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Learning objectives

Upon completion of this activity, participants should be able to:

1. Identify outcomes of treatment for chronic hepatitis C virus (HCV) infection.
2. Specify the recommended duration of treatment for chronic HCV infection.
3. Describe how treatment for chronic HCV infection may be altered on the basis of individual patient characteristics.
4. Describe potential new treatments for chronic HCV infection.

Competing interests

The author has declared associations with the following companies/organizations: Debiopharm, Gilead, Human Genome Sciences, Intermune, Novartis, Pharmasset, Roche, Schering-Plough, Tibotec, Vertex, and Wyeth. See the article online for full details of the relationships. The Journal Editor N Wood declared no competing interests. The CME questions author CP Vega declared that he has served as an advisor or consultant to Novartis, Inc.

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HCV genotype and treatment duration

The main baseline predictor of response to therapy is HCV genotype, and genotype is consequently the primary determinant of treatment duration and response monitoring procedures in current treatment recommendations.^{2, 3, 4, 5} Patients infected with HCV genotype 1 or 4 should receive 48 weeks of peginterferon plus RBV, while 24 weeks of treatment is recommended for patients with an HCV genotype 2 or 3 infection.

Data for patients infected with HCV genotypes other than 1–4 were limited or lacking when current treatment guidelines were developed; thus, it is recommended that such individuals are treated in the same way as patients with HCV genotype 1 infections. Data now indicate that this is an appropriate approach; for example, patients infected with HCV genotype 6 have a higher rate of SVR with 48 weeks of treatment than with 24 weeks.¹⁴ The response to treatment in patients infected with HCV genotype 4 seems to be at an intermediate level compared with that of patients infected with HCV genotype 1 or 3.¹⁵

The indicated doses for the two approved peginterferons, peginterferon 2a (180 g once weekly) and peginterferon 2b (1.5 g/kg once weekly), are independent of HCV genotype, but there are different recommendations for RBV dose depending on genotype and body weight.^{16, 17} For patients with an HCV genotype 1 or 4 infection, weight-based RBV doses of 800–1,200 mg per day (1,400 mg per day for patients who weigh >105 kg receiving peginterferon 2b) are recommended. For patients with an HCV genotype 2 or 3 infection the recommended dose of RBV is 800 mg per day, and there is no additional benefit associated with higher doses (at least for the 24-week standard treatment duration).

On-treatment response and treatment duration

Current recommendations for patients infected with HCV genotype 1 or 4 include the week 12 stopping rule. This rule states that if a patient fails to achieve an EVR, consideration should be given to stopping treatment as achieving an SVR is unlikely.¹² Almost all patients with an HCV genotype 2 or 3 infection have an EVR; therefore, recommendations do not suggest measuring HCV RNA at week 12 in these patients but simply treating them for 24 weeks.

Further individualization of therapy—the role of viral response

There is increasing evidence to suggest that current dosing regimens for peginterferon could potentially result in the overtreatment of some patients who respond well to treatment and are more likely to achieve an SVR or, conversely, the undertreatment of those patients who respond less well.¹⁸ Evidence is growing to support the taking of additional measurements of viral response to facilitate individualization of therapy for such patients.

Rapid virological response and shorter treatment duration

The presence of an RVR is the strongest independent positive predictor of the likelihood of achieving an SVR for all HCV genotypes.¹⁹ The rapid response seen in some patients has given rise to the question as to whether such individuals might respond equally well, in terms of SVR, to a shorter treatment duration.

Early studies using conventional IFN-, such as the study by Poynard and co-workers, indicated that patients infected with HCV genotype 1 who had low pretreatment viral loads (2,000,000 copies/ml; 800,000 IU/ml) could be treated for 24 weeks without compromising SVR rates.²⁰ In a study by Zeuzem and colleagues, response rates at the end of treatment with peginterferon 2b plus RBV were similar among HCV genotype 1 infected patients with low baseline viral load (600,000 IU/ml); however, overall SVR rates achieved with 24-week treatment were significantly lower than those observed in historical controls treated for 48 weeks, owing to a high virologic relapse rate in patients treated for 24 weeks.²¹

