earlier predictor of null response for SOC treatment

[HectorSF]

High Correlation Between Week 4 and Week 12 as the Definition for Null Response to
Peginterferon alfa (PEG) Plus Ribavirin (R) Therapy: Results From the IDEAL Trial

http://www.hcvadvocate.org/news/reports/AASLD%202010/AASLD%202010%20All%20Abstracts-1.htm

Aim
• To investigate the correlation between declines in HCV viral load at treatment weeks 4 and 12

Methods: 3070 treatment-naive, HCV genotype 1 infected patients were treated for up to
48 weeks with ribavirin 800-1400mg/day plus PEG2b 1.5 or 1 mcg/kg/week, or PEG2a 180mcg/
week plus ribavirin 1000-1200mg/day... Testing for IL28B was performed in
1604 patients.

Results: There is a high positive correlation between HCV viral load decline at TWs 4 and 12 for
patients receiving standard of care therapy: PEG2b 1.5/R (r=0.76), PEG2a/R (r=0.73), or PEG2b
1.0/R (r=0.78) (p<0.001 for each). Null response defined as a <2 log decline at TW12 corresponds
to ~0.7-1.1 log decline at TW4 for PEG2b 1.5/R. Concordance of null or ‘non-null’ response defined
by both TW4 and TW12 definitions was high for each of the treatment arms and for all
3 arms combined 89% (2459/2777) regardless of IL28b genotype, CC 98% (466/474) and CT/TT
83% (785/943). Nearly all patients who met the TW4 or TW12 definition for null response had the
less favorable CT or TT allele.

Conclusions: TW4 viral load decline of <1 log approximates to that of <2 logs at TW12 and is an
earlier predictor of null response. The TW4 definition of null response may have increased utility
in aiding early treatment decisions.

Conclusions
• The negative predictive value of week-4 viral load decline of <1 log10 is 96%
• A treatment-week-4 viral load decline of <1 log10 approximates that of a <2-log10 decline
at treatment week 12 and is an earlier predictor of null response based on correlation,
concordance, and CART analyses
• The treatment-week-4 correlation with week-12 null response may have increased utility in
aiding early treatment decisions

Main points:

—— A treatment-week-4 viral load decline of <1 log10 approximates that of a <2-log10 decline at treatment week 12 and is an earlier predictor of null response

—— 97% to 100% of genotype 1 patients who fail to attain an early virologic response (<2-log10 decline in
HCV-RNA at week 12 of treatment) will fail to attain sustained virologic response (SVR)

—— Patients with an undetectable HCV-RNA at week 12 had an SVR rate of 79% (975/1239), and those
with a detectable, ≥2-log10 decline in HCV-RNA from baseline had an SVR rate of 25% (220/889)

Hectorsf

[Trish77]

It means you're in yet another group that didn't go UND at Week 12.  That's the key part that matters.  There are all sorts of scenarios but this one is key, what you are at Week 12.

1,700,000 is 6.23 logs
100,000 is 5 logs.  

So that's a 1.23 log drop at Week 4, if my calculations are correct. So means it doesn't quite fit the <1 log drop at Week 4, fits instead the still detectable at Week 12 scenario.

[pcds]

I started out 1,7000,000.  At 4 weeks I was 100,000.  At 12 weeks still dectected.  I'm not great on figuring out the log drop but seems more than 1 log drop at week 4.  So how does that play out with this predictor?
Judy

[Trish77]

Other than those completely out of the loop, it's been a known approach for awhile that if not UND by 12 weeks as a Geno 1, you either extended treatment or stopped.  It used to be extend until the new PI's seemed imminent and in the case of many, they can wait. And if not - then extend.  This gives even greater weight to that approach.

"The negative predictive value of week-4 viral load decline of <1 log10 is 96% "

What I also get out of this is that it allows earlier treatment decisions to be made.  That if you have a <1 log decline at Week 4, it equates to a <2 log decline at Week 12 so people can be making an earlier decision whether to stop treatment or not, rather than wait all the way to Week 12 to see if they have an UND.  If less than 1 log at Week 4, then this study implies you won't get a whole lot of benefit out of waiting until Week 12 to see if you are UND but rather you make whatever decision at Week 4 with a <1 log drop that you would have at Week 12 if <2 log decline in viral load.  Interesting.  Pondering that one.

[HectorSF]

From the study you mention Bali...

