Katrien Janssen

Etravirine Has No Effect on QT and Corrected QT Interval in HIV-Negative Volunteers

Background: Etravirine (TMC125), a next-generation nonnucleoside reverse transcriptase inhibitor, has shown antiviral efficacy in 2 large Phase 3 trials. In vitro and in vivo studies have shown that etravirine is not associated with proarrhythmic potential. Electrocardiograms (ECGs) from healthy and HIV 1–infected volunteers showed no clinically relevant changes. Objective: To evaluate the effect of 2 etravirine dosing regimens on QT/corrected QT interval (QTc) in HIV-negative volunteers and assess pharmacokinetic and additional safety parameters. Methods: A double-blind, double-dummy, randomized, placebo- and active-controlled, 4-period crossover trial was conducted in 41 HIV-negative volunteers. Participants received 4 regimens: etravirine 200 mg twice daily, etravirine 400 mg once daily, moxifloxacin 400 mg once daily (positive control), and placebo in separate 8-day sessions, with each followed by a washout period of 14 or more days. On days -1, 1, and 8 of each session, ECGs were recorded at 11 time points over 12 hours. Pharmacokinetic profiles of etravirine regimens were evaluated and safety was assessed. Results: Thirty-seven subjects completed the study. For etravirine, the upper limit of the 90% CIs of mean time-matched differences in QTc determined using Fridericias formula (QTcF) was below 10 msec at all time points, the threshold for prolonged QT as defined by regulatory guidelines. The maximum mean (90% CI) difference of time-matched changes in QTcF versus placebo on day 1 was +0.1 msec (–2.6 to 2.9), -0.2 msec (-2.6 to 2.1), and +10.1 msec (7.3 to 12.8) for etravirine 200 mg twice daily, etravirine 400 mg once daily, and moxifloxacin, respectively. On day 8, these values were +0.6 msec (-2.1 to 3.3), -1.0 msec (-4.4 to 2.5), and +10.3 msec (6.8 to 13.9), respectively. Etravirine produced no clinically significant changes in other ECG parameters. No significant differences between males and females were observed. Both etravirine regimens had similar pharmacokinetic exposure and safety profiles. Conclusions: Etravirine does not prolong the QTc interval. No clinically relevant ECG changes were observed in HIV-negative volunteers. Short-term dosing of etravirine in HIV-negative volunteers was generally safe and well tolerated.

An OPTIMIZE Study Retrospective Analysis for Management of Telaprevir-Treated Hepatitis C Virus (HCV)-Infected Patients by Use of the Abbott RealTime HCV RNA Assay

ABSTRACT Protease inhibitor (PI)-based response-guided triple therapies for hepatitis C virus (HCV) infection are still widely used. Noncirrhotic treatment-naive and prior relapser patients receiving telaprevir-based treatment are eligible for shorter, 24-week total therapy if HCV RNA is undetectable at both weeks 4 and 12. In this study, the concordance in HCV RNA assessments between the Roche High Pure System/Cobas TaqMan and Abbott RealTime HCV RNA assays and the impacts of different HCV RNA cutoffs on treatment outcome were evaluated. A total of 2,629 samples from 663 HCV genotype 1 patients receiving telaprevir/pegylated interferon/ribavirin in OPTIMIZE were analyzed using the High Pure System and reanalyzed using Abbott RealTime (limits of detection, 15.1 IU/ml versus 8.3 IU/ml; limits of quantification, 25 IU/ml versus 12 IU/ml, respectively). Overall, good concordance was observed between the assays. Using undetectable HCV RNA at week 4, 34% of the patients would be eligible for shorter treatment duration with Abbott RealTime versus 72% with the High Pure System. However, using <12 IU/ml for Abbott RealTime, a similar proportion (74%) would be eligible. Of the patients receiving 24-week total therapy, 87% achieved a sustained virologic response with undetectable HCV RNA by the High Pure System or <12 IU/ml by Abbott RealTime; however, 92% of the patients with undetectable HCV RNA by Abbott RealTime achieved a sustained virologic response. Using undetectable HCV RNA as the cutoff, the more sensitive Abbott RealTime assay would identify fewer patients eligible for shorter treatment than the High Pure System. Our data confirm the <12-IU/ml cutoff, as previously established in other studies of the Abbott RealTime assay, to determine eligibility for shortened PI-based HCV treatment. (The study was registered with ClinicalTrials.gov under registration no. NCT01241760.)

