Refined prediction of week 12 response and SVR based on week 4 response in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) and ribavirin

Research Article

Refined prediction of week 12 response and SVR based on week 4 response in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) and ribavirin Patrick Marcellin1,⇑, Nancy Reau2, Peter Ferenci3, Stephanos Hadziyannis4, Diethelm Messinger5, Fernando Tatsch6, Donald Jensen7 1

Service d’Hepatologie and INSERM CRB3, University of Paris, Hopital Beaujon, Pavillon Abrami, 100 Boulevard General Leclerc, 92110 Clichy, France; 2The University of Chicago Medical Center, 5841 S. Maryland Ave., MC 7120, Chicago, IL 60637, United States; 3Univ. Klinik Für Innere Medizin IV AKH, Waehringer Guertel 18-20, A 1090 Wien, Austria; 4Department of Medicine and Hepatology, Henry Dunant Hospital, 107 Messogion Ave., 115 26 Athens, Greece; 5IST GmbH, Soldnerstrasse 1, 68219 Mannheim, Germany; 6F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Bldg. 074/3O.Z04.50, CH-4070 Basel, Switzerland; 7Center for Liver Diseases, University of Chicago Hospitals, 5841 S. Maryland, MC 7120, Chicago, IL, United States

Background & Aims: It is unclear whether the magnitude of reduction in hepatitis C virus (HCV) RNA between baseline and week 4 of treatment influences the probability of achieving a sustained virological response (SVR) in patients without a week 4 rapid virological response (RVR). Methods: Data were retrospectively analyzed from two studies in which treatment-naive patients received peginterferon alfa-2a (40KD) 180 lg/week plus ribavirin 1000/1200 mg/day for 48 weeks. Five hundred and fifty-eight genotype 1 patients with evaluable HCV RNA at baseline and week 4 were grouped according to RVR status: RVR (HCV RNA <50 IU/ml) or no RVR. Non-RVR patients were subdivided into discrete mutually exclusive categories according to week 4 HCV RNA; the proportion of patients with undetectable HCV RNA at week 12 was calculated per each category, and among them, the proportion with an SVR. Results: Overall, 88% of RVR patients and 43% of non-RVR patients achieved an SVR (p <0.0001). Among non-RVR patients, SVR rates were 77%, 61%, 43%, 27% and 13%, respectively (trend test p <0.0001) in those with unquantifiable HCV RNA or P3 log10, P2 log10, P1 log10, or <1 log10 drop to week 4. In patients HCV RNA positive at week 4, SVR rates were 67% for those negative at week 12 vs. 17% (HCV RNA positive patients or who had missing values at week 12 [p <0.0001]). Conclusions: The probability of achieving SVR is graded in relation to the magnitude of reduction in HCV RNA at week 4 and 12. Patients with a P3 log10 drop in HCV RNA at week 4 have a high probability of achieving an SVR. Ó 2012 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. Keywords: Hepatitis C; Peginterferon; Peginterferon alfa-2a; Sustained virological response; Week 4. Received 28 January 2011; received in revised form 13 December 2011; accepted 19 December 2011; available online 4 February 2012 ⇑ Corresponding author. Address: Hôpital Beaujon, 100 Boulevard Du General Leclerc, Clichy 92110, France. Tel.: +33 1 40 87 53 38. E-mail address: [email protected] (P. Marcellin). Abbreviations: RVR, rapid virological response; SVR, sustained virological response; HCV, hepatitis C virus; EVR, early virological response; PCR, polymerase chain reaction; cEVR, complete early virological response

