Ribavirin-induced Anemia Research Articles

Ribavirin-Induced Anemia: Mechanisms, Risk Factors and Related Targets for Future Research

Ribavirin (RBV) is an antiviral nucleoside analogue commonly used in combination with interferon for the treatment of chronic hepatitis C. Severe anemia develops in about 10% of treated patients, and requires close monitoring of hemoglobin and often RBV dose reduction, which may compromise sustained virologic response. Anemia is likely related to extensive RBV accumulation in erythrocytes subsequent to active unidirectional transmembraneous transport. RBV exerts its toxicity through an inhibition of intracellular energy metabolism and oxidative membrane damage, leading to an accelerated extravascular hemolysis by the reticulo-endothelial system. Concentration-dependent toxicity and improvement of anemia upon dose-reduction point towards the importance of pharmacokinetic factors for RBV-induced anemia. On the other hand, pronounced variability in the correlation between RBV concentration and Hb reduction limits the prediction of anemia based on plasma or erythrocyte concentrations in individual patients and points towards additional factors determining individual susceptibility to RBV-induced anemia. Recent studies suggest that erythrocyte oxidative defense mechanisms may play an important role in RBV-induced anemia. Clinical risk factors for severe RBV-induced anemia include impaired renal function, high age, high dose per body weight and female gender. Determination of RBV concentrations has little value in the management of anemia. The only proven effective prevention of RBV-induced anemia is the concomitant administration of erythropoietin. Future research on RBV pharmacokinetics and pharmacodynamics, as well as erythrocyte antioxidant defense mechanisms may improve safety and efficacy of RBV therapy and guide the development of new treatments for RBV-induced anemia and alternative antiviral agents.

Early decline of hemoglobin correlates with progression of ribavirin-induced hemolytic anemia during interferon plus ribavirin combination therapy in patients with chronic hepatitis C

The aim of this study was to examine the factors correlated with the progression of ribavirin-induced hemolytic anemia in patients with chronic hepatitis C treated by interferon and ribavirin combination therapy. This study was conducted on 505 patients by the Osaka Liver Disease Study Group. A decline of hemoglobin (Hb) concentration by 2 g/dl at the end of 2 weeks from the start of the treatment ("2 by 2" standard) was adopted as a predictive factor for progression to severe anemia. The ribavirin apparent clearance (CL/F) was also examined. Of 482 patients whose Hb value was more than 12 g/dl before the treatment, 68 patients (14%) had to discontinue ribavirin owing to severe anemia. Patients in the "2 by 2"-positive group (Hb decline over 2 g/dl) and the group with lower CL/F were significantly more likely to discontinue ribavirin owing to severe anemia. Discontinuation was more common among patients aged 60 years or older than for those under 60 years old (21% vs. 9%, P < 0.001). Among patients aged 60 years or older, only the "2 by 2" standard was significantly associated with the discontinuance of ribavirin owing to severe anemia in a multivariate analysis (odds ratio, 4.18; P < 0.001). The "2 by 2" standard of Hb decline can be used to identify patients likely to develop severe anemia. The early reduction of ribavirin can help prevent progression to severe anemia, thus allowing ribavirin therapy to be completed even in older patients.

417–2α‐Tocopherol and ascorbic acid attenuates the ribavirin‐induced decrease of eicosapentaenoic acid in erythrocyte membrane in chronic hepatitis C patients

Oxidative damage of the erythrocyte membrane plays an important role in ribavirin-induced anemia. The purpose of the present paper was to assess whether supplementation of alpha-tocopherol and ascorbic acid (vitamins) causes changes in the erythrocyte membrane fatty acid composition during interferon and ribavirin combination therapy for chronic hepatitis C patients. Fatty acid compositions in erythrocyte membrane phospholipids were determined by gas chromatography at 0, 2, 4, 8 weeks, and at the end of combination therapy (26 weeks) for interferon with ribavirin in 32 patients with chronic hepatitis C who were randomized to receive vitamins or not (controls). Good compliance with orally administered vitamins and ribavirin were confirmed by their concentrations in erythrocytes or plasma. The hemoglobin level was negatively correlated with the ribavirin concentration at 8 weeks (r = 0.59, P = 0.01) after initiation of therapy in controls, but not in the vitamin group. Among the 26 kinds of fatty acids analyzed, only eicosapentaenoic acid (EPA) significantly decreased at 8 weeks after initiation of therapy (P = 0.03) and at the end of therapy (P = 0.004) in controls. Vitamins did not inhibit ribavirin-induced anemia, but attenuated the decrease of EPA in erythrocytes. The EPA level was negatively correlated with the drop in hemoglobin levels at 8 weeks after initiation of therapy in controls (r = 0.58, P = 0.015), but not in the vitamin group. Supplementation of alpha-tocopherol and ascorbic acid attenuates the ribavirin-induced decrease of EPA in erythrocyte membrane phospholipids in chronic hepatitis C patients.

