Interleukin-17A (IL-17A) is involved in antibody specificity to conformational epitopes.

The specificity of antibodies (Ab) is essential for the precise recognition of foreign or dangerous molecules. We have shown that mice infected with non-pathogenic Lactate Dehydrogenase Elevating Virus (LDV) inoculated with human growth hormone (hGH) or Ovalbumin (OVA), exhibit modified specificity of anti-hGH or anti-OVA Ab associated with the secretion of IFN-γ, IL-13, and IL-17. Cytokines are directly or indirectly involved in the isotypes, specificity, and affinity of Ab. Accordingly, here we investigated the effect of IL-17 neutralization on Ab specificities to OVA and Diphtheria Toxoid (DTx) in a mouse model of viral infection. Thereby, we employed an anti-cytokine "auto-vaccination" with an OVA/IL-17A complex or a Monoclonal Ab (MAb) anti-IL-17A (MM17/F3). Competitive ELISA assays were used to estimate the quality of the humoral immune response and the amount of Abs to conformational versus linear antigenic determinants. Results indicated that the OVA/IL-17A complex increased Abs levels to conformational epitopes of OVA, while LDV prolonged antibodies for a longer period. Mice treated with MM17F3 MAb showed an increase in Abs to conformational epitopes of OVA. A similar effect, confirmed by a competitive Western-blot assay, was produced by LDV. Moreover, an increased level of IgM, IgG1, and IgG2a was found in infected animals. Similarly, MAb anti-IL-17A treatment increased the proportion of Ab to conformational epitopes of DTx in uninfected mice, while LDV decreased this parameter. In conclusion, our findings demonstrate a correlation between IL-17A neutralization and a change in Ab specificity to OVA or DTx, presenting a novel strategy for obtaining Abs with higher specificity.

Single-Point and Surface Quality Assessment Algorithm in Continuous Production with the Use of 3D Laser Doppler Scanning Vibrometry System.

In the current economic situation of many companies, the need to reduce production time is a critical element. However, this cannot usually be carried out with a decrease in the quality of the final product. This article presents a possible solution for reducing the time needed for quality management. With the use of modern solutions such as optical measurement systems, quality control can be performed without additional stoppage time. In the case of single-point measurement with the Laser Doppler Vibrometer, the measurement can be performed quickly in a matter of milliseconds for each product. This article presents an example of such quality assurance measurements, with the use of fully non-contact methods, together with a proposed evaluation criterion for quality assessment. The proposed quality assurance algorithm allows the comparison of each of the products' modal responses with the ideal template and stores this information in the cloud, e.g., in the company's supervisory system. This makes the presented 3D Laser Vibrometry System an advanced instrumentation and data acquisition system which is the perfect application in the case of a factory quality management system based on the Industry 4.0 concept.

Efficacy of a new fragmentation pattern in femtosecond laser-assisted cataract surgery with the Ziemer FEMTO LDV Z8.

PURPOSE: To determine the efficacy of different fragmentation patterns in femtosecond laser-assisted cataract surgery (FLACS) using Ziemer FEMTO LDV Z8. METHODS: We compared three different types of surgery: conventional cataract surgery (CCS), FLACS with conventional radial slices (named No-Spiderweb), and FLACS with a novel fragmentation pattern (radial slices combined with one or two rings) called "Spiderweb." Visual acuity (VA), nuclear opacity (NO) according to the Lens Opacities Classification System (LOCS lll), effective phacoemulsification time (EPT) and vacuum time were obtained for 845 eyes. RESULTS: Using FLACS (Spiderweb + No-Spiderweb), EPT was significantly reduced by 26% compared to CCS (FLACS: 2.46 ± 2.60 s; CCS: 3.34 ± 2.89 s; ΔM = - 0.88 s, p < .001). Furthermore, EPT as a function of progression of lens opacity was found to be not only lower in Spiderweb compared to CCS, but also in comparison with No-Spiderweb. At NO3, a significant reduction of 65% in EPT was observed by using Spiderweb compared to CCS (Spiderweb: 0.68 ± 1.23 s; CCS: 1.96 ± 1.53 s; ΔM = - 1.28 s, p <.001). Interestingly, EPT at NO3 was also significantly reduced by 57% in Spiderweb compared to No-Spiderweb (Spiderweb: 0.68 ± 1.23 s; No-Spiderweb: 1.57 ± 1 .59 s; ΔM = - 0.90 s, p <.001). The use of Spiderweb only marginally extends the vacuum time compared to No-Spiderweb by 11 s (Spiderweb: 209.13 ± 35.83 s; No-Spiderweb: 198.35 ± 36.84 s; p = .003) and the postoperative improved VA showed no significant difference among the different types of surgery (all ps ≥ .05). CONCLUSION: FLACS significantly reduces EPT compared to CCS. Furthermore, the novel Spiderweb pattern significantly reduces EPT in patients with a cataract of NO3 compared to CCS, but also to FLACS with the existing radial pattern (No-Spiderweb).

