Use of erythropoietin in the treatment of anemia induced by ribavirin/interferon in patients with hepatitis C

We are presenting 20 patients with hepatitis C, who developed anemia on interferon alpha-2b/ribavirin treatment and were treated with recombinant human c alpha. Median age was 43 years (range 25-72). Four patients received previous treatment. Interferon-alpha-2b was given at six million units three times a week to 10 patients and at three million units three times a week to five patients. PEG-interferon-alpha-2b (80-120 mug/week) was given to five patients. The dose of ribavirin was 800-1200 mg/day (19 patients) and 200 mg/day (one patient with renal failure). Duration of an interferon/ribavirin treatment was 6-12 months. Baseline median hemoglobin was 13.3 g/dl (range 12.2-15.8); median hemoglobin nadir: 9.8 g/dl (range 8.4-11.2). On erythropoietin, the hemoglobin increased to median 11.7 g/dl (range 9.6-12.8). The ribavirin dose had been decreased to 800 mg in four patients, to 600 mg in four patients, to 400 mg in one patient. Thirteen patients responded to interferon/ribavirin treatment, six patients (all genotype 1) did not. Of the 13 initial responders 11 had sustained response, one still under treatment and two patients relapsed. In conclusion, in our patients with chronic hepatitis C treated with interferon/ribavirin combination therapy, erythropoietin was beneficial in the treatment of ribavirin-induced anemia.     

A pilot study of eicosapentaenoic acid therapy for ribavirin-related anemia in patients with chronic hepatitis C

One of the major side effects of ribavirin/interferon alpha combination therapy for chronic hepatitis C is hemolytic anemia. One of the causes of hemolytic anemia is considered to be decreasing deformability of erythrocytes resulting from the accumulation of phosphorylated ribavirin in erythrocytes. The administration of eicosapentaenoic acid (EPA), which has a wide variety of pharmacological actions, increases the deformability of erythrocytes. We conducted an uncontrolled pilot study of EPA therapy for patients with ribavirin-related anemia. Six patients with chronic hepatitis C, who had developed anemia while receiving combination therapy, were treated with an oral ethyl ester of EPA (1800 mg/day) for two months. The hemoglobin level of all six patients increased following EPA therapy. The mean hemoglobin level significantly increased from 10.8 g/dl to 11.4 g/dl one month after therapy was initiated (P<0.05), and this level was obtained again one month later (11.5 g/dl). None of the patients developed an adverse reaction. These findings suggest that EPA has a beneficial effect in patients with ribavirin-related anemia. Further study is required to confirm our results.     

Common genetic polymorphism of ITPA gene affects ribavirin-induced anemia and effect of peg-interferon plus ribavirin therapy

An association between a single nucleotide polymorphism (SNP) in the inosine triphosphate pyrophosphatase (ITPA) gene and reduction of hemoglobin during peg‐interferon plus ribavirin combination therapy for patients with chronic hepatitis C virus (HCV) infection has been reported. However, the effect of the SNP on outcome of therapy has not been fully elucidated. Factors associated with anemia during combination therapy, including rs1127354 genotype, were analyzed in 1,002 treated patients. The effect of the SNP on outcome of therapy was analyzed in a subset of 830 patients with genotype 1. A rapid initial decrease in hemoglobin levels was observed in patients with rs1127354 genotype CC compared with a slow decrease in non‐CC patients. Cumulative reduction of ribavirin was significantly more frequent in genotype CC patients than non‐CC patients (odds ratio 1.928, P = 8.6 × 10^?8). The frequency of patients who received at least the recommended 80% of scheduled ribavirin was significantly lower among genotype CC patients, especially among those who had pretreatment hemoglobin levels between 13.5 and 15 g/dl (P < 0.03), and the sustained viral response rate was significantly lower in this group of patients. Independent predictive factors for sustained virological response included a SNP in the IL28B locus (rs809991), age, fibrosis, ITPA SNP rs1127354 as well as pretreatment hemoglobin levels. Our data suggests that measures to prevent anemia should be considered for patients who have pretreatment hemoglobin levels less than 13.5 g/dl or who have rs1127354 genotype CC and pretreatment hemoglobin levels between 13.5 and 15 g/dl. J. Med. Virol. 83:1048–1057, 2011. © 2011 Wiley‐Liss, Inc.     