The study by Zeuzem et al. found that a subset of HCV genotype 1 infected patients with baseline HCV RNA levels below 600,000 IU/ml plus undetectable serum levels of HCV RNA at week 4 of treatment (RVR) had a similar rate of SVR after 24 weeks of therapy to the historical control group treated for 48 weeks (89% and 85%, respectively).²¹ The importance of an RVR in predicting an SVR was confirmed in a retrospective analysis, which showed that HCV genotype 1 infected patients who achieved an RVR when treated with a standard regimen of peginterferon 2a plus RBV (around 24% of patients) were highly likely to achieve an SVR (89% vs 19% for patients with and without an RVR, respectively).²² Baseline viral load was shown to be predictive of an RVR, and patients with baseline HCV RNA levels of 800,000 IU/ml or lower were more likely to achieve an RVR than were those with baseline HCV RNA levels greater than 800,000 IU/ml.²²

Additional evidence supporting the shortening of treatment duration to 24 weeks in patients with low viral loads and an RVR has accumulated not only from studies in patients infected with HCV genotype 1, but also from those in patients infected with HCV genotype 4.^{23, 24} As a result, both peginterferon 2a and peginterferon 2b have been approved in the European Union for a shortened treatment duration of 24 weeks in HCV genotype 1 patients with a low viral load (defined as <800,000 IU/ml for peginterferon 2a and <600,000 IU/ml for peginterferon 2b) and an RVR.^{16, 17}

For patients infected with HCV genotype 2 or 3, the results of several studies have indicated that individuals who achieve an RVR could be candidates for a treatment duration of less than 24 weeks.^{25, 26, 27, 28} Indeed, a number of studies have demonstrated comparable SVR rates with 16 weeks and 24 weeks of treatment in patients who achieve an RVR.^{25, 26, 27, 28} Among patients who had an RVR in the large-scale, randomized, multinational ACCELERATE study, however, the SVR rate was significantly higher in the 24-week treatment group than in the 16-week treatment group (85% vs 79%; P <0.001), although patients who achieved an RVR were more likely to achieve an SVR overall.²⁹ The difference in SVR rates reflects a significantly higher relapse rate in the 16-week treatment group than in the 24-week treatment group (31% vs 18%; P< 0.001). This difference was seen in both patients infected with HCV genotype 2 and those infected with genotype 3.²⁹

It has been suggested that the discrepancy between the results of the ACCELERATE study and those of the other studies might be due to the fact that the ACCELERATE study used a standard 800 mg dose of RBV as opposed to a weight-based RBV dosing regime, which was used in the other studies.^{25, 26, 27, 28} On the other hand, in a trial by Dalgard and colleagues that used higher doses of RBV (800–1,400 mg per day) in HCV genotype 2 or 3 infected patients, the SVR rate was lower among patients who achieved an RVR with 14 weeks of treatment than among those who achieved an RVR with 24 weeks of treatment (81% vs 91%, respectively).³⁰

Baseline HCV RNA level has also been shown to influence SVR rates in patients with an HCV genotype 2 or 3 infection. Patients with low pretreatment serum HCV RNA levels who achieve an RVR have been reported to respond equally well to both 16 weeks and 24 weeks of therapy (SVR rates of 82–100% and 81–100%, respectively).^{25, 26, 27, 29} Given the high SVR rates achievable, the potential to reduce adverse effects, and the economic benefits, shorter treatment might be appropriate for HCV genotype 2 or 3 infected patients who have low baseline HCV RNA levels and achieve an RVR.³⁰

Slow virological response and longer treatment duration

There is increasing evidence to support extending the duration of treatment beyond 48 weeks in patients with an HCV genotype 1 infection who have a slow virological response (i.e. HCV RNA levels >50 IU/ml at week 12, but undetectable [<50 IU/ml] at week 24).^{31, 32, 33, 34} In a study of HCV genotype 1 infected patients treated with peginterferon 2a (180 g once weekly) plus RBV (800 mg per day), extending treatment duration to 72 weeks did not increase the SVR rate in the intention to treat population.³¹ Patients who still had detectable levels of HCV RNA (50 IU/ml) at week 12 according to the results of a sensitive molecular test, however, had a significantly higher SVR rate when treated for 72 weeks than for 48 weeks (29% vs 17%; P = 0.04), with the greatest benefit observed in patients who had HCV RNA levels below 6,000 IU/ml at week 12.³¹ These findings were subsequently confirmed in a study in HCV genotype 1 infected patients who met the criteria for an EVR and had detectable levels of HCV RNA at week 12, but had undetectable levels at week 24. In this trial, 72 weeks of treatment with pegylated interferon 2b plus weight-based dosing of RBV resulted in a better SVR rate than the same treatment for 48 weeks (39% vs 18%).³³

