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Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection. In QUEST-1, a phase 3, randomised, double-blind multicentre trial undertaken in 13 countries (Australia, Europe, North America, Puerto Rico, and New Zealand), 394 patients (aged ≥18 years) with chronic HCV genotype 1 infection and no history of HCV treatment, stratified by HCV subtype and host IL28B genotype, were randomly assigned in a 2:1 ratio with a computer-generated allocation sequence to receive simeprevir (150 mg once daily, orally) plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (simeprevir group), or placebo orally plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (placebo group). Treatment duration was 24 weeks or 48 weeks in the simeprevir group according to criteria for response-guided therapy (ie, HCV RNA <25 IU/mL [undetectable or detectable] at week 4 and <25 IU/mL undetectable at week 12) and 48 weeks in the placebo group. Patients, study personnel, and the sponsor were masked to the treatment group assignment. The primary efficacy endpoint was sustained virological response 12 weeks after the planned end of treatment (SVR12) and was assessed with an intention-to-treat analysis. The results of the primary analysis (week 60) are presented for safety and SVR12. This trial is registered with ClinicalTrials.gov, number NCT01289782. Treatment with simeprevir, peginterferon alfa 2a, and ribavirin was superior to placebo, peginterferon alfa 2a, and ribavirin (SVR12 in 210 [80%] patients of 264 vs 65 [50%] of 130, respectively, adjusted difference 29·3% [95% CI 20·1–38·6; p<0·0001). Adverse events in the first 12 weeks of treatment led to discontinuation of simeprevir in two (<1%) patients and discontinuation of placebo in one patient (<1%); fatigue (106 [40%] vs 49 [38%] patients, respectively) and headache (81 [31%] vs 48 [37%], respectively) were the most common adverse events. The prevalences of anaemia (42 [16%] vs 14 [11%], respectively) and rash (72 [27%] vs 33 [25%]) were similar in the simeprevir and placebo groups. Addition of simeprevir did not increase severity of patient-reported fatigue and functioning limitations, but shortened their duration. Simeprevir once daily with peginterferon alfa 2a and ribavirin shortens therapy in treatment-naive patients with HCV genotype 1 infection without worsening the adverse event profiles associated with peginterferon alfa 2a plus ribavirin. Janssen Infectious Diseases–Diagnostics.

Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerability of the combination of simeprevir, a one-pill, once-daily, oral HCV NS3/4A protease inhibitor versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin was assessed in treatment-naive patients with HCV genotype 1 infection. In the QUEST-2, phase 3 study, done at 76 sites in 14 countries (Europe, and North and South Americas), patients with confirmed chronic HCV genotype 1 infection and no history of HCV treatment were randomly assigned with a computer-generated allocation sequence in a ratio of 2:1 and stratified by HCV genotype 1 subtype and host IL28B genotype to receive simeprevir (150 mg once daily, orally), peginterferon alfa 2a (180 μg once weekly, subcutaneous injection) or 2b (according to bodyweight; 50 μg, 80 μg, 100 μg, 120 μg, or 150 μg once weekly, subcutaneous injection), plus ribavirin (1000–1200 mg/day or 800–1400 mg/day, orally; simeprevir group) or placebo (once daily, orally), peginterferon alfa 2a or 2b, plus ribavirin (placebo group) for 12 weeks, followed by just peginterferon alfa 2a or 2b plus ribavirin. Total treatment duration was 24 weeks or 48 weeks (simeprevir group) based on criteria for response-guided therapy (ie, HCV RNA <25 IU/mL undetectable or detectable at week 4 and undetectable week 12) or 48 weeks (placebo). Patients, study personnel, and the sponsor were masked to treatment assignment. The primary efficacy endpoint was sustained virological response at 12 weeks after the planned end of treatment (SVR12). Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01290679. Results from the primary (SVR12, week 60) analysis are presented. 209 (81%) of 257 patients in the simeprevir group and 67 (50%) of 134 in the placebo group had SVR12 (adjusted difference 32·2%, 95% CI 23·3–41·2; p<0·0001). The incidences of adverse events were similar in the simeprevir and placebo groups at 12 weeks (246 [96%] vs 130 [97%]) and for the entire treatment (249 [97%] vs 132 [99%]), irrespective of the peginterferon alfa used. The most common adverse events were headache, fatigue, pyrexia, and influenza-like illness at 12 weeks (95 [37%) vs 45 [34%], 89 [35%] vs 52 [39%], 78 [30%] vs 48 [36%], and 66 [26%] vs 34 [25%], respectively) and for the entire treatment (100 [39%] vs 49 [37%], 94 [37%] vs 56 [42%], 79 [31%] vs 53 [40%], and 66 [26%] vs 35 [26%], respectively). Rash and photosensitivity frequencies were higher in the simeprevir group than in the placebo group (61 [24%] vs 15 [11%] and ten [4%] vs one [<1%], respectively). There was no difference in the prevalence of anaemia between the simeprevir and placebo groups (35 [14%] vs 21 [16%], respectively, at 12 weeks, and 53 [21%] vs 37 [28%], respectively, during the entire treatment). Addition of simeprevir to either peginterferon alfa 2a or peginterferon alfa 2b plus ribavirin improved SVR in treatment-naive patients with HCV genotype 1 infection, without worsening the known adverse events associated with peginterferon alfa plus ribavirin. Janssen Infectious Diseases–Diagnostics.

