In phase 2 trials, the nucleotide polymerase inhibitor sofosbuvir was effective in previously untreated patients with chronic hepatitis C virus (HCV) genotype 1, 2, or 3 infection.
We conducted two ...phase 3 studies in previously untreated patients with HCV infection. In a single-group, open-label study, we administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4). In a noninferiority trial, 499 patients with HCV genotype 2 or 3 infection were randomly assigned to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks. In the two studies, the primary end point was a sustained virologic response at 12 weeks after the end of therapy.
In the single-group study, a sustained virologic response was reported in 90% of patients (95% confidence interval, 87 to 93). In the noninferiority trial, a sustained response was reported in 67% of patients in both the sofosbuvir-ribavirin group and the peginterferon-ribavirin group. Response rates in the sofosbuvir-ribavirin group were lower among patients with genotype 3 infection than among those with genotype 2 infection (56% vs. 97%). Adverse events (including fatigue, headache, nausea, and neutropenia) were less common with sofosbuvir than with peginterferon.
In a single-group study of sofosbuvir combined with peginterferon-ribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks. In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%). Adverse events were less frequent with sofosbuvir than with peginterferon. (Funded by Gilead Sciences; FISSION and NEUTRINO ClinicalTrials.gov numbers, NCT01497366 and NCT01641640, respectively.).
Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment with peginterferon is not an option, or who have not had a response to prior interferon treatment, ...currently have no approved treatment options. In phase 2 trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection.
We conducted two randomized, phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection. In one trial, patients for whom treatment with peginterferon was not an option received oral sofosbuvir and ribavirin (207 patients) or matching placebo (71) for 12 weeks. In a second trial, patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks (103 patients) or 16 weeks (98). The primary end point was a sustained virologic response at 12 weeks after therapy.
Among patients for whom treatment with peginterferon was not an option, the rate of a sustained virologic response was 78% (95% confidence interval CI, 72 to 83) with sofosbuvir and ribavirin, as compared with 0% with placebo (P<0.001). Among previously treated patients, the rate of response was 50% with 12 weeks of treatment, as compared with 73% with 16 weeks of treatment (difference, -23 percentage points; 95% CI, -35 to -11; P<0.001). In both studies, response rates were lower among patients with genotype 3 infection than among those with genotype 2 infection and, among patients with genotype 3 infection, lower among those with cirrhosis than among those without cirrhosis. The most common adverse events were headache, fatigue, nausea, and insomnia; the overall rate of discontinuation of sofosbuvir was low (1 to 2%).
In patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon and ribavirin was not an option, 12 or 16 weeks of treatment with sofosbuvir and ribavirin was effective. Efficacy was increased among patients with HCV genotype 2 infection and those without cirrhosis. In previously treated patients with genotype 3 infection, 16 weeks of therapy was significantly more effective than 12 weeks. (Funded by Gilead Sciences; POSITRON and FUSION ClinicalTrials.gov numbers, NCT01542788 and NCT01604850, respectively.).
Purpose
To ascertain the safety of soft contact lens (SCL) wear in children through a retrospective chart review including real‐world clinical practice settings.
Methods
The study reviewed clinical ...charts from 963 children: 782 patients in 7 US eye care clinics and 181 subjects from 2 international randomised clinical trials (RCTs). Subjects were first fitted while 8–12 years old with various SCL designs, prescriptions and replacement schedules, and observed through to age 16. Clinical records from visits with potential adverse events (AEs) were electronically scanned and reviewed to consensus by an Adjudication Panel.
