Treatment of hepatitis C virus genotype 4 in the DAA era

Review Article

Treatment of hepatitis C virus genotype 4 in the DAA era 
Antonio Di Biagio Email author View ORCID ID profile , Lucia Taramasso and Giovanni Cenderello Virology Journal 201815:180
https://doi.org/10.1186/s12985-018-1094-4© The Author(s).

2018 Received: 22 November 2017 Accepted: 13 November 2018
Published: 22 November 2018

Abstract

The recently approved interferon-free DAA (direct antiviral agents) regimens have shown not only to be effective in terms of sustained virological response (SVR) rates (> 90%) but also well tolerated in most hepatitis C virus (HCV) infected patients. Nevertheless HCV genotypes are different and only a small percentage of trials consider genotype 4 (GT4), which was associated with lower rates of SVR compared with other genotypes before the arrival of the DAA’s. In this review, we discuss the efficacy of DAA therapy in GT4 HCV infection with specific reference to more recent studies, including those conducted in a ‘field-practice’ scenario. Overall, DAA-based regimens appear more effective also in the poorly-explored setting of patients with HCV GT4 infection. Despite an overall limited number of patients was evaluated, favorable results are being derived from studies on ombitasvir/paritaprevir/ritonavir, sofosbuvir and velpatasvir, whether or not in association with voxilaprevir, and with the new combined therapy glecaprevir + pibentasvir.

Read complete article online: https://virologyj.biomedcentral.com/articles/10.1186/s12985-018-1094-4

Frequent antiviral treatment failures in patients infected with hepatitis C virus genotype 4

Hepatology. 2018 Aug 19. doi: 10.1002/hep.30225. [Epub ahead of print]

Frequent antiviral treatment failures in patients infected with hepatitis C virus genotype 4, subtype 4r.

Fourati S1,2, Rodriguez C1,2, Hézode C2,3, Soulier A1,2, Ruiz I2,3, Poiteau L1,2, Chevaliez S1,2, Pawlotsky JM1,2.

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Abstract

Hepatitis C virus (HCV) genotype 4 is highly heterogeneous. HCV subtype 4r has been suggested to be less responsive to direct-acting antiviral (DAA) drug treatment than other genotype 4 subtypes. Among 537 DAA-treated patients who experienced a virological failure in France between 2015 and 2018, 121 (22.5%) were infected with genotype 4 and 27 of them (22.3%) with subtype 4r; subtype 4r was thus over-represented as compared to its prevalence in the French general population. Population sequencing of the NS3, NS5A and NS5B genes was performed in all subtype 4r patients at treatment failure and in 6 of them at baseline, while full-length HCV genome sequencing was performed in 2 baseline and 3 treatment failure samples by means of an original shotgun metagenomics method based on deep sequencing. At treatment failure, all subtype 4r patients harbored 2 to 3 dominant NS5A resistance-associated substitutions (RASs), including at least L28A/C/I/M/V and L30R. Among 13 patients exposed to sofosbuvir and an NS5A inhibitor (daclatasvir, ledipasvir or velpatasvir), 5 (38.5%) also harbored NS5B S282C/T RASs at treatment failure. An additional patient harbored S282C/T RASs at treatment failure by deep sequencing. The prevalence of S282C/T RASs at treatment failure was significantly higher in patients infected with genotype 4r than with other genotypes, including other subtypes of genotype 4.

CONCLUSION: 

The lower rates of SVR in patients infected with subtype 4r are related to the frequent preexistence at treatment baseline and subsequent selection by DAA treatment of both NS5A and NS5B S282 RASs. Our study suggests that these patients should be identified and receive a triple DAA combination regimen as first-line treatment. 

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PMID: 30125371 DOI: 10.1002/hep.30225

Elbasvir and grazoprevir with or without ribavirin, treatment–naive participants HCV genotype 2, 4, 5 or 6

Patients with non-genotype 1 HCV infection differ with regard to response to DAAs. This study evaluated the efficacy and safety of EBR/GZR, with or without RBV, in HCV genotype 2, 4, 5, or 6 infection.

Efficacy and Safety of 12 Weeks of Elbasvir +/- Grazoprevir +/- Ribavirin in Participants With Hepatitis C Virus Genotype 2, 4, 5 or 6 Infection

A. Brown C. Hézode E. Zuckerman G. R. Foster A. Zekry S. K. Roberts F. Lahser C. Durkan C. Badshah B. Zhang M. Robertson J. Wahl E. Barr B. Haber on behalf of the C‐SCAPE Study Investigators

J Viral Hepat. 2018;25(5):457-464. 

Introduction

People with hepatitis C virus (HCV) infection other than genotype 1 represent a heterogeneous group of individuals who differ with regard to their profile of response to all–oral, direct–acting antiviral regimens.[1,2] The recent approval of sofosbuvir/velpatasvir for people infected with HCV genotypes 1–6 now provides a single treatment option across genotypes. However, prior to the introduction of sofosbuvir/velpatasvir, treatment recommendations for genotype 2, 3, 5 and 6 were based on small studies with limited numbers of participants, or on subgroup analyses where small numbers of participants were enrolled alongside participants with genotype 1 or 4 infection.

The fixed–dose combination of elbasvir (EBR, MK–8742), an NS5A inhibitor, and grazoprevir (GZR, MK–5172), an NS3/4A protease inhibitor, is approved in the US, Europe and Canada as a treatment for HCV genotype 1 and 4 infection.[12] In those with HCV genotype 1 or 4 infection, EBR/GZR has shown efficacy in the subpopulations of treatment–naive people,[13] HIV/HCV co–infected people,[14] people who have previously failed treatment[15,16] and people with chronic kidney disease.[17] In vitro, EBR and GZR have shown pangenotypic potency in HCV replicons;[18,19] however, less has been reported about the clinical efficacy and safety of EBR/GZR in people with HCV nongenotype 1/4 infection. The phase 2 C–SCAPE study evaluated the efficacy and safety of EBR/GZR, with or without ribavirin (RBV), in treatment–naive participants with HCV genotype 2, 4, 5 or 6 infection...

