HCV over 3 decades: From a disease with no name to a cure

HCV over 3 decades: From a disease with no name to a cure
Infectious Disease News, March 2017

To mark our 30th anniversary, Infectious Disease News will be examining some of the infectious diseases that have defined and changed the field over the past 3 decades

At the American Association for the Study of Liver Diseases annual meeting in 2011, Ed Gane, MBChB, MD, FRACP, MNZM, presented data on PS7977, an antiviral agent for the treatment of hepatitis C virus infection. The treatment approach changed slightly across patient groups — some participants were treated for longer than others, and some received PS7977 in combination with ribavirin and pegylated interferon — but the results were always the same.
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Of Interest
Hepatitis C Timeline
This timeline spans from the first recorded references to hepatitis epidemics, to the 1989 discovery of the hepatitis C virus, ending with the FDA approved treatments used today.

Superiority of Interferon-Free Regimens for Chronic Hepatitis C: The Effect on Health-Related Quality of Life and Work Productivity

Superiority of Interferon-Free Regimens for Chronic Hepatitis C: The Effect on Health-Related Quality of Life and Work Productivity

Younossi, Zobair M. MD, MPH; Stepanova, Maria PhD; Esteban, Rafael MD; Jacobson, Ira MD; Zeuzem, Stefan MD; Sulkowski, Mark MD; Henry, Linda PhD; Nader, Fatema MS; Cable, Rebecca BS; Afendy, Mariam BS; Hunt, Sharon MBA

Section Editor(s): Janczewska., Ewa
Medicine:
February 2017 - Volume 96 - Issue 7 - p e5914
doi: 10.1097/MD.0000000000005914
Research Article: Observational Study

1 Introduction

The new direct-acting antiviral agents (DAAs) for treatment of hepatitis C virus (HCV) have revolutionized HCV treatment with high sustained viral response (SVR) rates and superior patient-reported outcomes (PROs).^[1–12] Although new interferon (IFN)-free and ribavirin (RBV)-free regimens are currently being developed, both IFN and RBV remain a part of certain regimens.^[1–4]

Previous studies have shown that treatment-naïve HCV patients treated with RBV and IFN experience a significant PRO impairment.^[13,14] In particular, the use of IFN causes substantial side effects, including debilitating ones such as severe depression, which, in turn, affect patients’ ability to sustain treatment long enough to obtain a cure whether through medical discontinuation or through patients’ nonadherence. The use of RBV also has been shown to decrease PROs during treatment. However, the PRO data in patients who are retreated after having experienced another course of treatment have not been reported. Therefore, the aim of this study was to evaluate PROs during treatment with and without the use of IFN in patients who participated in a prior study of an IFN-containing or an IFN-free DAA-based regimen and has not achieved SVR.

Discussion Only

View Full Text Article Online

The purpose of this study was to investigate the impact of alternative hepatitis C treatment regimens on patient-reported outcomes (PROs).^[In this study, we have found that patients who were treated with a regimen containing IFN experienced a substantial decrease in their PRO scores during and even shortly after treatment. According to the multivariate analysis, the use of IFN was also found to be an independent predictor of substantial PRO impairment, and that association was observed up to 12 weeks after treatment discontinuation. Although PROs were also impacted by IFN-free regimens that contained RBV, the magnitude of such impact is much smaller. These data are consistent with previously published PRO data.^{[2–10,21–23]}

Across both IFN-free and IFN-containing treatment arms, PRO domains that were most affected by the treatment were the domains primarily associated with daily functioning and physical activity. Thus, it is imperative for healthcare practitioners to assist patients in dealing with these areas by identifying strategies patients can pursue to stay active and social.

A number of previous studies of the use of IFN for treatment of chronic HCV infection have shown the negative effect of IFN on PROs.^[13,14] In this study, we have shown that the impact of IFN-containing and IFN-free RBV-containing regimens on PROs of patients who are retreated is similar to those who have never been treated or have been treated with and IFN-free regimen only. In fact, experience with previous IFN-based treatment does not seem to predispose patients for better or worse experience during another course of treatment. Although HCV patients who were treatment-experienced with IFN had higher baseline PRO scores, most of these were likely due to previously applied strict treatment eligibility criteria.

A major limitation of this study is related to the original clinical trial design, which lacks both randomization and blinding. We, however, believe that the bias caused by this could be adequately accounted for by multivariate analysis.

In conclusion, treatment-experienced patients who were retreated with an IFN-containing regimen experienced significantly more impairment of their PROs in comparison to patients who were treated with an IFN-free regimen regardless of duration. However, it is important to note that, albeit accompanied by an unfavorable patients’ well-being profile, the IFN-containing regimen was still associated with a higher chance of SVR, especially in patients with HCV genotype 3. These 2 outcomes represent a trade-off that patients who have failed a DAA-based regimen may face, although the use of IFN, hopefully, will be revisited once new DAAs come to market and provide this cohort of patients with more treatment options.
http://journals.lww.com/md-

Interferon-free therapies improve liver function in HCV patients

Interferon-free therapies improve liver function in HCV patients

Antiviral therapy without interferon improved liver function in patients with hepatitis C virus infection-related advanced cirrhosis, according to data from an observational cohort study.

Researchers analyzed data of 80 patients with HCV-associated liver cirrhosis undergoing treatment with a combination of direct-acting antivirals without interferon. Of these patients, 43% had Child-Pugh B/C cirrhosis (n = 34), and 53% had platelet counts of less than 90,000/μL (n = 42). The combination regimens included Sovaldi (sofosbuvir, Gilead Sciences) with ribavirin (n = 56), Olysio (sofosbuvir/simeprevir, Janssen Therapeutics) with or without ribavirin (n = 15) and sofosbuvir and Daklinza (daclatasvir, Bristol-Myers Squibb) with or without ribavirin (n = 9). Most patients had HCV genotype 1 (n = 50), followed by 24 with genotype 3, four with HCV genotype 2 and two patients with genotype 4.

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Full text
Improvement of liver function parameters in advanced HCV-associated liver cirrhosis by IFN-free antiviral therapies

HCV Treatment: What Can I Do Now? What's Coming Next?