Results
The study encompassed 2713 years‐of‐wear and 4611 contact lens visits. The cohort was 46% male, 60% were first fitted with daily disposable SCLs, the average age at first fitting was 10.5 years old, with a mean of 2.8 ± 1.5 years‐of‐wear of follow‐up observed. There were 122 potential ocular AEs observed from 118/963 (12.2%) subjects; the annualised rate of non‐infectious inflammatory AEs was 0.66%/year (95% CI 0.39–1.05) and 0.48%/year (0.25–0.82) for contact lens papillary conjunctivitis. After adjudication, two presumed or probable microbial keratitis (MK) cases were identified, a rate of 7.4/10 000 years‐of‐wear (95% CI 1.8–29.6). Both were in teenage boys and one resulted in a small scar without loss of visual acuity.
Conclusion
This study estimated the MK rate and the rate of other inflammatory AEs in a cohort of SCL wearers from 8 through to 16 years of age. Both rates are comparable to established rates among adults wearing SCLs.
Contiguous bacterial osteomyelitis results from the spread of a variety of pyogenic bacteria from nearby skin, soft tissue, or joint infections into the underlying bone. This report describes a case ...of severe contiguous bacterial osteomyelitis in an 82-year-old female nursing home resident with newly diagnosed and comorbid peripheral arterial disease, along with a history of decubitus ulcers as a result of presumed neglect at her residence. The patient initially presented with multiple ulcerative lesions overlying the left foot and ankle with associated severe pain and chronic vascular insufficiency. The patient was empirically started on broad-spectrum antibiotics, with a subsequent wound culture demonstrating heavy growth of
. Multiple imaging modalities irrefutably demonstrated destructive bony changes characteristic of osteomyelitis. Left below-the-knee amputation was thereafter agreed upon as the most beneficial treatment method, with concomitant prolonged antibiotic therapy. This case emphasizes the importance of providing adequate medical and preventative care for elderly nursing home residents in an effort to reduce the incidence of contiguous bacterial osteomyelitis, a topic rarely discussed in current literature.
Velpatasvir (VEL, GS-5816) is a novel pan-genotypic hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor with activity against genotype 1 (GT1) to GT6 HCV replicons. In a phase 1b 3-day ...monotherapy study, patients treated with a 150-mg dose of GS-5816 had a mean maximal HCV RNA decline of ≥3.3 log10 IU/ml in GT1a, -1b, -2, -3, and -4. This report characterizes virologic resistance to VEL in these patients. NS5A resistance-associated substitutions (RASs) were detected by deep sequencing (1% cutoff) pretreatment in 22/70 patients, i.e., 10/35 (29%) patients with GT1a, 1/8 (13%) with GT1b, 4/8 (50.0%) with GT2, 5/17 (29.4%) with GT3, and 2/2 (100.0%) with GT4. In GT1a and GT3 patients, pretreatment RASs were associated with a slightly reduced HCV RNA response compared to that of patients without pretreatment RASs; among patients with GT1b, GT2, and GT4, no significant difference in response was observed in those with or without pretreatment RASs. Following treatment, the pattern of emergent RASs was more complex for GT1a than for the other genotypes. In GT1a, substitutions emerged at positions M28, Q30, L31, P32, H58, E92, and Y93, with the most prevalent substitutions at positions Y93, M28, and L31. RASs were observed at two positions in GT1b and GT2 (Y93 and L31), three positions in GT3 (Y93, L31, and E92), and four positions in GT4 (L28, M31, P32L, and Y93). RASs that were present pretreatment persisted through the 48-week follow-up period; however, RASs emerging during treatment were more likely to decline both in prevalence and in frequency within the viral population during follow-up. (This study has been registered at ClinicalTrials.gov under registration no. NCT01740791.).
Treatment of myopic children with a dual-focus soft contact lens (DFCL; MiSight 1 day) produced sustained slowing of myopia progression over a 6-year period. Significant slowing was also observed in ...children switched from a single vision control to treatment lenses (3 years in each lens).
This study aimed to evaluate the effectiveness of DFCLs in sustaining slowed progression of juvenile-onset myopia over a 6-year treatment period and assess myopia progression in children who were switched to a DFCL at the end of year 3.
