New hope for Geno 1's??

Detectable HCV RNA at Week 8 Is Best Predictor of Relapse in Genotype 1 Hepatitis C Patients Treated with Pegylated Interferon plus Ribavirin
By Liz Highleyman

Summary:  
Chronic hepatitis C patients who still have detectable HCV viral load after 8 weeks on pegylated interferon plus ribavirin have a higher risk of relapse and are more likely to benefit from extending treatment to 72 weeks, according to a presentation at the recent DDW 2009 meeting.

Introduction

Current standard therapy for chronic hepatitis C virus (HCV) infection -- pegylated interferon plus ribavirin for 48 weeks -- produces a sustained virological response (SVR) in about half of treated patients, prompting researchers to explore alternative treatment strategies and look for predictors of good outcomes.

Peter Ferenci from the University of Vienna in Austria and colleagues recently demonstrated in a large randomized controlled trial that extending the duration of treatment with pegylated interferon alfa-2a (Pegasys) plus ribavirin reduced the risk of relapse and increased the SVR rate in patients with hard-to-treat HCV genotypes 1 or 4 who did not achieve rapid virological response (RVR), or undetectable HCV RNA at week 4 of treatment.

In an analysis presented at the recent Digestive Disease Week annual meeting (DDW 2009) in Chicago, Ferenci and colleagues sought to determine which of these non-RVR patients would benefit most from extended treatment, looking at associations between SVR and relapse rates and HIV RNA levels at weeks 8 and 12.

The present analysis included 187 chronic hepatitis C patients enrolled at one center (34% of all recruited participants in the larger study). Participants who still had detectable HCV RNA at week 4, but who experienced more than a 2 log decrease or had HCV RNA < 50 IU/mL at week 12 (early virologic response, or EVR), were randomly assigned to receive treatment for either 48 or 72 weeks.

A total of 97 patients achieved EVR, of whom 52 were assigned to received the 48-week regimen (all competed treatment) and 45 received the 72-week regimen (41 completed treatment). Blood samples obtained at weeks 2, 4, 8, and 12 were retested using a sensitive viral load test with a limit of detection of 10 IU/mL.

Results

Patients with undetectable HCV RNA at weeks 8 and 12 had high SVR rates with either 48 or 72 weeks of treatment:


Undetectable HCV RNA at week 8: 91% with 48-week regimen, 100% with 72-week regimen;

Undetectable HCV RNA at week 12: 81% and 82%, respectively;

If HCV RNA remained detectable at weeks 8 and 12, SVR rates were low:


Detectable HCV RNA at week 8: 37% with 48-week regimen, 54% with 72-week regimen;

Detectable HCV RNA at week 12: 29% and 33%, respectively.

Regardless of treatment duration, only 2 of 35 participants (6%) with undetectable HCV RNA at week 8 experienced relapse, for a negative predictive value (NPV) of 94%.

Of the 25 patients who achieved undetectable HCV RNA between 8 and 12 weeks, 7 (28%) relapsed, yielding an overall NPV of 72% (60% for the 48-week regimen, 80% for the 72-week regimen).

Participants who had detectable HCV RNA at both 8 and 12 weeks had a lower relapse rate and a higher SVR rate with the longer treatment duration.

Based on these findings, the investigators concluded, "Measurement of HCV RNA at week 8 is the optimal time to identify patients most likely to benefit from extended [pegylated interferon alfa-2a] plus ribavirin combination therapy."

Internal Medicine 3, Medical University of Vienna, Vienna, Austria; Department of Clinical Virology, Medical University of Vienna, Vienna, Austria.

6/23/09

Reference
P Ferenci, TM Scherzer, H Kerschner, and others. Week 8 HCV-RNA Is the Optimal Predictor of Relapse in non-RVR Patients with Genotype 1/4 Randomized to 48 or 72 Weeks PEG-IFN Alfa-2a Plus RBV. Digestive Disease Week (DDW 2009). Chicago. May 30-June 4, 2009. Abstract M1811.

http://www.hivandhepatitis.com/2009icr/ddw/docs/062309_b.html

[Marc1955]

It looks like the longer researchers look at the 72 week treatment option, the more it comes into question.

The group with a two log drop at week 12 had cure rates of 29% and 33% depending on whether they treated for 48 or 72 weeks. This is the same group that Berg identified as benefitting the most from the extended treatment. His earlier findings are not confirmed by this study. It seems like the overwhelming predictor of SVR is the time it takes to clear the virus. Extending treatment doesn't make that much difference in most treatment categories.

All of this becomes moot at the new PIs advance toward approval. But it is important to those who are now in the course of treatment, who did not get a RVR, and are considering extending treatment.

[Marc1955]

otoh I would like to read the original study as opposed to a report about it. There are a number of things that are a bit curious. The idea of using the eight-week juncture as a critical point in treatment is new to me. I didn't know folks were pursuing this. I'd like to see the explanation for that. Also, the cure rates for the slower responders seem lower than what has been reported elsewhere. I'd like to see how many patients ended up in each cell of the study and the statistical calculations. If he started with 187 subjects, the cohort in each part of the study may be rather small.

[nygirl7]

Detectable HCV RNA at week 8: 37% with 48-week regimen, 54% with 72-week regimen;
Of the 25 patients who achieved undetectable HCV RNA between 8 and 12 weeks, 7 (28%) relapsed, yielding an overall NPV of 72% (60% for the 48-week regimen, 80% for the 72-week regimen).

I think either way you slice it if you extend to 72 it gives you a 20% boost in your odds that you will succeed? I am glad I did it and I wasn't even UND until somewhere between 12 - 24 let alone 8.  But using 8 as a critical guideline instead of 12-24 seems to me like it would really help the odds.  Only a lot of people are going to get stuck in the extending group and not going to want to do it........it's not a very easy thing to do or agree to do and right now it's those of us that are pretty desperate being not UND at week 12.

[justme53]

A couple things I like about this study.......first, it demonstrates the importance of earlier and more frequent PCR's prior to 12 weeks. Secondly, will doctors take a harder look at pushing the envelope to get that all important RVR? With the increased odds from extending, would insurance companies look more favorably on covering it without the usual battle.

One question, it doesn't answer for me, personally, is how cirrhotics figure into this. Usually there's a disclaimer, "except in the case of cirrhosis".

I agree, for those that can afford, time-wise to wait for the PI's, this probably has no bearing, but for those like me that don't have the wiggle room, I find 81-82% odds for a cEVR encouraging. Just not sure if 1% is worth the extra 6 months of tx, but I've got a ways to go before committing and perhaps more studies will be out by then.

[Marc1955]

If you're going to cite these findings, you need to include all of them not just a few:

"Detectable HCV RNA at week 12: 29% and 33%, respectively. "

This is the traditional group for extending treatment. Yes, there is a 4% difference in cure rates, but that is probably not statistically significant. So this study actually argues against extending treatment for most people with a slow response rate.

[frijole]

It is another decision making tool.  I think it all depends upon the level or your liver disease.  The differnece between a 29% and a 33% SVR rate is worth the shot if you are cirhhotic and maybe not if you are a grade 1 state 1 person.  

I think one of the key points here is dorng more PCR's earlier, and also using those sensitive tests.  There are far too many people still being tested with a test to 615.  Even tests to 50 are irrelevant except for before treating (to me).  I think as far as the general treating public goes, we are going to have a hard time increasing the number of PCRs.  I would advocate for the 4 week, and the 8 week is nice if you can afford it.

note to justme -- as I recall the the Berg study found that the highest benefit in doing 72 was achieved with those who had a VL uner 6000 at week 12 -- not just a 2 long drop.

frijole

frijole