Medscape Gastroenterology

COMMENTARY
HCV Treatment: What Can I Do Now? What's Coming Next?
Rowen K. Zetterman, MD

Treating an Underdiagnosed Disease
Approximately 170-200 million persons worldwide are infected with hepatitis C virus (HCV), including 3.2 million in the United States.[1] Many lack symptoms and are clinically unrecognized.[2]

Outcomes of HCV infection include chronic hepatitis; cirrhosis; hepatocellular carcinoma; and a need for orthotopic liver transplantation owing to complications, such as cirrhosis or cancer.[3] Estimating the quantity of fibrosis in a liver biopsy specimen from patients with HCV may help determine the risk for decompensation[4] and the need for HCV therapy. Approximately 40% of patients awaiting liver transplantation have underlying HCV infection, and recurrent HCV infection of the transplant allograft is virtually assured.[5] Eradication of HCV from infected patients improves survival of all patients, even if they have advanced liver disease.[6,7]

There are six major genotypes of HCV.[8] Genotype 1 accounts for approximately 75% of HCV infections in the United States, of which two thirds are genotype 1a and one third are genotype 1b. Genotype 1b is less likely to develop resistance during therapy, resulting in better cure rates with treatment than genotype 1a. Approximately 16% of HCV-infected patients have genotype 2; 12% have genotype 3; and 1% each have genotype 4, 5, and 6.

The development of direct-acting antivirals represents a significant improvement in HCV treatment. New combinations of drugs have led to improved response rates, even in patients with characteristics previously associated with having lower response rates: African American, high viral load, concomitant cirrhosis, infection with genotype 1a, and failed treatment with other anti-HCV drugs.[9]

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Treating an Underdiagnosed Disease
Surveying the Current Treatment Landscape
Emerging Drugs
Options for Difficult-to-Treat Patients

Interferon-free regimens for the treatment of hepatitis C virus in liver transplant candidates or recipients

World J Gastroenterol. 2015 August 28; 21(32): 9526-9533.
Published online 2015 August 28. doi: 10.3748/wjg.v21.i32.9526.

Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.

Interferon-free regimens for the treatment of hepatitis C virus in liver transplant candidates or recipients

Evangelos Cholongitas, 4th Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital of Thessaloniki, 54642 Thessaloniki, Greece
Chrysoula Pipili, Division of Nephrology, Royal Infirmary of Edinburgh, Scotland EH16 4SA, United Kingdom
George Papatheodoridis, Department of Gastroenterology, Athens University Medical School, Laiko General Hospital of Athens, 11527 Athens, Greece
Author contributions: Cholongitas E and Pipili C performed the literature search, wrote the first draft of the manuscript and approved the final version; Papatheodoridis GV wrote and edited the final draft of the manuscript and approved the final version.

Core tip: Treatment against hepatitis C virus has dramatically improved with the novel direct-acting antivirals (DAAs). The currently available DAAs are sofosbuvir, simeprevir, daclatasvir, ledipasvir/sofosbuvir, paritaprevir/ombitasvir and dasabuvir. IFN-free combinations of these novel DAAs with or without ribavirin give excellent sustained virological response in patients with decompensated cirrhosis awaiting liver transplantation and those with recurrence of hepatitis C post liver transplantation. More data regarding the safety and efficacy of these new DAAs are needed, but ongoing clinical trials and real life data will clarify better these issues.

INTRODUCTION
Chronic hepatitis C (CHC) has infected approximately 3% of the world population[1]. Patients with hepatitis C virus (HCV) infection can develop cirrhosis and hepatocellular carcinoma (HCC)[2,3], while CHC is considered the leading cause for liver transplantation (LT) in many Western countries[4]. The combination of pegylated interferon-α (pegIFN) and ribavirin (RBV) in patients with CHC had relatively low rates of sustained virological response (SVR)[5,6], but during the last years several direct acting antiviral agents (DAAs) have increased the efficacy of antiviral therapy[7].
The first approved DAAs (boceprevir and telaprevir) were associated with high rates of clinical complications, particularly among cirrhotic patients with serum albumin levels ≤ 3.5 g/dL and platelet counts ≤ 100000/mm3[8]. Very recently, newer DAAs have been licensed by the European Medicines Agency and Food and Drug Administration to be used mainly as part of IFN-free combinations offering high SVR rates (> 95%), short treatment duration and excellent safety profiles. These agents include sofosbuvir (Sovaldi, Gilead), the first nucleotide analogue NS5B polymerase inhibitor[9], simeprevir (Olysio, Janssen), a second-wave NS3/4A protease inhibitor (achieving SVR in 77%-92% of genotype 1 CHC patients, compared to 46% under pegIFN plus RBV)[10], daclatasvir (Dankliza, Bristol-Myers Squibb)[11], a NS5A inhibitor, the co-formulation of the NS5A inhibitor ledipasvir with sofosbuvir (Harvoni, Gilead)[12], the co-formulation of a ritonavir boosted NS3/4A protease inhibitor, paritaprevir, with the NS5A inhibitor ombitasvir (Viekirax, Abbvie) and dasabuvir (Exviera, Abbvie), a non-nucleos(t)ide NS5B polymerase inhibitor[13] (Table1). They are all given as one tablet daily, except for paritaprevir/ombitasvir (two tablets once daily) and dasabuvir (1 tablet twice daily). The purpose of this review is to summarize the recent findings concerning the use of the new IFN-free regimens in LT candidates or recipients with CHC.

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Key Management Decisions in HCV - Case-based Video Presentation Led By Ira M. Jacobson, MD.

Key Management Decisions in HCV

Hello folks, great news, check out this newly released case-based video presentation led by Ira M. Jacobson, MD., over at Clinical Care Options. 

Kick back and watch the good doctor explore the best treatment choice, based on three different case scenarios.

No Questions To Answer

Anyone can view this patient friendly learning activity, no viewer questions, only the audience taking part in the symposium responds.

Topics

Topics include; screening patients, alcohol use, fatigue, diabetes, HCV-related complications, imaging/assessing fibrosis(fibroscan), with a breakdown of HCV regimens used for each case study, including SVR rates. 