Part 1 was a 3-year clinical trial comparing DFCLs with a control contact lens (Proclear 1 day) at four investigational sites. In part 2, subjects completing part 1 were invited to continue for 3 additional years during which all children were treated with MiSight 1 day DFCLs (52 and 56 from the initially treated T6 and control T3 groups, respectively). Eighty-five subjects (45 T3 and 40 T6) completed part 2. Cyclopleged spherical equivalent refractive errors (SEREs) and axial lengths (ALs) were monitored, and a linear mixed model was used to compare their adjusted change annually.
Average ages at part 2 baseline were 13.2 ± 1.3 and 13.0 ± 1.5 years for the T6 and T3 groups, respectively. Slowed myopia progression in the T6 group observed during part 1 was sustained throughout part 2 (mean ± standard error of the mean: change from baseline SERE in diopters, -0.52 ± 0.076 vs. -0.51 ± 0.076; change in AL in millimeters, 0.28 ± 0.033 vs. 0.23 ± 0.033; both P > .05). Comparing progression rates in part 2 for the T6 and T3 groups, respectively, indicates that prior treatment does not influence efficacy (SERE, -0.51 ± 0.076 vs. -0.34 ± 0.077; AL, 0.23 ± 0.03 vs. 0.18 ± 0.03; both P > .05). Within-eye comparisons of AL growth revealed a 71% slowing for the T3 group (3 years older than part 1) and further revealed a small subset of eyes (10%) that did not respond to treatment.
Dual-focus soft contact lenses continue to slow the progression of myopia in children over a 6-year period revealing an accumulation of treatment effect. Eye growth of the initial control cohort with DFCL was slowed by 71% over the subsequent 3-year treatment period.
Velpatasvir (VEL; GS-5816) is a potent, pangenotypic hepatitis C virus (HCV), non-structural protein 5A inhibitor in clinical development for the treatment of chronic HCV infection. In vitro studies ...indicate that VEL may inhibit several drug transporters and be a substrate for enzyme/drug transport systems in vivo. The purpose of this study was to evaluate the potential of VEL as a perpetrator or victim of metabolic- and transporter-based drug-drug interactions using complementary probe drugs.
This Phase 1 study was a randomized, cross-over, open-label, single- and multiple-dose, five-cohort study. Serial blood samples were collected following oral administration of reference and test treatments. The primary pharmacokinetic parameters of each analyte were compared when administered alone or in combination. The 90% confidence intervals (CI) for the ratio of the geometric least-squares means of the test and reference treatments was calculated for each analyte and parameter of interest.
This study demonstrated that VEL is a weak (P-gp, OATP) to moderate (breast cancer resistance protein) transport inhibitor. As a victim of interactions, VEL is moderately affected by potent inhibitors and to a greater extent, potent inducers of enzyme/drug transporter systems.
The impact of specific transporters and overall contribution of drug transport vs. metabolizing enzymes on the disposition of VEL was characterized through the use of complementary probes, despite the lack of phenotypic specificity, and informs a broad range of drug-drug interaction recommendations.
To estimate the incidence of presumed microbial keratitis with and without loss of visual acuity among wearers of a silicone hydrogel contact lens (Lotrafilcon A, Night & Day, CIBA Vision, Inc., ...Duluth, GA), recently approved for up to 30 days of continuous wear.
Prospective cohort postmarket surveillance study.
Contact lens wearers (recruited from 131 practices) who had been prescribed the lens for intended continuous wear of as many as 30 nights.
The occurrence of a corneal infiltrate was ascertained through a combination of center report and direct contact with participants at 3 and 12 months. Whenever a corneal infiltrate was suspected, study and treatment medical records were systematically reviewed by an Endpoints Committee using a predetermined classification scheme for corneal infiltration. Cases of presumed microbial keratitis were determined based on the constellation of presenting signs and symptoms and clinical course.
The incidence of presumed microbial keratitis with and without loss of visual acuity.