Degenerative Myelopathy and Neuropathy in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) Mice Caused by Lactate Dehydrogenase-Elevating Virus (LDV).

Following implantation of patient-derived xenograft (PDX) breast carcinomas from three separate individuals, 33/51 female NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice presented with progressive, unilateral to bilateral, ascending hindlimb paresis to paralysis. Mice were mildly dehydrated, in thin to poor body condition, with reduced to absent hindlimb withdrawal reflex and deep pain sensation. Microscopically, there was variable axonal swelling, vacuolation, and dilation of myelin sheaths within the ventral spinal cord and spinal nerve roots of the thoracolumbar and sacral spinal cord, as well as within corresponding sciatic nerves. Results of PCR screening of PDX samples obtained at necropsy and pooled environmental swabs from the racks housing affected animals were positive for lactate dehydrogenase-elevating virus (LDV). LDV is transmitted through animal-animal contact or commonly as a contaminant of biologic materials of mouse origin. Infection is associated with progressive degenerative myelopathy and neuropathy in strains of mice harboring endogenous retrovirus (AKR, C58), or in immunosuppressed strains (NOD-SCID, Foxn1nu), and can interfere with normal immune responses and alter engraftment and growth of xenograft tumors in immunosuppressed mice. This is the first reported series of LDV-induced poliomyelitis in NSG mice and should be recognized as a potentially significant confounder to biomedical studies utilizing immunodeficient xenograft models.

The effectiveness and safety of direct-acting antivirals for hepatitis C virus treatment: A single-center experience in Saudi Arabia.

Background: The introduction of direct-acting antivirals (DAA) to treat the hepatitis C virus (HCV) overcame many drawbacks of interferon-based therapy. DAA achieved sustained viral response (SVR) rates above 90% and overcame many drawbacks of pegylated interferon regimens.The HCV genotype (GT) distribution varies by geographical area, with GT-4 being most prevalent in the Middle East region, including Saudi Arabia. Yet, the real-world evidence about using DAAs in the Saudi population is limited.Thus, the aim of this study to investigate the effectiveness and safety of DAAs in Saudi patients with HCV infection. Methods: A retrospective cohort study included patients treated with DAAs from 2015 to 2017 at a tertiary care hospital in Riyadh, Saudi Arabia. All patients with HCV treated with either ledipasvir plus sofosbuvir (LDS/SOF) ± ribavarin (RBV) or ombitasvir-paritaprevir-ritonavir (OBV/PTV/r) ± dasabuvir (DSV) ± RBV were included. Using a per-protocol analysis, the effectiveness outcome was the end-of-treatment response (EOTr) and Sustained virologic reponce12 weeks after competing the regimen (SVR12). The secondary safety outcome was the adverse event related to the therapy reported by the patients. Results: A total of 97 patients were included; with the majority infected with GT-4 (64 %), followed by GT-1 (18 %), in addition to 8 % having a mixed GT (1 + 4). The EOTr and SVR12 rates were 98 % and 96 %, respectively. SVR12 was 94.4 % within the LDS/SOF ± RBV group and 97.7 % within the OBV/PTV/r ± DSV ± RBV group. Only 4 % had a response failure due to relapse or breakthrough, and all were infected with mixed GT1 + 4. Medications were well tolerated with minimal side effects, including vomiting, nausea, and weakness. Conclusion: DAAs regimens are associated with high rates of SVR12 and are well tolerated with a good safety profile in Saudi HCV-infected patients.

