"Extended Treatment Duration to 72 Weeks in Chronic Hep C Genotype 1 Slow Responders: Final Results of the Success Study"

I was surfing the Web and came across this recently posted study (reported at the EASL Annual Meeting in Copenhagen in April, 2009). I don't recall it being posted to the discussion board yet. The full article can be found here:

http://www.natap.org/2009/EASL/EASL_89.htm

This purports to be the largest randomized study of 48- vs. 72-week treatment regimens for genotype 1 slow responders. Slow responders are defined as those who had a >2-log drop by week 12, but not undetectable until week 24.

The conclusion of this study is that although the SVR rates are somewhat higher for those who treated for 72 weeks, the improved rates of SVR are not statistically significant. Or, to put it in the words of the study, "This, the largest prospective study among G1 slow responders, demonstrated no statistically significant difference between 48 and 72 weeks of treatment. However, in these true slow responders, extending PEG-IFN alfa-2b/WBD ribavirin treatment is associated with better SVR and a similar incidence of adverse events. These results are in line with those observed in other WBD ribavirin trials in slow responders."

We're probably in the waning days of 72-week treatments because of the advent of the new PIs. But this study should certainly be considered as important evidence by anyone contemplating 72 weeks of treatment.

[Trinity4]

I saw that Mark.  I think I posted it on one of Portann's threads.  Anyway, I wasn't encouraged to say the least.  

Also, did you read the Chariot Study which suggests SVR rates are lower as fibrosis advances through each stage?  I've been told this and read it as well and EASL 2009 Chariot Study is one of the latest published which supports it.

[portann]

Yes, I'm not happy about this. It flies in the face of the core beliefs about tx extension that I've learned on the board.

I know it's just one study but this 48/72 week thing is a lot to swallow.

Can anyone turn the tables on this study and show it up for less than it claims to be or at least put it into perspective?

[jmjm530]

Yes, I'm not happy about this (new study). It flies in the face of the core beliefs about tx extension that I've learned on the board.
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It actually flies in the face of previous studies per the studies own introduction. Also in the face of treatment protocols recommended by many top docs either as related here or in the teaching modules on sites like Clinical Care Options and Proects-In-Knowledge. NYGirl is one example, and the doc that suggested 72 weeks to her is Dr. J., arguably one of the top five most respected hepatologists in this country. I don't have the old studies handy but the one thing that may set it apart is that this cohort was on WBD and the previous studies may not have been. Not sure. it will be interesting to see what the top hepatologists think and if they will use this study to change their treatment protocols of slow responders.

Trinity: Also, did you read the Chariot Study which suggests SVR rates are lower as fibrosis advances through each stage?
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LOL. Didn't we recently rehash all that and wasn't the point -- at least my point -- that SVR rates only advance at stage 4 per the body of knowledge to this point? Anyway, why spoil a nice day and rehash, maybe someone can pull up the old thread so we can battle vicariously :)

-- Jim

[Trinity4]

If my recollection serves me, the WIN-R study states SVR is the same for all except those with cirrhosis or at least that is what you implied on our last debate?  No trying to rehash, but am I missing something here?   The following suggests that SVR rates are *incrementally* lower as fibrosis advances through each stage.

“The sustained virological response (SVR) rate 24 weeks after completion of therapy was considerably lower in patients with advanced fibrosis or cirrhosis.

However, SVR rates were similar in the standard therapy and induction arms, regardless of fibrosis stage:


Stage F3-F4 standard therapy: 24%;
Stage F3-F4 induction regimen: 28%;
Stage F0-F2 standard therapy: 55%;
Stage F0-F2 induction regimen: 58%.”

[newleaf09]

This is part of being intimately involved in a very fast moving science.  Lots of bubble-bursting.  When I starting treating in mid-November, it was thought that interferon would regress fibrosis. I'm in a study and thought, "I'm stage 4, hope I don't end up in the 28 wk. arm".  With the publication of Halt-C results (it's not the interferon, it's clearing the virus and ending the assault on liver cells), now I'm praying to be in the 28 wk. arm.  They have been treating rapid responders in Europe for 6 mos, but not here.  Our docs can be overly cautious.

