Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial.

BACKGROUND & AIMS: Simeprevir (TMC435) is an oral NS3/4 protease inhibitor in phase III trials for chronic hepatitis C virus (HCV) infection. We performed a phase IIb, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the combination of simeprevir, peginterferon-α2a (PegIFN), and ribavirin (RBV) in patients with HCV genotype-1 infection previously treated with PegIFN and RBV. METHODS: We analyzed data from patients who did not respond (null response), had a partial response, or relapsed after treatment with PegIFN and RBV, randomly assigned to receive simeprevir (100 or 150 mg, once daily) for 12, 24, or 48 weeks plus PegIFN and RBV for 48 weeks (n = 396), or placebo plus PegIFN and RBV for 48 weeks (n = 66). All patients were followed for 24 weeks after planned end of treatment; the primary end point was the proportion of patients with sustained virologic response (SVR; undetectable HCV RNA) at that time point. RESULTS: Overall, rates of SVR at 24 weeks were significantly higher in the groups given simeprevir than those given placebo (61%-80% vs 23%; P < .001), regardless of prior response to PegIFN and RBV (simeprevir vs placebo: prior null response, 38%-59% vs 19%; prior partial response, 48%-86% vs 9%; prior relapse, 77%-89% vs 37%). All groups had comparable numbers of adverse events; these led to discontinuation of simeprevir or placebo and/or PegIFN and RBV in 8.8% of patients given simeprevir and 4.5% of those given placebo. CONCLUSIONS: In treatment-experienced patients, 12, 24, or 48 weeks simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks PegIFN and RBV significantly increased rates of SVR at 24 weeks compared with patients given placebo, PegIFN, and RBV and was generally well tolerated. ClinicalTrials.gov number: NCT00980330.

Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study.

UNLABELLED: The phase IIb, double-blind, placebo-controlled PILLAR trial investigated the efficacy and safety of two different simeprevir (SMV) doses administered once-daily (QD) with pegylated interferon (Peg-IFN)-α-2a and ribavirin (RBV) in treatment-naïve patients with HCV genotype 1 infection. Patients were randomized to one of five treatments: SMV (75 or 150 mg QD) for 12 or 24 weeks or placebo, plus Peg-IFN and RBV. Patients in the SMV arms stopped all treatment at week 24 if response-guided therapy (RGT) criteria were met; patients not meeting RGT continued with Peg-IFN and RBV until week 48, as did patients in the placebo control group. Sustained virologic response (SVR) rates measured 24 weeks after the planned end of treatment (SVR24) were 74.7%-86.1% in the SMV groups versus 64.9% in the control group (P < 0.05 for all comparisons [SMV versus placebo], except SMV 75 mg for 24 weeks). Rapid virologic response (HCV RNA <25 IU/mL undetectable at week 4) was achieved by 68.0%-75.6% of SMV-treated and 5.2% of placebo control patients. According to RGT criteria, 79.2%-86.1% of SMV-treated patients completed treatment by week 24; 85.2%-95.6% of these subsequently achieved SVR24. The adverse event profile was generally similar across the SMV and placebo control groups, with the exception of mild reversible hyperbilirubinemia, without serum aminotransferase abnormalities, associated with higher doses of SMV. CONCLUSION: SMV QD in combination with Peg-IFN and RBV significantly improves SVR rates, compared with Peg-IFN and RBV alone, and allows the majority of patients to shorten their therapy duration to 24 weeks.

Virologic response and characterisation of HCV genotype 2-6 in patients receiving TMC435 monotherapy (study TMC435-C202).