Treatment of dialysis patients with chronic hepatitis C using pegylated interferon and low-dose ribavirin

BACKGROUND: No safe and effective therapy exists for chronic hepatitis C in dialysis patients. Available data on the antiviral treatment of hepatitis C in dialysis population is mostly based on standard interferon monotherapy. OBJECTIVES: We conducted a prospective, cohort trial with combined therapy (pegylated-interferonalpha-2a (135 mcg/week) plus low dose ribavirin (200 mg/day)) for chronic hepatitis C in 15 patients undergoing long-term dialysis. Twelve patients had HCV genotype 1a/1b, three were co-infected with human immunodeficiency virus (HIV), and two had compensated cirrhosis. End-points were sustained viral response and adverse effects. RESULTS: Sustained virological response was obtained in four patients (including two with HCV genotype 1); the SVR rate was 28.6% (4/14), on an intention-to-treat analysis. One subject with SVR had compensated cirrhosis. All HIV co-infected patients had well controlled HIV and one of them (33%) reached SVR. Seven (50%) of the 14 patients were non-responders, two of which relapsed after discontinuation of therapy. Drop-out rate was 71.4% (10/14). The most frequent side-effect was anemia, which required ribavirin discontinuation in three patients; seven (47%) patients received blood transfusions. Two patients died (week 4 and 14) of causes related to cardiovascular disease, which was frequent in our cohort. Two subjects were hospitalized and discontinued therapy (week 1, and 27). CONCLUSIONS: Results from this study showed that about one-third of HD patients achieved sustained virological response with pegylated-interferon-alpha-2a plus low-dose ribavirin; however, tolerance to antiviral treatment was unsatisfactory. Well- controlled HIV infection should not be a contraindication to HCV therapy in dialysis patients. Prospective, controlled clinical trials of combined antiviral therapy targeted at HCV in chronic kidney disease population are indicated.     

Sequences in the interferon sensitivity-determining region and core region of hepatitis C virus impact pretreatment prediction of response to PEG-interferon plus ribavirin: data mining analysis

The aim of the present study was to clarify the significance of viral factors for pretreatment prediction of sustained virological response to pegylated-interferon (PEG-IFN) plus ribavirin (RBV) therapy for chronic hepatitis C using data mining analysis. Substitutions in the IFN sensitivity-determining region (ISDR) and at position 70 of the HCV core region (Core70) were determined in 505 patients with genotype 1b chronic hepatitis C treated with PEG-IFN plus RBV. Data mining analysis was used to build a predictive model of sustained virological response in patients selected randomly (n = 304). The reproducibility of the model was validated in the remaining 201 patients. Substitutions in ISDR (odds ratio = 9.92, P < 0.0001) and Core70 (odds ratio = 1.92, P = 0.01) predicted sustained virological response independent of other covariates. The decision-tree model revealed that the rate of sustained virological response was highest (83%) in patients with two or more substitutions in ISDR. The overall rate of sustained virological response was 44% in patients with a low number of substitutions in ISDR (0-1) but was 83% in selected subgroups of younger patients (<60 years), wild-type sequence at Core70, and higher level of low-density lipoprotein cholesterol (LDL-C) (≥ 120 mg/dl). Reproducibility of the model was validated (r(2) = 0.94, P < 0.001). In conclusion, substitutions in ISDR and Core70 of HCV are significant predictors of response to PEG-IFN plus RBV therapy. A decision-tree model that includes these viral factors as predictors could identify patients with a high probability of sustained virological response.     

