Replies to post #36632 on Biotech Values

[DewDiligence]

Re: HCV assays and cut-offs

Actually, the distinction between a 10 IU/ml and a 20 IU/ml cutoff is almost meaningless from a practical standpoint. 10-20 IU/ml is near the lower limit of detection of the TaqMan assay and is below the limit of quantitation of the assay. (In other words, at those levels, you can tell that the assay detected something, but you can’t tell how much.)

The important practical distinction is between the TaqMan assay and older Amplicor and Versant assays, which have a much higher limit of quantitation of about 600 IU/ml.

[gofishmarko]

re: VRTX & IDIX and HCV studies

IMO , the higher sensitivity cutoffs are significant when looking at end-of-treatment response , and trying to determine the chances that a patient will achieve SVR if treatment is halted. I don't know that there is any meaningful difference between 10 and 20 cutoffs in this regard , but there is a clear difference between 10 and 100 , and I'm also willing to bet there's a meaningful difference between 10 and 50 ( another common cutoff ). My guess is that the high-sensitivity assays probably make a bigger difference in evaluating retreatment of nonresponders ( see below ).

The idea that we may be able to move from a 6-month off-treatment period for SVR determination to 3 months is based on the belief that the high sensitivity assays will provide the same certainty that a 'cure' has been achieved. The VRTX P2 / P3 trials may go a long way toward providing the necessary documentation to do that.

For things like measuring log drops , e.g. for EVR determination , any old assay will do. In this case the important thing is to use the same assay consistently , as different assays do yield different numbers.

Look at the line in bold below that discusses week 20 and 24 results. When comparing candidate HCV drugs that show a certain % HCV-negative at week 24 , I'll feel most confident about those candidates that were assayed at low cutoffs , but that's JMHO.


1: Hepatology. 2006 Aug;44(2):360-7.

HCV RNA detection by TMA during the hepatitis C antiviral long-term treatment against cirrhosis (Halt-C) trial.

Morishima C, Morgan TR, Everhart JE, Wright EC, Shiffman ML, Everson GT, Lindsay KL, Lok AS, Bonkovsky HL, Di Bisceglie AM, Lee WM, Dienstag JL, Ghany MG, Gretch DR; HALT-C Trial Group.
Department of Laboratory Medicine, University of Washington, Seattle, WA 98104, USA. [e-mail]

For making treatment decisions related to chronic hepatitis C, the utility of HCV RNA tests with increased sensitivity has not been defined. Prior interferon nonresponders with advanced fibrosis (n = 1,145) were retreated with peginterferon alpha-2a and ribavirin. Patients who were HCV RNA-negative by a polymerase chain reaction (PCR)-based assay (Roche COBAS Amplicor HCV Test, v. 2.0; lower limit of detection [LOD] 100 IU/mL) at week 20 (W20) received treatment for 48 weeks. Stored specimens were tested using the Bayer VERSANT HCV RNA Qualitative (TMA) Assay (LOD 9.6 IU/mL) and compared to PCR results for the ability to predict sustained virological response (SVR; defined as undetectable HCV RNA by PCR at W72). Nearly all PCR-positive samples (1006/1007, 99.9%) were positive as assessed by TMA. Among 1,294 PCR-negative samples, 22% were TMA-positive. Negative TMA results were more predictive of SVR than were negative PCR results at W12 (82% vs. 64%, P < .001) and at W20 (66% vs. 52%, P = 0.001). SVR was more likely the earlier TMA had become negative during treatment (82% at W12, 44% at W20, 20% at W24). Among 45 patients who were TMA-positive but were PCR-negative at W20 and W24, none achieved SVR (95% CI: 0%-8%). Approximately 10% of patients with a single positive TMA result at the end of treatment still achieved SVR. In conclusion, negative TMA results at or after W12 were superior to negative PCR results for predicting SVR. In patients with negative PCR results during treatment, a single positive TMA test did not exclude SVR, although persistently positive tests did.

PMID: 16871570 [PubMed - indexed for MEDLINE]

http://tinyurl.com/yy5kmv