After each patient history is presented a short break is taken while the audience responds to the panel question. After the votes are in, or the question is answered, results are discussed, with follow up commentary by Andrew J. Muir, MD and Nancy Reau, MD.

Here is a snapshot of one question:

Learning Objectives

• Integrate the results of clinical studies of approved HCV treatments into current and future patient management strategies
• Implement practical strategies to optimize patient outcomes with HCV therapy
• Apply key insights from clinical trials and/or approved indications on the use of oral therapy for hepatitis C
• Pharmacists will be better able to provide accurate and appropriate counsel as part of the treatment team
• Nurses will be better able to provide appropriate care and counsel for patients and their families

***Free registration is required. 

Begin by clicking on the "Video" link .....

Released: 8/7/2015

A Study of Health-related Quality of Life - Interferon Plus Ribavirin to Interferon- and Ribavirin-free HCV Regimens

The Patient's Journey With Chronic Hepatitis C From Interferon Plus Ribavirin to Interferon- and Ribavirin-free Regimens

A Study of Health-related Quality of Life
How do interferon and ribavirin impact health-related quality of life during treatment for chronic hepatitis C, and are patients better off with different drug therapies?

August 10, 2015
Z. M. Younossi; M. Stepanova; F. Nader; B. Lam; S. Hunt

Aliment Pharmacol Ther. 2015;42(3):286-295. 

Article Source - Medscape

Discussion ONLY

Link To Full Article

• Abstract and Introduction
• Methods
• Results

Discussion
This is the largest analysis of  Health-related Quality of Life (HRQL) in over 3400 CH-C patients who were treated with a variety of anti-HCV regimens in nine phase 3 clinical trials. In this study, we clearly demonstrated a significant improvement of HRQL scores with regimens which were free of IFN, and more recently, regimens which are also free of both IFN and RBV. This significant improvement is in contrast to the substantial decrement seen in HRQL with the previous standard of care for chronic hepatitis C which included interferon and ribavirin and was associated with substantial side effects.^[19–21]

The results of this analysis also document that the physical aspects of HRQL in CH-C patients were primarily predicted by the presence of fatigue, depression, insomnia, and diabetes. Additionally, the strongest predictors of mental health aspects of HRQL were also depression, anxiety, and fatigue, all consistent with prior reports.^[11–18] Although some of these factors may be related to the host, it is possible that some factors, such as fatigue, may be related to HCV viremia and could improve after viral eradication. Indeed, viral eradication 12 weeks after treatment cessation was observed together with improvement in a number of HRQL domain scores which was especially prominent for the vitality domain.

In multivariate analysis, we showed that receiving a regimen that contained both IFN and RBV was the strongest negative predictor of HRQL during treatment, while IFN- and RBV-free (LDV/SOF) was the only regimen independently associated with HRQL improvement during treatment. Furthermore, LDV/SOF remained the only independent predictor of HRQL improvement after achieving SVR-12. We also have shown that the negative effect of IFN does lessen with longer follow-up in patients who cleared HCV infection. In fact, this is the first study which demonstrates that by 24 weeks after treatment cessation, post-treatment HRQL improvement after virologic clearance is manifested regardless of the regimen. Nevertheless, it is still possible that patients who receive interferon may have longer lasting effect which can be picked up by more in-depth neuropsychiatric testing. These potential changes were not detectable by SF-36 instrument.

To the study limitations, we could not strictly assess the magnitude of the impact of SVR to HRQL after treatment cessation due to short follow-up and small number of non-responders. Furthermore, limiting assessment to 24 weeks post-treatment limited the potential long-term implications of viral clearance. Also, some important and difficult to treat HCV subpopulations, such as patients with renal failure, decompensated cirrhosis or liver transplants, were not enrolled. Furthermore, the original clinical trials used in this study were not designed to be comparable, so adjustments were made to account for the bias in the study cohort, thus, introducing uncertainty. Additionally, a number of socio-economic and clinical factors which may also affect HRQL, including but not limited to the level of education, income, residence, marital status, social support, the route of HCV transmission, duration of the infection, family history of major comorbidities, etc., were not available so could not be adjusted for. Finally, none of the original trials were pragmatic, i.e. conducted in real-life, routine practice conditions, while efficacy observed in explanatory clinical trials may not necessarily translate into similarly high effectiveness in real life so the degree of generalisability of our results remain unclear.

In conclusion, the use of the new IFN-free and RBV-free regimens results in substantial improvement in patients' HRQL scores during and after treatment. These HRQL data, when considered together with the excellent efficacy and safety profile of these regimens, provides a more comprehensive picture of the true impact these new treatments have on patients' lives.

Medscape

New Treatment Cures Hepatitis C - Pills Are ‘Revolutionary,’ Liver Expert Says

New Treatment Cures Hepatitis C
Pills Are ‘Revolutionary,’ Liver Expert Says
By Lori Newman, Special to Lifescript
Published July 07, 2015

Reviewed by Edward C. Geehr, M.D., Lifescript Chief Medical Officer

The future is much brighter for people with a hepatitis C diagnosis, thanks to breakthroughs in the treatment of the deadly viral liver infection.

“The treatments we [have now] are revolutionary in terms of tolerability and ability to get over 90% of patients cured,” says Tram T. Tran, M.D., medical director of liver transplantation at the Liver Disease and Transplant Center at Cedars-Sinai Medical Center in Los Angeles.

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Successes and Challenges on the Road to Cure Hepatitis C

Successes and Challenges on the Road to Cure Hepatitis C

Stacy M. Horner , Susanna Naggie PLOS 
 Published: June 18, 2015
DOI: 10.1371/journal.ppat.1004854

Citation: Horner SM, Naggie S (2015) Successes and Challenges on the Road to Cure Hepatitis C. PLoS Pathog 11(6): e1004854. doi:10.1371/journal.ppat.1004854

Editor: Richard C. Condit, University of Florida, UNITED STATES

Published: June 18, 2015

Copyright: © 2015 Horner, Naggie. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Funding: SN is supported by the National Institute of Allergy and Infectious Disease of the National Institutes of Health under grant 1K23AI096913. SMH is supported by the National Institute of Allergy and Infectious Disease of the National Institutes of Health under grant K22AI100935, as well as the Duke University Center for AIDS Research (CFAR), an NIH funded program (5P30 A1064518), and a Whitehead Scholar Award. The funders had no role in the preparation of this manuscript and the views expressed here do not necessarily reflect those of the funders.

