Showing posts with label Viekira Pak. Show all posts
Showing posts with label Viekira Pak. Show all posts

Friday, August 24, 2018

Treatment in HCV genotype 1b patients with advanced fibrosis and cirrhosis

PLoS One. 2018 Aug 23;13(8):e0202777. doi: 10.1371/journal.pone.0202777. 

Hepatic decompensation during paritaprevir/ritonavir/ombitasvir/dasabuvir treatment for genotype 1b chronic hepatitis C patients with advanced fibrosis and compensated cirrhosis.
Hsieh YC1, Jeng WJ1,2,3, Huang CH1,2, Teng W1, Chen WT1, Chen YC1,2, Lin SM1,2,3, Tai DI1,2, Lin CY1,2, Sheen IS1,2.

Full Text

Abstract
BACKGROUND AND AIM: 
Hepatic decompensation is a severe on-treatment adverse event for chronic hepatitis C treated with paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD). Till now, few papers regarding on-treatment hepatic decompensation have been reported. The study aims to analyze the general feature and predictive factors of on-treatment hepatic decompensation in hepatitis C virus (HCV) genotype 1b-infected patients with advanced fibrosis and compensated cirrhosis who receive treatment with PrOD.

METHODS: A real-word cohort enrolled 189 HCV genotype 1b patients with advanced fibrosis and compensated cirrhosis treated with 12-week PrOD. Clinical and laboratory data were analyzed between patients with and without on-treatment hepatic decompensation.

RESULTS: The sustained virologic response rate at 12 weeks after treatment was 97.3% in HCV subtype 1b patients with advanced fibrosis and cirrhosis. On-treatment hyperbilirubinemia (total bilirubin >2 mg/dL) occurred in 27 (14.3%) patients, and the incidence of the increase of total and direct form bilirubin was significantly different during treatment between patients with Child-Turcotte-Pugh score 5 and score 6. Five (18.5%) hyperbilirubinemia patients progressed to hepatic decompensation. Older age (adjusted OR: 1.2, 95% CI: 1.0-1.4) and albumin ≤3.6 g/dL (adjusted OR: 10.4, 95% CI: 1.3-81.2) may be two predictors for on-treatment hepatic decompensation by multivariate analysis.

CONCLUSIONS: PrOD is an effective direct-acting antiviral agent for antiviral therapy in HCV genotype 1b patients with advanced fibrosis and cirrhosis. Hyperbilirubinemia is possibly the early warning feature of on-treatment hepatic decompensation. This serious adverse event of on-treatment hepatic decompensation is not common. Older age and low baseline albumin level may be predictive factors.


PMID: 30138456 DOI: 10.1371/journal.pone.0202777

Tuesday, August 21, 2018

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

Of Interest
March 14, 2018
March 24, 2018
May 30, 2018

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.

Tuesday, April 10, 2018

Sweden-Introduction of second-generation direct-acting antivirals in HCV:Register-based Study

Introduction of the second-generation direct-acting antivirals (DAAs) in chronic hepatitis C: a register-based study in Sweden
P. Frisk, K. Aggefors T. Cars N. Feltelius S. A. LoovB. Wettermark O. Weiland

First Online: 09 April 2018

The conditions for introducing the first six of the second-generation direct-acting antivirals for chronic hepatitis C infection in Sweden were outlined in a national introduction protocol. The overall cure rate was estimated to 96%, with some variation between genotypes. Despite regional variation in other cost containment strategies, the high level of adherence to recommendations among prescribers and similar introduction rates in the regions indicate that the protocol contributed considerably to a rapid uptake and equal distribution of DAAs in Sweden.

Full-Text

Abstract
Purpose Introduction of the direct-acting antivirals (DAAs) for treatment of chronic hepatitis C (CHC) infection has been challenging in all health systems. In Sweden, a national protocol for managed introduction was developed. It was optional, but all county councils agreed to implement and follow it. The purpose of this study was to study (a) cure rates among all patients initiated on treatment in 2014–2015, (b) prescribers’ adherence to the drug recommendations and treatment eligibility criteria in the protocol, and (c) introduction rate in the six Swedish healthcare regions.

Method
A cross-sectional study where national data from the Prescribed Drug Register and the quality register InfCare Hepatitis defined the study population, and clinical data from the Patient Register and InfCare Hepatitis were used to monitor outcomes. Descriptive statistics were used.

Results
A total of 3447 patients were initiated on treatment during 2014–2015. The overall cure rate, based on data from 85% of the cohort, was 96%, with variation between genotypes. Adherence to drug recommendations increased over time and varied between 43.2 and 94.2%. Adherence to the treatment eligibility criteria was initially 80% and increased to 87% when treatment restrictions were widened. The introduction rate differed initially between the regions and reached stable levels 15–18 months after the launch of the first DAA.

Conclusion
The estimated overall cure rate was 96%, with some variations between genotypes. A high level of adherence to the introduction protocol as well as similar introduction rates in the health care regions indicate that the introduction protocol, alongside with other measures taken, contributed considerably to a rapid uptake and equal distribution of DAAs in Sweden.

Continuer reading online: https://link.springer.com/article/10.1007%2Fs00228-018-2456-y

Wednesday, January 10, 2018

Effect of ombitasvir/paritaprevir/ritonavir + dasabuvir regimen on health-related quality of life for patients with hepatitis C

Accepted Article

Effect of ombitasvir/paritaprevir/ritonavir + dasabuvir regimen on health-related quality of life for patients with hepatitis C
Sammy Saab, Darshan Mehta, Stacie Hudgens, Nathan Grunow, Yanjun Bao, Brett Pinsky
Accepted manuscript online: 5 January 2018
DOI: 10.1111/liv.13690

Full-text article
Downloaded & shared by @HenryEChang via Twitter.
View Article: https://jumpshare.com/v/HJEqCzaQ8N23yhY1Bwoq

Abstract 
Background and Aims 
This study analyzes health related quality of life (HRQoL) data from 8 randomized clinical trials using ombitasvir/paritaprevir/ritonavir and dasabuvir (3D) ± ribavirin [RBV] to investigate: [1] the impact of the treatment vs. placebo during treatment on HRQoL; [2] the sustainability of such treatment effect after 12-week treatment period; and [3] if results from [1] and [2] differ in subgenotypes 1a vs. 1b.

Methods
Six registration trials and 2 post-approval trials were pooled and analyzed using longitudinal mixed models (MM) to estimate the effect of 3D + RBV on HRQoL outcomes adjusting for baseline scores, as well as patient demographics and clinical characteristics.

Results
Patients treated with RBV free 3D regimen reported statistically significant increase in HRQoL outcomes as compared to placebo patients. While 3D+RBV treatment saw statistically significant decline in HRQoL outcomes during treatment vs. baseline and vs. placebo, effect on HRQoL outcomes associated with RBV did not persist in the post treatment period for 3D patients followed for up to 52 weeks. The analysis also found GT1b patients reported greater improvements in HRQoL as compared to GT1a patients.

Conclusions
During active treatment period, small but statistically significant decrements in HRQoL outcomes were observed potentially driven by RBV, which were not sustained during the post treatment follow up period. Differences were observed by patient subgenotype, where HRQoL improvements were consistently higher for GT1b patients as compared to GT1a patients.

Tuesday, October 17, 2017

The changing HCV treatment cascade

Pharmacology Consult
The changing HCV treatment cascade
Infectious Disease News, October 2017
Jocelyn Mason, PharmD; Kimberly D. Boeser, PharmD, MPH, BCPS, AQ-ID
The rapid development of DAA combinations provides simplified regimens, shorter durations, improved efficacy and greater tolerability, unlike the previous interferon and ribavirin cornerstone regimens. Although the IDSA/AASLD guidelines provide the map to managing HCV, they do not identify the ideal interferon-free regimen to begin with, nor have they given a clear path to treating genotype 3 and those with decompensated cirrhosis. This ever-changing field will require collaboration among health care providers, including those specializing in infectious diseases, hepatology and gastroenterology, as well as pharmacists, to optimize treatment strategies. As the landscape of HCV continues to update with new literature and new medications, this subspecialty continues to be dynamic.
Continue to article - https://www.healio.com/infectious-disease/hepatitis-c/news/print/infectious-disease-news/%7B87b74536-f358-43d3-a804-f37a98402b0b%7D/the-changing-hcv-treatment-cascade

Monday, October 16, 2017

Merck targets high-risk military veterans for hepatitis C lessons

In case you missed it

“Despite their increased risk for chronic hepatitis C virus infection, too many veterans remain undiagnosed,” said Thomas F. Nealon III, chief executive officer of the American Liver Foundation. “We are proud to work with Merck on this important initiative, which we believe will help many veterans better understand their risk, as well as their options for getting tested and linked to care.” Link - http://www.businesswire.com/news/home/20171012005279/en/

Of Interest
Investment Commentary
Merck targets high-risk military veterans for hepatitis C lessons
by Carly Helfand |
Oct 16, 2017 9:15am
Veterans are three times more likely to have hepatitis C than the general population—and Merck & Co. wants to make sure they know that.

