Hepatitis C - Impact of treatment with direct-acting antivirals on anxiety and depression

Impact of treatment with direct-acting antivirals on anxiety and depression in chronic hepatitis C 
Marta Gallach , Mercedes Vergara, Joao Pedro da Costa, Mireia Miquel, Meritxell Casas, Jordi Sanchez-Delgado, Blai Dalmau, Núria Rudi, Isabel Parra, Teresa Monllor, Meritxell Sanchez-Lloansí, Angelina Dosal, Oliver Valero, Xavier Calvet
Published: December 19, 2018 https://doi.org/10.1371/journal.pone.0208112

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Abstract
Background and aim
Treatment of hepatitis C with direct-acting antiviral agents (DAA) has few side effects. Although pivotal studies suggested that DAA were safe in patients with psychiatric diseases who could not be treated with previous antiviral therapies, their effects on anxiety and depression have not yet been analysed in clinical practice. The aim of our study was to analyse anxiety and depression in the setting of DAA treatment in a clinical practice series.

Methods
All patients starting DAA treatment between November 1, 2014 and October 31, 2015 were eligible. Patients completed the Hospital Anxiety and Depression scale at different times during treatment. The results were plotted on line graphs and evaluated using a linear regression model with repeated measures.

Results
One hundred and forty-five patients were included (11% with major psychiatric disorders; 32% on psychiatric treatment). Sustained virologic response (SVR) was achieved in 97.3% of cases. Anxiety and depression measures did not differ between time points. No differences between patients on psychiatric treatment or with advanced fibrosis or cirrhosis were found at any time point analysed.

Conclusion
DAA treatment had no impact on anxiety or depression during or after chronic hepatitis C infection treatment, even in high-risk patients with major psychiatric disorders.
Read More: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208112

Minireview - Era of direct acting anti-viral agents for the treatment of hepatitis C

World J Hepatol. Oct 27, 2018; 10(10): 670-684
Published online Oct 27, 2018. doi: 10.4254/wjh.v10.i10.670

The different DAAs with their dose, efficacy, side effects, drug-drug interactions as well as specific treatment against different genotypes of HCV will be discussed.

Minireview

Era of direct acting anti-viral agents for the treatment of hepatitis C 

Monjur Ahmed 

Core Tip: Treatment of hepatitis C has now become much easy and simple with the advent of direct acting anti-viral agents (DAAs) against hepatitis C virus (HCV). Although the DAAs are highly effective in eradicating HCV infection, they have different mechanisms of action, side effects, resistance factors and drug-drug interactions. The treatment also varies in special situations like HCV/ human immunodeficiency virus co-infection and post-liver transplant patients. Physicians treating patients with HCV infection should have a clear knowledge about the DAAs as well as the current guidelines.

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https://www.wjgnet.com/1948-5182/full/v10/i10/670.htm

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https://f6publishing.blob.core.windows.net/eb90831d-fa9b-4df2-9419-4a0288414569/WJH-10-670.pdf

Hepatitis C - Potential drug‐drug interactions between DAAs and concomitant medications

Comorbidities, concomitant medications and potential drug‐drug interactions with interferon‐free direct‐acting antiviral agents in hepatitis C patients in Taiwan 
Chen‐Hua Liu Ming‐Lung Yu Cheng‐Yuan Peng Tsai‐Yuan Hsieh Yi‐Hsiang Huang Wei‐Wen Su Pin‐Nan Cheng Chih‐Lin Lin Ching‐Chu Lo Chi‐Yi Chen Jyh‐Jou Chen Qian Ma

First published: 25 October 2018 https://doi.org/10.1111/apt.15011

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Summary
Background
While direct‐acting antivirals have been approved for treating hepatitis C, the guidelines highlight the importance of considering potential drug‐drug interactions between DAAs and concomitant medications.

Aim
To assess comorbidity prevalence, concomitant medication use and potential drug‐drug interactions between DAAs and concomitant medications for hepatitis C patients in Taiwan.

Methods
This cross‐sectional study enrolled 822 patients from May to August 2016 in Taiwan. Patient demographics, comorbidities and concomitant medications were evaluated by physician surveys.

Results
A total of 709 (86.3%) patients had ≥1 comorbidity; the most prevalent comorbidity categories were diseases of the digestive system (40.1%), circulatory system (38.7%) and endocrine/nutritional/metabolic diseases (35.2%). Elderly patients had more comorbidities. A total of 622 (75.7%) patients received ≥1 concomitant medication; the average number of concomitant medications was 3.2. The most common concomitant medication classes were cardiovascular (34.4%), gastrointestinal (25.7%) and central nervous system drugs (22.7%). Among patients without cirrhosis or with compensated cirrhosis, contraindications were most prevalent with paritaprevir/ritonavir/ombitasvir plus dasabuvir, daclatasvir/asunaprevir and glecaprevir/pibrentasvir (13.3%, 6.0% and 5.4% respectively), and least prevalent with sofosbuvir, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir and sofosbuvir/velpatasvir (0.8%, 1.3%, 1.4% and 2.1% respectively). Sofosbuvir‐based regimens had no contraindications in patients with decompensated cirrhosis.