Competing interests: I have read the journal's policy and have the following conflicts: SN has served as a scientific advisor to Gilead, AbbVie, Janssen, Bristol Meyers Squibb, Merck, and Boehringer Ingelheim. SN's institution has received research funds on her behalf from Gilead, AbbVie, Bristol Meyers Squibb, and Janssen. This does not alter our adherence to all PLOS policies on sharing data and materials.

Introduction

Hepatitis C virus (HCV) represents a significant health burden worldwide, with an estimated 185 million people chronically infected [1]. A leading cause of liver transplantation, HCV infection can result in severe liver disease including cirrhosis and hepatocellular carcinoma [2]. Cure of HCV infection results in substantial decreases in such liver-related morbidity and mortality [3]. Prior therapies for HCV offered only 40% cure for the most difficult-to-treat genotype-1 infection, required 48 weeks of therapy with an injectable interferon, and included significant adverse events [4]. The past year has seen the approval of five interferon-free direct-acting antiviral (DAA) regimens for HCV, including combinations of DAAs and fixed-dose combination pills (Tables 1 and 2) [5–13]. Sustained virologic response (SVR), the virologic surrogate for clinical cure, has improved to >90% for most populations across all HCV genotypes (Table 2). While the successes attributable to DAA combination therapies will be many, there also remain challenges and much for us to learn as we embark on this journey to eradicate HCV. Here, we will discuss several of the greatest successes and future challenges in HCV therapeutics today.

Click Table To Enlarge

Table 1. All-oral direct acting antiviral regimens available for clinical use.
doi:10.1371/journal.ppat.1004854.t001

Click Table To Enlarge

Table 2. Sustained virologic response for all-oral direct acting antiviral regimens.

doi:10.1371/journal.ppat.1004854.t002

Potent DAA Combinations Are Closing the Gap for Unique Patient Populations

Although all patients with HCV infection will benefit from the availability of oral DAA combination therapies, several unique patient populations have seen dramatic improvements in SVR, revealing the great clinical impact of these therapies. Specifically, patients with HIV/HCV dual infection, patients with compensated and decompensated cirrhosis, and patients who have had liver transplantation for HCV-associated liver disease are exhibiting fantastic (87%–98%) SVR rates with oral DAA combination therapy [14–16]. These patients, who have a greater risk of progression of liver disease, hepatocellular carcinoma, and death, previously had low response rates or even absolute contraindications to treatments with interferon [17–18].

The potential impact of HCV eradication for these highest-risk populations could be enormous, including decreases in hepatocellular carcinoma and liver transplantation, as well as prolonged survival for those already living with liver grafts. And yet, we do not know for sure how this story ends. While the liver has the ability to repair injured tissue [19] and there is evidence to suggest that fibrosis induced by chronic HCV infection is reversible [3], is there a point of no return? Previously, patients with HCV-associated decompensated liver disease (ascites, hepatic encephalopathy, and variceal bleeding) had only one choice for survival: organ transplantation. Is viral eradication enough to change their fate? The largest study to date in patients with decompensated cirrhosis reported SVR of nearly 90% with a DAA combination regimen [15]. Importantly, the study also reported on improvement in serum markers of synthetic liver function for a majority (>50%) of patients at post-treatment week 4. Whether these improvements translate to improved clinical outcomes over time remains to be seen, but there is reason for optimism.

HCV Genotype Diversity Has Complicated the Search for a Pangenotypic Regimen

HCV is a positive-stranded RNA virus. Its 9.6-kb genome is translated into a polyprotein that is processed into structural and nonstructural (NS; including NS3, NS4A, NS4B, NS5A, and NS5B) proteins (Fig 1) [20]. The NS proteins are the targets for the current approved DAA, including NS3–4A protease inhibitors (PI), NS5A inhibitors, and NS5B nucleot(s)ide (NA) and non-nucleoside (NNA) analogues (Table 3). A major challenge to the design and implementation of DAA for HCV is the incredible genetic diversity of HCV. HCV contains six major genotypes, as defined by phylogenetic and sequence analysis of the viral genome. These genotypes vary by 30%–35% at the nucleotide level and contain nearly 70 subtypes [20]. Clinically, this genetic diversity has translated into different regimens based on genotype and even subtype (1a versus 1b).

Click On Figure To Enlarge

Fig 1. The HCV proteins.

The HCV polyprotein is processed into the structural and nonstructural proteins of the virus, as shown here. The NS3–4A, NS5A, and NS5B proteins, all targets of newly developed direct-acting antivirals for HCV, are highlighted in red and their major functions described.

doi:10.1371/journal.ppat.1004854.g001

Click Table To Enlarge

Table 3. Properties of HCV direct-acting antivirals.

doi:10.1371/journal.ppat.1004854.t003

The ideal HCV DAA regimen would have pangenotype efficacy. However, because of the viral genetic diversity and mechanisms of action of the DAAs, this has been difficult to achieve. Of the five interferon-free DAA regimens available in either the United States or Europe, only two have been approved as pangenotypic regimens. The regimen of sofosbuvir, a first-in-class NA, and ribavirin was approved for genotypes 1–4 and has in vivo evidence to support efficacy in genotypes 5 and 6 [13]. While this regimen remains the standard of care for genotypes 2 and 3, its efficacy was suboptimal in the most common HCV genotype in the US, genotype 1. Daclatasvir, a pangenotypic NS5A inhibitor, when combined with sofosbuvir, provides the most potent pangenotypic activity to date and was approved in Europe for genotypes 1–4. Daclatasvir has good activity against genotype 3 and maintains activity against genotype 2 polymorphisms [7]. Unfortunately, the recently reported efficacy of 12 weeks of this regimen in genotype 3 cirrhotic patients was quite poor [8]. Other DAA regimens either lack pangenotypic coverage or have pangenotypic activity but lack clinical data in all genotypes. Ledipasvir, an NS5A inhibitor approved in combination with sofosbuvir, loses activity for a majority of genotype 2 infections because of a common NS5A polymorphism and has suboptimal in vitro activity versus genotype 3 [10]. Simeprevir, a first-generation PI approved in combination with sofosbuvir, has limited activity versus genotype 3 and has not been studied in humans for genotypes 2, 5, or 6, although it has in vitro activity [21]. The most recently approved regimen, which combines three DAAs (all with low barrier to resistance): a pangenotypic NS5A inhibitor, ombitasvir, used with a first-generation PI (paritaprevir) and an NNA (dasabuvir), is limited by the narrow genotype 1 activity of the NNA [11].