Continue to full article: https://www.medscape.com/viewarticle/895954

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HCV genotype 4, 5 and 6 Cure Rates In Clinical Trials

In Case You Missed It

Journal of Viral Hepatitis
First published: 8 May 2018

HCV genotype 4, 5 and 6: Distribution of viral subtypes and sustained virologic response rates in clinical trials of approved direct‐acting antiviral regimens
S. D. Boyd P. Harrington T. E. Komatsu L. K. Naeger K. Chan‐Tack J. Murray D. Birnkrant K. Struble

First published: 25 March 2018 https://doi.org/10.1111/jvh.12896

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Summary
Multiple direct‐acting antiviral (DAA)‐based regimens are now available for all hepatitis C virus (HCV) genotypes (GTs). Because HCV GT 4, 5 and 6 are less common in the United States (US) and worldwide, relatively small numbers of participants with these GTs were evaluated in individual clinical trials. To provide a comprehensive description of subtype diversity and treatment outcomes in clinical trials for these less common GTs, we analysed data from 744 participants with HCV GT4 (n = 573), GT5 (n = 81), or GT6 (n = 90) across 18 clinical trials of DAA regimens. These data are from US New Drug Applications submitted between 2014 and 2017, and our analyses included only approved regimens. Excluding unresolved or mixed subtypes, the distribution of reported GT4 subtypes was 49% 4a, 31% 4d and 16% for one of 14 other subtypes. The distribution of GT6 subtypes was 39% 6a, 27% 6e, 8% 6 L and 23% for one of 11 other subtypes. Across approved regimens, sustained virologic response rates 12 weeks post‐treatment (SVR12) for GT 4, 5 and 6 ranged from 91% to 100%, 93% to 97% and 96% to 100%, respectively. SVR12 by GT4 subtype ranged from 96% to 100% for 4a and 81% to 100% for 4d. Virologic failures occurred in GT 4a, 4b, 4d and 4r. For GT6, SVR12 was 100% for all subtypes except 6 L, for which 1 of 7 participants experienced virologic failure. To our knowledge, this is the largest compilation of HCV GT 4, 5 or 6 clinical trial data. These analyses may be useful for clinicians treating HCV GT 4, 5 or 6.

Discussion

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The recent FDA approvals of various IFN‐free DAA regimens provide highly effective treatment options for HCV GT 4, 5 or 6 infection. Individual registrational trials generally demonstrated high SVR12 rates in these populations, with virologic failure occurring in a small proportion of patients. To conduct a more comprehensive analysis of HCV GT 4, 5 and 6 patient populations in HCV DAA clinical trials, including treatment outcomes and viral subtypes represented, we conducted independent analyses of 18 registrational trials submitted to FDA from 2014 to 2017 in new drug applications (NDAs) for elbasvir/grazoprevir, glecaprevir/pibrentasvir, ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir.

The analysis population comprises a substantially larger data set compared to individual clinical development programs for GT 4, 5 and 6 and allows for several observations. First, the combined clinical trial data in this analysis confirm that approved regimens for GT 4, 5 and 6 are all highly efficacious, with SVR12 rates similar to GT1. Overall, only a few participants did not achieve SVR12 with one of the FDA‐approved DAA regimens. No trends emerged associating virologic failure with baseline viral load, cirrhosis or prior treatment experience. Although limited sample sizes prevented statistical cross‐regimen comparisons, no clear differences in treatment efficacy emerged between any regimen with a reasonable sample size, and the few occurrences of virologic failure were distributed across different regimens.

A second observation is that the SVR12 rates for the most prevalent GT4 and GT6 subtypes either exceeded or corresponded with the SVR12 rates overall for these GTs. While the SVR12 rate for non‐4a, non‐4d GT4 subtypes was numerically lower, virologic failures in this group occurred only among participants with one of two uncommon subtypes, 4b and 4r. Extensive HCV genetic variability exists at multiple key NS5A resistance‐associated amino acid positions, both across and within different HCV subtypes.40 Recent studies have shown that reduced susceptibility to ledipasvir for some GT 4b and 4r isolates is associated with the presence of NS5A resistance‐associated substitutions, which may explain occurrences of ledipasvir/sofosbuvir virologic failure among patients with these subtypes.21, 41 Nevertheless, more data are needed with various NS5A inhibitor‐containing regimens before we can draw firm conclusions about the impact of NS5A genetic variability on treatment outcomes for patients with GT 4b, 4r and other less common subtypes. Importantly, the combined SVR12 rate for non‐4a, non‐4d GT4 subtypes across clinical trials still exceeded 90%. Because SVR12 rates were 100% for the most common GT6 subtypes, and only one participant with GT6 infection did not achieve SVR12, we cannot speculate on whether any of the less common GT6 subtypes may have a different response rate.

A third observation is our analysis confirms that the most common subtypes for GT4 and GT6 represented in clinical trials are consistent with previously published reports of subtype distribution in the United States, Europe and regions where these GTs are highly prevalent.40, 42, 43 For example, subtype 4a was not only the most common GT4 subtype in clinical trials that largely recruited participants located in the United States and Europe but is also the most common subtype in geographic areas with a high prevalence of GT4, such as Egypt.40, 42 Possibly, GT4 participants migrated from geographic areas where this genotype is highly prevalent, but specific demographic data such as geographic location of initial infection or country of origin usually were not available. Similarly, the two most common GT6 subtypes 6a and 6e observed in clinical trials are similar to previous reports.40

One limitation of our clinical trial analyses is the number of participants with uncommon subtypes was either low or not represented. This limitation makes it difficult to understand if treatment efficacy truly varies for certain infrequent subtypes and if baseline factors such as baseline viral load, presence of cirrhosis, HCV treatment history, or presence of baseline resistance‐associated substitutions affect response rates among different subtypes. However, we find the results reassuring because the SVR12 rates were close to 100% for the most common subtypes, and the overall SVR12 rates were high in the combined populations. Another limitation is that certain parts of the world (eg Sub‐Saharan Africa) are not well represented in clinical trials, and GT 4, 5 or 6 subtypes or other viral genetic characteristics may differ in these underrepresented regions.

This compilation of data from participants with HCV GT 4, 5 or 6 provides the largest pool of clinical trial data for FDA‐approved DAA regimens for these less common GTs. Combined clinical trial data enhance descriptive subgroup analysis such as frequency of viral subtypes and confirms high SVR12 or low virologic failure rates across FDA‐approved regimens. The geographic distribution of viral subtypes in our clinical trial database is consistent with the existing information on the general prevalence of these subtypes.

