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The inhibitory effect of interferon on hepatitis C virus replication is not mediated via nitric oxide in man
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Abstracts
AJG – Vol. 95, No. 9, 2000
385
387
Hyperuricemia associated with ribavirin treatment of chronic hepatitis C indicating IMPDH inhibition: A possible mode of antiviral activity? Akeel Halai, Gerond Lake-Bakaar*. VAMC, Northport, NY, United States.
Comparison of truncal hair distribution in alcoholic liver disease and alcohol-related chronic pancreatitis N Kumar, MD, SR Aggarwal, MD, BS Anand, MD, FACG. G. B. Pant Hospital, New Delhi, India.
Purpose: Ribavirin is a guanosine analogue and probably exerts its antiviral activity against Hepatitis C by interfering with RNA synthesis. Possible modes of action include inhibition of viral RNA polymerase, inhibition of guanylytransferase and methyltransferase and competition with guanosine for incorporation into the 5⬘ terminus of viral RNA. Ribavirin also competitively inhibits IMPDH (inosine monophosphate dehydrogenase), the enzyme necessary for synthesis of guanosine monophosphate, which could result in depletion of intracellular nucleotide pools of guanosine triphosphate. Inhibition of IMPDH by Ribavirin would also increase production of hypoxanthine and xanthine, which are precursors of uric acid. We hypothesized that significant inhibition of IMPDH by ribavirin during treatment of hepatitis C would result in increased serum uric acid levels. Methods: We followed during a fourteen day period, the sequence of changes in serum uric acid in patients during treatment with high dose interferon plus Ribavirin 1000 mg (n ⫽ 4) and compared these to changes in patients on high dose interferon alone (n ⫽ 4). Serum uric acid levels were measured through the routine chemistry laboratory. Results: Changes in daily serum uric acid levels were minimal and inconsistent during the 14 days of treatment in patients on interferon alone. By contrast, uric acids levels increased gradually to a peak at 1 to 10 days in the patients on ribavirin, and then gradually declined back to baseline levels. The mean maximal uric acid levels in the interferon alone group 8.85 ⫹ 1.05, was lower than the group treated with interferon and ribavirin, 10.6 ⫹ 3.8 (p ⫽ 0.09). Conclusions: These results suggest that inhibition of IMPDH may be one possible mechanism of antiviral activity of ribavirin. However the effect on uric acid metabolism is short-lived, which suggests that this may not be the only mode of action of ribavirin.
Background: The pathogenesis of alcohol-related liver disease is unclear. It has been observed that chronic alcoholics with scanty truncal hair distribution have increased risk of developing liver disease. The present study was carried out to examine this issue further by comparing hair distribution patterns in patients with alcoholic liver disease and alcoholic chronic pancreatitis. Methods: All consecutive patients with a history of heavy alcohol abuse (ⱖ80 grams of alcohol per day for a minimum of 5 years) and either chronic liver disease or pancreatic disease were invited to participate in the study. Detailed clinical data was collected including the amount (g/day) and duration of alcohol consumption, signs of hepatic decompensation and assessment of hair growth over the trunk (graded from 0 to 5; 0 ⫽ nil, 5 profuse). Results: A total of 86 subjects comprising of 44 patients with alcoholic liver disease and 42 with alcohol-related chronic pancreatitis were included in the study. There was no significant difference between the two groups with respect to the age at presentation, mean daily alcohol consumption and duration of alcohol use. The length of illness prior to presentation was significantly greater in alcoholic pancreatitis compared with alcoholic liver disease (2.5 ⫾ 2.4 vs 1.2 ⫾ 1.4 years). Patients with alcoholic liver disease had significantly less hair growth over the trunk compared to those with alcohol-related chronic pancreatitis (2.0 ⫾ 1.4 vs 3.8 ⫾ 1.1; p ⬍ 0.001). Comment: Our results confirm previous observations that individuals who develop alcohol-related liver disease have scanty premorbid truncal hair growth compared to alcoholic pancreatitis. This finding not only provides a useful clinical marker of identifying individuals at increased risk of alcohol-related liver damage but from the pathogenetic viewpoint suggests that at the tissue level the male hormone somehow protects against the toxic effects of excess alcohol use.
388 386 The inhibitory effect of interferon on hepatitis C virus replication is not mediated via nitric oxide in man Akeel Halai, Lynda Ruffini*, Gerond Lake-Bakaar. VAMC, Northport, NY, United States. Purpose: Interferon inhibition of the intracellular replication of HSV1, vaccinia and ectromelia viruses in mouse macrophages correlates directly with NO generation. The role of NO in interferon induced viral inhibition in humans less clear. We correlated the changes in serum HCV RNA levels with NO during treatment with high dose interferon in patients with chronic HCV liver disease. Methods: Serum HCV RNA and serum NO levels were simultaneously measured in seven male patients with chronic HCV liver disease at ⫺1, 0, 2, 4, 6, 8, 12, 24, 32, 36 and 48 hours, and then daily for a total of 14 days during daily treatment with 10 million units of Roferon with (n ⫽ 4) and without Ribavirin, 1000 mg daily (n ⫽ 3). All seven completed the study with no adverse effects. HCV RNA levels were measured using either the Chiron bDNA or the Roche COBAS PCR. NO was measured by the Brucine method after conversion of NO and nitrites to nitrates. Results: HCV RNA levels fell in all seven patients after a mean delay of 7.1 ⫹ 2.2 hours (range 2.8 to 9.38). The initial HCV viral clearance, 0.31 ⫹ 0.16 was rapid, reaching trough levels within the first 24 hours. Three peaks of NO levels were observed: A, an early peak within 24 hours (range 0 –17 hours) with a mean ⫹ SD of 73.1 ⫹ 54 uM; B, an inconsistent middle peak within 120 hours (range 24 –118) with a mean of 74.5 ⫹ 70 uM; and C, a late but major peak after 120 hours (range 165–300 hours) which generated the greatest amounts of NO, 103.7 ⫾ 64 uM.
