Correspondence Mitchell L. Shiffman, MD, Hepatology Section, Virginia Commonwealth University Medical Center, PO Box 980341, Richmond, VA 23298, USA Tel: +1 804 828 4060 Fax: +1 804 828 4945 e-mail: firstname.lastname@example.org
The optimal therapy for patients with the chronic hepatitis C virus (HCV) is a combination of peginterferon and ribavirin. Treating HCV without ribavirin or prematurely discontinuing, frequently missing doses of ribavirin is associated with a significant decline in virological response, and an increase in both breakthrough viraemia and relapse. The major limitation of ribavirin is adverse events, the most common of which is haemolytic anaemia. Haemolysis is modest when ribavirin is utilized as monotherapy, but is significantly increased when combined with interferon or peginterferon. For these reasons, attempts to replace ribavirin with a less toxic alternative have been advanced. Unfortunately, even when ribavirin is replaced by a potent protease inhibitor, relapse is significantly increased and SVR is reduced. The future of HCV treatment is to combine peginterferon and ribavirin with several protease and/or polymerase inhibitors. Whether this strategy will allow ribavirin to be removed from the treatment paradigm remains to be proven. However, based on the results of clinical trials conducted to date, it is much more likely that peginterferon, not ribavirin, could be expendable.
Ribavirin is a synthetic nucleoside analogue that structurally resembles guanosine. It has a broad spectrum of antiviral activity and has been utilized in clinical medicine since the early 1970s (1). Ribavirin was initially utilized to treat the respiratory syncytial virus in children but more recently has been shown to be effective against this virus in both the elderly and in lung transplant recipients (2, 3). Ribavirin is also highly effective for treatment of the virus that causes Lassa fever, measles and herpesvirus (4). However, the most common indication for ribavirin is for the treatment of chronic hepatitis C virus (HCV), where it is utilized in combination with interferon-α or peginterferon-α (5–7).
Despite nearly a decade of investigation, the mechanism(s) by which ribavirin exerts its antiviral effect against HCV remains obscure. Ribavirin is a direct antiviral agent but also appears to modulate the immune response. Both these mechanisms may contribute to the effectiveness of this agent in the treatment of chronic HCV. Ribavirin inhibits inosine 5′-monophosphate dehydrogenase (8). This enzyme is responsible for the intracellular synthesis of guanine from inosine. Thus, ribavirin reduces guanine stores and this in turn reduces RNA viral replication. More recently, it has been proposed that ribavirin-triphospate is directly incorporated into the viral RNA sequence in place of guanine and that this leads to extensive mutagenesis that is eventually lethal to the viral genome (9). Other studies have demonstrated that ribavirin reduces the immune response by affecting the secretion of interleukins and altering the activity of cytotoxic lymphocytes (10). Regardless of its mechanism of action, there is no doubt that the addition of ribavirin to interferon revolutionized the treatment of chronic HCV.
This manuscript will review the role that ribavirin plays in the treatment of chronic HCV, the adverse effects associated with ribavirin and why so many physicians and patients would like to replace this agent with others that have a mechanism of action that is less obscure and better tolerated. The future of HCV treatment is potent protease and polymerase inhibitors that directly suppress HCV. Whether these agents can replace ribavirin remains to be defined.
The impact of ribavirin in the treatment of chronic hepatitis C virus
When utilized as a monotherapy in patients with chronic HCV, ribavirin reduces serum alanine aminotrasferase activity but has only a minimal impact on the serum level of HCV RNA (11). This observation led to the hypothesis that ribavirin altered the immune response against HCV and led to studies where ribavirin was utilized in combination with interferon-α. When compared with the degree of viral suppression observed with interferon-α alone, the combination of interferon-α and ribavirin more than doubled the virological response rate (the percentage of patients who became HCV RNA undetectable with treatment) from 24 to 50% (5). As a result, the antiviral effect of interferon when combined with ribavirin was synergistic, greater than the sum of the antiviral responses observed with either agent alone. The antiviral affect of ribavirin and peginterferon was also synergistic (6, 7). However, because peginterferon is more potent than standard interferon, the increase in the virological response with combination therapy was only 17% (Fig. 1).