Introduction Hepatitis C virus (HCV) RNA levels decline rapidly after the initiation of interferon-based therapy for chronic hepatitis C. At least two phases of HCV RNA clearance can be observed during treatment [1,2]. The first phase of decline is more rapid and is reflected in a steep negative slope in the HCV RNA concentration vs. time curve. This change is thought to reflect the combined effects of abrupt interruption of HCV replication and clearance of HCV RNA from serum [1]. The second slower phase is thought to reflect immune clearance of HCV infected cells [1]. It has long been known that patients with more rapid clearance of HCV RNA tend to have a better chance of achieving a cure [3]. For this reason, researchers have sought to identify ‘rules’ that can be used to predict whether a patient will ultimately respond to therapy [4– 6]. For example, Davis and colleagues investigated whether early changes in HCV RNA (early virological response [EVR]) during treatment could accurately predict treatment response [6]. They found that most patients who completed the first 12 weeks of treatment with pegylated interferon alfa-2b plus ribavirin achieved an EVR (defined as a P2 log10 reduction vs. baseline in HCV RNA after 12 weeks of treatment) and had a high probability of achieving a sustained virological response (SVR) if they completed the rest of the treatment. Those who failed to achieve an EVR did not respond to further therapy [6]. A more recent study showed that measurement of the HCV RNA level 5 min prior to and 2 days after the first injection of pegylated interferon could be used to calculate statistics useful in predicting treatment outcome [7]. The most useful prediction rule would be easy to determine and simple to understand, would require few blood samples, and could be used to motivate patients to adhere to therapy. Rapid virological response (RVR), typically defined as undetectable HCV RNA (<50 IU/ml by qualitative polymerase chain reaction [PCR] assay) at week 4 of treatment with pegylated interferon plus ribavirin, is increasingly being used to identify patients most likely to achieve an SVR. For those infected with HCV genotype 1 and who achieve an RVR, approximately 90%

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JOURNAL OF HEPATOLOGY achieve an SVR after completing 48 weeks of treatment with the standard of care [5,8]. Moreover, abbreviated 24-week treatment regimens are appropriate for some genotype 1 patients with an RVR, particularly for those without cirrhosis and with low baseline HCV RNA levels [9]. In contrast, patients with detectable HCV RNA at week 4 have a much lower probability of achieving an SVR than those with an RVR. Such observations have led to the concept of variable treatment durations widely known as response-guided therapy. Tailoring the duration of treatment to the speed with which HCV RNA becomes undetectable is a recent innovation [2,4,5,10]. This treatment strategy was evaluated in a recent study in which patients who became HCV RNA negative at week 4, 8, or 12 were assigned to 24, 48, or 72 weeks of treatment with standard doses of pegylated interferon and ribavirin [11]. As expected, the SVR rate decreased with increasing length of time taken to achieve an HCV RNA-negative state, despite the progressively longer durations of therapy. The foregoing demonstrates that HCV RNA negativity, particularly at week 4 of treatment, is an important indicator of treatment success that can be used to tailor the duration of therapy. There is evidence to suggest that the presence of detectable levels of HCV RNA at week 4 is not a categorical negative prognostic factor, but that there is a graded association between the magnitude of the drop in HCV RNA levels and the probability of SVR. An analysis of data from the Study of Viral Resistance to Antiviral Therapy of Hepatitis C (Virahep-C) showed that SVR rates increased with the magnitude of the decrease in HCV RNA level over the first 28 days of treatment with peginterferon alfa-2a (40KD) plus ribavirin [12]. Similarly, there was a positive correlation between the magnitude of the decrease in HCV RNA at week 4 and the probability of SVR in the large multicentre, Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) trial [13]. If this phenomenon is consistently observed, then subdivision of patients into distinct subgroups on the basis of the drop in HCV RNA levels to week 4 could potentially be useful in refining the prediction of outcomes and in guiding treatment decisions. The objective of this analysis of data from patients without an RVR is to determine whether the magnitude of the reduction in HCV RNA level between baseline and week 4 of treatment influences the probability of achieving a complete EVR (cEVR) at week 12 and an SVR at the end of follow-up.

