Background and Aim: Current practice guidelines recommend that individuals chronically infected with the hepatitis C virus (HCV) be treated with pegylated interferon plus ribavirin. Ribavirin, however, is associated with serious adverse events (AE), especially anemia. We review its mechanism of action, its importance in treating chronic hepatitis C (CHC) patients, the AE associated with its use, and techniques used to lessen these AE.
Methods: Medline searches were performed using the keywords ribavirin and hepatitis, together with the keywords mechanism, anemia, liver transplant, renal function, pharmacokinetics, and dose reduction. Searches of abstracts of recent Digestive Diseases Week, American Association for the Study of Liver Diseases, and European Association for the Study of Liver Diseases meetings were also performed.
Results: Ribavirin may be effective in treating CHC by affecting the virus or the host; for example by inducing viral mutations, blocking cellular enzymes, or affecting the host immune response. Although the pegylated interferons are the primary drugs used to treat CHC, a combination with ribavirin is more effective than pegylated interferon alone. Ribavirin-associated AE may be lessened by ribavirin dose reductions and by maintenance of the hematocrit.
Conclusions: Treatments of ribavirin toxicities, especially anemia, can allow patients to continue full-dose combination therapy with peginterferon and ribavirin, enhancing their probability of attaining a sustained virologic response (SVR). Treatment of CHC should be tailored to individual patients, especially those with renal dysfunction, and should include agents that treat the side-effects of CHC treatment. Monitoring of plasma ribavirin concentrations during treatment may help in the future.

Introduction

Current practice guidelines recommend that individuals chronically infected with the hepatitis C virus (HCV) be treated with pegylated interferon (peginterferon) plus ribavirin.^[1] Although peginterferon is the backbone of treatment, combination with ribavirin enhances sustained virologic response (SVR) rates.^[2,3] During treatment with peginterferon-α-2a plus ribavirin, optimal ribavirin dose and treatment duration are dependent on the specific HCV genotype. Thus, in patients infected with genotypes 2/3, treatment for 24 weeks with 800 mg/d ribavirin plus peginterferon-α-2a (180 μg/week) have been adequate, whereas patients infected with genotype 1 required treatment for 48 weeks with peginterferon-α-2a (180 μg/week) plus ribavirin (1000 mg/d or 1200 mg/d for patients weighing <75 kg and ≥75 kg, respectively).^[4]

Ribavirin, however, is frequently associated with adverse events (AE), especially anemia, which may necessitate dose reduction or discontinuation.^[3-5] We therefore review the mechanism of action of ribavirin, its importance in treating chronic hepatitis C (CHC), its AE, and the methods used to treat these AE.

Ribavirin Structure and Pharmacokinetics

Ribavirin, or 1-β-D-ribofuranosyl-1H-1,2,4-
triazole-3-carboxamide, is a nucleoside analog of molecular weight 244.2 (Fig. 1).^[6,7] The pharmacokinetics of ribavirin have been assessed, both alone and in combination with interferon or peginterferon. Intravenous injection of 150 mg C13-labeled ribavirin into six healthy adult volunteers, followed 1 h later by 400 mg unlabeled ribavirin orally, showed that the mean ± SD plasma C_max for labeled and unlabeled ribavirin was 4187 ± 199.4 ng/mL and 538 ± 15.95 ng/mL, respectively. The mean ± SD bioavailability was 51.8 ± 21.8% and the mean ± SD γ-phase half-life was 37.0 ± 14.2 h.^[8] Oral administration of 600 mg ribavirin to six healthy volunteers yielded a mean (%CV) plasma C_max of 643 (37) ng/mL, increasing to 886 (43) ng/mL, 1046 (26) ng/mL, and 1273 (33) ng/mL in patients with stable chronic liver disease of Child-Pugh Classes A, B, and C, respectively (P = 0.029), although the severity of hepatic dysfunction did not affect any other pharmacokinetic parameter.^[9]

Figure 1. (click image to zoom)

Molecular structure of ribavirin.^[6]

The absence of pharmacokinetic interactions between standard interferon and ribavirin has been demonstrated in patients undergoing treatment for hepatitis C. Mean pharmacokinetic parameters were significantly higher at week 6 than at week 1, both in 12 patients receiving ribavirin alone (C_max, 3677 vs 782 ng/mL; area under the curve (AUC)_(0,t), 228 vs 13.4 μg·h/mL; AUC_(γ), 28.1 vs 4.3 μg·h/mL) and in 13 receiving ribavirin plus interferon (C_max, 3483 vs 1030 ng/mL; AUC_(0,t), 265 vs 16.9 μg·h/mL; AUC_(γ), 30.3 vs 5.9 μg·h/mL), but there were no differences between these two groups.^[10] Moreover, in 27 CHC patients treated for 24 weeks with 800 mg/d ribavirin and standard interferon-α-2b, mean pharmacokinetic parameters were significantly higher after final multiple dosing than after initial single dosing (C_max, 2734 vs 628 ng/mL; AUC_0−12h, 28.9 vs 4.1 μg·h/mL; t_1/2, 299 vs 27.3 h; t_max 3.0 vs 2.0 h), and the five patients who attained SVR had significantly higher steady-state concentrations than those who did not.^[11] During treatment of 24 patients infected with HCV genotype 1 with 1000 or 1200 mg/d ribavirin and standard interferon-α-2, the mean ± SD serum ribavirin concentrations at weeks 12 and 24 were 2.67 ± 0.21 and 3.23 ± 0.28 μg/mL, respectively.^[12] Moreover, the relative concentrations were significantly higher in the 11 patients who attained SVR than in the 13 who did not, both at week 12 (0.24 ± 0.03 vs 0.16 ± 0.20 μg/mL/dose; P < 0.03) and at week 24 (0.28 ± 0.03 vs 0.21 ± 0.32 μg/mL/dose; P < 0.049).