Efficacy, safety, and pharmacokinetics of simeprevir, daclatasvir, and ribavirin in patients with recurrent hepatitis C virus genotype 1b infection after orthotopic liver transplantation: The Phase II SATURN study

Recurrent hepatitis C virus (HCV) infection following liver transplantation is associated with accelerated progression to graft failure and reduced patient survival.

Incidence of virological failure and emergence of resistance with twice-daily vs every 8-h administration of telaprevir in the OPTIMIZE study

The OPTIMIZE study demonstrated noninferior efficacy between telaprevir (TVR) twice daily (bid) vs every 8‐h (q8h) administration. This analysis compared the selective pressure of both dosing regimens by characterisation of the hepatitis C virus (HCV) variants emerging in genotype 1 (G1) HCV‐infected patients who did not achieve sustained virological response (SVR). HCV NS3•4A population sequencing was performed at baseline and time of failure (viral breakthrough, stopping rule or relapse). TVR‐resistant variants were classified by fold change in inhibitory concentration (IC50). Baseline TVR‐resistance was low (<5%) and did not preclude achieving SVR in either arm. The proportion of patients with TVR‐resistant variants at time of failure was similar in the bid (15%) and q8h (17%) dosing arms. The majority of variants and virological failures occurred in G1a patients, and mutations V36M, R155K and R155T (G1a), and V36A, T54A and A156S (G1b) were significantly enriched in both treatment arms. The number and type of emerging TVR‐resistant variants in non‐SVR patients were comparable between treatment arms and were consistent with previous observations. No differences in viral resistance profiles were observed between TVR‐based treatment arms in non‐SVR patients, indicating a similar selective pressure of TVR bid and q8h dosing.

Telaprevir combination therapy in HCV/HIV co-infected patients (INSIGHT study): sustained virologic response at 12 weeks final analysis.

We report the SVR12 final analysis of a phase 3 study of telaprevir in combination with peginterferon (P)/ribavirin (R) in HCV‐genotype 1, treatment‐naïve and ‐experienced patients with HCV/HIV co‐infection (INSIGHT).

Telaprevir-based therapy in patients coinfected with chronic hepatitis C virus infection and HIV: INSIGHT study

OBJECTIVES INSIGHT (ClinicalTrials.gov NCT01513941) evaluated the efficacy, safety and pharmacokinetics of telaprevir-based therapy and specific antiretroviral agents in hepatitis C virus genotype 1 (HCV-1)/HIV-1-coinfected patients. PATIENTS AND METHODS Open-label, Phase IIIb, multicentre study of telaprevir with pegylated-IFN (Peg-IFN) α2a and ribavirin in treatment-naive or -experienced HCV-1/HIV-1-coinfected patients on stable HIV HAART comprising efavirenz, atazanavir/ritonavir, darunavir/ritonavir, raltegravir, etravirine or rilpivirine with two nucleos(t)ide analogues. Patients received 750 mg telaprevir (1125 mg, if on efavirenz) every 8 h plus 180 μg/week Peg-IFNα2a and 800 mg/day ribavirin for 12 weeks, followed by Peg-IFNα2a and ribavirin alone for 12 weeks (HCV treatment naive and relapsers without cirrhosis, with extended rapid virological response) or 36 weeks (all others). RESULTS Overall, 162 patients (median age of 46 years, 78% male, 92% Caucasian and mean CD4 count of 687 cells/mm(3)) were treated; 13% had cirrhosis. One-hundred-and-thirty-two patients (81%) completed telaprevir; 14 (9%) discontinued due to an adverse event (AE). Sustained virological response (SVR) 12 rates (<25 IU/mL HCV RNA 12 weeks after the last planned treatment dose) in treatment-naive patients, relapsers and non-responders were 64% (41 of 64), 62% (18 of 29) and 49% (34 of 69), respectively. SVR12 rates ranged from 51% (33 of 65) (patients receiving efavirenz) to 77% (13 of 17) (patients receiving raltegravir). Most frequently reported AEs during telaprevir treatment were pruritus (43%) and rash (34%) special search categories. Anaemia special search category occurred in 15% of patients; 6% of patients reported a serious AE. CONCLUSIONS In treatment-naive/-experienced HCV-1/HIV-1 patients there were significantly higher SVR rates with telaprevir-based therapy compared with pre-specified historical controls, and safety comparable to that in HCV-monoinfected patients.