Multipoint Wave Measurement in Tuned Liquid Damper Using Laser Doppler Vibrometer and Stepwise Rotating Galvanometer Scanner.

Liquid dampers, such as tuned liquid dampers (TLDs), are employed to improve serviceability by reducing wind-affected building vibrations. In order to maximize the vibration suppression efficiency of the liquid damper, the tuning frequency of the liquid damper should match the natural frequency of the building. Experimental evaluation of the tuning frequency of a liquid damper performed in a factory prior to installation in a building is a critical task to ensure correct performance, and for this, multipoint measurement of the TLD is required. In this study, a novel liquid level measurement system combining Laser Doppler Vibrometer (LDV) and a stepwise rotating galvanometer scanner was developed to observe liquid sloshing in TLD. The proposed system can measure the liquid level at multiple points simultaneously with a single laser point. In the experimental phase, the liquid damper's natural frequency and mode shape are experimentally evaluated utilizing the developed system. The performance of the proposed system was verified by comparison with the video sensing system.

Signal Diversity for Laser-Doppler Vibrometers with Raw-Signal Combination.

The intensity of the reflected measuring beam is greatly reduced for laser-Doppler vibrometer (LDV) measurements on rough surfaces since a considerable part of the light is scattered and cannot reach the photodetector (laser speckle effect). The low intensity of the reflected laser beam leads to a so-called signal dropout, which manifests as noise peaks in the demodulated velocity signal. In such cases, no light reaches the detector at a specific time and, therefore, no signal can be detected. Consequently, the overall quality of the signal decreases significantly. In the literature, first attempts and a practical implementation to reduce this effect by signal diversity can be found. In this article, a practical implementation with four measuring heads of a Multipoint Vibrometer (MPV) and an evaluation and optimization of an algorithm from the literature is presented. The limitations of the algorithm, which combines velocity signals, are shown by evaluating our measurements. We present a modified algorithm, which generates a combined detector signal from the raw signals of the individual channels, reducing the mean noise level in our measurement by more than 10 dB. By comparing the results of our new algorithm with the algorithms of the state-of-the-art, we can show an improvement of the noise reduction with our approach.

Using a Retro-Reflective Membrane and Laser Doppler Vibrometer for Real-Time Remote Acoustic Sensing and Control.

Microphones have been extensively studied for many decades and their related theories are well-established. However, the physical presence of the sensor itself limits its practicality in many sound field control applications. Laser Doppler vibrometers (LDVs) are commonly used for the remote measurement of surface vibration that are related to the sound field without the introduction of any such physical intervention. This paper investigates the performance and challenges of using a piece of retro-reflective film directly as an acoustic membrane pick-up with an LDV to sense its vibration to form a remote acoustic sensing apparatus. Due to the special properties of the retro-reflective material, the LDV beam can be projected to the target over a wide range of incident angles. Thus, the location of the LDV relative to the pick-up is not severely restricted. This is favourable in many acoustic sensing and control applications. Theoretical analysis and systematic experiments were conducted on the membrane to characterise its performance. One design has been selected for sensing sound pressure level above 20 dB and within the 200 Hz to 4 kHz frequency range. Two example applications-remote speech signal sensing/recording and an active noise control headrest-are presented to demonstrate the benefits of such a remote acoustic sensing apparatus with the retro-reflective material. Particularly, a significant 22.4 dB noise reduction ranging from 300 Hz to 6 kHz has been achieved using the demonstrated active control system. These results demonstrate the potential for such a solution with several key advantages in many applications over traditional microphones, primarily due to its minimal invasiveness.

Computed Poststenotic Flow Instabilities Correlate Phenotypically With Vibrations Measured Using Laser Doppler Vibrometry: Perspectives for a Promising In Vivo Device for Early Detection of Moderate and Severe Carotid Stenosis.