BACKGROUND & AIMS: TMC435 is a potent, once-daily, investigational hepatitis C virus (HCV) NS3/4A protease inhibitor in phase III clinical development. In the phase II trial TMC435-C202 (NCT00812331), TMC435 displayed potent activity in genotype 4, 5 and 6 patients and in 3/6 genotype 2 patients, whereas no activity was observed with genotype 3. METHODS: Thirty-seven patients received TMC435 monotherapy (200 mg once daily) for 7 days. HCV RNA, NS3 protease sequences and the corresponding phenotypes were evaluated. RESULTS: Genotype and isolate-specific baseline polymorphisms at NS3 positions known to affect HCV protease inhibitor activity were present in all genotypes. Consistent with the antiviral activity observed in genotypes 4 and 6, TMC435 was active in vitro against all genotype 4 isolates, and against most genotype 6 polymorphisms when tested as single or double mutants. In contrast, in genotype 3 where no HCV RNA decline was observed, isolates displayed >700-fold increases in EC(50) attributed to the D168Q polymorphism. In genotypes 2 and 5, HCV RNA changes from baseline to Day 3 ranged between -0.3 to -3.6 and -1.5 to -4.0 log(10)IU/ml, respectively, and isolates or site-directed mutants displayed intermediate in vitro susceptibility to TMC435 with fold changes in EC(50) between 15 and 78. Viral breakthrough in genotypes 4-6 was associated with emerging mutations including Q80R, R155K and/or D168E/V. CONCLUSIONS: Sequence and phenotypic analyses of baseline isolates identified polymorphisms which could explain the differences in antiviral activity between genotypes. Pathways of TMC435 resistance in genotypes 2-6 were similar to those identified in genotype 1.

Single-dose pharmacokinetics of pediatric and adult formulations of etravirine and swallowability of the 200-mg tablet: results from three Phase 1 studies.

OBJECTIVES: Three studies were conducted to assess the pharmacokinetics, methods of administration and ease of swallowability of etravirine tablets. METHODS: Two randomized studies in healthy adults investigated the single-dose pharmacokinetics of etravirine in various dosage strengths and the effects of dispersion in water and film-coating. A third study explored swallowability of etravirine 200-mg tablets in HIV-infected patients. First study: 37 volunteers received 1 × 100-mg non-coated tablet (reference), 4 × 25-mg noncoated tablets and 1 × 100-mg non-coated tablet dispersed in 100 ml water. Second study: 24 volunteers received 2 × 100-mg non-coated tablets (reference), 2 × 100-mg coated tablets, 1 × 200-mg non-coated and 1 × 200-mg coated tablet. Pharmacokinetic parameters were determined using non-compartmental analysis and least square means (LSM) ratios and 90% confidence intervals (CI) were calculated. Third study: 49 virologically-suppressed patients already on an etravirine-containing regimen rated the swallowability of two etravirine formulations (200-mg non-coated and 200-mg coated tablets). RESULTS: In the first study LSM ratios (90% CI) for the etravirine area under the plasma concentration-time curve (AUC) administered either as 4 × 25-mg tablets or 100-mg tablet dispersed were: 0.91 (0.85 to 0.98) and 0.97 (0.90 to 1.03), respectively. In the second study, when comparing a 200-mg non-coated and coated tablet to 2 × 100-mg non-coated tablets, LSM ratios for etravirine AUC were 98 to 99%. In the third study, more patients rated the 200-mg than the 100-mg tablets as acceptable to swallow (70% vs. 43%). CONCLUSIONS: Comparable etravirine exposures were observed regardless of formulation or method of administration (i.e., dispersion); 200-mg tablets were rated as easier to swallow than 100-mg tablets.

Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2-6: TMC435-C202, a phase IIa, open-label study.

BACKGROUND & AIMS: TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor currently in phase III development for the treatment of hepatitis C virus (HCV) infection. Phase I and II studies in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily dosing, and demonstrates potent antiviral activity. This phase IIa study (TMC435-C202; NCT00812331) was conducted to investigate the antiviral activity, safety, tolerability, and pharmacokinetics of TMC435 in treatment-naїve patients infected with HCV genotypes 2-6. METHODS: The study consisted of 7 days of monotherapy with TMC435 (200mg once daily). Patients could begin treatment with pegylated interferon/ribavirin from day 8 with a follow-up period up to days 37-42. RESULTS: Thirty-seven patients were enrolled in Germany, Belgium and Thailand. For the primary end point at day 8, the mean (± standard error) change in plasma HCV ribonucleic acid (log(10)IU/ml) from baseline was the greatest for genotypes 6 (-4.35 ± 0.29) and 4 (-3.52 ± 0.43), followed by genotypes 2 (-2.73 ± 0.71) and 5 (-2.19 ± 0.39). No antiviral activity was evident for genotype 3. Viral breakthrough occurred in six patients during the monotherapy phase and in six additional patients during PegIFN/RBV-only period. All adverse events were mild or moderate and there were no discontinuations during the TMC435 monotherapy period. CONCLUSIONS: The results of this phase IIa proof-of-concept trial provide evidence that TMC435 has a spectrum of activity against multiple HCV genotypes, except for genotype 3. In this study, TMC435 was generally safe and well tolerated.