Ribavirin pharmacokinetics have also been assayed in patients treated with peginterferon-α-2a plus ribavirin. Following 12 weeks of treatment with 1200 mg/d ribavirin in 39 patients with body weight >75 kg, mean ± SD AUC_0−12h was 25.4 ± 7.1 μg·h/mL and mean ± SD C_max was 2748 ± 818 ng/mL^[6] The mean steady-state γ-phase half-life of ribavirin in 380 patients treated with peginterferon-α-2a plus ribavirin was 303 h, which was predicted to be achieved after 7-11 weeks of treatment (4-6 half-lives of ribavirin).^[13] Population studies have shown that the most important factor affecting ribavirin clearance in patients also treated with standard or peginterferon is body weight.^[13-15] In addition, ribavirin clearance in 63 patients also treated with standard interferon-α-2b was dependent on renal function, as determined by glomerular filtration rate.^[16] Moreover, ribavirin-induced anemia was found to depend primarily on plasma ribavirin concentration, and not on dose per kilogram of body weight, suggesting that ribavirin should be dosed according to renal function.^[17]

Mutagenic Activities of Ribavirin

Although the mechanism of action of ribavirin in CHC is not completely understood, it has been shown to affect the virus and/or the host, including the immune response of the host to the virus. Since ribavirin is a nucleoside analog, its incorporation into the viral genome can lead to mutagenesis.^[18,19] In reacting with the HCV-RNA-dependent RNA polymerase (NS5B), ribavirin can pair with cytidine and uridine, thus acting as a mimic of guanine and adenine and blocking viral replication, a mechanism called 'error catastrophe'.^[20] The direct interaction between ribavirin and the HCV viral polymerase was indicated by the finding that, in five of five patients receiving ribavirin monotherapy, a specific Phe-Tyr amino acid substitution emerged in NS5B, suggesting that ribavirin selects for this mutation.^[21] Moreover, although ribavirin inhibited the replication of wild-type replicons in a human hepatoma cell line, it did not inhibit the replication of mutant replicons, indicating that ribavirin treatment selects for a resistant polymerase.^[21] Use of this replicon system also showed that mutagenesis induced by interferon plus ribavirin was greater than that induced by either drug alone,^[22] although similar findings were not observed in patients treated with ribavirin and interferon-α-2b.^[23] In Hantaan virus (HTNV) and foot-and-mouth disease virus (FMDV), ribavirin has been shown to inhibit the expression of viral cRNA, mRNA, and protein, to reduce the number of infectious particles, and to enhance viral mutation rate.^[24,25] The formation of ribavirin triphosphate, its primary intracellular metabolite, correlated with its effect on HTNV-RNA synthesis.^[26] Ribavirin triphosphate has also been shown to inhibit the 2'-O-methyltransferase activity of dengue virus and to act as a guanosine 5'-triphosphate (GTP) or RNA cap analog, binding to the RNA binding cap site and impeding cap methylation.^[27] Recent findings suggest, however, that the antiviral effects of ribavirin may not be dependent on its incorporation into the HCV genome.^[28]

Recent studies have tested whether treatment of CHC patients with ribavirin alone increases virus mutation rates. In a randomized, placebo-controlled trial, 31 patients infected with CHC genotype 1 were treated with 1200 mg/day ribavirin for 48 weeks, with patients in the placebo group subsequently crossed over to open-label ribavirin for 48 weeks.^[29] Viral RNA was extracted from blood samples obtained at the baseline and during both the randomized and cross-over phases, and the entire NS5B region was sequenced. During the randomized phase, there was no increase in the number of mutations or the mutation rate in either group at 24 weeks. During the cross over-phase, an increase in mutation rate was observed after 4, but not after 24, weeks. These findings suggest that, while ribavirin therapy is associated with an early, transient increase in the mutation rate of HCV, lethal mutagenesis and error catastrophe is unlikely to be the mechanism of action of ribavirin during treatment of CHC.