In HCV genotype 1 infected patients who do not achieve an RVR, extending treatment to 72 weeks also significantly increases the SVR rate compared with 48 weeks of therapy; for example, Sánchez-Tapias et al. reported SVR rates of 44% and 28% with 72 weeks and 48 weeks of treatment, respectively (P = 0.003).³² In an analysis of three European studies,^{31, 32, 35} 72 weeks of treatment was found to consistently improve the rates of SVR in patients who had a decline in HCV RNA levels of more than 2 log₁₀ IU/ml but still had detectable levels of HCV RNA at week 12 of treatment (Figure 2).³⁶ Taken together, the available data show that longer duration of therapy improves rates of SVR in 'slow' virological responders infected with HCV genotype 1.

Figure 2 HCV genotype 1 infected patients treated with interferon-based therapy plus RBV who had a partial early virologic response (defined as a >2 log₁₀ drop in HCV RNA levels but levels >50 IU/ml at week 12) and a subsequent SVR.

The three studies consistently show that considerably more patients achieve an SVR with 72 weeks of therapy than with 48 weeks. Data taken from Sánchez-Tapias JM et al. (2007) Hepatol Int 1: 36 [abstract #0-196]. Abbreviations: RBV, ribavirin; SVR, sustained virological response.

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HCV genotype 2 or 3 infected patients who have a high baseline viral load and/or do not achieve an RVR have low SVR rates after peginterferon plus RBV therapy.^{12, 27, 29, 37} High baseline HCV RNA levels (>600,000 IU/ml) are associated with a high rate of virological relapse (23%) in HCV genotype 3 infected patients,³⁷ and data from the ACCELERATE study showed that patients infected with HCV genotype 2 or 3 who did not achieve an RVR had only a 49% probability of achieving an SVR.²⁹ These data raise the question of whether such patients might benefit from more-intensive treatment than is currently used. In a retrospective analysis of data from two large clinical trials, most HCV genotype 2 or 3 infected patients were found to have achieved an RVR; however, among patients without an RVR, the SVR rate was higher and relapse rate lower for those receiving 48-week treatment with higher doses of RBV (1,000–1,200 mg per day) than for those receiving 24-week treatment with a lower dose of RBV (800 mg per day; Figure 3).^{38, 39} These results need to be confirmed in a prospective controlled study, but it is possible that patients with an HCV genotype 2 or 3 infection who do not achieve an RVR could benefit from longer treatment with peginterferon and higher doses of RBV (>800 mg per day).

Figure 3 Intensification of treatment in HCV genotype 2 or 3 infected patients who did not achieve a rapid virological response.

Retrospective analysis of two clinical trials³⁸ showed that the SVR rate was higher and relapse rate lower for patients receiving 48-week treatment with higher doses of RBV than for those receiving 24-week treatment with a lower dose of RBV. Abbreviations: 24W, 24-week treatment; 48W, 48-week treatment; RBV, ribavirin; SVR, sustained virological response.

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A final consideration concerns the assumption that HCV genotype 2 and genotype 3 infections require a similar duration of treatment. Evidence now indicates that this might not be the case. HCV genotype 2 infected patients seem to respond better to therapy and have consistently higher SVR rates than do HCV genotype 3 infected patients, with an overall SVR rate of 80–93% compared with 66–80%, respectively, after treatment for up to 24 weeks.^{25, 27, 30} These differences are also seen following the same duration of treatment in patients who achieved an RVR (SVR rate 87–95% for genotype 2 vs 76–89% for genotype 3).^{25, 27, 30} These findings indicate that separate management algorithms, possibly with a longer treatment duration for HCV genotype 3 infected patients, could be appropriate, and further studies are required to confirm whether this is the case.