Patients infected with hepatitis B virus or human immunodeficiency virus were excluded as were those with serious concomitant disease [14,15]. Treatment After providing written informed consent, eligible patients were randomized and received treatment with an interferon-based regimen. Only patients infected with HCV genotype 1 who were randomly assigned to receive 48 weeks of treatment with subcutaneous peginterferon alfa-2a (40KD) (PEGASYSÒ, Roche, Basel, Switzerland) 180 lg once weekly plus oral ribavirin (COPEGUSÒ, Roche, Basel, Switzerland) at a dosage of 1000 mg/day (body weight 675 kg) or 1200 mg/day (body weight >75 kg) were included in this analysis. Outcomes The primary efficacy outcome of both trials was SVR, defined as undetectable serum HCV RNA by qualitative PCR assay (COBAS AMPLICOR HCV Monitor Test, v2.0; limit of detection <50 IU/ml) at the end of a 24-week untreated follow-up period (i.e. study week 72) [14,15]. As noted above, serum HCV RNA was measured at baseline with a quantitative PCR assay. For patients with multiple measurements (HCV RNA) prior to the start of treatment (study day 1), the last measurement on or before study day 1 was used. During treatment, HCV RNA was determined with a more sensitive qualitative PCR assay at weeks 4, 12, 24, and 48. If HCV RNA was detectable at any of these time points then samples were re-tested with the quantitative assay. Definitions of virological responses at week 4 and 12 of treatment are presented in Table 1. The availability of both baseline and on-treatment samples allowed us to calculate the decrease in HCV RNA from baseline to week 4 and 12. Patients with an RVR were confirmed to have undetectable HCV RNA (<50 IU/ml) at week 4 of treatment. Patients with detectable HCV RNA at week 4 (i.e. no RVR) who had undetectable HCV RNA at week 12 were said to have a cEVR. For the purposes of this analysis, patients with evaluable HCV RNA response at week 4 were first grouped according to their virological response at week 4 as having an RVR (<50 IU/ml) or no RVR (P50 IU/ml). Patients without an RVR were then further subdivided into five discrete mutually exclusive categories on the basis of the magnitude of the decrease in HCV RNA from baseline to week 4: ? detectable but unquantifiable (i.e. P50 IU/ml, but <600 IU/ml) ? P3 log10 drop ? P2 log10 drop but <3 log10 drop ? P1 log10 drop but <2 log10 drop ? <1 log10 drop Next, the proportion of patients who did or did not achieve a cEVR at week 12 was calculated within each week 4 category. Finally the proportion of patients who did or did not achieve an SVR was calculated within each week 4 category for patients with or without a cEVR at week 12. Patients with missing HCV RNA assay results at week 12 or 72 were assumed to have had detectable HCV RNA for the purposes of calculations.

Statistical methods

Materials and methods This was a retrospective analysis of data from two large, randomized, multinational phase III studies of treatment-naive patients with chronic hepatitis C [14,15]. Patients The inclusion and exclusion criteria used to recruit patients into the two trials were similar and are published elsewhere [14,15]. Briefly, adults eligible for the two trials had chronic hepatitis C as defined by serological criteria, including the presence of anti-HCV antibodies, detection of HCV RNA by quantitative PCR assay (COBASÒ AMPLICOR HCV Monitor v2.0; Roche Diagnostics, Basel, Switzerland, limit of quantitation 600 IU/ml), and elevated alanine aminotransferase levels. Only individuals who had never received interferon-based therapies for chronic hepatitis C could be enrolled. All patients were required to have undergone a pre-treatment liver biopsy that showed histological evidence of chronic active hepatitis. Patients with cirrhosis were eligible provided that they had compensated liver disease (Child–Pugh class A).

Patients with missing HCV RNA values at baseline or week 4 were excluded from the analysis. Eligible patients were assigned to one of the six week 4 response categories specified above. Chi-square tests and Cochran–Armitage trend tests were used to investigate the association between various early response categories (at week 4 and/or week 12) and subsequent response rates (HCV RNA undetectable at week 12 and/or SVR, respectively). All statistical tests were exploratory and performed at a two-sided significance level of 0.05. The association between baseline and on-treatment viral responses and SVR were explored by logistic regression with stepwise selection.

Results A total of 569 genotype 1 patients were treated for 48 weeks with the combination of peginterferon alfa-2a (40KD) 180 lg/week plus ribavirin 1000/1200 mg/day in the two trials. Complete HCV RNA data for response categories at week 4 were available for all but

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Research Article Table 1. Definitions of virological responses at week 4 and 12 of treatment.

Response

Definition

Rapid virological response (RVR)

HCV RNA <50 IU/ml at week 4

Early virological response (EVR)

HCV RNA ≥50 IU/ml at week 4 but <50 IU/ml at week 12

Complete EVR Partial EVR

No EVR

HCV RNA ≥50 IU/ml at week 4 and 12 but ≥2 log10 drop from baseline to week 12 HCV RNA ≥50 IU/ml at week 4 and <2 log10 drop from baseline to week 12 or missing week 12 data

Table 2. Baseline characteristics according to HCV RNA status at week 4.

