Tara L. Kieffer

Telaprevir for Previously Untreated Chronic Hepatitis C Virus Infection

BACKGROUND In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. METHODS In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). RESULTS Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. CONCLUSIONS Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.).

Telaprevir and Peginterferon with or without Ribavirin for Chronic HCV Infection

BACKGROUND In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment. METHODS A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups. RESULTS The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia. CONCLUSIONS In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.)

Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients

Telaprevir (VX‐950) is an orally active, specifically targeted antiviral therapy for hepatitis C virus (HCV) that has been shown to profoundly reduce plasma HCV RNA in genotype 1 patients. Using a highly sensitive sequencing assay that detects minor populations of viral variants (≥5%), mutations were identified that conferred low‐level (V36M/A, T54A, or R155K/T) or high‐level (A156V/T and 36/155) resistance to telaprevir in vitro. We report a detailed kinetic analysis of these variants in 16 patients given telaprevir or telaprevir + pegylated interferon–alpha‐2a (PEG‐IFN–alpha‐2a) for 14 days. In 4 patients who had a viral rebound on telaprevir alone, the R155K/T and A156V/T variants were detected during the initial steep decline in HCV RNA. During the rebound phase, the R155K/T and A156V/T variants were replaced by V36(M/A)/R155(K/T) double mutant variants. In the remaining 12 patients given telaprevir alone or with telaprevir/PEG‐IFN–alpha‐2a, the A156V/T variant was detected in some patients, but viral levels continued to decline in all patients. Conclusion: These studies suggest that the initial antiviral response to telaprevir is due to a sharp reduction in wild‐type virus, which uncovers pre‐existing telaprevir‐resistant variants. In patients given telaprevir alone, viral rebound can result from the selection of variants with greater fitness. However, the combination of telaprevir and PEG‐IFN–alpha‐2a inhibited both wild‐type and resistant variants. In the present study, every patient who began PEG‐IFN–alpha‐2a and ribavirin after the 14‐day dosing period had undetectable HCV RNA levels at 24 weeks, indicating that telaprevir‐resistant variants are sensitive to PEG‐IFN–alpha‐2a and ribavirin. (HEPATOLOGY 2007.)

Antiviral activity of telaprevir (VX‐950) and peginterferon alfa‐2a in patients with hepatitis C

Telaprevir (VX‐950), an inhibitor of the hepatitis C virus (HCV) NS3/4A protease, substantially decreased plasma HCV RNA levels in a prior clinical study. The present study evaluated viral kinetics and safety during dosing with telaprevir alone and in combination with peginterferon alfa‐2a for 14 days. Previously untreated patients with genotype 1 hepatitis C were randomized to receive placebo and peginterferon alfa‐2a (n = 4); telaprevir (n = 8); or telaprevir and peginterferon alfa‐2a (n = 8). Telaprevir was given as 750 mg oral doses every 8 hours; peginterferon alfa‐2a was given as weekly 180 μg subcutaneous injections. The median change in HCV RNA from baseline to day 15 was −1.09 log10 (range, −2.08 to −0.46) in the placebo and peginterferon alfa‐2a group; −3.99 log10 (range, −5.28 to −1.26) in the telaprevir group, and −5.49 log10 (range, −6.54 to −4.30) in the telaprevir and peginterferon alfa‐2a group. Day 15 HCV RNA levels were undetectable in 4 patients who received telaprevir and peginterferon alfa‐2a and in 1 patient who received telaprevir alone. No viral breakthrough occurred in patients who received telaprevir and peginterferon alfa‐2a. The majority of adverse events were mild. There were no serious adverse events or premature discontinuations. Twelve weeks after starting off‐study standard therapy, HCV RNA was undetectable in all 8 patients in the telaprevir and peginterferon alfa‐2a group, 5 patients in the telaprevir group, and 1 patient in the placebo and peginterferon alfa‐2a group. Conclusion: This study confirmed the substantial antiviral effects of telaprevir and showed an increased antiviral effect of telaprevir combined with peginterferon alfa‐2a. (HEPATOLOGY 2007;46:640–648.)