Overall, the data presented provide comprehensive information about efficacy including SVR and virologic failure rates. These analyses may be useful for clinicians treating patients with HCV GT 4, 5 or 6.

https://onlinelibrary.wiley.com/doi/full/10.1111/jvh.12896

A pilot single arm observational study of sofosbuvir/ledipasvir (200 + 45 mg) in 6‐ to 12‐ year old children

A pilot single arm observational study of sofosbuvir/ledipasvir (200 + 45 mg) in 6‐ to 12‐ year old children

M. H. F. El‐Shabrawi N. M. Kamal H. R. El‐Khayat E. M. Kamal M. M. A. H. AbdElgawad M. Yakoot

First published: 25 April 2018 https://doi.org/10.1111/apt.14677

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Summary

Background

No available data on the use of sofosbuvir/ledipasvir combination in treatment of hepatitis C virus (HCV) infection in children 6‐ to 12‐ year old.

Aim
To assess the safety and efficacy of sofosbuvir plus ledipasvir in children 6‐ to 12‐ year old with chronic HCV genotype 4 infection.

Methods
This is a pilot prospective single arm observational open‐label multicentre study. A total of 20 consecutive eligible chronic HCV infected children, aged from 6‐ to 12‐ years were included in this study and treated with a fixed sofosbuvir/ledipasvir combination in half the adult dose (200/45 mg) once daily for 12 weeks. Laboratory tests including virological markers were measured at baseline, 2, 4, 8 and 12 weeks (end of treatment [EOT]), and 12 weeks after end of treatment for sustained virological response 12 (SVR12).

Results
The intention‐to‐treat (ITT) SVR12 rate was 19/20 (95%; 95% CI: 76.4%‐99.1%). SVR12 was not assessed in one patient who was lost to follow‐up after showing viral negativity at the EOT12. All the remaining 19 patients (100%, 95% CI: 83.18%‐100%) who completed the full protocol and follow‐up visits achieved SVR12 with normal liver, haematological, and renal function tests and no side effects or fatalities.

Conclusions
This pilot study demonstrated that the fixed dose sofosbuvir/ledipasvir combination could be safe and effective treatment in children 6‐ to 12‐ years with chronic hepatitis C genotype 4 infection. Our pilot results might encourage larger and multicentre studies in this age group.

Article: https://onlinelibrary.wiley.com/doi/full/10.1111/apt.14677

International Liver Congress 2018: 8-weeks of Zepatier (elbasvir/grazoprevir) may effectively treat HCV genotype 4

8-weeks of Zepatier may effectively treat HCV genotype 4
April 14, 2018
PARIS — In patients with hepatitis C virus genotype 4, 8 weeks of Zepatier showed effective treatment of the virus, according to a presentation at the International Liver Congress 2018.

“This is an ongoing study investigating a novel 8-week treatment regimen of elbasvir/grazoprevir in participants with genotype 4 infection,” Tarik Asselah, MD, University Paris Diderot, said in his presentation. “We have high rates of SVR among treatment-naive participants with mild to moderate fibrosis who have completed follow up.”

Continue reading....

View Slides @ NATAP
Efficacy and safety of 8 weeks of elbasvir/grazoprevir in HCV GT4-infected treatment-naive participants - (04/12/18)

Of Interest

Impact of HCV Viral Load on Elbasvir/Grazoprevir Effectiveness in Chronic Hepatitis C: Updated Retrospective Data Analyses from the TRIO Network - (04/13/18)

Effectiveness of Elbasvir/Grazoprevir in Patients with Cirrhotic Genotype 1 or 4 Chronic Hepatitis C: Updated Retrospective Data Analyses from the TRIO Network - (04/13/18)

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Coverage: International Liver Congress

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For Patients: The International Liver Congress 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.

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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

Elbasvir/grazoprevir in Asia‐Pacific/Russian participants with chronic hepatitis C genotype 1, 4, or 6 infection

Elbasvir/grazoprevir in Asia‐Pacific/Russian participants with chronic hepatitis C virus genotype 1, 4, or 6 infection
Jacob George Eduard Burnevich I‐Shyan Sheen Jeong Heo Kinh Van Nguyen Tawesak Tanwandee Pin‐Nan Cheng Do Young Kim Won Young Tak Svetlana Kizhlo Konstantin Zhdanov Vasily Isakov Liwen Liang Pauline Lindore Joy Ginanni Bach‐Yen Nguyen Janice Wahl Eliav Barr Michael Robertson Paul Ingravallo Rohit Talwani on behalf of the C‐CORAL Study Investigators

First published: 4 April 2018 https://doi.org/10.1002/hep4.1177

Read the full text article: https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep4.1177

Abstract

The prevalence of hepatitis C virus (HCV) infection in Asian countries is high. This study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) in participants with HCV infection from Asia‐Pacific countries and Russia. In this phase 3, randomized, placebo‐controlled, double‐blind study, treatment‐naive participants with HCV genotype (GT) 1, 4, or 6 infection were randomized to EBR 50 mg/GZR 100 mg (immediate‐treatment group [ITG]) or placebo (deferred‐treatment group [DTG]) once daily for 12 weeks (Protocol PN‐5172‐067, NCT02251990). The primary efficacy variable was a nonrandomized comparison of sustained virologic response at 12 weeks after the end of therapy (SVR12) for the ITG with a historical control. The primary safety outcome was a randomized comparison between the ITG and DTG. Three hundred thirty‐seven participants were randomized to the ITG (n = 251) or DTG (n = 86); 199 (59.2%) participants were Asian, and 250 (74.4%) had HCV GT1b infection. Overall, 232/250 (92.8%) participants in the ITG achieved SVR12 (97.5% confidence interval, 89.1, 96.5). Of the 18 participants who failed to attain SVR12, 1 was lost to follow‐up and 17 had virologic failure, 13 of whom had HCV GT6 infection. The incidence of adverse events was similar between participants receiving EBR/GZR and placebo (50.8% versus 51.2%; difference, −0.3%; 95% confidence interval, −12.3, 11.9).

Conclusion: EBR/GZR for 12 weeks provides an effective and well‐tolerated regimen for chronic HCV GT1 infection in treatment‐naive people from Asia‐Pacific countries and Russia, particularly for the large population with GT1b infection. EBR/GZR is not recommended for the treatment of individuals with HCV GT6 infection. (Hepatology Communications 2018)

Source: https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep4.1177

High SVR Rates: Ombitasvir/Paritaprevir-ritonavir plus Ribavirin for 12 wks in HCV Geno 4 patients w-advanced fibrosis

12 WEEKS OMBITASVIR/PARITAPREVIR-RITONAVIR + RIBAVIRIN ACHIEVE HIGH SVR RATES IN HCV-4 PATIENTS WITH ADVANCED FIBROSIS
Elisabetta Degasperi, Alessio Aghemo, Stefania Paolucci, Roberta D’Ambrosio, Marta Borghi, Riccardo Perbellini, Federica Novazzi, Stella De Nicola, Giovanna Lunghi, Fausto Baldanti, Pietro Lampertico

DOI: https://doi.org/10.1016/j.dld.2018.02.003
Publication stage: In Press Accepted Manuscript
Published online: February 12, 2018

Abstract
Background
Ombitasvir/Paritaprevir-ritonavir (OBT/PTV-r) plus Ribavirin (RBV) for 12 weeks in hepatitis C virus (HCV) genotype 4 patients with advanced fibrosis has been only investigated in clinical trials.