Virological response at week 4 (HCV RNA level)

558 (100)

Quantifiable Quantifiable Quantifiable RVR Unquantifiable Quantifiable (≥1 to <2 (<1 log10 (<50 IU/ml) (≥50 IU/ml but (≥3 log10 drop) (≥2 to <3 log10 drop) log10 drop) drop) <600 IU/ml) 90 (16.1) 113 (20.3) 51 (9.1) 81 (14.5) 119 (21.3) 104 (18.6)

Gender (M), n (%)

380 (68.1)

63 (70.0)

Mean age, yr ± SD

43.8 ± 10.4 40.7 ± 11.0

All patients Characteristic Patients, n (%)

79 (69.9)

33 (64.7)

51 (63.0)

82 (68.9)

72 (69.2)

41.8 ± 10.2

44.8 ± 10.0

44.1 ± 10.0

45.8 ± 10.6

45.6 ± 9.3

Race, n (%) White

476 (85.3)

77 (85.6)

98 (86.7)

44 (86.3)

74 (91.4)

98 (82.4)

85 (81.7)

Black

29 (5.2)

1 (1.1)

2 (1.8)

0

4 (4.9)

10 (8.4)

12 (11.5)

Asian

30 (5.4)

11 (12.2)

8 (7.1)

7 (13.7)

0

2 (1.7)

2 (1.9)

Other

23 (4.1)

1 (1.1)

5 (4.4)

0

3 (3.7)

9 (7.6)

5 (4.8)

Mean weight, kg ± SD

79.4 ± 16.9 74.7 ± 15.6

76.7 ± 16.4

76.0 ± 13.9

79.6 ± 18.5

80.5 ± 15.2

86.9 ± 18.1

Mean BMI, kg/m2 ± SD

26.8 ± 4.8

25.3 ± 4.1

26.0 ± 4.9

25.9 ± 3.4

26.6 ± 4.7

27.2 ± 4.8

29.3 ± 5.4

Alanine aminotransferase quotient*, n (%) ≤3

381 (68.3)

54 (60.0)

73 (64.6)

31 (60.8)

56 (69.1)

93 (78.2)

74 (71.2)

>3

177 (31.7)

36 (40.0)

40 (35.4)

20 (39.2)

25 (30.9)

26 (21.8)

30 (28.8)

Histological diagnosis, n (%) Minimal fibrosis

443 (79.4)

79 (87.8)

95 (84.1)

43 (84.3)

62 (76.5)

88 (73.9)

76 (73.1)

Advanced fibrosis/cirrhosis

115 (20.6)

11 (12.2)

18 (15.9)

8 (15.7)

19 (23.5)

31 (26.1)

28 (26.9)

1.89 ± 1.82

3.81 ± 2.87

2.08 ± 2.01

2.08 ± 2.12

1.72 ± 2.00

Mean HCV RNA, x 106 IU/ml ± SD 1.97 ± 2.10 1.06 ± 1.28 ⁄

Qualifying alanine aminotransferase value divided by the upper limit of normal. BMI, body mass index; SD, standard deviation; RVR, rapid virological response.

11 (1.9%) of the patients (10 did not have a week 4 HCV RNA assay result and one did not have a baseline HCV RNA level recorded). The baseline characteristics of the 558 patients included in the analysis are presented according to their virological response at week 4 in Table 2. In general, there appeared to be a numerical relationship between patient age, body weight, fibrosis stage, and serum HCV RNA level and the extent of the decrease in HCV RNA level at week 4. Patients with an RVR tended to be younger with a lower body weight and HCV RNA level than those with detectable HCV RNA at week 4 (Table 2). Moreover, a smaller proportion of patients with an RVR had advanced fibrosis on the pre-treatment liver biopsy than those with detectable HCV RNA at week 4 (Table 2). Subdividing the 558 patients by baseline viral load into quartiles shows that those in the lowest quartile (HCV RNA <0.45  106 IU/ml) achieved the highest RVR rate (33%), those in the highest quartile (HCV RNA >2.74  106 IU/ ml) achieved the lowest RVR rate (6%), and those in the two middle quartiles achieved an intermediate RVR rate (11–14%). A total of 90 out of 558 patients (16%) had an RVR at week 4. When grouped according to RVR status (RVR vs. no RVR) it was 1278

apparent (and not surprising) that patients without an RVR were much less likely to be HCV RNA negative at week 12 than those who achieved an RVR (51% vs. 93%, respectively; p <0.0001) (Fig. 1). Of the six patients with an RVR but no cEVR, only one had a missing value at week 12 and was categorized as not achieving a cEVR. The remaining five patients all had a documented positive HCV RNA result at week 12. These proportions remained largely unchanged at the end of untreated follow-up (week 72), at which time 88% of those with an RVR and 43% of those without an RVR achieved an SVR (p <0.0001) (Fig. 1). Of the 11 patients with an RVR but no SVR, eight discontinued treatment prematurely and either had missing values at week 72 or a documented positive HCV RNA result. Three patients completed treatment and had a documented positive HCV RNA result at week 72. Subdivision of the patients without an RVR according to the magnitude of the reduction in HCV RNA level between baseline and week 4 revealed a graded probability of SVR (trend test p <0.0001), with the highest being in those with unquantifiable (77%) or P3 log10 drop (61%) at week 4 (Fig. 2). Similar results