Ribavirin enhances the virological response by accelerating the rate of decline in HCV RNA over that observed with interferon alone (12). Although the combination of peginterferon and ribavirin does not increase the percentage of patients who achieve a rapid virological response (becoming HCV RNA undetectable by treatment week 4), the use of ribavirin more than doubles the percentage of patients who become HCV RNA undetectable by treatment week 12: from 18 to 38% (13).
In addition to enhancing the virological response, ribavirin also helps to maintain the response and enhances the sustained virological response (SVR) by preventing breakthrough and reducing relapse (5–7, 14). In a randomized-controlled trial, 12% of patients with HCV genotype 1 developed recurrence of HCV RNA in serum after discontinuing ribavirin at treatment week 24 even though they remained on peginterferon for 48 weeks. In contrast, none of the patients who remained on peginterferon and ribavirin combination therapy for the full duration of treatment developed a breakthrough (14). In large randomized-controlled trials where standard interferon or peginterferon monotherapy was compared with combination therapy with ribavirin, relapse rates were reduced from 45 and 51% to only 22 and 19% respectively (5, 6). A higher starting dose of ribavirin has also been demonstrated to reduce relapse. In a controlled trial where patients were randomized to receive either 800 or 1000–1200 mg of ribavirin, the relapse rate was reduced from 32 to 25% respectively (15). In another study, where patients were randomized to receive either 800 mg of ribavirin or a dose of 800–1600 mg/day based on body weight, a marginal decline in the relapse rate (from 19 to 15%) was also observed in those patients treated with the weight-based dosing regimen (16). The greatest difference in relapse rates was observed in those patients in the highest weight grouping who received twice the ribavirin dose with the variable dosing regimen.
Ribavirin toxicity and the impact of dose deduction
The major limitation of ribavirin it that this agent causes side effects, which significantly impairs the ability of many patients to remain on full doses of this medication (17). Table 1 lists the major adverse events attributed to ribavirin; the most common and significant of these is haemolytic anaemia. Once ribavirin enters the cells, it undergoes repeated phosphorylation to form ribavirin-triphosphate (18). In nucleated cells, dephosphorylation can occur and as the serum ribavirin concentration declines, ribavirin-triphosphate is hydrolysed back to ribavirin and transported out of the cell. In contrast, erythrocytes lack the enzymes to dephosphorylate the triphosphate and as a result the concentrations of ribavirin in red cells exceed that found in plasma by 60-fold. This alters erythrocyte membrane fluidity and leads to extravascular haemolysis of erythrocytes and extraction of these cells from the circulation by the spleen (19). When utilized as monotherapy, a brisk reticulocytosis compensates for this haemolysis and a mean decline in haemoglobin of only 1 g is observed (11). However, interferon and peginterferon suppress this bone marrow response to haemolysis and as a result a significantly greater decline in haemoglobin is observed in patients treated with combination therapy. The mean decline in haemoglobin is 2.5–3 g and nearly 20% of patients show a decline in their haemoglobin by >4 g (20). Anaemia significantly lowers quality of life and exacerbates the fatigue experienced by patients receiving HCV therapy (21). Approximately 20% of patients require that the dose of ribavirin be reduced during treatment and 5% have such a profound anaemia that treatment must be terminated. This typically occurs within the first 8–12 weeks of treatment.
Table 1. Most common adverse events attributed to ribavirin
The impact of ribavirin dose reduction on SVR remains controversial. The initial study to evaluate dose reduction suggested that SVR was reduced in those patients who received <80% of the ideal total cumulative ribavirin dose over 48 weeks of treatment (22). In contrast, a reanalysis of this study, and other studies where the dose reduction analysis was more extensive, have suggested that interrupting ribavirin dosing, not dose reduction, reduces the virological response and increases the risk of breakthrough and relapse (23–25). Although maintaining the maximal ribavirin dose by utilizing erythropoietin has been advocated by some (26, 27), two randomized-controlled trials have demonstrated that the routine use of epoetin-α in lieu of dose reduction does not negatively impact SVR (28, 29).