Erythrocyte ribavirin concentration for assessing hemoglobin reduction in interferon and ribavirin combination therapy

Ribavirin-induced hemolytic anemia is one of the important adverse effects for the premature cessation of interferon and ribavirin combination therapy for hepatitis C virus clearance. To elucidate the mechanism of this matter, we examined the effects of plasma and erythrocyte ribavirin concentration on hemoglobin (Hb) reduction to assess hemolytic anemia in this combination therapy. Nineteen patients, treated with the interferon alpha-2b and ribavirin combination therapy, were included. Plasma and erythrocyte ribavirin concentrations were monitored for the first 28 days of the combination therapy, in relation to changes in hematological parameters, Hb and hematocrit values. The initial dose of ribavirin was 11.5+/-1.5mg/kg/day. Steady-state plasma and erythrocyte ribavirin concentrations were 8.9+/-2.6 and 1218+/-270muM, respectively. Significant correlation was observed between erythrocyte ribavirin and Hb reduction (r=0.360, p<0.05), but not between plasma ribavirin and Hb reduction. The patients with higher levels of erythrocyte ribavirin (>/=1000muM) had greater Hb reduction compared to those with lower levels (<1000muM) (3.8+/-1.2g/dL versus 2.6+/-0.9g/dL, p<0.05). Nine cases out of 12 patients who developed anemia within the first 28 days of the combination therapy had higher levels of erythrocyte ribavirin (>/=1000muM). We confirmed that erythrocyte ribavirin was strongly associated with Hb reduction in interferon and ribavirin combination therapy.

Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients

Standard therapy for chronic hepatitis C (HCV) is pegylated interferon in combination with ribavirin. There is limited experience with either drug in dialysis [end stage renal disease (ESRD)]. Six haemodialysis patients, four with HCV genotype 1, one with genotype 4 and one genotype 2 were treated with pegylated interferon-alfa-2b (n = 4) and pegylated interferon-alfa-2a (n = 2) for 24-48 weeks according to genotype with a dose of 50 or 135 mug/week respectively. All patients were given reduced ribavirin doses, initially 200-400 mg/day. Ribavirin trough plasma concentrations were measured with a HPLC method previously developed for earlier treatment studies, aiming at a target concentration of 10-15 micromol/L. Interferon related side-effects were common, in one patient peg-alfa-2b was permanently reduced to 50 mug every 9-10 days with improvement in tolerance. Average ribavirin dose was 170-300 mg/day. Ribavirin-induced anaemia was treated with high doses of erythropoietin and low doses of iron. Blood-transfusions were not needed. All patients became HCV-RNA-PCR negative during treatment which was completed or nearly completed in four patients. One patient terminated therapy prematurely due to pronounced interferon related side-effects and another died of myocardial infarction probably not related to therapy. Three patients have remained HCV-RNA negative with extended follow-up, two of whom have had a successful kidney transplant. Pegylated interferons are likely to become a valuable addition for HCV therapy in ESRD and are possible to combine with ribavirin. However the pharmacokinetics and tolerability of both peg-alfa-2a and 2b need to be studied more closely in prospective studies before definite dosing recommendations can be made.

