Serum procalcitonin levels in chronic hepatitis C patients under pegylated interferon-alpha plus ribavirin treatment

Serum procalcitonin levels in chronic hepatitis C patients under pegylated interferon-alpha plus ribavirin treatment

Journal of Clinical Virology 37 (2006) 329–331 Letter to the Editor Serum procalcitonin levels in chronic hepatitis C patients under pegylated inter...

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Journal of Clinical Virology 37 (2006) 329–331

Letter to the Editor

Serum procalcitonin levels in chronic hepatitis C patients under pegylated interferon-alpha plus ribavirin treatment

Abstract Objectives: To evaluate the alterations of serum procalcitonin (PCT) levels in patients with chronic hepatitis C during pegylated interferonalpha (PEG-IFNa) plus ribavirin (RIB) treatment and to correlate them with clinical and virological outcomes. Study design: Fifty-two consecutive patients (29 males, age = 41.2 ± 14.7 years) with chronic HCV-related liver disease (six cirrhotics) were evaluated for PCT levels at baseline and during the treatment course (at week 12, 24, 48 and 72) with PEG-IFNa plus RIB. Sustained virological response (SVR) was confirmed by undetectable serum HCV-RNA at the end of treatment and again 6 months after completion of treatment. Results: Two patients exhibited culture-proved bacterial infections during the treatment course. Thirty-six patients (69.2%) exhibit SVR and 16 (30.8%) were non-responders. Serum PCT levels remained within normal limits (0.1–0.5 ng/mL) in all treated patients throughout the followup period except those two who exhibited bacterial infections during the treatment course. Virological responders exhibited significant decline of serum PCT levels over time compared to non-responders (p < 0.001), even when adjusted for multiple baseline parameters (p = 0.037). Conclusion: Serum PCT levels decline in chronic hepatitis C patients during PEG-IFNa plus RIB treatment, especially in the sustained virological responder group, while they elevate only when bacterial infections complicate the treatment course. © 2006 Elsevier B.V. All rights reserved. Keywords: Procalcitonin; Hepatitis C; Pegylated interferon; Ribavirin

Bacterial infections are frequently observed in patients with liver disease and are life threatening, especially in cirrhotic ones, so early diagnosis of them is mandatory (Navasa and Rodes, 2004). Pegylated interferon-alpha (PEG-IFNa) plus ribavirin (RIB) is currently the treatment of choice in patients with chronic hepatitis C virus (HCV)-related liver disease (NIH, 2002). Interferon therapy causes a commonly observed flu-like syndrome and a significant decrease in neutrophil counts in about a third of treated patients (NIH, 2002). Interferon-alpha (IFNa) treated patients are susceptible to bacterial infections (Soza et al., 2002). Procalcitonin (PCT) is a valid marker of bacterial infections, even in patients with liver disease (Simon et al., 2004; Elefsiniotis et al., 2006). The administration of endotoxin in normal human volunteers results in a rapid rise in serum tumor necrosis factor (TNF) and inteleukin-6 (IL-6) levels followed by elevation of serum PCT levels, a finding also observed after the administration of various cytokines (Maruna et al., 2000). It could be suggested that the administration of IFNa for the treatment of chronic viral hepatitis might elevate serum PCT levels decreasing its diagnostic 1386-6532/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jcv.2006.08.014

value for bacterial infections in those patients. The aim of our study was to investigate the alterations over time of serum PCT levels in patients with chronic HCV-related liver disease under PEG-IFNa plus RIB treatment and to correlate them with the clinical outcome and the virological response of these patients. A total of 52 consecutive patients (29 males) with serologically, virologically and histologically confirmed chronic HCV-related liver disease were evaluated and included in our study (PEG NAIVE trial, Schering-Plough, Greece). All patients were evaluated on admission clinically, hematologically, biochemically, serologically and virologicaly, using routine commercially available methods, as well as with chest X-ray and with ultrasound of the upper and lower abdomen. Blood and urine cultures were taken from all patients on admission and during the treatment course as well as when symptoms or signs of bacterial infection were observed. All patients were treated with pegylated interferon-a2b and ribavirin. The duration of treatment was genotype-based (24 weeks for genotype 2/3 infected patients and 48 weeks for genotype 1/4-infected ones). Sustained virological response

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Letter to the Editor / Journal of Clinical Virology 37 (2006) 329–331

(SVR) was confirmed by undetectable serum HCV-RNA at the end of treatment and again 6 months after completion of treatment. Serum PCT levels were measured at baseline and during treatment, at weeks 12, 24 and 48 of treatment in genotype 2/3 infected patients and at weeks 12, 24, 48 and 72 of treatment in genotype 1/4-infected, respectively, using an immunoluminometric assay (Lumitest PCT, B.R.A.H.M.S.-Diagnostica, Berlin, Germany). Baseline characteristics of the study population are presented in Table 1. Thirty-six of them (69.2%) exhibited SVR and 16 (30.8%) were characterized as non-responders. Baseline characteristics among virological responder and nonresponder patients of the study population are presented in Table 2. Culture-proved urinary tract infection (due to E. coli) was detected in one patient and pneumonia-bacteremia (due to Klebsiella pneumonia) in another one during the treatment course. Both patients exhibited significant elevation of serum PCT levels at the time of diagnosis of the bacterial infection (1.26 and 1.51 ng/mL, respectively), whereas they were