This fragmentation of treatment by genotype complicates the clinical approach to care and limits the feasibility of HCV treatment in the resource-limited setting, where genotyping and access to multiple regimens is not feasible. Moving forward, investigational second-generation PIs with broad genotypic coverage (such as MK-5172), highly potent pangenotypic NS5A inhibitors (including GS-5816), and triple DAA combinations with NA backbones are expected to help us achieve more potent pangenotypic coverage, including better options to treat genotype 3.

The Clinical Role of Resistance-Associated Variants (RAVs) Is Becoming More Clear

Viral sequences with preexisting polymorphisms can present a therapeutic challenge. The best clinical example is the preexisting NS3 Q80K polymorphism, found in 5%–48% of those with genotype 1a. This polymorphism confers resistance to simeprevir and limits its efficacy (SVR 58% versus 84%; in combination with pegylated interferon and ribavirin), thereby necessitating pretreatment polymorphism testing [12]. Combining simeprevir with the potent DAA sofosbuvir appears to overcome this limitation only in patients without cirrhosis [22,23]. Nucleotide analogues including sofosbuvir have exceptional genetic barriers to resistance. The signature RAV with sofosbuvir is the S282T mutation, which was not detected in any patient at baseline or time of virologic failure in the sofosbuvir phase 3 program [24]. Other treatment-emergent variants (TEVs) have been reported in the phase 3 program, including the L159F and V321A mutations. The change in sofosbuvir EC50 for these TEVs does not appear to be clinically significant, and retreatment of subjects with these TEVs with sofosbuvir-containing regimens did not support a role for them in treatment failure. Baseline NS5A polymorphisms that confer resistance are significantly more common and will likely be more problematic in the setting of retreatment. In a pooled resistance analysis of the ledipasvir/sofosbuvir phase 3 programs, while only 16% of patients had NS5A RAVs at baseline, significantly more patients (43%) suffering virologic failure harbored these RAVs at baseline [25]. There are now several patient subgroups in which baseline NS5A RAVs may lower SVR, including genotype 3 patients with cirrhosis treated with daclatasvir and sofosbuvir and treatment-experienced patients receiving ledipasvir and sofosbuvir [25,26]. While baseline polymorphism testing is not recommended at this time because of the overall high SVR (>90%), it may become more relevant in the setting of retreatment. The first retreatment study of prior NS5A failures confirmed that evidence of NS5A RAVs at time of retreatment confers greater risk of relapse [27].

The ability of HCV to develop de novo resistance to antiviral drugs is quite high. HCV replicates as a quasispecies; therefore, RAVs can preexist within the viral population at baseline and emerge as the dominant species during treatment. The high mutability of HCV has to do with the high error-prone nature of the HCV RNA-dependent RNA polymerase and large viral populations [28]. In fact, it has been predicted that in a single day, HCV can generate genomes with all possible single and double nucleotide changes, and as long as these genomes maintain fitness, they could confer antiviral resistance [28]. This same model predicted that combination DAA regimens would require a genetic barrier of four or more resistance mutations to achieve clinical efficacy.

Each class of DAAs can select for RAVs; however, the genetic barriers and fitness of these RAVs varies. NAs inherently have high barriers to resistance, because they directly target the conserved polymerase active site and resistant variants have low fitness [28]. On the other hand, NS5A inhibitors, PIs, and NNAs all have low barriers to resistance, with single amino acid substitutions conferring high-level resistance. In the minority of patients who suffer virologic failure during DAA combination therapy, dual and triple RAVs are being reported [10–13].

What happens to RAVs after the cessation of treatment? This depends on the fitness of those variants. For first-generation PIs, a recent report of long-term follow-up of patients treated with boceprevir (first-generation NS3–NS4A PI) found that after 3 years, 27% of patients still had RAVs and that the median time for all RAVs to become undetectable was 1.11 years [29]. This carries important clinical implications for retreatment decisions in a patient with RAVs. For example, NS5A RAVs exhibit more replicative fitness and can persist for >96 weeks [30]. Early retreatment studies suggest this will impact success of retreatment and thus significantly limit options for patients with NS5A RAVs for the foreseeable future [27].

Even with Highly Effective DAA Combination Therapies, Some Historic Baseline Predictors of SVR Remain

One of the greatest surprises thus far in the new era of treating HCV is that some of the same factors that predicted response to interferon therapies still play a role in DAA response rates. Although SVR rates are high across all subgroups, recent pooled multivariable analyses of phase 3 trials provide some granularity on treatment response. While these predictors may vary across regimens, higher rates of relapse are being reported in patients based on genotype subtype, presence of cirrhosis (in particular those with prior treatment failure), IL28B TT genotype, sex, race, and higher baseline HCV RNA [31,32]. Based on the presence or absence of these predictors, some patients may achieve SVR with 8 weeks of therapy, while others require 24 weeks. Moving forward, these “difficult-to-treat” populations should be targeted for innovative approaches to therapy so that no patient is left without a chance of cure.

