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Antimicrobial Agents and Chemotherapy, October 2002, p. 3280-3282, Vol. 46, No. 10
0066-4804/02/$04.00+0 DOI: 10.1128/AAC.46.10.3280-3282.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.
Liver Diseases Unit, University of Manitoba, Winnipeg, Manitoba, Canada
Received 19 March 2002/ Returned for modification 17 June 2002/ Accepted 15 July 2002
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ABSTRACT |
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Fluoroquinolones are antimicrobial agents that have been reported to be effective in the treatment of conditions associated with liver failure, including portal systemic encephalopathy (PSE) and spontaneous bacterial peritonitis (2, 14) (S. Esposito, D. Barbra, D. Galanta, G. B. Gaeta, and O. Laghezza, Rev. Infect. Dis. 10:S197, 1996). They have also been reported to possess antiviral properties against both DNA and RNA viruses, including HCV (6, 10, 11). However, their value in HCV has largely been limited to patients with relatively mild, precirrhotic chronic hepatitis (7, 12, 13). If equally effective in patients with more advanced disease, these agents would represent an attractive therapeutic option for HCV-infected patients awaiting liver transplantation who require PSE and spontaneous bacterial peritonitis prophylaxis.
Five of 21 participants in a recent prospective, double-blind, placebo-controlled trial of ciprofloxacin treatment for subclinical PSE were known to have chronic HCV infections. Each patient had histologic and/or radiologic evidence of cirrhosis and had been listed for liver transplantation. The diagnosis of HCV was based on positive serologic (third-generation anti-HCV enzyme immunoassay) and virologic (HCV-RNA by PCR) testing. In all five cases, patients had been randomized to receive ciprofloxacin (500 mg orally twice a day for 30 days). None of the patients had received antiviral therapy in the past, and none was receiving immunosuppressive or other antimicrobial agents at the time of the study. All patients provided informed consent for participation in the subclinical PSE study and subsequently for HCV-RNA testing. The study was approved by the University of Manitoba Conjoint Ethics Committee for Human Experimentation.
Stored sera (-40°C) were available for testing from visits immediately prior to ciprofloxacin treatment (baseline) and again after 2 and 4 weeks of therapy. Posttreatment sera were also available at 4 and 8 weeks postciprofloxacin (follow-up samples). At each visit, sera were tested for liver enzymes (alanine and aspartate aminotransferases, alkaline phosphatase, and glutamyltransferase) and function tests (albumin, bilirubin, and prothrombin time/international normalized ratio) by standard laboratory procedures while stored sera were batched and tested for HCV-RNA quantitation by real-time PCR (see below) and genotyping by line probe assay (INNO-LiPA HCV II; Innogenetics, Toronto, Canada).
Measurement of HCV-RNA by real-time reverse transcriptase PCR (RT-PCR). HCV-RNA levels were determined using a LightCycler-RNA Amplification Kit SYBR Green I (Roche Diagnostics GmbH). Forward and reverse primers (5'-GAGGAACTACTGTCTTCACGCAGAA-3' and 5'-CTTTCGCGACCCAACACTACTC-3') were designed to amplify a 229-bp segment of the 5' noncoding region of HCV-RNA.
Twenty microliters of the PCR mixture contained LightCycler-RT-PCR Reaction Mix SYBR Green (Roche), 5 mM MgCl2, 0.25 µM forward primer, 0.5 µM reverse primer, LightCycler-RT-PCR Enzyme Mix, and template RNA. RT-PCR amplification was started with 30 min at 55°C for reverse transcription and followed by 30 s at 95°C for denaturation, which in turn was followed by 45 cycles of amplification at 57°C for 10 s and 72°C for 10 s. All reactions were performed in a LightCycler (Roche Diagnostics GmbH). The lower limit of detection for this assay is 1,000 viral copies/ml, and intrinsic variability < 10%.
Demographic and baseline laboratory findings of the five patients are provided in Table 1. The mean age was 53.2 ± 10.9 years. Baseline HCV-RNA levels ranged from 2.87 x106 to 7.81 x 106 copies/ml (mean, 5.19 ± 2.18 x 106 copies/ml). All HCV were genotype 1a or -b.
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To date, there has been only one previous study documenting the effects of fluoroquinolones as single-agent therapy in patients with chronic HCV (12). In that study, five patients with HCV-induced chronic hepatitis and four patients with compensated cirrhosis received 100 to 900 mg of ofloxacin per day for 1 to 8 weeks. Regardless of viral genotype, HCV-RNA levels decreased by at least 1 log in four patients, three of whom had chronic hepatitis. Treatment was well tolerated at lower doses (<600 mg/day) but caused diarrhea, anorexia, and insomnia at higher doses (900 mg/day). The duration of antiviral effects was not reported.
In two additional studies, fluoroquinolones were used in combination with interferon (7, 13). In a study by Tsutsumi et al., 20 noncirrhotic interferon nonresponders were randomized to either 12 weeks of combination therapy with ofloxacin (600 mg/day) superimposed on a 6-month course of high-dose interferon or high-dose interferon alone (13). In the combination group, alanine aminotransferase values improved and HCV-RNA levels decreased to a greater extent than in those who received interferon alone. The only sustained HCV responses occurred in two patients who received combination therapy. In a similar study reported by Komatsu et al., 20 noncirrhotic interferon nonresponders were randomized to either 22 weeks of ofloxacin (600 mg/day) plus interferon (3 x 106 to 6 x 106 U/wk) or interferon alone (7). Once again, the only two sustained viral responders were in the combination group. Moreover, alanine aminotransferase levels were significantly lower during treatment in the combination group than in those who received interferon alone. However, not all studies have been supportive. In a more recent report by Negro et al., combination therapy with interferon and ofloxacin was ineffective both virologically and biochemically in 26 patients who had previously failed to respond to interferon alone (9).
Because the mechanism(s) whereby fluoroquinolones inhibit viral replication remains to be defined, it is difficult to explain why ciprofloxacin was ineffective in our study. Possibilities to be considered include the following: (i) like interferon, the fluoroquinolones are disease stage specific (more effective in early than in late disease), (ii) the specific type and dose of the fluoroquinolone employed are important, (iii) the treatment period in our study (30 days) may have been inadequate, (iv) the response to fluoroquinolones may be genotype specific, and/or (v) our patient population was too small to detect a therapeutic benefit (type II error), particularly when response rates of only 40 to 60% are expected with more potent antiviral agents. Clearly, further studies are required to determine which of these possibilities will explain our findings.
In conclusion, although fluoroquinolone antimicrobial prophylaxis may be of benefit to patients with advanced liver disease who are at risk of developing hepatic encephalopathy and/or spontaneous bacterial peritonitis, their value as an antiviral agent in this setting appears to be limited.
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ACKNOWLEDGMENTS |
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This work was supported by the Health Sciences Centre Research Foundation, Winnipeg, Manitoba, Canada.
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FOOTNOTES |
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REFERENCES |
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-interferon plus ofloxacin in patients not responding to -interferon alone. J. Hepatol. 29:369-374.[CrossRef][Medline]
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