The 36-week Rule --- The Study Behind It -- Full Text

[jmjm530]

Finally found a link to what appears to be a full-text version of the Drusano statistical model -- the study behind the so-called 36-week rule.

For those unfamiliar, the 36-week rule says that geno 1's should treat for 36 after being non-detectible for a 90% chance of SVR and 32 weeks for if I remember correctly around an 80% of SVR. Keep in mind that this is a conservative estimate in that they didn't do monthly PCR's. So for example, if someone was non-detectible at week 12, the Drusano model says treat for 48-weeks total. However, since week 12 was the first PCR it's possible that the person was actually non-detect at let's say week 6. Therefore, adding a few more weeks to the model might make sense. In my case, my doc suggests 46-weeks tx after being non-detec, partly based on age ands level of fibrosis.

Also interesting is Drusano's interest in creatine clearance and ribavirin. Very much the same areas of interest as the Sweedish researchers where riba dosing is based more on renal function than body weight. At first glance this seems to be a very important and thorough study/analysis and I'm a bit perplexed why there has not been some serious follow-up studies as Drusano himself suggested. The study is certainly quoted by enough people, including some very well known hepatologists but I guess most of them are busy testing the newer drugs. But isn't that always the case

Hope this finds everyone with kind sides today and having a happy and relatively healthy holiday season. Here's the link to the full-text version: http://tinyurl.com/86p8e  -- Jim

[jmjm530]

The web site does not seem to be taking re-direction at least with my browser -- funny it worked earlier.

Try this to get the full-text:

(1) Go to: http://tinyurl.com/8kp26

(2) Then click on the little box that says "University of Chicago Free Press" It's on the left-hand side of the page just above the title of the article. Hopefully, that will take you to the full-text version.

-- Jim

[jmjm530]

For those who read the article and want to get a rough estimate of their creatine clearance, here's a calculator: http://www.intmed.mcw.edu/clincalc/creatinine.html

It seems that the numbers generated by Durason were based on those with creatine clearance of 100 ml/min and seems to suggest that a higher creatine clearance might indicate the need to investigate either longer treatments or higher doses of ribavirin. At least I think that's where they are going.

Unfortunately, the whole issue of riba dosing in this country seems locked into body weight so creatine clearance tests prior to tx don't seem to be the norm.

In it's most simplified form -- the better your kidneys (the more efficiently they clear the riba) the more riba you need to maintain what some researchers call a therapeutic blood plasma level of ribavirin. . One can theorize this is why the same dose of riba effects people differently in terms of their treatment.

Because we don't have plasma riba testing in this country, all we have are formulas based on creatine clearance or the degree of anemia we experience which is what the Sweedish researchers say is directly related to serum riba concentrations. The way my unprofessional mind sees it is that if you're not anemic, and not on Procrit, you probably aren't taking enough ribavirin and a creatine clearance test could probably help verify.

-- Jim

[jmjm530]

Another point of interest in the Duranso study is that the average study participant didn't become non-detectible until week 31. This would then suggest a minium of 67 weeks of treatment and could account for a much higher relapse rate in slow responders who only treat for 48-weeks.

-- Jim

[avidreader]

Hi Jim,

Could you post the original url? I couldn't get either of your tiny URL's to work and this is of tremendous interest to me. I did not clear at 12 weeks (2.5 million to 3,500) and my insurance would not pay for a 16 week PCR. My 24 week pcr is coming up in 2 weeks and if I am not clear my insurance will cut me off treatment. I'm meeting with my doc prior to the PCR to discuss everything. I agree with you about the RIBA dosing from everything I have read but he is in the very standard treatment mode. I have upped my RIBA from 1,200 to 1,400 a day and plan to continue this dosage until my 24 week PCR (w'out his blessing) and am still holding on to my RBC levels which is pretty weird since I was anemic prior to starting treatment. I also have continued to have high ALT/AST levels throughout treatment--they were in the 200's but have now fallen to the high 100's. Any ammunition you could give me to take to my appointment would be appreciated.

Peace and joyfilled holidays!

Tracy

[jmjm530]

Have no idea why the links stop working.