Re-treatment of patients

The management of patients with chronic hepatitis C who relapse after treatment (i.e. those who achieve an end of treatment virological response but not an SVR) or who fail to respond to current standard IFN-based therapy presents a particular problem. In patients who relapse after a first treatment course of IFN- alone, combination therapy with IFN- plus RBV has been shown to lead to substantially higher SVR rates than an additional course of IFN- monotherapy.³⁷ In the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial, 18% of patients who did not respond to or had relapsed after treatment with conventional IFN- or conventional IFN- plus RBV had an SVR in response to re-treatment with 48 weeks of peginterferon 2a plus RBV.⁴⁰ Factors associated with an SVR included previous treatment with IFN- monotherapy, infection with HCV genotype 2 or 3, a low serum aspartate aminotransferase to serum alanine aminotransferase (ALT) ratio, and the absence of cirrhosis. Similar findings were reported in the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC-3) trial, with 23% of patients who did not respond or who had relapsed after previous IFN-based treatment achieving an SVR following re-treatment with peginterferon 2b plus RBV.⁴¹

Patients who relapse after treatment with conventional IFN-based regimens often respond to re-treatment with peginterferon plus RBV, with SVR rates of 41–59% being reported.³⁷ Peginterferon plus RBV re-treatment should, therefore, be considered for all patients who have previously responded to a conventional IFN-based regimen and subsequently relapsed.

Re-treatment of nonresponders to IFN- is generally associated with poor SVR rates, especially in HCV genotype 1 infected patients or patients with cirrhosis.³⁷ Evidence now suggests, however, that prolonged re-treatment of nonresponders significantly improves SVR rates. In the Retreatment with Pegasys in Patients Not Responding to Peg-Intron Therapy (REPEAT) study, 72 weeks of treatment produced an overall SVR rate of 16% compared with 8% after 48 weeks of treatment (P = 0.006).⁴² In this study, patients who had undetectable levels of HCV RNA after 12 weeks of treatment were more likely to achieve an SVR after 72 weeks treatment than were those who had detectable levels of HCV RNA (57% vs 4%). These findings indicate that duration of therapy could be pivotal to improving the outcome in nonresponders to IFN-.

Another potential strategy to achieve a response in patients who are unresponsive to the standard of care is to use increased doses of RBV, as described by Lindahl et al. in a small study of previously untreated patients.⁴³ In their study, the authors used high doses of RBV (1,600–3,600 mg per day), tailored to each patient according to an individualized schedule. Although 9 out of 10 patients achieved an SVR, suggesting that this approach is feasible, the use of such high RBV doses was associated with more-frequent and more-serious adverse effects such as anemia.

Even in patients who do not achieve an SVR, IFN-based regimens can reduce hepatic inflammation. Given that progression of fibrosis to cirrhosis is a function of hepatic inflammation, it has been suggested that IFN-based maintenance therapy might slow disease progression.^{44, 45} In addition, although some patients are classified as virological relapsers and/or nonresponders, they might have a biochemical response to treatment (i.e. reduction or normalization of ALT levels). Results from the NIH-sponsored HALT-C trial showed that peginterferon 2a maintenance therapy improved ALT level, HCV viral load, and necroinflammation.⁴⁴ Despite these results, however, there was no long-term effect on the rate of disease progression.⁴⁴ In a similar study that compared the effects of low-dose peginterferon 2b with those of low-dose colchicine (Colchicine Versus PEG-Intron Long Term [COPILOT] study), the rate of bleeding from esophageal varices observed in patients treated with peginterferon 2b for up to 4 years was lower than that in patients who received colchicine.⁴⁵

Guidelines recommend that decisions regarding re-treatment should include consideration of the severity of the underlying liver disease, adherence and/or compliance, tolerance issues, the previous therapy and type of response to it, viral genotype, and other predictive factors for response.²

Protease inhibitors

The first potent and specific inhibitor of NS3-4A serine protease to be tested in a randomized, placebo-controlled pilot study in patients with chronic hepatitis C was ciluprevir (BILN 2061).⁴⁶ In previously untreated patients infected with HCV genotype 1, treatment with ciluprevir for 2 days resulted in viral RNA reductions of 2–3 log₁₀ copies/ml in most patients, thus providing proof of concept that inhibitors of HCV NS3-4A protease are a therapeutic option for patients with chronic hepatitis C. Further clinical development of ciluprevir has been suspended, however, following reports of cardiotoxicity in animal studies.⁴⁶ The NS3-4A protease inhibitors telaprevir⁴⁷ and boceprevir⁴⁸ have since been shown to reduce serum HCV RNA levels when used alone and to produce additive reductions in serum HCV RNA levels when administered with peginterferon plus RBV.