Treatment with ribavirin of Huh7 cells harboring a subgenomic HCV replicon system led to higher NS5B mutation frequencies than treatment with the ribavirin L-enantiomer leucovorin.^[30] After a mean of 5 weeks of ribavirin monotherapy of patients infected with HCV genotype 1b, the overall mutational frequencies within the NS3 and NS5B sequences of the virus were higher than at the baseline (P < 0.01), whereas the overall mutational frequencies after treatment with standard or pegylated interferon for 5 weeks were lower than at the baseline. These findings suggest that, while ribavirin monotherapy has an early, transient mutagenic effect on the virus, this effect is not seen when patients are treated with combination therapy.

Effects of Ribavirin on Host Factors

Ribavirin has also been shown to inhibit the activity of the cellular enzyme, inosine monophosphate dehydrogenase (IMPDH), depleting cellular GTP pools and consequently inhibiting the in vitro replication of several flaviviruses and paramyoviruses.^[31] Moreover, the antiyellow fever virus activity of ribavirin has been shown to be independent of error-prone replication.^[32] More recently, however, the anti-HTNV activity of ribavirin has been shown to correlate with the production of ribavirin-5'-triphosphate, not with the inhibition of IMPDH, suggesting that the mechanism of antiviral activity of ribavirin may be virus specific.^[26]

Effects of Ribavirin on the Immune System

Ribavirin has also been shown to affect the immune response of the host to virus. For example, the number of activated T cells expressing the cytokine, γ−interferon, was significantly reduced in CHC patients treated with interferon-α and ribavirin, but not in those treated with interferon-α alone.^[33] Similar results were observed when cytokine concentrations were measured in supernatants of unfractionated, activated peripheral blood mononuclear cells (PBMC) and in the peripheral blood of these patients, and γ-interferon production was significantly lower in patients who attained normal serum alanine aminotransferase (ALT) levels than in those who did not (Fig. 2).^[33] Following stimulation with HCV core protein and phorbol myristate acetate (PMA) and ionomycin (IO), the expression of CD40 ligand (CD40L), a cell surface protein present on activated T cells that regulates cellular immune responses, was significantly higher on CD4 lymphocytes from liver transplant recipients treated with ribavirin for recurrent CHC than on CD4 lymphocytes from untreated transplant recipients and normal healthy subjects; in the former, CD40L expression was higher in patients who showed a ≥0.5 log reduction in HCV-RNA concentration than in those who did not.^[34] Ribavirin also dose-dependently reduced the expression of γ-interferon by phytohemagglutinin (PHA)-stimulated PBMC, with the decrease greater in PBMC from CHC patients than in PBMC from healthy individuals.^[35] In addition, incubation of PHA-activated PBMC from CHC patients with ribavirin dose-dependently decreased synthesis of total DNA, RNA, and protein, and led to a dose-dependent increase in apoptosis rate. These effects of ribavirin could be mitigated by the addition of guanosine.^[35] In contrast to results demonstrating that ribavirin reduced γ-interferon expression, incubation of PBMC with HCV core protein was found to increase γ-interferon production, with the increase greater in patients who achieved SVR after treatment with interferon-α plus ribavirin than in patients who achieved SVR after treatment with interferon-α alone or in those who did not respond to either treatment.^[36]

Figure 2. (click image to zoom)

Mean production of γ-interferon (IFN-γ) by activated PBMC from patients (□) before and after (▪) 4 months of treatment with ribavirin and interferon-α-2 or interferon-α-2 alone. Adapted with permission.^[33]

Ribavirin has also been found to affect the immune system by other mechanisms. For example, serum concentrations of the proinflammatory cytokine, interleukin (IL)-18, were increased in CHC patients treated with interferon-α-2b plus ribavirin, but not in patients treated with interferon-α-2b alone.^[37] Ribavirin treatment of PMA/IO-stimulated PBMC from CHC patients significantly increased the Th1, but not the Th2, T cell population; similar results were observed when ribavirin was cultured with CD4+ T cells in the presence of HCV core protein.^[38] Ribavirin also enhanced γ-interferon secretion by HCV core protein-treated CD4+ T cells and by untreated PBMCs; in the latter, ribavirin enhanced expression of IL-12R β-2 chain, γ-interferon, and IL-4 mRNA, and reduced secretion of IL-10.^[38]

The ability of ribavirin to inhibit respiratory syncytial virus (RSV) particle release and RSV gene expression by infected airway epithelial cells was found to be associated with reductions in IL-8 secretion, IL-8 mRNA expression, and nuclear factor-kappa B (NF-κB) activation.^[39] Using microarrays, ribavirin was shown to inhibit expression of the RSV-inducible chemokines MIP-1α and MIP-1β and interferon, to up-regulate expression of RSV- and interferon-stimulated response genes, and to increase RSV-induced STAT-1 binding to the interferon-stimulated response element encoding antiviral proteins, suggesting that ribavirin potentiates interferon-stimulated response element signaling induced by RSV, thus enhancing the expression of antiviral interferon-stimulated response genes.^[40]