A total of 6245 participants were recruited between August 13, 2002 and July 2, 2003. Of these, 4999 subjects (80%) completed 12 months of follow-up, and these participants contributed a total of 5561 person years of lens wearing experience. Approximately 80% of participants routinely wore their lenses continuously for 3 or more weeks. The overall annual rate of presumed microbial keratitis was 18 per 10,000 (95% confidence interval (CI): 8.5-33.1). There were 2 cases of presumed microbial keratitis with loss of visual acuity, an annual rate of 3.6 per 10,000 (95% CI: 0.4-12.9), and an additional 8 cases without loss of visual acuity, an annual rate of 14.4 per 10000 (95% CI: 6.1-28.4). The rate of presumed microbial keratitis was lower for users reporting typical wear of 3 or more weeks than for those wearing the lens for less than a 3-week continuous period (P = 0.02).
The incidence of loss of visual acuity due to microbial keratitis among users of the silicone hydrogel contact lens was low. The overall rate of presumed microbial keratitis with the wearing schedule of as many as 30 nights was similar to that previously reported for conventional extended-wear soft lenses worn for fewer consecutive nights.
The nucleotide analog NS5B polymerase inhibitor sofosbuvir was approved by the U.S. Food and Drug Administration (FDA) in December 2013 for the treatment of chronic hepatitis C virus (HCV) infection ...in combination with ribavirin or peginterferon and ribavirin. Sofosbuvir was developed to meet an urgent medical need for shorter, safer, simplified, more effective HCV treatment regimens and to reduce or eliminate the need for peginterferon. New treatment regimens were especially required for patient populations with limited treatment options, including patients who had failed prior HCV therapy, those with compensated and decompensated cirrhosis, and those who were either intolerant of or had contraindications to interferon. Sofosbuvir plus ribavirin for patients with genotype 2 or 3 HCV infection was the first approved all‐oral treatment option. Sofosbuvir is also the backbone of the first regimen available for patients awaiting liver transplantation to prevent HCV recurrence, as well as the first oral interferon‐free regimen for patients coinfected with HCV and HIV. This paper describes the development of sofosbuvir up to its original FDA approval.
Taking off fromThe Creative Writer's Survival Guide, John McNally'srelentlessly blunt, bracingly cheerful, and immensely helpful map tobeinga writer,Vivid and Continuousis an equally blunt, cheerful, ...and helpful map tolearningto be a writer. While acknowledging that many fine books cover such essentials of fiction writing as point of view, characterization, and setting, McNally sets out in this new book-intended as a supplement to beginning fiction-writing classes or as the sole text for upper-level or graduate courses-to solve the tricky second-tier problems that those books cover only in footnotes.
Vivid and Continuoustakes its inspiration from John Gardner, whose essential truths inOn Becoming a Novelistclarified McNally's goal of communicating a "vivid and continuous dream" with his own writing. In fifteen concise, energizing chapters, he dispenses advice gained from almost thirty years of studying, writing, and teaching. How do you avoid the pitfalls inherent in the most common subjects for stories? How do you create memorable minor characters? What about managing references to pop culture without distracting your readers, revising a story to bring its subtext into focus, or exploring the twenty most common craft-related quirks that lessen immediacy for your readers? How do you keep from overdosing on similes and metaphors or relying on too many flashbacks to provide necessary backstory? How do you learn to listen when your story tries to talk to you? Finally, how can you resist "John McNally's Sure-Fire Formula for Becoming Funnier in 30 Days"?
McNally cites many novels and short stories as examples that best illustrate the lessons he wants to impart, the writer's life, or the writer's craft, as well as his own favorite authors' novels and short story collections. Exercises at the end of each chapter reinforce its point and serve as practical catalysts for new writings and directions.
Just blunt enough to get your attention but not blunt enough to crush you, challenging but not discouraging, personal but not ego-ridden, snarky but not mean, John McNally will prompt you to think more deeply about a variety of issues that will push you toward writing more meaningful, more accomplished work.
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