Early detection of asymptomatic carotid stenosis is crucial for treatment planning in the prevention of ischemic stroke. Auscultation, the current first-line screening methodology, comes with severe limitations that create urge for novel and robust techniques. Laser Doppler vibrometer (LDV) is a promising tool for inferring carotid stenosis by measuring stenosis-induced vibrations. The goal of the current study was to evaluate the feasibility of LDV for carotid stenosis detection. LDV measurements on a carotid phantom were used to validate our previously verified high-resolution computational fluid dynamics methodology, which was used to evaluate the impact of flowrate, flow split, and stenosis severity on the poststenotic intensity of flow instabilities (IFI). We evaluated sensitivity, specificity, and accuracy of using IFI for stenoses detection. Linear regression analyses showed that computationally derived pressure fluctuations correlated (R2 = 0.98) with LDV measurements of stenosis-induced vibrations. The flowrate of stenosed vessels correlated (R2 = 0.90) with the presence of poststenotic instabilities. Receiver operating characteristic analyses of power spectra revealed that the most relevant frequency bands for the detection of moderate (56-76%) and severe (86-96%) stenoses were 80-200 Hz and 0-40 Hz, respectively. Moderate stenosis was identified with sensitivity and specificity of 90%; values decreased to 70% for severe stenosis. The use of LDV as screening tool for asymptomatic stenosis can potentially provide improved accuracy of current screening methodologies for early detection. The applicability of this promising device for mass screening is currently being evaluated clinically.

Development of a High-Resolution All-Fiber Homodyne Laser Doppler Vibrometer.

Based on the homodyne detection, a compact and cost-effective all-fiber laser Doppler vibrometer (LDV) with high resolution is presented. For the signal processing, the discrimination algorithm combined with the nonorthogonal correction is applied. The algorithm corrects the quadrature imbalance and other nonlinearity. In the calibration experiment, with the glass pasted on a piezoceramic transducer (PZT), the velocity resolution of 62 nm/s at 4 kHz and displacement resolution of 2.468 pm are achieved. For the LDV-based acousto-optic communication, the minimum detectable sound pressure level (SPL) reached 0.12 Pa under the hydrostatic air-water surface. The results demonstrate that the designed homodyne LDV has a low system background noise and can offer high precision in the vibration measurement.

Measurement of In-Plane Motions in MEMS.

We report a technique to measure in-plane and out-of-plane motions of MEMS using typical out-of-plane (single-axis) Laser Doppler Vibrometers (LDVs). The efficacy of the technique is demonstrated by evaluating the in-plane and out-of-plane modal response and frequency response of an interdigitated comb-drive actuator. We also investigate the validity of observing planar modes of vibration outside their dominant plane of motion and find that it leads to erroneous results. Planar modes must be evaluated in their plan of motion.

Sustained virologic response after eight weeks of treatment with sofosbuvir, ledipasvir, and ribavirin in a decompensated cirrhotic patient with hepatitis C virus genotype 1b.

A 68-year-old Japanese man with decompensated cirrhosis due to hepatitis C virus (HCV) genotype 1b infection was treated with sofosbuvir (SOF; 400 mg/day), ledipasvir (LDV; 90 mg/day), and ribavirin (RBV; 400 mg/day). Before treatment, his Child-Pugh and Model for End-Stage Liver Disease (MELD) scores were 10 (class C) and 13 points, respectively. Although RBV was initially given at two-thirds the normal dose due to anemia, his hemoglobin level gradually declined, and RBV was reduced to 200 mg daily on day 11, and 200 mg every other day on day 14. His alanine aminotransferase level gradually decreased during combination therapy; and HCV-RNA was undetectable on day 28. He complained of fatigue from day 49, and RBV was ceased. On day 56, he asked to discontinue treatment because of strong fatigue and insomnia. As hepatic encephalopathy occurred just after the cessation of direct-acting antivirals, diuretics were discontinued, and treatment with synthetic disaccharides and intractable antibiotics were given, after which his consciousness returned to normal. Ascites gradually disappeared, and a sustained virologic response (SVR) was achieved. At 1.5 years after treatment, his Child-Pugh and MELD scores had improved to 6 (class A) and 10 points, respectively. Although he did not experience hepatic encephalopathy during the observation period, his blood ammonia concentration persistently increased. We reported a case of decompensated cirrhosis in a patient who achieved SVR with SOF/LDV plus RBV for 8 weeks. Although his liver function improved after treatment, careful long-term observation is required for complications of liver cirrhosis, even after HCV elimination.