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JOURNAL OF HEPATOLOGY Patients with undetectable HCV RNA (<50 IU/ml), %

100

Week 12 Week 72 (SVR)

93.3 87.8

80 60

50.9 42.5

40 20 0 n = 84 79

Patients with an RVR at wk 4 (n = 90)

238 199

Patients without an RVR at wk 4 (n = 468)

Fig. 1. Virological response rates (HCV RNA <50 IU/ml) at week 12 and 72 (sustained virological response [SVR]) in genotype 1 patients with and without a rapid virological response (RVR) at week 4. The numerators used in calculations are shown at the base of each bar and the denominators are shown in brackets.

Patients with undetectable HCV RNA (<50 IU/ml), %

100

93.3 87.8

Week 12 Week 72 (SVR) 90.3

74.1 60.8

60 43.2

40

26.9 21.0

20

13.5 6.7

0 n = 84 79

u.d. (<50 IU/ml) (n = 90) Patients with an RVR

102 87

Discussion

86.3

77.0

80

12 and who achieved an SVR (Fig. 3) only one had a missing value at week 12, while all the remaining patients had a documented positive HCV RNA result at week 12. The overall SVR rate decreased progressively among patients with an RVR (88%), cEVR (67%), partial EVR (26%), and no EVR (5%) (trend test p <0.0001) (Fig. 4). Considering baseline parameters known to be associated with SVR and the categorized week 4 virological response variable (6 levels) logistic regression analyses showed that the 6-level response variable at week 4 was the strongest factor for SVR prediction (Table 3; model 1), and only baseline HCV RNA entered the model in addition. When virological responses at both week 4 (6 levels) and 12 (cEVR) were considered, the selection procedure showed that cEVR was a slightly better predictor than the response variable at week 4. Nevertheless, both variables enter the model together with baseline HCV RNA and increased the predictability of SVR (Table 3; model 2) as assessed by the corresponding area under the ROC curve (0.842 and 0.823 for model 2 and 1, respectively).

44 31

u.q. ≥3 log10 (≥50 but drop <600 IU/ml) (n = 51) (n = 113)

60 35

≥2 log10 drop (n = 81)

25 32

7 14

≥1 log10 <1 log10 drop drop (n = 119) (n = 104)

HCV RNA level at week 4 in patients without an RVR

Fig. 2. Virological response rates (HCV RNA <50 IU/ml) at week 12 and 72 (sustained virological response [SVR]) in genotype 1 patients without a rapid virological response (RVR) according to the magnitude of the decrease in HCV RNA between baseline and week 4 (mutually exclusive groups). The numerators used in calculations are shown at the base of each bar and the denominators are shown in brackets. u.d., undetectable; u.q., unquantifiable.

were seen in the proportion of patients within each subgroup who were HCV RNA negative at week 12. Overall, 254 of the 558 patients included in the analysis had undetectable, unquantifiable, or P3 log10 drop in HCV RNA at week 4. Among this subgroup, 78% (n = 197) achieved an SVR. More profound reductions in HCV RNA at week 4 were associated with higher cEVR rates (HCV RNA <50 IU/ml) at week 12 (Fig. 3). Thus, among patients with quantifiable HCV RNA values at week 4 and a decrease of P3 log10, P2 log10, or P1 log10 in HCV RNA at week 4, a total of 86%, 74% and 21% of patients, respectively, had undetectable HCV RNA at week 12. Patients with a cEVR at week 12 had consistently high rates of SVR (Fig. 3). Of the 238 patients who had detectable HCV RNA at week 4 and who became HCV RNA negative at week 12, 160 individuals (67%) achieved an SVR. Conversely, only 39 out of the 230 individuals (17%) with detectable HCV RNA at week 4 and detectable or missing HCV RNA at week 12 achieved an SVR (p <0.0001). Among the 43 patients without undetectable HCV RNA at week

