Anyone Got A "Typical" Viral Load Drop Graph?

[RobertBeWell]

I sat down with the research doctor today at my study visit, because I wanted to discuss with him his feelings on whether or not I should continue on. Though he couldn't come right out and say it, he absolutely didn't disagree when I told him that based on my results, I was not getting the study drug.

Anyhow... he told me that as time goes on, and the viral load drops, the remaining virus are "harder" to kill, because they are "tougher". In other words, in patients that respond to treatment, they usually expect to see large viral drops initially, followed by progressively smaller and smaller drops until UND.

I was a bit skeptical, but I didn't let on because I didn't want to insult the man, as he's pretty respected in his field as a researcher.

How can one virion be any harder to kill than another.

Anyone got a link to a graph of a "typical" viral load drop in a "good response" scenario?

Thanks

RBW

[exaddict24]

Hi Bali05, I am exaddict24. i am now on my 42 weeks of treatment. The last Vl load test is done on my 24week. Und. The next test will be on the 47 week.The doctors just told me that i have both Type 1b and 4.One doctor recommend that i should push for 72 weeks if my vl load is und on the 47 week. I achieve RVR. Here we have a panel of doctors which see us on alternately. I started the treatment well. Not much sides i cannot take, Doing most of the things you are doing accept the Alinia, Sam, predose and high dose riba. I am on SOC.But i am feeling the blues now. Staying at home mostly, use to exercise during the first 32 weeks, now no longer . I hope to get this over soon.

[willbb]

Hi.. What Geno type are you and what treatment you are taking would be helpful to give you some idea of how those results are?

You say lead-in ....possibly Vic therapy?

If it is.... then you must be UND. at week 24 in order to continue

Good luck..
Will

[flcyclist]

You'll likely get a much better response if you start your own thread.  The last post prior to yours is over a year old.  Hope that helps.

[rk6]

Starting 400,000
after 4 week lead-in 38,020
between 7 & 8 weeks 90
between 8 & 9 weeks 25
between 13 & 14 weeks 19
waiting for latest results between weeks 17&18
Anyone with a theory about what is going on - please reply... thanks

[merryBe]

the sam-e has a tendency to overstimulate. Since riba already does that, and since the SSRI's do as well, it might be helpful to just do a morning dose with the sam-e. That was HR's thought.
I had to discontinue, I went also to a tetracyclic for anti-dep...that makes one drowsy at night and sleep better, unlike the ssri's...but I still had trouble.
Then I added melatonin, it helped some, but not enough, like you I seemed to get a rebound night (like alcohol causes) where no matter what you do you end up sleeping in a split shift, being awake for hours and hours between 2 naps basically.
I would suggest Ambien, it does work, but it is highly addictive and has left me with tremors.
Permanent ones...which worsen again if I do take it for a night or 2, and then don't take it...so I know it's related to what that drug does to the GABA receptors...so I wouldn't recommend any benzo or GABA effecting drugs, but you could try cutting back to half the evening sam-e...or just take it in the morning.

mb

[Bali05]

Sounds very very familiar , Willing
Sleep,stomach ect....
When are you taking your SAM-e and what dosage at this point?

[willing]

thanks for asking  - I posted a journal article with a vl pic and summary since it may be of use to others planning their next PI-based attack. Insomnia is a problem with me in any case and none of this has helped but I couldn't tell you whether the SAMe is a factor. I've just gotten in the habit of  being up for a couple of hours somewhere between 3 and 5 and have re-arranged my life to sleep later in the mornings. Also, I  make a protein-powder shake every night which helps with  the middle-of-the night stomach growling.

I'm actually fairly clueless about diet-related issues (topologically, human anatomy is isomorphic to a doughnut and I've  assumed whatever goes through the middle of the doughnut has little more impact on the doughnut than what's outside). Though normally I keep to a pretty good diet (low sugar/fat, high fiber, yadda, yadda)  for now I could care less. My stomach has given me so much grief this tx that as long as it keeps quiet it can eat whatever it wants (weird stuff : lots of bok choy and plates of plain noodles with butter...) Fine by me - if it stays happy I'm happy.

Good luck with your tx planning!

[merryBe]

the CTLs?  well isn't that regulated by how well the antigens are recognized..?

I mean the nose knows right??

That's why I opted to up the LDL profile, the softer fats create a less hydrophobic cell...meaning more permeation by the drugs to the surface, but also, if macrophages are sensory, we don't know by what process they detect...chemical detection...the little buggers may have plenty of adenoidal tissue who nose (jk).

But however they do it, they may be able to detect better through a more permeable shell.

