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Gane EJ, Roberts SK, Stedman CA, Angus PW, Ritchie B, Elston R, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2010;376:1467-1475. (Reprinted with permission.).

Abstract

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  2. Abstract
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  4. References

Background: Present interferon-based standard of care treatment for chronic hepatitis C virus (HCV) infection is limited by both efficacy and tolerability. We assessed the safety, tolerability, and antiviral activity of an all-oral combination treatment with two experimental anti-HCV drugs—RG7128, a nucleoside polymerase inhibitor; and danoprevir, an NS3/4A protease inhibitor—in patients with chronic HCV infection.

Methods: Patients from six centres in New Zealand and Australia who were chronically infected with HCV genotype 1 received up to 13 days oral combination treatment with RG7128 (500 mg or 1000 mg twice daily) and danoprevir (100 mg or 200 mg every 8 h or 600 mg or 900 mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or web response system to either active treatment or placebo. Patients were separately randomly assigned within each cohort with a block size that reflected the number of patients in the cohort and the ratio of treatment to placebo. The random allocation schedule was computer generated. Dose escalation was started in HCV treatment-naive patients; standard of care treatment experienced patients, including previous null responders, were enrolled in higher-dose danoprevir cohorts. Investigators, personnel at the study centre, and patients were masked to treatment allocation. However, the pharmacist who prepared the doses, personnel involved in pharmacokinetic sample analyses, statisticians who prepared data summaries, and the clinical pharmacologists who reviewed the data before deciding to initiate dosing in the next cohort were not masked to treatment allocation. The primary outcome was change in HCV RNA concentration from baseline to day 14 in patients who received 13 days of combination treatment. All patients who completed treatment with the study drugs were included in the analyses. This study is registered with ClinicalTrials.gov, NCT00801255.

Findings: 88 patients were randomly assigned to a study drug treatment regimen (n=74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n=14, all of whom received at least one dose). The median change in HCV RNA concentration from baseline to day 14 ranged from −3·7 to −5·2 log(10) IU/mL in the cohorts that received 13 days of combination treatment. At the highest combination doses tested (1000 mg RG7128 and 900 mg danoprevir twice daily), the median change in HCV RNA concentration from baseline to day 14 was −5·1 log(10) IU/mL (IQR −5·6 to −4·7) in treatment-naive patients and −4·9 log(10) IU/mL in previous standard of care null responders (−5·2 to −4·5) compared with an increase of 0·1 log(10) IU/mL in the placebo group. The combination of RG7128 and danoprevir was well tolerated with no treatment-related serious or severe adverse events, no grade 3 or 4 changes in laboratory parameters, and no safety-related treatment discontinuations.

Interpretation: This oral combination of a nucleoside analogue polymerase inhibitor and protease inhibitor holds promise as an interferon-free treatment for chronic HCV.

Comment

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  2. Abstract
  3. Comment
  4. References

Combination therapy with pegylated interferon (Peg-IFN)/ribavirin (RBV) has been the mainstay therapy of chronic hepatitis C virus (HCV) infection for the last decade.1 However, sustained virological response rates (SVR), which range from 40%-80%, vary considerably with HCV genotypes. Genotype 1 is the most common genotype worldwide and has the lowest SVR rates (40%-50%) with 48 weeks of Peg-IFN/RBV therapy.1 However, not all patients are candidates for Peg-IFN/RBV therapies, and the multiple side effects associated with this therapy can be a major factor for lack of patient tolerance and treatment discontinuation. Thus, more effective and better tolerated therapies for individuals infected with genotype 1 are needed.

Over the past decade, predictors of SVR besides genotype have been identified that have allowed refinement of therapy; these include African American and Hispanic race, coinfection with human immunodeficiency virus, insulin resistance, viral level, and the recently identified interleukin-28B (IL-28) polymorphism. In addition to the above factors, the concept of response-guided therapy, whereby treatment duration is based on the rate of viral clearance from the serum during treatment, has allowed tailoring of therapy, allowing shorter duration of therapy in those who clear HCV RNA rapidly at week 4 (rapid virological response).

Identification of the structural and nonstructural (NS) proteins of the hepatitis C genome has led to identification of targets to directly inhibit viral replication. The NS3/4A is a serine protease (NS3) and cofactor (NS4A) that catalyzes the posttranslational processing of NS proteins from the polyprotein that is essential for viral replication.2 The NS3 protease cleaves NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B junctions.2 The products released go on to form a replicative complex responsible for forming viral RNA. Thus, NS3/4A provides an ideal target for antiviral therapy.3, 4 The HCV NS5B RNA-dependent RNA polymerase is a key enzyme involved in HCV replication, catalyzing the synthesis of the complementary minus-strand RNA and subsequent genomic plus-strand RNA from the minus-strand template and is also an ideal target for inhibiting HCV replication. Direct-acting antiviral agents (DAAs) target the HCV-encoded proteins and when added to Peg-IFN/RBV have resulted in improved SVR rates compared to standard of care.5, 6

Telaprevir and boceprevir are two NS3/4a protease inhibitors for which phase 3 trials are nearing completion. In these trials,5-7 telaprevir and boceprevir are both added to Peg-IFN/RBV, with substantial improvement in SVR rates in both treatment-naive patients and prior nonresponders. These agents are associated with additional side effects including anemia, skin rash, and gastrointestinal symptoms. Both telaprevir and boceprevir have been shown to cause rapid selection of resistance-associated variants when given as monotherapy, and neither DAA should be administered without Peg-IFN/RBV.8 Studies with both drugs have shown that optimal doses of RBV are needed to maximize SVR rates and minimize the development of resistance-associated variants. The resistance profile of triple therapy with boceprevir is similar to that of telaprevir in patients who fail to achieve SVR,5 and cross-resistance against other NS3 protease inhibitors may occur.8, 9 These resistant strains have been found to persist after withdrawal of therapy with telaprevir and boceprevir in combination with Peg-IFN/RBV and can persist up to 3 years.8, 9

