Richard Vinisko

Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

BACKGROUND Interferon-free regimens would be a major advance in the treatment of patients with chronic hepatitis C virus (HCV) infection. METHODS In this phase 2b, randomized, open-label trial of faldaprevir (a protease inhibitor) and deleobuvir (a nonnucleoside polymerase inhibitor), we randomly assigned 362 previously untreated patients with HCV genotype 1 infection to one of five groups: faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, plus ribavirin, for 16, 28, or 40 weeks (TID16W, TID28W, or TID40W, respectively); faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg twice daily, plus ribavirin, for 28 weeks (BID28W); or faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, without ribavirin, for 28 weeks (TID28W-NR). The primary end point was a sustained virologic response 12 weeks after the completion of therapy. RESULTS The primary end point was met in 59% of patients in the TID16W group, 59% of patients in the TID28W group, 52% of patients in the TID40W group, 69% of patients in the BID28W group, and 39% of patients in the TID28W-NR group. The sustained virologic response 12 weeks after the completion of therapy did not differ significantly according to treatment duration or dosage among ribavirin-containing regimens. This response was significantly higher with TID28W than with TID28W-NR (P=0.03). Rates of a sustained virologic response 12 weeks after the completion of therapy were 56 to 85% among patients with genotype 1b infection versus 11 to 47% among patients with genotype 1a infection and 58 to 84% among patients with IL28B CC versus 33 to 64% with non-CC genotypes. Rash, photosensitivity, nausea, vomiting, and diarrhea were the most common adverse events. CONCLUSIONS The rate of a sustained virologic response 12 weeks after the completion of therapy was 52 to 69% among patients who received interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin. (Funded by Boehringer Ingelheim; SOUND-C2 ClinicalTrials.gov number, NCT01132313.).

Level of Systolic Blood Pressure Within the Normal Range and Risk of Recurrent Stroke

CONTEXT Recurrent stroke prevention guidelines suggest that larger reductions in systolic blood pressure (SBP) are positively associated with a greater reduction in the risk of recurrent stroke and define an SBP level of less than 120 mm Hg as normal. However, the association of SBP maintained at such levels with risk of vascular events after a recent ischemic stroke is unclear. OBJECTIVE To assess the association of maintaining low-normal vs high-normal SBP levels with risk of recurrent stroke. DESIGN, SETTING, AND PATIENTS Post hoc observational analysis of a multicenter trial involving 20,330 patients (age ≥50 years) with recent non-cardioembolic ischemic stroke; patients were recruited from 695 centers in 35 countries from September 2003 through July 2006 and followed up for 2.5 years (follow-up ended on February 8, 2008). Patients were categorized based on their mean SBP level: very low-normal (<120 mm Hg), low-normal (120-<130 mm Hg), high-normal (130-<140 mm Hg), high (140-<150 mm Hg), and very high (≥150 mm Hg). MAIN OUTCOME MEASURES The primary outcome was first recurrence of stroke of any type and the secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. RESULTS The recurrent stroke rates were 8.0% (95% CI, 6.8%-9.2%) for the very low-normal SBP level group, 7.2% (95% CI, 6.4%-8.0%) for the low-normal SBP group, 6.8% (95% CI, 6.1%-7.4%) for the high-normal SBP group, 8.7% (95% CI, 7.9%-9.5%) for the high SBP group, and 14.1% (95% CI, 13.0%-15.2%) for the very high SBP group. Compared with patients in the high-normal SBP group, the risk of the primary outcome was higher for patients in the very low-normal SBP group (adjusted hazard ratio [AHR], 1.29; 95% CI, 1.07-1.56), in the high SBP group (AHR, 1.23; 95% CI, 1.07-1.41), and in the very high SBP group (AHR, 2.08; 95% CI, 1.83-2.37). Compared with patients in the high-normal SBP group, the risk of secondary outcome was higher for patients in the very low-normal SBP group (AHR, 1.31; 95% CI, 1.13-1.52), in the low-normal SBP group (AHR, 1.16; 95% CI, 1.03-1.31), in the high SBP group (AHR, 1.24; 95% CI, 1.11-1.39), and in the very high SBP group (AHR, 1.94; 95% CI, 1.74-2.16). CONCLUSION Among patients with recent non-cardioembolic ischemic stroke, SBP levels during follow-up in the very low-normal (<120 mm Hg), high (140-<150 mm Hg), or very high (≥150 mm Hg) range were associated with increased risk of recurrent stroke. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00153062.