Single- and multiple-dose pharmacokinetics of etravirine administered as two different formulations in HIV-1-infected patients.

BACKGROUND: An open-label, randomized, crossover study to evaluate the pharmacokinetics of two different formulations of etravirine after single and multiple dosing. METHODS: Treatment-experienced HIV-1-infected patients with viral load <50 copies/ml continued their current antiretroviral regimen and added etravirine twice daily for 7 days with a morning intake on day 8. Etravirine was administered following food as either 800 mg twice daily of the Phase II formulation or 100 mg or 200 mg twice daily of the Phase III formulation. A 12 h pharmacokinetic assessment was performed on days 1 and 8. RESULTS: After single- and multiple-dose administration, the exposure to etravirine was lower with 100 mg twice daily and higher with 200 mg twice daily compared with 800 mg twice daily. On day 8, the mean (+/-SD) area under the plasma concentration-time curve over 12 h (AUC0-12 h) was 1,284 (+/-958) ng x h/ml when etravirine was administered as 100 mg twice daily (n=33), 3,713 (+/-2,069) ng x h/ml when administered as 200 mg twice daily (n=27) and 2,607 (+/-2,135) ng x h/ml when administered as 800 mg twice daily (n=32). Both formulations and all doses of etravirine tested were generally safe and well tolerated. CONCLUSIONS: The range of exposure to etravirine was comparable between 200 mg twice daily dose and 800 mg twice daily. The Phase III formulation of etravirine significantly improves the bioavailability of etravirine over the Phase II formulation with reduced interpatient variability in etravirine pharmacokinetics.

Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial.

BACKGROUND: 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). METHODS: 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. FINDINGS: 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). INTERPRETATION: 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.

Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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.

Pharmacokinetic and pharmacodynamic study of the concomitant administration of methadone and TMC125 in HIV-negative volunteers.

TMC125 is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant HIV-1. TMC125 is an inducer of CYP3A and an inhibitor of CYP2C. This trial evaluated the effect of TMC125 on the pharmacokinetics and pharmacodynamics of methadone. In an open-label, add-on, 1-way interaction trial, 16 male HIV-negative volunteers on stable methadone maintenance therapy received 100 mg TMC125 bid for 14 days. Plasma concentrations and pharmacokinetic parameters of R- and S-methadone isomers were determined on days -1, 7, and 14 and of TMC125 on days 7 and 14. Safety and tolerability were assessed. The LSmeans ratios (90% confidence interval) for AUC(24h), C(max), and C(min) of the pharmacologically active R-methadone were 1.08 (1.02-1.13), 1.03 (0.97-1.09), and 1.12 (1.05-1.19), respectively, on day 7 and 1.06 (0.99-1.13), 1.02 (0.96-1.09), and 1.10 (1.02-1.19), respectively, on day 14 compared with methadone alone. No withdrawal symptoms were observed; dose adjustment of methadone was not required. The concomitant administration of TMC125 and methadone was generally safe and well tolerated. TMC125 has no clinically relevant effect on the pharmacokinetics or pharmacodynamics of methadone. No dose adjustment for methadone is anticipated when coadministered with TMC125.

A pharmacokinetic study of etravirine (TMC125) co-administered with ranitidine and omeprazole in HIV-negative volunteers.

AIMS: Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant HIV. Proton pump inhibitors and H(2)-antagonists are frequently used in the HIV-negative-infected population, and drug-drug interactions have been described with other antiretrovirals. This study evaluated the effect of steady-state omeprazole and ranitidine on the pharmacokinetics of a single dose of etravirine. METHODS: In an open-label, randomized, one-way, three-period crossover trial, HIV-negative volunteers randomly received a single dose of 100 mg etravirine alone (treatment A); 11 days of 150 mg ranitidine b.i.d. (treatment B); and 11 days of 40 mg omeprazole q.d. (treatment C). A single dose of 100 mg etravirine was co-administered on day 8 of sessions 2 and 3. Each session was separated by a 14-day wash-out. RESULTS: Nineteen volunteers (seven female) participated. When a single dose of etravirine was administered in the presence of steady-state ranitidine, etravirine least squares means ratios (90% confidence interval) for AUC(last) and C(max) were 0.86 (0.76, 0.97) and 0.94 (0.75, 1.17), respectively, compared with administration of etravirine alone. When administered with steady-state omeprazole, these values were 1.41 (1.22, 1.62) and 1.17 (0.96, 1.43), respectively. Co-administration of a single dose of etravirine and ranitidine or omeprazole was generally safe and well tolerated. CONCLUSIONS: Ranitidine slightly decreased etravirine exposure, whereas omeprazole increased it by approximately 41%. The increased exposure of etravirine when co-administered with omeprazole is attributed to CYP2C19 inhibition. Considering the favourable safety profile of etravirine, these changes are not clinically relevant. Etravirine can be co-administered with proton pump inhibitors and H(2) antagonists without dose adjustments.