Aims
To assess safety and efficacy of OBT/PTV-r + RBV for 12 weeks in real-life HCV-4 patients with advanced fibrosis.

Methods
HCV-4 patients with advanced fibrosis consecutively receiving OBT/PTV-r + RBV for 12 weeks in a single center were enrolled. Fibrosis was staged by transient elastography (TE) (F3: ≥10 kPa; F4 ≥11.9 kPa) or histologically. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks post-treatment.

Results
Between January 2016 and February 2017, 49 HCV-4 patients were included: median age 54 (39-72) years, 84% males, 59% Egyptians, 35% fibrosis F3 and 65% F4, all Child Pugh class A. Median RBV dose was 1,200 (200-1,200) mg/day. At ITT analysis, 47 (96%) patients achieved an SVR (100% at PP analysis). SVR was not affected by ancestry (Egyptian vs. Italian 97% vs. 95%, p = 1.0), fibrosis stage (F3 vs. F4 100% vs. 94%, p = 0.53), presence of baseline resistance associated substitutions (RASs) or RBV reduction.

Conclusions
We report 100% SVR with 12-weeks of OBT/PTV-r + RBV in HCV-4 patients with advanced liver disease, including compensated cirrhotics.

http://www.dldjournalonline.com/article/S1590-8658(18)30179-8/fulltext

Generic daclatasvir plus sofosbuvir, with or without ribavirin, in treatment of chronic hepatitis C: real-world results from 18 378 patients in Egypt

Alimentary Pharmacology and Therapeutics - November 29, 2017

Generic daclatasvir plus sofosbuvir, with or without ribavirin, in treatment of chronic hepatitis C: real-world results from 18 378 patients in Egypt
H. Omar, W. El Akel, T. Elbaz, M. El Kassas, K. Elsaeed, H. El Shazly, M. Said, M. Yousif, A. A. Gomaa, A. Nasr, M. AbdAllah, M. Korany, S. A. Ismail, M. K. Shaker, W. Doss, G. Esmat, I. Waked, Y. El Shazly

Full Text Article - http://onlinelibrary.wiley.com/doi/10.1111/apt.14428/full

Abstract

Summary

Background
Treatment of chronic hepatitis C using combination of sofosbuvir (SOF) and daclatasvir (DCV) was used in several clinical trials and multicentre studies, which were somewhat limited to genotypes 1-3. The national program in Egypt is using SOF-DCV combination for large scale treatment.

Aim
To assess the efficacy and safety of combined SOF-DCV in treating patients with HCV-G4 in a real-world setting.

Methods
Data and outcome of chronic HCV patients who were treated for 12 weeks with generic medications: DCV 60 mg plus SOF 400 mg ± ribavirin (RBV) within the national hepatitis C treatment program in Egypt are presented. Treatment-naïve patients without cirrhosis were treated without RBV, and those who had cirrhosis or were treatment-experienced (interferon experienced or SOF experienced) received RBV. Efficacy and safety were assessed, and baseline factors associated with sustained virological response at post-treatment week 12 (SVR12) were explored.

Results
During the first 2 months of the programme, 18 378 patients with HCV-G4 started treatment with SOF-DCV with or without RBV. Overall, 95.1% achieved SVR12 (95.4% among patients treated without RBV and 94.7% for patients treated with RBV, P = .32). Treatment was prematurely discontinued in only 1.5% of patients. The most common events leading to discontinuation were patient withdrawal (n = 76) and pregnancy (n = 5). Five deaths occurred within this group.

Conclusions
Real-world experience of generic SOF-DCV in patients with chronic HCV-G4 proved to be safe and associated with a high SVR12 rate, in patients with different stages of fibrosis.

Continue to full text article... http://onlinelibrary.wiley.com/doi/10.1111/apt.14428/full

Impact of hepatitis C virus genotype-4 eradication following direct acting antivirals on liver stiffness measurement

Impact of hepatitis C virus genotype-4 eradication following direct acting antivirals on liver stiffness measurement

Tag-Adeen M, Sabra AM, Akazawa Y, Ohnita K, Nakao K

     

Received 25 May 2017
Accepted for publication 18 July 2017
Published 6 October 2017 Volume 2017:9 Pages 45—53
DOI https://doi.org/10.2147/HMER.S142600

Background: Liver fibrosis is the most important prognostic factor in chronic hepatitis C virus (HCV) patients, and Egypt shows the highest worldwide HCV prevalence with genotype-4 predominance. The aim of this study was to investigate the degree of liver stiffness measurement (LSM) improvement after successful HCV eradication.

Patients and methods: The study included 84 chronic HCV Egyptian patients, and was conducted at Qena University Hospital from November 1, 2015 till October 31, 2016. LSM was obtained by FibroScan® before starting direct acting antiviral (DAA) treatment and after achieving sustained virologic response-24 (SVR-24). Based on baseline LSM, patients were stratified into F0–F1, F2, F3 and F4 groups (METAVIR). LSM and laboratory data after achieving SVR-24 was compared with that before starting therapy in each fibrosis group (F0-F4), p-value <0.05 was statistically significant.

Results: Following DAA treatment, 80 patients achieved SVR-24; of these, 50 were males (62.5%), mean age: 54.2±7.6 years, and mean body mass index: 28.6±2.2 kg/m2. Mean baseline LSM dropped from 15.6±10.8 to 12.1±8.7 kPa post-SVR; the maximum change of −5.8 occurred in F4 versus −2.79, −1.28 and +0.08 in F3, F2 and F0–F1 respectively (p<0.0001). At baseline, 41 patients were in the F4 group; only 16 (39%) regressed to non-cirrhotic range (<12.5 kPa), while 25 (61%) were still cirrhotic despite achieving SVR-24 (p<0.0001). Patients who achieved LSM improvement (n=64) have had significantly higher baseline aspartate transferase (AST) and alanine transaminase (ALT). Also, those patients showed significant improvement in AST, AST/platelets ratio index (APRI) and fibrosis-4 index (Fib-4) after achieving SVR; 91% showed AST improvement (p=0.01) and APRI improvement (p=0.01) and 81% showed Fib-4 improvement (p=0.04). Females, diabetics, patients with S3 steatosis and patients older than 50 years showed less LSM improvements than their counterparts. Baseline LSM ≥9 kPa, bilirubin ≥1 mg/dl, ALT ≥36 U/L and AST ≥31 U/L were significant predictors for LSM improvement.