Who knew?  Things change fast in virology.  Wonderful, but it will be a little disillusioning, too.  I'm sorry for all who treated for so long with 'no statistical difference', but glad to know that few will have to continue that course.  Change is good.

[RCM829]

If I read the results to the study correctly, providing one is 80/80/80 compliant (and why wouldn't you be?) there was a difference in SVR of 43% for 48 weeks of treatment versus 57% for 72 weeks of treatment.
No, it's not a blow-away number but in my book 13% is statistically significant. If you can't wait for new treatments - or choose not to - a 13% figure would motivate me.
Thanks for the link Marc!

[eureka254]

Someone help me here... so I'm reading the full text...

The summary states this:
"This, the largest prospective study among naive G1 slow responders, demonstrated no statistically significant differences in SVR or relapse rates between 48 and 72 weeks of treatment.." Then it goes on to say, "However, there is a numerical trend toward improved SVR and reduced relapse rates for the 72 weeks therapy."  Sounds like a foot on each side of the fence to me...!

So what's "statistically significant" vs. "numerical trend"?!?

The raw stats from the study state the following:
"Results: In total, 1427 patients were treated. Mean age was 42 years; 61% were males, and 95% were white. HCV RNA was >800,000 IU/mL in 80% of patients. HCV RNA became undetectable at week 12 in 816 (57%) patients. At week 24, 159 (11%) patients were identified as slow responders. These patients were randomized to 48- or 72-week treatment. In an intent-to-treat analysis, SVR rates were 43% (A), 48% (B), and 79% (C). Patients who were 80/80/80 compliant had SVR rates of 44% (A) and 57% (B) (no 80/80/80 analysis was performed for group C)."

So my interpretation is that of the 159 patients randomized, of the compliant patients, the 48wk (A) group had SVR rates of 44%, while the 72wk (B) group had SVR rates of 57%. (Someone please correct me if I'm misinterpreting.)  Does not "statistically significant" refer to the fact that it's a small number of patients?  A 13% improvement in SVR seems pretty significant to me... or have I got it all wrong?
~eureka

[RCM829]

I take it to mean the "numerical trend" of a 13% improvement in SVR did not qualify as "statistically significant" to the study coordinators.
Like you, I disagree with them. Frankly, I don't get it either....

[eureka254]

And the relapse rate differential is even more (not?) "significant": 48-weekers had a relapse rate of 47.1% while 72-weekers had a relapse rate of 32.7%.  Didn't see your post until after I wrote mine, but I'm definitely with you on this one.  Guess it's another case of same study, different conclusions.  ~eureka

[jmjm530]

Trinity: If my recollection serves me, the WIN-R study states SVR is the same for all except those with cirrhosis or at least that is what you implied on our last debate?  No trying to rehash, but am I missing something here?   The following suggests that SVR rates are *incrementally* lower as fibrosis advances through each stage.
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Yes, you are missing something :) and it was all said in our last "debate". I'll try once again to give it my best shot cause I'm outta here for awhile.

The WinR study -- largest of its kind -- was quite clear that there was no difference in SVR rates between stages 1, 2 and 3. Only with stage 4 (cirrhosis) is there a difference. Your study -- the 'Chariot' -- does not contradict WinR because it lumps geno's 3 and 4 together and then compares SVR rates to geno's 1 and 2. This in fact was why previous studies (previous to WinR) also suggested same. But if you do not lump stage 4's with stage 3's, then there is no difference in SVR rates. Of course you can argue that biopsies aren't perfect and that fibrosis can advance quickly in some cases, but let's at least try and get straight what the data says in the studies we both reference.

(From Win-R)
"In the entire population of patients logistic regression showed no statistically significant difference in SVR rates between Stage 0 (44%), Stage 1 (46%), Stage 2 (44%) and Stage 3 (44%)"


(WinR Study) http://www.hivandhepatitis.com/2006icr/ddw/docs/052306_e.html
(Chariot Study) http://www.natap.org/2009/EASL/EASL_86.htm

[Marc1955]

A few points:

• This study (SUCCESS) does not contradict previous studies. No study exists that has established a statistically significant increase in cure rates for 72 weeks vs. 48 weeks for any class of patients. The studies that are cited on this discussion board have small samples and are suggestive at best. It is possible that a study with a much larger sample would establish a statistically significant variance, but no study has to date. Certainly the current research suggests that if there were a statistically significant variance it would be slight at best.