The pharma giant, which makes the hep C-fighting therapy Zepatier, has partnered up with the American Liver Foundation, which will join educational events in Boston, Philadelphia, Phoenix and San Diego to speak with veterans about their risk factors, dole out tips and resources for living with hep C, and provide info about testing and treatment.

The awareness push comes as Merck has been focusing on veterans as a market for Zepatier, which was third to the next-gen hep C market after Gilead Sciences, with its megablockbuster meds, and AbbVie's Viekira Pak. In May of last year, executives at rival AbbVie told investors the New Jersey drugmaker had introduced steeper-than-expected discounts for the U.S. Department of Veterans Affairs, snapping up a good portion of AbbVie’s market share in that segment.
Link - http://www.fiercepharma.com/marketing/merck-teams-up-american-liver-foundation-to-educate-high-risk-vets-hep-c

Wednesday, October 11, 2017

Hepatitis C Treatment With Direct-Acting Antivirals Confers Survival Benefit

In Case You Missed It

Today over at Infectious Disease Advisor, media coverage on the study; Effect of Paritaprevir/Ritonavir/Ombitasvir/Dasabuvir and Ledipasvir/Sofosbuvir Regimens on Survival Compared With Untreated Hepatitis C Virus–Infected Persons: Results From ERCHIVES, is highlighted, the full-text article shared by @HenryEChang via Twitter, can be reviewed here.

Links
Hepatitis C Treatment With Direct-Acting Antivirals Confers Survival Benefit
October 11, 2017
Among patients with hepatitis C, direct-acting antiviral regimens paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) and ledipasvir/sofosbuvir (LDV/SOF) were shown to be associated with a significant improvement in survival, according to the results of a study published in Clinical Infectious Diseases ...

Full-Text Article

Paritaprevir/Ritonavir/Ombitasvir/Dasabuvir and Ledipasvir/Sofosbuvir Regimens on Survival Compared With Untreated Hepatitis C Virus–Infected Persons: Results From ERCHIVES

Thursday, October 5, 2017

Healio - Viekira Pak safe for patients with HCV, Child-Pugh A cirrhosis

New In Hepatology At Healio

October 5, 2017
Viekira Pak safe for patients with HCV, Child-Pugh A cirrhosis
Poordad F, et al. J Hepatol. 2017;doi:10.1016/j.jhep.2017.06.011.
Patients with hepatitis C and Child-Pugh A cirrhosis had similar rates of treatment-related adverse events and lower rates of hepatic decompensation after treatment with Viekira Pak compared with untreated patients, according to recently published data. However, those with a history of advanced cirrhosis were more likely to experience treatment-related adverse events.
Read More - https://www.healio.com/hepatology/hepatitis-c/news/online/%7Be4ff72dc-3ade-4e42-b1bb-83109f95e69f%7D/viekira-pak-safe-for-patients-with-hcv-child-pugh-a-cirrhosis

Study - Safety of the 2D/3D direct-acting antiviral regimen in HCV-induced Child-Pugh A cirrhosis – A pooled analysis
Published in The Journal of Hepatology
October 2017 Volume 67, Issue 4, Pages 700–707

Liver cancer remains a leading cause of cancer-related mortality worldwide
Primary liver cancer incidence increased by 75% between 1990 and 2015, and the disease remains one of the leading causes of cancer death in the world, according to a report from the Global Burden of Diseases Study 2015. Further, hepatitis B virus was the leading cause of new cases of liver cancer in 2015, the research showed.

In Case You Missed It
Oct 4, 2017
The AASLD and the Infectious Diseases Society of America have updated their guidelines and resources for the diagnosis and treatment of hepatitis C virus infection…

Despite treatment, severe steatosis predicts severe fibrosis in HBV
Severe steatosis correlated with severe fibrosis in patients with chronic hepatitis B, whether patients were on treatment or treatment-naive, according to recently…

Free registration may be required 

Tuesday, August 29, 2017

Treatment Of HCV Infection with New Drugs: Real World Experience in Southern Brazil

2017 Sep-Oct;16(5):727-733. doi: 10.5604/01.3001.0010.2717.

Treatment of Chronic HCV Infection with the New Direct Acting Antivirals (DAA): First Report of a Real World Experience in Southern Brazil.
Cheinquer H1, Sette-Jr H2, Wolff FH1, de Araujo A1, Coelho-Borges S1, Soares SRP2, Barros MFA2.

Full Text 

Abstract
INTRODUCTION AND AIM:
There is almost no data regarding the efficacy of direct acting antivirals (DAAs) therapy in Brazil. The aim of this historical cohort study is to describe the sustained virologic response (SVR) rate among real-world compensated chronic hepatitis C patients in three hepatology centers from Southern Brazil.

MATERIALS AND METHODS:
Patients were included if they had at least 12 weeks follow-up after the end of therapy. Patients that were lost to follow-up or had treatment prematurely interrupted for any reason were considered treatment failure in this intention to treat analysis.

RESULTS:
219 patients were analyzed. Mean age was 57.4 ± 10.9 years and 142/219 (64.8%) were male. Genotype 1 was present in 166 patients (75.8%; 1a 29.2%, 1b 46.6%); Genotypes 2, 3 and 4 in 8 (3.7%), 43 (19.6%) and 2 (0.9%), respectively. 96 (43.8%) were cirrhotic. 134 (59.5%) were treatment experienced. DAA therapies were: sofosbuvir (SOF) + ribavirin (RBV) in 10 patients; SOF + simeprevir (SMV) ± RBV in 73; SOF + pegylated interferon (PEG-IFN) + RBV in 6; SOF + daclatasvir (DCV) ± RBV in 51, SOF + ledipasvir (LDV) ± RBV in 61, and paritaprevir/ ritonavir + ombitasvir + dasabuvir (PTVr/OBV/DSV) ± RBV in 18 patients. SVR-12 was achieved in 208/219 (95%). Ten patients had virologic failure: 6 cirrhotic, 7 treatment experienced, and 6 either genotype 3 or 1a. No adverse event was attributed to the DAA therapy.

CONCLUSIONS:
Real world experience with DAA therapy in Southern Brazil showed a high rate of SVR and excellent tolerability. Failure to achieve SVR was mainly observed among patients with at least one negative predictor of response: cirrhosis and/or genotypes 1a or 3.

Full text

Saturday, August 26, 2017

The new paradigm in the treatment of chronic hepatitis C disease: Faster, Higher and Stronger

Citius Altius Fortius: The new paradigm in the treatment of chronic hepatitis C disease

Aug 26, 2017

Download Full Text Article
Provided By Henry E. Chang‏ via Twitter

Abraham GM, et al. – This study focuses on the treatment of chronic hepatitis C disease. Findings reveal that most of the direct–acting antiviral agents (DAAs) for chronic hepatitis C infection had a high barrier to resistance and are extremely well–tolerated by patients. DAAs, in addition, demonstrate 90% or higher efficacy rates.
  • The treatment paradigm for chronic hepatitis C infection has dramatically changed with the advent of the direct–acting antiviral agents (DAAs), especially the duration, tolerability and response to therapy.
  • The DAAs are classified in to several classes and are variously indicated in the treatment of one or more genotypes of infection.
  • All these agents are orally administered, and they, in majority, are eliminated renally (with exceptions), and don'’t require adjustment in mild to moderate renal insufficiency.
Abstract
With the advent of the direct-acting antiviral agents (DAAs) for chronic hepatitis C infection, the treatment paradigm has dramatically changed, especially the duration, tolerability and response to therapy. The DAAs fall into several classes and are variously indicated in the treatment of one or more genotypes of infection. All these agents are orally administered, and they are largely renally eliminated (with exceptions), don’t require adjustment in mild to moderate renal insufficiency. Most of these agents demonstrate a high barrier to resistance and are extremely well-tolerated by patients. Overall efficacy rates are 90% or higher.
Download Article

Of Interest
Systematic review: cost-effectiveness of DAAs for treatment of HCV genotypes 2-6

New At Hepatitis C Online:
Vosevi and Mavyret
Information on Gilead's newly FDA approved Vosevi and AbbVie's Mavyret  is now available.