The results of this analysis of data from two large international trials that enrolled patients from Europe, North America and South America demonstrate that the magnitude of the virological response at week 4 predicts the likelihood of achieving an SVR in genotype 1 patients treated for 48 weeks with standard doses of peginterferon alfa-2a (40KD) plus ribavirin. As previously reported, patients achieving an RVR have the highest rates of SVR [8,9,11,14,16,17]. The novel aspect of this analysis is the demonstration that the probability of achieving an SVR is graded according to the magnitude of the decrease in HCV RNA between baseline and week 4 in patients, and that the drop of HCV RNA within the 4 weeks categorized by 6 levels is highly predictive, more than any baseline factor. Those with detectable but unquantifiable HCV RNA or P3 log10 drop at week 4 had a very high probability of achieving an SVR (72%) after the recommended 48-week duration of treatment. Thus, even among patients without an RVR, the magnitude of the decrease in HCV RNA between baseline and week 4 should be used to motivate patients to remain on treatment. These results are in close agreement with the analysis of two trials conducted in the USA. Hoofnagle and colleagues [12] showed that the SVR rate increased among patients with increasing week 4 decline in HCV RNA. However, their analysis did not have separate categories for patients with undetectable or unquantifiable HCV RNA at week 4. An important additional finding in the analysis of Hoofnagle et al. [12] was that for a given decrease in HCV RNA level at week 12, the likelihood of achieving an SVR was higher in white patients than in African American patients. McHutchison et al. [13] filled the gap in the data from the Virahep-C study by showing that the probability of SVR is graded. In the IDEAL study [13], the probability of an SVR increased with each log drop in HCV RNA (from <1 log to P4 log) at week 4, and with each log drop from P2 to P4 log at week 12. Our analysis also confirms that patients who are HCV RNA negative by week 12 have a very high probability of achieving an SVR, especially among those who were also HCV RNA negative at week 4 (89%), and is consistent with that from the IDEAL trial

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Research Article Week 4 HCV RNA

<50 IU/ml (n = 90)

50-600 IU/ml (n = 113)

≥3 log10 drop (n = 51)

≥2 log10 drop (n = 81)

≥1 log10 drop (n = 119)

<1 log10 drop (n = 104)

Week 12 HCV RNA

Week 72 SVR

<50 IU/ml n = 84 (93.3%)

n = 75 (89.3%)

≥50 IU/ml* n = 6 (6.7%)

n = 4 (66.7%)

<50 IU/ml n = 102 (90.3%)

n = 79 (77.5%)

≥50 IU/ml* n = 11 (9.7%)

n = 8 (72.7%)

<50 IU/ml n = 44 (86.3%)

n = 29 (65.9%)

≥50 IU/ml* n = 7 (13.7%)

n = 2 (28.6%)

<50 IU/ml n = 60 (74.1%)

n = 31 (51.7%)

≥50 IU/ml* n = 21 (25.9%)

n = 4 (19.0%)

<50 IU/ml n = 25 (21.0%)

n = 15 (60.0%)

≥50 IU/ml* n = 94 (79.0%)

n = 17 (18.1%)

<50 IU/ml n = 7 (6.7%)

n = 6 (85.7%)

≥50 IU/ml* n = 97 (93.3%)

n = 8 (8.2%) ⁄

Fig. 3. Sustained virological response (SVR) rates according to virological response rates at week 4 and 12. Or missing week 12 data.

SVR: 5% (5/101)

SVR: 26% (34/129)

No EVR 18% (101/558) pEVR 23% (129/558)

RVR 16% (90/558)

cEVR 43% (238/558)

SVR: 88% (79/90)

SVR: 67% (160/238)

Fig. 4. Sustained virological response (SVR) rates among patients with a rapid virological response (RVR), complete early virological response (cEVR), partial early virological response (pEVR), or no EVR. Patients with missing week 4 data were excluded.