Antiretroviral agents active against drug-resistant HIV-1 are needed for treatment-experienced patients. The aim of this trial was to assess the efficacy, safety, and tolerability of TMC125 (etravirine), a non-nucleoside reverse transcriptase inhibitor (NNRTI). DUET-1 is a continuing, multinational randomised, double-blind, placebo-controlled, phase III trial. Treatment-experienced adult patients with virological failure on stable antiretroviral therapy, documented genotypic evidence of NNRTI resistance, viral load over 5000 copies per mL, and three or more primary protease inhibitor mutations were randomly assigned to receive 200 mg TMC125 or placebo twice daily. All patients also received darunavir with low-dose ritonavir and investigator-selected nucleoside reverse transcriptase inhibitors. Enfuvirtide use was optional. The primary endpoint was a confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, with the number NCT00254046. 612 patients were randomised and treated (304 in the TMC125 group, 308 in the placebo group). By week 24, 42 (14%) patients in the TMC125 group and 56 (18%) in the placebo group had discontinued, mainly due to virological failure. At week 24, 170 (56%) patients in the TMC125 group and 119 (39%) patients in the placebo group achieved a confirmed viral load of less than 50 copies per mL (difference in response rates 17%; 95% CI 9–25; p=0·005). Most adverse events were mild or moderate in severity. The type and incidence of adverse events, including neuropsychiatric events, seen with TMC125 were generally comparable with placebo, with the exception of rash (61 [20%] patients on TMC125 vs 30 [10%] on placebo) and diarrhoea (36 [12%] patients on TMC125 vs 63 [20%] on placebo). In treatment-experienced patients with NNRTI resistance, treatment with TMC125 achieved better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.

TMC125 (etravirine) is a non-nucleoside reverse-transcriptase inhibitor (NNRTI) with activity against NNRTI-resistant HIV-1 in phase IIb trials. The aim of DUET-2 is to examine the efficacy, tolerability, and safety of TMC125 in treatment-experienced patients. In this continuing randomised, double-blind, placebo-controlled, phase III trial, HIV-1-infected patients on failing antiretroviral therapy with evidence of resistance to currently available NNRTIs and at least three primary protease inhibitor mutations were eligible for enrolment if on stable (8 weeks unchanged) antiretroviral therapy with plasma HIV-1 RNA greater than 5000 copies per mL. Patients were randomly assigned to receive either TMC125 (200 mg) or placebo, each given twice daily with darunavir-ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors, and optional enfuvirtide. The primary endpoint was the proportion of patients with confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00255099. 591 patients were randomised and treated (295 patients in the TMC125 group and 296 in the placebo group). By week 24, 51 (17%) patients in the TMC125 group and 73 (25%) in the placebo group had discontinued, mainly because of virological failure. 183 (62%) patients in the TMC125 group and 129 (44%) in the placebo group achieved confirmed viral load below 50 copies per mL at week 24 (difference 18%, 95% CI 11–26; p=0·0003). The type and frequency of adverse events were much the same in the two groups. In treatment-experienced patients, treatment with TMC125 led to better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.