Conclusion

Our population represented an elderly demographic, with a high prevalence of comorbidities and widespread use of concomitant medications. The potential drug‐drug interactions between these concomitant medications and DAA regimens differed, with the fewest potential interactions with sofosbuvir‐based regimens.

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Serum asunaprevir concentrations showing correlation with the extent of liver fibrosis as a factor inducing liver injuries in patients with genotype-1b hepatitis C virus receiving daclatasvir plus asunaprevir therapy

Serum asunaprevir concentrations showing correlation with the extent of liver fibrosis as a factor inducing liver injuries in patients with genotype-1b hepatitis C virus receiving daclatasvir plus asunaprevir therapy
Yoshihito Uchida, Kayoko Naiki, Jun-ichi Kouyama, Kayoko Sugawara, Masamitsu Nakao, Daisuke Motoya, Mie Inao, Nobuaki Nakayama, Yukinori Imai, Tomoaki Tomiya, Satoshi Mochida Published: October 11, 2018 https://doi.org/10.1371/journal.pone.0205600

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Abstract
Aims
Liver injury can occur during antiviral therapies with direct-acting antivirals (DAAs), potentially necessitating discontinuation of the therapies, with consequent worsening of the sustained viral response (SVR) rates, in patients with hepatitis C virus (HCV). To clarify the mechanisms involved in serum transaminase level elevation, we performed a retrospective evaluation of the serum concentrations of daclatasvir and asunaprevir, both classified as DAAs, in patients receiving treatment with a combination of the two drugs.

Methods
Subjects were 278 Japanese patients with genotype-1b HCV who received daclatasvir plus asunaprevir therapy for more than 4 weeks. Serum concentrations of both the DAAs were measured at 4 weeks after the initiation of therapy.

Result
Liver injuries including serum AST and/or ALT level elevation to 150 U/L or over were found in 34 patients (12.2%). Multivariate logistic regression analysis identified serum asunaprevir concentrations as being significantly associated with developing liver injury, with an odds ratio of 1.046 (95% confidence interval 1.011–1.082, p<0.05). Serum asunaprevir concentrations showed correlation with the extent of liver fibrosis, estimated by peripheral platelets counts and serum albumin levels and baseline and FIB4 index and serum Mac-2 binding protein glycosylation isomer (M2BPGi) levels at 4 weeks of the therapy; the concentrations were significantly higher among patients showing 3.0 or more of M2BPGi levels than among those with the levels less than 3.0; on the other hand, no such correlation/difference was found in serum daclatasvir concentrations.

Conclusion

High serum concentrations of serum asunaprevir, which were associated with the extent of liver fibrosis, appear to provoke the occurrence of liver injury in patients with genotype-1b HCV receiving combined daclatasvir plus asunaprevir therapy.

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https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205600

Recommended Reading

Asunaprevir - Wikipedia

Asunaprevir (formerly BMS-650032, brand name in Japan and Russia[1] Sunvepra) is an experimental drug candidate for the treatment of hepatitis C. It is undergoing development by Bristol-Myers Squibb and is currently in Phase III clinical trials.[2] 

Cardiovascular Risk Management and Hepatitis C: Combining Drugs

Cardiovascular Risk Management and Hepatitis C: Combining Drugs
Elise J. SmoldersPeter J. G. ter HorstSharon WoltersDavid M. Burger Elise J. Smolders

Article First Online: 27 September 2018

Abstract
Direct-acting antivirals (DAAs) are known victims (substrate) and perpetrators (cause) of drug–drug interactions (DDIs). These DAAs are used for the treatment of hepatitis C virus (HCV) infections and are highly effective drugs. Drugs used for cardiovascular risk management are frequently used by HCV-infected patients, whom also are treated with DAAs. Therefore, the aim of this review was to describe DDIs between cardiovascular drugs (CVDs) and DAAs. An extensive literature search was performed containing search terms for the marketed DAAs and CVDs (β-blocking agents, ACE inhibitors, angiotensin II antagonists, renin inhibitors, diuretics, calcium channel blockers, statins/ezetimibe, fibrates, platelet aggregation inhibitors, vitamin K antagonists, heparins, direct Xa inhibitors, nitrates, amiodarone, and digoxin). In particular, the drug labels from the European Medicines Agency and the US Food and Drug Administration were used. A main finding of this review is that CVDs are mostly victims of DDIs with DAAs. Therefore, when possible, monitoring of pharmacodynamics is recommended when coadministering these drugs with DAAs. Nevertheless, it is sometimes better to discontinue a drug on a temporary basis (statins, ezetimide). The DAAs are victims of DDIs in combination with bisoprolol, carvedilol, labetalol, verapamil, and gemfibrozil. Despite there are many DDIs predicted in this review, most of these DDIs can be managed by monitoring the efficacy and toxicity of the victim drug or by switching to another CVD/DAA.

Key Points

Drug-drug interactions (DDIs) can be of major concern in hepatitis C patients with cardiovascular issues as there are many potential DDIs.

Especially clopidogrel and ticagrelor are drugs of which the potential drug-interactions are complex and hard to manage.

With increasing number of new direct-acting antivirals (DAAs) available the number clinical relevant DDIs are decreasing.