Glutathione peroxidase, thioredoxin, and membrane protein changes in erythrocytes predict ribavirin-induced anemia

Low erythrocyte membrane protein sulfhydril concentrations are a risk factor for ribavirin-induced anemia. We further studied the role of oxidative stress and erythrocyte membrane alterations in ribavirin-induced anemia. The levels of thioredoxin, glutathione peroxidase, protein sulfhydrils, and protein-mixed disulfides, as well as the electrophoretic membrane protein pattern, were determined in freshly isolated erythrocytes from healthy control subjects, patients without severe anemia during previous ribavirin treatment (still hepatitis C virus [HCV]-positive), and patients who had had severe anemia with ribavirin (still HCV-positive or HCV-negative), 6 months after full recovery. Erythrocytes were also incubated with buffer, ribavirin, phenylhydrazine, or dehydroepiandrosterone, and concentrations of protein sulfhydrils, protein-mixed disulfides, thiobarbituric acid-reactive substances, and total and oxidized glutathione, as well as osmotic resistance, were determined. Patients with previous severe ribavirin-induced anemia had lower levels of protein sulfhydrils (30.9 nmol/mg protein versus 43.2 nmol/mg protein, P<.001) and thioredoxin (0.6 nmol/g hemoglobin versus 1.2 nmol/g hemoglobin, P<.001), higher levels of protein-mixed disulfides (1.5 nmol/g hemoglobin versus 0.5 nmol/g hemoglobin, P<.001) and glutathione peroxidase (618 mU/mg protein versus 393 mU/mg protein, P<.001), and a membrane protein pattern consistent with band 4 dimer disaggregation. These differences were independent of HCV seropositivity. There were negative correlations between levels of glutathione peroxidase and thioredoxin (r=-0.87) and between levels of protein sulfhydrils and protein-mixed disulfides (r=-0.93). In vitro studies showed that erythrocytes of patients who had had hemolysis during treatment of HCV are more susceptible to oxidative stress. Pronounced differences in markers of oxidative stress and membrane proteins exist between patients with and without a history of ribavirin-induced anemia. Our findings suggest that there are erythrocyte-related risk factors for ribavirin-induced severe anemia.

Factors Associated with Ribavirin-Induced Anemia

Background: During treatment of hepatitis C, ribavirin-induced anemia (RIA) requires reduction of the ribavirin dose or initiation of erythropoietin in up to 20% of patients. RIA usually occurs in the first 8 weeks of treatment, and a decrease &gt;3 g/dL or a nadir &lt;10 g/dL is considered significant. Objective: To prospectively examine factors associated with RIA in a population of patients with hepatitis C. Methods: Consecutive patients with hepatitis C (hepatitis B virus and HIV negative) underwent treatment with pegylated interferon and weight-based ribavirin. Prospectively gathered data included demographics, alcohol consumption, and hepatitis C virus risk factors. Patients underwent laboratory studies at baseline and at intervals of 4–8 weeks after starting treatment. Results: One hundred eight patients were enrolled. Of these, 30 (27.8%) experienced a &gt;3 g/dL fall in hemoglobin levels in the first 8 weeks; in 10 (33%) patients, the change occurred by week 4. The initial hemoglobin level was higher in those with a decrease compared with those without a fall (15.3 vs 14.1 g/dL; p &lt; 0.001). In addition, for patients with a decrease, the iron saturation was higher (44.6% vs 30.1%; p = 0.002). Finally, those with fibrosis stage 6/6 (cirrhosis) had a greater percent fall in hemoglobin (27.0% vs 14.0%; p = 0.009) than those with less severe fibrosis. By logistic regression analysis, only iron saturation was associated with RIA (p = 0.002). Conclusions: In our patients, initial hemoglobin, serum iron, and fibrosis were associated with a potentially clinically important decrease in hemoglobin. In approximately one-third of the population, RIA occurred in the first 4 weeks of treatment. No patient had a severe complication.

