hepatitisresearcher

[spcecst2]

Your opinion please? Lets say a patient went thru treatment (1b) pegasys/copegus 180/1200 for 48 weeks, starting VL was 10 mil, middle aged male, slight liver damage, still detectable at 600 week 12, clear week 16 (less than 50), relapsed, waited 3 months and started treatment over, VL 500,000, double dose pegasys 4 weeks, 1400 copegus, no VL detected at week 4 using heptimax, did shot every five days from week 4 thru week 12, did 1600 copegus for month and half, waited full seven days at week 12 and got negative heptimax, doing 180/1200 rest of treatment, ast/alt normal at week 12, does this person have the same chance with RVR statistics (as high as 85% SVR) with 48 weeks, or are those RVR statistics only good for someone who does treatment the first time using the SOC? I hope you can understand what I’m asking here?

[Hepatitis Researcher]

I understand. There is no trial data on this scenario, but by mechanistic conceptual considerations it seems likely that your second time RVR has the same predictive power in this case as it normally has in the IFN/riba settting. This predicitive power might be a bit different with direct HCV antiviral blockages as part of the game.

[jmjm530]

These studies (and I assume more) appear to suggest that RVR is RVR, whether treatment naive or treatment experienced, as in your case.

As to how you got to RVR, from everything I've read, it makes no difference -- be it double-dosing, high-dose riba, adding a PI, etc -- as long as you got there.

Looking good, Space Fellow. Keep up the good work.

http://www.natap.org/2007/AASLD/AASLD_61.htm

http://www.hivandhepatitis.com/2007icr/aasld/docs/111307_a.html

[spcecst2]

Thanks for the reply and links! My first reply must of went into the abyss! Anyway I think with these numbers I'll be SVR or Non-Svr and 72 weeks won't be the deal breaker!! I've been going along time and the first 12 weeks this time took a toll !!

[jmjm530]

Personally, I think 48 weeks is more than adequate considering your RVR. In fact, you might look at 48 weeks as a 24-week extension of the 24-week shorter course for RVRs. You know, I was thinking of extending to 72 weeks at one point, primarily for two reasons: histology and age. After a couple of big-time consultations, what came out clear was that as long as I wasn't a stage 4 -- 48 weeks should be more than enough based on my RVR. I did end up doing 54 but partly to placate my tx doc who worried the sh*t out of me when he wanted me to continue. In your case, your're not stage 4 and  you're not old ( I was 58 at the time). Also, you had a legit RVR at week 4 and I had a "give-me" RVR at week 6. The other thing they felt important was that I was UND via sesitive tests (Heptimax) throughout treatment. For that reason, I'd avise a Heptimax maybe very 8-12 weeks, including one at EOT, which would be 6-7 days after your last Peg shot.

-- Jim

[spcecst2]

Reading some of your early post help convince me that I had to do heptimax this time because in the past I could have been positve longer than I though and the numbers for SVR with a VL at week 12 are not very good, I didn't even plan on doing this round but it fell into place and I could do the 72 weeks but at what cost? I have a couple of months to ponder the 72!! Thanks and have a good one!

[jmjm530]

Remember 48 and 72 are just numbers. There's also 60, or like in my case "54" which btw as computed by adding 48 weeks to the week I became UND which was week 6. Kind of variation of Drusano. Still think 48 is your number, but like you say, you still have time to ponder, and it's your liver, not anyone else's.

All the best this holiday season,

-- Jim

[FlGuy]

I thought that you had done more than 60 weeks (68?) in the prior tx, guess I misremember.  But the und at four, compared to the prior week 16 has got to give you some reassurance.  Hey, you've got a launch in your backyard this afternnoon, shortly after 4:00

[spcecst2]

I did but my basic question is do people who relapse have the same % for SVR if they have RVR, and both previous und at 16 were not with heptimax, my percentage for SVR those times were almost fricking zilch! I feel like it was such a waste of time, but we have to keep looking ahead! I keep waiting to read that you are SVR this time! I want to stop sooooooo bad! I'm almost out of fat to pull for those wonderful injections! Almost half way to 72 but so close to 48! Third time down this road maybe my body is trying to talk me into stopping! I've now entered the Twilight Zone! Just like ground hog day it never changes! No AD this time lets my brain play games but I'm more alert! Launch no-go for eco (engine cut off) sensor, keeps main engines from running dry and a bad day! There has to be a launch every 2.5 months (average) with the windows to finish 2010! Schedule is tight! Hope next years hurricane season is just like this one for us!
Happy Holidays and Merry Christmas to everyone! All the best back at you jmjm!