An Open-Label, Single-Arm, Phase 2 Trial of the Polo-Like Kinase Inhibitor Volasertib (BI 6727) in Patients With Locally Advanced or Metastatic Urothelial Cancer

Polo‐like kinases (Plks) control multiple steps during the cell cycle, and Plk1 is overexpressed in urothelial cancer (UC). Volasertib (BI 6727), a Plk inhibitor, has demonstrated antitumor activity in several malignancies, including UC. In this phase 2 trial, the authors investigated volasertib as a second‐line treatment in advanced/metastatic UC.

Obesity and Recurrent Vascular Risk After a Recent Ischemic Stroke

Background and Purpose— Although obesity is an established risk factor for the occurrence of a primary stroke, little is known about the impact of baseline obesity on recurrent vascular risk among patients with recently symptomatic cerebrovascular disease. We evaluated the association of obesity with future vascular risk in patients with a recent history of stroke. Methods— We analyzed the database of a multicenter trial involving 20 332 patients with recent ischemic stroke followed for 2.5 years. Subjects were divided into 3 groups according to recognized body mass index categories representing lean, overweight, and obese. Primary outcome was time to first recurrent stroke and secondary outcome time to stroke, myocardial infarction, or vascular death. The independent association of obesity with outcome was assessed by controlling for other known risk factors. Results— Of 20 246 eligible subjects, 4805 (24%) were obese. After adjusting for confounders, compared with the lean group, being overweight (hazard ratio, 0.95; 95% CI, 0.85–1.06) or obese (hazard ratio, 0.95; 95% CI, 0.83–1.08) was not associated with increased recurrent stroke risk, but being overweight (hazard ratio, 0.84; 95% CI, 0.77–0.92) or obese (hazard ratio, 0.86; 95% CI, 0.77–0.96) was associated with lower risk of a major vascular event. Conclusions— Obesity is not related to recurrent stroke risk, but obese patients with stroke are at lower overall vascular risk than their leaner counterparts, supporting the widely held notion of the existence of a cardiovascular “obesity paradox.”

Chronic pain syndromes after ischemic stroke: PRoFESS trial

Background and Purpose— Chronic pain syndromes are reported to be common after stroke, but most previous epidemiological studies have generally included small cohorts of patients with relatively short-term follow-up. In a large cohort with ischemic stroke (Prevention Regimen for Effectively avoiding Second Stroke [PRoFESS] trial), we determined the prevalence, risk factors, and clinical consequence of new poststroke pain syndromes. Methods— Within the PRoFESS trial (mean follow-up 2.5 years), a standardized chronic pain questionnaire was administered (at the penultimate follow-up visit) to all participants who reported chronic pain since their stroke and did not have a history of chronic pain before their index stroke. Multivariable logistic regression analyses were used to determine risk factors for poststroke pain (and pain subtypes), and the association between poststroke pain and cognitive (≥3 reduction in Mini-Mental State Examination score) and functional decline (≥1 increase in m-Rankin). Results— In total, 15 754 participants were included; of which 1665 participants (10.6%) reported new chronic poststroke pain, and included 431 participants (2.7%) with central poststroke pain, 238 (1.5%) with peripheral neuropathic pain, 208 (1.3%) with pain from spasticity, and 136 participants (0.9%) with pain from shoulder subluxation. More than 1 pain subtype was reported in 86 participants (0.6%). Predictors of poststroke pain included increased stroke severity, female sex, alcohol intake, statin use, depressive symptoms, diabetes mellitus, antithrombotic regimen, and peripheral vascular disease. A new chronic pain syndrome was associated with greater dependence (odds ratio, 2.16; 95% confidence interval, 1.82–2.56). Peripheral neuropathy and pain from spasticity/shoulder subluxation were associated with cognitive decline. Conclusions— Chronic pain syndromes are common after ischemic stroke and are associated with increased functional dependence and cognitive decline.

Single-Pill Combination of Telmisartan/Amlodipine in Patients With Severe Hypertension: Results From the TEAMSTA Severe HTN Study

J Clin Hypertens (Greenwich). 2012;14:206–215. ©2012 Wiley Periodicals, Inc.

Interferon-free treatment of chronic hepatitis C with faldaprevir, deleobuvir and ribavirin: SOUND-C3, a Phase 2b study.

The safety and efficacy of the interferon‐free combination of faldaprevir (NS3/A4 protease inhibitor), deleobuvir (BI 207127, non‐nucleoside polymerase inhibitor), and ribavirin in treatment‐naïve patients chronically infected with HCV genotype‐1 was explored.