Full Text Articles
I highly suggest you follow Henry E. Chang on Twitter if you are interested in reading full text articles about the treatment and management of hepatitis C.

Wednesday, August 16, 2017

Hepatitis C - DAAs reduces the risk of mortality in the first 18 months after the completion of treatment

Source - infohep

Treatment with DAAs reduces the risk of mortality in the first 18 months after the completion of treatment
Michael Carter
Published:10 August 2017
The study – published in Clinical Infectious Diseases – matched people who received therapy with all-DAA regimens with untreated controls. Mortality rates in the first 18 months after therapy were significantly lower among people who received DAAs. After controlling for other factors, treatment with DAAs was associated with a 57% reduction in the risk of death.

A recent Cochrane Collaboration systematic review concluded that, due to the lack of long-term follow-up studies, there was no evidence that DAAs prolonged life or reduced liver-related ill-health in people who achieved SVR to DAA treatment. The Cochrane review has been strongly criticised by European and United States associations of liver experts for ignoring the short-term nature of the studies of DAAS designed for registration and for ignoring previous evidence from the treatment of hepatitis C, which showed that achieving SVR to interferon-based treatment was associated with a reduction in the risk of death and liver disease......
Continue reading.....

View full text article online at NATAP
Effect of paritaprevir/ritonavir/ombitasvir/dasabuvir and ledipasvir/sofosbuvir regimens on survival compared with untreated hepatitis C virus-infected persons: results from ERCHIVES

Saturday, July 8, 2017

Hepatitis C - Effectiveness of dasabuvir/ombitasvir/paritaprevir/ritonavir

Effectiveness of dasabuvir/ombitasvir/paritaprevir/ritonavir for hepatitis C virus in clinical practice: A population-based observational study
Maya Leventer-Roberts , Ariel Hammerman, Ilan Brufman, Moshe Hoshen, Marius Braun, Yaffa Ashur, Nicky Lieberman, Ran Balicer

Published: July 7, 2017
https://doi.org/10.1371/journal.pone.0176858

Link
Full Text Article

Abstract
Background
Direct acting antivirals for hepatitis C virus have shown dramatic results in clinical trials. However, their effectiveness has yet to be demonstrated within observational cohorts which lack exclusion criteria found in randomized control trials.

Aim
To determine the effectiveness of dasabuvir/ombitasvir/paritaprevir/ritonavir in achieving sustained virological response.

Methods
Retrospective observational cohort study of all Clalit Health Services members with hepatitis C virus genotype 1 who were dispensed dasabuvir/ombitasvir/paritaprevir/ritonavir from January 1, 2015 to-November 31, 2015.

Results
There were 564 participants during the study period. The average age was 61.9 years, 52.0% were male, and 61.5% were born Eastern/Central Europe or Central Asia. The prevalence of diabetes was 31.7% and 70.3% were overweight/obese. Cirrhosis was present in 41.0% of participants, of whom 52.8% had stage 4 fibrosis. Of the cohort, 416 (74.8%) had follow-up viral load testing at 10 or more weeks after the end of treatment. We report a sustained virological response of 98.8% among those tested.

Conclusions
Treatment with dasabuvir/ombitasvir/paritaprevir/ritonavir demonstrated a near universal effectiveness in achieving a sustained virological response among HCV patients in a large cohort.

Wednesday, June 21, 2017

Safety of the 2D/3D direct acting antiviral regimen in HCV-induced Child-Pugh A cirrhosis - a pooled analysis

Journal of Hepatology -
Articles in Press

DOI: http://dx.doi.org/10.1016/j.jhep.2017.06.011
Publication stage: In Press Accepted Manuscript
Published online: June 20, 2017

Safety of the 2D/3D direct acting antiviral regimen in HCV-induced Child-Pugh A cirrhosis - a pooled analysis
Fred Poordad Correspondence information about the author Fred Poordad Email the author Fred Poordad , David R. Nelson, Jordan J. Feld, Michael W. Fried, Heiner Wedemeyer, Lois Larsen, Daniel E. Cohen, Eric Cohen, Niloufar Mobashery, Fernando Tatsch, Graham R. Foster

Highlights
  • OBV/PTV/r ± DSV ± RBV was well-tolerated in patients with Child-Pugh A cirrhosis.
  • Low rates of serious adverse events and those leading to discontinuation of study drugs.
  • Events consistent with hepatic decompensation occurred in 1.2% of patients (13/1066)
  • Decompensation events occurred across the treatment period and post-treatment.
  • Rates of decompensation events were comparable in treated and untreated patients.

Abstract
Background & aims

Chronic hepatitis C virus (HCV)-infected patients with cirrhosis are a high-priority population for treatment. To help inform the benefit–risk profile of the all-oral direct-acting antiviral (DAA) combination regimen of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir (OBV/PTV/r ± DSV) in patients with Child-Pugh A cirrhosis, we undertook a comprehensive review of AbbVie-sponsored clinical trials enrolling patients with Child-Pugh A cirrhosis.

Methods

Twelve phase II or III clinical trials of the 2-DAA regimen of OBV/PTV/r ± ribavirin (RBV) or the 3-DAA regimen of OBV/PTV/r + DSV ± RBV that included patients with Child-Pugh A cirrhosis were reviewed; patients who completed treatment by November 16, 2015 were included in a pooled, post hoc safety assessment. The number and percentage of patients with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs consistent with hepatic decompensation were reported.

Results

In 1066 patients with Child-Pugh A cirrhosis, rates of serious TEAEs and TEAEs leading to study drug discontinuation were 5.3% (95% CI: 4.1–6.8) and 2.2% (95% CI: 1.4–3.2), respectively. Thirteen patients (1.2%; 95% CI: 0.7–2.1) had a TEAE that was consistent with hepatic decompensation. The most frequent TEAEs consistent with hepatic decompensation were ascites (n=8), esophageal variceal hemorrhage (n=4), and hepatic encephalopathy (n=2).

Conclusions

This pooled analysis in 1066 HCV-infected patients with Child-Pugh A cirrhosis confirms the safety of OBV/PTV/r ± DSV ± RBV in this population. These results support the use of OBV/PTV/r ± DSV ± RBV in this high-priority population.

Lay summary

This pooled safety analysis in 1066 HCV-infected patients with compensated cirrhosis, receiving treatment with ombitasvir, paritaprevir, and ritonavir with or without dasabuvir, with or without ribavirin, shows that the rate of hepatic decompensation events was comparable to rates from historical reports for untreated patients.

Friday, June 2, 2017

Direct-acting antivirals in elderly patients with chronic hepatitis C

European Journal of Gastroenterology & Hepatology:
doi: 10.1097/MEG.0000000000000871

Clinical efficacy and tolerability of direct-acting antivirals in elderly patients with chronic hepatitis C
Sherigar, Jagannath M.a; Gayam, Vijayb; Khan, Arifab; Mukhtar, Osamab; Arefiev, Yavgeniya; Khalid, Mazinb; Siddiqui, Imranb; Rangaraju, Ayyappa M.b; Budhathoki, Nibashb; Mansour, Mohammedb; Guss, Debraa; Mohanty, Smruti R

Conclusion
The age of the patient does not seem to have a major impact on the virologic response rate when treating chronic HCV infection. Older patients (age 65 years and older) do not appear to have a higher frequency of adverse events compared with younger patients. Increased fibrosis, cirrhosis, some of the baseline laboratory studies including AST, ALT, Hemoglobin, and platelet levels seem to affect the SVR in the elderly and require further studies. More studies should be carried out in an older population of patients to assess the safety, efficacy, and adverse reactions of newer DAAs regimens. Treatment should not be withheld purely on the grounds of advanced age.

Abstract
Background: There is a lack of evidence-based data on aged patients with newer direct-acting antivirals (DAAs) and with shorter duration of treatment regimens involving DAAs with or without ribavirin (RBV) and pegylated interferon (Peg IFN).