[Forseegood]

yeah, inquiring minds? when are you going to know? pulling for you...me and spacey it seems, spacey, hope you get to where youre going in style!

[spcecst2]

Me Toooooooooooo!! Thanks and SVR for FLGUY!!

[FlGuy]

I have 3 month pcr scheduled for next Friday.  But, am now told I'm heading to N. Florida the night before on a college-visit for the older kid.  Got to figure that out. In any event, pcr and results before year end.

[spcecst2]

Enjoy your trip, I had one at FSU!! Thats a party hard school!!!!!! Go Noles!!!!!!!!! Drop Bowden his time is over!!!!!!!!!!!

[willing]

sorry to bring up bad news but you might also want to look at some of the recent data on the effectiveness (or lack of ) of induction dosing . Eg

Carr C, Blaine Hollinger F, Yoffe B, Wakil A, Phillips J, Bzowej N, Leung J, Mirro K, Poordad F, Moore DH, Gish RG.

Efficacy of interferon alpha-2b induction therapy before retreatment for chronic hepatitis C.Liver Int. 2007 Oct;27(8)

a large, four arm, study out of SF, which concluded "RESULTS: Induction did not increase SVR compared with non-induction, but did increase the on-treatment response among genotype non-1 patients in Study 2." and only saw a beneficial effect in one subgroup:
"CONCLUSION: For chronic HCV patients who have failed IFN, induction with retreatment does not improve SVR, but may be beneficial for patients with genotype non-1 HCV."

or

Enomoto S, Tamai H, Oka M, Shingaki N, Shiraki T, Takeuchi M, Deguchi H, Magari H, Inoue I, Iguchi M, Yanaoka K, Arii K, Fujishiro M, Yahagi N, Yotsuyanagi H, Ichinose

Potent induction therapy with interferon and ribavirin combination therapy does not achieve a higher sustained virological response rate in chronic hepatitis C with genotype 1b and high hepatitis C virus RNA level.Hepatol Res. 2007 Sep;37(9):692-700.

a Japanese study that concluded "Conclusions: There was no difference between the effects of the two induction therapies; potent induction therapy does achieve higher early viral clearance but not a higher SVR rate."

the implication seems to be that, at least in some cases, it's possible to push the virus below the level of detectability by sufficient early "shock and awe" without necessarily affecting the longer term negotiation  between virus and host immune response that determines SVR. If anyone knows of recent data indicating success from induction dosing please post. Common sense suggests it *should* help and studies like the above (and there are a couple of other recent ones) seem counterintuitive.

[Forseegood]

hey, my doc is on that interferon alpha b2 abstract!!!! hope youre well, nice to see you.

Spacey: I'm just hoping for the best for you...hang in there...

[GoofyDad]

Curious what would happen if they were to double up at the end... the proverbial final nail in the coffin....but that approach flies in the face of the taper off crowd that seeks to ease the transition from forced to voluntary immune response...

[GoofyDad]

Oh. And of course best wishes to the dudes in FL.....

[spcecst2]

Here is info (below) from a small study that might suggest that "severe fibrosis (METAVIR F3)" was cause for these individuals to not clear the first time vs "affecting the longer term negotiation  between virus and host immune response" also you might note in the study that jmjm posted (http://www.natap.org/2007/AASLD/AASLD_61.htm) 221 naive; 187 non-naive were used in the study and RVR was a major factor in determining SVR, Also ""One study reports that more than one-third of hepatitis C genotype 1 patients who previously failed to respond to conventional interferon plus ribavirin achieved a sustained virological response (SVR) following re-treatment with a 12-week induction dose of PEGASYS"" from http://www.natap.org/2004/AASLD/aasld_21.htm -- one more small note if  "affecting the longer term negotiation  between virus and host immune response" played the mojor role in the failures of the studies you mentioned, then the majority (all) of geno 1's who do not clear or relapse would be wasting there time with any follow up treatment polymerase inhibitor's, longer treatment (72 weeks),  infergen etc.. of which all of these have had success with retreatment of geno relapsers ---so there is bad news and good news! Is the glass half full or half empty!


More Frequent Dosing of Pegasys/Ribavirin Improves SVR Rate in Prior Non-responder Genotype 1 HCV Patients with Severe Fibrosis

Once weekly injection of pegylated interferon alfa in combination with ribavirin is the current standard therapy for chronic hepatitis C. However, this regimen frequently fails to clear infection in individuals with genotype 1 HCV.

Pegylated interferon was designed as a longer-acting form of interferon that is injected once weekly, as compared to 3 times weekly with the older conventional interferon alfa. However, viral kinetics studies suggest that a rebound of viral replication often occurs at the end of each week, before the next injection of pegylated interferon. This rebound could be responsible for treatment failure and could theoretically be prevented by more frequent peginterferon injections, the authors of the current study hypothesized.