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 https://link.springer.com/article/10.1007%2Fs40262-018-0710-1

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https://link.springer.com/content/pdf/10.1007%2Fs40262-018-0710-1.pdf

Hepatitis C - Adverse events from DAAs can persist for months after treatment

Of Interest
March 14, 2018

Side effects associated with different hepatitis C direct-acting antiviral drugs 

March 24, 2018

Patient-Reported Outcomes After HCV Treatment With Sofosbuvir and Velpatasvir, With or Without Voxilaprevir 

May 30, 2018

Prospective Study: No psychiatric side effects with new IFN-free treatment for HCV 

Article

Adverse events from DAAs can persist for months after treatment, study finds

Liz Meszaros, MDLinx | August 21, 2018
Adverse events (AEs) related to treatment with direct-acting antivirals (DAAs) may persist after treatment in a significant number of patients with chronic hepatitis C, according to results from a study published in the European Journal of Gastroenterology and Hepatology. Clinicians and patients should be aware of this possibility.

Abstract: Outcome and adverse events in patients with chronic hepatitis C treated with direct-acting antivirals: a clinical randomized study

“This real-life study is to the best of our knowledge the first to examine the rate of AEs in patients with hepatitis C virus (HCV) genotype (GT) 1 infection, randomized to one of two different DAA regimens in a real-world setting,” noted these authors, led by Christina Sølund, MD, PhD, Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.

Recently, the development of DAA agents has revolutionized the treatment of chronic hepatitis C, which is estimated to affect more than 70 million people worldwide. Before the advent of DAAs, the standard of care for these patients consisted of treatment with pegylated-interferon and ribavirin (RBV), lasting for 24 to 48 weeks, which not only had significantly lower cure rates and tolerability, but also carried a high incidence of severe AEs.

Now in their second iteration, DAAs have changed the playing field in the treatment of chronic hepatitis C by directly targeting the proteins responsible for viral replication. Improved sustained virologic responses (SVR) of 90% or more and good tolerability and efficacy in patients who have historically been difficult to treat—such as those with liver cirrhosis, liver transplantation, or previous treatment failures—have characterized the second-generation DAAs.

Few studies, however, have compared different DAA regimens. For this reason, Dr. Sølund and colleagues conducted their investigation. They included 96 patients with chronic hepatitis C with either GT1 or GT3, who were randomized to two different treatment arms. The first was comprised of 72 patients infected with GT1, who were treated for 12 weeks with ledipasvir/sofosbuvir/RBV vs paritaprevir/ombitasvir/ritonavir/dasabuvir/RBV. The second group consisted of 24 patients infected with GT3, who were treated with daclatasvir/sofosbuvir/RBV for 12 weeks vs a 24-week course of sofosbuvir/RBV.

Unfortunately, due to a change in national treatment guidelines, the GT3 treatment arm was prematurely terminated. Therefore, efficacy data are available from both GT3 and GT1 patients, but the incidence of AEs is available only for GT1 patients.

Cure was achieved by 97% of GT1 patients and 83% of GT3 patients, with SVR at 12 months. Virologic failure occurred in only one G3 patient.

Adverse events occurred in 97% of GT1 patients with the most common being anemia, fatigue, and headache.

“We found no statistically significant difference in AEs, neither between treatment groups nor in relation to anemia or cirrhosis. The overall rate of AEs was comparable to other real-world studies, but the frequency of the most common AEs, such as anemia (78%), fatigue (74%), headache (74%), pruritus/eczema (46%), and heartburn/abdominal discomfort (38%), was higher in our study,” they added.

Only 3% of GT1 patients discontinued treatment due to AEs. Notably, 45% of patients with AEs thought to be related to a DAA regimen still manifested the AEs at 4 weeks after treatment. At 12 weeks this was still the case in 11% of patients.

“We consider this an important finding that can be used when informing the patient about AEs that might be caused by the DAA regimen, despite the number of patients included in our study being relatively small,” noted the authors. “The low discontinuation rate reflects that AEs possibly induced by DAA treatment are rarely treatment limiting, even when DAA treatment is given in combination with RBV,” they concluded.

This study received support from the Faculty of Health and Medical Sciences, University of Copenhagen and from Hvidovre Hospital Research Foundation, the Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, the Capital Region of Denmark’s Research Foundation, the Innovation Fund Denmark project 060-2009-3, the Novo Nordisk Foundation, and the Danish Research Council.

https://www.mdlinx.com/infectious-disease/article/2470

Prospective Study: No psychiatric side effects with new IFN-free treatment for HCV

BMC Psychiatry
Direct-acting antiviral treatment in real world patients with hepatitis C not associated with psychiatric side effects: a prospective observational study
Isak Sundberg, Anders Lannergård, Mia Ramklint and Janet L. Cunningham

BMC Psychiatry 2018 https://doi.org/10.1186/s12888-018-1735-6
Received: 26 September 2017
Accepted: 11 May 2018
Published: 29 May 2018

Abstract
Background
Treatment of Hepatitis C virus (HCV) infection has evolved from interferon (IFN)-based treatments to direct-acting antivirals (DAAs). Patients with HCV have an elevated psychiatric morbidity (including substance abuse) and patients with such comorbidity have often been excluded from treatment with IFN. To date, little is known about psychiatric adverse effects of DAA-based regimens. We therefore aimed to study the psychiatric side effects of new IFN-free treatment for HCV (including depressive symptoms and sleep) in real world patients also including those with a history of psychiatric diagnosis, substance abuse or drug dependence.

