Summary
Background
In Hong Kong, most patients with hepatitis C virus (HCV) have either genotype 6a or 1b infection.
Aim
To evaluate the efficacy and safety of sofosbuvir with ribavirin in ...treatment‐naïve patients in Hong Kong with HCV genotype 1 or 6.
Methods
In an open‐label study, patients were randomised to sofosbuvir 400 mg once daily plus ribavirin 1000–1200 divided twice daily for 12 (n = 10), 16 (n = 11) or 24 (n = 10) weeks. The primary endpoint was the percentage of patients with HCV RNA < LLOQ (lower limit of quantification, 25 IU/mL) 12 weeks after cessation of therapy (SVR12).
Results
All 31 patients (20 HCV genotype 1 and 11 genotype 6) had HCV RNA < LLOQ by Week 4 of treatment and at their last on‐treatment visit. SVR12 rates were high in all treatment groups: 100% (10/10) for 12 weeks, 100% (11/11) for 16 weeks and 90% (9/10) for 24 weeks of therapy. The only patient who did not reach SVR12 had genotype 1 HCV and relapsed at post‐treatment Week 4. Sofosbuvir with ribavirin was generally well tolerated. The most common adverse events were malaise (13%) and upper respiratory tract infection (13%), followed by anaemia (10%). No patients experienced serious adverse events. One patient discontinued treatment at Week 16 because of an adverse event. The event, upper respiratory tract infection, was not considered treatment related by the investigator. This subject achieved SVR12.
Conclusions
The all‐oral regimen sofosbuvir plus ribavirin is effective in treatment‐naïve patients in Hong Kong with genotype 1 or 6 HCV. Trial registration number: NCT02021643.
Summary
The study aimed to evaluate the effects of baseline hepatitis C virus (HCV) nonstructural protein 5A (NS5A) resistance‐associated substitutions (RASs) on sustained virologic response to ...ledipasvir (LDV)‐containing regimens in the absence of sofosbuvir (SOF) in patients with HCV genotype (GT) 1 infection across 6 phase 2 clinical studies. We analysed data from 1103 patients who received either LDV + vedroprevir (NS3 protease inhibitor) + tegobuvir (NS5B inhibitor) ± ribavirin or LDV + ribavirin + pegylated interferon. Population sequencing of HCV NS5A was performed at baseline and at virologic failure from patient plasma samples. Of 1045 patients with available baseline sequences, 747 (67.7%) had GT1a, and 298 (26.9%) had GT1b infection. The overall prevalence of NS5A RASs at baseline was 9.4%; 7.6% (57/747) and 13.8% (41/298) of patients with GT1a and GT1b infection, respectively. The majority of GT1a‐infected patients with NS5A RASs at baseline had a single NS5A RAS (78.9%) at NS5A positions K24R, M28T, Q30H/L, L31M and Y93H/N/C/S. The spectrum of NS5A RASs detected in GT1b patients was much less diverse compared to GT1a patients, with all patients harbouring a single NS5A RAS either L31M or Y93H/C. For patients treated with LDV‐containing regimens in the absence of SOF, the presence of baseline NS5A RASs was associated with low SVR rates. In patients with virologic failure, nearly all had either pre‐existing and/or emergent NS5A RASs: 287/287 (100%) and 40/42 (95.2%) patients with GT1a and GT1b infection, respectively. Three novel NS5A substitutions were identified as emergent NS5A RASs: K26E and S38F in GT1a; and L31I in GT1b. In conclusion, the presence of NS5A RASs at baseline reduced the SVR rate in patients treated with LDV in combination vedroprevir + tegobuvir ± ribavirin or ribavirin + pegylated interferon. Virologic failure was associated with the detection of NS5A RASs in nearly all patients. These results suggest that the resistance barrier may differ depending on HCV drug combination and may be more important than that of the individual DAAs.
Vision provides information about the properties and identity of objects. The ease with which we perceive object properties belies the difficulty of the underlying information-processing task. In the ...case of object color, retinal information about object reflectance is confounded with information about the illumination as well as about the object's shape and pose. There is no obvious rule that allows transformation of the retinal image to a color representation that depends primarily on object surface reflectance. Under many circumstances, however, object color appearance is remarkably stable across scenes in which the object is viewed. Here, we review a line of experiments and theory that aim to understand how the visual system stabilizes object color appearance. Our emphasis is on models derived from explicit analysis of the computational problem of estimating the physical properties of illuminants and surfaces from the retinal image, and experiments that test these models. We argue that this approach has considerable promise for allowing generalization from simplified laboratory experiments to richer scenes that more closely approximate natural viewing. We discuss the relation between the work we review and other theoretical approaches available in the literature.
Introduction
Chronic hepatitis C virus (HCV) infection is prevalent among patients with inherited bleeding disorders and is a leading cause of mortality in those with haemophilia.
Aim
We evaluated ...the efficacy and safety of ledipasvir–sofosbuvir and sofosbuvir plus ribavirin in patients with chronic HCV genotype 1–4 infection and an inherited bleeding disorder.
Methods
Ledipasvir–sofosbuvir was administered for 12 weeks to patients with genotype 1 or 4 infection and for 12 or 24 weeks to treatment‐experienced cirrhotic patients with genotype 1 infection. Patients with genotype 2 and 3 infection received sofosbuvir plus ribavirin for 12 and 24 weeks respectively.
