Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin

doi:10.1016/j.jhep.2005.04.009

Journal of Hepatology

Volume 43, Issue 3, September 2005, Pages 425-433

https://doi.org/10.1016/j.jhep.2005.04.009 Get rights and content

Background/Aims

Prediction of sustained virological response (SVR) during treatment would allow clinicians to identify patients most likely to benefit from therapy.

Methods

Retrospective analysis of data from 1121 adults with chronic hepatitis C treated for 48 weeks with peginterferon alfa-2a (40 KD) 180 μg/week plus placebo or ribavirin (1000/1200 mg/day), or interferon alfa-2b 3 MIU three times/week plus ribavirin in a randomized, multinational, study.

Results

67% of patients treated with peginterferon alfa-2a (40 KD)/ribavirin with early virological responses (HCV RNA negative or ≥2 log₁₀ decrease) at week 12 had SVRs at week 72 (HCV RNA <50 IU/mL). The negative predictive value (NPV) was 97%. The probability of an SVR increased with the rapidity of HCV RNA suppression. The highest SVR rates were achieved in patients with rapid virological responses at week 4, but the corresponding NPV (74%) is too low for a decision criterion. In patients with early virological responses by week 12, the SVR rate was ≈20% lower in those who received <80% compared with patients who received ≥80% of the planned ribavirin dose.

Conclusions

Early, sustained suppression of HCV replication portends an SVR. Cessation of treatment may be contemplated in patients without a ≥2 log₁₀ reduction in HCV RNA after 12 weeks.

Introduction

The combination of a pegylated interferon plus ribavirin has produced sustained virological response (SVR) rates up to 63% in patients with chronic hepatitis C [1], [2], [3]. The ability to predict, either before or during treatment, whether a patient will achieve an SVR would be of great utility because this combination is more expensive and has side effects similar to conventional interferon/ribavirin. Useful predictors of non-response to therapy must have high negative predictive value (NPV); conversely, useful predictors of an SVR must have a high positive predictive value (PPV).

The observation [2] that patients without an early virological response (EVR) after 12 weeks of treatment with peginterferon alfa-2a (40 KD)/ribavirin were highly unlikely to develop an SVR (NPV=97%) was adopted as an assessment criterion by the National Institutes of Health (NIH) Consensus Development Conference [4]. The predictive potential of an EVR has also been confirmed for patients treated with pegylated interferon alfa-2b (12 KD) plus ribavirin [5].

The current prediction algorithm is not ideal. The PPV at week 12 was only 65% with peginterferon alfa-2a (40 KD)/ribavirin [2]. We hope to refine the treatment algorithm by analyzing virological responses at time points other than week 12, by considering overall exposure to treatment, and by including follow-up data for non-responders. Our results have led to the development of a dynamic prediction model based on the virological response at multiple time points.

Section snippets

Patients and Methods

This analysis is based on data from a randomized, phase III study of 48 weeks of treatment in patients with chronic hepatitis C with peginterferon alfa-2a (40 KD) (PEGASYS^®, Roche, Basel, Switzerland) 180 μg/week plus ribavirin (COPEGUS^®, Roche) 1000 or 1200 mg/day (for bodyweight <75 or ≥75 kg, respectively), peginterferon alfa-2a (40 KD) plus placebo, or interferon alfa-2b 3 MIU three times/week plus ribavirin given as described above. The study design and primary results have been published [2].

Virological response

The various definitions of virological responses are presented in Table 1.

Exposure to therapy

Patients were considered to have been exposed to the full planned dose of study drug if they received all prescribed doses. Events that resulted in reduced exposure to study drugs, including poor patient adherence and physician-initiated dosage modifications, were combined and included in the exposure analysis.

Statistical methods

Explorative statistical methods were used in this analysis. PPV was defined as the probability that the outcome

Results

The flow of patients through the trial is illustrated in Fig. 1 and, as reported previously [2], the baseline characteristics of the patients were similar across the three treatment groups.

Static prediction models

Static prediction models are based on measurement of serum HCV RNA levels at baseline and at a fixed timepoint during treatment.

Dynamic prediction models

Dynamic prediction models are based on sequential sampling of HCV RNA before and during treatment and provide information about the rapidity of viral clearance. Among patients treated with peginterferon alfa-2a (40 KD)/ribavirin, 87% (104/120) of those who were HCV RNA negative by week 4 developed an SVR. In contrast, an SVR occurred in 52% (43/82) of those whose HCV RNA level dropped by ≥2 log₁₀ by week 4, but remained quantifiable (600 IU/mL).

In patients treated with peginterferon alfa-2a (40

Discussion

Perhaps the most intriguing new finding of this analysis was the consistent evidence of a relationship between the rapidity of HCV RNA suppression and the likelihood of achieving an SVR. Furthermore, the high NPV of the absence of an EVR at week 12 and the importance of adherence to therapy was reconfirmed and serves to reinforce the recommendations in the NIH Consensus Statement [4]. These data can be used to tailor treatment for individual patients.

The high NPV of the absence of an EVR at

Acknowledgements

This study was supported by a grant from Roche, Basel, Switzerland.

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^☆: The authors who have taken part in the research of this paper have a relationship with the manufacturers of the drug involved in the past or present. The author Peter Ferenci is a member of the Roche advisory board (Pegasys-chronic hepatitis C). The author declares he did not receive funding from any source to carry out this study.

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Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin☆

Background/Aims

Methods

Results

Conclusions

Introduction

Section snippets

Patients and Methods

Virological response

Exposure to therapy

Statistical methods

Results

Static prediction models

Dynamic prediction models

Discussion

Acknowledgements

Lancet

Hepatology

J Hepatol

Hepatology

Gastroenterology

Hepatology

Hepatology

Hepatology