Aasld 2006 10.pmd
Better prediction of SVR in patients with HCV genotype 1 (G1) with peginterferon alfa-2a (PEGASYS
plus ribavirin: Improving differentiation between low (LVL) and high baseline viral load (HVL)
E. Zehnter1, S. Mauss2, C. John3, R. Heyne4, B. Möl er4, T. Lutz5, B. Bokemeyer6, R. Kihn7, G. Moog8, U. Alshuth9, D. Hüppe10
1Center of Gastroenterology, Dortmund; 2Center of Gastroenterology and Hepatology, Düsseldorf; 3Center of Gastroenterology, Berlin; 4Livercenter, Berlin; 5Center of Infectiology, Frankfurt; 6Center of Gastroenterology, Minden;
7Center of Gastroenterology, Frankfurt; 8Center of Gastroenterology, Kassel; 9Hepatitis/HIV/Infectiology, Roche Pharma AG, Grenzach-Wyhlen; 10Center of Gastroenterology, Herne; all Germany
Baseline viral load has recently become a very important predictivefactor in the development of a treatment algorithm in patients withgenotype 1 (G1), but it is not clear whether the cut-off of 600,000or 800,000 IU/ml is ideal. Both were derived from former 2 millioncp/ml due to different factors of the used PCR assay.
The “Association of German Independent Gastroenterologists”(bng, Berufsverband Niedergelassener GastroenterologenDeutschlands e.V.) in cooperation with Roche, Germany, isconducting a nationwide observational study including screeningand treatment phases to determine the quality of treatment forchronic hepatitis C (CHC) in routine clinical practice.
In preceding analyses of our data on predictive factors (DDW 2006,# 219003), the categorized baseline viral load (800,000 IU/ml) wasnot significant neither in uni- nor in multivariate analyses.
Figure 3. Cut-off categories and SVR rates
Figure 4. SVR in patients with LVL and HVL and different cut-offs
The documented data should reflect the clinical routine as intended by
discontinuation due to insufficient efficacy or tolerability). In 727/963
Other predictive factors
the doctors in charge. Therefore, the statistical analysis remains
patients (75.5%) treatment was completed as planned. 236/963 patients
In order to identify other reliable predictive factors for the response to
The aim of this evaluation was to find an optimal cut-off between low
(24.5%) discontinued treatment either due to insufficient efficacy
treatment, the following factors were estimated: age <40 years, BMI
(LVL) and high viral load (HVL), which gave better prediction of SVR.
Due to the ongoing character of the study, the status of data was frozen
(n=159, 16.5%) and/or to insufficient tolerability (n=89, 9.2%).
<25 kg/m², sex (m/f), GPT male >50, female >35 U/l, GGT male >66,
This analysis was based on an ongoing observational study of patients
on May 31st, 2006, including queries solved.
Cut-off data set: In 642 patients viral load was documented in IU/ml.
female >39 U/l, platelets >150,000 /µl, serum ferritin <200 µg/l
with chronic hepatitis C and genotype 1 being treated with peginter-
Multivariate logistic regression (MLR) analyses: To approximate the
(p>0.001) and VL(<400,000 IU/ml HCV RNA).
feron alfa-2a (40KD) (PEGASYS®) plus ribavirin in everyday practice.
optimal cut-off for viral load, multivariate logistic regression analyses
Early Virological Response: 575 of 737 G1 patients (78.0%) achieved an
In univariate analyses, all above predictions could be established
were performed in steps of 100,000 and subsequently 10,000 IU/ml.
Early Virological Response at week 12 (EVR; ≥2-log drop in HCV RNA
Statistical significance was evaluated by two-sided Fisher‘s exact test.
or HCV RNA undetectable; see Figure 2).
In a multivariate analysis, age was the strongest independent significant
Receiver operating characteristic (ROC) curve: The influence of
This evaluation is part of a large ongoing German multicentre, open-
EOT-Responses were achieved by 672 of 963 G1 patients (69.8%).
predictive factor (p<.0001, OR=0.32, CI:0.19-0.52) controlled for the
logarithmized viral load on SVR was estimated as a continuous variable
label observational study including anti-HCV-positive adults with
Sustained Virological Response (SVR) was achieved by 507 of 963 G1
effect of GGT (p<.002, OR=0.48, CI:0.22-0.86), serum ferritin (p<.006,
in univariate logistic regression (ULR) analysis and by analyzing the ROC
detectable HCV RNA. The nature of this study allowed dosing and
OR=0.49, CI:0.30-0.81), platelets (p<017, OR=0.43, CI:0.22-0.86) and
curve. The optimized cut-off was then tested against both existing cut-
duration of both peginterferon alfa-2a (40KD) and RBV to be at the
VL (p<.022, OR=0.58, CI:0.37-0.93). GPT (p<.243), BMI (p<.592) and
MLR analyses of viral load
gender (p<.611) were non-significant.