Our Greatest Challenge Just Might Be of Our Own Making

Direct-acting antivirals for HCV are likely to be heralded as one of medicine’s greatest advancements. The possibility of eradicating HCV from the globe seems within arm’s reach. With SVR pushing 100% for many HCV-infected populations and ongoing studies pushing the limits of treatment to just 6 weeks with triple DAA combinations, there is much reason for hope. Yet, the unfortunate reality is that because of the high cost of these medications, many patients will be denied coverage and the opportunity for cure. Many payers are only providing coverage to those patients with the highest stages of fibrosis. Is there another precedent in medicine in which we don’t treat a curable transmissible disease? The recent exclusivity agreements between Express Scripts and AbbVie and CVS/Caremark and Gilead mark a new era in the battle against HCV, although in this case we seem to be battling against ourselves. We should carefully consider the consequences of pricing and such relationships, as much of this has overshadowed the bright light of medical innovation—what a shame.

Source - http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004854

References

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Utility of Hepatitis C Viral Load Monitoring On Directly Acting Antiviral Therapy.

Clin Infect Dis. 2015 Mar 2. pii: civ170. [Epub ahead of print]

Utility of Hepatitis C Viral Load Monitoring On Directly Acting Antiviral Therapy.

Sidharthan S1, Kohli A1, Sims Z1, Nelson A2, Osinusi A3, Masur H1, Kottilil S2.

Author information

1Critical Care Medicine Department, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, Maryland.
2Institute of Human Virology, University of Maryland, Baltimore, Maryland Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
3Gilead Sciences Inc., Foster City, California.

Abstract

BACKGROUND: Hepatitis C (HCV) viral loads aided as predictors of treatment response during interferon-based therapy. We evaluated the predictive ability of HCV RNA levels at end of treatment (EOT) for sustained virologic response (SVR12) during interferon-sparing directly acting antiviral (DAA) therapies.

METHODS: HCV genotype 1, treatment naive patients were treated with sofosbuvir and ribavirin for 24 weeks (n=55), sofosbuvir and ledipasvir for 12 weeks (n=20), sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (n=20), or sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (n=19). Measurements of HCV RNA were performed using the Roche COBAS TaqMan HCV test and the Abbott RealTime HCV assay. Positive and negative predictive values (PPV, NPV) of HCV RNA less than the level of quantification (<LLOQ) at EOT for SVR12 were calculated.

RESULTS: All patients treated with sofosbuvir and ribavirin (55/55) had HCV RNA <LLOQ at EOT by the Roche and Abbott assays, but only 38 achieved SVR12 (PPV: 69%). Among patients treated with sofosbuvir, ledipasvir, +/- GS-9669 or GS-9451, 100% (59/59) had HCV RNA <LLOQ by Roche and one relapsed (PPV: 98%). By Abbott, 90% (53/59) had HCV RNA <LLOQ out of which one patient relapsed (PPV: 98%). Notably, six patients with HCV RNA ≥LLOQ at EOT (range: 14-64 IU/mL) achieved SVR12 (NPV: 0%). Quantifiable HCV RNA (range: 15-57 IU/mL) was measured two weeks post-treatment in four individuals, and four weeks post-treatment in one (14 IU/mL).

CONCLUSIONS: Contrary to past experience with interferon-containing treatments, low levels of quantifiable HCV RNA at EOT do not preclude treatment success.

Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Sofosbuvir and Ribavirin in HCV Genotypes 2 and 3

Frontline Gastroenterology
Interferon-free Treatment for Genotypes 2 and 3 Patients With Hepatitis C

Nowlan Selvapatt, Philip Hendy

Medscape

Zeuzem S, Dusheiko G, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 2014;370:21.

Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in Patients without Treatment Options. N Engl J Med 2013;368:1867–77.

This paper reviews the outcomes of the VALENCE study which evaluated an interferon-free treatment regime for patients with genotypes 2 and 3 hepatitis C virus (HCV).1 While demonstrating promising efficacy in the treatment of genotype 2 infected patients and certain subtypes of patients with genotype 3 infection, it also provides a timely reminder that careful patient selection is required.

Sofosbuvir (trade name Sovaldi) is an oral direct acting antiviral agent (NS5B polymerase inhibitor) licensed in the UK for the treatment of hepatitis C. It is currently under review at the National Institute for Health and Care Excellence. The study was designed as a phase III blinded placebo controlled trial of treatment of genotype 2 and 3 HCV infected patients. Both treatment-naive patients and those with previous interferon treatment were included, and presence of cirrhosis was not an exclusion criterion. It was originally designed for all patients to receive 12 weeks of treatment with either sofosbuvir plus ribavirin or with matching placebo. The dose of sofosbuvir was 400 mg once daily given orally and ribavirin was given orally in a split dose, dose dependent on weight (1000 mg daily in patients with a body weight of <75 kg and 1200 mg daily in patients with a body weight of ≥75 kg). However, after initiation of the VALENCE study, published results from the FUSION study demonstrated significant benefit in extending treatment of genotype 3 HCV infection beyond 12 weeks.2 The study was therefore altered from hypothesis generating to descriptive. The genotype 2 HCV treatment arm remained unchanged with 12 weeks of treatment, while the genotype 3 HCV treatment arm was made open label and extended to 24 weeks. The primary end point was sustained virological response at 12 weeks after completion of therapy (SVR12) and HCV RNA below the limit of quantification (25 IU/mL).

A total of 475 patients were screened for enrolment and 421 underwent randomisation with 419 starting treatment. Enrolment was in a 4:1 ratio of genotype 3 to genotype 2. Overall 60% were men, 21% had cirrhosis and 58% had received previous interferon treatment, of whom 30% were primary non-responders. Overall, 99% of patients receiving sofosbuvir and ribavirin had undetectable HCV RNA by week 4. Of the 73 genotype 2 infected patients, 93% of patients achieved SVR12.

There was greater variation in virological response in patients with genotype 3 infection. Among treatment naïve patients, SVR12 was 95% in non-cirrhotics and 92% in cirrhotics. However, for those with past exposure to interferon, SVR12 was 87% in non-cirrhotics and 62% in cirrhotics. Treatment was well tolerated with only 1% discontinuation. There were 10 serious adverse events out of 250 treated patients in the 24-week treatment arm but nil adverse events in either of the 12-week treatment groups. In common with previous published data, no resistance to sofosbuvir was demonstrated on viral resistance testing.