Telaprevir

In a trial by Reesink and co-workers, telaprevir monotherapy for 2 weeks was associated with a median reduction in HCV RNA levels of more than 4 log₁₀ IU/ml in patients with chronic hepatitis C who had a genotype 1 infection.⁴⁷ When used as monotherapy, however, telaprevir has a low barrier against the development of genetic resistance by HCV, which is a potential problem for antiviral agents given the high rate and error-prone nature of HCV replication.⁴⁹

Triple therapy with telaprevir, peginterferon 2a and RBV not only improves antiviral activity, but also significantly reduces the incidence of resistance.^{50, 51} Preliminary data from two phase II trials in HCV genotype 1 infected patients (PROVE 1 and PROVE 2) demonstrated that triple therapy significantly increased the incidence of RVR at week 4 and complete EVR at week 12 compared with peginterferon 2a plus RBV.^{50, 51} Final data presented during the 2008 annual meeting of the European Association for the Study of the Liver showed SVR rates as high as 61% (PROVE 1) and 68% (PROVE 2) in HCV genotype 1 infected patients treated for 12 weeks with the triple therapy regimen followed by 12 weeks of standard-dose peginterferon 2a plus RBV (Figure 4).^{52, 53} The total incidence of adverse events in patients treated with telaprevir, peginterferon 2a and RBV was similar to that in the control group; however, discontinuation because of adverse events was more frequent in the triple therapy arm than in the control arm (9% vs 3%). Gastrointestinal events, rashes (in several cases severe) and anemia were more common in the triple therapy arm than in the standard combination treatment arm.

Figure 4 Proportion of patients infected with HCV genotype 1 who had an SVR (HCV RNA levels <10 IU/ml) in two phase II studies of triple therapy with telaprevir, peginterferon 2a and followed by standard-dose peginterferon 2a plus RBV.^{52, 53}

Abbreviations: RBV, ribavirin; SOC, standrard of care; SVR, sustained virological response.

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Boceprevir

Boceprevir in combination with peginterferon 2b has been compared with either agent alone in patients with an HCV genotype 1 infection who were previous nonresponders to peginterferon-based therapy.⁴⁸ In this three-period crossover trial, patients were randomly allocated to receive, in a random sequence, boceprevir (200 mg or 400 mg every 8 h) as monotherapy for 7 days, peginterferon 2b as monotherapy for 14 days, and boceprevir plus peginterferon 2b combination therapy for 14 days, with a 3-week washout between treatments. Mean maximum changes in HCV RNA levels were highest when patients received combination therapy (-2.45 0.22 log₁₀ IU/ml and -2.88 0.22 log₁₀ IU/ml for peginterferon 2b plus 200 mg and 400 mg boceprevir, respectively) compared with either monotherapy (-1.08 0.22 log₁₀ IU/ml and -1.61 0.21 log₁₀ IU/ml for boceprevir 200 mg and 400 mg, respectively, and -1.08 0.22 log₁₀ IU/ml and -1.26 0.20 log₁₀ IU/ml for peginterferon 2b alone in the 200 mg and 400 mg boceprevir groups, respectively).⁴⁸ A sensitive clonal analysis of HCV quasispecies present in patients treated with boceprevir has revealed that there is selection of different variants of NS3 protease, with different resistance levels to NS3 inhibitors and resistance frequencies proportional to HCV RNA levels.⁵⁴