Patients and methods: Medical records of 240 patients treated with DAAs with or without Peg IFN and RBV between January 2013 and July 2015 were retrospectively analyzed. Patients were divided into two groups: patients aged 65 years and older (N=84) and patients aged younger than 65 years (N=156). Pretreatment baseline patient characteristics, treatment efficacy, factors affecting sustained virologic response at 12 weeks after treatment, and adverse reactions were compared between the groups.

Results: No statistically significant difference was observed with end of treatment response (98.8 vs. 98%, P=0.667) and sustained virologic response at 12 weeks after treatment (93.1 vs. 94.1%, P=0.767) between patients aged 65 and older and those younger than 65 years of age. Fatigue was the most common adverse event recorded (32.5%), followed by anemia (19.6%), leukopenia (11.7%), thrombocytopenia (10%), skin rash (8.3%), and headache (7.9%). The RBV dose was reduced in eight (8%) patients and four patients discontinued the RBV treatment because of severe anemia. RBV dose reduction or discontinuation did not reach statistical significance (P=0.913). Increased fibrosis, cirrhosis, aspartate aminotransferase, alanine aminotransferase, hemoglobin, and platelet levels seem to affect the sustained virologic response in the elderly. Twelve (6.28%) patients failed to respond to treatment and the failure rate was not significant (P=0.767) between the groups.

Conclusion: DAAs with or without IFN and RBV in the standard recommended 12 or 24-week treatment regimens are effective, well tolerated, and may be safely extended to elderly patients infected with chronic hepatitis C.

Discussion Only
Full Text Article Available Online
Eradication of HCV reduces the risk of progression to cirrhosis, HCC, and liver-related mortality, and thus leads to an improvement in overall survival and quality of life 9. Historically, the standard longer duration of IFN and RBV treatment produced significant adverse events in elderly patients, necessitating dose reduction or discontinuation of medications 10,11. The overall SVR rate was less than 50% with standard dual therapy with Peg IFN and RBV regimens. With the introduction of first DAAs in 2011, the triple therapy (boceprevir or telaprevir with Peg IFN and RBV) increased the SVR12 to 65–70% in GT 1 patients. Subsequent, substantial progress with further trials including combination NS5A and NS5B inhibitors, SVR12 approached more than 90%.

Current guidelines do not specify the age limit for treating elderly patients. The American Association of Study of Liver Disease recommends one of the six- DAA combination regimens for GT 1, the most common type of chronic HCV infection in the United States 12. RBV is still an integral part of the treatment regimen and utilized in combination with DAAs in GT 4 and as an alternative treatment regimen in GTs 1 and 3 patients with compensated cirrhosis.

A recent meta-analysis by Yang et al. 8 concluded that the overall SVR in patients aged older than or equal to 65 years treated with a prolonged course of IFN/RBV regimens was significantly lower and had a significantly higher risk of relapse than in patients younger than 65 years of age. IFN and RBV discontinuation rate were also significantly higher in older patients than in younger patients. We did not find any significant difference in RBV dose reduction or discontinuation rate (P=0.913) in patients aged 65 years and older compared with younger patients. These findings indicate that elderly patients are tolerating equally the shorter course of treatment involving IFN-based and RBV-based regimens as younger patients. ETR and SVR12 for elderly patients were similar to those of younger patients (93.06 vs. 94.12%), supporting previous observations, but with the improved virologic response rate in combination with DAAs 13. Fatigue is the most common adverse event observed in both IFN-based and IFN-free treatment regimens (Tables 6 and 7). Most of the incidences of anemia and leukopenia noted in IFN-free regimens were because of RBV in combination with newer agents. None of the patients discontinued the treatment because of adverse events, supporting the fact that a shorter duration of IFN/RBV-based treatment is better tolerated and can be administered to any age group safely with close monitoring during the treatment.

In most initial trials on protease inhibitors, a small number of patients older than 65 years of age were included. Although there was no upper age limit in NS5B nucleotide polymerase inhibitor SOF and NS3/4A second-generation protease inhibitor simeprevir trials, the number of elderly patients included was too small to draw any conclusion 14,15. In most of the trials involving SOF, most of the patients treated were in their 50s 16–21. In our study, 54 (27 in each group) patients treated with SPV and the SOF regimen showed similar SVR12 rates (P=0.607) and adverse events profile. Overall, SVR12 treated with an SOF-based regimen was 91–98%, in agreement with the results observed from the major trials involving SOF 18–22. In trials involving Viekira Pak, the study group involved were younger than 71 years, with a mean age in the 50s, and the SVR rate was well above 88% 22–26. Overall, the response rate with Viekira Pak in our study was 100% (12<65 and 6> 65 years), with good tolerance to medication in elderly patients.

Clinical trials involving IFN and RBV-free regimens also did not include enough patients aged 65 years and older to determine whether they respond differently from a younger population. Trials involving the NS5A inhibitor LDV and SOF in ION1, 2, and 3 trials included only 117 patients aged 65 years and older, and the patient population included in LONESTAR Study involving the LDV and the SOF combination was younger than 70 years 27–30. No overall difference in tolerability and effectiveness was observed with elderly patients, but the data available for the treatment of the aged population with newly approved therapies are still limited not only in registration trials but also in real-world treatments and community-based HCV regimens. Results of evaluation of 80 (52<65 and 28> 65 years) patients treated with Harvoni in our study yielded an ETR of 97% and an SVR12 of 94%, consistent with the results observed in clinical trials. No statistically significant difference was noted in our study with ETR (P=0.209) or SVR12 (P=0.120) between the two age groups, consistent with the recently published study by Saab et al. 31. They analyzed the data from four open-label phase 3 clinical trials that evaluated the safety and efficacy of LDV+SOF and concluded that the combination of LDV and SOF is safe, effective, and well tolerated in patients older than 65 years of age who have GT 1 hepatitis C infection 31. Of the 2293 patients enrolled in four phase 3 trials, 264 (12%) were older than or equal to 65 years of age, of whom 24 were aged older than or equal to 75 years. 97% of patients aged younger than 65 years achieved SVR12 (1965/2029) and 98% (258/264) of patients aged older than or equal to 65 years achieved SVR12. The most common adverse events in both age groups that occurred in 10% or more patients were headache and fatigue. Most adverse events noted in our study were minor and did not require any intervention, comparable with the study reports from major trials involving similar treatment regimens (Table 5). Adverse events did not differ significantly between the groups, except abdominal pain (P=0.018). Ten (6.4%) patients, all younger than 65 years of age, complained of nonspecific abdominal pain on treatment. Considering that the population involved had significant pain issues at baseline, it appears that this symptom may not be entirely related to the medication agent used. There were two serious adverse reactions during treatment with the regimen involving RBV with severe anemia requiring a blood transfusion and two patients received darbepoietin infusion for correction of anemia. None of the patients discontinued the complete treatment regimen in our study because of adverse reactions, although four patients discontinued the RBV during the treatment; they all achieved SVR12. In 12% of the patients, the RBV dose was reduced during treatment. A recent study by Pernas 32 raised a concern about possible drug interactions and RBV dose reduction because of adverse reactions in a significant number of patients after following 125 patients 65 years and older who were treated for hepatitis C with newer DAA agents. Of the 61.2% of patients who received RBV, in almost half, the dose was reduced during treatment 32. Clinical trials involving a recently approved IFN-free regimen for GTs 1 and 4, elbasvir, and grazoprevir (Zepatier; Merck & Co Inc, Kenilworth, New Jersey, USA) with or without RBV included 187 patients aged 65 years or older 33. The higher rate of late ALT elevation was observed in elderly patients; however, no dosage adjustment was required and the ALT level of most patients normalized after the completion of treatment.

SVR differs with GTs. We found a statistically significant low SVR rate with GT 1 in an elderly age group. There are no data identifying which patients will achieve an SVR among older patients with a DDA-based treatment. Our analysis indicates that cirrhosis and increased MELD score are important factors for low SVR in general and in elderly patients. Univariate analysis showed that baseline BMI, ALT, AST, and hemoglobin are factors that are associated significantly with an SVR (P=0.020, 0.020, 0.000, and 0.013, respectively).

In our study, 12 (6.28%) patients failed to respond to treatment (7<65 and 5≥65 years). Age was not a factor for the poor virologic response and the failure rate between the groups was not significant (P=0.767). All patients reported adherence to the medication regimen, and there was no clinical evidence of any reinfection in relapsed patients. None of these patients had any pretreatment-resistant or post-treatment-resistant associated variants and are awaiting further treatment. Seventy-five (nine out of 12) percent of the patients who failed to respond to treatment were cirrhotic and 41% (five out of 12) were coinfected with HIV. Further studies are required to evaluate these significant numbers of relapses in HIV-coinfected patients. Nine patients who failed to treatment received one or the other SOF-based regimen.