Using multivariate regression analysis, the study investigators demonstrated four possible predictors of sustained viral response among genotype 3 infected patients: absence of cirrhosis; low viral load at baseline; female sex; and younger age. This requires further validation before utilisation as a pretreatment predictor score.

The authors acknowledge the limitations of this study. First, the trial was altered from a hypothesis generating exercise to a descriptive study without any formal hypothesis or statistical comparisons. Second, very few pretreatment biopsies were available meaning that questions regarding levels of fibrosis and steatosis and links to treatment response could not be adequately addressed. Overall, the study is well powered to deliver definitive conclusions regarding the drug efficacy for both genotype 2 and 3 HCV, but it is not sufficiently powered to make definitive conclusions regarding the subgroup of genotype 2 patients who exhibit pretreatment characteristics associated with a lower response rate.

Comment

This study reaffirms the potential for shortened duration of treatment when compared with interferon based regimes, particularly for genotype 2 HCV. It also demonstrates the efficacy of this treatment regime for those numerous patients unable to take an interferon based regimen due to contraindications or intolerance. Importantly, it also provides a timely reminder that there are limitations to this therapy, with SVR₁₂ lower in certain difficult to treat groups (especially patients with cirrhosis and previous exposure to interferon therapy). Future work should evaluate the addition of interferon and/or other direct acting agents, as well as longer treatment durations, for those patients with pretreatment characteristics associated with decreased treatment response. This study also highlights our lack of understanding of the basis for differences in response to sofosbuvir between genotype 2 and 3 patients, especially given the similarities in viral kinetics between these two groups

Medscape

Current and Future HCV Therapy-Do We Still Need Other Anti-HCV Drugs?

Liver International
Current and Future HCV Therapy-Do We Still Need Other Anti-HCV Drugs?

Salvatore Petta, Antonio Craxì
Liver International. 2015;35(s1):4-10.

Abstract and Introduction
Abstract
Eradication of hepatitis C virus (HCV) infection, at least in compensated patients, can help improve the outcomes of liver disease such as cirrhosis, hepatocellular carcinoma (HCC) and liver transplantation, as well as perhaps extra-hepatic complications such as diabetes and cardiovascular risk. In the past few years, the landscape of antiviral therapy has evolved at a breathtaking pace from pegylated interferon (PEG-IFN) plus ribavirin (RBV) (PEG-IFN/RBV) to IFN-based strategies combining direct acting antivirals (DDAs) with PEG-IFN/RBV and finally IFN-free combinations of DAAs. In particular with these most recent developments, treatment regimens have become shorter, safer and even more effective, with a wide range of indications. Nevertheless, research continues and newer antiviral drugs are still under development. At a point when a >90% sustained virological response (SVR) is being claimed with all new available regimens, pharmacological and clinical research should be addressing unresolved areas, such as cases of suboptimal SVR or to increase effectiveness rather than pursuing the development of new 'me-too' drugs. The issues which should be given priority for further development include the following:

• Improving the results of IFN-free regimens in patients with genotype 3 (HCV-3) infection.
• Identifying the indications for the treatment in patients with compensated and decompensated cirrhosis.
• Identifying standardized or personalized backup strategies in patients who do not respond to IFN-free regimens. Finally, because of financial constraints, the high cost of IFN-free strategies prevents their universal use in CHC patients and coverage by national healthcare systems. Thus, efforts must be made to document cost-effectiveness in all clinical scenarios and to develop more affordable IFN-free regimens.

The estimated global prevalence of hepatitis C virus (HCV) infection is 2.2%, corresponding to roughly 130 million HCV-infected individuals worldwide.^[1] HCV is one of the main causes of chronic liver disease leading to cirrhosis, hepatocellular carcinoma (HCC) and liver transplantation worldwide. In addition, recent data also suggests that HCV infection increases the risk of morbidity and mortality because of cardiovascular diseases.^[2]

A sustained virological response (SVR) is a well validated clinically relevant surrogate outcome in the management of chronically infected HCV patients because viral eradication not only prevents the occurrence of cirrhosis in chronic hepatitis C (CHC),^[3] but also the development of its complications in patients with compensated cirrhosis.^[4–7] In addition, as observed for HBV-related cirrhosis, SVR might improve the prognosis in patients with decompensated cirrhosis who are or are not awaiting liver transplantation, by compensating liver disease, or by influencing the recurrence of HCV-related cirrhosis and liver failure in the post-transplant setting.

In the past few years, the landscape of antiviral care in patients with chronic HCV has changed quickly; thanks to the increased understanding of the biology of HCV replication and the identification of proteins blocking the key steps. In patients with genotype1 (HCV-1) dual therapy (DT) with peginterferon alfa (PEG-IFN) and ribavirin (RBV) was replaced by PEG-IFN-based triple therapies (TT) with first generation protease inhibitors (PI)-boceprevir (BOC) or telaprevir (TVR). Recently these latter regimens were replaced by simeprevir (SIM) or sofosbuvir (SOF)-based schedules.^[8–10] The two latter regimens, combined with PEG-IFN/RBV, resulted in SVR rates ranging from 30% to 92%, also reducing the treatment duration and side-effects. In HCV genotypes 2 and 3 patients, PEG-IFN/RBV strategies were replaced by SOF plus RBV for HCV-2 patients with SVR rates above 90%,^[8,11–13] and by SOF plus RBV or SOF plus PEG-IFN/RBV in HCV-3 patients where the addition of PEG-IFN increases SVR rates.^[8,11–13] Finally, data on small cohorts of HCV-4 patients showed that compared to DT, TT regimens based on SOF or SIM achieved SVR rates similar to that reported in HCV-1 patients.^[8]

At present, drugs registered in Europe include SIM, SOF and Daclatasvir (DAC), which are combined with PEG-IFN/RBV in HCV-1 and HCV-4 patients with the SVR rates mentioned above, by an off-label combination (SOF/SIM or SOF/DAC or DAC/SIM) with/without RBV in pilot studies of small groups of patients, or in combination with RBV in HCV-2 and HCV-3 patients (for SOF only).