Role of erythrocytes as a reservoir for ribavirin and relationship with adverse reactions in the early phase of interferon combination therapy for chronic hepatitis C virus infections

We investigated the relationship between serum ribavirin concentrations and clearance, as well as therapeutic efficacy and adverse reactions, in 97 Japanese patients with chronic hepatitis C virus infections treated with a 6-month course of high-dose alpha2b interferon (6 million units/day) plus ribavirin (600 to 800 mg/day) combination therapy. This randomized trial showed that the saturation of ribavirin uptake after taking ribavirin capsules does not occur within a dose range of 600 to 800 mg/day, which is a standard dosage used clinically in Japan. Serum ribavirin concentrations and clearance did not correlate with sustained virological response rates. Fourteen patients discontinued therapy because of adverse reactions, and sustained virological response rates were significantly reduced by discontinuation of therapy, while dose reduction of ribavirin did not alter the therapeutic effects. Ribavirin concentrations after 1 week and ribavirin clearance were significantly correlated with discontinuation of ribavirin; however, a multiple-regression analysis revealed that only hemoglobin concentration, but not ribavirin clearance, was a significant factor for discontinuation of therapy (odds ratio, 0.514; 95% confidence interval, 0.311 to 0.85; P = 0.0095). It appears that peripheral erythrocytes may act as a reservoir for ribavirin and regulate serum ribavirin levels in the very early phase of treatment.     

Exacerbation of oral erosive lichen planus by combination of interferon and ribavirin therapy for chronic hepatitis C

Hepatitis C virus (HCV) induces extrahepatic manifestations such as oral lichen planus (OLP) as well as chronic liver diseases. The treatment of HCV-related chronic liver disease has evolved from the use of a single agent, mainly interferon (IFN), to the combination of IFN and ribavirin. We present a case of erosive OLP, cutaneous lichen planus (CLP), and leukoplakia of the vocal cord in a man with chronic hepatitis C infection treated with IFN and ribavirin. A 65-year-old man suffered from OLP before undergoing combination of IFN and ribavirin therapy for chronic hepatitis C. He was initially treated with IFNbeta (6 million units (MU) /day for 2 weeks), then a combination of IFNalpha-2b (6 MU/day for 2 weeks and 3 times a week for 14 weeks) and ribavirin (400-600 mg/day). The OLP lesion was not aggravated by application of steroids during the 7 weeks after the treatment, but after 18 weeks, the combination of IFN and ribavirin was stopped because of aggravation of the OLP. Elevated aminotransferase levels returned to normal during the therapy. But 7 weeks after discontinuation, aminotransferase levels rose to 10 times the normal range. Five months after discontinuation, the papules of CLP appeared. Eight months after discontinuation, the OLP erosion had gradually reduced, but some erosion remained. Aminotransferase levels were decreased, but serum HCV RNA had not disappeared. Caution should be exercised when IFN or ribavirin therapy is given to chronic hepatitis C patients with prior erosive OLP.     

Functional impairment of dendritic cells in patients infected with hepatitis C virus genotype 1 who failed peginterferon plus ribavirin therapy

Although chronic hepatitis C patients have a lower frequency and functions of dendritic cells (DCs) than healthy subjects, little is known about the serial changes in frequency and functions of DCs following anti-viral treatment and the relationship with treatment outcomes. Twenty patients with hepatitis C virus genotype 1 receiving peginterferon (PEG-IFN) and ribavirin for 24 weeks were enrolled. The frequency and functions of DCs were assayed at baseline and 24 weeks post-treatment. Ten sex and age-matched healthy adults served as controls. Nineteen of the 20 chronic hepatitis C patients completed 24 weeks of combination therapy. Fifteen patients achieved rapid virologic response and 12 achieved sustained virologic response (SVR). The baseline frequency of peripheral blood myeloid DCs and plasmacytoid DCs was significantly lower in chronic hepatitis C patients than in healthy controls. In patients who achieved SVR, the frequency of DCs subsets at the end of follow-up increased to a level comparable to healthy controls. Although no functional defects of DCs was found in chronic hepatitis C patients in comparison with healthy controls, in patients without SVR had a lower CD83 expression and higher interleukin-10 production of DCs than SVR patients. The results suggest that low CD83 expression and high IL-10 production of DCs at the baseline may predict a poor virologic response to 24-week PEG-IFN plus ribavirin therapy in HCV genotype 1 patients.     