Natural Prevalence of Hepatitis C Virus Variants with Decreased Sensitivity to NS3·4A Protease Inhibitors in Treatment-Naive Subjects

BACKGROUND The prevalence and clinical implications of naturally occurring variants that are resistant to hepatitis C virus (HCV) protease inhibitors in treatment-naive patients has not been reported. We report here the prevalence of such variants and their effect on clinical response. METHODS Population sequence analysis of the NS3.4A protease was conducted in 570 treatment-naive subjects. RESULTS Most subjects (98%) had wild-type virus. The remaining subjects had the following variants present in significant proportions (100%): V36M, 0.9%; R155K, 0.7%; V170A, 0.2%; and R109K, 0.2%. The V36M, R109K, and V170A substitutions confer low-level resistance (<7-fold) to protease inhibitors in replicon cells. The R155K substitution confers low-level resistance to telaprevir (TVR) and boceprevir and confers high-level resistance (>70-fold) to BILN 2061 and ITMN-191. Five subjects with the V36M or R109K variant were treated with 8-24 weeks of TVR and peginterferon-alpha2a (P) with or without ribavirin (R). Four achieved a sustained viral response, and 1 was lost to follow-up. In subjects with the R155K variant, TVR/PR provided greater antiviral activity than PR alone; however, the antiviral response was lower than that observed in subjects with wild-type virus. CONCLUSION High levels of naturally occurring protease inhibitor-resistant variants were uncommon (<1% each) in HCV treatment-naive patients. TVR/PR efficiently inhibited V36M and R109K variants and contributed partial antiviral activity against the R155K variant. As new HCV agents are evaluated in clinical trials, it will be important to monitor the effect of baseline variants on sensitivity.

Hepatitis C virus drug resistance-associated substitutions: State of the art summary.

Hepatitis C virus (HCV) drug development has resulted in treatment regimens composed of interferon‐free, all‐oral combinations of direct‐acting antivirals. While the new regimens are potent and highly efficacious, the full clinical impact of HCV drug resistance, its implications for retreatment, and the potential role of baseline resistance testing remain critical research and clinical questions. In this report, we discuss the viral proteins targeted by HCV direct‐acting antivirals and summarize clinically relevant resistance data for compounds that have been approved or are currently in phase 3 clinical trials. Conclusion: This report provides a comprehensive, systematic review of all resistance information available from sponsors’ trials as a tool to inform the HCV drug development field. (Hepatology 2015;62:1623–1632)

Antiviral effects and safety of telaprevir, peginterferon alfa-2a, and ribavirin for 28 days in hepatitis C patients.

BACKGROUND/AIMS This study assessed the safety and antiviral effects of telaprevir (VX-950) in combination with peginterferon alfa-2a and ribavirin. METHODS Twelve treatment-naïve patients with chronic genotype 1 hepatitis C virus infection received telaprevir (750 mg q8h), peginterferon alfa-2a (180 microg/week), and ribavirin (1000 or 1200 mg/day) for 28 days. Patients could then start off-study treatment with peginterferon alfa-2a and ribavirin for up to 44 weeks, at the discretion of the investigator and patient. RESULTS The combination of telaprevir, peginterferon alfa-2a, and ribavirin was well tolerated, with no serious adverse events or treatment discontinuations. Rash or pruritus occurred in 5 of the 12 patients; all cases resolved either during or after the end of telaprevir treatment. All 12 patients had undetectable HCV RNA levels by day 28 (rapid viral response, RVR). Eight patients completed 44 weeks of off-study peginterferon alfa-2a and ribavirin treatment. Eight patients achieved a sustained viral response (SVR), including one patient who received only 22 weeks of treatment. CONCLUSIONS The combination of telaprevir, peginterferon alfa-2a, and ribavirin was generally well tolerated. Events of pruritus and rash resolved during or after end of telaprevir dosing. All 12 patients achieved an RVR.