Experimental and Numerical Design and Evaluation of a Vibration Bioreactor using Piezoelectric Patches.

In this present study, we propose a method for exposing biological cells to mechanical vibration. The motive for our research was to design a bioreactor prototype in which in-depth in vitro studies about the influence of vibration on cells and their metabolism can be performed. The therapy of cancer or antibacterial measures are applications of interest. In addition, questions about the reaction of neurons to vibration are still largely unanswered. In our methodology, we used a piezoelectric patch (PZTp) for inducing mechanical vibration to the structure. To control the vibration amplitude, the structure could be excited at different frequency ranges, including resonance and non-resonance conditions. Experimental results show the vibration amplitudes expected for every frequency range tested, as well as the vibration pattern of those excitations. These are essential parameters to quantify the effect of vibration on cell behavior. Furthermore, a numerical model was validated with the experimental results presenting accurate results for the prediction of those parameters. With the calibrated numerical model, we will study in greater depth the effects of different vibration patterns for the abovementioned cell types.

[Clinical and functional outcomes of correcting low to moderate myopia with FemtoLASIK performed with Russian and Swiss femtolaser platforms]. / Kliniko-funktsional'nye rezul'taty korrektsii miopii slaboi i srednei stepenei metodom FemtoLASIK s ispol'zovaniem otechestvennoi i zarubezhnoi femtolazernykh ustanovok.

PURPOSE: To compare the effectiveness, safety, predictability and stability of FemtoLASIK procedure in low to moderate myopia using Femto Visum and Femto LDV Z6 femtosecond laser platforms and to evaluate the effect of these procedures on corneal higher-order aberrations. MATERIAL AND METHODS: Russian femtolaser platform (1 MHz) was used to form the corneal flap in the main group consisting of 98 patients (98 eyes) with mean spherical equivalent (SE) of -3.73±1.42 D. Swiss femtolaser platform (5 MHz) was used in the control group (94 patients, 94 eyes; mean SE -3.81±1.44 D). Excimer laser ablation was performed using the Russian platform (500 Hz) in both groups. All patients underwent complete ophthalmological examination. The follow-up period was 12 months. RESULTS: Twelve month postoperatively, in the '1 MHz' group uncorrected visual acuity (UCVA) of 1.0 or better was achieved in 91.8% of patients, and in the '5 MHz' group - in 90.4% (p>0.05). There were no registered losses of 2 or more lines of best-corrected visual acuity (BCVA) in either group. In the '1 MHz' group, predictability of targeted refraction within ±0.5 D was achieved in 91.8% of patients, within ±1.0 D - in 99.0%; in the '5 MHz' group - in 91.5% and 98.9% of patients, respectively (p>0.05). Root-mean-square (RMS) deviation of corneal higher-order aberrations in the 6-mm optical zone was increased by 0.072 µm (by 1.21 times) and by 0.077 µm (by 1.22 times) in the '1 MHz' and '5 MHz' groups (p>0.05), respectively. CONCLUSION: The FemtoLASIK procedures performed using Russian (1 MHz) and Swiss (5 MHz) femtosecond laser platforms are effective, safe, predictable, have stable postoperative visual and refractive outcomes, and lead to increase in RMS of corneal higher-order aberrations using both platforms in patients with low to moderate myopia. There were no statistically significant differences between the two femtolaser platforms (p>0.05) for all examined parameters.

Efficacy and Safety of Ledipasvir/Sofosbuvir for the Treatment of Chronic Hepatitis C in Persons With Sickle Cell Disease.