The INFORM-1 (Interferon-Free regimen for the Management of HCV) trial is the first randomized, double blind, placebo-controlled, dose escalation trial performed in six centers in New Zealand and Australia. This trial was designed to examine the safety of two new direct-acting antiviral drugs: RG7128 and danoprevir. RG7128 is a 3′5′-di-isobutyric acid ester prodrug of the cytosine nucleoside analogue β-D-2′-deoxy-2′-fluoro-2′C-methylcytidine. This compound's triphosphate form inhibits HCV NS5b RNA polymerase. Danoprevir is a macrocyclic inhibitor of HCV NS3/4A protease, which differs from the linear protease inhibitors telaprevir and boceprevir. The addition of RG7128 to danoprevir is an important milestone as the combination of DAAs in the treatment of hepatitis C has the potential to reduce the emergence of resistant associated variants. Moreover, therapies that can be effective in patients with hepatitis C genotype 1 infection without Peg-IFN/RBV will make treatment possible for the many patients who have contraindications to Peg-IFN therapy.

Eighty-eight genotype 1–infected Caucasian patients without cirrhosis who had a minimum HCV RNA of 105 IU/mL were randomized in the INFORM-1 trial, including both treatment-naïve (n = 66) and treatment-experienced patients (n = 22). The group of treatment-experienced patients included those with prior relapse, non-null responders, or null responders (less than 1 log10 IU/mL reduction in HCV RNA concentration after 1 month, or less than 2 log10 IU/mL reduction after 12 weeks). Patients were randomized into nine different treatment groups and placebo, where all groups received therapy with danoprevir and RG7128 in ascending dose combinations for 7-13 days followed by standard therapy with RBV and Peg-IFN, with the highest doses tested being RG7128 at 1000 mg twice daily and danoprevir at 900 mg twice daily. The primary outcome in this study was the change in HCV RNA concentration from baseline to day 14 in patients who received 13 days of combination treatment.

In the highest dose cohorts, five of eight treatment-naive patients and two of eight null responders had HCV RNA concentrations below the limit of detection (<15 IU/mL), and seven of eight treatment-naive patients and four of eight null responders had HCV RNA concentrations below the limit of quantification (43 IU/mL) (Fig. 1). During the treatment period, viral kinetics were biphasic and similar to that of danoprevir with Peg-IFN/RBV, providing proof of concept that SVR can possibly be achieved with an all-oral regimen. Importantly, the drugs were well tolerated with no evidence of treatment-emergent resistance to either compound being identified during the study, and 72 of 73 patients had a continuous decline in viral load throughout dosing. IP-10 is an interferon gamma–inducible protein with chemotactic activity for T lymphocytes, natural killer cells, and monocytes. Null responders with higher IP-10 levels were noted to have reductions in this chemokine during treatment, suggesting that the combination of danoprevir and RG7128 may reduce endogenous activation of interferon.

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Figure 1. Week 13 viral response rates for INFORM-1 cohorts F and G.

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Several new questions raised with the advent of interferon-free regimens will need to be addressed over the next few years. What will be the ideal combination of DAA agents to treat hepatitis C? This study used a nucleoside analogue (NS5b inhibitor) and an NS3 protease inhibitor for 13 days with no resistance noted. Given that the moderately potent nucleoside analogues have a high genetic barrier to resistance, because the resistant strains have markedly impaired replication fitness, the use of RG7128 appears to be a logical backbone to which additional therapies may be added. Danoprevir is a potent NS3 inhibitor with a lower barrier to development of resistance; however, no danoprevir resistance was identified in this study, suggesting that both RG7128 and danoprevir may prevent resistance to the other agent.

Several other potent classes of DAAs are currently being studied for the treatment of hepatitis C including the NS5a inhibitors, non-nucleoside NS5b inhibitors, and cyclophilin inhibitors in combination with Peg-IFN/RBV and in various combinations.10-13 The optimal combination of agents will need to be determined to achieve the highest rate of viral suppression while minimizing toxicity. In addition, the role of RBV in an all-oral regimen will need to be explored. RBV has already been shown to be essential for treatment with telaprevir and boceprevir with interferon, and preliminary studies suggest that RBV will augment the response with all-oral therapy for hepatitis C.5, 6 The authors in the INFORM-1 study speculate that SVR could potentially be achieved with 8-12 weeks of antiviral therapy. Finally, because of differing thresholds of resistance in genotype 1a and 1b, future studies will need to determine if one genotype may be more readily suppressed or treated to SVR with all-oral regimens.

Host factors such as IP-10 levels and the role of IL-28b genotype will also need to be explored in interferon-free regimens. The authors in this study examined IP-10 levels, and a recent publication suggested that the combination of IL-28b genotype and IP-10 levels may be a powerful tool to predict SVR with Peg-IFN/RBV.14

In summary, this landmark study has demonstrated for the first time that the combination of DAA therapies can effectively suppress HCV replication within a 13-day period without Peg-IFN/RBV and provides proof of concept that the combination of DAAs can prevent the emergence of resistance-associated variants over a short treatment period. Moreover, viral suppression was achieved in previous null responder and treatment-naive patients. The final results of therapy with Peg-IFN/RBV will be anticipated eagerly, particularly in previous nonresponders.

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