Background. Etravirine (ETR; also known as TMC125) is a new nonnucleoside reverse-transcriptase inhibitor with activity against wild-type and nonnucleoside reverse-transcriptase inhibitor–resistant human immunodeficiency virus type 1 (HIV-1). Methods. This randomized, phase IIb, placebo-controlled, 2-stage, dose-escalating trial evaluated the safety, tolerability, and preliminary efficacy of 3 twice-daily doses of ETR (experimental formulation TF035; compared with placebo), administered with an individually optimized background regimen, in treatment-experienced HIV-1–infected patients. In stage 1 of the trial, 166 patients received ETR (400 mg or 800 mg twice daily) or placebo. In stage 2 of the trial, 74 patients received ETR (800 mg or 1200 mg twice daily) or placebo. The primary objective was to assess the safety and tolerability of the regimens over 48 weeks. Results. Neuropsychiatric adverse events (AEs) of interest occurred in 46.6% of patients in the combined ETR group and in 45.5% of patients in the combined placebo group (P=.89). Clinically relevant hepatic AEs occurred in 3.4% of patients who received ETR and in 6.1% of patients who received placebo (P=.47), and rash occurred in 19.5% and 12.1%, respectively (P=.25). In general, there was no evidence of a relationship between ETR dose and specific AEs. Most AEs were severity grade 1 or 2; the incidence of grade 3 or 4 AEs was comparable between groups (27.0% in the combined ETR group vs. 27.3% in the placebo group). Plasma preparation tubes were used for viral load measurement. In stage 1, there was no statistically significant difference in efficacy between ETR and placebo. In stage 2, the decrease in log10 plasma viral load between baseline and week 24 was statistically significantly greater in patients who received ETR, compared with patients who received placebo; a trend in favor of ETR persisted until week 48. Conclusions. ETR was generally safe and well tolerated during long-term administration in treatment-experienced, HIV-1–infected patients, and it had a safety profile comparable to that of placebo.

Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy. Simeprevir is metabolized by the cytochrome P450 (CYP) system, primarily CYP3A, and is a substrate for several drug transporters, including the organic anion transporting polypeptides (OATPs). It is susceptible to metabolic drug–drug interactions with drugs that are moderate or strong CYP3A inhibitors (e.g. ritonavir and erythromycin) or CYP3A inducers (e.g. rifampin and efavirenz); coadministration of these drugs may increase or decrease plasma concentrations of simeprevir, respectively, and should be avoided. Clinical studies have shown that simeprevir is a mild inhibitor of CYP1A2 and intestinal CYP3A but does not inhibit hepatic CYP3A. The effects of simeprevir on these enzymes are of clinical relevance only for narrow-therapeutic-index drugs that are metabolized solely by these enzymes (e.g. oral midazolam). Simeprevir does not have a clinically relevant effect on the pharmacokinetics of rilpivirine, tacrolimus, oral contraceptives and several other drugs metabolized by CYP enzymes. Simeprevir is a substrate and inhibitor of the transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and OATP1B1/3. Cyclosporine is an inhibitor of OATP1B1/3, BCRP and P-gp, and a mild inhibitor of CYP3A; cyclosporine causes a significant increase in simeprevir plasma concentrations, and coadministration is not recommended. Clinical studies have demonstrated increases in coadministered drug concentrations for drugs that are substrates of the OATP1B1/3, BRCP (e.g. rosuvastatin) and P-gp (e.g. digoxin) transporters; these drugs should be administered with dose titration and or/close monitoring.