Pharmacodynamic assays of free virions and immune complexes showed that the decline in immune complexes during the second phase of treatment was greater in HCV genotype 1-infected patients treated with interferon and ribavirin than in those treated with interferon alone.^[41] This decline was associated with SVR, suggesting that ribavirin may modulate the humoral immune response against HCV and trigger a favorable responseto interferon.^[41] Compared with biopsy specimens from patients treated with peginterferon-α-2a alone, specimens from patients treated with peginterferon-α-2a plus ribavirin showed enhanced induction of interferon-related genes, including the interferon-α receptor, and down-regulation of genes involved in interferon inhibition, apoptosis, and hepatic stellate cell activation.^[42]

Importance of Ribavirin in the Treatment of Hepatitis C

Antiviral Mechanisms

Ribavirin montherapy is not efficacious in the treatment of chronic hepatitis C infection. Several placebo-controlled clinical trials have shown that ribavirin reduces serum ALT and HCV-RNA concentrations during treatment, but that both returned to pretreatment levels after treatment was halted.^[43-47] Moreover, ribavirin alone had no effects on liver histology.^[43-47] When combined with standard or pegylated interferon, however, ribavirin enhanced virologic, biochemical, and histologic response rates compared with interferon alone.^[2,3,48-50] The third phase of viral decay, beginning after about 7-28 days, was significantly faster in patients receiving peginterferon-α-2a plus ribavirin than in those receiving peginterferon-α-2a alone, and this phase was associated with SVR.^[51] Further model development, taking into account the anti-HCV activity of ribavirin, provides a good fit with experimental data, showing that the addition of ribavirin enhances SVR rates by about 25% to 30% and suggests a mechanism by which ribavirin enhances HCV-RNA decline and improves long-term outcome.^[52]

Logistic regression analysis in patients treated with peginterferon-α-2b and ribavirin has shown that the doses of both drugs are important and predictive of SVR.^[5] To account for the possible interaction between the two drugs, a term for the product of the two doses was included in the model. Fitted regression lines show that the observed response rates increase as ribavirin dose increases to about 13 mg/kg/day (Fig. 3).

Figure 3. (click image to zoom)

Logistic regression analyses: Sustained virologic response (SVR) as a function of ribavirin dose (mg/kg) and dose of peginterferon-α-2b. Reprinted with permission.^[5]

Prevention of Relapse

Reductions in ribavirin dose during treatment have been found to negatively affect SVR in patients infected with HCV genotype 1, and higher relative ribavirin doses have been associated with higher SVR rates in patients treated with peginterferon-α-2b plus ribavirin.^[5,53] In addition, genotype 1-infected patients randomized to peginterferon-α-2a plus 1000/1200 mg/d ribavirin had higher SVR rates than those randomized to peginterferon-α-2a plus 800 mg/d ribavirin, further indicating the importance of adequate ribavirin dosaging.^[4] Both the timing of dose reduction and lower relative dose affect SVR. For example, a retrospective analysis showed that reductions in ribavirin dose during the first 12 weeks of treatment reduced early virologic response (EVR) rates in patients infected with HCV genotype 1.^[54]

Adverse Effects of Ribavirin

Anemia

As confirmed in patients administered ribavirin monotherapy, the most significant AE is hemolytic anemia.^[43-46] Anemia is frequently observed in patients receiving combination treatment with standard interferon or peginterferon plus ribavirin.^[3,5,48,49] Ribavirin-induced anemia was shown to depend primarily on plasma ribavirin concentration, not on dose per kilogram body weight.^[17,55]

The mechanism of ribavirin-induced anemia has been shown to involve reductions in reticulocyte counts and erythrocyte Na-K pump activity, and increases in K-Cl cotransport, membrane bound IgG, and C3, and erythrocyte band 3.^[56] In patients treated with interferon and ribavirin, there was a significant association between erythrocyte ribavirin concentration and hemoglobin decrease from the baseline (P < 0.001) (Fig. 4).^[57,58] Moreover, retrospective modeling has shown a relationship between anemia and exposure of erythrocytes to ribavirin.^[59] Pooling of data from 1732 patients treated with peginterferon-α-2a plus ribavirin showed that the probability of anemia increased as a function of ribavirin dose/kg, whereas the relationship between SVR and ribavirin dose/kg was influenced by HCV genotype.^[60]

Figure 4. (click image to zoom)

Effects of erythrocyte ribavirin concentration on change in hemoglobin concentration. Reprinted with permission.^[57]

Among the factors influencing ribavirin-induced hemolysis are amount of interferon administered, pretreatment platelet level, and haptoglobin phenotype.^[61] Patients treated with peginterferon plus ribavirin showed decreases in platelets and white blood cells, possibly due to bone marrow suppression, as well as inappropriately diminished production of endogenous serum erythropoietin for their degree of anemia.^[62] Treatment with interferon and ribavirin was also associated with significant alterations in red cell membrane lipids.^[63]