Adverse Effects of Ribavirin and Outcome in Severe Acute Respiratory Syndrome: Experience in Two Medical Centers

Study objectivesTo assess the effect of ribavirin-induced anemia on the outcome of severe acute respiratory syndrome (SARS).DesignA retrospective observational study.SettingTwo medical centers in Taiwan.PatientsForty-four patients with SARS who received ribavirin and 7 patients with SARS who did not receive ribavirin.Measurements and resultsThe mean peak C-reactive protein and lactate dehydrogenase levels were higher in SARS patients who were receiving ribavirin therapy than in SARS patients who were not receiving ribavirin therapy. The mortality was also higher, but the difference was not statistically significant. On multivariate analysis, hemoglobin level was an independent prognostic correlate of hypoxemia or mortality (odds ratio, 2.0; 95% confidence interval, 1.1 to 3.8; p = 0.03). The hemoglobin began decreasing in two thirds of SARS patients (32 of 44 patients; 73%) who were receiving ribavirin 3 days after therapy with the antiviral drug was started. Patients with a drop in hemoglobin level of > 2 g/dL had a significantly higher mortality rate than the other patients. Hypoxemia developed in one third of SARS patients (17 of 44 patients; 39%) who were receiving ribavirin, all of whom were anemic. Of the 17 hypoxemic patients, 11 (65%) had a drop in hemoglobin of > 2 g/dL, and 4 patients (24%) required a blood transfusion. The mean slope of the hemoglobin decrease was significantly steeper (p = 0.001) in hypoxemic patients with SARS who were receiving ribavirin than in the nonhypoxemic patients with SARS who were receiving ribavirin. Only one of seven SARS patients (14%) who was not receiving ribavirin became anemic, but this individual was not hypoxemic. Eventually, 5 of 17 hypoxemic and anemic SARS patients (29%) who were receiving ribavirin died. The combination of hypoxia with anemia was thus significantly associated with a higher mortality (p < 0.001).ConclusionsHypoxia combined with anemia increased the risk for death in SARS patients. Unless ribavirin can be shown to be effective against SARS-coronavirus, the risk of anemia posed by this drug argues against its use in SARS patients.

Phosphorylation of Ribavirin and Viramidine by Adenosine Kinase and Cytosolic 5′-Nucleotidase II: Implications for Ribavirin Metabolism in Erythrocytes

Many nucleoside analog drugs, such as ribavirin and viramidine, are activated or metabolized in vivo through 5'-phosphorylation. In this report, we determined the steady-state kinetic parameters for 5'-monophosphorylation of ribavirin and viramidine by adenosine kinase. The apparent Km for ribavirin is 540 microM, and k(cat) is 1.8 min-1. Its catalytic efficiency of 3.3 x 10(-3) min-1 . microM-1 is 1,200-fold lower than that of adenosine. In contrast to the common belief that ribavirin is exclusively phosphorylated by adenosine kinase, cytosolic 5'-nucleotidase II was found to catalyze ribavirin phosphorylation in vitro. The reaction is optimally stimulated by the physiological concentration of ATP or 2,3-bisphosphoglycerate. In phosphate-buffered saline plus ATP and 2,3-bisphosphoglycerate, the apparent Km for ribavirin is 88 microM, and k(cat) is 4.0 min-1. These findings suggest that cytosolic 5'-nucleotidase II may be involved in ribavirin phosphorylation in vivo. Like ribavirin, viramidine was found to be phosphorylated by either adenosine kinase or cytosolic 5'-nucleotidase II, albeit with a much lower activity. The catalytic efficiency for viramidine phosphorylation is 10- to 330-fold lower than that of ribavirin, suggesting that other nucleoside kinase(s) may be involved in viramidine phosphorylation in vivo. Both ribavirin and viramidine are not phosphorylated by deoxycytidine kinase and uridine-cytidine kinase. The coincidence of presence of high concentrated 2,3-bisphosphoglycerate in erythrocytes suggests that cytosolic 5'-nucleotidase II could play an important role in phosphorylating ribavirin and contribute to anabolism of ribavirin triphosphate in erythrocytes. Elucidation of ribavirin and viramidine phosphorylation mechanism should shed light on their in vivo metabolism, especially the ribavirin-induced hemolytic anemia in erythrocytes.