Conclusion: Successful HCV genotype-4 eradication results in significant LSM improvement; the best improvement occurs in F4 patients. But as the majority of cirrhotics are still at risk for liver decompensation and hepatocellular carcinoma development despite achieving SVR-24, early detection and treatment are highly recommended.

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Real-life results of sofosbuvir based therapy in chronic hepatitis C -naïve and -experienced patients in Egypt

Real-life results of sofosbuvir based therapy in chronic hepatitis C -naïve and -experienced patients in Egypt

Real-life results of sofosbuvir based therapy in chronic hepatitis C -naïve and -experienced patients in Egypt
Ahmed Nagaty, Ekram W. Abd El-Wahab Published: October 5, 2017

https://doi.org/10.1371/journal.pone.0184654

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Abstract
Background
More than ten million Egyptians are infected with HCV. Every one of them is going to infect about three to four persons every year. Treating those patients is a matter of national security. A dramatic improvement in hepatitis C virus (HCV) infection treatment was achieved in the last five years. A new era of direct-acting antivirals is now dawning in Egypt.

Objective(s)
We share in this report our clinical experience in treating chronic HCV Egyptian patients with Sofosbuvir based regimens to evaluate its safety and efficacy on real life practical ground.

Methods
A total of 205 chronic HCV patients (195 naive and 15 experienced) were enrolled in the study. Patient were treated with Sofosbuvir+Ribavirin 24 weeks as standard of care. Two interferon eligible patients were treated with PEG-INF+ Sofosbuvir+Ribavirin for 12 weeks. The primary efficacy endpoint was the proportion of patients with sustained virologic response at 24 weeks after cessation of therapy.

Results
The overall response rate was 97.1%. Sustained virological response rate did not differ among treatment-naive patients and patients with previous history of IFN-based therapy. Portal hypertension, prediabetes, and lack of early virologic response were predictors of non response. No clinically significant treatment-emergent adverse effects were noted. No treatment discontinuation was encountered.

Conclusion
In the real-life setting, Sofosbuvir based regimens for 24 weeks has established an efficacious and well tolerated treatment in naïve and experienced patients with chronic HCV genotype 4 infection; although shorter treatment durations may be possible. However, patient follow up should extent to at least 6 months post-treatment and verifying viral load on yearly basis is warranted to track any late relapse.

Source - http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184654

Most patients with HCV genotypes 2, 4, 5, 6 achieve SVR with Mavyret

Most patients with HCV genotypes 2, 4, 5, 6 achieve SVR with Mavyret
Asselah T, et al. Clin Gastroenterol Hepatol. 2017;doi:10.1016/j.cgh.2017.09.027.
September 26, 2017

Most patients with hepatitis C genotype 2, 4, 5 or 6 who received Mavyret for 8 weeks achieved sustained virologic response with a high safety profile, according to results from three phase 3 studies. The rate of virologic failure was less than 1%.

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Effect of DAA therapy on type 2 diabetes patients with HCV genotype 4 infection.

Diabetes Metab J. 2017 Aug;41(4):316-321. doi: 10.4093/dmj.2017.41.4.316.

Factors Associated with Improved Glycemic Control by Direct-Acting Antiviral Agent Treatment in Egyptian Type 2 Diabetes Mellitus Patients with Chronic Hepatitis C Genotype 4.
Dawood AA1, Nooh MZ2, Elgamal AA3.

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Abstract
BACKGROUND:
The association of chronic hepatitis C virus (HCV) infection with type 2 diabetes mellitus (T2DM) was first reported in 1994. Little is known about the effect of direct-acting antiviral agents (DAAs) on glycemic control in T2DM patients. The aim of the present study was to evaluate the factors associated with improved glycemic control (IGC) by DAA treatment in Egyptian T2DM patients with chronic HCV genotype 4 infection.

METHODS:
This study included 460 T2DM patients with chronic HCV genotype 4 infection. Four hundred patients received DAAs and 60 patients did not receive DAAs. Patients with sustained virological response after 3 months of DAAs (378 patients) were allocated into two groups: first group included 292 patients (77.2%) with IGC and second group included 86 patients (22.8%) with non-improved glycemic control (NIGC).

RESULTS:
In IGC group, 78 patients (26.7%) needed to decrease the dose of antidiabetic treatment. There were no significant differences between IGC and NIGC groups as regards age, sex, and body mass index. The percentage of patients with positive family history of T2DM, those with Child B class and duration of T2DM were significantly higher in NIGC group compared to IGC.

CONCLUSION:
Diabetic patients receiving DAAs should be closely monitored for reduction of antidiabetic drugs especially insulin and sulfonylurea to avoid hypoglycemic events. Improvement of glycemic control with DAAs is more in patients without family history of T2DM, short duration of diabetes mellitus, and mild liver disease.

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

Ann Hepatol. 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.

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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.

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http://annalsofhepatology.com/revista/numeros/2017/HP175-06-Treatment%20(F_110817V)_PROTEGIDO.pdf

(grazoprevir-ruzasvir-uprifosbuvir) Shorter anti-HCV regimen effective in patients with or without cirrhosis

In Case You Missed It

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Shortening the duration of therapy for chronic HCV
Lancet Published online August 9, 2017
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Shorter anti-HCV regimen effective in patients with or without cirrhosis

Last Updated: 2017-08-18
By Will Boggs MD
NEW YORK (Reuters Health) - An eight-week regimen containing grazoprevir-ruzasvir-uprifosbuvir appears to be effective for treating hepatitis C virus (HCV) infection in patients with or without cirrhosis, according to findings from a pair of randomized phase 2 open-label trials.

Dr. Edward J. Gane from Auckland Clinical Studies, in Auckland, New Zealand, and colleagues - in part A of the C-CREST-1 and C-CREST-2 trials - randomly assigned 240 patients with HCV genotype 1, 2 or 3 and without cirrhosis to receive an eight-week course of a daily three-drug combination:

- grazoprevir 100 mg, plus

- either elbasvir 50 mg or ruzasvir 60 mg, plus

- either 300 mg or 450 mg of uprifosbuvir.