Background: Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against both wild-type HIV and viruses harboring NNRTI resistance. Etravirine is mainly eliminated via the hepatobiliary route. Objectives: This study in HIV− patients with mild or moderate hepatic impairment and healthy matched controls was conducted to explore the effects of mild and moderate hepatic impairment on the steady-state pharmacokinetics of etravirine and to provide guidance for the treatment of HIV+ patients with hepatic impairment. Methods: This open-label, multiple-dose study enrolled HIV− patients aged 18 to 65 years with mild or moderate hepatic impairment (Child-Pugh score, 5–6 or 7–9, respectively) and healthy volunteers matched for age, sex, race, and body mass index (BMI). All subjects received etravirine 200 mg BID with food for 7 days and a morning dose on day 8. Etravirine pharmacokinetics over a period of 12 hours on days 1 and 8 were determined using noncompartmental methods and analyzed using linear mixed-effects modeling. Tolerability of etravirine was assessed based on the reported adverse events, laboratory investigations, ECG, and physical examination. Results: Each group comprised 8 subjects (mild hepatic impairment patients: 5 men, 3 women; median age, 57 years [range, 41–65 years]; BMI, 26 kg/m 2 [range, 20–32 kg/m 2]; moderate hepatic impairment patients: 6 men, 2 women; age, 54 years [range, 44–64 years]; BMI, 26 kg/m 2 [range, 22–32 kg/m 2]). All patients were white and light smokers. On day 8, the least squares mean ratios (90% CIs) of the logtransformed pharmacokinetic properties in patients with mild and moderate hepatic impairment were, respectively: C min, 0.87 (0.65–1.17) and 0.98 (0.68–1.42) μg/mL; C max, 0.79 (0.63–1.00) and 0.72 (0.54–0.96) ug/mL; and AUC 0–12, 0.87 (0.69–1.09) and 0.82 (0.60–1.11) μg/mL/h. All treatment-emergent adverse events were considered mild to moderate; the most common were headache (50% in healthy controls) and fatigue and nausea (both 25% in patients with mild hepatic impairment). No clinically significant changes in laboratory parameters, physical examination including vital signs, or ECG were observed. One serious adverse event was reported during the follow-up period in a patient with moderate hepatic impairment due to hepatic cirrhosis secondary to alcoholism. This patient presented at screening with dilated cardiomyopathy and cardiac arrhythmia. Conclusions: In this Phase I pharmacokinetic study, no clinically relevant differences were observed between patients with mild or moderate hepatic impairment and healthy matched subjects with regard to the pharmacokinetics of etravirine. Based on these findings in these HIV− volunteers, no dose adjustment of etravirine appears to be necessary in patients with mild or moderate hepatic impairment. Etravirine was generally well tolerated.

Background Fatigue is a common symptom of chronic hepatitis C virus (cHCV) infection and a common side effect of interferon-based treatment for cHCV. This study provides confirmatory evidence of the reliability and validity of the Fatigue Severity Scale (FSS) to document fatigue in cHCV research and identifies values that indicate clinically important differences in FSS to aid in interpreting fatigue in cHCV clinical trials. Methods The study used data from two double-blind, randomized, placebo-controlled, Phase IIb trials evaluating the efficacy and safety of simeprevir plus peginterferon-α/ribavirin in treatment-naïve (PILLAR, n = 386) and treatment-experienced patients (ASPIRE, n = 462) with cHCV infection. Patients completed the FSS and EuroQoL 5 dimension questionnaire (EQ-5D) at baseline and at regular intervals throughout both trials. Reliability was assessed using Cronbach’s coefficient α at Week 24 (internal consistency reliability) and intraclass correlation (ICC) between FSS at Weeks 12 and 24 in stable patients (<0.5 g/dL hemoglobin [Hb] change between Weeks 12/24). Correlation with the EQ-5D visual analog scale (VAS) and “Usual Activity” domain score was used to assess concurrent validity. Clinical validity was evaluated using a case-control method to link spontaneously reported fatigue and anemia adverse events (AEs) during the study to FSS scores. Results FSS total scores demonstrated good reliability (Cronbach’s α: 0.95, 0.96; ICC: 0.74, 0.86 for PILLAR and ASPIRE, respectively) and concurrent validity (correlation with EQ-5D VAS: -0.63, -0.66) with a monotonic relationship between the EQ-5D “Usual Activities” item response and FSS. Clinical validity was confirmed by a significant difference between cases and controls for fatigue AEs (p < 0.05); however, anemia defined by AE or Hb abnormalities was only weakly related to FSS score. Analyses indicate that a change of 0.33–0.82 in mean FSS scores represents a meaningful improvement in fatigue, and a one-point change is a conservative indicator of an important change in individual FSS scores. Conclusion A difference of ≥0.7 in mean FSS scores can be considered a clinically important difference within groups over time or between groups. A one-point change or less in individual FSS scores indicates a clinically relevant change in fatigue.