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 Fridericia's 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.

Pharmacokinetics of darunavir/ritonavir and TMC125 alone and coadministered in HIV-negative volunteers.

OBJECTIVE: To evaluate the pharmacokinetics of TMC125 (etravirine) and darunavir (DRV) with low-dose ritonavir (DRV/r). DESIGN: Open-label, randomized, two-way crossover Phase I trial. METHODS: Thirty-two HIV-negative volunteers were randomized 1:1 to two panels. All received TMC125 100 mg twice daily for 8 days and, after 14 days washout, DRV/r 600/100 mg twice daily for 16 days. During days 9-16, TMC125 100 or 200 mg twice daily was coadministered (Panel I or II, respectively). RESULTS: Twenty-three volunteers completed the trial. With DRV/r coadministration, mean exposure (area under the plasma concentration-time curve from 0 to 12 h [AUC12h) to TMC125 given as 100 mg twice daily was decreased by 37%; maximum and minimum plasma concentrations (Cmax and Cmin) were decreased by 32% and 49%, respectively. For TMC125 200 mg twice daily coadministered with DRV/r, AUC12h, Cmax and Cmin of TMC125 were 80%, 81% and 67% greater, respectively, versus TMC125 100 mg twice daily alone. DRV pharmacokinetics were unchanged except a 15% increase in AUC12h when given with TMC125 200 mg twice daily. CONCLUSIONS: No clinically relevant changes in DRV pharmacokinetics were observed when combined with TMC125; therefore DRV dose adjustment is not required. Coadministration of TMC125 100 mg twice daily with DRV/r decreased TMC125 exposure by 37%. The increase of TMC125 exposure by 80% when given as 200 mg twice daily reflects the higher dose and the interaction with DRV/r. The magnitude of this interaction is comparable to TMC125 interactions with other boosted PIs observed in Phase IIb trials in HIV-1-infected patients. As these trials demonstrated TMC125 efficacy, no dose adjustment of TMC125 is needed when combined with DRV/r.

Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial.

OBJECTIVE: The first episode of psychotic illness is a key intervention point. The initial experience with medication can affect willingness to accept treatment. Further, relapse prevention is a treatment cornerstone during the first years of illness because active psychotic illness may affect lifetime outcomes. Thus, initial treatment of active symptoms and subsequent relapse prevention are central goals of pharmacotherapy. This study compared long-term effectiveness of risperidone versus haloperidol in first-episode psychosis patients. METHOD: First-episode psychosis patients (N=555, mean age=25.4 years) participated in a double-blind, randomized, controlled flexible-dose trial that compared risperidone (mean modal dose=3.3 mg) and haloperidol (mean modal dose=2.9 mg). The median treatment length was 206 days (maximum=1,514). RESULTS: Positive and Negative Syndrome Scale scores and Clinical Global Impression ratings improved significantly relative to baseline, with no significant differences between groups. Three-quarters of the patients achieved initial clinical improvement, defined as >20% reduction in total Positive and Negative Syndrome Scale score. However, among those who achieved clinical improvement, 42% of the risperidone group experienced a relapse compared with 55% of the haloperidol group. The median time to relapse was 466 days for risperidone-treated subjects and 205 days for those given haloperidol. These differences were statistically significant based on Kaplan-Meier survival analysis. Adverse effects distinguished the treatments: there were significantly more extrapyramidal signs and symptoms and adjunctive medication use in the haloperidol group and greater prolactin elevation in the risperidone group. There was less weight gain with haloperidol initially but no significant differences between groups at endpoint. CONCLUSIONS: Relatively low doses of antipsychotic drugs lead to significant symptom amelioration in the majority of first-episode psychosis patients. In the long term, risperidone prevents relapse in more patients and for a longer time and also induces less abnormal movements than haloperidol.

