Direct gene transfer into cardiac myocytes in vivo

Recent studies have demonstrated that cardiac and skeletal myocytes share the ability to take up and stably express plasmid DNA injected directly into myocardium or skeletal muscle in vivo. Although this is a relatively inefficient process, with less than 1% of the myocytes expressing the injected recombinant DNA, expression in these cells is stable for periods of at least 6 months. The majority of the injected DNA is maintained in myocytes as an episome and apparently does not undergo DNA replication. The direct DNA injection approach has been used to map cardiac-specific transcriptional regulatory elements in cellular promoter/enhancers. Expression of recombinant proteins in the heart following direct DNA injection also holds promise for the treatment of a variety of acquired and inherited cardiovascular diseases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29917/1/0000274.pd

Safety and Efficacy of Elbasvir/Grazoprevir in Patients With Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis

Background & Aims Persons with hepatitis C virus (HCV) infection are at risk of progressive liver disease, cirrhosis, and decompensation. We analyzed the effects of the direct-acting antiviral agents elbasvir and grazoprevir in patients with HCV infection and compensated cirrhosis, combining data from 6 clinical trials. Methods We performed an integrated analysis of 402 patients with HCV genotype 1, 4, or 6 infection and Child-Pugh A compensated cirrhosis enrolled in 6 clinical trials. All patients received elbasvir/grazoprevir 50 mg/100 mg once daily, with or without ribavirin, for 12−18 weeks. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12), defined as a level of HCV RNA <15 IU/mL. Results Among treatment-naïve and treatment-experienced patients receiving elbasvir/grazoprevir for 12 weeks, 97.8% (135 of 138) and 88.9% (48 of 54) achieved SVR12, respectively. Among patients receiving elbasvir/grazoprevir for 12 weeks, addition of ribavirin did not increase the proportion of treatment-naïve patients (90.3%, 28 of 31) or treatment-experienced patients who achieved an SVR12 (91.4%, 74 of 81). All (49 of 49) treatment-experienced patients receiving elbasvir/grazoprevir with ribavirin for 16 or 18 weeks, and 93.9% (46 of 49) of patients receiving elbasvir/grazoprevir without ribavirin for 16 or 18 weeks achieved SVR12. Virologic failure was higher among patients with HCV genotype 1a infections compared with patients with genotype 1b or 4 infections, particularly in patients who had not responded to previous interferon therapy. Baseline tests for resistance-associated substitutions (RASs) led to an individualized approach for selecting treatment duration and established a need for ribavirin for patients with HCV genotype 1a infection and RASs, regardless of treatment history. Among patients with HCV genotype 1a infection with and without baseline RASs in HCV nonstructural protein 5A who received elbasvir/grazoprevir for 12 weeks, 73% (8 of 11) and 98% (96 of 98) achieved SVR12, respectively. Both patients with HCV genotype 1a infection with baseline RASs who received 16 or 18 weeks of elbasvir/grazoprevir and ribavirin achieved SVR12. Grade 3 or 4 increases in levels of alanine aminotransferase and aspartate aminotransferase, which did not cause symptoms, were reported in 2.3% (6 of 264) of patients receiving elbasvir/grazoprevir. Serious adverse events were reported in 3% (8 of 264) patients and no patient had a decompensation-related event. Conclusions In an analysis of data from 6 clinical trials, rates of SVR12 ranged from 89% to 100% in patients with HCV genotype 1, 4, or 6 infections and compensated cirrhosis treated with elbasvir/grazoprevir, with or without ribavirin. Addition of ribavirin to a 12-week regimen of elbasvir/grazoprevir had little effect on the proportion of treatment-naïve or treatment-experienced patients who achieved an SVR12. However, virologic failure did not occur in any treatment-experienced patients when the duration of elbasvir/grazoprevir and ribavirin therapy was extended to 16 or 18 weeks. Baseline analysis of RASs (or in the absence of this test, a history of nonresponse to interferon) can be used to determine treatment duration and the need for ribavirin in patients with HCV genotype 1a infection

A phase I study to evaluate a human papillomavirus (HPV)

Abstract Human papillomavirus (HPV) infection can cause genital warts and cervical cancer. HPV types 6 and 11 cause &gt;90% of genital wart cases; HPV16 and 18 cause 70% of cervical cancers. A prophylactic HPV (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine may substantially reduce the incidence of these lesions. This report describes the results of a phase I study of the HPV18 component of such a vaccine. Forty women were randomized to receive either HPV18 L1 VLP vaccine or placebo. Anti-HPV18 responses were measured using a competitive radioimmunoassay (cRIA). Tolerability was evaluated using vaccination report cards (VRC). The study showed that the HPV18 L1 VLP vaccine was generally well-tolerated and highly immunogenic. Peak anti-HPV18 geometric mean titers (GMT) in vaccines were 60-fold greater than those observed in women following natural HPV18 infection. Further studies of a multivalent HPV L1 VLP vaccines are warranted

