Increased SVR Rate with 48 Wks' Treatment and Higher RBV Dose Geno 2/3

Question

http://www.natap.org/2007/DDW/DDW_01.htm

Increased SVR Rate with 48 Wks' Treatment and Higher RBV Dose in HCV Genotype 2/3 Pts Without a Rapid Virologic Response (RVR) Treated with Peginterferon Alfa-2a (40KD) (PEGASYS) Plus RBV (COPEGUS)
 
 
  	Reported by Jules Levin
DDW May 20, 2007
 
B. Willems1; S. J. Hadziyannis2; T. R. Morgan3; M. Diago4; P. Marcellin5; D. E. Bernstein6; P. J. Pockros7; A. Lin8; M. L. Shiffman9; S. Zeuzem10
1. Hopital Saint-Luc-Centre Hospitalier de l'Universite de Montreal, Montreal, QC, Canada.
2. Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece.
3. Gastroenterology-11, VA Medical Center, Long Beach, CA, USA.
4. Hospital General de Valencia, Valencia, Spain.
5. Hopital Beaujon, Clichy, France.
6. North Shore University Hospital, Manhasset, NY, USA.
7. Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, CA, USA.
8. Roche, Nutley, NJ, USA.
9. Virginia Commonwealth University Medical Center, Richmond, VA, USA.
10. Department of Internal Medicine, Saarland University Hospital, Homburg/Saar, Germany.
 
Background: ACCELERATE, a large-scale (n=1469) prospective study recently showed that, overall, peginterferon alfa-2a (40KD) plus ribavirin (RBV) for 24wks was superior to 16wks in hepatitis C virus (HCV) genotype 2/3 pts (EASL 2006:A734). In this study, two-thirds of pts achieved a rapid virologic response (RVR; HCV-RNA <50IU/mL at wk 4). These early-responder pts had a >80% probability of achieving an SVR with 16wks of therapy, suggesting that this shortened treatment regimen may be a reasonable customized option for RVR pts who cannot tolerate a full course of therapy. Conversely, pts without an RVR had an SVR rate of only 49% with 24wks' treatment, suggesting that these pts may benefit from more intensive treatment regimens. To determine whether an intensified regimen of peginterferon alfa-2a plus RBV may be beneficial in genotype 2/3 pts without an RVR, we retrospectively examined available data from other pivotal clinical studies.
 
Methods: SVR and relapse rates following peginterferon alfa-2a (PEGASYS) plus RBV (COPEGUS) were analyzed in HCV genotype 2/3 pts who did not achieve RVR in two studies (NV15942, NV15801). In NV15942 (Hadziyannis. Ann Int Med 2004), pts were randomized to 24 or 48wks of peginterferon alfa-2a 180

orphanedhawk · Answer

Thanks for the heads up :)

GoofyDad · Answer

Yup - out smart him and you're the smartest guy in the world. Gamble and miss the cut... and well, that's a lotta egg to be cleaning.  You know what's right - even if it changes from hour to hour. 

I have this little squeeky voice in my butt that always pipes up at the most inopportune moments...

FlGuy · Answer

The G3 and 48 assessemnt might be a little more telling with the phrase'hard to treat cases'.  And I would guess that mostly 'hard to treat' is a retrospective view as in 'you relpased, maybe we should have gone 48, not 24'  With the benefit of hindsight, I probably would have considered myself hard to treat (cirrhosis, older, smoker, stupd).  On tother hand there are people who are seemingly hard to treat who get out, successfully, at say 26.

GoofyDad · Answer

26 weeks hhuh? Odd number - who would do that?

But I only smoke after sex - and a cool wash cloth usually puts it out fairly quickly. Did you see the bar charts in the Accelerate sudy? Interesting breakdown on how diffferent factors affect SVR in the geno 2/3 population. RIBA weight/dose ration being a biggie. RVR and cirrhosis also big. Surprise Surprise.

FlGuy · Answer

Yeah.  Even if it's overkill, and I think it is, trying to cover all those bases.  At this point, I knew I'd be looking at week 38 and asking myself if that's the stop for this train.  But somewhere in my wallet a small voice says 'hey jerky, you paid hard cash for that guy who said 46 and you'd look pretty stupid if you did not take the train all the way to the last stop.  Kind of funny the different places where small voices come from.

GoofyDad · Answer

When I was at Dr. Jacobson's he told me that the docs were quickly finding that the relapse rates for 2/3 were much higher than they had previously thought 

OK. I'll bite. How are they quickly finding out the the relapse rate is higher? They have several years of data that establishes the relapse rate - then they quickly find out it's wrong? We're people mistaken about their SVR status?  Did they forget they relapsed? Something new in the water supply? Or was it when they started using recycled interferon from cancer patients? 

There are like a bazzilion studies that fix SVR rates for geno 2/3 - what's changed? Conspiracy uncovered?

GoofyDad · Answer

Well, you caused me to glance at it a little more closely: 

http://www.natap.org/2006/AASLD/AASLD_28.htm

It's particulalry worthwhile to note this study was fixed dose riba = 800 mg. That's of course a whole different kettle of fish in terms of short course treatment. Being of low enough weight to get even a relatively meager riba exposure of 9.9 mg/kg was a more favorable prognosticator of SVR that any other variable. The short course protocols I've seen all call for a lot more riba than that.....    