[13] in demonstrating that the relationship between the drop in HCV RNA at week 4 and 12 and the probability of SVR is graded. An important additional novel finding in our analysis is the demonstration that the prognostic value of an undetectable HCV RNA result at week 12 is further improved when accompanied by a week 4 quantitative assay result. For example, in patients with a cEVR at week 12 but a detectable HCV RNA at week 4, the SVR rate ranged from 52% in patients who had only a P2 to <3 log10 drop at week 4, to 66% in patients with at least a 3 log10 drop and finally to 77% in patients with HCV RNA values between 50 and 600 IU/ml at week 4. Neumann and colleagues recently showed that prediction of SVR rates among patients treated with albinterferon alfa-2b or peginterferon alfa-2a could be improved by integrating both absolute levels of HCV RNA and reductions of HCV RNA at weeks 2 and 4 of treatment [16]. While incorporating both absolute levels of HCV RNA and reductions of HCV RNA into our analysis would have probably improved the positive and negative predictive value of early responses to treatment in our analysis, our intention was to create a very simple algorithm to encourage

1280

adherence to treatment among patients with a high likelihood of achieving an SVR. Treatment guidelines have historically recognized the importance of measuring HCV RNA at baseline and after 12 weeks of combination therapy [18–20]. The purpose of the week 12 assessment is to identify those patients unlikely to achieve an SVR. Available data suggest that incorporating a week 4 HCV RNA assessment in the treatment algorithm may allow clinicians to tailor the duration of therapy for individual patients [20]. For example, genotype 1 patients with an RVR at week 4 have high rates of SVR after completing 24 weeks of treatment [8,9,11]. In contrast, patients with detectable HCV RNA at week 4 and 12 have a lower probability of achieving an SVR. While several studies suggest that slow responders may benefit from an extended 72 week combination regimen (i.e. lower relapse rates vs. 48 weeks) [21–24], others have reported that extending treatment to 72 weeks does not provide further benefit [25]. Some patients find it difficult to comply with an extended regimen. For this reason, careful patient selection, counseling, and monitoring are necessary to ensure that this strategy is successful. The present analysis shows that the probability of SVR is graded according to the magnitude of the HCV RNA response at week 4. In future studies, it would be interesting to investigate adjusting the duration of treatment based on the magnitude of the HCV RNA response at week 4. Such a strategy has previously been hypothesized by Drusano and Preston [26]. Their retrospective analysis of data from genotype 1 patients suggested that the probability of achieving an SVR was 90% if treatment was continued for 36 weeks after HCV RNA became undetectable. A randomized prospective trial evaluated individualized treatments for patients with HCV genotype 1 infection [11]. Patients were randomized to either a standard 48 week regimen of combination therapy or to an individualized regimen (24, 48, or 72 weeks if they became HCV RNA negative at week 4, 8, or 12, respectively). The overall SVR rate was similar in the patients randomized to the standard (45.1%) or individualized regimens (48.8%); however, the authors argued that the individualized

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JOURNAL OF HEPATOLOGY Table 3. Baseline parameters and on-treatment virological responses at week 4 and 12 of treatment associated with SVR.

Parameter Model 1 (baseline parameters and week 4 viral responses only)

Odds Ratio (95% CI)

p value

HCV RNA per log10 IU/ml increase HCV RNA at week 4 (≥1 to <2 log10 drop vs. <1 log10 drop) HCV RNA at week 4 (≥2 to <3 log10 drop vs. <1 log10 drop) HCV RNA at week 4 (≥3 log10 drop vs. <1 log10 drop) HCV RNA at week 4 (50-600 IU/ml vs. <1 log10 drop) HCV RNA at week 4 (RVR [<50 IU/ml] vs. <1 log10 drop) Model 2 (baseline parameters and week 4 and 12 viral responses)

0.52 (0.35, 0.77) 2.54 (1.26, 5.13) 5.33 (2.59, 11.01) 14.34 (6.22, 33.10) 22.90 (11.09, 47.29) 39.02 (16.61, 91.68)

0.0011 0.0091 <0.0001 <0.0001 <0.0001 <0.0001

HCV RNA per log10 IU/ml increase HCV RNA at week 12 (undetectable vs. detectable) HCV RNA at week 4 (≥1 to <2 log10 drop vs. <1 log10drop) HCV RNA at week 4 (≥2 to <3 log10 drop vs. <1 log10 drop) HCV RNA at week 4 (≥3 log10 drop vs. <1 log10 drop) HCV RNA at week 4 (50-600 IU/ml vs. <1 log10 drop) HCV RNA at week 4 (RVR [<50 IU/ml] vs. <1 log10 drop)

0.57 (0.38, 0.86) 4.27 (2.42, 7.55) 1.92 (0.92, 3.99) 1.85 (0.80, 4.30) 4.32 (1.64, 11.37) 7.38 (3.11, 17.51) 11.06 (4.22, 29.02)