Factors accelerating liver fibrosis progression in renal transplant patients receiving ribavirin monotherapy for chronic hepatitis C

In untreated hepatitis virus (HCV)-positive renal transplant patients, the rate of liver fibrosis progression is low. In contrast, in those treated by ribavirin monotherapy, liver fibrosis score increased significantly after only 1 year of ribavirin monotherapy. The aim of this study was to identify the factors that might contribute to accelerate liver fibrosis progression in this population. Eleven patients were included in the study. Intrahepatic transforming growth factor (TGF)-beta, interferon (IFN)-gamma, and interleukin (IL)-10 mRNA quantification determined by real-time reverse transcription-polymerase chain reaction (RT-PCR) were similar before and after ribavirin therapy. The number of amino acid substitutions observed in the hypervariable region (HVR)-1 of the HCV genome between baseline and 1 year after ribavirin monotherapy was low, i.e., 3 (1-11) amino acid substitutions, suggesting the absence of a high selection pressure induced by ribavirin. In contrast, due to ribavirin-induced hemolysis, there was a significant increase in serum ferritin levels (P = 0.02) and in intrahepatic iron deposition (P = 0.04). Transferrin level and total iron-binding capacity decreased significantly during ribavirin monotherapy (P = 0.004). The increased liver fibrosis observed in renal transplant patients receiving ribavirin monotherapy could be related to ribavirin-induced anemia. Severe chronic hemolysis is responsible for iron overload, liver iron deposition, and an acceleration in the progression of liver fibrosis.

Does smoking effect ribavirin-induced anemia during combination therapy in hepatitis C patients?: Keyur Patel, John G McHutchinson, Shanon Heaton, Cynthia A Behling, David Bylund, Paul J Pockros, Lawrence M Blatt, Scripps Clinic and Research Foundation, La Jolla, CA

Does smoking effect ribavirin-induced anemia during combination therapy in hepatitis C patients?: Keyur Patel, John G McHutchinson, Shanon Heaton, Cynthia A Behling, David Bylund, Paul J Pockros, Lawrence M Blatt, Scripps Clinic and Research Foundation, La Jolla, CA

The impact of ribavirin-induced anemia on health-related quality of life: Lisa M Martin, Zobair M Younossi, Inova Fairfax Hosp, Ctr for Liver Diseases, Falls Church, VA; Lori Lyn Price, Cleveland Clinic Fdn, Cleveland, OH; Arthur McCullough, MetroHealth Medical Ctr, Cleveland, OH; Janus P Ong, Manirah Srishord, Inova Fairfax Hosp, Ctr for Liver Diseases, Falls Church, VA; Navdeep Boparai, Cleveland Clinic

The impact of ribavirin-induced anemia on health-related quality of life: Lisa M Martin, Zobair M Younossi, Inova Fairfax Hosp, Ctr for Liver Diseases, Falls Church, VA; Lori Lyn Price, Cleveland Clinic Fdn, Cleveland, OH; Arthur McCullough, MetroHealth Medical Ctr, Cleveland, OH; Janus P Ong, Manirah Srishord, Inova Fairfax Hosp, Ctr for Liver Diseases, Falls Church, VA; Navdeep Boparai, Cleveland Clinic

Pharmacokinetic/Pharmacodynamic and Time-to-Event Models of Ribavirin-Induced Anaemia in Chronic Hepatitis C

Interferon (IFN)-alpha and ribavirin combination therapy is the standard treatment for patients with chronic hepatitis C. However, ribavirin induces anaemia, especially by haemolysis, an adverse effect that is dose-limiting. The aim of this study was to determine the relationships between ribavirin exposure and haemoglobin time-course, the time-to-anaemia and the covariates influencing these relationships in a population of patients treated for chronic hepatitis C. In addition, we also intended to establish a simple rule defining the need for dosage adjustment, using data obtained during the first month of treatment. A retrospective analysis of 99 patients treated with IFNalpha plus ribavirin, with known dosage administration history, liver biopsy, demographic data, red blood cell counts, haemoglobin level (1037 measurements, median 10 per patient, range 2-31) and serum creatinine during the entire treatment period (178 days, range 53-382 days) was conducted. The data were analysed by a pharmacokinetic/pharmacodynamic population model and Weibull time-to-anaemia model. The rule defining the need for dosage adjustment was as follows: adjustment was needed if haemoglobin at steady state (H(ss)), estimated by the Bayesian method based on data obtained during the first month of treatment, was <12 g/dL for men or <11 g/dL for women. In both models, anaemia was related to the exposure of erythrocytes to ribavirin at time t (RT in mg/kg/day) by a maximum effect model, with RT(50) (dosage administration rate at which half the maximal effect is reached) approximately 12 mg/kg/day, and the significant covariates were initial haemoglobin level and bodyweight. Performances of a Bayesian prediction of H(ss) based on two early haemoglobin level measurements were encouraging (mean prediction error 0.12 g/dL, precision 0.85 g/dL). The proposed rule for the need of dosage adjustment was able to predict the actual evolution of the dosage regimen in 76% of non-adapted patients and 69% of adapted patients. The current guidelines for ribavirin dosage administration, based on bodyweight, are adequate, at least in the 45-105 kg range. Results indicate that Bayesian therapeutic monitoring could be helpful in controlling ribavirin-induced anaemia.