Methods

Consecutive patients were monitored during treatment with three of the latest DAA agents (sofosbuvir, simeprevir and daclatasvir). Repeated expert psychiatric assessments from baseline to 12 weeks post-treatment were performed with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) clinical version and the self-report versions of the Montgomery Åsberg Depression Rating Scale (MADRS-S) and the Pittsburgh Sleep Quality Index (PSQI). Friedman’s test was performed to calculate differences in the MADRS-S and PSQI over time. In a post-hoc analysis Wilcoxon’s test was used to compare baseline depressive symptoms with those at post-treatment. Spearman’s rank correlation test was conducted in another post-hoc analysis to evaluate the correlation between symptoms of depression and HCV viral load at baseline.

Results
At baseline, 15/17 patients (88%) had a history of any psychiatric diagnosis; 11 (65%) had a history of substance abuse or dependence; and 11 (65%) had previously been treated with IFN and six of those had experienced psychiatric side effects. There was no correlation between depressive symptoms and HCV viral load at baseline. Symptoms of depression did not increase during DAA treatment and were lower 12 weeks post-treatment compared with baseline: MADRS-S 10.7 vs. 8.3 (p = 0.01). This observation held when excluding patients taking antidepressant medication. Sleep quality did not significantly change during treatment. Adherence to treatment was estimated to 95% and sustained virological response was 88%.

Conclusions
Despite high psychiatric morbidity, including previous substance abuse, patients successfully completed DAA treatment without increasing depressive symptoms or sleep disturbance. Symptoms of depression were significantly reduced 12 weeks after DAA treatment.

Keywords
Hepatitis C virus Direct-acting antiviral Depression Sleep Side effects

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Watch - The Truth about Hepatitis C Treatment long term Side Effects

Karen Hoyt is devoted to offering support and accurate information to people coping with the effects of liver disease through a series of informative videos, topics include ascites, hepatic encephalopathy and other liver-related complications.

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May 6, 2018

The Truth about Hepatitis C Treatment long term Side Effects

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Blog
Karen shares her own journey living with cirrhosis and liver cancer, to the emotional ups and downs of her lifesaving liver transplant. If you haven't found Karen yet, she is a master at providing patient-friendly diet and lifestyle tips for liver disease patients, filling a much needed void for people living with the hepatitis C virus (HCV) and fatty liver disease. Visit her blog: I Help C.

The Liver Loving Diet

To help guide you through a well-balanced diet, which is essential to help fight or curtail liver damage, Karen published: The Liver Loving Diet. The book is a labor of love, a huge undertaking for someone dealing with Hepatic Encephalopathy (HE), a serious disorder that can happen without warning if you have advanced liver disease, causing confusion, brain fatigue (brain fog) and problems with hand movements, making concentration and typing difficult. Get to know Karen better by reading an excerpt from her book: Emergency Room Diagnosis with Liver Cirrhosis.

Of Interest
HCV Advocate
Weekly Special: HCV Treatment Side Effect Management

Patient-Reported Outcomes After HCV Treatment With Sofosbuvir and Velpatasvir, With or Without Voxilaprevir

This is an extensive evaluation of Patient-Reported Outcomes (PROs) during and after treatment with 2 pangenotypic regimens for HCV. Our data clearly show that both regimens improve several PRO scores shortly after initiation of treatment. This improvement in PROs persisted throughout treatment and was even more considerable after achieving SVR-12. Moreover, the gains in PROs were not only sustained 12 weeks post-treatment but continued to further improve by Week 24 of follow-up.

Clinical Gastroenterology and Hepatology

April 2018 Volume 16, Issue 4, Pages 567–574.e6

Patient-Reported Outcomes Following Treatment of Chronic Hepatitis C Virus Infection With Sofosbuvir and Velpatasvir, With or Without Voxilaprevir

Young-A HeoEmail authorEmma D. Deeks

Background & Aims
Chronic infection with hepatitis C virus (HCV) has many hepatic and extrahepatic manifestations, measured by patient-reported outcomes (PROs). We measured changes in PROs during HCV treatment with recently developed pangenotypic regimens and from a sustained virologic response 12 weeks after treatment ended (SVR12).

Methods
We collected PRO data from 2 multi-center, blinded, international phase 3 trials of sofosbuvir, velpatasvir, and voxilaprevir, from 748 patients previously treated with direct-acting antivirals for chronic infection with HCV of any genotype (59% HCV genotype 1, 43% with compensated cirrhosis) (POLARIS-1 and POLARIS-4). The combination of sofosbuvir, velpatasvir, and voxilaprevir was given to 445 patients, the combination of sofosbuvir and velpatasvir to 151 patients, and placebo to 152 patients. Patients completed the SF-36, FACIT-F, CLDQ-HCV, and WPAI:SHP questionnaires at baseline, during treatment, and during the follow-up period.

