Elsevier

Journal of Hepatology

Volume 59, Issue 5, November 2013, Pages 972-977
Journal of Hepatology

Research Article
A diagnostic score for the prediction of spontaneous resolution of acute hepatitis C virus infection

https://doi.org/10.1016/j.jhep.2013.06.028Get rights and content

Background & Aims

IL28B polymorphisms, jaundice, decline in HCV-RNA, IP-10, and gender have been proposed to be indicative of spontaneous clearance of acute hepatitis C virus infection. The aim of this study was to define a score enabling the discrimination of patients with spontaneous clearance of HCV from those with development of viral persistence and need for early antiviral treatment.

Methods

136 patients (74 male; 35 ± 15 years) were analyzed. From variables predictive of spontaneous clearance, calculated by univariate analysis, three scores were built. Analogous cut-offs were evaluated by computing area under the receiver operating characteristic curves. Candidate variables and cut-offs were: (I) presence of IL28B C/C (p = 0.027), (II) age (p = 0.031; cut-off: 35 years), (III) peak-bilirubin (p = 0.018; cut-off: 6 mg/dl), (IV) HCV-RNA decline within 4 weeks (p <0.001;cut-off: >2.5 log), (V) serum IP-10 (p = 0.003; cut-off: 546 pg/ml), (VI) presence of CD4(+) Th1 cells (p = 0.024). Each variable was allocated to 0 or 1 point, an HCV-RNA decline of ⩾1 log10 but <2.5 log10 to 1 point, a decline of ⩾2.5 log10 to 2 points. Three scores were evaluated (Score 1: I–IV; Score 2: I–V; Score 3: I–VI).

Results

A cut-off of ⩾3 points out of 5 in Score 1 (AUROC: 0.82; DeLong 95% CI: 0.76–0.93) predicted spontaneous clearance with a sensitivity of 71% (95% CI: 0.53–0.86) and specificity of 87% (95% CI: 0.73–0.95). PPV and NPV were 79% and 82%. Corresponding findings for Score 2 including IP-10 (AUROC: 0.93; DeLong 95% CI: 0.86–0.93) at a cut-off of ⩾4 were: sensitivity 81%, specificity 95% (PPV: 100%; NPV: 77%). A cut-off of ⩾5 in Score 3 (AUROC: 0.98; DeLong 95% CI: 0.95–1.0) predicted spontaneous resolution with a sensitivity of 75% and specificity of 100% (PPV: 100%; NPV: 88%).

Conclusions

The scores enable a reliable discrimination between AHC-patients with high potential for spontaneous clearance from candidates for early therapeutic intervention due to marginal chance of spontaneous resolution.

Introduction

Chronic infection with hepatitis C virus (HCV) remains a major global health burden. Hepatitis C virus infection commonly runs asymptomatic with only a minority of patients presenting with symptomatic, acute hepatitis C (AHC). Spontaneous viral resolution occurs in about 20–40% of infected patients. Considerable evidence has accumulated that particularly those patients with an icteric, symptomatic course of AHC have higher chance to resolve HCV infection spontaneously [1], [2], [3], [4], [5], [6], [7], [8]. In this respect, it was shown that a fast decline of HCV-RNA during early stages of infection is indicative of viral clearance [9]. As a genetic marker, a single nucleotide polymorphism (SNP) on chromosome 19 (rs12979860) near the IL28B region was found to be associated with spontaneous resolution of AHC [8], [10], [11], [12]. Moreover, it was reported that in the early stages of hepatitis C infection, the appearance of HCV specific CD4(+)Th1 cells is more common in patients with consecutive viral clearance [13]. Recently, high serum levels of interferon-gamma inducible protein 10 (IP-10) were also shown to be associated with spontaneous resolution of acute HCV infection [8], [14], [15].

Taken together, spontaneous clearance of HCV is dependent on both host and pathogen related factors [16], [17], [18], [19]. Nevertheless, a proportion of patients, even with acute symptomatic presentation, develop chronic infection and, therefore, optimal therapy strategies to prevent this evolution are still under debate. Early antiviral therapy for AHC has been shown to exert a favorable outcome [20], [21], but is associated with substantial toxicity and costs and is dispensable in patients who would clear the virus spontaneously during the course of the disease.

However, discussion is ongoing if delayed treatment-initiation impairs response to antiviral treatment [22]. A study performed in Germany suggested comparable outcome for both, the early treatment intervention and delayed initiation of antiviral therapy [23].

Hence, the aim of this study was to develop a simple and reliable score, based on clinical and laboratory parameters, found to be predictive of spontaneous viral resolution, to discriminate patients needing early antiviral treatment from those who could be monitored by watchful waiting due to high probability of SC.

Section snippets

Patients

This retrospective study included 136 Caucasian patients (male: 74 [54.4%]; mean age at time of infection: 35 ± 15 years) with proven acute hepatitis C virus infection, diagnosed in Austrian tertiary referral centers. AHC was defined either by an elevation of alanine aminotransferase (ALT) serum levels of more than 5 times the upper limit of normal (ULN), with or without jaundice in anti-HCV antibody and HCV-RNA positive patients (N = 103), with exclusion of chronic hepatitis C and exclusion of other

Patient characteristics and clinical presentation

Seventy-four (54%) of all patients and twenty-nine (55%) of patients with SC were male. HCV-genotyping could be performed in 109 patients (80%) as follows: HCV-GT 1: 67 (61%); GT2: 6 (6%); GT3: 30 (28%); GT4: 4 (3%), GT6: 2 (2%), mixed GT (2/4): 1 (1%). Spontaneously clearing patients were younger than patients who developed viral persistence (31 ± 13 [17–81] vs. 37 ± 16 [16–81] years; mean ± SD [range]; p = 0.031). Quantitative HCV-RNA levels at first presentation were higher in patients developing

Discussion

In view of high sustained virologic response (SVR) rates reached by early initiation of antiviral therapy in patients with acute hepatitis C virus infection, identification of patients probably not clearing HCV spontaneously is of particular importance, as a delayed start of treatment may diminish efficacy of antiviral therapy [5], [19], [25], [26], [27], [28]. Thus, optimal timing and an appropriate patient selection are crucial in the treatment of patients with acute hepatitis C and still

Conflict of interest

PF is a member of the global advisory board and of the speaker’s bureau of ROCHE, Basel CH and Rottapharm-Madaus, Monza, Italy. He is also advisor to Böhringer-Ingelheim, Vertex/Tibotec, Idenix, Achilleon, Glaxo Smith-Kline, and MSD and receives an unrestricted research grant from ROCHE Austria and MSD Austria. HH, AM, CD, MS, and RS serve as speakers for Roche Austria, MSD Austria, Bristol-Myers Squibb, and Janssen Austria. All other authors have no financial disclosures to report.

Authors’ contributions

Sandra Beinhardt: acquisition, analysis and interpretation of data; statistical analysis; drafting of the manuscript. Berit Anna Payer, Michael Strasser, Emina Dulic-Lakovic, Evelyn Grilnberger-Franz, Hermann Laferl: acquisition of data. Andreas Maieron: acquisition of data; critical revision of the manuscript for important intellectual content. Christian Datz: acquisition of data; critical revision of the manuscript for important intellectual content. Rudolf Stauber: acquisition of data;

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