Assessment of the relationship between anemia and patient baseline characteristics in patients treated with peginterferon-α-2a and ribavirin showed that the most important prognostic factors for anemia were sex and ribavirin dose per kilogram, followed by baseline hemoglobin concentration, age, baseline ALT quotient, and presence of cirrhosis.^[60]

Lower baseline creatinine clearance, higher baseline hemoglobin levels, and increased age were independently associated with an increased risk of hemoglobin decrease.^[64] In a cohort of 466 Asian patients, 39% of whom developed severe anemia (<10 g/dL hemoglobin), age ≥50 years (odds ratio [OR] = 1.935; P = 0.001) and baseline hemoglobin concentration ≥14 g/dL (OR = 2.975; P < 0.001) were significantly associated with maximal decreases in hemoglobin; pretreatment platelet count <150 000/mm³ (OR = 1.821; P < 0.001), age ≥50 years (OR = 1.789; P = 0.001), female gender (OR = 1.739; P < 0.001), and body weight <65 kg (OR = 1.493; P = 0.027) were independent factors predicting severe anemia; and there was a significant linear correlation between SVR rate and time of severe anemia during therapy.^[65]

Among the factors contributing to ribavirin dose reductions due to anemia during treatment with interferon-α-2b and ribavirin were low (<14 g/dL) pretreatment hemoglobin concentration and age >55 years.^[66] The rate of reduction of hemoglobin concentration at week 2 was significantly associated with the severity of anemia (P < 0.01), with factors such as female sex, age ≥60 years, and ≥12 mg ribavirin/kg body weight significant on univariate analysis.^[67] Moreover, discontinuations for anemia were significantly more likely in patients showing a hemoglobin decline >2 g/dL after 2 weeks of treatment, those with lower ribavirin apparent clearance, and those ≥60 years old.^[68] A study of 41 patients aged <60 years and 30 aged ≥60 years showed that the latter were more likely to require dose modifications and discontinuations, as well as being at greater risk for anemia, thrombocytopenia, and neutropenia.^[69]

Ribavirin in Patients With Renal Failure and After Liver Transplantation

Ribavirin is largely cleared through the kidneys and therefore tends to accumulate in the presence of renal dysfunction and is not effectively removed by hemodialysis.^[7] Pharmacokinetic analysis in 44 patients with normal creatinine clearance (glomerular filtration rate (GFR) = 57-144 mL/min) and 19 with reduced creatinine clearance (GFR = 5-57 mL/min) showed that ribavirin clearance was linearly dependent on renal function (Fig. 5).^[16] To maximize therapeutic efficacy and minimize side-effects, especially hemolytic anemia, a ribavirin dosing schedule based on GFR and body weight to reach an intended target concentration was recommended, with monitoring of serum ribavirin concentration used to adjust dosage.^[16] Similar findings, of ribavirin dose adjustment based on renal function, have been reported in a group of 19 Japanese patients with CHC, and treatment with peginterferon-α-2a and ribavirin was successfully attempted in 35 hemodialysis patients awaiting renal transplant.^[70,71]

Figure 5. (click image to zoom)

Plot of ribavirin clearance as a function of creatinine clearance. Adapted with permission.^[16]

Recurrence of CHC is universal in patients who require liver transplantation for this indication, but many transplant recipients have some degree of renal impairment. In a group of transplant patients treated with interferon and ribavirin, the incidence of hemolysis was related to degree of renal impairment, suggesting that ribavirin dose should be adjusted to reduce hemolysis.^[72] In addition, pharmacokinetic studies in HCV-positive kidney or liver transplant patients showed that ribavirin dosage was dependent on renal function and that monitoring of plasma ribavirin concentration during treatment could maximize efficacy while reducing side-effects.^[73,74]

Bone Mineral Density

Another systemic AE associated with ribavirin is loss of bone mineral density (BMD). For example, when parameters of BMD were assessed in 13 patients treated with interferon alone and 19 treated with interferon plus ribavirin, the latter had significantly lower BMD (1.108 ± 0.08 g/cm²vs 0.877 ± 0.07 g/cm²; P < 0.001), T-scores (0.19 ± 0.6 vs−1.94 ± 0.6; P < 0.001) and Z-scores (0.26 ± 0.6 vs−1.76 ± 0.5; P < 0.001) on magnetic resonance imaging, urinary calcium excretion (218 ± 97 mg/24 h vs 76 ± 36 mg/24 h; P < 0.001), and calcium/creatinine ratio (1.9 ± 0.3 mg/mg vs 0.06 ± 0.02 mg/mg; P < 0.01).^[75] Others, however, have reported no loss of BMD in a group of 12 patients with recurrent CHC after orthotopic liver transplantation,^[76] and pre- and post-treatment measurements showed no differences in BMD between 13 pediatric patients treated with interferon-α-2b and ribavirin and seven patients treated with interferon alone.^[77] While incubation of human osteoclast-like cells with interferon for up to 14 days had no effect on cell growth, ribavirin significantly reduced cell proliferation, increased cell death, and reduced alkaline phosphatase (ALP) activity, indicating that this agent suppresses osteoblast differentiation.^[78] In contrast, ribavirin had little effect on the proliferation or ALP activity of murine osteoblasts, and no direct effect on osteoclast differentiation or function, although it indirectly induced TRANCE/RANKL gene expression in osteoblasts, thus enhancing osteoclast formation.^[79] Taken together, these findings suggest that, at present, the involvement of ribavirin in reducing BMD is unclear and further research is necessary.