That the viron always puts on a raincoat, a fat layer, before jumping out into the bloodstream for a day at Disneyland (rollercoasters) seems to me the greatest argument for calorie restriction because they are pulling their coats from the livers stores, yes??

While I agree that recognition is a big part of the equation, I think that Riba penetration is even greater, especially when viewing the Lindahl studies where SVR and Riba plasma levels were so integrally linked. What do you think??

Could the type of fat we consume be more crucial than once thought?
I'm kind of likening the idea to maybe wearing a wool coat vs. a vinyl coat. The vinyl is impervious to the water coming by, none gets in, inside its all dry and the rain has no effect....whereas the woolen coat offers so protections, but not completely. Even if it's a thicker coat it's still got a permeability factor that the vinyl just doesn't have, so eventually, given enough rain, the person will eventually get wet...the coat will fail to some extent.
Now imagine that HDL is the vinyl coat, and LDL being sofeter and more permeable, is the fatty layer that eventually the riba can penetrate. So then which should I eat the tough coat or the tender one?

Am I making any sense here?

I wish they would test Riba plasma levels...it would make life so much easier...we could all get more quickly to steady state and have a much better chance at SVR without going over. Do you think that will EVER happen?? I think just watching blood labs is inept, since age and marrow health can effect blood results regardless of whether riba is optimum.

mb

[merryBe]

First, how are you holding up?? How's your bloodwork holding??
Is the Sam-E making it hard to sleep?  I'm very curious as to how others are fairing with this adjunct while on tx.

I was with you on nixing the IL28 until I realized for a relasper having the proof of genetic incompetance would make the case for ntz more valid.
Assuming we use a four pronged approach (4 pharmaceuticals) as well as our adjuncts would provide a lesser chance of resistant mutations so why not get the test??  The liklihood is high that relapsers would have CT or TT, and this give my doc rational for ordering anything off label he wants to.
I've even given thought to buying a pound of clemizole..same reasons, more prongs.

BTW, can you PM me the studies you have on the 4 pronged stuff..I can't find them.

Also, how are you doing???

Did you see the thread on isonine genetics??
It came on the heels of a thread of mine on purines and isonine from last week.
It would be great if you could take a look there, I'd value your opinion.
It might also help you to be aware of what purines and isonine do to riba absorption if you don't already know that.
take care.

mb

[justfinethanks]

i dont think that critter exists   typical results is kind of an oxymoron when it comes to hcv and treatment  also imo the hcv virus is capable of producing trillions of copies daily the more in the body the easier for the meds to target them  as far as mutation with peg and riba theres not much of that on treatment unless they are inf resistant  is this a mutation  im not sure  as we get more advanced genetically with our dna and the viral rna  things will change  there are so many positive and negative predictive factors involved - all we can tell from a graph is if we are undetectable before 12 weeks - treatment will most likely work  and if we arent undetectable by 6 months treatment will most likely fail

[willing]

yes, there's this eternal dance between  host, virus and  meds and the games they all play. The host can fail to respond to ifn for various reasons which regularly come up here. It's amazing how often this can be reversed : stories like CS's or jt57's are very dramatic but even I saw a better vl curve this time around by adding ntz, high dose rbv and SAMe.

Regardless of the host response, Trin's paper suggests that just as PIs  have a clearly defined set of sequences which will not be affected by the drug, there are "tougher buggers", mostly already present, but some of which can come into existence during tx, that thrive notwithstanding the ifn. Ifn's mechanism of action is way more complicated that that of PIs - after binding to its cell receptor it fires off on the order of a hundred genes with wide ranging effects  so what it takes for the "tough buggers" to withstand that firestorm remains a  mystery.

As I wrote above, my hunch is that at least part of the problem is a failure of the class-I MHC/CTL mechanism. This is the major component of the immune system that enables the immune police to detect infected cells by scanning the cell surface for bits of "foreign" antigen. Virus that presents no MHC-binding antigen, just like the stealth fighter jet China tested last week, is invisible to radar and the infected cells presumably remain in business until some mutation in viral sequence finally gives them away.