Boceprevir has also been evaluated in combination with peginterferon 2b with and without RBV, in one instance for 24 weeks or 48 weeks in a phase II dose-ranging study in patients with an HCV genotype 1 infection who were nonresponders to previous treatment with peginterferon plus RBV,⁵⁵ and also in the phase II Serine Protease Inhibitor Therapy-1 (SPRINT-1) study in treatment-naive HCV genotype 1 infected patients.⁵⁶ The virologic response rates in previous nonresponders were generally low in the dose-ranging study.⁵⁵ In the SPRINT study, however, 55% and 57% of previously untreated patients achieved undetectable levels of HCV RNA 12 weeks after the end of 24 weeks of triple therapy with peginterferon 2b, RBV and boceprevir without and with a 4-week lead phase consisting of peginterferon 2b plus RBV alone, respectively.⁵⁶

Polymerase inhibitors

The polymerase inhibitor class of antiviral agents includes nucleoside analogs and non-nucleoside analogs. Nucleoside analogs target the catalytic site of HCV polymerase and inhibit the initiation of HCV RNA transcription and the elongation of the nascent RNA chain. By contrast, non-nucleoside analogs bind to a number of discrete sites on HCV polymerase. Several inhibitors of HCV polymerase have been evaluated in clinical trials, including the nucleoside inhibitors valopicitabine, R1626 and R7128 and the non-nucleoside inhibitors GS-9190, HCV-796 and VCH-759.

Nucleoside analog polymerase inhibitors

In a trial by Zhou and co-workers, patients infected with HCV genotype 1 who were nonresponders to IFN-based antiviral treatment showed a mean reduction in HCV RNA levels of 0.15–1.21 log₁₀ IU/ml after 14 days of treatment with 50–800 mg/day valopicitabine.⁵⁷ When valopicitabine was administered in combination with peginterferon 2b, a decline in HCV RNA levels of 3.75–4.41 log₁₀ IU/ml was reported after 36 weeks of treatment.⁵⁸ Significant gastrointestinal adverse effects were observed in particular at doses above 200 mg/day. Thus, on the basis of the overall risk–benefit profile observed in clinical testing, the clinical development of valopicitabine for the treatment of hepatitis C has been placed on hold.

R1626 is an oral prodrug of the potent and selective nucleoside analog polymerase inhibitor R1479.⁵⁹ In a multiple-dose, dose-ascending, phase I study in previously untreated patients with an HCV genotype 1 infection, 14 days of treatment with twice daily doses of 1,500 mg, 3,000 mg or 4,500 mg R1626 resulted in mean viral load reductions of 1.2 log₁₀ IU/ml, 2.6 log₁₀ IU/ml and 3.7 log₁₀ IU/ml, respectively.⁵⁹ A phase II trial in HCV genotype 1 infected patients showed that triple therapy with R1626, peginterferon 2a and RBV produces a synergistic effect, achieving a more-profound reduction in HCV RNA levels at week 4 of treatment than peginterferon 2a plus RBV (Figure 5).⁶⁰ A total of 81% of patients treated with the triple therapy regimen had undetectable levels of HCV RNA (<50 IU/ml) at week 4 compared with 5% of those treated with the standard regimen of peginterferon 2a plus RBV. Adverse events reported in patients receiving R1626 were mild to moderate, although grade 4 neutropenia was observed in 39 patients (78%) receiving triple therapy and was the main reason for dose reductions.⁶⁰ So far there is no evidence of resistance to R1626 in clinical isolates taken from patients treated with the drug, implying that R1626 has a high genetic barrier to the development of resistance by HCV.⁶¹

Figure 5 HCV RNA levels in patients with HCV genotype 1 infection following 4 weeks of therapy with R1626 and/or PEG-IFN and/or RBV.

Permission obtained from John-Wiley and Sons, Inc. © Pockros PJ et al. (2008) Hepatology 48: 385–397. Abbreviations: PEG-IFN, peginterferon 2a; RBV, ribavirin.