Background. Simeprevir is an oral, once-daily, hepatitis C virus (HCV) NS3/4A protease inhibitor for the treatment of chronic HCV genotype 1 infection. Human immunodeficiency virus (HIV) coinfection accelerates progression of liver disease. This uncontrolled, open-label trial explored the safety and efficacy of simeprevir in patients with HCV genotype 1/HIV type 1 (HIV-1) coinfection. Methods. Patients received simeprevir (150 mg once daily) with pegylated interferon alfa-2a/ribavirin (peg-IFN/RBV) for 12 weeks. Noncirrhotic HCV treatment-naive patients and prior relapsers received responseguided therapy (RGT) with peg-IFN/RBV for 24 or 48 weeks. Prior null responders, prior partial responders, and patients with cirrhosis received peg-IFN/RBV for 48 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Results. One hundred and six patients (93 on antiretroviral therapy) were enrolled and treated. SVR12 rates were 79.2% in HCV treatment-naive patients, 57.1% in prior null responders, 86.7% in prior relapsers, and 70.0% in prior partial responders. Fifty-four of 61 eligible patients (88.5%) met RGT criteria for 24 weeks of peg-IFN/RBV, of whom 87.0% (47/54) achieved SVR12. SVR12 rates were 80.0% (36/45) and 63.6% (14/22) for patients with METAVIR scores of F0-F2 and F3-F4, respectively. Common adverse event (AE) rates were consistent with peg-IFN/RBV therapy (fatigue, headache, nausea, neutropenia). Most AEs were grade 1/2; serious AEs occurred in 5.7% of patients, none of which were fatal. Conclusions. Simeprevir was generally well tolerated with safety similar to that observed in HCV-monoinfected patients and high SVR12 rates in HCV treatment-naive patients, prior relapsers, prior partial responders, and prior null responders with HIV-1 coinfection.

Background Simeprevir is a N3/4 protease inhibitor approved for the treatment of hepatitis C virus (HCV) infection. HCV prevalence is higher in patients with chronic kidney disease compared with the general population; safe and efficacious therapies in renal impairment are needed. Objectives To evaluate simeprevir renal excretion in healthy subjects and to compare the simeprevir steady-state pharmacokinetics between subjects with severe renal impairment and healthy subjects. Methods In the mass balance study, healthy adults received a single 200-mg dose of 14 C-simeprevir; radioactivity in the urine and feces was quantified until concentrations were <2 % of the administered dose and seven or more stools were produced. In the pharmacokinetic study, non-HCV-infected adults with severe renal impairment (estimated glomerular filtration rate ≤29 mL/min/1.73 m 2 ) and matched healthy subjects (estimated glomerular filtration rate ≥80 mL/min/1.73 m 2 ) received 150 mg simeprevir for 7 days. Pharmacokinetic analysis was performed post-dose on Day 7. Results 14 C-simeprevir recovery from the urine was low (0.009–0.138 % of total dose). The minimum plasma concentration, maximum plasma concentration, and area under the plasma concentration-time curve at 24 h were 71, 34, and 62 % higher, respectively, in subjects with severe renal impairment compared with healthy subjects. The mean fraction of simeprevir unbound to protein was <0.0001 (all subjects). Most adverse events were grade I or II; one subject with renal impairment who was receiving fenofibrate presented with grade 3 rhabdomyolysis. Conclusions Simeprevir plasma concentrations were mildly elevated in subjects with severe renal impairment. The results suggest that simeprevir may be administered without dose adjustment in patients with renal impairment.