Session Title: Category 5g. VIRAL HEPATITIS: g. HEPATITIS C - CLINICAL (THERAPY)
Presentation Date: Apr 15, 2010
DISCREPANCIES BETWEEN DEFINITIONS OF NULL RESPONSE TO TREATMENT WITH PEGINTERFERON- ALFA-2A AND RIBAVIRIN: IMPLICATIONS FOR NEW HCV DRUG DEVELOPMENT
G. Picchio1*, D. Luo1, S. George2, A. Kwong2, T. Kieffer2, J. Mc Hutchison3, J.-M. Pawlotsky4
1Tibotec, Inc, Yardley, PA, 2Vertex Pharmaceuticals Incorporated, Cambridge, MA, 3Duke University Medical Center, Durham, NC, USA, 4Hôpital Henri Mondor, Créteil, France. *email@example.com
Background: Current definitions of Null Response(NULL-R) to peginterferon(P) and ribavirin(R) include: < 1 log10 HCV-RNA decline at week 4 or < 2 log10 HCV-RNA decline at week 12. We investigated the concordance between these two definitions in PROVE1 and PROVE2 study patients in the control arm(treated with PR) whose HCV-RNA was quantified using real-time PCR technology.
Methods: 144 patients who received P 180µg/wk and R 1000-1200mg/d and with available week-4 and week-12 HCV-RNA data were evaluated. The proportion of NULL-R patients according to the two definitions and their concordance were determined. The correspondence in 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 log decline at week-12 were considered as the reference.
Results: Twenty-four(17%) and 22(15%) patients met the definition of NULL-R according to the < 1 log at week-4 and < 2 log at week-12, respectively. Fifteen(68%) out of the 22 patients who met the definition of NULL at week-12 also met the week-4 NULL definition. Among 16 discrepant cases, 9 (bold numbers) met the week-4 NULL definition but had a ≥2 log10 HCV-RNA drop by week-12. This group represents 38%(9/24) of all week-4 NULLs. Patients with a modest HCV-RNA decline at week-4 (≤0.5 log10) were most likely to retain the same magnitude of response (43%) and remain within the NULL-R category at week-12(6/7).
Concordance of HCV-RNA decline (log10) at week-4 and week-12
| ||Week-12 ≤0.5 (n=5) ||Week-12 >0.5-<1.0 (n=4) ||Week-12 ≥1.0-<1.5 (n=8) ||Week-12 ≥1.5-<2.0 (n=5) ||Week-12 ≥2 (n=45) ||Patients1 n/N (%) |
|Week-4 ≤0.5 (n=7) ||3 ||1 ||1 ||1 ||1 ||3/7 (43%) |
|Week-4 >0.5-<1.0 (n=17) ||2 ||1 ||4 ||2 ||8 ||1/17 (6%) |
|Week-4 ≥1.0-<1.5 (n=24) ||0 ||2 ||3 ||1 ||18 ||3/24 (13%) |
|Week-4 ≥1.5-<2.0 (n=19) ||0 ||0 ||0 ||1 ||18 ||1/19 (5%) |
|1Patients with similar magnitude of response at week-4 and week-12 |
Conclusions: A proportion of week-4 NULLs (< 1 log10) may not be defined as such based on their week-12 response. As this criterion is used for inclusion in new HCV direct acting antiviral drug development trials, this may have implications in the classification of prior non-responder patients participating in these studies.