Leukopenia: Synergism between interferon and ribavirin during combination therapy for chronic hepatitis C virus liver disease Gerond Lake-Bakaar, Akeel Halai*, D Bernstein. VAMC, Northport, NY, United States. Purpose: Treatment of chronic Hepatitis C with combination of Ribavirin and Interferon has significantly influenced the outcome of Hepatitis C compared to Interferon monotherapy. The commonly reported side effects of interferon monotherapy include flu-like symptoms, leukopenia, and thrombocytopenia, whereas Ribavirin therapy is most commonly associated with a dose dependent hemolytic anemia. A treatment protocol using combination Interferon and Ribavirin for six months followed by Interferon alone, provided us with a unique opportunity to evaluate the potential confounding effects of Ribavirin on the WBC count. Methods: We evaluated 12 patients who had all previously failed monotherapy with interferon (non-responders and relapsers). All received Interferon (Intron A) at a dose of 5 million units three times a week for up to 48 weeks. During the first 24 weeks, patients also received Ribavirin, either 600 mg or 100 mg daily. We measured serum hemoglobin, WBC and platelet counts pretreatment, after 12 and 24 weeks of combination treatment, and up to 12 weeks after reverting back to Interferon alone. Results: A progressive decline in the mean WBC count was noted in patients while on combination treatment, with subsequent improvement in the white cell count on discontinuation of Ribavirin. The difference between groups was highly statistical significant (ANOVA, p ⫽ 0.0008). By contrast, the differences in the means for RBC and platelets were not statistically significant (ANOVA, p ⫽ 0.4 and 0.48 respectively). The expected drop in the mean hemoglobin associated with Ribavirin was seen, which improved on discontinuation of the drug. We also noted a gradual
Abstracts
AJG – Vol. 95, No. 9, 2000
385
387
Hyperuricemia associated with ribavirin treatment of chronic hepatitis C indicating IMPDH inhibition: A possible mode of antiviral activity? Akeel Halai, Gerond Lake-Bakaar*. VAMC, Northport, NY, United States.
Comparison of truncal hair distribution in alcoholic liver disease and alcohol-related chronic pancreatitis N Kumar, MD, SR Aggarwal, MD, BS Anand, MD, FACG. G. B. Pant Hospital, New Delhi, India.
Purpose: Ribavirin is a guanosine analogue and probably exerts its antiviral activity against Hepatitis C by interfering with RNA synthesis. Possible modes of action include inhibition of viral RNA polymerase, inhibition of guanylytransferase and methyltransferase and competition with guanosine for incorporation into the 5⬘ terminus of viral RNA. Ribavirin also competitively inhibits IMPDH (inosine monophosphate dehydrogenase), the enzyme necessary for synthesis of guanosine monophosphate, which could result in depletion of intracellular nucleotide pools of guanosine triphosphate. Inhibition of IMPDH by Ribavirin would also increase production of hypoxanthine and xanthine, which are precursors of uric acid. We hypothesized that significant inhibition of IMPDH by ribavirin during treatment of hepatitis C would result in increased serum uric acid levels. Methods: We followed during a fourteen day period, the sequence of changes in serum uric acid in patients during treatment with high dose interferon plus Ribavirin 1000 mg (n ⫽ 4) and compared these to changes in patients on high dose interferon alone (n ⫽ 4). Serum uric acid levels were measured through the routine chemistry laboratory. Results: Changes in daily serum uric acid levels were minimal and inconsistent during the 14 days of treatment in patients on interferon alone. By contrast, uric acids levels increased gradually to a peak at 1 to 10 days in the patients on ribavirin, and then gradually declined back to baseline levels. The mean maximal uric acid levels in the interferon alone group 8.85 ⫹ 1.05, was lower than the group treated with interferon and ribavirin, 10.6 ⫹ 3.8 (p ⫽ 0.09). Conclusions: These results suggest that inhibition of IMPDH may be one possible mechanism of antiviral activity of ribavirin. However the effect on uric acid metabolism is short-lived, which suggests that this may not be the only mode of action of ribavirin.