Some of the limitations of this study are the retrospective nature of our study, the fact that documentation of the common adverse events may not be complete, and that elderly patients involved are still a small number compared with registration trials. However, to our knowledge, our study is the first study involving a real-world community-based treatment comparing HCV patients younger than 65 years of age and 65 years of age and older. Going forward, the IFN-free regimens seem to be the standard of care in both age groups. RBV in combination with other DAAs may still be useful in treating some of the difficult to treat patient groups and in less developed countries, where the cost of newer antiviral medicines is a major hurdle. Shortened treatment course may reduce the drug-related adverse events in general including elderly patients. There is a pressing need to include older patients in future trials involving IFN-free agents. They require more complex decision-making because of their age and comorbid conditions with multiple medications.

Conclusion
The age of the patient does not seem to have a major impact on the virologic response rate when treating chronic HCV infection. Older patients (age 65 years and older) do not appear to have a higher frequency of adverse events compared with younger patients. Increased fibrosis, cirrhosis, some of the baseline laboratory studies including AST, ALT, Hemoglobin, and platelet levels seem to affect the SVR in the elderly and require further studies. More studies should be carried out in an older population of patients to assess the safety, efficacy, and adverse reactions of newer DAAs regimens. Treatment should not be withheld purely on the grounds of advanced age.

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Thursday, April 20, 2017

International Liver Congress/Healio - Three HCV drugs may not be better than two

Expert: Three HCV drugs may not be better than two
AMSTERDAM — The benefits of both double and triple direct-acting antiviral therapy combinations depend on myriad patient and disease factors, according to findings presented at the International Liver Congress.

Pawlotsky ran down a laundry list of agents in the pipeline, including NS5A inhibitors odalasvir (Achillion), pibrentasvir (AbbVie), and ruzasvir (Merck), and NS5B inhibitors AL-335 (Achillion), pibrentasvir (AbbVie) and uprifosbuvir (Merck). Although trials are currently underway, he suggested that ruzasvir has improved on previous compounds. “This drug has a virtually no resistance in vitro,” he said, noting that the resistance barrier was lower than Daklinza (daclatasvir, Bristol-Myers Squibb) or ledipasvir (Gilead). “You can see we’re making progress.”
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Monday, April 17, 2017

Drug Induced Pneumonitis Secondary to Treatment with VIEKIRA PAK® Hepatitis C: Case Report of an Unexpected Life-Threatening Adverse Reaction

Case Rep Med. 2017; 2017: 4895736.
Published online 2017 Mar 20. doi: 10.1155/2017/4895736
PMCID: PMC5376942

Drug Induced Pneumonitis Secondary to Treatment with Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir (VIEKIRA PAK®) for Chronic Hepatitis C: Case Report of an Unexpected Life-Threatening Adverse Reaction

Abstract
VIEKIRA PAK (ritonavir-boosted paritaprevir/ombitasvir and dasabuvir) is an approved treatment for compensated patients with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection. This oral regimen has minimal adverse effects and is well tolerated. Cure rates are 97% in patients infected with HCV GT 1a and 99% in those with HCV GT 1b. We report the first case of life-threatening allergic pneumonitis associated with VIEKIRA PAK. This unexpected serious adverse event occurred in a 68-year-old Chinese female with genotype 1b chronic hepatitis C and Child-Pugh A cirrhosis. One week into treatment with VIEKIRA PAK without ribavirin, she was admitted to hospital with respiratory distress and acute kidney injury requiring intensive care input. She was initially diagnosed with community acquired pneumonia and improved promptly with intravenous antibiotics and supported care. No bacterial or viral pathogens were cultured. Following complete recovery, she recommenced VIEKIRA PAK but represented 5 days later with more rapidly progressive respiratory failure, requiring intubation and ventilation, inotropic support, and haemodialysis. The final diagnosis was drug induced pneumonitis.

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Monday, March 20, 2017

2017 / Hepatitis C: Down but Not Out - Oral Direct-Acting Agent Therapy for HCV

Media Coverage Of This Article
Wednesday, March 22, 2017
Hepatitis C Cures Lag While New Drugs Wait in the Wings
Will new hepatitis C treatments eliminate the virus for good?

NEJM Journal Watch
All FDA-Approved, Oral Direct-Acting Antivirals for Hepatitis C Safe and Effective for Genotype 1
By Kelly Young
Edited by Jaye Elizabeth Hefner, MD   
The FDA-approved interferon-free regimens for treating hepatitis C appear to be safe and effective, suggests an Annals of Internal Medicine review.

Researchers examined 42 randomized trials of oral hepatitis C treatments that included at least two direct-acting antivirals. Among the findings:
  • For genotype 1 infection, the most common HCV type, sustained virologic response rates were above 95% for six regimens.
  • For patients with HCV genotype 3 and without cirrhosis, sofosbuvir plus velpatasvir or daclatasvir for 12 weeks seemed to be most effective.
  • For genotype 3 with cirrhosis, velpatasvir-sofosbuvir had higher response rates. That drug combination was also highly effective (99% response rate) for genotypes 2, 4, 5, and 6.
  • Patient groups traditionally considered difficult to treat — including those with HIV, severe kidney disease, or liver transplant — had high response rates and limited adverse events.
Editorialists conclude that "hepatitis C is down but not out," noting that screening for HCV is not yet routine, and the drugs are still priced high.
NEJM Journal Watch

Editorials |21 March 2017
Annals of Internal Medicine
Hepatitis C: Down but Not Out
Jay H. Hoofnagle, MD; Averell H. Sherker, MD                   
Within the past 4 years, no fewer than 10 potent, orally available antiviral drugs have received U.S. Food and Drug Administration (FDA) approval as therapy for chronic hepatitis C virus (HCV) infection. These small molecules are directed at 1 of 3 HCV targets: NS3/4A protease (“-previrs” [simeprevir, paritaprevir, and grazoprevir]), NS5B RNA polymerase (“-buvirs” [sofosbuvir and dasabuvir]), or NS5A polypeptide (“-asvirs” [daclatasvir, elbasvir, ledipasvir, ombitasvir, and velpatasvir]). Most important, combinations of 2 or 3 of these agents have proven highly effective in inducing a sustained virologic response (SVR), with persistent loss of HCV RNA from serum. Long-term follow-up of patients who have achieved SVR shows resolution of the accompanying liver disease and permanent loss of HCV RNA from both serum and the liver, suggesting a “cure” of the chronic viral infection. These new all-oral regimens typically have SVR rates of 95% or more with only 8 to 12 weeks of treatment and minimal adverse effects; in contrast, previous interferon-based regimens yielded rates of 50% to 60%, but only in highly selected patients and after 48 weeks of poorly tolerated treatment with serious adverse effects and significant contraindications. The new antiviral regimens have transformed management of chronic HCV infection.
http://annals.org/aim/article/2613307/hepatitis-c-down-out

Annals of Internal Medicine
Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection: A Systematic Review
Oluwaseun Falade-Nwulia, MBBS, MPH (*); Catalina Suarez-Cuervo, MD (*); David R. Nelson, MD; Michael W. Fried, MD; Jodi B. Segal, MD, MPH; Mark S. Sulkowski, MD
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Abstract
Background:

Rapid improvements in hepatitis C virus (HCV) therapy have led to the approval of multiple oral direct-acting antiviral (DAA) regimens by the U.S. Food and Drug Administration (FDA) for treatment of chronic HCV infection.Purpose:
To summarize published literature on the efficacy and safety of oral DAAs for treatment of persons with chronic HCV infection.

Data Sources: MEDLINE and EMBASE from inception through 1 November 2016.Study Selection:

42 English-language studies from controlled and single-group registered clinical trials of adults with HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs.

Data Extraction: Two investigators abstracted data on study design, patient characteristics, and virologic and safety outcomes sequentially and assessed quality independently.

Data Synthesis: Six DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child–Turcotte–Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (<10% in the general population); regimens that included ribavirin had more mild or moderate adverse events than those without.

Limitations: Twenty-three studies had moderate risk of bias (10 were open-label single-group trials, 11 had limited information on concealment of the allocation scheme, and 5 had selective outcome reporting). All but 1 of the studies were industry-funded. Heterogeneity of interventions precluded pooling.

