_m_tn
So does anyone else see something fundamentally wrong with the AASLD research I quoted above?

You have a group of patients ALL undetectable at 24 week. But then 67%(!) of them become detectable at week 48. How is this possible?! Mass viral breakthrough?

Or am I reading the research wrong?
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Avatar_m_tn
I think it's just bad writing perpetuated by a system that doesn't penalize it. One day they should do a study on how good (or bad) doctors interpret studies. I think the results would be disturbing.
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131817_tn?1209532911
Oh, I know I am already disturbed by the way my doc read my 10 week PCR as UND. Now I don't know... I think some writers write in a confused way possibly because they themselves don't understand what they are writing.
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Avatar_dr_m_tn
"Intent to treat" analysis is one in which you include everyone who started treatment, but stopped, disappeared etc.  

"Per protocol" analysis includes only such patients which followed the protocol all the way through...
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131817_tn?1209532911
Thanks HR! I never would have guessed that Intent to treat would mean people that stopped tx. Good to have someone around that knows the lingo.
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Avatar_m_tn
The "Berg" figures get tossed around a lot, but seemingly not that relevant for those of us who actually follow protocol. Also, the fact that Berg used fixed dose riba (800 mg) seems to get lost when we compare out own treatment response which in almost all cases is weight-based riba for geno 1's. Again, careful reading and analysis of the studies seems to be very key. Thanks for putting at least this aspect into perspective.

-- Jim
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Avatar_m_tn
Would following protocol be as specific as full dose compliance, i.e. no dose reductions, or do they have some leeway here. The first question my consulting hep doctor asked was what dose of riba was I taking, any riba reductions and any missed shots. Obviously, he was heavily factoring in compliance before he suggested how long to treat and what my chances of SVR were.
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131817_tn?1209532911
Yep, if I'm out the big bucks to go to the appt. I might as well spend a few extras and get all the studies. I have Berg. Saved me a few dimes from Friole...LOL  

Yes, I do understand what you are saying about the intent to treat  skewing down the SVR rates, except wouldn't they skew them upwards if these were included? Maybe, I'll have to read that Pearlman study again...maybe I mixed that up. Hey, you didn't answer me about what you would do. Don't want to put you on the spot and I promise I won't follow you like the pied piper...just like some different points of view. Those studies sure do seem like a no brainer though....Even John is wrapping his head around this one.
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131817_tn?1209532911
Do you think this Perlman et al. study is more important for those  of us that do weight based Riba and are hard to tx? Granted it is a small study...
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Avatar_m_tn
Not sure which is the "Pearlman" study, but if Berg uses fixed dose riba (800mg) I don't think the results translates to those of us who do weight-based riba. Before making any tx decisions, always best to order the full-text version of a study and go over with your doctor. Besides understanding the study, harder still is to put the study in a context to make tx decisions. I find the Clinical Options -- and similar sites -- helpful in this regard as the studies are filtered through some very good clinicians such as Dieterich, Jensen and others.

-- Jim
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131817_tn?1209532911
The Pearlman study is the one posted by Valtod from the AASLD. It talks about weight based Riba, high risk groups and good pecentages of SVR for 72 weeks. Would you extend to 72 weeks with a kp? 6.1? I got an appt. with Goof's doc for the 18th of Dec. I am happy about this! I want to make a decision based on several opinions, including those of you who have extended. Thanks!
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Avatar_m_tn
I know you don't like spending the big bucks LOL but since you asked...

If it were me, I'd order up full-text for the Pearlman study you mentioned, the Ferenci study I linked to in the same post, and maybe Berg and the Tapias study Dr. J discussed with NY girl.

If you want to save some money :) then maybe just print out the abstracts for Berg and Tapias which I believe are older.  

Then, I'd study them up as best you can with special attention to how your viral response matches the study definiton of viral response -- then bring them all with you to Goofy's doctor -- he has a good reputation (the doctor not goofy :) -- and he should be familiar with all the studies and hopefully will be able to put them in proper context per your own individual stats and treatment response.

I'd be  curious on the doctor's take on the Berg statistics in light of both the fixed-dose riba as well as their "intent to treat" data which should skew down the SVR data.  

Hope this makes sense.

Jim
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Avatar_n_tn
Viral breakthrough isn't all that unusual.  If you're talking about HCV, the treatment is only about 50% effective to eliminate the virus to the point of a SVR.  All those who are on the bad side of the 50% either 1) didn't respond at all, 2) responded but slowly and removed from treatment or 3) were UND at some point but the virus came back.  UND just means that the viral level is below the detection limit of the test - it doesn't mean that the virus is gone.
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Avatar_m_tn
If you want to re-cap your pre-tx stats (age, weight, geno, vl, enzymes, how long you had the virus, an acute phase or not, biopsy results, rescue drugs, tx side effects and how you're handling them, etc) plus tx history incld vl tests, dosages, hemoglobin reaction, etc. and then re-link all four studies in one thread, I'll give it an uneducated shot like I did with my own stats when I treated. But as mentioned before, the key is sitting down with a hepatologist you have confidence in who can put the academics in a clinical perspective.

That said, when it came time for me to make a decison regarding tx length, I presented my doc with the Drusano data but he urged me to treat 48 weeks beyond non-detctible  verus 36 per Drusano -- based on my age (58) and histology (stage 3). Of course both my NP and another two consultants thought 36 weeks would be fine for 48 weeks total. (I ended adding 48 weeks for 54 total and now wonder based on more recent studies if 24 weeks would have been sufficient based on my RVR).  So much for clarity in these decisions :)

-- Jim
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