Patients with sickle cell disease are at high risk for chronic hepatitis C infection. Prior treatment has been limited due to the use of ribavirin causing hemolytic anemia and interferon causing cytopenias. We demonstrate the safety and efficacy of fixed-dose combination ledipasvir and sofosbuvir for 12 weeks in this population.

Type I interferon signaling is required for the APOBEC3/Rfv3-dependent neutralizing antibody response but not innate retrovirus restriction.

BACKGROUND: APOBEC3/Rfv3 restricts acute Friend retrovirus (FV) infection and promotes virus-specific neutralizing antibody (NAb) responses. Classical Rfv3 studies utilized FV stocks containing lactate-dehydrogenase elevating virus (LDV), a potent type I interferon inducer. Previously, we showed that APOBEC3 is required for the anti-FV activity of exogenous IFN-alpha treatment. Thus, type I interferon receptor (IFNAR) signaling may be required for the APOBEC3/Rfv3 response. RESULTS: To test if the APOBEC3/Rfv3 response is dependent on type I IFN signaling, we infected IFNAR knockout versus IFNAR/APOBEC3 double-knockout mice with FV/LDV or LDV-free FV, and evaluated acute FV infection and subsequent NAb titers. We show that LDV co-infection and type I IFN signaling are not required for innate APOBEC3-mediated restriction. By contrast, removal of LDV and/or type I IFN signaling abrogated the APOBEC3-dependent NAb response. CONCLUSIONS: APOBEC3 can restrict retroviruses in a type I IFN-independent manner in vivo. By contrast, the ability of APOBEC3 to promote NAb responses is type I IFN-dependent. These findings reveal novel insights on the interplay between type I IFNs and APOBEC3 in vivo that may have implications for augmenting antiretroviral NAb responses.

Clinical evaluation of sofosbuvir/ledipasvir in patients with chronic hepatitis C genotype 1 with and without prior daclatasvir/asunaprevir therapy.

AIM: This study explored treatment outcomes of sofosbuvir (SOF)/ledipasvir (LDV) therapy for chronic hepatitis C patients with and without prior daclatasvir (DCV)/asunaprevir (ASV) therapy. METHODS: Overall, 530 Japanese patients who were infected with hepatitis C virus genotype 1 received SOF/LDV therapy for 12 weeks, and resistance-associated variants (RAVs) in the hepatitis C virus non-structural protein (NS)5A and NS5B regions were assessed at baseline and virological relapse by direct sequencing. RESULTS: Sustained virological response (SVR) rates did not significantly differ between patients with and without NS5A Y93H/N (94.2% [113/120] vs. 97.7% [345/353]), but the SVR rate was significantly lower in patients with prior DCV/ASV therapy compared to those without (69.2% [18/26] vs. 98.4% [496/504], P < 0.001). Among 26 patients with prior DCV/ASV therapy, the prevalence of NS5A multi-RAVs (≥2) was similar between responders and non-responders (61% [11/18] vs. 75% [5/8]), but all patients without RAVs achieved SVR. Multivariate analysis showed that prior DCV/ASV therapy and history of hepatocellular carcinoma were independently associated with treatment failure (odds ratio, 37.55; 95% confidence interval, 10.78-130.76; P < 0.001 for prior DCV/ASV therapy; odds ratio, 4.42; 95% confidence interval, 1.09-18.04; P = 0.03 for the history of HCC). All SOF/LDV failure patients (n = 8) with prior DCV/ASV treatment had two or more factors of cirrhosis, IL28B unfavorable genotype, and baseline NS5A multi-RAVs. The multiple NS5A RAVs had increased but NS5B substitutions, C316N/A207T/A218S or L159F, had not changed at the time of relapse. CONCLUSIONS: Prior DCV/ASV therapy is associated with failure of SOF/LDV therapy due to multiple RAVs.

Cure with ledipasvir/sofosbuvir for chronic hepatitis C virus in an individual with gastric bypass.