Conclusion:
Multiple oral DAA regimens show high rates of safety, tolerability, and efficacy for treatment of HCV genotype 1 infection, particularly among persons without cirrhosis.

Primary Funding Source:Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42014009711)

In the United States, 3.2 to 5 million people are chronically infected with hepatitis C virus (HCV) and are at risk for cirrhosis, liver cancer, and death if untreated (1, 2). Infection with HCV is the primary indication for liver transplantation and causes more deaths than all other notifiable infectious diseases in the United States combined (3, 4). Cure of this infection, defined as the absence of detectable HCV RNA in the blood at least 12 weeks after treatment completion (sustained virologic response [SVR]), is strongly associated with reduced liver-related morbidity and mortality (5, 6). The development of drugs that directly inhibit key steps in viral replication has led to availability of several oral HCV treatment regimens (7). We systematically reviewed the efficacy and safety of oral interferon-free HCV treatment regimens that have been approved by the U.S. Food and Drug Administration (FDA) and include at least 2 direct-acting antivirals (DAAs). We also assessed the effect of ribavirin on rates of SVR and adverse events. We reviewed phase 2 and 3 clinical trial data for patients infected with HCV genotypes 1 to 6 and patients previously considered difficult to cure with decompensated cirrhosis, HIV infection, renal failure, or liver transplantation.

Methods
Data Sources and Searches
We developed a protocol for this systematic review and registered it in PROSPERO (CRD42014009711). We searched MEDLINE and EMBASE for literature published in English from inception through 1 November 2016. The search strategy included terms for HCV infection and the medications of interest (Figure 1). We also searched ClinicalTrials.gov and hand-searched the reference lists of included articles and related systematic reviews.

Study Selection

We included English-language, single-group, randomized, controlled trials (RCTs) of adults with chronic HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs. We included trials that used DAA combinations—including inhibitors of HCV NS3 protease (grazoprevir, paritaprevir, and simeprevir), NS5A (daclatasvir, elbasvir, ledipasvir, ombitasvir, and velpatasvir), and NS5B polymerase (sofosbuvir and dasabuvir), as well as the oral antiviral ribavirin—and for which the primary outcome was SVR. We excluded studies published only as abstracts; dose-finding studies; those in which the primary outcome was pharmacokinetics; or those in which the regimens included interferon, DAAs that were not FDA-approved, or only 1 DAA (for example, sofosbuvir plus ribavirin). Trials were included regardless of participants' cirrhosis, HIV, or liver transplantation status, but trials of limited populations (for example, DAA-experienced patients or those of a single race) were excluded.

Data Extraction and Quality Assessment

Two reviewers independently screened titles and abstracts and then the full text of potentially eligible articles to identify studies meeting inclusion criteria. Using standardized forms, 1 reviewer extracted information from the selected studies about study characteristics, design, outcomes, and the funding source. A second reviewer confirmed the accuracy of the extractions. Differences were resolved through consensus. Two reviewers independently assessed risk of bias for each selected study by using 5 items from the Cochrane risk-of-bias tools for RCTs and a Cochrane tool for assessment of risk of bias in nonrandomized trials and observational studies (8, 9).

Data Synthesis and Analysis

Detailed evidence tables were generated, and studies were summarized by outcomes. The results were organized by genotype and then by the specific population studied. The heterogeneity of the interventions precluded quantitative pooling of results.

Role of the Funding Source

The Patient-Centered Outcomes Research Institute (PCORI) funded the study and reviewed the report but did not participate in the formulation of the review's questions, data searches, study appraisals, evidence interpretation, or the preparation or approval of the manuscript for publication.

Results
Study and Quality Characteristics

Of 1796 citations evaluated, we included 42 studies published in 40 articles (Figure 1). All but 1 of the studies were funded by industry (10). Ten were open-label, single-group studies (10–19); 5 had a placebo group with deferred treatment (20–24); 11 evaluated different durations of therapies and the addition of ribavirin (for example, 8 vs. 12 weeks or 12 vs. 24 weeks of therapy with or without ribavirin) (25–35); 5 evaluated the same duration of therapy with and without ribavirin (36–39); 6 evaluated different durations with ribavirin (40–45); and 3 evaluated different durations of therapy without ribavirin (46–48). Only 2 studies had an active comparator group receiving an HCV treatment regimen other than that being evaluated in the trial (49). Three studies had 48 weeks of posttreatment follow-up, whereas the remainder had 12 or 24 weeks of follow-up.

Of the 42 studies, 19 had low risk of bias and 23 had moderate risk. Sources of possible bias included single-group design (n = 10), lack of information on sequence generation or concealment of the allocation scheme (n = 11), and selective reporting of outcomes (n = 5). Because SVR is a highly objective outcome measure, lack of blinding was not considered an important threat to validity. Rates of loss to follow-up were low (<10% for all studies).

HCV Genotype 1 Infection

Thirty-two studies enrolled persons with HCV genotype 1 infection (Table; Figure 2, continued Figure 2; and Table 1 of the Supplement). Download Supplemental Content

Regimens That Include NS3/4A Protease Inhibitors

Grazoprevir–Elbasvir.

Grazoprevir is an NS3 protease inhibitor that is available in a fixed-dose combination with elbasvir, an NS5A inhibitor. This regimen was studied in 4 multicenter randomized trials published in 6 articles (11, 20, 21, 25–27). Risk of bias was moderate in 3 of these studies due to lack of a comparator group (n = 1) and selective reporting (n = 2). Daily grazoprevir–elbasvir for 12 weeks was associated with SVR rates of 92% and 99% to 100% in treatment-naive and treatment-experienced patients with genotype 1a and 1b infection, respectively (20, 26, 27). Among patients with genotype 1a but not genotype 1b infection, lower SVR rates were associated with pretreatment presence of naturally occurring resistance-associated substitutions (RASs) at positions 28, 30, 31, and 93 of the NS5A region (20, 27). Prolongation of therapy to 16 weeks and addition of ribavirin led to SVR among 49 treatment-experienced patients, including all 6 patients with baseline NS5A RASs (27). Ribavirin was associated with greater incidence of anemia (3% to 16% vs. 0%), fatigue, and nausea (25–27). With the exception of patients with genotype 1a infection with baseline RASs, the SVR rate was similar in those treated with or without ribavirin. Cirrhosis was not associated with lower SVR rates (14, 16).

Paritaprevir–Ritonavir–Ombitasvir and Dasabuvir.

Paritaprevir is an NS3 protease inhibitor that is coformulated with ritonavir (to provide pharmacologic boosting) and ombitasvir (an NS5A inhibitor). For patients with genotype 1 infection, dasabuvir (a nonnucleoside NS5B polymerase inhibitor) was added. We identified 1 study with low risk of bias that used the two-DAA regimen without dasabuvir (45) and 9 studies (5 with low risk of bias and 4 with moderate risk of bias) that used the three-DAA regimen for 12 or 24 weeks (12, 13, 22, 23, 37, 38, 40, 41). Moderate risk of bias was due to lack of a comparator group (n = 2) and unclear sequence generation and allocation scheme concealment (n = 2). The three-DAA regimen without ribavirin yielded lower SVR rates in persons with genotype 1a infection (90%) than those with genotype 1b infection (99%); however, with the addition of ribavirin, the SVR rate among noncirrhotic patients with genotype 1a infection increased to 97% (38). Compared with placebo, ribavirin was associated with more anemia, fatigue, insomnia, and rash (22, 38). Among cirrhotic patients with genotype 1a infection, the three-DAA regimen plus ribavirin for 24 weeks led to higher SVR rates than 12 weeks of treatment (94.2% vs. 88.6%) (41). High rates of SVR were seen among cirrhotic and noncirrhotic patients with genotype 1b infection treated for 12 weeks with the three-DAA regimen alone or with ribavirin (97% to 100%) (22, 23, 37, 38, 41, 45).

Simeprevir and Sofosbuvir.

Simeprevir is an NS3 protease inhibitor that is used once daily in combination with sofosbuvir, a nucleoside analogue NS5B polymerase inhibitor. We identified 3 studies using this regimen (14, 28, 46). Risk of bias was moderate in 2 studies due to unclear sequence generation (n = 1) and lack of a comparator group (n = 1). When used for 12 weeks, the regimen was associated with high rates of SVR (97%) in persons with HCV genotype 1a or 1b infection without cirrhosis (46). In this population, pretreatment presence of naturally occurring simeprevir RASs at position 80 of the NS3 region (Q80K) was not associated with lower SVR rates (46). However, lower SVR rates were observed among patients with cirrhosis (79% to 88%) and, in this population, the presence of the Q80K RAS was associated with lower SVR rates in patients with genotype 1a infection (74% with Q80K and 92% without) (14).