The studies were funded by Merck and Co.

Sustained virologic response rates 12 weeks after the end of therapy (SVR12) were 92% with both doses of the grazoprevir-ruzasvir-uprifosbuvir regimen and ranged from 85% to 88% (depending on uprifosbuvir dose) with grazoprevir-elbasvir-uprifosbuvir, according to one of the reports, both online August 9 in The Lancet Gastroenterology and Hepatology.

All four regimens were well-tolerated.

"These results support the selection of grazoprevir plus ruzasvir plus uprifosbuvir 450 mg as the regimen for further clinical investigation in broader populations," the researchers conclude.

Dr. Eric Lawitz from Texas Liver Institute at the University of Texas Health San Antonio and colleagues extended these findings in part B of C-CREST-1 and C-CREST-2. In this trial, 675 patients with HCV-1, -2, -3, -4 or -6, with or without cirrhosis, received eight, 12, or 16 weeks of grazoprevir-ruzasvir-uprifosbuvir 450 mg, with or without ribavirin.

SVR12 rates with eight weeks of therapy were 93% in individuals with genotype 1a, 98% with genotype 1b, 86% with genotype 2 (without cirrhosis; patients with HCV-2 and cirrhosis received a longer course), 95% with genotype 3 (treatment naive, without cirrhosis) and 100% with genotypes 4 and 6.

"We were surprised by the relatively lower efficacy of an 8-week duration of this regimen among those with genotype 2 infection," Dr. Lawitz told Reuters Health by email. "However, extending therapy to 12 weeks overcame this effect."

SVR12 rates were generally higher among participants with or without cirrhosis who received 12 or 16 weeks of therapy.

There were no documented virologic failures after week 12 of follow-up, although 10 participants who achieved SVR12 were lost to follow-up.

As in part A of the study, treatment with this fixed-dose combination with or without ribavirin was generally well tolerated.

"Results from the current studies support further investigation of grazoprevir, ruzasvir, and uprifosbuvir as a pan-genotypic regimen in individuals infected with HCV with and without cirrhosis, and suggest that this combination has the potential to provide a safe, single-duration regimen in most populations, including individuals with cirrhosis infected with genotype 3 who had previously received treatment with pegylated interferon and ribavirin," the researchers conclude.

"We await data from phase 3 to know how this regimen might impact the current treatment landscape," Dr. Lawitz said. "We hope that this regimen will be able to give providers more options with regard to pan-genotypic regimens for the treatment of HCV."

Dr. Eleanor M. Wilson from the University of Maryland School of Medicine, Baltimore, who coauthored an accompanying comment in the journal, told Reuters Health by email, "The safety and efficacy data seem promising, but it's still investigational, so not sure about its impact on the field of hepatitis C treatment yet."

"With the recent approvals of Vosevi and Mavyret, in addition to the previously available options, I think the overall take-away is that it's fantastic that there are more hepatitis C treatment options for patients and providers," she said. "It's tremendous that previously so-called 'difficult-to-treat patients' including those with previous treatment experience, comorbid conditions like HIV or renal disease, and those with advanced fibrosis and cirrhosis now have a variety of safe and highly effective options to treat their hepatitis C."

"My area of expertise is in novel treatment approaches, including strategies to reduce the treatment duration in order to increase access and decrease treatment cost, as well as options for patients who haven't successfully cleared HCV with first-line therapy (due to problems of adherence or viral resistance), and from that standpoint, it's an exciting time to be a hepatitis C provider," Dr. Wilson said.

Dr. Mark Sulkowski, who directs the viral hepatitis center at Johns Hopkins University in Baltimore, told Reuters Health by email, "We currently have multiple outstanding HCV regimens for the treatment of all genotypes of hepatitis C, which typically include combinations of direct-acting antiviral inhibitors of HCV protein targets NS3 (protease), NS5A and NS5B (polymerase). While we have seen the regulatory approval of multiple inhibitors of the NS3 and NS5A proteins, to date, only one (nucleotide) inhibitor of the NS5B polymerase active site has been approved, sofosbuvir."

"The C-CREST-1 and -2 studies provide a phase 2 evaluation of another (nucleotide) analogue inhibitor of NS5B, uprifosbuvir," said Dr. Sulkowski, who was not involved in the research. "Based on the results of these studies, uprifosbuvir appears to be poised to move to phase 3 studies, and if successful in phase 3 trials, this agent could become a valuable addition to the available drugs to treat hepatitis C."

Dr. Gane did not respond to a request for comment.
Merck funded the trials and employed most of the authors.

SOURCE: Lancet Gastroenterol Hepatol 2017.
Abstract 

Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials

Abstract 

Safety and efficacy of a fixed-dose combination regimen of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin in participants with and without cirrhosis with chronic hepatitis C virus genotype 1, 2, or 3 infection (C-CREST-1 and C-CREST-2, part B): two randomised, phase 2, open-label trials

Abstract 

Shortening the duration of therapy for chronic hepatitis C infection

Full Text
Shortening the duration of therapy for chronic HCV
Lancet Published online August 9, 2017
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Hepatitis C - Newly Approved Mavyret Has High Response Rates

The Lancet
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Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial
Xavier Forns, Samuel S Lee, Joaquin Valdes, Sabela Lens, Reem Ghalib, Humberto Aguilar, Franco Felizarta, Tarek Hassanein, Holger Hinrichsen, Diego Rincon, Rosa Morillas, Stefan Zeuzem, Yves Horsmans, David R Nelson, Yao Yu, Preethi Krishnan, Chih-Wei Lin, Jens J Kort, Federico J Mensa

Summary Background
The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis......
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The Lancet
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Comment 

New anti-HCV drug combinations: who will benefit?

Peter Ferenci

Published: 14 August 2017

Publication stage: In Press Corrected Proof
DOI: http://dx.doi.org/10.1016/S1473-3099(17)30486-3
In The Lancet Infectious Diseases1 Xavier Forns and colleagues present the results of a phase 3 trial assessing the efficacy and safety of 12 weeks of treatment with glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) in patients with chronic hepatitis C virus (HCV) genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Of 146 enrolled patients, 145 (99%, 95% CI 98–100) achieved a sustained virological response. The study did not include patients with decompensated cirrhosis; the same is true for studies of sofosbuvir, velpatasvir, and voxilaprevir.2....
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Newly Approved Hepatitis C Drug Has High Response Rates

By Amy Orciari Herman
Edited by David G. Fairchild, MD, MPH, and Lorenzo Di Francesco, MD, FACP, FHM
Nearly all patients with chronic hepatitis C virus (HCV) infection treated with glecaprevir-pibrentasvir achieved sustained virologic response after 12 weeks of therapy, according to results of an industry-funded, phase 3 trial in the Lancet Infectious Diseases. The once-daily combination drug (brand name, Mavyret) was approved by the FDA earlier this month to treat all HCV genotypes.

