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Discrepancies Between Definitions of Null Response to Treatment with Peginterferon Alfa-2a and Ribavirin: Implications for New HCV Drug Development
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Reported by Jules Levin
45th Annual Meeting of the European Association for the Study of the Liver (The International Liver Congress 2010), Vienna, Austria, 14-18 April 2010.
Gaston Picchio,1 Donghan Luo,1 Shelley George,2 Ann Kwong,2 Tara Kieffer,2 John McHutchison,3 Jean-Michel Pawlotsky4
1Tibotec Inc., Titusville, NJ, USA; 2Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA; 3Duke Clinical Research Institute & Division of Gastroenterology, Duke University, Durham, NC, USA; 4Hôpital Henri Mondor, Créteil, France
Gaston Picchio, Tibotec Inc., 1125 Trenton Harbourton Road, Titusville, NJ 08560, USA. E-mail: gpicchio@its.jnj.com
Introduction
Current accepted definitions of null response (NULL-R) to peginterferon and ribavirin (Peg-IFN/RBV) include: <1 log10 HCV RNA decline at Week 4 or <2 log10 HCV RNA decline at Week 12. Since the efficacy of regimens containing direct- acting antiviral (DAA) drugs is likely to depend on a patient's prior treatment response1 or magnitude of HCV RNA decline (in case of treatment-naïve patients) after 4 weeks of Peg-IFN/RBV,2 it is important to understand the concordance between these two definitions. However, limited information is available.
We investigated the concordance between these two accepted definitions of NULL-R in PROVE 1 and PROVE 2 study patients from the control arm (treated with Peg-IFN/RBV for 48 weeks) whose HCV RNA was quantified using real-time PCR technology, a more sensitive and precise technology than conventional PCR.
METHODS
One hundred and forty-four HCV genotype 1 chronically infected patients who received Peg-IFN 180 µg/week and RBV 1000-1200 mg/day and had available Week 4 and Week 12 HCV RNA data were evaluated.
Definitions of NULL-R included:
- <1 log10 HCV RNA decline at Week 4
-- <2 log10 HCV RNA decline at Week 12.
The proportion of patients with NULL-R according to the two definitions and their concordance were determined.
The baseline characteristics of NULL-R were compared with those of the rest of the population.
The magnitude of response, defined by intervals of 0.5 log10 HCV RNA, at Weeks 4 and 12 was also assessed.
Patients meeting the definition of NULL-R as <2 log10 decline at Week 12 were considered as the reference.
Plasma HCV RNA was measured with the COBAS TaqMan HCV Test, v2.0.
RESULTS
Among 31 patients who met either NULL-R definition at Week 4 or Week 12, 24 (17%) and 22 (15%) patients met the definition of NULL-R according to the <1 log10 at Week 4 and <2 log10 at Week 12, respectively. Fifteen patients (10%) met both definitions (Table 1).
Fifteen (68%) out of the 22 patients who met the definition of NULL-R at Week 12 also met the Week 4 NULL-R definition.
Among 16 discrepant cases (Table 1), 9 met the Week 4 NULL-R definition but subsequently had a ≥2 log10 HCV RNA drop by Week 12 (shaded cells Table 2). This group represented 38% (9/24) of all Week 4 NULLs.
Patients with a modest HCV RNA decline at Week 4 (≤0.5 log10) (Table 2) were more likely to retain the same magnitude of response (43%) and remain within the NULL-R category at Week 12 (6/7) than those with an HCV RNA response >0.5 to <1.0 (6% and 9/17, respectively).
NULL-R was associated with older age and a higher proportion of bridging fibrosis (P<0.05) (Table 3).
SUMMARY & CONCLUSIONS
A proportion (38%, 9/24) of Week 4 NULLs (<1 log10) may not be defined as such based on their Week 12 response
- Patients with HCV RNA declines <0.5 log10 at Week 4 were more frequently classified as NULL-R and retained the same magnitude of response at Week 12.
As this criterion is used for inclusion in new DAA drug development trials, this may have implications in the classification of prior non-responder patients participating in these studies.
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