Time to response and the impact of ribavirin
It has recently been demonstrated that the time at which a patient becomes HCV RNA undetectable during treatment is the most important factor in determining the likelihood that a patient will achieve an SVR. Patients with a rapid virological response, those who become HCV RNA undetectable within the first 4 weeks after initiating treatment, have an SVR rate of approximately 90% (13, 30). These patients are so sensitive to the effects of interferon and become HCV RNA undetectable so quickly that they may not require full-dose ribavirin to maximize SVR (23). For example, patients who achieved a rapid response when treated with peginterferon-α and ribavirin, peginterferon-α monotherapy or standard interferon and ribavirin all had SVR rates of 90% (13). As a result, if a patient with a rapid virological response develops toxicity related to ribavirin, reducing the ribavirin dose is an appropriate manoeuvre (23). In contrast, preserving the ribavirin dose in those patients who become HCV RNA undetectable after week 4 is likely to be more important in reducing relapse and maximizing SVR.
Terabavirin is a ribavirin prodrug that is preferentially taken up by the liver. Inside the hepatocyte, terabavirin is converted to ribavirin by the enzyme adenosine deaminase (31). Ribavirin is then phosphorylated or may diffuse back into the circulation. The entry of ribavirin into red cells is therefore significantly reduced in patients treated with terabavirin compared with ribavirin. As a result, terabavirin is associated with significantly less anaemia than comparable doses of ribavirin (21). In two phase III randomized, controlled clinical trials, patients treated with terabavirin had significantly less anaemia compared with patients treated with ribavirin (32, 33). Unfortunately, the SVR rates for patients treated with terabavirin were also significantly reduced compared with patients who received ribavirin in these studies. However, other data suggest that the dose of terabavirin administered in this study was insufficient and that dosing terabavirin by body weight would yield results that are superior to ribavirin. Studies investigating a weight-based terabavirin dosing regimen are nearing completion.
The role of ribavirin in the era of STAT-C therapy
The future of HCV treatment involves the use of Specifically Targeted Antiviral Therapy against HCV (STAT-C). Several protease and polymerase inhibitors have already been developed and evaluated in clinical trials for this purpose. Many other antiviral compounds are currently under investigation. The addition of a potent protease or a polymerase inhibitor to peginterferon and ribavirin (triple combination therapy) leads to a rapid decline in the serum level of HCV RNA and increases the percentage of patients who achieve both a rapid virological response and an SVR. In preliminary studies, rapid virological response rates in the range of 50–85% and SVR rates of 55–70% have been observed (34–38). These responses are significantly greater than those achieved with peginterferon and ribavirin.
The excellent preliminary responses observed with triple combination therapy have raised the possibility that HCV could possibility be treated with only a protease or a polymerase inhibitor and peginterferon, thereby eliminating the need for ribavirin. This hypothesis has recently been explored in the PROVE* 2 and PROVE 3 studies with the protease inhibitor telaprevir, the results of which have been reported recently (37, 39). These studies have clearly demonstrated the superior efficacy of triple combination therapy in both the treatment-naïve and the retreatment setting. For the current discussion regarding the need for ribavirin, only a portion of these data will be addressed.