STARTVerso4: faldaprevir and pegylated interferon α-2a/ribavirin in individuals co-infected with hepatitis C virus genotype-1 and HIV.

Objective:Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. STARTVerso4 assessed the efficacy and safety of faldaprevir and response-guided pegylated interferon &agr;-2a/ribavirin (PegIFN/RBV) in individuals with HCV/HIV co-infection. Design:A phase 3 open-label study (NCT01399619). Methods:Individuals (N = 308) co-infected with HCV genotype 1 (treatment-naive or prior interferon relapsers) and HIV [96% on antiretroviral therapy (ART)] received faldaprevir 120 mg (N = 123) or 240 mg (N = 185) and PegIFN/RBV. Those receiving a protease inhibitor or efavirenz ART were assigned to faldaprevir 120 or 240 mg, respectively. Individuals achieving early treatment success (ETS; HCV RNA <25 IU/ml at week 4 and undetectable at week 8) were randomized to 24 or 48 weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Results:SVR12 was achieved in 221 (72%) individuals, and the rates were comparable across faldaprevir doses. ETS was achieved in 80%, and of these 86% achieved SVR12, with comparable rates with 24 and 48 weeks of PegIFN/RBV (87 and 94%, respectively). In multivariate analysis, age below 40 years, IL28B CC genotype, and baseline HCV RNA below 800 000 IU/ml were associated with SVR12 (P = 0.027, P < 0.0001, and P = 0.0002, respectively), whereas treatment (ART regimen and faldaprevir dose), liver cirrhosis, and genotype 1 subtype were not. The safety profile was comparable to that of faldaprevir in HCV-monoinfected individuals. Conclusions:High SVR12 rates were achieved with faldaprevir and PegIFN/RBV in HIV/HCV co-infected individuals, regardless of faldaprevir dose and background ART, HCV genotype 1 subtype, or cirrhosis status. SVR rates mirrored those obtained with similar regimens in HCV monoinfected individuals.

Concomitant Administration of BILR 355⁄r with Emtricitabine⁄ Tenofovir Disoproxil Fumarate Increases Exposure to Emtricitabine and Tenofovir: A Randomized, Open-Label, Prospective Study

The objective of this study was to evaluate the pharmacokinetic interaction of ritonavir-boosted BILR 355 (BILR 355/r) with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). This was an open-label, prospective study. For Group A, 26 healthy subjects were given FTC/TDF (200/300 mg) once daily (QD) for 7 days and then co-administered with BILR 355/r (150/100 mg) twice daily (bid) for an additional 7 days. Pharmacokinetics assessments were performed at days 7 and 14. For Group B, eight subjects were given BILR 355/r (150/100 mg) bid for 7 days. The pharmacokinetic data from Group B were also pooled with Group B subjects from other similar studies performed in parallel to this study. After co-administration with BILR 355/r, the geometric mean ratio (GMR, %) and 90% confidence interval (CI, %) of combined versus alone treatment for FTC AUC(0-24,ss) , C(max,ss) and C(0-12,ss) were 160 (154-166), 128 (121-136) and 223 (206-241), respectively; and for tenofovir AUC(0-24,ss) , C(max,ss) and C(24,ss) were 126 (121-132), 131 (117-146) and 132 (124-140), respectively. Co-administration with FTC/TDF resulted in an 18% increase in AUC(0-12,ss) , 14% increase in C(max,ss) and 19% increase in C(12,ss) for BILR 355. BILR 355 was well tolerated in this study. There was no evidence of increased risk of TFV or FTC toxicity upon co-administration of FTC/TDF with BILR 355/r.

Evaluation of steady-state pharmacokinetic interactions between ritonavir-boosted BILR 355, a non-nucleoside reverse transcriptase inhibitor, and lamivudine/zidovudine in healthy subjects

What is known and Objective:  BILR 355 is a second generation non‐nucleoside reverse transcriptase inhibitor. It has shown promising in vitro anti‐HIV‐1 activities and favourable human pharmacokinetic properties after co‐administration with ritonavir (RTV). Lamivudine (3TC) is a nucleoside reverse transcriptase inhibitor. It is excreted predominantly in urine by a transporter‐mediated pathway. These two drugs are likely to be given together to HIV‐infected patients. The objective of this study was to investigate any steady‐state pharmacokinetic interactions between RTV‐boosted BILR 355 and 3TC/zidovudine (ZDV).