Results
There was no difference in baseline clinical or demographic features or PRO scores among the groups (all P > .05). The group that received the combination of sofosbuvir, velpatasvir, and voxilaprevir had more gastrointestinal symptoms than the groups that received sofosbuvir and velpatasvir or placebo (P = .0001). An SVR12 was achieved by 90.1% of patients who received sofosbuvir and velpatasvir vs 96.9% of patients who received sofosbuvir, velpatasvir, and voxilaprevir (P = .0008). After 12 weeks of treatment, some PRO scores improved in both treatment groups (by 2.5 or by 9.1 points, on a 0–100 scale; P < .05) but not in the placebo group. All increases in PRO scores were sustained or increased after treatment ended (an increase of up to 11.1 points at 12 weeks after treatment and an increase of up to 16.6 points at 24 weeks after treatment ended) (P < .05 for all but 2 PROs). There were no differences in PROs between the sofosbuvir and velpatasvir group vs the sofosbuvir, velpatasvir, and voxilaprevir group (all P > .05). In multivariate analysis, after adjustment for clinical and demographic factors and baseline PRO scores, receiving treatment was associated with higher PROs scores than receiving placebo (beta as high as 5.1) (P < .05).

Conclusions
In an analysis of data from 2 phase 3 clinical trials of patients with chronic HCV infection of any genotype, we found the combination of sofosbuvir, velpatasvir, with or without voxilaprevir, to increase PRO scores compared with placebo. These findings indicate the comprehensive benefit of these regimens during treatment and after SVR.

Discussion
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This is an extensive evaluation of Patient-Reported Outcomes (PROs) during and after treatment with 2 pangenotypic regimens for HCV. Our data clearly show that both regimens improve several PRO scores shortly after initiation of treatment. This improvement in PROs persisted throughout treatment and was even more considerable after achieving SVR-12. Moreover, the gains in PROs were not only sustained 12 weeks post-treatment but continued to further improve by Week 24 of follow-up.

We believe that initial gains in PROs are related to viral suppression that can occur with both regimens. Indeed, no similar improvement was seen in subjects who received placebo in a blinded fashion. In addition, unlike previously studied interferon + ribavirin-containing and interferon-free ribavirin-containing regimens, which resulted in decrements in PROs during treatment and weeks after treatment cessation,¹⁸x18Younossi, Z.M., Stepanova, M., Nader, F. et al. The patient's journey with chronic hepatitis C from interferon plus ribavirin to interferon- and ribavirin-free regimens: a study of health-related quality of life. Aliment Pharmacol Ther. 2015; 42: 286–295

Crossref | PubMed | Scopus (43) | Google ScholarSee all References^{, 22}x22Younossi, Z.M., Stepanova, M., Henry, L. et al. An in-depth analysis of patient-reported outcomes in patients with chronic hepatitis C treated with different anti-viral regimens. Am J Gastroenterol. 2016; 111: 808–816

Crossref | PubMed | Scopus (25) | Google ScholarSee all References no treatment-emergent PRO decrements were observed in actively treated patients in this study. Furthermore, presented PRO gains were similar to those reported for other all-oral interferon- and ribavirin-free regimens regardless of their duration.⁸x8Younossi, Z. and Henry, L. Systematic review: patient-reported outcomes in chronic hepatitis C: the impact of liver disease and new treatment regimens. Aliment Pharmacol Ther. 2015; 41: 497–520

Crossref | PubMed | Scopus (64) | Google ScholarSee all References^{, 15}x15Younossi, Z.M., Stepanova, M., Pol, S. et al. The impact of ledipasvir/sofosbuvir on patient-reported outcomes in cirrhotic patients with chronic hepatitis C: the SIRIUS study. Liver Int. 2016; 36: 42–48

Crossref | PubMed | Google ScholarSee all References^{, 16}x16Younossi, Z.M., Stepanova, M., Marcellin, P. et al. Treatment with ledipasvir and sofosbuvir improves patient-reported outcomes: results from the ION-1, -2, and -3 clinical trials. Hepatology. 2015; 61: 1798–1808

Crossref | PubMed | Scopus (67) | Google ScholarSee all References^{, 20}x20Younossi, Z.M., Stepanova, M., Feld, J. et al. Sofosbuvir/velpatasvir improves patient-reported outcomes in HCV patients: results from ASTRAL-1 placebo-controlled trial. J Hepatol. 2016; 65: 33–39

Abstract | Full Text | Full Text PDF | PubMed | Scopus (36) | Google ScholarSee all References^{, 21}x21Younossi, Z.M., Stepanova, M., Sulkowski, M. et al. Ribavirin-free regimen with sofosbuvir and velpatasvir is associated with high efficacy and improvement of patient-reported outcomes in patients with genotypes 2 and 3 chronic hepatitis C: results from Astral-2 and -3 clinical trials. Clin Infect Dis. 2016; 63: 1042–1048

Crossref | PubMed | Scopus (17) | Google ScholarSee all References^{, 23}x23Younossi, Z.M., Stepanova, M., Sulkowski, M. et al. Patient-reported outcomes in patients co-infected with hepatitis C virus and human immunodeficiency virus treated with sofosbuvir and velpatasvir: the ASTRAL-5 study. Liver Int. 2017; 37: 1796–1804

Crossref | Scopus (2) | Google ScholarSee all References This suggests that patients’ experience was not adversely affected by the side effects of the studied regimens and supports excellent tolerability of these regimens for HCV treatment.