The trial enrolled 146 adults with HCV genotype 1a, 1b, 2, 4, 5, or 6 and compensated cirrhosis who either had not been previously treated, or had not responded to interferon-based treatment or to treatment with sofosbuvir plus ribavirin (with or without pegylated interferon). At 12 weeks after treatment ended, all but one patient had sustained virologic response. A patient with HCV genotype 1a and a history of treatment with pegylated interferon plus ribavirin relapsed at week 8.

Nearly 70% of patients had adverse events, most of which were mild (e.g., fatigue). No serious events were related to the study drug.

Link(s):
The Lancet
Lancet Infectious Diseases article (Free abstract)
Lancet Infectious Diseases comment (Subscription required)
Background: Physician's First Watch coverage of glecaprevir-pibrentasvir (Free)

Source-

http://www.jwatch.org/fw113213/2017/08/16/newly-approved-hepatitis-c-drug-has-high-response-rates

Hepatitis C Treatment Regimens Are Cost-Effective: But Compared With What?

Hepatitis C Treatment Regimens Are Cost-Effective: But Compared With What?T. Joseph Mattingly II, PharmD, MBA1, Julia F. Slejko, PhD1, and C. Daniel Mullins, PhD1

DOI: 10.1177/1060028017722007 | First Published July 17, 2017

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Abstract

Background: Numerous economic models have been published evaluating treatment of chronic hepatitis C virus (HCV) infection, but none provide a comprehensive comparison among new antiviral agents.

Objective: Evaluate the cost-effectiveness of all recommended therapies for treatment of genotypes 1 and 4 chronic HCV.

Methods: Using data from clinical trials, observational analyses, and drug pricing databases, Markov decision models were developed for HCV genotypes 1 and 4 to compare all recommended drugs from the perspective of the third-party payer over a 5-, 10-, and 50-year time horizon. A probabilistic sensitivity analysis (PSA) was conducted by assigning distributions for clinical cure, age entering the model, costs for each health state, and quality-adjusted life years (QALYs) for each health state in a Monte Carlo simulation of 10 000 repetitions of the model.

Results: In the lifetime model for genotype 1, effects ranged from 18.08 to 18.40 QALYs and total costs ranged from $88 107 to $184 636. The lifetime model of genotype 4 treatments had a range of effects from 18.23 to 18.43 QALYs and total costs ranging from $87 063 to $127 637. Grazoprevir/elbasvir was the optimal strategy followed by velpatasvir/sofosbuvir as the second-best strategy in most simulations for both genotypes 1 and 4, with drug costs and efficacy of grazoprevir/elbasvir as the primary model drivers.

Conclusions: Grazoprevir/elbasvir was cost-effective compared with all strategies for genotypes 1 and 4. Effects for all strategies were similar with cost of drug in the initial year driving the results.

Keywords hepatitis C, cost-effectiveness, cost-utility, genotype 1, genotype 4

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Response Tailored Protocol Versus the Fixed 12 Weeks of Dual Sofosbuvir/Daclatasvir Treatment in Egyptian Patients With Chronic Hepatitis C Genotype-4 Infection

Response Tailored Protocol Versus the Fixed 12 Weeks of Dual Sofosbuvir/Daclatasvir Treatment in Egyptian Patients With Chronic Hepatitis C Genotype-4 Infection: A Randomized, Open-label, Non-inferiority Trial
Mostafa Yakoot Correspondence information about the author Mostafa Yakoot Email the author Mostafa Yakoot , Alaa M. Abdo, Siham Abdel-Rehim, Sherine Helmy

Highlights
It would be prudent to consider vRVR to therapy at week 2 before shortening HCV treatment duration with SOF/DCV to 8 weeks.

This will consider the variability of response as a factor at individualized level not just a point of estimate at a population level.

Response-tailored duration of 8 or 12 weeks based on achieving vRVR was non-inferior to the fixed 12 weeks course.

The decision of shortening the duration of therapy of non-cirrhotic chronic hepatitis C genotype-4 patients with dual sofosbuvir plus daclatasvir to 8 weeks instead of the recommended 12 weeks, if based on achieving viral negativity in serum at week 2 as an on-treatment qualifier, could provide a prudent basis to avoid unnecessary long treatment courses. This could not only reduce the drug exposure and the risk of adverse drug reactions, but also cut the cost of full treatment course with such expensive medications by one third.

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Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection

New England Journal of Medicine

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Abstract

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection

Marc Bourlière, M.D., Stuart C. Gordon, M.D., Steven L. Flamm, M.D., Curtis L. Cooper, M.D., Alnoor Ramji, M.D., Myron Tong, M.D., Natarajan Ravendhran, M.D., John M. Vierling, M.D., Tram T. Tran, M.D., Stephen Pianko, M.D., Meena B. Bansal, M.D., Victor de Lédinghen, M.D., Robert H. Hyland, D.Phil., Luisa M. Stamm, M.D., Ph.D., Hadas Dvory-Sobol, Ph.D., Evguenia Svarovskaia, Ph.D., Jie Zhang, Ph.D., K.C. Huang, Ph.D., G. Mani Subramanian, M.D., Diana M. Brainard, M.D., John G. McHutchison, M.D., Elizabeth C. Verna, M.D., Peter Buggisch, M.D., Charles S. Landis, M.D., Ph.D., Ziad H. Younes, M.D, Michael P. Curry, M.D., Simone I. Strasser, M.D., Eugene R. Schiff, M.D., K. Rajender Reddy, M.D., Michael P. Manns, M.D., Kris V. Kowdley, M.D., and Stefan Zeuzem, M.D., for the POLARIS-1 and POLARIS-4 Investigators^*

N Engl J Med 2017; 376:2134-2146

June 1, 2017 DOI: 10.1056/NEJMoa1613512

Background
Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options.

Methods
We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir–velpatasvir–voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir–velpatasvir–voxilaprevir (163 patients) or sofosbuvir–velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir–velpatasvir–voxilaprevir group.

Results
In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir–velpatasvir–voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir–velpatasvir–voxilaprevir and 90% with sofosbuvir–velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower.