• Jim is correct when he says that 72-week treatments are not simply trumpeted on this board. Many prominent and leading practitioners, both in the US and abroad, are proponents of 72 week treatments. But I think Newleaf09 makes the most salient point – we are in the very early days of treatment for HCV. There are bound to be many treatment paths that are tried then abandoned as knowledge increases. The 72-week approach could easily fit in that category regardless of how many proponents in currently has.

• People who want to pursue a 72-week treatment need to understand that insurance companies seem to have the preponderance of evidence on their side for denying coverage beyond 48 weeks. That's not to say an individual cannot get 72 week treatments covered. I did. But the insurance companies are not acting arbitrarily or irrationally if they deny the extension of treatment.

• Finally, some of the responses on this thread show some of the problematic aspects of this discussion board – cherry-picking evidence to support previously held points of view, ignoring standards of scientific research, making very arbitrary and one-sided interpretations. Unfortunately, we all know from past experience that these misreadings are just as or more likely to be trumpeted in the future on discussion threads giving readers an entirely inaccurate understanding of the status of research. Bottom line – extremely few of the people who participate in this forum have any relevant professional training at all. It is a serious mistake for anyone to base a treatment approach on information posted on this forum. The most important step in treatment is to find the most knowledgeable hepatologist you possibly can. The forum can be of great value, but it is not a reliable source of treatment information.

[nygirl7]

48-weekers had a relapse rate of 47.1% while 72-weekers had a relapse rate of 32.7%

That means you have about a 50% chance of relapsing with 48 weeks and only a third of a chance with 72.  That is HUGE motivation if you ask me, it kept me going for sure.

it's not ALL About the Sanchez Tapias study and 72 week thought though, you have to remember to figure in Berg and several other different aspects of thought.  That is why we are all encouraged to read and study the data ourselves and draw the best conclusions we can. I figured the doc who was the lead investigator of Berg would have the best thoughts about it and he advised me to go for it.

That 1/3 relapse rate number to me was more than sufficient reasoning to continue onwards and it worked. Obviously it won't work for everybody (look at people like Susan who have such strong mutations that nothing will work except probably the right dosing of PIs...) but if it works to drop that 1/2 down to 1/3.......well that is a good enough reason to go for it I think.

[jmjm530]

It is a serious mistake for anyone to base a treatment approach on information posted on this forum. The most important step in treatment is to find the most knowledgeable hepatologist you possibly can. The forum can be of great value, but it is not a reliable source of treatment information.
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Good post, Marc, I agree with a lot. In fact, I commented in a similar fashion at the end of this thread, here:
http://www.medhelp.org/posts/Hepatitis-C/Info-regarding-Dr-Dieterich-/show/958792?post_id=post_4507668

That said, your implication that "suggestive" studies are flawed belies the reality of how HCV has to be treated. Frankly, that's all we got to go by, and one a study is suggestive -- suggestive enough for doctors like Dr. J., D., S. (and the rest of the alphabet :) ) -- to incorporate those studies in their practice. Then yes, reporting all that here, as has been done is the right time and quite responsible. People here have challenged some of those studies, including myself because some did not use Weight -based riba -- but still, and I think this is consistent with your last paragraph -- one should follow the most knowledgeable hepatologist you possibly can. You said it yourself and hepatologists promoting 72 weeks just happened to be the most knowledgeable hepatologists in the country. Hopefully, this will become mute soon as SOC becomes replaced with triple PI therapy,.

[nygirl7]

By the way -

• People who want to pursue a 72-week treatment need to understand that insurance companies seem to have the preponderance of evidence on their side for denying coverage beyond 48 weeks.


The insurance company said it was "experimental" and they wouldn't pay the extra cost but would gladly pay for a transplant when/should I need it.  That was their reasoning and nothing more, $$$$$ in the end on the meds. Fortunately the drug companies come through for most of us and provide them for free. Remember I had one of the top hepa docs in the world arguing my case and still Aetna wouldn't spring for the extra $$$.  