Effect of Ribavirin Dosing

Impact of Dose Reductions

The impact of dose reduction on SVR was retrospectively assessed by analyzing drug exposure in genotype 1-infected patients randomized to peginterferon-α-2a (180 μg/week) plus ribavirin (1000 or 1200 mg/d) who completed 48 weeks of treatment.^[80] Neither EVR nor SVR was adversely affected by ribavirin dose reduction as long as cumulative ribavirin exposure was >60%, whereas the SVR rate in patients receiving ≤60% ribavirin was significantly lower than in those receiving >60% ribavirin (33% vs 64%; P < 0.0001; Table 1 ^[80]). Patients who received ≤60% ribavirin dosing had prolonged periods of dose reduction, interruption of therapy, or premature discontinuations. Even in patients with >97% cumulative ribavirin dose over weeks 1-12, the SVR rate was significantly lower in those with ≤80% ribavirin exposure than in those with >80% exposure during weeks 13-48 (48% vs 67%; P = 0.372). In contrast, ribavirin dose reductions during weeks 5-48 had minimal impact on SVR in patients who achieved rapid virologic response (RVR), defined as undetectable serum HCV-RNA levels at 4 weeks, even when the cumulative ribavirin dose was <60%. In patients who did not achieve RVR, however, ribavirin dose reductions after week 4 had a negative impact on SVR rate in all ribavirin exposure categories.

When non-responders to standard interferon, with or without ribavirin, were re-treated with peginterferon-α-2a plus ribavirin, ribavirin dose reductions during weeks 1-20 were associated with reduced SVR rate (21% to 11%; P = 0.031), whereas later ribavirin dose reductions did not affect SVR rates.^[81] In addition, patients initially treated with interferon monotherapy had a higher probability of attaining SVR during retreatment with peginterferon-α-2a plus ribavirin than did patients initially treated with interferon and ribavirin. Further analysis of the impact of dose reductions on SVR in re-treated patients found that reductions in ribavirin dose during the first 12 or 20 weeks of treatment, even to below 60% cumulative dose, did not significantly affect SVR rate as long as patients remained on full-dose peginterferon-α-2a, although ribavirin discontinuations during the first 20 weeks, and ribavirin interruptions for at least 7 consecutive days during the first 12 weeks, had a negative impact on SVR. Ribavirin dose reductions during weeks 20-40 also did not have a consistent effect on SVR, as long as peginterferon-α-2a dose was maintained and ribavirin was not discontinued ( Table 2 ).^[82]

To assess the role of ribavirin in HCV clearance and to evaluate the consequences of ribavirin discontinuation, 516 patients infected with HCV genotype 1 were treated with 180 μg/week peginterferon-α-2a and 800 mg/day ribavirin, and those who were virus negative at week 24 were randomized to further treatment with peginterferon-α-2a plus ribavirin or peginterferon-α-2a alone.^[83] Responders at week 24 who stopped ribavirin had a significantly higher rate of breakthrough during treatment and relapses after therapy than those who continued on both agents (SVR rates, 52.8% vs 68.2%; P = 0.004). However, the side-effect profile and quality of life of patients who discontinued ribavirin tended to improve. These findings indicate that ribavirin primarily acts by sustaining the virologic response to peginterferon-α and that ribavirin must be administered for the full treatment period in most genotype-1 infected patients who respond. Multiple logistic regression analysis in the combination treatment group, however, identified responders at week 24 who could discontinue ribavirin without jeopardizing SVR.

Impact of Higher Dosing or Longer Duration

To further assess the effect of cumulative ribavirin dosing on treatment response, 455 patients infected with HCV genotype 1 were randomized to treatment with peginterferon-α-2a (180 μg/week) plus ribavirin (800 mg/d) for 48 or 72 weeks.^[84] There was no difference in SVR rates, although patients randomized to 72 weeks were significantly more likely to discontinue treatment (41% vs 24%; P < 0.001). There were no differences in the frequency or timing of dose reductions. Patients who did not achieve EVR at week 12, however, were significantly more likely to achieve SVR if treated for 72 weeks rather than for 48 weeks (P = 0.04; Fig. 6).^[84]

Figure 6. (click image to zoom)

Sustained virologic response (SVR) as a function of rapid virologic response (RVR) at week 4 and early virologic response (EVR) at week 12 in patients treated for 48 or 72 weeks. Reprinted with permission.^[84]

In a similar trial, of 326 patients (291 with genotype 1) with detectable HCV-RNA levels at week 4, SVR rates were significantly higher in the 165 patients treated for 72 weeks with peginterferon-α-2a (180 μg/week) plus ribavirin (800 mg/d) than in the 161 treated for 48 weeks (45% vs 32%; P = 0.024) as well as in the 149 and 142, respectively, infected with HCV genotype 1 (44% vs 28%; P = 0.003).^[85] Treatment discontinuations, however, were significantly more frequent in patients treated for 72 than for 48 weeks (36% vs 18%; P = 0.0004), although dose reduction rates were similar. Duration of ribavirin treatment, but not dose of ribavirin by weight, was significantly associated with SVR.