Hydroxychloroquine augments early virological response to pegylated interferon plus ribavirin in genotype‐4 chronic hepatitis C patients

The therapeutic effect of pegylated interferon (peg‐IFN) alfa‐2a combined with ribavirin (RBV) on chronic hepatitis C Egyptian patients is low and further efforts are required to optimize this therapy for achievement of higher rates of virological response. This study aimed to evaluate the safety and efficacy of hydroxychloroquine (HCQ) in combination with pegylated interferon plus ribavirin on early virological response (EVR) in chronic hepatitis C Egyptian patients. Naïve 120 Egyptian patients with chronic hepatitis C virus infection were divided into two groups. Group 1 have administered the standard of care therapy (pegylated interferon alfa‐2a plus ribavirin) for 12 weeks, (n = 60). Group 2 have administered hydroxychloroquine plus standard of care therapy for 12 weeks, (n = 60). Therapeutics included hydroxychloroquine (200 mg) oral twice daily, peginterferon alfa‐2a (160 μg) subcutaneous once weekly and oral weight‐based ribavirin (1000–1200 mg/day). Baseline characteristics were similar in the two groups. The percentage of early virological response was significantly more in patients given the triple therapy than in patients given the standard of care [54/60 (90%) vs. 43/60 (71.7%); P = 0.011; respectively]. Biochemical response at week 12 was also significantly higher in patients given the triple therapy compared with the standard of care [58/60 (96.7%) vs. 42/60 (70%); P < 0.001; respectively]. Along the study, the observed adverse events were mild and similar across treatment groups. Addition of hydroxychloroquine to pegylated interferon plus ribavirin improves the rate of early virological and biochemical responses in chronic hepatitis C Egyptian patients without an increase in adverse events. J. Med. Virol. 88:2170–2178, 2016. © 2016 Wiley Periodicals, Inc.

     

Use of epoetin beta during combination therapy of infection with hepatitis c virus with ribavirin improves a sustained viral response

The aim of the study was to evaluate the effects of epoetin‐beta on anemia and sustained viral response in patients with chronic hepatitis C receiving treatment with pegylated interferon and ribavirin. Forty‐two Caucasian patients with chronic hepatitis C infection, treated with pegylated interferon α‐2a or α‐2b plus ribavirin, who experienced at least a 2 log decline in HCV‐RNA in the first month of therapy and a ≥2.5 g/dl hemoglobin drop from baseline, were recruited. They were divided into two groups: 22 patients received epoetin‐beta 30,000 U administered s.c. q.w. (group A) and 20 patients received a reduced ribavirin dose of 600 mg daily (group B). The end‐of‐treatment response was 95.4% (21/22) in group A and 80% (16/20) (P = 0.2) in group B. Sustained viral response in group A was 81.8% (18/22), statistically higher than in group B (45%, 9/20) (P = 0.03). Mean corpuscular volume of erythrocytes was statistically lower in group A than in group B 4 weeks after starting epoetin‐beta or reduced ribavirin dose (P < 0.001), end‐of‐treatment (P < 0.001) and after 6 months follow‐up (P < 0.001). A negative correlation between the levels of ferritin serum was found in group A at the baseline and mean corpuscular volume value after 1 month of combination antiviral therapy (r = ?0.45; P = 0.35), 4 weeks after starting epoetin‐beta (r = ?0.43; P = 0.04) and after 6 months follow‐up (r = ?0.45; P = 0.03). Administration of epoetin‐beta increases sustained viral response rates among patients developing anemia, because the standard dose of ribavirin is maintained, thereby reducing the side‐effects of antiviral treatment. J. Med. Virol. 82:49–56, 2010. © 2009 Wiley‐Liss, Inc.     

Durability of a sustained virological response in chronic hepatitis C patients treated with pegylated interferon alfa and ribavirin

Background/Aims

The reappearance rates of hepatitis C virus (HCV) RNA after a sustained virological response (SVR) have been reported to be 1-2%. We investigated the reappearance rate of HCV RNA after SVR in chronic hepatitis C (CHC) patients treated with pegylated interferon (PEG-IFN) and ribavirin.

Methods

In total, 292 CHC patients who achieved an SVR after PEG-IFN and ribavirin treatment were included. They were treated with subcutaneous injections of either PEG-IFN-α 2a or 2b plus ribavirin orally. Liver function tests and qualitative HCV RNA assays were performed every 6 months during the follow-up period after an SVR.