Risperidone in children with disruptive behavior disorders and subaverage intelligence: a 1-year, open-label study of 504 patients.

OBJECTIVE: To determine the long-term safety and effectiveness of risperidone for severe disruptive behaviors in children. METHOD: A multisite, 1-year, open-label study of patients aged 5 to 14 years with disruptive behaviors and subaverage intelligence was conducted. RESULTS: Seventy-three percent of the 504 patients enrolled completed the study. The mean +/- SE dose of risperidone was 1.6 +/- 0.0 mg/day. The most common adverse events were somnolence (30%), rhinitis (27%), and headache (22%). The incidence of movement disorders was low, and mean Extrapyramidal Symptom Rating Scale scores decreased during risperidone treatment. No clinically significant changes in mean laboratory values were noted, except for a transient increase in serum prolactin levels. Scores on the Nisonger Child Behavior Rating Form Conduct Problem Scale improved significantly as early as week 1, and improvement was maintained throughout the trial (p < .001 at each time point). Significant improvements were noted on positive social behavior and other Nisonger Child Behavior Rating Form subscales, Aberrant Behavior Checklist, Clinical Global Impressions scale, and tests of patients' cognitive function (each p < .001). CONCLUSIONS: Risperidone was well tolerated and effective in the long-term treatment of disruptive behavior disorders in children with subaverage intelligence.

Darunavir/cobicistat once daily for the treatment of HIV.

A current focus in HIV management is improving adherence by minimizing pill burden with convenient formulations, including fixed-dose combinations (FDCs). Darunavir, a HIV protease inhibitor, co-administered with low-dose ritonavir (800/100 mg once daily), is recommended in guidelines in combination with other antiretrovirals for HIV patients with no darunavir resistance-associated mutations. Cobicistat is an alternative agent to ritonavir for boosting plasma drug levels of darunavir among other antiretrovirals. Cobicistat is a more specific cytochrome P450 3A inhibitor than ritonavir without enzyme-inducing properties. This review describes the differing effects of cobicistat and ritonavir on metabolic enzymes, which explains their differing drug-drug interactions, and summarizes some of the studied drug-drug interactions for cobicistat. It also outlines the clinical development and data for a once-daily darunavir/cobicistat FDC. This FDC thus allows for a once-daily treatment regimen (including background antiretrovirals) with reduced pill burden.

Relationship between premorbid functioning and symptom severity as assessed at first episode of psychosis.

OBJECTIVE: Investigating the relationship between premorbid and prodromal status and the clinical manifestations of the first psychotic episode is relevant for understanding the pathophysiology of psychosis and for improving management of the disease. This study examined patterns of premorbid functioning of persons interviewed during their first episode of psychotic illness and examined the relationship of premorbid characteristics with symptom severity and cognitive functioning during the first illness episode. METHOD: The data were derived from the baseline assessments of a multicenter international drug trial that enrolled 535 patients in their first episode of psychosis. Subjects' scores on the Premorbid Adjustment Scale were used to assign them to groups according to whether their premorbid functioning was stable-good, stable-poor, or deteriorating. The three groups' scores on the Positive and Negative Syndrome Scale, Clinical Global Impression (CGI) severity scale, and a cognitive battery were compared. RESULTS: Almost half of the patients (47.5%) had stable-good premorbid functioning, 37.3% had stable-poor premorbid functioning, and 15.1% had initially good, but later deteriorating, premorbid functioning. Compared to the stable-poor and deteriorating groups, the stable-good group had lower (better) negative syndrome and general psychopathology scores on the Positive and Negative Syndrome Scale and a lower CGI severity scale score. Differences between the stable-poor and stable-good groups were also found on some cognitive measures and on the positive syndrome subscale of the Positive and Negative Syndrome Scale. CONCLUSIONS: More than half of the subjects, who were interviewed during their first episode of psychotic disorder, had evident premorbid behavioral disturbances. Poor premorbid functioning before onset of psychosis was associated with more severe symptoms and more severe cognitive manifestations of illness during the first illness episode.

Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence.