Try this, then click on "University of Chicago Free Press" box just above the title of article.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14999598

[jmjm530]

Or try this link and let me know how it works out. What you want is the full-text article, not the abstract:

http://www.journals.uchicago.edu/JID/journal/issues/v189n6/31190/31190.html

[jmjm530]

Alternatively, go here and then click on "HTML" under "Availability"

http://www.journals.uchicago.edu/cgi-bin/resolve?id=doi:10.1086/382279

This is one pesky url to post. I think it originally may have been a paid article the original web site is only taking hits in a very narrow time window. I'll get it to you one way or another so let me know if you get it.

-- Jim

[avidreader]

Got it with the first link and had no trouble clicking onto the full paper. Ironically I live only 12 miles outside of Albany where the study was done. Would that I knew then what I know now--I would have doctor shopped more aggressively!

Thanks for you persistence with the link.

[jmjm530]

Glad you got it and good luck with your treatment.

You'll notice right under the bold abstract where you can order reprints which might be nice and impressive when you visit your doc. Hopefully, the email and address is current.

Reprints or correspondence: Dr. G. L. Drusano, Ordway Research Institute, 150 New Scotland Ave., Albany, NY 12208 (***@****).

Article title:

"A 48-Week Duration of Therapy with Pegylated Interferon α2b plus Ribavirin May Be Too Short to Maximize Long-Term Response among Patients Infected with Genotype-1 Hepatitis C Virus

G. L. Drusano and S. L. Preston

The Journal of Infectious Diseases    2004;189:964-970
© 2004 by the Infectious Diseases Society of America. All rights reserved.

[jaroman]

Interesting that around the same time I got an increase in viral load, I also was increasing my Hgb.  Hmmm, time to up the riba.

[couldn't think of a nickname]

A couple of questions came to mind when I was reading that. The first, was, how sensitive was the PCR test? If it was to <50, then undetectable could have come after the average of 30 weeks. Another question in my mind, is, what model were they using? I wonder if it was the same as the ones that SGP and VRTX are using. I think the big problem highlighted is that it took over 30 weeks on average to clear. That is way too much time, and viral variants become a big issue, thus making it harder to clear, and harder to attain SVR. I think this highlights the need for something that gets it to <5 as quick as possible. I know the viral variant study VRTX did is not standard, but since they have, I think that standard should be applied to these futher studies. I am willing to bet that if the same viral variant study were done on current SOC, people would be surprised at how much of an issue it is. Much has been made of it about 950, which is the least likely to see that in my opinion. Time to find out about SOC. The rule of thumb has been to tx for 3-4 times the length of time it takes to go undetectable. This case, it was 1 time, although the same number of weeks post undetect.

I think the only real conclusion to draw in my opinion, is, that if you clear late (week 24, 30, etc.) then 48 weeks total is not likely to get SVR. Docs should see this and extend tx. My PCP has tx'd (he is not a liver specialist, but does tx some) some for 18 months for geno 1. I think he is very up to date in his views and knowledge, and is willing to tx longer. He has also had contact with some of best in the U.S, so maybe that is why he is more open-minded.

Now I am just rambling, in between Christmas visits.

Happy Holidays to all.

[Wasabi Pea]

Jim, thank you so much for this timely post.  I had an appt. last Thursday with nurse, and she informed me we would be stopping my treatment at 49 weeks despite the fact that I didn't clear until a little later than 12 weeks and despite the fact that I'm on a severely lowered dose of riba and despite the fact that I stopped riba for a whole month at one point.  I was informed she extended tx a whole week to cover for that one month without riba.

I told her about the 36-week rule and she pretty much scoffed at me.  I can't even begin to express how angry I have been about the way I've been treated.  I've sought out advice from three other doctors outside of this nurse and her supervising GI doc (who panicked and pulled me off of tx early on for a week because he wasn't even familiar with the sx of riba rash), and explained to them that I wanted to extend tx and I was doing this in October because I needed to know whether I needed to change my insurance if they weren't going to actually listen to me and work with me in making decisions.  And my hgb dropped from 9.0-9.3 to 8.7.  Big Whoop.  I've been operating at this low hgb level for almost a year now.  Now she's threatening to lower my riba from 400 to 200 again.  And when I say threatening, that's how I feel it's coming across.  

Anyway, I better stop because I'll start ranting again.  

In any event, thank you so much again for posting this.  I'm making copies for both her, my stupid GI doc, and I'll be taking a copy over to the hepatologist in L.A.  If they don't do this right, I'm considering paying for it myself to extend it the extra two months I need.  