In this small study, researchers tested their hypothesis in 3 men and 4 women with genotype 1 HCV and severe fibrosis (METAVIR F3) who did not clear infection after weekly administrations of pegylated interferon alfa-2b (PegIntron) plus ribavirin.

The patients were retreated with pegylated interferon alfa-2a (Pegasys), 180 mcg administered every 5 days for 12 weeks, followed by 180 mcg/week for an additional 36 weeks, in combination with ribavirin (1,000 mg/day if weight  75 kg) for 48 weeks.

Results

6 of the 7 patients experienced an early virological response (EVR) (> 2 log drop in HCV RNA at week 12) and an end-of-treatment response (ETR) (HCV RNA < 50 IU/mL).

The mean HCV RNA decline at week 12 was significantly more pronounced during the second course of treatment (frequent pegylated interferon administration) than during the first course (standard weekly administration): 3.66 +/- 1.35 log IU/mL vs 0.70 +/- 0.46 log IU/mL, respectively.

Overall, 4 patients achieved sustained virological response (SVR), 2 patients relapsed, and 1 patient did not respond to therapy.

Tolerance was similar to previous reports with weekly administrations of pegylated interferon combined with ribavirin.

No dose interruptions or treatment discontinuations were required due to adverse events or laboratory abnormalities.


Conclusion

In conclusion, the authors wrote, "More frequent administrations of pegylated interferon alfa in combination with ribavirin induce a sustained virological response in a substantial proportion of patients with HCV genotype 1 infection and severe fibrosis who did not respond to prior standard pegylated interferon/ribavirin combination."

"Prospective, randomized controlled studies are now needed to confirm the interest and evaluate the global results of frequent pegylated interferon injections in difficult-to-treat patients with chronic hepatitis C."

[willing]

space: well.. the Diago'04 study seems to directly contradict the recent Carr'07 Enomoto'07 results - but note the sample sizes in Diago'04. It looks like the number of SVR patients is down to 5,6 and 9 in the three dosing regimens and they include no mention of whether the differences  observed can be considered statistically significant given such a small sample size. Carr'07 on the other hand started with sample sizes of 232, 237, 201 and 206 in their 4 arms and does include significance results. The effect here is not huge, so having a sample size large enough to distinguish it from noise seems important. Likewise, the "More Frequent Dosing" study gives results from very few patients. I haven't read the whole  Carr paper yet - maybe they were following up on suggestions of these earlier studies?

The AASLD '07 abstract  Jim cited seems very much on point for estimating your SVR odds based on VL curve - but applies directly only if you're following the  dosing regimen of those patients (standard SOC). Heavier dosing incontrovertibly leads to better  on-treatment response but I don't see anything in the French study that helps decide whether the same RVR/SVR correlation applies.

Overall the benefits of induction seem murky - but hey, absolutely better half-full than half-empty!

goof: ramp up the dose after 72 week of SOC? uh..not clear whose coffin is getting nailed shut...

4C:  well-connected as always... maybe you should ask him what he thinks about start/end or pre/post dosage variations.  been away awhile, good to hear from you.

[jmjm530]

Can't we extrapolate from other studies that RVR means better shot at SVR, no matter how it's reached -- double dosing, high-dose ribavirin, or with a PI study? Combine this extrapolation with studies like this showing no difference in tx naive RVR versus treatment experienced RVR, and I think it's reasonable for SpaceGuy to conclude that 48 weeks should ring his bell.

Good to see you posting and have a Happy Holiday Season,

-- Jim

[jmjm530]

Actually, the oft quoted Interenet Dr. C, has suggested amping up the interferon at the end for similar reasons as you cite. Not sure, however, that this contradicts tapering off, or maybe it does. Duh. I know I personally struggled -- a bit of an overstatment -- with tapering off at the end of my treatment, but in the end chickened out because I was doing so well on paper (RVR) that I didn't want to go into uncharted (or let's say diluted) waters.

-- Jim

[spcecst2]

I am curious, do you think that longer treatment, or going longer after undetectable can "affect the longer term negotiation  between virus and host immune response that determines SVR" after someone who is geno 1 relapses?

[FlGuy]

It is FSU but am trying to nudge him to UCF or UF, they're closer. His choice though. Goof: certainly unchartered waters for me, winging parenthood. Thanks.

