OK - stop or go the distance - what to do, what to do?

[motheroffour]

Oh man, H's PCR was 75 at 24 weeks.  We ran another PCR at 27 weeks and this time it is 32, tested UND <50 but a more sensitive trest showed 32.  Physician's assistant is going nuts because they got the big UND<615 at 12 weeks and she thought UND <615 meant zero - really.  I'm loosing my mind because even if he clears this week (30 weeks) he's got all the signs of a slow responding relapser.  He told the PA in no uncertain terms that he wasn't stopping (which I agree because he's a "probable cirrhosis by bx and improving liver histology is of the utmost importance.)  He's tolerating treatment, no rescue drugs, HGB hovering about 10.5 and platelets, Aboslute neuts low but OK.  AST/ALT low normal now.  Haven't tested albumin, creatine, INR, etc. since start of treatment. Endo was totally clear and "clean as a baby's butt" according to doc.  Starting Viral Load around 550,000, 4 week PCR 20,000 something, 8 week PCR 2,400, 12 week PCR UND<615, 24 week PCR 75, 27 week PCR 32.  What to do, what to do????  He totally Riba Raged with the PA (I wasn't there) and told her the only person he would listen to is me.  Half of me wants to just let him go the 48, stop and figure he'll relapse and then I can say "I told you so" to the docs, but I can't take the stress of these PAs anymore.  H hasn't seen a doc since before he started treatment.  H thinks all is well and he's getting rid of the virus slowly but surely.

[motheroffour]

Hubby is a probable 4by bx.  His liver enzymes were never high, just moderately above normal.  Normal liver enzymes previously every year at his physical.  His liver enzymes now are at the very low normal levels and have been in normal since his 4 week blood tests.  His dosage is weight based PegIntron (1.5) and 1200 Ribarain (he weighs 160 lbs.)  He has been 100% compliant with treatment. His Hemo dropped to 11.6 and hasn't budged since week 3.  His white blood cells, platelets, neuts, etc. are all low but not extremely low and they bounce up and down. TSH is normal, glucose is normal.  Few sx from drugs.  He has genetic high blood pressure treated with drugs and BP has not changed during treatment, other than that he's been healthy his entire life. He is on low dose of Lexapro.  His PegIntron was at the high end dosage for his weight according to PA and there was discussion of lowering it when his weight dipped to 155.  He refused.  He is pretty steady at 160# now. After a long talk he will finish the 48 weeks (week 32 shot tonight) and we will regroup after tx and have a plan B when he relapses. We are assuming his liver histology is improving and will request a Fibrosure or similar test sometime after treatment and see what turns up. I'm very hopefully his probable 4 is really a 3 now.  We'll run one more heptimax in 2 weeks and see if he is undectable with the TMA portion.  If so, no more Heptimax until end of treatment, the stress is too much and it won't change anything if you know what I mean. I will keep you all posted.

[dlr2007]

Hi- I just wanted to say I read more on your situation and I SO relate to what you're going thru although I still don't know if my hubby is stage 3 or 4. I was hoping for 2, but I'm thinking that may be more than a bit too optomistic. I also spend HOURS on the internet looking for info on liver damage/hep C/statistics... it really takes over your life, I know. I worry about my husband cuz he spends a lot of time sleeping and complains of "no ambition"- could be advancing liver damage or depression from all the awful stuff that's happened in his life these past couple years.
I don't know much about tx since hubby and I haven't gone thru it sincxe the first interferon came out 10+ years ago. But I know how frightening it is to think about your life partner who has always been strong and indepedent being sick. Hang in there. I'll keep watching your posts to see how things are going for you. Best wishes and prayers- Dee

[Eisbein]

Most people here have some kind of insurance, and all insurance companies negotiate discounts.
Yes, Heptimax bills are around $350, but my insurance forks over only $80 per test, which is very reasonable.

I think her hubbies dosage should have been increased long ago, but it wasn't.
But what do you think of icreasing them now, hopefully getting him undetected by week 30, and going for the very long haul, by that I mean 2 1/2 years total.
He tolerates tx, and is willing to go longer. There are really no studies what happend to very slow responders who tx beyond the norm.
I mean Sandy and I survived over 2 years of tx, and we have a member here who does not show up anymore, who became undetected at W24 and has started his 2nd year going for 2 years, also early cirrhosis.


Just a thought...

If this were my hubby I would contact an aggressive tx hep c specialist, like Dr.C and ask for guidance. Dr.C has at any given time about 200 patients going for 2 years, now he would be able to answer SVR questions in difficult patients.