In addition to the PRO benefit during treatment, the data clearly show that achieving SVR leads to sustainable gains in PROs, again consistent with previous reports for other DAA-based regimens.⁹x9Younossi, Z.M., Stepanova, M., Afdhal, N. et al. Improvement of health-related quality of life and work productivity in chronic hepatitis C patients with early and advanced fibrosis treated with ledipasvir and sofosbuvir. J Hepatol. 2015; 63: 337–345

Abstract | Full Text | Full Text PDF | PubMed | Scopus (55) | Google ScholarSee all References^{, 10}x10Younossi, Z.M., Stepanova, M., Sulkowski, M. et al. Sofosbuvir and ribavirin for treatment of chronic hepatitis C in patients co-infected with hepatitis C virus and HIV: the impact on patient-reported outcomes. J Infect Dis. 2015; 212: 367–377

Crossref | PubMed | Scopus (33) | Google ScholarSee all References^{, 11}x11Younossi, Z.M., Stepanova, M., Nader, F. et al. Patient-reported outcomes in chronic hepatitis C patients with cirrhosis treated with sofosbuvir-containing regimens. Hepatology. 2014; 59: 2161–2169

Crossref | PubMed | Scopus (46) | Google ScholarSee all References^{, 12}x12Younossi, Z.M., Stepanova, M., Henry, L. et al. Minimal impact of sofosbuvir and ribavirin on health related quality of life in chronic hepatitis C (CH-C). J Hepatol. 2014; 60: 741–747

Abstract | Full Text | Full Text PDF | PubMed | Scopus (58) | Google ScholarSee all References^{, 13}x13Younossi, Z.M., Stepanova, M., Henry, L. et al. Effects of sofosbuvir-based treatment, with and without interferon, on outcome and productivity of patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2014; 12: 1349–1359

Abstract | Full Text | Full Text PDF | PubMed | Scopus (51) | Google ScholarSee all References^{, 14}x14Gerber, L., Estep, M., Stepanova, M. et al. Effects of viral eradication with ledipasvir and sofosbuvir, with or without ribavirin, on measures of fatigue in patients with chronic hepatitis C virus infection. Clin Gastroenterol Hepatol. 2016; 14: 156–164

Abstract | Full Text | Full Text PDF | PubMed | Scopus (19) | Google ScholarSee all References^{, 15}x15Younossi, Z.M., Stepanova, M., Pol, S. et al. The impact of ledipasvir/sofosbuvir on patient-reported outcomes in cirrhotic patients with chronic hepatitis C: the SIRIUS study. Liver Int. 2016; 36: 42–48

Crossref | PubMed | Google ScholarSee all References^{, 16}x16Younossi, Z.M., Stepanova, M., Marcellin, P. et al. Treatment with ledipasvir and sofosbuvir improves patient-reported outcomes: results from the ION-1, -2, and -3 clinical trials. Hepatology. 2015; 61: 1798–1808

Crossref | PubMed | Scopus (67) | Google ScholarSee all References^{, 17}x17Younossi, Z.M., Stepanova, M., Zeuzem, S. et al. Patient-reported outcomes assessment in chronic hepatitis C treated with sofosbuvir and ribavirin: the VALENCE study. J Hepatol. 2014; 61: 228–234

Abstract | Full Text | Full Text PDF | PubMed | Scopus (49) | Google ScholarSee all References^{, 18}x18Younossi, Z.M., Stepanova, M., Nader, F. et al. The patient's journey with chronic hepatitis C from interferon plus ribavirin to interferon- and ribavirin-free regimens: a study of health-related quality of life. Aliment Pharmacol Ther. 2015; 42: 286–295

Crossref | PubMed | Scopus (43) | Google ScholarSee all References^{, 19}x19Stepanova, M., Nader, F., Cure, S. et al. Patients' preferences and health utility assessment with SF-6D and EQ-5D in patients with chronic hepatitis C treated with sofosbuvir regimens. Aliment Pharmacol Ther. 2014; 40: 676–685

Crossref | PubMed | Scopus (19) | Google ScholarSee all References^{, 20}x20Younossi, Z.M., Stepanova, M., Feld, J. et al. Sofosbuvir/velpatasvir improves patient-reported outcomes in HCV patients: results from ASTRAL-1 placebo-controlled trial. J Hepatol. 2016; 65: 33–39

Abstract | Full Text | Full Text PDF | PubMed | Scopus (36) | Google ScholarSee all References^{, 21}x21Younossi, Z.M., Stepanova, M., Sulkowski, M. et al. Ribavirin-free regimen with sofosbuvir and velpatasvir is associated with high efficacy and improvement of patient-reported outcomes in patients with genotypes 2 and 3 chronic hepatitis C: results from Astral-2 and -3 clinical trials. Clin Infect Dis. 2016; 63: 1042–1048