Money makes the world go round and seriously from what I heard that had no more evidence than that.

[JennyPenny]

This is an excerpt from Medscape: Expert Opinion on the Treatment of Patients With Chronic Hepatitis C: Extending Treatment Duration for Slow Virological Responders

S. Zeuzem,1 T. Berg,2 B. Moeller,3 H. Hinrichsen,4 S. Mauss,5 H. Wedemeyer,6 C. Sarrazin,1 D. Hueppe,7 E. Zehnter,8 M. P. Manns 6

Evidence from three randomized clinical trials support the case for extending treatment duration beyond 48 weeks in HCV genotype 1 patients with a slow virological response, i.e. HCV RNA > 50 IU/mL at week 12 but undetectable ( 50 IU/mL at week 4) to treatment with pegylated interferon alfa-2a (180 µg, qw) and RBV (800 mg, qd) for 48 or 72 weeks.[46] Extending treatment to 72 weeks significantly increased the SVR rate compared with the standard 48 weeks of therapy (45% vs 32%, respectively; P = 0.01). In genotype 1-infected patients, this effect was particularly evident, with 44% of patients who received 72 weeks of treatment achieving SVR compared with 28% of patients who were treated for 48 weeks (P = 0.003). The incidence of adverse events was similar between the two groups, although treatment discontinuation was significantly more frequent in the 72-week group (36% vs 18%; P = 0.0004). A retrospective analysis of patients from the European-based trials, including that of Berg et al., demonstrated that patients without RVR but achieving subsequent early viral response (EVR) (> 2 log10 HCV RNA decrease), benefited from extending treatment duration and achieved a higher SVR rate (77% after 72 weeks vs 31% after 48 weeks.[48]

Pearlman et al. examined the effect of longer treatment duration with pegylated interferon alfa-2b plus weight-based RBV in patients infected with HCV genotype 1 who met EVR criteria at week 12 (> 2 log10 drop in baseline HCV RNA), but who had detectable HCV RNA at week 12 and became HCV RNA-negative at week 24.[47] This group of 'slow' viral responders was then treated for either 48 or 72 weeks. Results showed a 39% SVR in the 72-week arm compared with 18% SVR in the 48-week arm; treatment extension did not seem to result in an increase in dose reductions of RBV or discontinuations. Taken together, the available data suggest that longer duration of therapy improves sustained response rates in 'slow' virological responders.

Proportion of HCV Genotype 1-Infected Patients who Could Be Considered for Shortened or Extended Therapy Duration
An extended treatment duration of 72 weeks can be considered in 'slow' virological responders, defined as patients who are HCV RNA positive at week 12 but become undetectable at week 24. These patients comprise approximately 20% of the HCV genotype 1-infected population, a not insubstantial proportion.[45] Similarly, around 15% of all HCV genotype-1 infected patients could benefit from a shorter treatment duration without compromising the SVR rate; again constituting a clinically relevant proportion of patients.[30]

http://www.medscape.com/viewarticle/589014_7

[FloridaMouse]

Wish it was the case for me.  I finished 72 weeks on 4/21/09 and found out Thursday that my Qualitative PCR came back detectable.

Mouse

[justme53]

I am so saddened to hear about your PCR. Any news on the numbers? Grasping at straws, but could it possibly be a false positive?

Thinking of you........Pam (22/72)

[Proactive]

Sh*t!! Gosh Mouse, I am so sorry to hear about your relapse.. You are one heck of a fighter..Take some time and collect yourself, enjoy the Summer and recoop. Should you chose, the PI's are not to far in the future.
Pro

[Trish77]

Mouse, I'm so sorry to hear this news.  I don't know what to say. :(   All I can say is..what Pro said.  Take care, Mouse and my thoughts are with you.

Trish

[FloridaMouse]

I'm going Monday to have the Quantative draw to find out the VL.   I'll keep you guys posted.

I wanted to also thank everyone that sent me notes and messages, I was stunned and warmed to see them all.   I did try to respond to all of them and hope that I did it right.

Mouse (Missy)