Table 1 Baseline characteristics of chronic hepatitis C patients of the study population Baseline characteristics

Study population (N = 52)

Age (years) BMI (kg/m2 ) Hb (g/dL) WBC (/␮L) PLT (/␮L) ALT (IU/L) Albumin (g/dL) Globulin (g/dL) Grade (0–18) Stage (0–6) PCT (ng/mL)

41.21 23.46 14.28 6637.25 229140 80.37 4.31 3.04 5.27 2.25 0.17

± ± ± ± ± ± ± ± ± ± ±

14.74 3.52 1.36 745.73 68751 60.16 0.35 0.47 1.72 1.59 0.14

within normal values (0.1–0.5 ng/mL) during the treatment course. When formally testing PCT course over time in all patients, PCT values not only did not increase but actually declined over time (β = −0.004 PCT quintiles for each addi-

Table 2 Comparison of baseline characteristics among virological responder and non-responder chronic hepatitis C patients of the study population Responders (N = 36) Age (years) BMI (kg/m2 ) Hb (g/dL) WBC (␮L) PLT (␮L) ALT (IU/L) Albumin (g/dL) Globulin (g/dL) Grade (0–18) Stage (0–6) PCT-baseline (ng/mL)

34.72 23.67 14.57 7060 240800 88.08 4.36 2.92 5.24 1.68 0.19

± ± ± ± ± ± ± ± ± ± ±

9.67 3.60 1.33 1684 63957 57.46 0.33 0.38 1.56 0.74 0.15

Non-responders (N = 16) 47.22 23.26 14.00 6230 217920 73.22 4.20 3.35 5.30 2.78 0.15

± ± ± ± ± ± ± ± ± ± ±

16.18 3.51 1.35 1737 72524 62.78 0.39 0.57 1.89 1.96 0.14

p-Value 0.002 0.682 0.135 0.09 0.239 0.379 0.304 0.037 0.908 0.012 0.382

Fig. 1. Regression lines (GEE predicted PCT quintile scores) (y-axis) over the course of follow-up in weeks (y-axis) separately for all subjects combined (graph A) and separately for responders (dashed line) and non-responders (solid line) (graph B).

Letter to the Editor / Journal of Clinical Virology 37 (2006) 329–331

tional week of follow-up, p = 0.011, Fig. 1A). Results were similar in a model simultaneously adjusting for a long list of possible confounders: β = −0.006 PCT quintiles for each additional week of follow-up, p = 0.032. Exclusion of the two subjects who manifested bacterial infections did not change the results. Despite the absence of an association between SVR and PCT values at baseline (β = 0.27, p = 0.34), there was a significant association between SVR status and change of PCT values over time: subjects who exhibited SVR had faster PCT decline over time (β = −0.006 additional PCT quintiles decline for each week of follow-up, p = 0.026; Fig. 1B). Results were similar (or even stronger) in fully adjusted models: β = −0.010 additional PCT quintiles decline for each week of follow-up, p = 0.025. We found that serum PCT levels did not elevate but actually decline in chronic hepatitis C patients treated with PEG-IFNa plus RIB, except in those complicated by a culture-proved bacterial infection during the treatment course. Moreover we found that compared to non-responders, who exhibited an almost stable PCT curve on treatment, serum PCT levels had a more precipitous decline in patients who exhibited SVR. Our finding suggests that exogenous administration of IFNa does not significantly influence serum PCT levels in, uncomplicated by bacterial infections, treated chronic hepatitis C patients. The clinical significance of these findings is that serum PCT levels possibly represent a useful marker of bacterial infection in chronic viral hepatitis patients even if they are being treated with IFNa-based regimens.

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Ioannis S. Elefsiniotis ∗ Department of Internal Medicine, Hepatology Unit, Hippokration Hospital, Athens, Greece Aikaterini Petrocheilou Department of Microbiology, Hippokration Hospital, Athens, Greece Nikolaos Scarmeas Taub Institute, Columbia University Medical Center, NY, USA Ioannis Ketikoglou Department of Internal Medicine, Hepatology Unit, Hippokration Hospital, Athens, Greece Konstantinos D. Pantazis Department of Internal Medicine, Hepatology Unit, Hippokration Hospital, Athens, Greece Marina Toutouza Department of Microbiology, Hippokration Hospital, Athens, Greece Epameinondas V. Tsianos First Division of Internal Medicine, Hepatogastroenterology Unit, Medical School, University of Ioannina, Greece ∗ Correspondence

to: Carchidonos 9, A. Glyfada GR-16562, Greece. Tel.: +30 210 9630312; fax: +30 210 7787807. E-mail address: [email protected] (I.S. Elefsiniotis) 9 August 2006