Regimens That Do Not Include NS3/4A Protease Inhibitors

Daclatasvir and Sofosbuvir.

Daclatasvir is an NS5A inhibitor used with sofosbuvir. Clinical trial data on this combination are limited but suggest high SVR rates with 12- and 24-week treatment (96% to 100%), based on data from 2 studies with moderate risk of bias (29, 48). Among patients with advanced liver disease, SVR rates were lower (82%) (15).

Ledipasvir–Sofosbuvir.

Ledipasvir, an NS5A inhibitor, is coformulated with sofosbuvir as a once-daily tablet. Eight studies (4 with low risk of bias and 4 with moderate risk of bias) evaluated different treatment durations (8, 12, and 24 weeks) and the addition of ribavirin (17, 30–34, 43, 44). Moderate risk of bias was due to lack of a comparator (n = 1) and unclear sequence generation or allocation scheme concealment (n = 3). In treatment-naive patients, SVR rates were greater than 95% with 12 weeks of treatment, and longer treatment did not yield higher rates (30, 31, 33). Although 8 weeks of therapy was assessed in 1 RCT and was found to lead to high SVR rates in noncirrhotic persons with pretreatment HCV RNA levels less than 6 × 106 IU/mL (33), the most data on efficacy are for 12 weeks. In treatment-naive patients, ribavirin was not associated with higher SVR rates regardless of cirrhosis status, whereas in treatment-experienced patients, either longer therapy (24 weeks) with ledipasvir–sofosbuvir or the addition of ribavirin to the regimen for 12 weeks was associated with higher SVR rates in patients with cirrhosis (97% vs. 96%) (34). The addition of ribavirin led to more adverse events, notably anemia, fatigue, and insomnia (31–33).

Velpatasvir–Sofosbuvir.

Velpatasvir, a pangenotypic NS5A inhibitor, is coformulated with sofosbuvir as a once-daily tablet. This regimen for 12 weeks was associated with high SVR rates (97% to 99%) in patients with HCV genotype 1a or 1b infection, including those with cirrhosis and prior treatment experience (24). In this placebo-controlled, double-blind trial with low risk of bias, the incidence of adverse events was similar in patients receiving velpatasvir–sofosbuvir and those receiving placebo.

HCV Genotype 2 Infection

Six studies enrolled patients with HCV genotype 2 infection (Table and Figure 3); 3 studies (2 with low risk of bias and 1 with moderate risk of bias) evaluated the fixed-dose combination of velpatasvir–sofosbuvir (24, 35, 49), and 3 with moderate risk of bias evaluated daclatasvir plus sofosbuvir (15, 29, 48).

Daclatasvir and Sofosbuvir

In the ALLY-2 study, all 13 HIV-infected patients with genotype 2 infection who were treated for 12 weeks achieved SVR (48). In another study, 24 of 26 (92%) treatment-naive, noncirrhotic, HIV-seronegative patients treated for 24 weeks with or without ribavirin achieved SVR; 2 patients were lost to follow-up (29).

Velpatasvir–Sofosbuvir

The ASTRAL-1 and ASTRAL-2 studies reported SVR in 237 of 238 patients (99%) with genotype 2 infection who received velpatasvir–sofosbuvir for 12 weeks; 1 patient was lost to follow-up (24, 49). Rates of SVR were not affected by cirrhosis or prior treatment experience. In an RCT, velpatasvir–sofosbuvir was superior to sofosbuvir plus ribavirin (SVR of 99% vs. 94%) and was associated with fewer adverse events (49).

HCV Genotype 3 Infection

Eight studies enrolled patients with HCV genotype 3 infection (Table and Figure 3).

Daclatasvir and Sofosbuvir

In a phase 2 study, 16 of 18 noncirrhotic patients treated with or without ribavirin for 24 weeks achieved SVR (29). In the single-group ALLY-3 trial, which had moderate risk of bias, 94% to 97% of noncirrhotic treatment-naive and treatment-experienced patients achieved SVR with 12 weeks of treatment (16). In the same study, cirrhosis was associated with a marked reduction in SVR (58% to 69%) (16). The addition of ribavirin to the regimen for 12 or 16 weeks in patients with advanced liver disease led to SVR in 86% of cirrhotic patients (n = 36) in the ALLY-3+ study, which had moderate risk of bias due to unclear sequence generation and allocation scheme (42).

Ledipasvir–Sofosbuvir

In a single-center study with low risk of bias, all 26 treatment-naive patients treated with ledipasvir–sofosbuvir plus ribavirin for 12 weeks achieved SVR (39). The SVR rate was lower without ribavirin (64%) and in treatment-experienced patients (82%) (39).

Velpatasvir–Sofosbuvir

In a phase 3 RCT with 552 patients and low risk of bias, velpatasvir–sofosbuvir for 12 weeks (95%) was superior to sofosbuvir plus ribavirin for 24 weeks (80%) and was associated with fewer adverse events, particularly less anemia (49). Lower SVR rates were observed in patients with pretreatment presence of velpatasvir NS5A RASs, particularly at position 93 (88%), compared with those without RASs (97%).

HCV Genotype 4 Infection

Twelve studies enrolled persons with HCV genotype 4 infection (Table and Figure 3).

Grazoprevir–Elbasvir

In the C-EDGE study, efficacy of grazoprevir–elbasvir was demonstrated among 18 of 18 treatment-naive patients with genotype 4 infection (SVR of 100%) who received the regimen for 12 weeks; baseline presence of NS5A RASs did not affect SVR (20). Among treatment-experienced patients in a randomized trial of 12 or 16 weeks of the regimen with or without ribavirin, SVR rates were below 95% in all groups except patients who received 16 weeks of the regimen with ribavirin (27).

Paritaprevir–Ritonavir–Ombitasvir

In 1 trial with low risk of bias, paritaprevir–ritonavir–ombitasvir plus ribavirin resulted in high efficacy (SVR of 100%) in both treatment-naive (n = 42) and treatment-experienced (n = 44) patients with genotype 4 infection (36). The absence of ribavirin was associated with a lower SVR rate (91%).

Simeprevir and Sofosbuvir

In an RCT with moderate risk of bias due to unclear sequence generation and allocation scheme concealment, simeprevir plus sofosbuvir was associated with SVR in all 43 patients (100%) treated for 12 weeks, including those with cirrhosis (n = 23); however, SVR rates were lower in 20 patients treated for 8 weeks (75%) (47).

Ledipasvir–Sofosbuvir

In a single-group trial of 21 patients, 95% who received 12 weeks of ledipasvir–sofosbuvir achieved SVR; the study included few patients with cirrhosis (n = 7) or prior treatment experience (n = 8) (10). In a similar trial conducted in France, 41 of 44 patients (93%) who were treated for 12 weeks achieved SVR (19). No serious adverse events were reported in these studies (10, 19).

Velpatasvir–Sofosbuvir

In the ASTRAL-1 RCT, which had low risk of bias, velpatasvir–sofosbuvir led to SVR in all 116 treatment-naive and treatment-experienced patients (100%) who were treated, including those with cirrhosis (24).

HCV Genotype 5 and 6 Infection

Six studies enrolled persons with HCV genotype 5 and/or 6 infection (18, 20, 24, 27, 35, 39) (Figure 3).

Ledipasvir–Sofosbuvir

This combination led to high SVR rates in persons with genotype 5 (n = 41; SVR of 95%) and genotype 6 (n = 25; SVR of 96%) infection (18, 39). Although the numbers of patients in these subgroups were small, SVR rates were high in treatment-experienced patients (≥95%) and those with cirrhosis (89%) (18).

Velpatasvir–Sofosbuvir

In 1 RCT with low risk of bias, patients with genotype 5 (n = 35) and genotype 6 (n = 41) infection achieved high rates of SVR (97% and 100%, respectively) with 12 weeks of treatment; only 1 patient did not achieve SVR (death unrelated to treatment) (24).

Subpopulations

Patients With HIV Co-infection

Direct-acting antiviral regimens used for 12 or 24 weeks showed high SVR rates (91% to 98%) and low adverse event rates (<10%). These rates were similar to those observed in persons without HIV (11, 17, 26, 40, 48). Shorter therapy (8 weeks) was evaluated in 1 RCT of daclatasvir plus sofosbuvir and led to lower rates of SVR (76%) than 12 weeks of therapy (97%) (48).