Results
The majority of the 120 treated patients had a severe bleeding disorder (55%); overall, 65% of patients had haemophilia A and 26% of patients had haemophilia B; 22% were HIV coinfected. Sustained virologic response at 12 weeks posttreatment was 99% (98/99) in patients with genotype 1 or 4 infection; 100% (5/5) in treatment‐experienced cirrhotic patients with genotype 1 infection; 100% (10/10) in patients with genotype 2 infection; and 83% (5/6) in patients with genotype 3 infection. There were no treatment discontinuations due to adverse events (AEs). The most frequent non‐bleeding AEs were fatigue, headache, diarrhoea, nausea and insomnia. Bleeding AEs occurred in 22 patients, of which all but one were considered unrelated to treatment.
Conclusion
Treatment with ledipasvir–sofosbuvir for patients with HCV genotype 1 or 4 infection or sofosbuvir plus ribavirin for patients with genotype 2 or 3 infection was highly effective and well tolerated among those with inherited bleeding disorders.
Summary
Background
For liver transplant recipients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co‐infection, recurrence after LT is associated with a higher risk of graft loss ...than for HCV mono‐infected patients. Prior HCV treatment options were limited by side effects and drug–drug interactions.
Aim
To evaluate treatment outcomes with sofosbuvir (SOF)‐based therapy among HIV/HCV coinfected liver transplant recipients.
Methods
Access to SOF and ribavirin (RBV) prior to regulatory approval was attained via an international compassionate access program for transplant recipients with a life expectancy of 1 year or less in the absence of HCV treatment. This report focuses on the short and longer term outcomes in HCV‐HIV co‐infected liver transplant recipients.
Results
Twenty patients were treated, nine with early severe recurrence and 11 with cirrhosis. Eleven patients received SOF and RBV, one SOF, RBV and Peg‐interferon, three SOF, RBV and simeprevir and five SOF, RBV and daclatasvir. Of the 18 patients who completed treatment, 16 (89%) achieved sustained virological response 12 weeks after the end of treatment (SVR12). Liver function tests (including bilirubin and albumin) improved significantly over time. Nineteen serious adverse events occurred in eight (40%) patients, none of them related to SOF. Two patients died during treatment and another, 1 year after the end of therapy, due to progressive end‐stage liver disease. Importantly, HIV suppression was not compromised. No significant drug‐drug interactions were reported.
Conclusions
Sofosbuvir‐based regimens are safe, well‐tolerated and provide high rates of SVR in HCV‐HIV co‐infected patients with severe recurrence after‐liver transplant.
There is a large literature characterizing human perception of the lightness and color of matte surfaces arranged in coplanar arrays. In the past ten years researchers have begun to examine ...perception of lightness and color using wider ranges of stimuli intended to better approximate the conditions of everyday viewing. One emerging line of research concerns perception of lightness and color in scenes that approximate the three-dimensional environment we live in, with objects that need not be matte or coplanar and with geometrically complex illumination. A second concerns the perception of material surface properties other than color and lightness, such as gloss or roughness. This special issue features papers that address the rich set of questions and approaches that have emerged from these new research directions. Here, we briefly describe the articles in the issue and their relation to previous work.
We report for the first time that primary human neutrophils can undergo persistent, directionally biased movement away from a chemokine in vitro and in vivo, termed chemorepulsion or fugetaxis. ...Robust neutrophil chemorepulsion in microfluidic gradients of interleukin‐8 (IL‐8; CXC chemokine ligand 8) was dependent on the absolute concentration of chemokine, CXC chemokine receptor 2 (CXCR2), and was associated with polarization of cytoskeletal elements and signaling molecules involved in chemotaxis and leading edge formation. Like chemoattraction, chemorepulsion was pertussis toxin‐sensitive and dependent on phosphoinositide‐3 kinase, RhoGTPases, and associated proteins. Perturbation of neutrophil intracytoplasmic cyclic adenosine monophosphate concentrations and the activity of protein kinase C isoforms modulated directional bias and persistence of motility and could convert a chemorepellent to a chemoattractant response. Neutrophil chemorepulsion to an IL‐8 ortholog was also demonstrated and quantified in a rat model of inflammation. The finding that neutrophils undergo chemorepulsion in response to continuous chemokine gradients expands the paradigm by which neutrophil migration is understood and may reveal a novel approach to our understanding of the homeostatic regulation of inflammation.
Summary
In Korea, patients with chronic hepatitis C virus (HCV) infection are typically treated with pegylated interferon‐alpha plus ribavirin, but interferons are contraindicated in many patients ...and are often poorly tolerated, particularly by the elderly and those with advanced liver disease. No interferon‐free treatment regimens are approved in Korea. Sofosbuvir is an oral nucleotide analog inhibitor of the HCV nonstructural 5B RNA polymerase. It is approved in the USA, European Union and Japan for treating a number of HCV genotypes, including genotype 2. Genotype 2 has a seroprevalence of 38–46% in Korea. This single‐arm, phase 3b study (NCT02021643) examined the efficacy and safety of sofosbuvir plus ribavirin (12‐week duration) in chronic genotype 2 HCV‐infected treatment‐naive and treatment‐experienced Korean patients with and without cirrhosis. The proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12) was 97% (125/129), with 96% (101/105) of treatment‐naive and 100% (24/24) of treatment‐experienced patients achieving SVR12. Two patients experienced virologic failure (n = 1, on‐treatment failure; n = 1, relapse). No patient discontinued study treatment due to an adverse event (AE). The most common treatment‐emergent AEs were headache (18%, 23/129) and pruritus (15%, 19/129). Few patients had grade 3 AEs (5%, 6/129) or grade 3 laboratory abnormalities (12%, 15/129). No grade 4 AE was reported. These data suggest that 12 weeks of treatment with the all‐oral, interferon‐free regimen of sofosbuvir plus ribavirin is effective and well tolerated in Korean patients with chronic genotype 2 HCV infection.
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