That PCP pimpel of hers is worth less than ....
I am under the impression her hubby is stage 4, but maybe I am wrong, and in that case he may have time to wait for Vertex.


Ina

[jmjm530]

Here is a more complete trial report on the above:
http://www.natap.org/2006/HCV/080106_03.htm

Here is another study on the utility of TMA testing:
http://www.natap.org/2005/HCV/122805_04.htm

[nygirl7]

By the way my starting VL was 568,000 - just a tad higher than your hubby's and I have seen that sometimes this "low" viral load is much much MUCH harder to kill than someone with a 50,000,000 VL.
Week 4 = 411
Week 12 = 419
Week 24 = UND (but ONLY to 315)
Week 46 = UND <5

So even though I responded super fast it was obvious I had a huge flatline after that with something going on.

I believe that it starts off so "low" because our immune systems are doing well in trying to fight it and they are totally amped up.

So when we start the IFN...it doesn't work as well because our body has been naturally making this stuff to fight it. So in the end.......we don't respond as well.

I've seen a number of people with this problem. When it's UNDER a million sometimes it's just the hardest hardest road to be on.


Of course there is no science behind it (who'd ever do a study about that?) but I think it's true.  Getting to UND with an <1mil VL is just REALLY important.

I hope you can get a specialist to have him rethink his current course.

[motheroffour]

Thanks for the suggestions.  I'm just totally freaking out about this.  A year and over a half ago we were going along our merry ways and wham. I wish I knew more about whether or not this improves liver histology the bx alone combined wtih the Hep C dx was the bigger shocker.  Regardless I guess he's planning on finishing the 17 weeks he has left and deal with the next step - if his rage at the PA plays out. The closest Hepatologist who has any kind of Hep C practice is 3 hours away at U of Michigan and I think there are some 3.5 hrs. away in Detroit.  I can't imagine I can get this doc's office to let him go the 72 if they are running around patting themselves on the back for UND<615 and are scratching their head freaking out about 32 at week 27.  Guess I'll have a heart to heart with H tonight and spell it all out for him.  He hasn't wanted to even know the details, but he's got to now.  Unfortunately both his buddies who got Hep C from blood transfusions cleared so he probably isn't going to believe that he might not. I also wish I knew more about progression of Hep C on the liver at this point, too.  I just can't even internalize liver failure even though I know it's lurking out there somewhere to me that is way scarrier than the Hep C.

[motheroffour]

I think I agree with you regarding the immune system.  H has had this virus for at least 30 years if he got it from his little itty bitty stupid tatoo which is the most likely way he got it.  In the 25 years we've been together I've only seen him get sick once or twice.  That's why it's just shocking that he's got this life threatening liver condition.  Really, really hard for me to wrap my arms around it and come to terms with  it.  He's always been larger than life to me....that's why I married him :-)  When his initial viral load came in and he had two within a couple months, the second one was 480,000, my initial reaction was that he must have been fighting this all these years. I also think from reading about everyone on these boards that length of time of disease + lower viral load + more liver damage + over 50 is not where you want to be.  Not to mention my H like many young men I think was a heavy drinker in his twenties, how bad can that be on top of Hep C?  Not to mention moderate drinking from age 30 to 50?  It's just a recipe for yuck. We were on vacation a few weeks ago with our college kid who was drinking a  4th Corona and yapping about getting a tatoo and I was just laying in my lounger loosing it and thought my H was going to have a stroke.

[GrandmaA]

The other suggestions are better than mine. Obviously, they know a lot more about all those numbers than I do.

It also depends on a person's age. This was my last chance to try treatment. I'll be 65 next month.

[willing]

it's a hard spot to be in and I'm sorry you're having to face these decisions without the benefit of expert medical advice. A couple of thoughts/suggestions:

- as Mike points out its very unlikely that even the advice of a trained hepatologist would make this decision much easier. Currently there is nothing about a Dr's training that gives any significant insight into why tx, properly followed, fails or succeeds. What little guidance is available comes not from a sophisticated understanding of mechanism, but from simple statisical compilations of patient outcomes and these are as readily available to patients as to their Drs.

- one of the key data compilations supporting the "quit if not und by 24" is Davis(03)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12939591&query_hl=4&itool=pubmed_DocSum

which includes the observation:
"Of those who remained PCR positive at week 24, only 1 of 4 (4%) achieved SVR compared with 14 of 43 (33%) of those who lost virus between weeks 12 and 24"

This is in a group who achieved the 2-log drop by 12. Testing was done at a level not considered sensitive today:

"Serum HCV RNA levels were measured before initiation of treatment and during therapy at weeks 4, 12, 24, and 48 by a quantitative polymerase chain reaction (PCR) assay with a dynamic range from 100 to 100 million copies/mL (National Genetics Institute, Los Angeles, CA)"

which should clock in around 600 IU/ml.