In the PROVE 2 study, naïve genotype 1 patients were randomized to one of four treatment groups: (i) peginterferon α-2a (180 mcg/week) and ribavirin (1000–1200 mg/day) for 48 weeks; (ii) peginterferon α-2a, ribavirin and telaprevir (750 mg three times daily) for 12 weeks; (iii) peginterferon α-2a and telaprevir without ribavirin for 12 weeks; and (iv) peginterferon α-2a, ribavirin and telaprevir for 12 weeks, followed by an additional 12 weeks of peginterferon and ribavirin. Patients treated in the ribavirin-free arm (peginterferon α-2a and telaprevir) had a rapid virological response rate that was 20–30% lower and an SVR that was nearly half of that observed in the triple combination therapy arm treated for the same duration (Fig. 3). The SVR rate observed in the ribavirin-free arm was somewhat lower, although not significantly different, than that observed with the standard of care, 48 weeks of peginterferon and ribavirin (46%). The absence of ribavirin yielded a relapse rate of 48%, similar to the relapse rate observed with interferon and peginterferon monotherapy (Fig. 2).
In the PROVE 3 study, genotype 1 patients who previously failed to achieve an SVR following treatment with peginterferon and ribavirin were randomized to 4 treatment groups: (i) peginterferon α-2a (180 mcg/week) and ribavirin (1000–1200 mg/day) for 48 weeks; (ii) peginterferon α-2a, ribavirin and telaprevir (750 mg three times daily) for 24 weeks; (iii) peginterferon α-2a and telaprevir without ribavirin for 24 weeks; and (iv) peginterferon α-2a, ribavirin and telaprevir for 24 weeks, followed by an additional 24 weeks of peginterferon and ribavirin. As in the PROVE 2 study, patients treated in the ribavirin-free arm (peginterferon α-2a and telaprevir) had a rapid virological response rate that was approximately 20% lower and an SVR that was approximately half of that observed in the triple combination therapy arm treated for the same duration (Fig. 3). Patients with prior relapse had an SVR of 73% and those with a prior non-response had an SVR of 41% when treated with triple combination therapy compared with only 46 and 11%, respectively, when treated without ribavirin.
The results of the PROVE studies clearly demonstrate that ribavirin will remain an essential ingredient in the treatment of chronic HCV. Furthermore, and despite a clear understanding of its mechanism of action, ribavirin remains the single most important ingredient in the HCV therapy cocktail to prevent relapse.
Eventually, several protease and polymerase inhibitors will be available for the treatment of chronic HCV. At that time, studies will again explore the possibility that ribavirin could be removed from the cocktail of drugs utilized to treat chronic HCV. Figure 4 illustrates the sequence of development for HCV treatment in the past and a possible scenario for the clinical trials that will be required to determine whether the current backbone of HCV treatment, peginterferon and ribavirin, will be required in the future. The first step will be to determine whether an SVR can be further maximized by adding a fourth drug, a second protease inhibitor or a polymerase inhibitor, to the triple-therapy HCV cocktail. Only after an SVR has been maximized with this approach will studies be initiated to evaluate the possibility that ribavirin and/or peginterferon could be eliminated from the treatment paradigm. The possibility that both peginterferon and ribavirin could be eliminated and that HCV will be treated with only protease and polymerase inhibitors will also be explored. However, given that the ultimate goal when treating HCV is a ‘cure’ and that this will soon be achieved in nearly 75% of patients, it is not likely that prolonged viral suppression of HCV without a ‘cure’ will be an acceptable end point in this disease.
Eliminating ribavirin from HCV treatment in the future is predicated upon the premise that a combination of protease and/or polymerase inhibitors will be equally efficacious and better tolerated than ribavirin. Unfortunately, adverse events have been observed with nearly all the protease or polymerase inhibitors developed to date, and clinical trials of three protease inhibitors have been discontinued because of significant bone marrow, gastrointestinal or hepatic toxicity. Furthermore, based on the results of the PROVE studies and our understanding of the role that ribavirin plays in reducing relapse, it is probably much more likely that interferon could be dropped from the treatment paradigm as opposed to ribavirin. I conclude that the future of ribavirin remains bright and secure.
Conflicts of interest
The author has received grant support from, and acted as a speaker and consultant to Roche and Schering-Plough.
* The PROVE studies of phase 2 clinical trials conducted by Vertex Pharmaceuticals to explore the use of telaprevir in combination with pegintereferon alfa-2a and ribavirin in patients with chronic hepatitis C virus infection.