AASLD 2010
#79
http://www.hcvadvocate.org/news/reports/AASLD%202010/AASLD%202010%20Interferon.htm

"36 versus 48 weeks of treatment with peginterferon alfa-2a plus ribavirin for genotype 1/4 patients with undetectable HCV RNA at week 8: Final results of a randomized multicenter study".  S. S. Lee; M. Sherman; A. Ramji; S. Greenbloom; M. Elkashab; H. Pluta; N. Hilzenrat; R. Balshaw; C. Usaty; R. P. Myers

Those who were HCV RNA negative (Roche Taqman Limit of detection 15 IU/mL) at week 4 (RVR) were randomized to 24 or 48 weeks of treatment; those who were negative at week 8 were randomized to 36 or 48 weeks.

Results: A total of 236 patients started treatment and 195 were randomized at week 4 (n=50), 8 (n=61) or 12 (n=84).  Those randomized to either 36 or 48 weeks at week 8 had SVR rates of (73% and 74%, respectively).

Conclusion: The most novel finding of this prospective randomized multicenter trial is that a 36 week treatment duration provides similar SVR rates to a standard 48-week treatment duration in genotype 1/4 patients who become HCV RNA negative between week 4 and 8 of treatment with PegIFNα2a plus RBV. Such patients may be considered for a shorter 36-week treatment duration.

Looks like you have great odds equal to new STAT-C drugs plus SOC.
Good luck!
Hectorsf

[Bali05]

Thanks for the link Hector , great post

I am geno4 and there is little info out there on SVR rates for UND
in between wk4-wk12. I was 170 IU wk4 ,UND<43wk6,wk9 and UND<5 by TMA wk10
low baseline VL.

"The most novel finding of this prospective randomized multicenter trial is that a 36 week treatment duration provides similar SVR rates to a standard 48-week treatment duration in genotype 1/4 patients who become HCV RNA negative between week 4 and 8 of treatment with PegIFNα2a plus RBV. Such patients may be considered for a shorter 36-week treatment duration."

I am also on Alinia (trial was with 36wk SOC)  and Pre/Highdose Riba.
Still thinking of doing the full monty (48wks). Being geno4  I can`t count on Tela/Boc.
for back up and than there is the psych. factor , if I relapse after 36wk I will always wonder
about if 48wk would have made the difference in my case.

thanks again , the only time I have seen this type of data before was from Egypt (Kamal)

b
34of48

[spectda]

Thanks for the information and posting Hector. I hope you are managing okay these days.
Happy Holidays,
- Dave

[HectorSF]

From original doc...

SVR was defined as undetectable HCV-RNA at the end of follow-up (week 24 or, if missing, week 12)
—— HCV-RNA was measured using COBAS® TaqMan® (Roche; lower limit of quantitation, 27 IU/mL)

[spectda]

I found the chart in the link about ct and tt genotypes very informative. Very interesting that only 14.5 % of geno ct and o% of geno tt were und by week 12 and that higher dose IFN seems to be suggested.

"Conclusions: Most patients who fail to respond to pegylated IFN and ribavirin carry either TT or CT rs12979860 genotypes. CT patients are significantly more likely to respond to higher doses of IFN and the difference is significant at week 2. This indicates that the IL28B genotype is a marker of host cell responsiveness to IFN. These findings will have major implications in the treatment of HCV infection with higher peg-IFN doses in combination with ribavirin and direct acting antivirals. "

[spectda]

I wish they posted what sensitivity of test they used for the study (did I miss it). I think this is important although for the most part stopping at week 12 if detectable makes the most sense and is supported by many studies at this point. Stopping at week 12 especially makes sense since new drugs are on the horizon and these numbers are based on SOC.

[copyman]

Thanks Hector, very interesting . If I read it right it reinforces what I have been saying for some time now.....
I have said all along if not Und by 12 weeks treatment should be discontinued. The old protocol of a 2 log drop at 12 weeks should be changed.  And forget about treating until 24 weeks to see if you become Und. That is just plain wrong unless someone has advanced fibrosis. Even treating until 72 weeks does not increase the chance of SVR that much. Just not worth the risk of permanent damage from the drugs.

The plan for anyone with "minimal" fibrosis that doesn't want to wait for the new drugs should check viral load at 4 & 12 weeks. If not Und at 12 weeks STOP and wait for new drugs.
Just my opinion of course