New HCC Risk Score System
Hepatitis C: New points system helps with disease prognosis
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July 29 2013, medicalexpress.com
Between 40,000 and 80,000 Austrians suffer from hepatitis C. With new infections the prompt and appropriate treatment is of great importance as this can prevent it developing into a chronic illness which in turn can progress to inoperable liver cancer. Now a research team led by scientists of the MedUni Vienna has succeeded in developing a points system enabling a better prognosis as to whether the illness will become chronic or whether the acute hepatitis C will spontaneously heal itself.
"This is significant by virtue of the fact that, for patients with a tendency towards developing a chronic illness, early treatment with antiviral medication affords a better chance of healing," explains hepatologist Harald Hofer of the University Department of Internal Medicine III at the MedUni Vienna, Clinical Department of Gastroenterology and Hepatology (Chief: Michael Trauner).
The points system was developed by the MedUni Vienna researchers from a combination of clinical and biochemical parameters. Says Hofer: "Using this, the clinical course of the acute hepatitis C can be much better predicted, which means that the costly antiviral therapy with its many side effects can be much more efficiently deployed." The results of the study have been now published in the leading Journal of Hepatology.
Towards an interferon-free therapy
The advances made in treating hepatitis are generally remarkable. Two new, direct acting antiviral substances (DAA/"Direct Acting Antiviral Therapy") have been submitted for licensing not only in Europe but also in the USA (Simeprevir and Sofosbuvir), and will, according to Hofer, also be available in the foreseeable future. "For some of the patients this means that interferon-free therapy is becoming a reality outside clinical trials as well."
Current standard treatment is a combination therapy with interferon-alpha, which possesses an immune-stimulating, antiviral effect. In cases of hepatitis C interferon is injected once a week over a period of up to twelve months - although with undesirable side effects such as aching limbs, fever, headaches, as well as depressive episodes or malfunctions of the thyroid. The advantage of direct antiviral therapy (DAA) is that it acts directly on the hepatitis C virus and is thus more effective - with fewer side effects.
Article in Press
Journal of Hepatology July 2013
A Diagnostic Score for the Prediction of Spontaneous Resolution of Acute Hepatitis C Virus Infection
Sandra Beinhardt1, Berit Anna Payer1, Christian Datz2, Michael Strasser3, Andreas Maieron4, Livia Dorn5, Evelyn Grilnberger-Franz6, Emina Dulic-Lakovic7, Rudolf Stauber8, Hermann Laferl9, Judith H. Aberle10, Heidemarie Holzmann10, Christoph Krall11, Wolfgang Vogel5, Peter Ferenci1, Harald Hofer1*
1Internal Medicine III, Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; 2Hospital Oberndorf, Austria; 3Paracelsus Medical University Salzburg, Salzburg, Austria;
4Hospital Elisabethinen, Linz, Austria; 5Department of Internal Medicine II - Gastroenterology and
Hepatology, Medical University of Innsbruck, Innsbruck, Austria; 6Otto Wagner Spital, Vienna, Austria; 7Department of Internal Medicine IV, Wilhelminenspital, Vienna, Austria; 8Department of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria; 9Department of Internal Medicine, Kaiser-Franz-Josef-Spital, Vienna, Austria; 10Department of Virology, Medical University of Vienna, Vienna,Austria; 11Institute of Medical Statistics, Medical University of Vienna, Vienna, Austria
Background & aims
IL28B-polymorphisms, jaundice, decline in HCV-RNA, IP-10 and gender have been proposed to be indicative for spontaneous clearance of acute hepatitis C virus infection. Aim of this study was to define a score enabling the discrimination of patients with spontaneous clearance of HCV from those with development to viral persistence and need for early antiviral treatment.