Ｃ型肝炎患者におけるリバビリン誘導性貧血及び酸化ストレスに対するエイコサペンタエン酸の効果

A major side effect of ribavirin (RBV) is a hemolytic anemia. One of the causes of hemolytic anemia is considered to be oxidative stress to erythrocytes. Recently, a beneficial effect of eicosapentaenoic acid (EPA) for ribavirin-induced anemia has been reported. This study evaluated effects of EPA for ribavirin-induced anemia and thioredoxin (TRX) as an indicator of oxidative stress in chronic hepatitis C patients within 8 weeks. Nighteen of 41 patients who had received interferon/ribavirin therapy were treated with EPA (1800 mg/day) (EPA group). EPA therapy significantly prevented progression of anemia (P<0.01). Moreover, serum TRX levels were significantly decreased in EPA group at 4 weeks (P<0.01). Reduction of oxidative stress by EPA might play an important role for preventing ribavirin-induced anemia.

Herbal medicine Ninjinyoeito ameliorates ribavirin-induced anemia in chronic hepatitis C: A randomized controlled trial

Ribavirin (RBV) shows a strong antiviral effect on hepatitis C virus when used in combination with interferon. However, RBV-induced anemia is a major problem in this therapy. It would be of great clinical importance to ameliorate the anemia without reducing the RBV dose. We report here that, Ninjinyoeito (NYT), a herbal medicine can reduce the RBV-induced anemia. Twenty-three patients with chronic hepatitis C were treated with interferon alpha 2b plus RBV with (NYT group) or without (control group) NYT by a randomized selection. Eighteen patients completed the treatment schedule, and hemato-biochemical and virological effects were evaluated. There was no significant difference in biochemical and virological responses between the two groups. However, anemia was significantly reduced in the NYT group compared with the control group. The maximal decrease of Hb in the NYT group (2.59+/-1.10 g/dL) was significantly (P = 0.026) smaller than that in the control group (3.71+/-0.97 g/dL). There was no significant difference in serum glutathione peroxidase activity, serum RBV concentration, and Th1/Th2 balance between the two groups. There was no specific adverse effect in NYT administration. These results suggest that NYT could be used as a supportive remedy to reduce the RBV-induced anemia in the treatment of chronic hepatitis C.

Factors contributing to ribavirin-induced anemia.

Interferon and ribavirin combination therapy for chronic hepatitis C produces hemolytic anemia. This study was conducted to identify the factors contributing to ribavirin-induced anemia. Eighty-eight patients with chronic hepatitis C who received interferon-alpha-2b at a dose of 6 MU administered intramuscularly for 24 weeks in combination with ribavirin administered orally at a dose of 600 mg or 800 mg participated in the study. A hemoglobin concentration of <10 g/dL was defined as ribavirin-induced anemia. Ribavirin-induced anemia occurred in 18 (20.5%) patients during treatment. A 2 g/dL decrease in hemoglobin concentrations in patients with anemia was observed at week 2 after the start of treatment. The hemoglobin concentration in patients with > or =2 g/dL decrease at week 2 was observed to be significantly lower even after week 2 than in patients with <2 g/dL decrease (P < 0.01). A significant relationship was observed between the rate of reduction of hemoglobin concentrations at week 2 and the severity of anemia (P < 0.01). Such factors as sex (female), age (> or =60 years old), and the ribavirin dose by body weight (12 mg/kg or more) were significant by univariate analysis. Careful administration is necessary in patients > or =60 years old, in female patients, and in patients receiving a ribavirin dose of 12 mg/kg or more. Patients who experience a fall in hemoglobin concentrations of 2 g/dL or more at week 2 after the start of treatment should be monitored with particular care.