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R7128 is a prodrug of PSI-6130, which is an oral cytidine nucleoside analog. No toxicity has been observed with R7128 in preclinical studies in various human cell lines, including liver cells, bone marrow cells, and white blood cells.⁶² It appears that R7128 is more active at lower concentrations than other such compounds in development.⁶² In preclinical assays, PSI-6130 was found to have additive effects on the activity of IFN- alone.⁶² A phase I trial of R7128 in combination with peginterferon 2a plus RBV is currently underway in treatment-naive patients with an HCV genotype 1 infection.⁶³ Preliminary results showed potent antiviral activity in patients treated with R7128 1,500 mg per day, peginterferon 2a and RBV, with 17 (85%) of 20 patients achieving an RVR.⁶³

Non-nucleoside polymerase inhibitors

HCV-796 is a non-nucleoside inhibitor of the RNA polymerase NS5B. This inhibitor has demonstrated potent antiviral activity, with Villano et al. recording a maximum antiviral effect after 4 days of treatment that resulted in a mean reduction in HCV RNA levels of 1.4 log₁₀ IU/ml; however, an increase in viral load thereafter indicated that resistance might be an issue.⁶⁴ In a study of treatment-naive patients with chronic hepatitis C, the combination of HCV-796 and peginterferon 2b resulted in a mean reduction in viral load of 3.3–3.5 log₁₀ IU/ml after 14 days of treatment compared with 1.6 log₁₀ IU/ml with peginterferon 2b alone; antiviral activity was greatest in patients who had a non-genotype 1 infection.⁶⁴ Safety issues concerning clinically significant elevations of liver enzyme levels in phase II trials have, however, led to the discontinuation of the phase II program.

GS-9190 is another non-nucleoside polymerase inhibitor that has been investigated in a phase I clinical trial in treatment-naive patients with an HCV genotype 1 infection.⁶⁵ Following single-dose exposure (40–480 mg), a maximum antiviral effect was observed at 24 h, with median declines in HCV RNA levels of 0.46–1.49 log₁₀ IU/ml across doses.⁶⁵ An instance of possible QT elongation was observed during a multidose exposure trial and a specific study of the effect of GS-9190 on QT interval in healthy volunteers is underway.

A proof of concept study has also been completed for VCH-759 in treatment-naive HCV genotype 1 infected patients.⁶⁶ Declines in HCV RNA level of 2 log₁₀ IU/ml or more were achieved with 800 mg three times daily over a 10-day dosing period. As has been found with other non-nucleoside polymerase inhibitors, however, selection of mutants conferring drug resistance has been observed in patients treated with VCH-759.⁶⁷

Other inhibitors of HCV

Other inhibitors of HCV in early clinical development include the cyclophilin inhibitor Debio-025,⁶⁸ celgosivir (an oral prodrug of castanospermine that inhibits the enzyme glucosidase in the host),⁶⁹ and nitazoxanide (an oral prodrug of the thiazolide tizoxanide that inhibits HCV replication by an unknown mechanism of action).⁷⁰

Combination therapy with direct antivirals

The high error rate of the RNA polymerase for HCV means that HCV variants are continuously produced during replication, and infected cells thus have the potential to produce multiple drug-resistant mutants over time. The emergence of such mutants could limit the success of HCV-specific antiviral compounds and is, therefore, a highly relevant clinical issue. Experience from the HIV field indicates that combining antiviral agents not only has the potential to improve efficacy, but also, if compounds with different resistance profiles are used, to reduce the risk of developing treatment-resistant mutations of HCV. In vitro studies suggest that combined treatment with a protease inhibitor and a polymerase inhibitor results in more-potent suppression of HCV replication than either drug alone, and could increase the barrier against the development of resistance. For example, Standring et al. found that the combination of the protease inhibitor boceprevir and the nucleoside analog valopicitabine suppressed the emergence of resistance to either drug.⁷¹ A variety of different three-drug combinations have also been shown to have additive or synergistic effects on HCV activity in vitro.⁷² Such combination therapy is still in the very early stages of development, and it will be several years before these in vitro results can be tested in large-scale clinical trials.

Novel anti-HCV agents belonging to all the new classes are being tested in combination with peginterferon , with or without RBV. Viral suppression with such combination therapy has been superior to that with monotherapy in all cases. The combination of an antiviral agent with peginterferon plus RBV seems to reduce the rapid selection of drug-resistant HCV strains—as reported in a study of telaprevir.⁷³ Despite the tremendous potential of the new antiviral agents, many questions remain to be answered regarding their use, especially within the context of the current standard of care. Careful research is required to balance the unmet need of patients on the one hand and the requirements of comprehensive clinical development programs on the other.