[Trish77]

From the study:  "The persistence of variants present before treatment in patients who fail to respond or who experience a breakthrough during therapy strongly suggests the preexistence of viral strains with inherent resistance to IFN. Thus, the study of the evolution of the HCV quasispecies provides prognostic information as early as the first 2 weeks after starting therapy and opens perspectives for elucidating the mechanisms of treatment failure in chronic hepatitis C. "

willing:  "On one hand it's well accepted that there is no such as soc resistance and if one fails it's perfectly reasonable to try again. On the other that study suggests that if one's tx is reasonably successful there is a great narrowing of sequence diversity towards the end of tx. "

Hm - well, the way I read that excerpt I quoted from Trinity's post is that there already existed a tougher bugger amongst the virons and it's identifiable as early as 2 weeks in.  The others may die off but this one doesn't and is likely the one responsible if there is a relapse or failure to respond.  To me, this is less of an explanation as to why you don't jump back in right away but moreso why it's generally accepted that, if you do this again, you do something differently next time around.  Either you double-dose with interferon for awhile, increase the ribavirin, add Alinia or a PI - but not the same thing.  Why?  Because you've already learned that the virons you have need something more.  

Whatcha think, willing?  Interested in your take on this.

Trish

[eureka254]

"Are they interspersed among UNDs? My solution to the blip problem is to make like an ostrich - I'm going to put off further testing until it comes time to add a PI. The results would change nothing but maybe add stress, ditto an il28b.

Yes, the blips were spread out (about a two month gap between each if memory serves me correctly)... and I actually like your ostrich trick... less extraneous data can make for better focus.  

"Sequencing  soc-recalcitrant virus is unfortunately a long ways off from being clinically useful. "

I realize it would have little clinical application to test "breakthrough" virions, but my academic curiosity makes me wonder if still sequencing detectable RNA post long term SOC exposure might later provide some clues towards the development of the perfect cocktail or immunization.  Ah, dreams, dreams...

[willing]

Eureka: well that und5 at w13 seems  confirmation that the decline held at a  steady rate of 0.5/wk, give or take a few days.  A VL curve that doesn't flatten is a good VL curve in my book. The 'blips' are not great news but if there's no steady rise your Dr's hesitancy to say breakthrough seems on point. Are they interspersed among UNDs? My solution to the blip problem is to make like an ostrich - I'm going to put off further testing until it comes time to add a PI. The results would change nothing but maybe add stress, ditto an il28b.
Sequencing  soc-recalcitrant virus is unfortunately a long ways off from being clinically useful. It would be a bit like trying to sort out the plot of a movie by studying the 1s and 0s on the CD - noone  has  a clue how to read the story  yet. For PIs on the other hand it comes down    to watching  for changes in a few amino acids in the neighborhood of the drug binding  site - much easier.

Trin: agreed - the virus mutates 24/7 regardless of what we're throwing at it (if anything). The word 'mutation' has an ominous sound to it, maybe because of the association with cancer in human dna, but only seems to have started coming up in posts here since discussion of PIs.

Trish: there seems to be a bit of contradiction between the results Trin posted and standard practice. On one hand it's well accepted that there is no such as soc resistance and if one fails it's perfectly reasonable to try again. On the other that study suggests that if one's tx is reasonably successful there is a great narrowing of sequence diversity towards the end of tx. So if you relapse or breakthrough and then jump right back in it would seem you'd be  fighting the descendants   of the soc-resistant holdovers. Maybe a good argument to give it a rest and let wild type diversity resurface before trying again (which most seem to).  

[Trish77]

That's what we do here on the forum.  We discuss things to clarify on points in an effort towards accurate representation and understanding of the information and a number of other folks made useful contributions.  I don't see where the personal insults are a positive contribution in any way - clearly you're taking this personally for some reason so I would agree on your final note  - best to leave it as a case of misperception with a little semantics thrown in.

Trish

[Trinity4]

Silly me, must be some kind of language barrier going on.  I know what said and I know what I meant.  No words like stronger, resistance to INF were said by me.

I am well aware to the PI resistance profiles and have done more research than I care think about.

In any event, this is beginning to bore me so I'll leave it as a case of misperception with a little semantics thrown in.

Trinity

[Trish77]

""They do NOT mutate in general aside from PI'.s" and that is simply not a true statement. "

You took that incorrectly, however it was also poorly worded on my part.  You suggested that the virus mutates,making it stronger and harder to kill - suggesting that treatment with ribavirin and interferon that does not result in SVR leaves behind virons who have become stronger and have developed resistance profiles.  This would be misleading to suggest that this is the case and the only reason I said anything at all - I wouldn't want people on treatment who don't acheive SVR to be concerned that now the remaining virus has gotten even stronger as a result and is even more resistant.  It is what it already was.  Tough little buggers that maybe need a different kind of firepower.  