Patients & methods
136 patients (male:74;35±15years) were analyzed. From variables predictive for spontaneous clearance, calculated by univariate analysis, three scores were built. Analogous cutoffs were evaluated by computing area under the receiver operating characteristic curves. Candidate variables and cutoffs were: (I)presence of IL28B-C/C (P=0.027), (II)age (P=0.031;cutoff:35years), (III)peak-bilirubin (P=0.018;cutoff:6mg/dl), (IV)HCV-RNA-decline within 4 weeks (P<0.001;cutoff:>2.5log), (V)serum IP-10 (P=0.003;cutoff:546pg/ml), (VI)presence of CD4(+)Th1-cells (P=0.024). Each variable was allocated to 0 or 1 point, an HCV-RNA-decline of 1log10 but <2.5log10 1 point, a decline of 2.5log10 to 2 points. Three scores were evaluated (Score1:I-IV; Score2:I-V; Score3:I-VI).
A cutoff of 3 points out of 5 in Score1 (AUROC:0.82; DeLong95%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 Score2 including IP-10 (AUROC:0.93; DeLong95%CI:0.86-0.93) at a cutoff 4 were: sensitivity 81%, specificity 95% (PPV:100%;NPV:77%). A cutoff of 5 in Score3 (AUROC:0.98; DeLong95%CI:0.95-1.0) predicted spontaneous resolution with a sensitivity of 75% and specificity of 100% (PPV:100%;NPV:88%).
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.
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 for viral clearance . 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 . 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 as well as 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 . A study performed in Germany suggested comparable outcome for both, the early treatment intervention and the delayed initiation of antiviral therapy .
Hence, aim of this study was to develop a simple and reliable score, based on clinical and laboratory parameters, found to be predictive for spontaneous viral resolution, to discriminate patients in need of early antiviral treatment from those who could be monitored by watchful waiting due to high probability of SC.
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 with development of 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 chronic HCV infection than in patients with SC (5.2±1.4 vs. 4.3±1.7 log10 IU/ml; mean±SD; P=0.002). HCV-RNA decline at week 4 after first presentation was stronger in patients with spontaneous resolution of AHC (2.7±2.3 vs. 0.7±1.6 HCV-RNA decline log10 in IU/ml; mean±SD; P<0.001). Peak levels of bilirubin were higher (6.6±6.3 vs. 4.0±5.0 mg/dl; mean±SD; P=0.018) and IP-10 levels were lower in spontaneous clearers compared to those with development of chronic HCV infection (417 [113 - 2232] vs. 1355 [141 - 4412] pg/ml; median [range]; P=0.002). HCV-specific antiviral CD4(+)Th1 cell response was detectable in 87.5% of patients spontaneously resolving AHC but only in 50% of patients developing viral persistence (P=0.02). Mean ALT elevation of included patients was 27.2 ± 25.1 (range: 0.8 - 125.1) and ALT levels were not different between patients who cleared the virus spontaneously and patients with evolution of chronicity.
Thirteen (9.6%) patients were co-infected with human immunodeficiency virus (HIV), two (1.5%) patients with hepatitis B virus. Patient's demographic data are given in table 1.
Predictive Parameters for spontaneous clearance & Cutoffs
Variables predictive for SC computed by univariate analysis were: IL28B (rs12979860) C/C-genotype (P=0.027), age at infection (P=0.031), detectability of HCV-specific CD4(+)Th1 cells (P=0.024) and serum IP-10 levels (pg/ml; P=0.003) at time of first presentation as well as peak bilirubin levels (mg/dl; P=0.018) and HCV-RNA decline till week 4 after diagnosis (log10; P<0.001) as well. By calculating predictive parameters for SC separately for HCV mono-infected patients, no difference could be detected. Female sex, ALT serum-levels as well as HCV-genotype did not show any significances (table 1). Appropriate cut-offs for variables found to be predictive for SC were: age at infection <35 years, peak bilirubin >6 mg/dl, HCV-RNA decline till week 4 after diagnosis ≥2.5 (log10) as well as serum IP-10-levels <546.0 pg/ml (binary variables excluded; table 2A; Supplementary material, figure 1).