0.0072 <0.0001 0.0828 0.1532 0.0030 <0.0001 <0.0001

Factors considered in the stepwise selection procedure: ALT quotient, advanced fibrosis/cirrhosis, body mass index, HCV RNA per log10 IU/ml, race, sex, weight per 10 kg, viral response category at week 4 and viral response category at week 12 (model 2 only).

treatment strategy minimized the potential exposure to side effects among those patients able to shorten treatment. Response-guided therapy may also be useful in tailoring the treatment duration with triple therapy. In the SPRINT-1 study, genotype 1 patients achieving <1.5 log10 reduction in HCV RNA at the end of a 4-week lead-in with peginterferon alfa-2b plus ribavirin benefited most from 48 weeks of triple therapy with the direct-acting antiviral agent boceprevir [27]; patients with HCV RNA >1.5 log10 showed a similar SVR rate irrespective of treatment duration (24 or 48 weeks) and did not benefit further from boceprevir triple therapy. In a recent genome-wide association study that searched for genetic determinants of response to treatment with pegylated interferon plus ribavirin, a polymorphism upstream of the gene IL28B was identified that was associated with a twofold difference in SVR rates in a large cohort of genotype 1 patients [28]. An intent-to-treat analysis has since confirmed the clinical relevance of the polymorphism and found that, while RVR remains a stronger positive predictor of SVR [29], the IL28B genotype has important utility prior to therapy and at week 4 for patients who do not achieve an RVR [30]. In conclusion, this analysis of data from two large randomized phase III studies demonstrates that the probability of achieving an SVR is graded in relation to the magnitude of the reduction in HCV RNA level at week 4 and 12. Future studies should evaluate whether this information, combined with recent knowledge of genetic determinants, can be used to more precisely tailor the duration of therapy for patients infected with HCV genotype 1.

Conflict of interest Prof. Patrick Marcellin reports acting as a consultant for Roche, Schering-Plough, Gilead, BMS, Vertex, Novartis, Tibotec, MSD, Boehringer, Biolex, InterMune; has received grant/research support from Roche, Schering-Plough, Gilead; and has been involved as a speaker for Roche, Schering-Plough, Gilead, BMS, Vertex, Novartis, Pharmasset, Tibotec, MSD, Biolex, InterMune, and Zymogenetics.

Dr. Peter Ferenci – reports involvement on Advisory Committees or Review Panels for Roche, Novartis, Vertex, Salix, Madaus Rottapharm and Tibotec and has received grant/research support from Human Genome Sciences, Vertex, Madaus Rottapharm, also has a patent held/filed with Madaus Rottapharm and has been involved as a speaker with Roche, Gilead and Salix. Prof. Stephanos Hadziyannis reports involvement on advisory committees/review panels for Gilead, Bristol-Myers Squibb, Novartis; and has received grant/research support from Roche, Gilead, Schering Plough; and has been involved as a speaker for Roche. Mr. Diethelm Messinger reports serving as a consultant for Roche. Dr. Fernando Tatsch is an employee of F. Hoffmann-La Roche Ltd. Prof. Donald M. Jensen reports involvement on advisory committees/review panels for Abbott, Boehringer-Ingelheim, Genentech/Roche, GlobeImmune, Tibotec, Vertex, Human Genome Sciences, Pharmasset; and has received grant/research support from Boehringer-Ingelheim, Genentech/Roche, Tibotec and Vertex. Acknowledgements Support for third-party writing assistance for this manuscript was provided by F. Hoffman-La Roche Ltd. References [1] Dienstag JL, McHutchison JG. American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology 2006;130:231–264. [2] Zeuzem S, Pawlotsky JM, Von Lukasiewicz E, Wagner M, Goulis I, Lurie Y, et al. International, multicenter, randomized, controlled study comparing dynamically individualized versus standard treatment in patients with chronic hepatitis C. J Hepatol 2005;43:250–257. [3] Marcellin P, Benhamou JP. Treatment of chronic viral hepatitis. Baillieres Clin Gastroenterol 1994;8:233–253. [4] Jessner W, Gschwantler M, Steindl-Munda P, Hofer H, Watkin-Riedel T, Wrba F, et al. Primary interferon resistance and treatment response in chronic hepatitis C infection: a pilot study. Lancet 2001;358:1241–1242.

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