The reason today's sensitive tests are not always all that helpful is that there's not yet enough accumulated data to guide the interpretation of the results (there is more for comparing 12 week results). How many among the 14 who achieved a 2 log drop, became UND by 24 and went on to SVR actually would have shown residual VL by a more sensitive test is anyone's guess. It's worth hunting around PUBMED to see if there's more recent data.

- kicking anyone off tx when they want to continue and are bearing it well seems ill advised, all the more so if stage is advanced. At a bare minimum, virus-induced damage is being slowed/stopped and there's incomplete but encouraging evidence (often reported on this board and something I experienced personally) that this pause gives the liver a chance to improve during tx. And then there's that ongoing battle between the statistics and the psychology - *someone* has to be in that 4%.

[willing]

sorry - important typo in the above quote. That should be "only 1 of 24(4%) achieved SVR"

[motheroffour]

Yeah, "willing", that's kind of where I'm at.  I can't help but think that finishing the 17 weeks isn't going to hurt his liver histology and treatment has not stopped this man.  In fact he skied more vertical feet this year than when he was in his 20s so physically it's not hurting him.  I figure the reflux in the AM is payback for the reflux I had for 9 months with the kids :-)  I have spent the last hour searching and searching.  What I find puts him at a 10% chance of SVR IF he gets to TMA Negative.  4% might be more accurate. His odds at 72 do increase for SVR but it still isn't even 80%.  

[motheroffour]

OK, so I've spent my afternoon not on work, but on trying to find the definitions so that I can interpret all this research. OK, so does "Virus Undetectable" in studies that I'm reading correlate to TMA undetectable or PCR undetectable?  They seem to be two different things.  So if "Virus Undetectable" correlates to PCR undetectable then do these studies suggest <100 or <50?  In many cases it's not specified. Seems to be the goal is TMA negative and the Halt-C findings seem to make the most sense - 82% chance of SVR with negative TMA at week 12, 44% change at week 20, 20% change at week 24, 10% anytime after week 24...and approximately 10% of patients with a single positive TMA at end of treatment still achieved SVR.  Am I reading correctly?  I think I'll let him go the 17 more weeks, take the 10% chance and give him a chance to get rid of the interferon so if/when he relapses he can start fresh.  If he relapses it will be interesting to see if the viral load "soars".  Well...I'll keep you all posted what happens to him at the end.  If he hits TMA negative somewhere along the line I'll let you all know,. No biopsy for him according to docs for 5 years, so I'll sure I'll be pitching questions about fibrosure and fribroscan in the months to come.  I'd be estatic if his bx of probable chirrosis turned into a 3 Fibrosis!

[willing]

TMA ("transcription mediated amplification"), bDNA ("branched DNA") and PCR ("polymerase chain reaction") are just different laboratory techniques for quantifying the number of HCV RNA molecules in a given amount of blood serum.

Though the nuts and bolts of the chemistry are different, the goal is the same. Sensitivity is measured in in terms of the number of copies detectable per mL. To make it easier to compare different tests standardized "international units" were introduced and each test has its own copies<>IU conversion. The level of sensitivity is independent of the technique: TMA tests are generally more sensitive but there are also very sensitive tests that use standard PCR.

For HALT-C it looks like they used COBASv2 which is not all that sensitive:

"All serum samples were frozen at -70

[jmjm530]

Mother: approximately 10% of patients with a single positive TMA at end of treatment still achieved SVR. Am I reading correctly?
------------------------------

I don't think so. The 10% figure seems to be referring to patients WITH A SINGLE POSITIVE TMA result  BY the end of treatment", even though they worded it AT the end of treatment.  To me, this means they had a positive TMA once but then cleared. Badly worded abstract.

I interpret that thus because earlier the study states " Among 45 patients who were TMA-positive but PCR-negative at week 20 and week 24, NONE  ACHIEVED SVR. (capital letters mine).

Furthermore, the study concludes: "In patients with negative PCR results during treatment, a single positive TMA test did not exclude SVR, although persistently positive tests did.

[nygirl7]

I agree with the other guys.  First off 48 won't do anything I don't think - he'd have to be willing to do 72 (they just won't let you do more or I'd say he needs more).

He'd probably be better off stopping, waiting a few months and then restarting on a stronger Interferon - Infergen treatment.  It is good for people who are slow responders.

Now that they have proved that it is so important to be "the earlier the better UND" he's not even there yet after half way through treatment.