Recently presented results in patients infected with HCV genotype 1 have shown that, relative to 48 weeks of treatment, 72 weeks of treatment with peginterferon-α-2b (1.5 μg/kg/week) or consensus interferon (9 μg/d) plus ribavirin (800-1400 mg/d) enhanced SVR rates.^[86,87] In addition, interim results from a four-armed study of patients infected with HCV genotype 1 and a high viral load (>800 000 IU/mL) treated with peginterferon-α-2a (180 or 270 μg/week) plus ribavirin (1200 or 1600 mg/d) for 48 weeks have shown that more intensive treatment was associated with higher SVR rate, as well as with more dose reductions and a higher incidence of anemia.^[88] Recently presented interim results in groups of patients infected with HCV genotypes 2/3 or 1/4 have shown that total exposure to both peginterferon-α-2a and ribavirin enhances SVR rates independent of other factors.^[89,90]

As described above, successful treatment of HCV with peginterferon and ribavirin is often limited by anemia. To determine if administration of erythropoietin-α, with or without a higher dose of ribavirin, could increase SVR rates, 150 treatment-naïve patients infected with HCV genotype 1 were randomized to treatment with (1) peginterferon-α-2b (1.5 μg/kg/week) plus ribavirin (13 mg/kg/day, equivalent to 800-1400 mg/day); (2) peginterferon-α-2b (1.5 μg/kg/week) plus ribavirin (13 mg/kg/day) plus erythropoietin-α (40 000 U/week); or (3) peginterferon-α-2b (1.5 μg/kg/week) plus ribavirin (15.2 mg/kg/day, equivalent to 1000-1600 mg/day), plus erythropoietin-α (40 000 U/week).^[91] Erythropoietin-α treatment was initiated at the start of therapy to maintain a hemoglobin concentration of 12-15 g/dL. Significantly smaller percentages of group 2 patients had a decline in hemoglobin concentration, to less than 10 g/dL (9% vs 34%; P < 0.05), and required ribavirin dose reductions (10% vs 40%; P < 0.05) compared to group 1 patients, but SVR rates were similar (19% vs 29%). In contrast, the SVR rate was significantly higher in group 3 (49%; P < 0.05), due to a significant decline in relapse rate in group 3 compared with groups 1 and 2 (8% vs 38%; P < 0.05). These findings indicated that a higher starting dose of ribavirin was associated with a lower relapse rate and a higher SVR rate.

Taken together, these findings suggest that extension of treatment and/or more intensive treatment may increase SVR in selected patients.

Treatment of the Adverse Effects of Ribavirin

For CHC patients without cardiac disease, the current standard of care (SOC) during treatment with peginterferon and ribavirin is to reduce ribavirin dosage to 600 mg/d when hemoglobin is <10 g/dL, and to discontinue ribavirin when hemoglobin is <8.5 g/dL^[6,7] For CHC patients with a history of stable cardiac disease, the SOC is to reduce ribavirin to 600 mg/d when hemoglobin decreases ≥2 g/dL during any 4-week period, and to discontinue ribavirin when hemoglobin is <12 g/dL despite 4 weeks at a reduced dose.^[6,7] Since reductions in ribavirin dose during treatment can have a negative impact on SVR, agents that counteract ribavirin AE and thus maintain ribavirin dose can enhance the likelihood of SVR.

Among the agents employed to maintain adequate ribavirin dosing is the hematopoietic growth factor epoetin-α. When patients who became anemic during treatment with standard interferon and ribavirin were randomized to once weekly epoetin-α (40 000 U, adjusted based on hemoglobin response; n = 36) or SOC (i.e. dose reductions, discontinuations, and transfusions; n = 28) for 16 weeks, the final mean hemoglobin concentration was significantly higher in the former (13.8 ± 1.8 g/dL vs 11.4 ± 1.3 g/dL; P < 0.0001) and there were increases in mean ribavirin dosage and quality of life parameters, but epoetin-α had no impact on SVR.^[92] A larger study, in which patients who developed anemia during treatment with interferon and ribavirin were randomized to epoetin-α (n = 93) or placebo (n = 92) for 8 weeks, showed that ribavirin dose maintenance was significantly higher in the former group (88% vs 60%; P < 0.001; Fig. 7^[93]), as were mean hemoglobin levels (13.0 ± 1.3 g/dL vs 10.9 ± 1.1 g/dL; P < 0.001) and quality of life scores.^[93,94] Moreover, all of these findings were observed in patients who switched from placebo to epoetin-α during a subsequent 8-week, open-label phase.