Progression and regression of incident cervical HPV 6, 11, 16 and 18 infections in young women

<p>Abstract</p> <p>Background</p> <p>We describe type-specific progression, regression and persistence of incident human papillomavirus (HPV)-6-11-16 and -18 infections, along with type distribution in cervical intra-epithelial neoplasia (CIN) lesions.</p> <p>Methods</p> <p>The study population consisted of 16–23 year-old women undergoing Pap testing and cervical swab polymerase chain reaction testing for HPV DNA at approximate 6 month intervals for up to 4 years in the placebo arm of a clinical trial of an HPV 16-vaccine. HPV types in incident infections were correlated with types in lesion biopsy specimens.</p> <p>Results</p> <p>56.7% of CIN-1 and nearly one-third of CIN-2/3 lesions following incident HPV-6-11-16 or -18 infections did not correlate with the incident infection HPV type. Cumulative 36-month progression rates to CIN-2/3 testing positive for the relevant HPV type were highest for HPV-16 infections (16.5%), followed by HPV-18 (8.2%). Overall, 26.0% of CIN-1, 50.0% of CIN-2 and 70.6% of CIN-3 biopsies tested positive for HPV-6-11-16-18 infections.</p> <p>Conclusion</p> <p>Women with a given HPV type may often be co-infected or subsequently infected with other types which may lead to subsequent cervical lesions. This issue has been addressed in this study reporting data for the natural history of HPV-6-11-16 and -18 infections and is a relevant consideration in designing future studies to evaluate the incidence/risk of CIN following other type-specific HPV infections.</p

Efficacy and Safety of Elbasvir/Grazoprevir in Hepatitis C Virus GT1- and GT4-Infected People Aged 65 Years or Older

Background: In elderly individuals aged ≥65 years with hepatitis C virus (HCV) infection, efficacious and safe HCV therapy is complicated by frequent comorbidities and concomitant medications. The aim of this analysis was to evaluate the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) in people aged ≥65 years. Methods: This is an integrated retrospective analysis of EBR/GZR administered for 12 weeks in participants with HCV genotype 1 or 4 infection enrolled in 12 Phase 2/3 clinical trials. The primary end point was sustained virologic response 12 weeks after completing therapy (SVR12; HCV RNA below the lower limit of quantification). Results: Most participants aged ≥65 years were receiving ≥1 concomitant medication (322/339; 95.0%) and had ≥1 comorbidity (334/339; 99%). SVR12 rates were 95.3% (323/339) in participants aged ≥65 years and 95.4% (2,041/2,139) in those aged <65 years. Rates of adverse events, drug-related adverse events, serious adverse events, and discontinuations were similar in participants aged ≥65 years and those aged <65 years. In participants aged ≥65 years, median estimated glomerular filtration rate was similar at baseline and at the end of treatment. Conclusion: The efficacy and safety of EBR/GZR were similar in participants with HCV infection aged ≥65 years and those aged <65 years

Efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 4 infection:A pooled analysis

The aim of this integrated analysis was to assess the efficacy of the once-daily combination of elbasvir (EBR) 50 mg and grazoprevir (GZR) 100 mg, with and without ribavirin (RBV) in HCV genotype 4 (GT4)-infected participants enrolled in the Phase 2/3 clinical program with EBR/GZR. Treatment-naïve and treatment-experienced participants 18 years of age or older with chronic HCV GT4 infection and baseline HCV RNA ≥10,000 IU/mL were included in the analysis. The analysis population was the full analysis set (FAS; all participants who received at least 1 dose of study medication) and a total of 155 HCV GT4 participants were evaluated. The primary endpoint was sustained virologic response at week 12 (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after completion of study therapy). Overall, among GT4-infected participants treated with 12 or 16 weeks of EBR/GZR ± RBV, the SVR12 efficacy rates were 96.4% (107/111) in treatment-naïve participants and 88.6% (39/44) in treatment-experienced participants. The SVR12 rates were 96.0% (97/101) in treatment-naïve participants treated with 12 weeks of EBR/GZR, and 100% (8/8) in treatment-experienced participants treated with 16 weeks of EBR/GZR plus RBV. Efficacy was not impacted by GT4 subtype. The regimens of 12 weeks of EBR/GZR without RBV, and 16 weeks of EBR/GZR plus RBV, were efficacious in HCV GT4-infected treatment-naïve and treatment-experienced participants, respectively. Baseline NS5A resistance-associated substitutions did not impact the efficacy of EBR/GZR in GT4-infected participants. This article is protected by copyright. All rights reserve

Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent

BACKGROUND & AIMS: The Phase-2 C-SALVAGE study evaluated an investigational interferon-free combination of grazoprevir (a NS3/4A protease inhibitor) and elbasvir (a NS5A inhibitor) with ribavirin for patients with chronic HCV genotype-1 infection who had failed licensed DAA-containing therapy. METHODS: C-SALVAGE was an open-label study of grazoprevir 100 mg and elbasvir 50 mg QD with weight-based ribavirin BID for 12 weeks in cirrhotic and non-cirrhotic patients with chronic HCV genotype-1 infection who had not attained SVR after ⩾4 weeks of peginterferon and ribavirin plus either boceprevir, telaprevir, or simeprevir. Exclusion criteria included decompensated liver disease, hepatocellular carcinoma, and HIV or HBV co-infection. The primary efficacy outcome was SVR12 defined as a HCV RNA level below the assay limit of quantification 12 weeks after the end of treatment. RESULTS: Of the 79 patients treated with ⩾1 dose of study drug, 66 (84%) patients had a history of virologic failure on a regimen containing a NS3/4A protease inhibitor; 12 of the other 13 patients discontinued prior treatment because of adverse experiences. At entry, 34 (43.6%) of 78 evaluable patients harbored NS3 RAVs. SVR12 rates were 76/79 (96.2%) overall, including 28/30 (93.3%) patients with genotype 1a infection, 63/66 (95.5%) patients with prior virologic failure, 43/43 (100%) patients without baseline RAVs, 31/34 (91.2%) patients with baseline NS3 RAVs, 6/8 (75.0%) patients with baseline NS5A RAVs, 4/6 (66.7%) patients with both baseline NS3 and RAVs, and 32/34 (94.1%) cirrhotic patients. None of the five reported serious adverse events were considered drug-related. CONCLUSIONS: Grazoprevir and elbasvir plus ribavirin for 12 weeks provides a promising new treatment option for patients after failure of triple therapy containing an earlier-generation protease inhibitor

Grazoprevir, Elbasvir, and Ribavirin for Chronic Hepatitis C Virus Genotype 1 Infection After Failure of Pegylated Interferon and Ribavirin With an Earlier-Generation Protease Inhibitor: Final 24-Week Results From C-SALVAGE

BACKGROUND: The phase 2 C-SALVAGE study (Hepatitis C-Salvage Study for Patients who Failed DAA/PR Therapy) demonstrated a 96.2% sustained virologic response at 12 weeks (SVR12) rate using the NS3/4A protease inhibitor grazoprevir and the NS5A inhibitor elbasvir together with ribavirin in treatment-experienced patients with chronic hepatitis C virus (HCV) genotype 1 infection. METHODS: C-SALVAGE was a prospective open-label trial of grazoprevir 100 mg once daily and elbasvir 50 mg once daily coadministered with weight-based ribavirin twice daily for 12 weeks in genotype 1-infected cirrhotic and noncirrhotic patients who had failed treatment with ≥ 4 weeks of pegylated interferon and ribavirin plus either boceprevir, telaprevir, or simeprevir. Although the primary efficacy outcome was SVR12, patients were also evaluated 24 weeks after cessation of study therapy. Population sequencing was performed at baseline and periodically in virologic failures throughout the 24-week posttherapy follow-up period. RESULTS: SVR24 rates were 76 of 79 (96.2%) overall, with all 3 relapses occurring by posttherapy week 8. Every NS3 and NS5A variant detected at baseline reappeared at the time of relapse and persisted throughout the available follow-up period. NS3_A156T emerged in virus from each patient at relapse, but rapidly disappeared over the ensuing 2 weeks in 2 patients. NS5A_Y93H emerged in virus from 2 patients at relapse and persisted for the entire follow-up period. CONCLUSIONS: Grazoprevir and elbasvir with ribavirin for 12 weeks maintained HCV suppression for at least 24 weeks posttherapy without late relapses. Baseline resistance-associated variants (RAVs) stably reappeared at relapse in all 3 patients with virologic failure. NS5A_RAVs emerging at relapse persisted for the full 24-week follow-up period. If confirmed, this finding could complicate retreatment of the small number of patients failing regimens containing an NS5A inhibitor. CLINICAL TRIALS REGISTRATION: NCT02105454