It just goes to show - I wonder HOW MANY people truly believed they were UND that never really were.

If a doctor doesn't give a really really sensitive test (like Heptimax) at week 24 - you just DONT know if you are or not.

But.........most people don't know that and at least you do.

Hub needs to change treatment - you are right.  It's just not working.  I pray all of the best for you and he. God this disease just isn't fair! I(But it's not like any of them are I guess).

Debby

[orphanedhawk]

Although my situation is quite different it may give you and option.  I had an early response but wasn't UND at my first viral load test.  To help get rid of the few stragglers HCVs, my doc suggested upping my riba. I can't say whether that helped or not but I did become UND.  Your husband needs a better heptologist and not just someone reading the pharmaceutical companies hand out.

[jmjm530]

Another study that state the advantage of more sensitive TMA testing:

"...A negative TMA result at any time point was also better
at predictingwhich patients would go on to develop SVR
than a negative Amplicor result. For example,
approximately74%of patientswith a negative TMAresult
at week 12 went on to SVR compared to 58% of those
with a negative Amplicor result."

http://www.haltctrial.org/haltc_sept2005.pdf (see second article)

----------------------------------------------------

[Kalio1]

Sorry the UND is coming so slow. One good thing is he IS slowing that virus, so he is slowing the assault on his liver. The goal of treatment for some of us is not singularly SVR so if it was me, I'd stay on it. There is quite a bit of evidence that treatment can improve histology for some so the tx is not in vain. His VL is VERY tiny at this point so his liver is getting a breather.

In his damage situation, has his doctor recommended maintenance therapy? In those cases people stay on it to maintain viral supression if SVR is out of their grasp. Unfortunately, damage can get in the way of our SVR ing. If tx is reducing damage, that is a big plus and you know by his tiny VL that he has suppressed the virus almost completely.

Try not to get too tangled up in it and make yourself crazy. He is making progress just not the hoped for progress. I vote for him going forward, I'd extend tx not stop it short given his damage level.

I thnk most of your stress is born out of these PA's you are dealing with. They sound like they are realy hard to work with.
Hang in there, try to think about something else!

[motheroffour]

Aargh.  Yes, I just copied off the Vertex clinical trial info.  THere is one at Henry Ford in Detroit - not too close but maybe doable.  OK, I'm going to stop thinking about Hep C for a while.  It's after 5, time to shut off the laptop.  We actually have a party to go to tonight.  Not too many of those now that we are in our ripe old age even the second marriage weddings are few and far between.  Gosh, what to wear - a much more enjoyable thing to think about on the drive home than what the heck is going to happen to my husband!  (Don't worry I don't think my H would touch alcohol even for a million dollars at this point in his life - me I'm going for the wine! I have a designated driver!)

[willing]

thanks for the link to that study - I hadn't seen it before and think it really helps  shed some light on the long-standing argument here about how to interpret high-sensivity (<5IU or better) tests. Overall the conclusion of the paper seems to be that results from HS tests, that is the ability to monitor VL in the 5-600m range, can be a stronger predictor than conventional PCRs but that fluctuations in low-level VL make individual tests less reliable than a trend obtained from multiple tests.

For example, from their Fig. 3, exactly the same 22% of patients go to SVR who were TMA+ at 20 and TMA- at 24 as were TMA- at 20 and TMA+ at 24. On the other hand, as Jim emphasized, 0% got to SVR if they were TMA+ at both( "Thus, achieving an SVR appeared futile for patients receiving a full course of therapy who had positive TMA results through W24"). Another example of fluctuation is that somewhat misleading sentence from the abstract indicating that among all patients who were TMA+ on exactly one among their four TMA tests 12,20,24 and 48 10% went on to SVR. Interestingly, this includes 2 who were TMA+ at 48!.

The HS tests were run retroactively and did not affect tx decisions. The authors don't propose new tx algorithms based on their results and there's still quite a bit of gray area in interpretation ("how many TMA+ before quitting?") - presumably this is coming down the pipe. For the short term, the take-home message for those now on tx frm this study seems to be

- getting a HS test at week 12 is all important. If positive, one's odds are definitely no longer the 50% one has at start of tx, regardless of 2-log drop:

"At W12, the likelihood of SVR was low if HCV RNA was detectable by either PCR or TMA; SVR occurred in 7.3% of patients who were HCV RNA-positive by TMA, compared to 4.8% of those positive by PCR (data not shown). Thus, a positive result forHCVRNA atW12 did not exclude the possibility of SVR, although it was uncommon."