The sad thing is, when I showed less than 600 copies, and then nonreactive to a qualitative, the hepatologist was like "Yay!"  My nurse informed me very straight-faced, we're stopping at 49 weeks, and you only had a 30-40% chance of SVR even with the full dosages of meds.  She's expecting me to relapse and won't even consider doing a PCR one month post tx.  

Time to transform into Miss Pain in the Butt, arm myself with as much literature as I can, and friggin' write it out for my GI doc, Mr. Doogie Howser.  The funny thing is I picked him because he was more aggressive than the last one.  He later told me he's extremely conservative and I am not at a research hospital.  

Wuff! <g>  Thanks, Jim, for staying on top of all of this.  You're really great.

[avidreader]

I think you misread my post. They expect me to clear at 24 weeks. I had an almost 3-log drop at 12 weeks. I'm just gearing up to advocate for treatment extension if I do clear at 24 since I didn't at 12. Thanks for your concern--peace and joy in the holiday season.
T.

[jmjm530]

Not sure if the viral variant issue is relevant to combo tx as I if I remember correctly that issue didn't present itself in the Vertex trials when Vertex was combined with the Peg, but I could be wrong.
I believe the sensitivity of the tests Drusano used were <100 but I'd have to take another look.

As far as the concept of getting the virus down fast to promote SVR, this is another important concept alongside Drusano's propositions. And then, of course, there is much speculation on the predictive factors of genetics as well as other blood markers. Not sure one single factor excludes another, but we have to make decisions based on what drugs we're currently treating with, what tests are available to us, etc., etc.

I hope this finds you well during the holiday season. Any prediction on Vertex the stock first quarter? I was thinking of investing but afraid the traders might run it down soon to shake out some of the speculators. That crazy Jim (Mad Money) gave it a buy prediction the other day.

-- Jim

[jmjm530]

I just want to reinterate that by Drusano's own admission, his 36 or 32 week rule is conservative due to not testing viral load every week.

So, for example, if someone tested non-detect at week 12, the suggestion was to treat for 48 weeks (36 plus 12). However, if there were more frequent PCR's, it may have been found this that person may have cleared the virus at week 6. So in this hypothetical, the treatment was not 36 weeks past non-detect but indeed 42 weeks. For that reason, it may be prudent to add on some to the 36 week rule as my doctor tends to do. He adds 46 weeks in many cases, especially if he thinks there're a lot of negative pre-tx predictors. This seems to contradict the observations of other hepatologists who feel that EVR trumps pre-tx predictors which makes the whole treatment/decision experience part science and part voodoo. I cleared at week 6 and currently am planning on 52-60 weeks of treatment depending on how I hold up and some information I'm waiting for via email from one of my consults.

-- Jim

[jmjm530]

I hope things work out for you. If you can't get your current med team on board, it might be worthwhile shopping around for another doctor if feasible. From my experience, in most cases doctors will come around if you present them with a reasonable alternative based on logic and studies -- something for them to hang their hat on. Unfortunately, some doctors could care less about anything other than their own ego. I've got one of those but fortunately not my hepatologist.

-- Jim

[couldn't think of a nickname]

I try to avoid Cramer like I avoid the plague LOL! I bought at 9.18, and 26.33, but as I say, not every stock is for every one. The reason I did buy was because I had researched their compound, and all of the others, and felt theirs could show to be the most potent. The risk is, if a future trial shows tox. or doesn't quite meet elevated expectations, it could drop it. It has been trading in a well-defined channel, and I am hoping that continues. One thing I would never do is recommend a stock to someone-everybody has different risk tolerances and circumstances. But, I am aggressive. Also, I have followed pharma and biotechs for about 11 years, so I am familiar with things.

Actually, the resistance issue I was thinking of was with current SOC. I am hypothesizing that it must be because of how long it takes to get one to undetectable. If it takes 30 weeks, that is plenty of opportunity for the virus to mutate. Just another reason why I feel the faster to 0 the better.

I am posting in between stops, and right before church. Our midnight mass here is at 10 PM (yes, people do call and ask what time our midnight mass is).

To you and all in here, have a Blessed Holiday season, and may we all experience healing.

Jm, thanks for all of your work in here, and for everyone else who makes this forum great. Agreeing with everything isn't the important thing, it is the exchange of information and ideas. That is the strength of this board in my opinion. Sometimes I think Doc's should read this board! LOL