Crossref | PubMed | Scopus (17) | Google ScholarSee all References^{, 22}x22Younossi, Z.M., Stepanova, M., Henry, L. et al. An in-depth analysis of patient-reported outcomes in patients with chronic hepatitis C treated with different anti-viral regimens. Am J Gastroenterol. 2016; 111: 808–816

Crossref | PubMed | Scopus (25) | Google ScholarSee all References^{, 23}x23Younossi, Z.M., Stepanova, M., Sulkowski, M. et al. Patient-reported outcomes in patients co-infected with hepatitis C virus and human immunodeficiency virus treated with sofosbuvir and velpatasvir: the ASTRAL-5 study. Liver Int. 2017; 37: 1796–1804

Crossref | Scopus (2) | Google ScholarSee all References The magnitudes of post-SVR PRO improvements suggest their clinical relevance because most PROs increased by more than 3%–5% of a PRO range size, which is believed to be the minimal clinically important difference in PROs.³⁸x38Spiegel, B.M., Younossi, Z.M., Hays, R.D. et al. Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment. Hepatology. 2005; 41: 790–800

Crossref | PubMed | Scopus (244) | Google ScholarSee all References^{, 39}x39Walters, S.J. and Brazier, J.E. What is the relationship between the minimally important difference and health state utility values? The case of the SF-6D. Health Qual Life Outcomes. 2003; 11: 4

Crossref | Scopus (265) | Google ScholarSee all References

Furthermore, such improvements are comparable with long-term improvements in PRO scores observed in patients who had cardiac bypass surgery for their coronary artery disease or patients with rheumatoid arthritis after 24 weeks of treatment with methotrexate.⁴⁰x40Martin, L.M., Holmes, S.D., Henry, L.L. et al. Health-related quality of life after coronary artery bypass grafting surgery and the role of gender. Cardiovasc Revasc Med. 2012; 13: 321–327

Crossref | PubMed | Scopus (9) | Google ScholarSee all References^{, 41}x41Bingham, C.O. 3rd, Weinblatt, M., Han, C. et al. The effect of intravenous golimumab on health-related quality of life in rheumatoid arthritis: 24-week results of the phase III GO-FURTHER trial. J Rheumatol. 2014; 41: 1067–1076

Crossref | PubMed | Scopus (7) | Google ScholarSee all References Accompanied by high efficacy of SOF/VEL ± VOX regimens, these PRO data provide support to the comprehensive benefit (to include clinical, or SVR, and patients’ experience, or PROs) of these new regimens for HCV-infected patients.

Finally, we have confirmed that the presence of cirrhosis, fatigue, and psychiatric comorbidities contributes to impaired PROs in patients with HCV; this is consistent with similar findings from prior studies.⁹x9Younossi, Z.M., Stepanova, M., Afdhal, N. et al. Improvement of health-related quality of life and work productivity in chronic hepatitis C patients with early and advanced fibrosis treated with ledipasvir and sofosbuvir. J Hepatol. 2015; 63: 337–345

Abstract | Full Text | Full Text PDF | PubMed | Scopus (55) | Google ScholarSee all References^{, 10}x10Younossi, Z.M., Stepanova, M., Sulkowski, M. et al. Sofosbuvir and ribavirin for treatment of chronic hepatitis C in patients co-infected with hepatitis C virus and HIV: the impact on patient-reported outcomes. J Infect Dis. 2015; 212: 367–377

Crossref | PubMed | Scopus (33) | Google ScholarSee all References^{, 11}x11Younossi, Z.M., Stepanova, M., Nader, F. et al. Patient-reported outcomes in chronic hepatitis C patients with cirrhosis treated with sofosbuvir-containing regimens. Hepatology. 2014; 59: 2161–2169

Crossref | PubMed | Scopus (46) | Google ScholarSee all References^{, 12}x12Younossi, Z.M., Stepanova, M., Henry, L. et al. Minimal impact of sofosbuvir and ribavirin on health related quality of life in chronic hepatitis C (CH-C). J Hepatol. 2014; 60: 741–747

Abstract | Full Text | Full Text PDF | PubMed | Scopus (58) | Google ScholarSee all References^{, 13}x13Younossi, Z.M., Stepanova, M., Henry, L. et al. Effects of sofosbuvir-based treatment, with and without interferon, on outcome and productivity of patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2014; 12: 1349–1359

Abstract | Full Text | Full Text PDF | PubMed | Scopus (51) | Google ScholarSee all References^{, 14}x14Gerber, L., Estep, M., Stepanova, M. et al. Effects of viral eradication with ledipasvir and sofosbuvir, with or without ribavirin, on measures of fatigue in patients with chronic hepatitis C virus infection. Clin Gastroenterol Hepatol. 2016; 14: 156–164

Abstract | Full Text | Full Text PDF | PubMed | Scopus (19) | Google ScholarSee all References^{, 15}x15Younossi, Z.M., Stepanova, M., Pol, S. et al. The impact of ledipasvir/sofosbuvir on patient-reported outcomes in cirrhotic patients with chronic hepatitis C: the SIRIUS study. Liver Int. 2016; 36: 42–48