PI's on the other hand DO develop resistance profiles that make them harder to kill with the PI drugs that that were used at the time.  They do NOT however become resistant to SOC drugs - ribavirin and interferon and in fact, these PI-mutated virons are weaker than regular virons and still susceptible to interferon and ribavirin.  So there is hope in that regard.  The difficulty comes in when using a PI and not getting SVR, that not only is there PI-mutated virons ... but ones that seem to require a different kind of firepower than interferon and ribavirin.  So developing a resistance to a PI and knowing that interferon and ribavirin didn't kill all the virons means that yet another drug on top of interferon, ribavirin and a PI with a DIFFERENT resistance profile of the one used will be required.  So it gets more complex when adding in a PI and not getting an SVR first time around.

Hopefully I chose my own words a little better that time around.

[eureka254]

Being a person of average ways and means and medians, indeed I was expecting and hoping for him just getting to undetectable at about week 12... and in fact, we did indeed request a higher sensitivity test for week 13, and it was indeed undetected <5.  However, subsequent to week 13, he had 3 detectable VLs thereafter, and those VLs were 19, 61, and 89, though his doctor has not used the term "breakthrough" because of the low levels.  From a scientific standpoint, though, I wonder if testing those detectable virions for sequences would have shed any light...

[Trinity4]

That study was really not in response to mutation but an example of cause and effect to response.

It was stated "They do NOT mutate in general aside from PI'.s" and that is simply not a true statement.

Your words:  "The viral replication mechanism is error-prone by design so the mutation rate is always high. The combination of constant mutation and selection gives evolution:  the virus figures out how to improve its game in the new, narrower, survival space left by the drug.

The virus mutates constantly whether we are on SOC or not to avoid the attack by the immune system.  The mutation process is a game of survival; a means by which it changes itself to become unrecognizable by immune system.  Eventually the immune system figures it out but until that time and even after the mutations still evolve.  One of the primary reasons for this is to resist or provide resilience from attack by the immune system.  

Trinity

[willing]

Eureka:  looks to me like your husband's decline could well have been   on target. The 2nd phase VL decline stays close to linear in log units when all is going well.  Unfortunately you can't use the w0 to w4 drop to estimate that slope since at the start of tx there is a very rapid (1st phase) drop that is not representative. Since you have no w1 or w2 data the best estimate of 2nd phase slope is the w4-w8 drop  (log 9170)=3.96 = log(71)=1.85 or 2.11 over 4wks, which is 0.52/wk. This is a pretty respectable drop, better than what I've seen in my current tx and I've been happy with the results. So if VL kept dropping at 0.5/wk past 1.85,  a complete UND would only have been expected  between weeks 11 and 12. It would have been nice to confirm higher sensitivity  und with a w13/14 test, but there may be no call for being discouraged with those results.

It really helps to focus on the log units, from 1.85 to 0 is further than the iu count of '71' would suggest.

Trin: I think the paper you cited primarily related to selection, not mutation. A mutation is  just a change in sequence, no more. The viral replication mechanism is error-prone by design so the mutation rate is always high. This rate remains constant and is not affected by any drug, with the possible exception of rbv (ie neither PI nor ifn cause the virus to start making even more mistakes during replication.

On the other hand the drugs exercise a strong selection effect such that only some sequences remain in business. With tela/boce only sequences that have the dozen or so patterns required to make the PI ineffective keep replicating. The paper you linked shows that with successful soc you get a similar effect ( a narrowing of the diversity of the surviving sequences). The patterns that distinguish soc survivors from pi survivors are more complex and not understood but the same  narrowing of sequence diversity can clearly be measured in both cases.

The combination of constant mutation and selection gives evolution: the virus figures out how to improve its game in the new, narrower, survival space left by the drug.

All of which just underscores RBW's starting point: some sequences already present are harder to get rid of than others.

[nygirl7]

Although the genetic basis for this resistance is unknown, accumulated evidence SUGGESTS that changes in the heterogeneous viral population (quasispecies) may be an important determinant of viral persistence and response to therapy. "



Actually I thought the study that Trinity introduced had much more hard data than any of the snot guessing going on.

I much prefer the word of an expert scientist saying it SUGGESTS rather than a lay person just guessing and disagreeing with it for giggles.

[eureka254]

Harassment of nonsense is preferable to harassment of good sense.

[Trinity4]

I can't recall ever mentioning a study or a removed study, only that we disagreed about  Methylene Blue so let's not twist words ok? I don't how your study got removed but I certainly didn't report it.  Apparently you still harbor a tremendous amount of animosity about that.  Sorry, but I'm not your point man.  By the way, how's that Methylene Blue working for ya?  

Snot Swapper came from your head to your fingers, not mine.

Trinity

[aaCharley]

You will find that it was Trinity4 who found it necessary to introduce the subject of the study report that was removed.  And, yes, I agree that it added nothing to the thread.