For the 642 patients of the cut-off data set, the optimal cut-off to
This data set includes only naive genotype 1 patients who initiated
The best baseline predictors for chance of cure with antiviral therapy in
discriminate between high and low viral load was 460,000 IU/ml
treatment with peginterferon alfa-2a (40KD) plus ribavirin. The data
HCV-patients are age <40 years, normal GGT, normal serum ferritin,
collection was performed online via the internet.
normal platelets (>150,000) and a VL <400,000 IU/ml HCV-RNA. The
Figure 3 demonstrates the descriptive SVR rates for different cut-offs
The screening data include age, sex, weight, height, duration and
determining of a new cut-off for low and high VL revealed that even
A total of 10326 treatment naive patient screenings (see Figure 1) have
according to the cut-off categories of the first approximation of MLR
source of infection, prior antiviral treatment, clinical symptoms,
under real life conditions VL is an important predictive factor of
been completed and 4377 of these patients (42.4%) have been treated
histology, genotype, viral load, concomitant diseases and social status.
with peginterferon alfa-2a (40KD), in almost all cases plus ribavirin.
ROC analysis of viral load
Genotype 1 (G1) was diagnosed in 2522/4377 patients.
In the ULR analysis continuous viral load was a strong predictor of SVR
In 1239/2522 G1 patients treatment documentation was finished. The
(p<.0001, OR=0.79, CI:0.69-0.89), but the effect of viral load was non-
mean age was 44.1 years. 58.1% of the patients were male. The mean
linear. The ROC-plot revealed a cut-off level of viral load of 5.6 log
BMI was 24.9 kg/m2 and the mean duration of infection was 12.2 years.
The well accepted formerly used cut-off of 2 million cp/ml
Sources of infection were (multiple answers possible): iv drug abuse
According to this result, an additional discrete cut-off level of 400,000
translated with different factors into IU/ml was statistically
35.9%, transfusion 20.8% or medical measures 11.1%. The source of
IU/ml in addition to the old ones (600,000 and 800,000 IU/ml) was
optimized for treatment with standard interferon.
infection was unknown in 26.6% of the patients.
compared by MLR analysis. 400,000 IU/ml was the best cut-off level
The determining of a new cut-off for low and high VL revealed that
In 118/1239 patients treatment was discontinued due to reasons not
(<.0001, OR=0.48, CI:0.37-0.63) between LVL and HVL.
even under real life conditions VL is an important predictive factor
related to virological nonresponse or tolerability: lost-to-follow-up
Using this cut-off of 400,000 IU/ml, G1 patients with LVL reached SVR
(n=49), personal reasons (n=30), lack of compliance (n=24), concomitant
rates of 62.0% and with HVL 43.7%. SVR-rates of other viral load cut-
In the era of pegylated interferon this cut-off is not the best way to
disease (n=5) or other reason (n=10).
offs are shown in Figure 4. While SVR in patients with LVL increased with
differentiate between LVL and HVL with regard to SVR. To use VL
In 158/1239 patients the data cleaning process is still ongoing.
decreasing cut-off levels, SVR in patients using different HVL cut-offs
as a reliable predictor of successful treatment outcome in hepatitis
The remaining 963 G1 patients formed the database for the following
remained at 43%. This result indicated that patients with higher viral
C the optimized cut-off of 400,000 IU/ml should be adopted in the
evaluation. These patients were treated according to the current
load than 400,000 IU/ml had similar low SVR rates as patients with viral
consensus recommendations (i.e. treatment according to guidelines or
load of more than 800,000/ml and belong to the same category.
Presented at the 57th Annual Meeting of the American Association for the Study of Liver Diseases: 2006 October 27-31: Boston, Massachusetts, USA
This research was funded by Roche, Grenzach-Wyhlen, Germany
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