I flagged OH because this study looks at many of the issues she's facing, including riba dose, cirrhosis, duration, geno 2/3. Somebody might point here here if they see her.....

jmjm530 · Answer

Good point about the fixed dose. I believe the earlier studies using weight-based ribavirin showed similiar SVR rates for the shorter course for RVRs treating for  16 weeks (Pegasys) or 12 weeks (Peg Intron). I think we're on the same page that the shorter course the best option for RVRs, with the exception of those with significant liver damage, which I believe was why your docors originally were thinking shorter course, and then treated for around 24 weeks. I am becoming more and more convinced that interferon should only be reserved for those with significant liver damage, but if one decides to treat, then the shorter the course the better even if the odds are incrementally worse, which in this case they may not be. 

All the best,

-- Jim

nygirl7 · Answer

When I was at Dr. Jacobson's he told me that the docs were quickly finding that the relapse rates for 2/3 were much higher than they had previously thought and that some doctors were beginning to look at 48 for their patients as standard care.

I never asked him about doing any short course treatment, stopping early at RVR or anything because at the time nobody would think to even try that - it just sounded foolish.

Cindy10 · Answer

I was <615 at week 4 but still detected and I have to extend. Dr wanted 48 weeks, but I decided on 36 and he agreed.

jmjm530 · Answer

Ah, maybe I did misread your previous post. The abstract was referring to the ACCELERATE study where I believe they found 8% better chance of SVR with 24 versus 16 weeks in RVRs. Thus they recommended 24 weeks with 16 weeks as a good option for those having a difficult time with sfx as SVR was still over 80%. Again, this differs from two previous studies showing similar rates. But in any event, the stats are stats but the recommendations are subjective as to whether the xtra weeks of drug exposure make sense.

-- Jim

jmjm530 · Answer

Goofy says: "In the abstact posted in this thread - no support is offered for 16 weeks being reserved for those with problems on treatment. Nothing here says RVR's could do better by staying on treatment."
-----------------------
Maybe I'm misunderstanding your statement, but I was referring to the following from the posted abstract as well as other commentary I've read previously about the study referenced. There were also a couple of earlier studies (not referenced here) that showed that 16 weeks (Pegasys) or 12 weeks (Peg Intron) did not compromise SVR rates in RVRs. 

From the abstract: 

"These early-responder pts had a >80% probability of achieving an SVR with 16wks of therapy, suggesting that this shortened treatment regimen may be a reasonable customized option for RVR pts who cannot tolerate a full course of therapy."

GoofyDad · Answer

In the abstact posted in this thread - no support is offered for 16 weeks being reserved for those with problems on treatment. Nothing here says RVR's could do better by staying on treatment. 

There are contradicting studies out there - some showing RVRs can't do materially better with longer - some showing they can. Bottom line: if you have RVR going 24 might be better than 16, might not. Note too that these 80% numbers generally include those who stop early for whatever reason. If you make it to 16 weeks on full compliance - it makes sense that your odds improve a fair amount beyond 80%.

GoofyDad · Answer

The viral decline curve flattens out a bit at the bottom. If you plot that decline mentally, it looks like it was dropping by 1 log, or 90% each week. Allowing for some flattening of the curve, I would guess at UND by ultra sensitive test sometime between week 5 & 6. Many studies though were using <50 or even <615. All in all, it's a judgement call, and as Jim points out, tollerance for 'failure' is a big factor.  Lower damage makes one more risk tollerant. 

All the above is pure speculation. I'm an aspiring roto-rooter guy, not a doctor.

welderman · Answer

my 4 week pcr was at 490 I started at 1,500,000 the day before treatment by that study I didn't make the RVR should I be looking at 48 weeks instead of 24 weeks I'm a geno 2b I took a 6 week pcr haven't got the resuts yet hoping for und. If I am und did I become und one day after the 4 week pcr test or the full two weeks later. Liver stage 2 grade 2.  

Lynn

jmjm530 · Answer

Thanks for posting. Another reason to get a sensitive week 4 PCR to help determine treatment length. Also to note is that the author finds 16 weeks to be a reasonable option for RVR's who are having problems during treament as this short course group still has an SVR rate >80%.

My own opinion is that 16 weeks is a reasonable option for ALL RVRs who do not have significant liver damage, as the 16 week data for RVRs (>80%) is actually slightly better than the 48-week data for non-RVRs (76%).

The study also points to the advantage of weight-based ribavirin in treating geno 2's and 3's, as opposed to a flat 800mg dose as sometimes prescribed.

Overall, another study pointing to the importance of individualizing treatment according to viral response. And while side effects are brought up in terms of the shorter-course (16 week) treatment decision -- this study, as well as some others, does not touch upon factoring in liver damage in that decision.

IMO (as in MY opinion) these longer courses of treatment (48 weeks in this case) make the most sense for those with significant liver damage and the least sense to those with less liver damage who have the luxury of waiting for better treatments should they not SVR.

In fact, one reasonable strategy for those with little or no liver damage who have made the treatment decision, is to agree with their doctors on a 4-week stop rule. If not in the majority who are <50 IU/ml at week 4, then stop treatment as opposed to extending to 24 or 48 weeks. If <50 (RVR) then treat for 16 weeks with a >80% chance of SVR.

-- Jim

Increased SVR Rate with 48 Wks' Treatment and Higher RBV Dose Geno 2/3

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