- if you don't get <5 at 12 lobby your DR. to start testing at least every four weeks. Consecutive +s are a concern : "Whereas a single positive result by TMA could not rule out the possibility of an SVR, serial sample testing could".

BTW - as noted earlier there are HS tests other than TMA-based ones. The fact that the lead author discloses a financial link to Bayer (makers of the standard TMA test) may indicate a tendency to gloss over that detail...

The fluctuating nature of low-level during tx revealed by their data is pretty interesting. IMHO, it may add evidence that SVR has less to do with eliminating the virus than with suppressing it.

[jmjm530]

My doctor does Heptimax (PCR plus TMA) every week till non-detectible and then monthly till end of treatment. All your points withstanding -- and not sure I agree with them all -- in order to maximize treatment decisions based on viral predictors, I can't see any reason to use less sensitive tests or less frequency.

When I went for my Fibroscan mid treatment, I asked the study doctor to ballpark my chances of SVR for "x" number of weeks treating. After he threw me a number, the three points he came back at in terms of support, where my RVR (two log at week 1 and non-detectible by week 6), the high sensitivity of the tests I used (5 IU/ml), and the frequency of those tests (at least every other month throughout treatment).

I do understand that one can argue here and there, that a treatment outcome will be the same regardless, but as an overall treatment approach I can't see any reason why someone would want anything less than a sensitive viral load test during the treatment process, assuming it is available. Would you ask for a less sensitive test?

-- Jim

[jmjm530]

Among other points, this stood out : "The earlier TMA first became negative during therapy, the better a predictor it was of SVR: 85% at W12, 44% at W20, and 21% at W24..."  

Again, suggesting frequent and sensitive testing over less frequent and/or less sensitive testing. BTW I agree it makes no difference what kind of technology is used -- PCR or TMA -- as long as it's sensitive. Possibly at the time of the article, the more sensitive PCR tests weren't readily available, or maybe they were just pushing their tests by trying to brand "TMA" with "sensitive", but that really doesn't affect the principal. The thing I like about "Heptimax" during treatment is that in effect you're getting two different technolgies with the PCR somewhat keeping the TMA result honest. In other words,
the TMA is only run if the PCR comes up negative and the real-time PCR used is supposedly quite reliable. After treatment I scraped Heptimax and just starting using their Qual TMA. You're probably aware that Vertex will be releasing what we hope is preliminary SVR data mid-day tomorrow. Let's keep our fingers crossed.

Hope this finds you well.

-- Jim

[jmjm530]

I guess all I'm really saying is that while it's true that not every treatment will be affected by TMA versus PCR testing, it's almost impossible to know in advance if a particular treatment will. For that reason it seems to make the most sense to order (and advise others) to have frequent and sensitive viral load testing to the limits of what is available and what their insurance allows -- which in many cases is what their doctor will order. Not sure if we really differ here but I'm sure you'll straighten me out if we do.

-- Jim

[willing]

nope - no real difference. It comes down to your qualification "assuming it is available".  At (ballpark) $350 for a heptimax testing every-week to UND and every month thereafter is a lot of $ for testing.  If your Dr., or more likely ins. co, questions the diagnostic value of all that testing there hasn't been (until Morishima) much to answer them with. The predictive value of a HS sensitive W12 test is  pretty solidy established (Berg, etc.) but beyond that things are still  murky. I trust your Fibroscan Dr. gave you a % in the 90s - but what number do you think he would have given you if you had included say one very low level breakthrough at W13 - and what data do you think that opinion would have been based on ?

Figure 3 from the paper pretty much drives home that at least for patients who aren't in the clear-cut SVR class, low-level VL does bounce around and that fluctuation doesn't seem to say too much about  SVR odds. Motherof4's H's SVR outlook based on the Morishima HALT-C data seems pretty clear cut but what of someone who's TMA- at 12 but is  completely falling apart on tx and gets two consecutive TMA+s at say W16 and W20. Do you think there's any Dr. out there who'll have a (rationally-based) clue whether their SVR odds have dropped enough to warrant quitting ?

Personally, given the choice, I'd opt for the HS tests and lots of them on the grounds that partial information is better than none but would only go so far as to actually change Drs  if they refused to order HS tests at 4 and 12.  In fact, I had to convince my Dr. to, grudgingly, switch to heptimax, but only found out about them after week 12. So not getting a TMA at 12 likely cost me an extra 36 weeks of tx fun - though I may have gotten some benefit out of it.

The Vertex data will be interesting - but that's still too much ifn/riba for my tastes. Did you happen to see in easl abstracts whether anyone reported data from combined PI/polymerase tx? Stay well.