Background: The pathogenesis of alcohol-related liver disease is unclear. It has been observed that chronic alcoholics with scanty truncal hair distribution have increased risk of developing liver disease. The present study was carried out to examine this issue further by comparing hair distribution patterns in patients with alcoholic liver disease and alcoholic chronic pancreatitis. Methods: All consecutive patients with a history of heavy alcohol abuse (ⱖ80 grams of alcohol per day for a minimum of 5 years) and either chronic liver disease or pancreatic disease were invited to participate in the study. Detailed clinical data was collected including the amount (g/day) and duration of alcohol consumption, signs of hepatic decompensation and assessment of hair growth over the trunk (graded from 0 to 5; 0 ⫽ nil, 5 profuse). Results: A total of 86 subjects comprising of 44 patients with alcoholic liver disease and 42 with alcohol-related chronic pancreatitis were included in the study. There was no significant difference between the two groups with respect to the age at presentation, mean daily alcohol consumption and duration of alcohol use. The length of illness prior to presentation was significantly greater in alcoholic pancreatitis compared with alcoholic liver disease (2.5 ⫾ 2.4 vs 1.2 ⫾ 1.4 years). Patients with alcoholic liver disease had significantly less hair growth over the trunk compared to those with alcohol-related chronic pancreatitis (2.0 ⫾ 1.4 vs 3.8 ⫾ 1.1; p ⬍ 0.001). Comment: Our results confirm previous observations that individuals who develop alcohol-related liver disease have scanty premorbid truncal hair growth compared to alcoholic pancreatitis. This finding not only provides a useful clinical marker of identifying individuals at increased risk of alcohol-related liver damage but from the pathogenetic viewpoint suggests that at the tissue level the male hormone somehow protects against the toxic effects of excess alcohol use.
388 386 The inhibitory effect of interferon on hepatitis C virus replication is not mediated via nitric oxide in man Akeel Halai, Lynda Ruffini*, Gerond Lake-Bakaar. VAMC, Northport, NY, United States. Purpose: Interferon inhibition of the intracellular replication of HSV1, vaccinia and ectromelia viruses in mouse macrophages correlates directly with NO generation. The role of NO in interferon induced viral inhibition in humans less clear. We correlated the changes in serum HCV RNA levels with NO during treatment with high dose interferon in patients with chronic HCV liver disease. Methods: Serum HCV RNA and serum NO levels were simultaneously measured in seven male patients with chronic HCV liver disease at ⫺1, 0, 2, 4, 6, 8, 12, 24, 32, 36 and 48 hours, and then daily for a total of 14 days during daily treatment with 10 million units of Roferon with (n ⫽ 4) and without Ribavirin, 1000 mg daily (n ⫽ 3). All seven completed the study with no adverse effects. HCV RNA levels were measured using either the Chiron bDNA or the Roche COBAS PCR. NO was measured by the Brucine method after conversion of NO and nitrites to nitrates. Results: HCV RNA levels fell in all seven patients after a mean delay of 7.1 ⫹ 2.2 hours (range 2.8 to 9.38). The initial HCV viral clearance, 0.31 ⫹ 0.16 was rapid, reaching trough levels within the first 24 hours. Three peaks of NO levels were observed: A, an early peak within 24 hours (range 0 –17 hours) with a mean ⫹ SD of 73.1 ⫹ 54 uM; B, an inconsistent middle peak within 120 hours (range 24 –118) with a mean of 74.5 ⫹ 70 uM; and C, a late but major peak after 120 hours (range 165–300 hours) which generated the greatest amounts of NO, 103.7 ⫾ 64 uM.
Leukopenia: Synergism between interferon and ribavirin during combination therapy for chronic hepatitis C virus liver disease Gerond Lake-Bakaar, Akeel Halai*, D Bernstein. VAMC, Northport, NY, United States. Purpose: Treatment of chronic Hepatitis C with combination of Ribavirin and Interferon has significantly influenced the outcome of Hepatitis C compared to Interferon monotherapy. The commonly reported side effects of interferon monotherapy include flu-like symptoms, leukopenia, and thrombocytopenia, whereas Ribavirin therapy is most commonly associated with a dose dependent hemolytic anemia. A treatment protocol using combination Interferon and Ribavirin for six months followed by Interferon alone, provided us with a unique opportunity to evaluate the potential confounding effects of Ribavirin on the WBC count. Methods: We evaluated 12 patients who had all previously failed monotherapy with interferon (non-responders and relapsers). All received Interferon (Intron A) at a dose of 5 million units three times a week for up to 48 weeks. During the first 24 weeks, patients also received Ribavirin, either 600 mg or 100 mg daily. We measured serum hemoglobin, WBC and platelet counts pretreatment, after 12 and 24 weeks of combination treatment, and up to 12 weeks after reverting back to Interferon alone. Results: A progressive decline in the mean WBC count was noted in patients while on combination treatment, with subsequent improvement in the white cell count on discontinuation of Ribavirin. The difference between groups was highly statistical significant (ANOVA, p ⫽ 0.0008). By contrast, the differences in the means for RBC and platelets were not statistically significant (ANOVA, p ⫽ 0.4 and 0.48 respectively). The expected drop in the mean hemoglobin associated with Ribavirin was seen, which improved on discontinuation of the drug. We also noted a gradual