[cascades91]

I respectfully disagree with these comments jmjm530.  You wrote:
>> These studies (and I assume more) appear to suggest that RVR is RVR, whether treatment naive or treatment experienced, as in your case.
As to how you got to RVR, from everything I've read, it makes no difference -- be it double-dosing, high-dose riba, adding a PI, etc -- as long as you got there. <<

Here is the way I see it:  Predictability from RVR was estasblished within  specific dosing protocols and it applies specifically to that protocol'  For illustration of my point:  under such a dosing protocol I may not achieve UND status until week 12 and may not achieve SVR due to host genetic factors and viral genetic factors eg drug resistant quasi-species. (I've experienced that twice)   However,  I could bomb the heck out of that virus for the first 4 weeks with gigantic doses of antivirals and achive RVR by week 4-6. (I've done that also) However, this does not change my host genetic factors nor viral genetic factors, eg; drug  resistant quasi-species so I may still experience viral breakthrough or relapse after EOT.   I don't think you can change these genetic factors by forcing an RVR or EVR by very high dosing at the beginning of treatment, so the predictability of SVR in the case of a forced RVR is not the same.  (I tried that approach and it didn't work)  It's much more complicated  than just achieving these VL markers (RVR, EVR) as I learned it's  more to do with complicated genetic factors.  

However, achieving RVR under these standard dosing protocols is quite apparently due to favorable genetic  factors in the first place which resulted in SVR. and thus the RVR has predictive value within that protocol.  Forcing RVR or EVR with extremely high dosing at the beginning of treatment is not the same thing, does not equal favorable genetic factors  and thus would not have the same predictive value.  This is not to rule out success in the case of  a forced RVR situation because we are really only talking about averages in treatment statistics for  a very complicated disease  which is not well understood and anything can happen.  Sponteneous clearance after decades of chronic infection is one such mystery.  

That's my perspective based on my own knowlege and experience.  Basically, I am saying that complex genetic factors rule, not achieving certain VL measures (RVR) by whatever means it takes to achieve those measures.  

Further, I've learned that longer treatment is more effective than a shorter  high dose treatment. There is evidence from studies  to support that.  Again this must be do to genetic factors and viral attrition (new term I made up).  Longer treatment  is what I would chose, since I already tried the high dosing route including very high doses  at the beginning (Peg Intron plus standard IFN-Intron A  for 9 weeks + ribavirin)  As far as tapering off-  Interesting theory that's been around a long time but- not a good idea unless you extend the period of treatment and taper off during that extension.  Heavy dosing at the end? I tried that and ended up in a wheelchair for 2-1/2 months as a result.  It's much easier said by someone who is not on treatment than done by someone who is on treatment!  It was both the Ribavirin, forcing doses above my safe tolerance and that last dose of Peg Intron (that actually hurt), I knew at that point I kinda over did it.  That treatment ended in Aug 2003.  I'm beginning  to get in shape and prepare for another round, probably my last chance so I have to make the best possible decisions.  I am very skeptical of VX950 and not buying the hype.  I have genotype 1A,  very high viral load, 40 yrs infection, medically disabled from it, probably  over the edge into cirrhosis now,  two intensive  treatment failures behind me.  I am looking toward my last chance and I want to be sure it works so I am very critical of the research data and not buying the hype.  This is my first post-  I'll probably be back

[jmjm530]

Thanks for your thoughts.

I based my conclusion on the fact that studies other than those with SOC, seem to bear out that RVR correlates with SVR. Two examples are the double-dosing studies and more recently the Telaprevir studies. That said, I did share you skepticism of PI induced RVR (before the trials) even though the medical community seemed to be saying that RVR rules. The Telaprevir trials have seemed to show that my concerns were unecessary and the medical community correct.

Why are you skeptical of VX950 (Telaprevir) and "not buying the hype". Studies show around 60% chance of SVR with half the interferon exposure (24 weeks). And if they allowed helper drugs and got the rash treated better, no doubt those SVR figures would be higher.

As to "longer" versus "shorter/high dose" -- I think it depends on what is better for the individual. For example, for someone that had a rapid viral decline, became UND early-on, but relapsed -- then going longer on re-treatment seems to make sense. However, if someone was a slow responder the first time, then hitting the virus early with higher doses -- such as double dosing -- might make more sense. This topic was discussed over at the Clinical Care Options Web Site in the Dietich/Jensen Video "Doc Eye for the Hep Guy". Free registration is required.

Regarding the tapering issue -- I think we're in agreement here, that if one is to taper --  better to do it as an extension of SOC as opposed to in effect cutting SOC short.
The idea of amping up at the end wasn't mind, I was just putting it out for discussion, and I believe it was only the Peg the doctor was talking about, and only for the last week or two. I would have tried it myself except I felt like sh*t at the end and barely made it with the normal dose.

I wish you the very best on re-treatment.

-- Jim