Results

Among the 292 patients, 224 (genotype 1, 92; genotype non-1, 132) were followed up for more than 6 months after SVR. These 224 patients were aged 48.1±11.5 years (mean±SD), and 129 of them were male. The median follow-up duration was 18 months (range 6-60 months). The reappearance rate of HCV RNA during follow-up was 0%. Two patients who achieved an SVR developed hepatocellular carcinoma during the follow-up period.

Conclusions

An SVR was maintained in all CHC patients treated with PEG-IFN plus ribavirin during a median follow-up of 18 months. However, a screening test for hepatocellular carcinoma is needed for patients with an SVR.     

Present treatment expectations and risks of chronic hepatitis C

During recent years, the treatment of chronic hepatitis C has increased in efficacy. Initially, the only approved treatment for this disease was interferon-alpha (IFN- α ) monotherapy, achieving a 15% rate of sustained response. Subsequently, a combination of IFN- α plus ribavirin showed a greater efficacy: up to 40% success with 3 MU of IFN- α three times weekly and 1000–1200 mg of ribavirin daily in naive patients and in those who had relapsed after a course of IFN- α therapy. Pegylated interferon (PEG-IFN), due to its better efficacy and tolerance, has displaced the use of recombinant IFN. Nevertheless, the sustained response rate mainly depends on HCV RNA load and HCV genotype. Presumably, in future, new strategies based on gene therapy will play an important role in the treatment of chronic hepatitis C.     

Hepatitis C virus amino acid sequence diversity correlates with the outcome of combined interferon/ribavirin therapy in Chinese patients with chronic hepatitis C

Evidence has shown that the p7, NS2 and NS3 genes affect the outcome of pegylated-IFN-α/ribavirin (PEG-IFN/RBV) combination therapy in different populations with HCV infections. Here, we test the hypothesis that diversity in the p7, NS2 and NS3 genes influences the probability of obtaining either a sustained (SVR) or non-sustained (non-SVR) viral response in Chinese patients with genotype 1b chronic hepatitis C. There were significantly more unique variations in the p7, NS2 and NS3 genes in the sequences from SVR than non-SVR patients. Inter-patient variations related to treatment outcome in NS3 were concentrated in the protease domain. There were no significant differences in the frequency of variations in the core, E1 and E2 proteins between the groups. In conclusion, increased amino acid sequence diversity in the p7, NS2 and NS3 genes is associated with an SVR to PEG-IFN/RBV therapy in Chinese patients with genotype 1b chronic hepatitis C.     

Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C

Hematologic abnormalities during current therapy with pegylated interferon and ribavirin (PEG-IFN/RBV) for chronic hepatitis C (CHC) often necessitate dose reduction and premature withdrawal from therapy. The aim of this study was to identify host factors associated with IFN-induced thrombocytopenia by genome-wide association study (GWAS). In the GWAS stage using 900K single-nucleotide polymorphism (SNP) microarrays, 303 Japanese CHC patients treated with PEG-IFN/RBV therapy were genotyped. One SNP (rs11697186) located on DDRGK1 gene on chromosome 20 showed strong associations in the minor-allele-dominant model with the decrease of platelet counts in response to PEG-IFN/RBV therapy [P = 8.17 × 10(-9); odds ratio (OR) = 4.6]. These associations were replicated in another sample set (n = 391) and the combined P-values reached 5.29 × 10(-17) (OR = 4.5). Fine mapping with 22 SNPs around DDRGK1 and ITPA genes showed that rs11697186 at the GWAS stage had a strong linkage disequilibrium with rs1127354, known as a functional variant in the ITPA gene. The ITPA-AA/CA genotype was independently associated with a higher degree of reduction in platelet counts at week 4 (P < 0.0001), as well as protection against the reduction in hemoglobin, whereas the CC genotype had significantly less reduction in the mean platelet counts compared with the AA/CA genotype (P < 0.0001 for weeks 2, 4, 8, 12), due to a reactive increase of the platelet count through weeks 1-4. Our present results may provide a valuable pharmacogenetic diagnostic tool for tailoring PEG-IFN/RBV dosing to minimize drug-induced adverse events.     