Development of Scores
According to computed cutoff-levels, evaluated to be predictive for SC, Score1 includes following parameters: IL28B rs12979860 C/C-genotype, age at infection, peak bilirubin and HCV-RNA decline till week 4. Although IP-10 and detectability of HCV-specific CD4(+)Th1 cells are not routinely determined variables, but nevertheless strengthened statistically significance, we added them up to build Score2 and Score3 in a stepwise manner. Score1 is built at week 4 after diagnosis by 1 point for each criterion (see table 3 A, B and C). For Score2 an additional point is added if IP-10 serum levels are <546
pg/ml; for Score3 an additional point is added if HCV-specific CD4(+)Th1 cells were detectable at first presentation as well (see table 3C).
Accordingly AUROCs could be computed as follows: Score1: 0.863, Score2: 0.914 and Score3: 0.973 respectively (figure 2). Comparing areas under the curve of all evaluated scores, increased predictability for spontaneous resolution of AHC, compared to individual AUROCs of variables found to be significant by means of univariate analysis (figure 1 and 2). The "simple" diagnostic score (Score1) with a cutoff of ≥3 points reveals a sensitivity for SC of 71% and a specificity of 88% with a PPV of 79% and NPV of 82% (table 4), allowing to recognize patients with high probability for development of
chronicity (2 points - NPV: 92%; 1 point - NPV: 100%). The more comprehensive scores, including IP-10 (Score2) and HCV-specific CD4(+)Th1 cell-response (Score3) and their cutoffs of ≥4 and ≥5 points increased PPV for spontaneous clearance up to 100% (table 4).
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 cause controversy to some extent . As symptomatic presentation of acute hepatitis C virus infection is infrequent and hence it is difficult to
conduct adequately powered prospective randomized clinical trials; a recent study addressed this issue by building a mathematical modeling .
In our study we aimed to develop a simple score (Score1) to facilitate a diagnostic tool for the differentiation of patients with high probability for SC from those in need for early antiviral treatment. Patients with 3 and more points could be managed by watchful waiting, as they showed a high likelihood to resolve AHC infection and an unnecessary therapy, causing costs and side effects, could be avoided. On the other hand, patients with less than 3 points should be considered for early antiviral therapy, as there is a marginal chance that AHC resolves spontaneously. As calculation of the proposed scores is already available at week four after first diagnosis of AHC, antiviral treatment could be started early in these patients, which might have beneficial effects on HCV eradication rates. Moreover, patients often prefer the "more active approach" of beginning antiviral therapy than just follow the natural course of the disease . Thus, patients might be lost to follow-up by a prolonged observational period before treatment even can be initiated.
All scores, whether they are preferentially clinically orientated (Score1) or more scientific (Score2 and Score3) can be calculated very early during follow-up period at week 4 and therefore might improve patients concealing as well as compliance. Although IP-10 is not yet a routinely tested variable, it's role as a marker for the prediction of spontaneous resolution of AHC becomes more and more evident [8,14,15]. By adding IP-10 as additional variable (Score2) specificity and PPV for SC could be increased up to 95% and 100%, favoring an watchful waiting strategy in patients with an high aggregate score. By adding HCV-specific CD4(+)Th1 cells the performance could be even more improved. However determination of HCV-specific CD4(+)Th1 cells remains a time consuming and costly procedure and is therefore hardly useful in everyday clinical practice.
One major drawback of this study is the retrospective character as well as the relatively low number of patients within subgroup analysis, reflecting the rarity of acute hepatitis C as discussed above. Thus, our data should be prospectively validated in other large patient groups.
Our scoring system does not include HCV-genotype, as it apparently does not influence rates of spontaneous clearance in our cohort. Nevertheless, HCV-genotypes carry substantial impact on the clinical approach to patients with acute hepatitis C virus infection: in view of high sustained virological response rates reported in chronically infected HCV-genotype 2 and 3 patients, one could postulate that there is no need to treat these patients during the acute phase of infection. And even in chronic HCV-genotype 1 patients advances in antiviral treatment are fast, with SVR rates similar to the high HCV eradication-rates reported during acute hepatitis C.