Patients With Decompensated Cirrhosis

Relatively few patients with decompensated liver disease (for example, those with jaundice, ascites, encephalopathy, or variceal hemorrhage) have been enrolled in DAA trials. Because of impaired metabolism, NS3 protease inhibitors are not recommended (simeprevir) or are contraindicated (paritaprevir or grazoprevir) in patients with Child–Turcotte–Pugh class B and C disease. These patients have been treated in trials of sofosbuvir plus NS5A inhibitors, including daclatasvir, ledipasvir, and velpatasvir (15, 35, 43, 44). In 1 RCT, velpatasvir–sofosbuvir with ribavirin for 12 weeks was more effective than velpatasvir–sofosbuvir alone for 12 or 24 weeks; however, ribavirin was associated with more treatment discontinuation due to adverse events (35). Across all studies, rates of serious adverse events were higher in patients with decompensated cirrhosis (10% to 52%) than in the general HCV patient populations (<10%).

Patients After Liver Transplantation

Four trials evaluated DAAs in patients who had undergone liver transplantation. Overall, SVR rates observed in these trials were similar to those reported in patients without a transplant (12, 15, 43, 44). However, among liver transplant patients with decompensated liver disease due to recurrent HCV infection, SVR rates were lower (50% to 80%) and adverse event rates were higher (16% to 75%) than those observed in liver transplant patients with compensated cirrhosis or those with minimal liver disease (6% to 21%) (12, 43, 44).

Patients With Chronic Kidney Disease

In 2 studies of patients with advanced renal dysfunction, including those receiving hemodialysis, high SVR rates were reported in those with HCV genotype 1 infection (13, 21). In 1 study with low risk of bias, grazoprevir–elbasvir for 12 weeks resulted in SVR in 94% of patients (n = 111) (21). In a smaller study with moderate risk of bias due to lack of a comparator group, a regimen of paritaprevir–ritonavir–ombitasvir and dasabuvir was effective (SVR of 90%), but ribavirin, which was used for patients with genotype 1a infection, was poorly tolerated and was discontinued due to adverse events in 8 of 14 patients (48).

Discussion
Multiple interferon-free, oral DAA regimens are available for treatment of chronic HCV infection. We found high SVR rates for all FDA-approved DAA regimens, with some evidence of variable response influenced by specific patient and virus characteristics. Rates of serious adverse events (<10%), loss to follow-up (<10%), and treatment discontinuation (<5%) were low even in patients with comorbid conditions, such as HIV infection and cirrhosis.

The evidence was robust for persons with genotype 1 infection, which is the most common genotype worldwide, infecting approximately 84 million persons (50). We reviewed 6 distinct DAA regimens for genotype 1 infection, with SVR rates greater than 95% for most drug combinations and patient populations. Our findings represent an important update of other systematic reviews of DAA regimens with and without interferon for treatment of HCV genotype 1 infection, which reported SVR rates in the range of 95% (50, 51) and 92% (52). The high treatment response rates in persons with genotype 1 infection are particularly important in light of the historically poor SVR rates observed with interferon in this population.

In contrast, fewer DAA regimens are available and effective for the treatment of HCV genotype 3 infection, which is the second most prevalent HCV genotype globally, infecting approximately 54 million persons. Our findings indicate that the most effective DAA regimens for patients who have genotype 3 infection without cirrhosis are sofosbuvir plus the NS5A inhibitors velpatasvir or daclatasvir for 12 weeks, whereas higher SVR rates were observed with velpatasvir–sofosbuvir in patients with cirrhosis. This agrees with recent systematic reviews, identified through MEDLINE searches from 2014 to 2016, that identified velpatasvir–sofosbuvir as the most effective treatment for genotype 3 infection (51, 52). Our findings also suggest that lower SVR rates were achieved in patients with compensated and decompensated cirrhosis, prior treatment experience, or NS5A RASs; the addition of ribavirin and longer treatment duration were associated with higher SVR rates in these patient groups (42, 53).

Although relatively few studies enrolled patients with genotype 2, 4, 5, or 6 infection, high rates of SVR (>92%) were observed for all regimens administered for at least 12 weeks. Rates of SVR were particularly high (99%) for patients with genotype 2, 4, 5, or 6 infection treated with velpatasvir–sofosbuvir (24). For treatment of genotype 4 infection, all but 1 of the DAA regimens (paritaprevir–ritonavir–ombitasvir) led to high SVR rates (93% to 100%) without ribavirin and were associated with minimal adverse effects in treatment-naive patients.

Oral DAA regimens also showed high SVR rates and minimal adverse events in patient populations that were poorly responsive or could not be treated with interferon, including those with HIV co-infection, decompensated cirrhosis, severe chronic kidney disease, and a liver transplant. Patients co-infected with HIV and HCV and those receiving immunosuppressive agents after liver transplantation had SVR rates similar to those of persons without immune dysfunction, suggesting that oral DAAs mitigate the effect of an impaired HCV immune response (54–56). Direct-acting antiviral options for persons with severe chronic kidney disease remain limited, and although high SVR rates (85% to 100%) were observed in 2 RCTs for persons with HCV genotype 1 infection, no trials were identified in persons with genotype 2 or 3 infection, for whom interferon is still recommended (57). Treatment options also remain limited in patients with decompensated liver disease. Current NS3 protease inhibitors are hepatically metabolized and are contraindicated in this population; as such, trials have been restricted to sofosbuvir plus NS5A inhibitors. The evidence indicates that these regimens provide high rates of SVR (>85%), but serious adverse events are common (10% to 52%). In addition, questions remain with regard to the long-term clinical benefit of cure of HCV infection in persons with severe liver dysfunction.

Across multiple trials, our findings indicate that ribavirin continues to have a role in maximizing SVR rates in certain patients, including those with genotype 1a or 3 infection, cirrhosis, or prior treatment experience. Clinical trials for patients with decompensated cirrhosis and a liver transplant have also largely included ribavirin. Although ribavirin was associated with an increase in anemia, fatigue, and insomnia, the rates of serious adverse events and treatment discontinuation were similar in patients treated with and without it.

Limitations of this study include the fact that safety data from clinical trials may not fully represent patient experience in clinical practice. Persons with chronic hepatitis B virus infection were excluded from trials, and the risk for hepatitis B virus reactivation was not examined. We also included noncontrolled trials; however, spontaneous cure of HCV infection is rare. Most of the studies were industry-funded; such studies are more likely to be published if results are favorable (58), but we are not aware of large, unpublished studies in this field and the risk of bias with the objective outcome of SVR is low. The heterogeneity of the interventions studied also prevented quantitative pooling of results, and the relatively short follow-up limits our ability to comment on late relapse of HCV infection. Several studies were also population-specific, thus limiting generalizability of findings to all patients. Given the multitude of effective oral DAA regimens with similar rates of SVR and adverse events, RCTs will be needed to determine the best HCV treatments for different patient populations. One such trial, the PRIORITIZE study (ClinicalTrials.gov: NCT02786537), is under way in persons with genotype 1 infection (59).

Finally, our systematic review is limited by the rapidly evolving HCV treatment landscape and the inability to include all DAA regimens in ongoing or recently completed clinical trials that we identified on ClinicalTrials.gov (Table 7 of the Supplement). These ongoing clinical trials include 2 novel nucleotide analogue NS5B polymerase inhibitors, MK-3682 and AL-335, which are being evaluated in combination with approved NS3 protease inhibitors and novel NS5A inhibitors (ruzasvir and odalasvir), as well as 2 novel pangenotypic NS3 protease inhibitors, voxilaprevir and glecaprevir, which are being evaluated in combination with approved (sofosbuvir–velpatasvir–voxilaprevir) and novel (glecaprevir–pibrentasvir) DAAs (60).

In conclusion, oral DAA regimens that are highly efficacious, well-tolerated, and relatively short in duration are now available for all HCV genotypes and for patient populations historically considered difficult to cure. The ease of dosing, safety profile, and effectiveness of these agents provide an opportunity to expand the number of patients who can be treated for HCV infection and the pool of treating providers. Rapid developments in oral DAA therapies can be beneficial only if they are linked to efforts to improve rates of HCV detection, linkage to care, and access to DAA therapy.

References
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