Efficacy and long-term follow up of combination therapy with interferon alpha and ribavirin for chronic hepatitis C in Korea

Combination therapy with interferon alpha (IFN-alpha) and ribavirin for 24 or 48 weeks according to HCV genotype has improved the overall sustained virological response (SVR) rates to approximately 40%. The aim of this study was to investigate the long-term efficacy of combination therapy with IFN-alpha and ribavirin for chronic hepatitis C in Koreans. One hundred thirty-eight patients with chronic hepatitis C who received this combination therapy between 1995 and 2003 were analyzed retrospectively. All patients were treated with IFN-alpha 3-6 million units three times weekly in combination with 900-1200 mg/day of ribavirin for 24 weeks. The overall SVR rate was 41.3%. Patients were followed up for a median of 41 months (range, 12-105 months) after completion of therapy. In all of the SVR patients (57 patients), SVR was conserved during the follow-up period. None of the patients progressed to decompensated liver disease or hepatocellular carcinoma (HCC). However, 5 of the 81 non-SVR patients (6.2%) progressed to decompensated liver disease or HCC. In conclusion, combination therapy with IFN-alpha and ribavirin shows good long-term efficacy in patients with chronic hepatitis C in Korea, one of the highest endemic areas of hepatitis B virus (HBV) infection.     

A reduced dose of ribavirin does not influence the virologic response during pegylated interferon alpha-2b and ribavirin combination therapy in patients with genotype 1 chronic hepatitis C

Background/Aims

When combined with pegylated interferon alpha-2b (Peg-IFN α-2b) for the treatment of genotype 1 chronic hepatitis C (CHC) in Korea, the current guideline for the initial ribavirin (RBV) dose is based on body weight. However, since the mean body weight is lower for Korean patients than for patients in Western countries, current guidelines might result in Korean patients being overdosed with RBV.

Methods

We retrospectively reviewed the medical records of patients with genotype 1 CHC who were treated with Peg-IFN α-2b and RBV combination therapy. We divided the patients into groups A (≥15 mg/kg/day, n=23) and B (<15 mg/kg/day, n=26), given that the standard dose is 15 mg/kg/day. The clinical course in terms of the virologic response, adverse events, and dose modification rate was compared between the two groups after therapy completion.

Results

The early response rates (92.0% vs. 83.3%, P=0.634) and sustained virologic response rates (82.6% vs. 73.1%, P=0.506) did not differ significantly between the two groups. During the treatment period, the RBV dose reduction rate was significantly higher in group A than in group B (60.9% vs. 23.1%, P=0.01).

Conclusions

RBV dose reduction is performed frequently when patients are treated according to the current Korean guidelines. Given that lowering the RBV dose did not appear to decrease the virologic response during therapy, reducing RBV doses below the current Korean guideline may be effective for treatment, especially in low-weight patients.     

Interferon-alpha (IFN alpha) daily dose versus IFN alpha plus ribavirin for treatment-naive chronic hepatitis c patients infected by genotype 1b

INTRODUCTION: Infection with hepatitis C virus genotype 1b (HCV1b) is known to be a predictive factor of poor response to both interferon-alpha (IFN alpha) alone and IFN alpha plus ribavirin combination therapy.STUDY DESIGN, PATIENTS AND METHODS: This randomised study evaluated the efficacy and safety of daily IFN alpha administration versus the combination of IFN alpha plus ribavirin in treatment-naive patients infected with chronic HCV1b. Sixty-two patients were randomised to receive either human leucocyte IFN alpha 6MU three times weekly for 12 months plus ribavirin 15 mg/kg/day for the first 6 months (group A: 29 patients), or human leucocyte IFN alpha 3MU daily for 12 months (group B: 33 patients). Response was evaluated by monitoring serum alanine aminotransferase (ALT) and HCV-RNA levels during treatment and follow-up (12 months). RESULT AND CONCLUSION: Both treatment schedules were relatively well tolerated. Normal ALT levels and negative serum HCV-RNA were observed in 16 of 29 patients (55%) of group A and in 18 of 33 patients (54.5%) of group B at the end of treatment, as well as in 10 of 29 patients (34.5%) of group A and in 12 of 33 patients (36%) of group B at the end of the follow-up. There was no significant difference between the response rates obtained with the two regimens. In naive patients with chronic HCV1b infection, the efficacy of daily administration with IFN alpha is similar to that of IFN alpha plus ribavirin administered three times a week.     