OBJECTIVE: The short-term efficacy and safety of risperidone in the treatment of disruptive behaviors was examined in a well-characterized cohort of children with subaverage intelligence. METHOD: In this 6-week, multicenter, double-blind, parallel-group study of 118 children (aged 5-12 years) with severely disruptive behaviors and subaverage intelligence (IQ between 36 and 84, inclusive), the subjects received 0.02-0.06 mg/kg per day of risperidone oral solution or placebo. The a priori primary efficacy measure was the change in score from baseline to endpoint on the conduct problem subscale of the Nisonger Child Behavior Rating Form. RESULTS: The risperidone group showed significantly greater improvement than did the placebo group on the conduct problem subscale of the Nisonger Child Behavior Rating Form from week 1 through endpoint (change in score of -15.2 and -6.2, respectively). Risperidone was also associated with significantly greater improvement than placebo on all other Nisonger Child Behavior Rating Form subscales at endpoint, as well as on the Aberrant Behavior Checklist subscales for irritability, lethargy/social withdrawal, and hyperactivity; the Behavior Problems Inventory aggressive/destructive behavior subscale; a visual analogue scale of the most troublesome symptom; and the Clinical Global Impression change score. The most common adverse effects reported during risperidone treatment were headache and somnolence. The extrapyramidal symptom profile of risperidone was comparable to that of placebo. Mean weight increases of 2.2 kg. and 0.9 kg occurred in the risperidone and placebo groups, respectively. CONCLUSIONS: Risperidone was effective and well tolerated for the treatment of severely disruptive behaviors in children with subaverage IQ.

Prolactin levels during long-term risperidone treatment in children and adolescents.

BACKGROUND: This analysis was designed to investigate prolactin levels in children and adolescents on long-term risperidone treatment and explore any relationship with side effects hypothetically attributable to prolactin (SHAP). METHOD: Data from 5 clinical trials (total N = 700) were pooled for this post hoc analysis. Children and adolescents aged 5 to 15 years with subaverage intelligence quotients and conduct or other disruptive behavior disorders received risperidone treatment (0.02-0.06 mg/kg/day) for up to 55 weeks. Outcome measures analyzed included serum prolactin levels, reported adverse events, and the conduct problem subscore of the Nisonger Child Behavior Rating Form. RESULTS: Mean prolactin levels rose from 7.8 ng/mL at baseline to a peak of 29.4 ng/mL at weeks 4 to 7 of active treatment, then progressively decreased to 16.1 ng/mL at weeks 40 to 48 (N = 358) and 13.0 ng/mL at weeks 52 to 55 (N = 42). There was no relationship between pro-lactin levels and age. Females returned to a mean value within the normal range (

Cross-national cognitive assessment in schizophrenia clinical trials: a feasibility study.

Clinical trials for the treatment of schizophrenia now often include cognitive assessments in addition to clinical ratings of symptoms. Recently, these trials have included cross-national assessments. It is not clear if translated psychological tests produce consistent results across different languages. This paper presents the results of a study of the comparability of the results of cognitive assessments in different English-speaking countries and a number of countries where tests were translated into other languages. Performance on tests of executive functioning, verbal and visuo-spatial learning and memory, language skills, psychomotor speed, and vigilance was compared across the first episode patients with schizophrenia (n = 301) assessed in six different languages (English, French, Finnish, German, Hebrew, and Afrikaans), including two different countries where patients were assessed in English and other languages: Canada (French) and South Africa (Afrikaans). The variance in performance across the sites tested in English was as large as the variance between English and non-English speakers when all tests were considered. Performance differences across English and other languages were found only for executive functions, vigilance, and psychomotor speed, with executive functioning differences nonsignificant when education was considered. No differences were found between English and non-English speakers in Canada. These results suggest that the translation of tests of memory and verbal skills can lead to consistent results across translated versions of the tests. Differences between countries were greater than differences between languages, suggesting the need to consider representativeness of patient samples in terms of local educational attainment. In general, these data support the validity of cross-national neuropsychological assessments.

Schizophrenia and osteoporosis.

Although it has been suggested that antipsychotic-induced hyperprolactinaemia in schizophrenic patients may lead to an increased risk of osteoporosis, this has not been proven. Osteoporosis is a multifactorial disease, and untreated patients with schizophrenia are at risk due to both the consequences of the disease and related lifestyle factors. Evidence from available studies does not show that antipsychotic-induced hyperprolactinaemia is an independent risk factor for osteoporosis in schizophrenic patients. Osteoporosis would be expected in women who develop amenorrhoea as a result of hyperprolactinaemia secondary to antipsychotics, but there is no plausible mechanism in men. The uncertainty over this issue underlines the need for full medical and metabolic assessment and monitoring of psychiatric patients.