Figure 7. (click image to zoom)

Ribavirin dose maintenance in patients also treated with epoetin-α or placebo. DBP, double blind placebo. Reprinted with permission.^[93]

Epoetin-α was also effective in counteracting the anemia experienced by all 10 patients infected with HCV genotype 1 and a viral load (>800 000 IU/mL) who were treated with peginterferon-α-2a and high-dose ribavirin (mean, 2540 mg/d) to maintain a steady state concentration of <15 μM, although two of these patients required blood transfusions and reduction or temporary discontinuation of ribavirin for 1 week.^[95] Nine of these patients attained SVR. The increased endogenous erythropoietin production observed in 18 CHC patients in response to ribavirin-induced anemia was similar to that observed in patients with uncomplicated, non-renal anemia, suggesting that the dosing regimen of recombinant epoetin-α be more patient tailored.^[96] The addition of epoetin-α has also been shown to be effective during treatment of liver transplant recipients for recurrent CHC.^[72,97]

Other agents, including traditional Asian medicines and vitamins, may be effective in counteracting ribavirin-induced anemia. For example, in one trial, 67 CHC patients were randomized to 24 weeks of interferon-α-2b and ribavirin (800 mg/d and 600 mg/d for patients weighing ≥60 kg and <60 kg, respectively) plus the Kampo medicine juzen-taiho-to (TJ-48; n = 32), which is traditionally used to ameliorate anemia, or placebo (n = 35).^[98] The reductions in hemoglobin levels at weeks 4, 8, and 12 were significantly attenuated in the TJ-48 group, but not in the placebo group (P < 0.05 each), and significantly fewer TJ-48-treated patients required ribavirin dose reductions or withdrawals for severe anemia (Hb <10 g/dL; 13% vs 43%; P < 0.001).^[98] In a second trial, CHC patients treated with interferon-α-2b and ribavirin were randomized to additional treatment with the herbal medicine ninhinyoeito (NYT), which reportedly has anti-HCV and antioxidant properties, or placebo. The maximal decrease in hemoglobin was significantly less during treatment in the 13 patients randomized to NYT than in the 10 randomized to placebo (2.59 ± 1.10 g/dL vs 3.71 ± 0.97 g/dL; P = 0.026).^[99]

A relationship has been observed between the parameters of oxidative stress and antioxidants and the AE of ribavirin, suggesting that agents that normalize these markers may be effective in treating CHC. For example, serum oxidative stress markers were shown to be significantly increased, and serum and liver antioxidant levels significantly decreased, in CHC patients compared with controls, with these changes related to the degree of fibrosis and inflammation.^[100-102] Moreover, in cirrhotic CHC patients, plasma-α-tocopherol was reduced, along with the arachidonic acid and eicosapentaenoic acid (EPA) contents of mononuclear cells, suggesting that supplementation with EPA would be beneficial.^[103] A pilot study of six anemic CHC patients found that EPA significantly increased mean hemoglobin concentration after 1 and 2 months.^[104] Although high-dose vitamin E supplementation did not diminish ribavirin-associated hemolysis in CHC patients during treatment with interferon and ribavirin, supplementation with vitamins C and E for up to 8 weeks maintained the EPA content of mononuclear cells, which was significantly decreased in the absence of vitamin supplementation.^[105,106] In contrast, the EPA content of erythrocyte membranes was enhanced significantly in patients supplemented with EPA and vitamins C and E for 24 weeks, but decreased in patients supplemented with vitamins C and E alone, although vitamins C and E attenuated the ribavirin-induced decrease of EPA in erythrocyte membranes.^[107,108] Recent findings suggest that, in patients infected with HCV genotype 1b and high viral load, EPA can prevent ribavirin dose reduction during the first 12 weeks of treatment.^[109] The role of strategies to maintain hemocrit during ribavirin during riabavrin therapy requires further clarification, particularly whether these strategies consistently enhance SVR rates.^[91]

Conclusions

Ribavirin remains key to achieving SVR with current antiviral strategies for chronic HCV. The mechanism of action of ribavirin in CHC includes effects on the virus and/or the host, including the immune response of the host to the virus. These can include the enhancement of viral mutagenesis, the inhibition of cellular IMPDH, and effects on cytokine secretion and T-cell responses. Clinical evidence has shown the importance of ribavirin in the treatment of CHC patients, but this agent is associated with frequent AE, necessitating dose reductions and/or discontinuations. Ribavirin reductions, however, can have a negative impact on SVR. Thus, management of ribavirin toxicity, especially anemia, can allow patients to continue full-dose combination therapy with peginterferon and ribavirin, hopefully enhancing their probability of attaining SVR. Treatment of CHC should be tailored to individual patients, especially those with renal dysfunction, including future monitoring of plasma ribavirin concentrations during treatment, as well as the use of agents that treat ribavirin AE.

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