Factors contributing to ribavirin dose reduction due to anemia during interferon alfa2b and ribavirin combination therapy for chronic hepatitis C.

Recent studies indicate that combination therapy with ribavirin and interferon alfa2b (IFNAlpha2b) is effective for chronic hepatitis C virus (HCV) infection. However, reversible hemolytic anemia is a common side effect of this therapy. We determined those factors that contribute to ribavirin dose reduction due to anemia during this treatment by using multiple logistic regression analysis in Japanese patients. The study included 123 patients with chronic hepatitis C (85 male, 38 female; mean age, 50 years; range, 20-70 years), who received 24-week combination therapy. All patients were treated with IFNAlpha2b daily for 2 weeks, followed by three times weekly dosing for 22 weeks, with oral ribavirin twice daily, at a total daily dose of 600 or 800 mg. Of the 123 patients, 34 patients required dose reduction of ribavirin, and 78 patients required no dose reduction. Overall, 20 patients discontinued. On univariate analysis, reduction of the ribavirin dose correlated significantly with pretreatment hemoglobin (Hb) levels of less than 14 g/dl, female sex, and patient age 55 years or older. On multivariate analysis, pretreatment Hb of less than 14 g/dl level and age 55 years or older were significantly associated with ribavirin dose reduction. The hazard ratios were 3.56 (95% confidence interval [CI], 1.48-8.53) for pretreatment Hb levels of less than 14 g/dl, and 2.50 (95% CI, 1.05-5.94) for age 55 years or more. Because patient age of 55 years or more, and Hb levels of less than 14 g/dl are significant factors that influence ribavirin-induced hemolytic anemia, more careful monitoring is necessary during combination therapy for patients with these risk factors.

Severe acute respiratory syndrome in dialysis patients.

Reviewed are the clinical features and outcome of 12 chronic dialysis patients (six men) who contracted severe acute respiratory syndrome (SARS) compared with 23 sex- and age-matched nonuremic SARS patients as controls. Eight were on peritoneal dialysis (PD) and four on hemodialysis. Mean age was 58 +/- 12 yr for the dialysis patients, and 57 +/- 12 yr for the controls. The presenting symptoms of dialysis patients were similar to the controls. With appropriate protection measures, hemodialysis was performed in a dedicated area of the SARS isolation ward, while PD was continued as intermittent PD. In all seven patients with PD effluent tested, SARS-related coronavirus (CoV) could not be identified by polymerase chain reaction (PCR) or viral culture. Three dialysis patients had persistent positive stool PCR after 5 wk, whereas all nondialysis patients had negative stool PCR after 1 wk. Despite dosage adjustment, ribavirin-induced hemolytic anemia was more severe in the dialysis patients. Dialysis patients required longer hospitalization than the controls, but the mortality was similar. With appropriate protective measures, dialysis could be safely performed. Dialysis patients with SARS often require prolonged hospitalization. Furthermore, these patients may have an extended period of viral shedding, which should be carefully monitored for the purpose of infection control.

Managing the hematologic side effects of antiviral therapy for chronic hepatitis C: anemia, neutropenia, and thrombocytopenia.

Hematologic abnormalities such as anemia, neutropenia, and thrombocytopenia are common during combination therapy with pegylated (or standard) interferon and ribavirin for chronic hepatitis C. Ribavirin-induced hemolytic anemia is a common cause of dose reduction or discontinuation. Bone marrow suppression also contributes to the anemia and is the predominant mechanism for interferon-induced neutropenia and thrombocytopenia. Although dose reduction or discontinuation of combination therapy can reverse these abnormalities, they may reduce virologic response. Hematopoietic growth factors may provide a useful alternative for managing these hematologic side effects without reducing the optimal dose of the combination antiviral regimen. Treatment of anemia also may improve patients' health-related quality of life and their adherence to combination antiviral therapy. The impact of growth factors on sustained virologic response and their cost-effectiveness in patients with chronic hepatitis C need further assessment.

Prevention and treatment of HCV recurrence after liver transplantation

Prevention and treatment of HCV recurrence after liver transplantation