Conclusions
Sofosbuvir–velpatasvir–voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247.)

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http://www.nejm.org/doi/full/10.1056/NEJMoa1613512?query=featured_home

NEJM Journal Watch - Commentary On The Article

When DAA Treatment for Hepatitis C Fails, 3-Drug Regimen "Highly Effective"

By Kelly Young
Edited by Susan Sadoughi, MD, and Richard Saitz, MD, MPH, FACP, DFASAM
The combination of sofosbuvir, velpatasvir, and voxilaprevir is effective for hepatitis C in patients with virologic failure after direct-acting antiviral agent (DAA) treatment, according to two phase 3, industry-funded trials in the New England Journal of Medicine.

For POLARIS-1, roughly 300 patients with genotype-1 hepatitis C infection whose prior NS5A-inhibitor treatment had failed were randomized to either daily sofosbuvir-velpatasvir-voxilaprevir or placebo for 12 weeks. An additional 100 patients with non-genotype 1 infection were enrolled in the treatment group.

For POLARIS-4, over 300 patients with hepatitis C who had taken a direct-acting antiviral other than an NS5A inhibitor were randomized to receive sofosbuvir-velpatasvir with or without voxilaprevir.

Sustained virologic response 12 weeks after treatment ended was 96% for the POLARIS-1 treatment group (vs. 0% with placebo).

In POLARIS-4, the three-drug regimen had a 98% response rate, compared with 90% for sofosbuvir-velpatasvir. Sustained response rates were high for all genotypes.

Infectious disease expert Dr. Paul Sax comments: "This triple-therapy treatment strategy provides a highly effective option for that small proportion of patients who failed prior treatment for hepatitis C with non-interferon-based regimens. Although few in number, candidates for this treatment (and their clinicians) will welcome this treatment when it is FDA approved."
http://www.jwatch.org/fw112944/2017/06/01/when-daa-treatment-hepatitis-c-fails-3-drug-regimen

MEDPAGE TODAY
Triple-DAA Pill Offers HCV Retreatment Option
Most patients, all unsuccessful on previous DAA regimens, cleared the virus
combination of three drugs that act directly to block hepatitis C (HCV) replication successfully cured most patients who had previously failed therapy with such agents, researchers reported.

In two phase III trials, the investigational combination of sofosbuvir, velpatasvir, and voxilaprevir cleared the virus in 96% and 98% of patients, regardless of whether they had compensated cirrhosis or not, according to Marc Bourlière, MD, of Hôpital Saint-Joseph in Marseille, France, and colleagues.
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Media Coverage Of This Article

New Combo Pill Offers Hope to Hepatitis C Patients Who Fail Other Treatment

Updated: May 31, 2017 — 7:00 PM EDT

by Steven Reinberg HealthDay Reporter

WEDNESDAY, May 31, 2017 (HealthDay News) -- A pill that contains three powerful antiviral drugs might offer a cure for many hepatitis C patients who have failed other treatments, researchers report.

The pill -- which contains the antiviral drugs sofosbuvir (Sovaldi), velpatasvir and voxilaprevir -- was nearly 100 percent effective in curing hepatitis C in patients whose disease returned after treatment with other antiviral drugs, the researchers said.

"Currently, we have very good treatments for hepatitis C, and we are able to achieve a cure in over 90 percent of patients. So globally, although only a few patients relapse, it still is a significant number," said lead researcher Dr. Marc Bourliere, from the Hospital Saint Joseph in Marseilles, France.

This new pill is being developed as a rescue treatment for patients who have failed other therapy, he said. When it was used as an initial treatment in another study, the combination pill fared no better than the usual treatment, he added.

The data from these and other trials, funded by Gilead Sciences, the maker of the combination pill, is in the hands of the U.S. Food and Drug Administration, where it is undergoing the approval process, Bourliere said.

The bottom line, according to Bourliere, is: "We have other options even if you fail the first treatments."

The new combination pill is likely to be expensive. In 2014, Gilead introduced a combination drug for hepatitis C called Harvoni, which was priced at more than $1,000 a dose with a 12-week course of treatment running $94,500, the Associated Press reported.

Hepatitis is an inflammation of the liver that can be caused by several viruses, including hepatitis C. Hepatitis C is usually spread when blood from an infected person enters the body of someone not infected. Most people become infected with hepatitis C by sharing needles or other equipment to inject drugs, the U.S. Centers for Disease Control and Prevention says.

Approximately 75 percent to 85 percent of people who have hepatitis C will develop chronic infection. In the United States, as many as 4 million people have chronic hepatitis C, according to the CDC.

Many people infected with hepatitis C don't know they have it because they don't look or feel sick.

Chronic hepatitis C is serious and can result in long-term health problems, including liver damage, liver failure, liver cancer or death. Hepatitis C is the leading cause of cirrhosis and liver cancer, and the most common reason for liver transplantation in the United States.
In two, phase 3 trials, Bourliere and his colleagues treated patients with the combination pill or a placebo or other antiviral drugs.

In the first trial, 300 patients were randomly assigned to the combination pill or a placebo. These patients all had hepatitis C genotype 1. In addition, 114 patients with other genotypes of hepatitis C were given the combination pill. Patients took the pill daily for 12 weeks.

Among patients taking the combination pill, 96 percent responded to treatment. None on the placebo showed a response, the researchers found.

The second trial included 314 patients with hepatitis C genotypes 1, 2 or 3. All had failed other treatments, but hadn't been given a NS5A inhibitor, such as velpatasvir or daclatasvir. This group received either the combination pill (163 patients) or sofosbuvir-velpatasvir (151 patients).
In addition, 19 patients with genotype 4 hepatitis C were given the combination pill.

In this trial, 98 percent of the patients taking the combination pill responded to 12 weeks of treatment. And 90 percent of those who received sofosbuvir-velpatasvir responded to treatment, the findings showed.

The most common side effects were headache, fatigue, diarrhea and nausea, Bourliere said. Only 1 percent or fewer patients stopped treatment because of the side effects, he said.

Dr. David Bernstein is chief of hepatology at Northwell Health in Manhasset, N.Y. He called the new drug "a very important advance. This is really for salvage therapy. I don't think this is first-line therapy, but it gives hope to the people who fail the current therapies we have."
The report was published June 1 in the New England Journal of Medicine.

https://consumer.healthday.com/infectious-disease-information-21/hepatitis-news-373/new-combo-pill-offers-hope-to-hepatitis-c-patients-who-fail-other-treatment-723205.html