Virology analyses of HCV genotype 4 isolates from patients treated with simeprevir and peginterferon/ribavirin in the Phase III RESTORE study

Simeprevir is a hepatitis C virus NS3/4A protease inhibitor. Hepatitis C virus baseline NS3/4A polymorphisms and emerging mutations were characterized in treatment‐naїve and treatment‐experienced genotype 4‐infected patients treated with simeprevir+peginterferon/ribavirin in the RESTORE study. Population sequencing of the NS3/4A region was performed and in vitro simeprevir activity against site‐directed mutants or chimeric replicons with patient‐derived NS3 protease sequences was assessed in a transient replicon assay. Simeprevir remained active against most (83/91 [91%]) baseline isolates tested in the chimeric replicon assay. Eight baseline isolates reduced simeprevir activity; these carried I132L or D168E substitutions reducing simeprevir median activity by 4.6‐ and 39‐fold, respectively. Six of these eight isolates were from patients achieving sustained virologic response. Baseline NS3 Q80K polymorphism was not observed in the genotype 4‐infected patients. Of the 107 simeprevir‐treated patients, 37 did not achieve sustained virologic response for any reason. Of the 32 patients who failed treatment and had sequencing information, 28 (88%) had emerging mutations at NS3 positions 80, 122, 155, 156 and/or 168 at time of failure, similar to those in genotype 1. Emerging mutations were mainly D168V and D168E alone or combined with mutations at position 80. In general, isolates obtained at time of failure displayed high‐level in vitro resistance to simeprevir (fold change ≥50) in a chimeric replicon assay with a median simeprevir fold change value of 440, consistent with observed mutations. In conclusion, emerging mutations in genotype 4 patients failing simeprevir+peginterferon/ribavirin treatment were similar to those in genotype 1 and conferred high‐level resistance to simeprevir.

Efficacy of telaprevir-based therapy in stable liver transplant patients with chronic genotype 1 hepatitis C

BACKGROUND AND RATIONALE The REPLACE study (NCT01571583) investigated telaprevir-based triple therapy in patients who have recurrent genotype 1 hepatitis C virus (HCV) infection following liver transplantation and are on a stable immunosuppressant regimen of tacrolimus or cyclosporin A. Patients received telaprevir 750 mg 8-hourly with pegylated interferon 180 μg weekly and ribavirin 600 mg daily, followed by a further 36 weeks of pegylated interferon and ribavirin alone and 24 weeks of follow-up. Efficacy (sustained virological response [SVR] 12 weeks after last planned study dose), safety and tolerability of telaprevir throughout the study were assessed. Pharmacokinetics of telaprevir, tacrolimus and cyclosporin A were also examined. RESULTS In total, 74 patients were recruited. Overall, 72% (53/74; 95% CI: 59.9 to 81.5) of patients achieved SVR at 12 weeks following completion of treatment. Anticipated increases in plasma concentrations of tacrolimus and cyclosporin A occurred during telaprevir treatment and were successfully managed through immunosuppressant dose reduction and, for tacrolimus, reduced dosing frequency. Safety and tolerability of telaprevir-based triple therapy were generally comparable with previous data in non-transplant patients, although rates of reported anemia (55% [41/74]) were higher. Elevated plasma creatinine (46% [34/74]) was observed during REPLACE - consistent with the post-liver transplant population and the co-administered immunosuppressants. CONCLUSION Telaprevir-based triple therapy in patients with recurrent genotype 1 HCV infection following liver transplantation produced high rates of SVR. Therapeutic concentrations of immunosuppressants were maintained successfully through dose modification during telaprevir treatment.