Crossref | PubMed | Google ScholarSee all References^{, 16}x16Younossi, Z.M., Stepanova, M., Marcellin, P. et al. Treatment with ledipasvir and sofosbuvir improves patient-reported outcomes: results from the ION-1, -2, and -3 clinical trials. Hepatology. 2015; 61: 1798–1808

Crossref | PubMed | Scopus (67) | Google ScholarSee all References^{, 17}x17Younossi, Z.M., Stepanova, M., Zeuzem, S. et al. Patient-reported outcomes assessment in chronic hepatitis C treated with sofosbuvir and ribavirin: the VALENCE study. J Hepatol. 2014; 61: 228–234

Abstract | Full Text | Full Text PDF | PubMed | Scopus (49) | Google ScholarSee all References^{, 18}x18Younossi, Z.M., Stepanova, M., Nader, F. et al. The patient's journey with chronic hepatitis C from interferon plus ribavirin to interferon- and ribavirin-free regimens: a study of health-related quality of life. Aliment Pharmacol Ther. 2015; 42: 286–295

Crossref | PubMed | Scopus (43) | Google ScholarSee all References^{, 19}x19Stepanova, M., Nader, F., Cure, S. et al. Patients' preferences and health utility assessment with SF-6D and EQ-5D in patients with chronic hepatitis C treated with sofosbuvir regimens. Aliment Pharmacol Ther. 2014; 40: 676–685

Crossref | PubMed | Scopus (19) | Google ScholarSee all References^{, 20}x20Younossi, Z.M., Stepanova, M., Feld, J. et al. Sofosbuvir/velpatasvir improves patient-reported outcomes in HCV patients: results from ASTRAL-1 placebo-controlled trial. J Hepatol. 2016; 65: 33–39

Abstract | Full Text | Full Text PDF | PubMed | Scopus (36) | Google ScholarSee all References^{, 21}x21Younossi, Z.M., Stepanova, M., Sulkowski, M. et al. Ribavirin-free regimen with sofosbuvir and velpatasvir is associated with high efficacy and improvement of patient-reported outcomes in patients with genotypes 2 and 3 chronic hepatitis C: results from Astral-2 and -3 clinical trials. Clin Infect Dis. 2016; 63: 1042–1048

Crossref | PubMed | Scopus (17) | Google ScholarSee all References^{, 22}x22Younossi, Z.M., Stepanova, M., Henry, L. et al. An in-depth analysis of patient-reported outcomes in patients with chronic hepatitis C treated with different anti-viral regimens. Am J Gastroenterol. 2016; 111: 808–816

Crossref | PubMed | Scopus (25) | Google ScholarSee all References^{, 23}x23Younossi, Z.M., Stepanova, M., Sulkowski, M. et al. Patient-reported outcomes in patients co-infected with hepatitis C virus and human immunodeficiency virus treated with sofosbuvir and velpatasvir: the ASTRAL-5 study. Liver Int. 2017; 37: 1796–1804

Crossref | Scopus (2) | Google ScholarSee all References Although the exact causes of the observed association of location with baseline PROs are unclear, this is also consistent with prior reports on the contribution of cultural and ethnic factors to various PRO measures.⁴²x42Wild, D., Grove, A., Martin, M. et al. Principles of go–od practice for the translation and cultural adaptation process for patient-reported outcomes (PRO) measures: report of the ISPOR task force for translation and cultural adaptation. Value Health. 2005; 2: 94–104

Abstract | Full Text PDF | Scopus (997) | Google ScholarSee all References^{, 43}x43Two, R., Verjee-Lorenz, A., Clayson, D. et al. A methodology for successfully producing global translations of patient reported outcome measures for use in multiple countries. Value Health. 2010; 13: 128–131

Abstract | Full Text PDF | PubMed | Scopus (19) | Google ScholarSee all References Nevertheless, the sociodemographic reasons for this difference requires future investigation. Furthermore, our multivariate analysis clearly shows that receiving active treatment with SOF/VEL or SOF/VEL/VOX is independently and similarly associated with improvement of PROs during treatment and in post-treatment follow-up. It is important to note, however, that other major predictors of greater on-treatment and post-treatment PRO gains were factors associated with lower baseline scores, such as history of depression, anxiety, and clinically overt fatigue, suggesting that these conditions, potentially associated with the extrahepatic manifestations of HCV, may also potentially resolve with virologic clearance; further prospectively designed studies are needed to confirm this hypothesis.

The main limitation of this study is the setting where PRO data were collected. Given that the PRO improvements were documented in the clinical trials setting, similar data from real-world clinical practices are needed; this issue applies both to clinical outcomes and PROs. Other limitations include open-label design of POLARIS-4, which might have affected PROs in participants; limited follow-up duration; and the lack of data on other potentially important PRO predictors, such as patients’ education, family status, and other socioeconomic parameters.

In summary, our study assessed the effect of 2 anti-HCV regimens, SOF/VEL and SOF/VEL/VOX, on PRO scores. The data are supportive of the comprehensive benefit of the new all-oral pangenotypic regimens for patients infected with HCV who had failed another DAA-based regimen and might have been left with no treatment options otherwise.
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