Effects of ribavirin on intrahepatic and extrahepatic expression of hepatitis C virus in interferon nonresponsive patients

Response to ribavirin therapy (1,000-1,200 mg/day for 6 months) was evaluated in nine patients with chronic hepatitis C virus (HCV) infections who had previously failed to respond to a 6-month course of alpha-interferon. All had chronic active hepatitis with elevated serum aminotransferase activities (mean ± SD = 138 ± 66IU/I). During ribavirin therapy, three showed a complete response (normalized serum ami-notransferase), although in one patient this returned to the pretreatment level 2 months after treatment was stopped. Three others showed a partial response (serum aminotransferase reduction by ?50;%) and the remainder showed no response. There were no consistent changes in HCV-RNA (positive strand) in serum, liver, or peripheral blood mononuclear cells during therapy, but two patients lost HCV-RNA from serum and three of five patients with negative strand HCV-RNA in their livers lost this putative replicative form of the virus. The findings suggest that ribavirin may exert its effects by suppressing viral replication rather than by eradicating the virus, at least in this group of patients, and that the drug may have some benefit in selected cases of chronic hepatitis C that are resistant to inter-feron. However, peripheral blood mononuclear cells represent a major extrahepatic reservoir of HCV and the present regimen of ribavirin therapy did not significantly affect this situation. More prolonged therapy may be required to eradicate the virus from this large pool of cells with the potential to continually reinfect the liver. © 1995 Wiley-Liss, Inc.     

Hepatitis C viral RNA titers in serum prior to,during, and after oral treatment with ribavirin for chronic hepatitis C

Ten patients with biopsy verified chronic hepatitis C virus (HCV) infection were treated with oral ribavirin at a dose of 1,000–1,200 mg per day in two divided doses for 12 weeks. Serum alanine aminotransferase (ALT) levels and hepatitis C viral ribonucleic acid (RNA) levels in serum were followed prior to, during, and 12 weeks posttreatment. ALT levels decreased significantly in all patients during therapy from a mean level of 3.21 μkat/l (range 1.22 to 7.79) before, to 1.25 μkat/l (range 0.78 to 2.04) at the end of treatment (P < 0.005). Hereafter, relapse to pretreatment levels was seen within 12 weeks after treatment stop. The hepatitis C viral RNA levels decreased from a mean 10 log titer of 4.1 (range 1–6) before treatment to 3.4 (range 1–5) at treatment stop. Five patients did not change their HCV RNA titers during treatment. Twelve weeks posttreatment only 3 patients had lower titers than prior to treatment. We conclude that oral ribavirin seems to reduce the viral load, at least temporarily, in some patients with chronic viremic HCV infection. Further studies are needed to evaluate fully the effect of oral ribavirin on chronic HCV infection.     

Combination therapy with ribavirin and amantadine in renal transplant patients with chronic hepatitis C virus infection is not superior to ribavirin alone.

BACKGROUND: Standard treatment of chronic hepatitis C virus (HCV) infection based on interferon is not an option in renal transplant recipients due to the high risk of acute allograft rejection. OBJECTIVES: To assess efficacy and tolerability of combined treatment with ribavirin and amantadine regarding viral clearance, normalization of liver enzymes, and improvement of HCV-related hepatopathy and graft nephropathy in HCV-RNA-positive renal transplant patients. STUDY DESIGN: Prospective randomized controlled study comparing ribavirin, 1000 mg daily (n=7), versus ribavirin, 1000 mg, in combination with amantadine, 200 mg daily (n=8), for 12 months, versus no therapy (controls, n=26). Results were evaluated by intention-to-treat analysis. RESULTS: No relevant differences among treatment groups were found regarding liver enzymes, HCV viremia, liver histology and renal parameters. However, antiviral treatment was limited by anemia, resulting in premature withdrawal from therapy and requiring substitution with recombinant erythropoietin in most patients. The best predictor for tolerability of active treatment was a creatinine clearance rate>50 ml/min. CONCLUSIONS: Addition of amantadine to ribavirin seems not to be superior to ribavirin monotherapy in renal transplant patients with chronic replicating HCV infection. However, this may be explained in part by the poor tolerability of both ribavirin and amantadine in patients with impaired renal function, resulting in drop-outs and subtherapeutic drug dosage.