WHAT IS KNOWN AND OBJECTIVE: The impact of gastric bypass surgery on the pharmacokinetics of various medications has been reported. Presently, no data exist for the treatment of chronic hepatitis C virus with ledipasvir/sofosbuvir (LDV/SOF) in an individual with a history of gastric bypass. CASE DESCRIPTION: We report the successful cure of an individual who was treated with LDV/SOF who had a history of gastric bypass. The patient tolerated LDV/SOF well while only experiencing a minor headache. WHAT IS NEW AND CONCLUSION: Ledipasvir/sofosbuvir treatment may still be effective in those with a history of gastric bypass surgery.

Sofosbuvir and ledipasvir improve patient-reported outcomes in patients co-infected with hepatitis C and human immunodeficiency virus.

A fixed-dose combination of ledipasvir and sofosbuvir (LDV/SOF) has been approved for treatment of HCV patients. We assessed the effect of LDV/SOF on patient-reported outcomes (PROs) in HIV-HCV-co-infected patients. Patient-reported outcomes data from HIV-HCV-co-infected patients who were treated with LDV/SOF for 12 weeks were collected as a part of a clinical trial (ION-4). Historical controls were HIV-HCV-co-infected patients treated with SOF and ribavirin (RBV) in PHOTON-1. We included 335 HIV-HCV-co-infected patients (SVR-12 in HCV genotype 1 was 96%) who received LDV/SOF, while 223 patients (SVR-12 in HCV genotype 1 was 76.3%) received SOF/RBV. During treatment, patients receiving LDV/SOF showed improvement in all of their PRO scores (+6.0% in activity/energy of CLDQ-HCV, +5.0% in fatigue score of FACIT-F, +6.8% in physical component of SF-36; all P < 0.0001) while those receiving SOF+RBV showed moderate decline in some of their PRO scores (-4.8% in physical functioning of SF-36, -4.4% in fatigue score of FACIT-F, both P < 0.001). Patients who achieved sustained virologic response with LDV/SOF also showed improvement of PROs (average +5.1%) while those treated with SOF/RBV showed less or no improvement (average +1.4%). In a multivariate analysis, in addition to depression and fatigue, receiving SOF+RBV (vs LDV/SOF) was independently associated with more PRO impairment during treatment (beta -6.1 to -12.1%, P < 0.001). Hence, HIV-HCV patients treated with LDV/SOF show significant improvement of their health-related quality of life and other patient-reported outcomes during treatment and after treatment cessation.

The impact of ledipasvir/sofosbuvir on patient-reported outcomes in cirrhotic patients with chronic hepatitis C: the SIRIUS study.

BACKGROUND: Interferon- and ribavirin (RBV)-free regimens can improve patient-reported outcomes (PROs) during treatment. AIM: To compare PROs during treatment with ledipasvir and sofosbuvir (LDV/SOF) to placebo and to LDV/SOF + RBV. METHODS: Treatment-experienced CH-C genotype 1 patients with compensated cirrhosis (N = 154) were randomized to receive 24 weeks of LDV/SOF or 12 weeks of placebo followed by 12 weeks of LDV/SOF + RBV (the SIRIUS clinical trial). While blinded to their HCV RNA level and study treatment, patients completed PRO questionnaires (SF-36, FACIT-F, CLDQ-HCV, WPAI:SHP) at baseline, during and post-treatment. RESULTS: Baseline PRO scores were similar between the two study arms. Patients receiving LDV/SOF showed improvement in a number of PROs (predominantly related to mental health) starting as early as 4 weeks after treatment initiation; no PRO decrement from baseline were noted, and no PRO scores were inferior to placebo (all P > 0.05). In the second 12 weeks, patients who were receiving LDV/SOF continued to improve PROs (up to +9.2% from a 100% maximum possible score, P < 0.05), while patients receiving LDV/SOF + RBV had less gains or no improvement in their PRO scores. However, regardless of the regimen, patients who successfully cleared the virus (N = 149) had significant improvement in all aspects of PROs (up to +12.2% by post-treatment week 12, up to +16.9% by week 24). CONCLUSIONS: Treatment-experienced cirrhotic patients experience a notable improvement of their PROs during treatment with LDV/SOF. Furthermore, achieving SVR-12 is associated with significant PRO improvement, which further improves at post-treatment week 24 in this difficult to treat group of patients with chronic hepatitis C.