Hepatitis C virus variants

HBV replicates through reverse transcription of an RNA intermediate; the inherent lack of proofreading causes a high mutation frequency. Mutations in the precore and core promoter regions that abolish or reduce the production of hepatitis B e antigen occur most commonly. Patients with these HBV variants remain viremic and can develop progressive liver disease. Mutations in the core promoter region are associated with an increased risk of hepatocellular carcinoma. Exogenous selection pressure might favor certain mutations. Mutations in the HBV polymerase that confer resistance to nucleoside and nucleotide analog treatments are a major barrier to the success of therapy for hepatitis B. The development of antiviral drug resistance negates the initial treatment response and can lead to hepatitis flares and hepatic decompensation. Prompt addition of another drug to which the virus is not cross-resistant is required. Mutations in the HBV surface protein that facilitate escape from host immunity are responsible for the failure of immune prophylaxis in infants who received HBV vaccine and in liver transplant recipients who received hepatitis B immune globulin.

Evolution of Treatment-Emergent Resistant Variants in Telaprevir Phase 3 Clinical Trials

BACKGROUND Telaprevir (TVR), a hepatitis C virus (HCV) NS3/4A protease inhibitor, has been approved to treat genotype 1 HCV. To understand the clinical impact of TVR-resistant variants, we analyzed samples from patients in phase 3 clinical trials to determine the frequency and retention of TVR-resistant variants in patients who did not achieve sustained virologic response (SVR). METHODS A total of 1797 patients were treated with TVR. Resistant variants (V36A/G/I/L/M, T54A/S, I132V [subtype 1a only], R155G/K/T/M, A156F/N/S/T/V, and D168N) were identified after treatment failure and at visits thereafter, by direct (population) sequencing of the NS3/4A region. Kaplan-Meier analysis was used to determine median time to loss of these variants. RESULTS Resistant variants were observed in 77% (299/388) of patients who did not achieve SVR. Resistance occurred more commonly in subtype 1a (86%; 232/269) than subtype 1b infections (56%; 67/119). After treatment failure, 355 patients had at least 1 follow-up visit (median follow-up period: 9.6 months). Of patients with resistance at time of failure and at least 1 follow-up visit, 60% (153/254) lost resistance. Kaplan-Meier analysis, including all patients with any sequence data after treatment failure, indicated that median time to wild type was 10.6 months (95% confidence interval [CI], 9.47-12.20) in subtype 1a and 0.9 months (95% CI, 0.00-2.07) in subtype 1b infections. CONCLUSIONS After failure to achieve SVR with TVR-based treatment, resistant variants are observed in most patients. However, presumably due to the lower fitness of those variants, they tend to be replaced with wild-type virus over time.

Viral resistance to specifically targeted antiviral therapies for hepatitis C (STAT-Cs)

Promising results have been observed with an investigational drug class for hepatitis C (HCV), the specifically targeted antiviral therapies for hepatitis C (STAT-Cs), when combined with peginterferon plus ribavirin (Peg-IFN/RBV). This class has the potential to increase sustained virological response (SVR) rates and reduce therapy duration in genotype 1 chronic HCV patients compared with Peg-IFN/RBV alone. However, because of the remarkable sequence variation in HCV (resulting from the high viral replication rate and intrinsically error-prone nature of HCV polymerase), variants with reduced susceptibility to STAT-Cs can occur naturally before treatment, usually at low levels, and can be selected in patients not responding to potent STAT-C treatment. This review first describes how resistance to a STAT-C can develop and then provides an overview of mutations that confer varying levels of resistance to STAT-Cs, which have been identified and characterized using both genotypic and phenotypic tools. We will discuss why an understanding of the selection of variants with reduced susceptibility to a treatment regimen may be important in optimizing the use of this new class of HCV therapy. Strategies for optimizing treatment regimens to increase response rates, and thereby minimize resistance, will be discussed. Finally, although resistance can be a consequence of not achieving an SVR on an initial regimen, there may be alternative treatment options for patients to achieve an SVR in the future. Future potential therapeutic strategies to address patients who do develop resistance to STAT-Cs are discussed, including combination therapy with multiple STAT-Cs with non-overlapping resistance profiles.