Recent clinical trials have shown that all oral IFN-free regimens combining the different DAA–SOF/Ledipasvir(LED) and Paritaprevir(PAR)/Dasabuvir(DAS)/Ombitasvir(OMB) achieve SVR rates ranging from 90% to 100%, independent of the severity of liver damage, the pattern of previous response to DT or first-generation PI, and without significant side-effects.^[12–18] These combinations, which should be registered and available in Europe in early 2015, are characterized by a short duration (8–12 weeks), oral administration with a few pills, and by a pangenotypic profile of effectiveness for SOF/LED, but restricted efficacy in HCV-1 (and perhaps HCV-4) for the AbbVie combination.

The next steps in the clinical development of anti-HCV therapy are expected in late 2015–early 2016 with the availability of pangenotypic ultrarapid (4–8 weeks) single pill regimens such as Grazoprevir/MK8742, SOF/GS5816, and BMS791325/DAC/Asunaprevir.

These advances have obviously resulted in innovations in IFN-based regimens.^[19] They have resulted in SVR rates >90% with well tolerated IFN-free regimens that represent a new challenge for the treatment of HCV-related liver disease, and create new frontiers for tolerability, safety and the consequences of treatment in untreated groups such as those with decompensated cirrhosis waiting or not for liver transplantation. Thus, the key question is whether future developments should focus on new antiviral regimens, or clinical development in as yet unresolved areas? We feel that available and soon to be available drugs are generally extremely effective even if certain issues (Fig. 1) require further study: (i) suboptimal performance in patients with HCV-3; (ii) treatment of patients with compensated and decompensated cirrhosis; (iii) backup strategies in patients who do not respond to IFN-free regimens; (iv) the costs of drugs.

Figure 1.

Hot topics for the treatment of patients with chronic hepatitis C using IFN-free regimens.

The next section of this review will focus on these issues, reporting available data and suggesting future directions for clinical development.

Patients With Genotype 3 Infection are the Most Difficult to Treat With DAAs
When PEG-IFN/RBV was the treatment for HCV, the same regimen was administered to all subjects and patients were defined as easy or difficult to treat according to viral genotype. HCV- 1 and 4 were considered to be difficult-to-treat and 2 and 3 were considered to be easy to treat.^[20] The SVR rates in the latter group were above 80% with shorter treatment.

The availability of IFN-free regimens has confirmed that HCV-2 patients are easy to treat while the paradigm for HCV-3 patients has been reversed compared to 'older, difficult-to-treat' HCV-1 patients. In fact, today with available DAAs, patients with HCV-3 are the most difficult to treat patients (Fig. 2). Results with an IFN-free regimen in HCV-3 patients were initially very encouraging in a small phase II study showing that 12-weeks of SOF/RBV resulted in an SVR in all HCV-2 and 3 patients.^[21] In other promising preliminary results, large phase III studies in HCV-2 and 3 treatment-naïve (Fission),^[8] experienced (Fusion),^[11] and IFN intolerant or unwilling patients (Positron),^[8] were begun to assess the effectiveness of 12–16 weeks of SOF/RBV. Overall, these studies have shown that surprisingly, while 12 weeks of SOF/RBV resulted in an SVR in HCV-2 patients independent of previous exposure to PEG-IFN/RBV and the severity of fibrosis, the latter two factors were significant for HCV-3 patients. Specifically, 12 weeks of therapy in treatment-naïve patients resulted in an SVR in 61% and 34% of non-cirrhotic and cirrhotic patients respectively.^[8] Moreover the SVR rates in non-cirrhotic patients were 37% and 63% in experienced patients, in the 12- and 16- week course, respectively, and 19% and 61% in the 12- and 16-week course in non-cirrhotic patients respectively.^[8,11] In particular, treatment failures were all related to relapse but not virological breakthrough confirming the high genetic barrier to resistance of SOF. These results suggest that strategies to improve SVR rates with an SOF containing regimen in HCV-3 patients should take into account an extension of prior therapy, or the addition of another anti-HCV drug (DAA or immunomodulator). Extending treatment to 24 weeks of SOF/RBV was evaluated in the Valence trial resulting in an overall SVR rate of 83%.^[12,13] In particular, this was the result of higher SVR rates in treatment-naïve (93% and 92% in patients without and with cirrhosis respectively), and experienced patients without cirrhosis (87%) while rates were lower in experienced (61%) patients with cirrhosis. These results identified the difficult- to-treat category of patients and suggested that the SVR could be improved by adding another anti-HCV drug. This hypothesis was tested in two small studies. The Lonestar-2 study tested TT with PegIFN/SOF/RBV for 12 weeks in treatment-experienced HCV-2 and 3 patients.^[22] The SVR in HCV-3 patients was 83% with no difference in relation to baseline cirrhosis (SVR 83% vs 83% respectively). The second study tested a combination of DAC/SOF resulting in an SVR of 89% of 18 treatment-naïve patients with HCV-3.^[23]

Figure 2.

Treatment strategies in treatment naïve (A) and experienced (B) patients with HCV-3 infection with direct antiviral agents. Results from Fission (8) Fusion (11), Valence (12), Lonestar-2 (22) RCTs and Sulkowski et al. (23).

These data suggest that SOF/PEG-IFN/RBV is the most effective treatment in HCV-3 treatment-experienced patients with cirrhosis, and that this regimen is also as effective in all other HCV-3 patients as a 24 week course of SOF/RBV. Despite these strategies certain unresolved issues remain: (i) the inability to treat patients with advanced cirrhosis using an IFN- based regimen, and (ii) the high cost of a 24- week course of SOF. Thus, further research in DAAs is necessary in patients with HCV-3 to validate available data in larger cohorts and test promising new DAA combinations such as Grazoprevir/MK8742, SOF/GS5816, BMS791325/DAC/Asunaprevir, and others.

Patients With Compensated or Decompensated Cirrhosis are Candidates for IFN-free Regimens
The option of using DAAs and combining them in safe and effective IFN-free regimens extends the landscape of antiviral treatment. This is especially true in patients who are at risk of complications or in whom IFN-containing strategies are contraindicated and for whom an SVR could significantly improve the liver-related prognosis. These patients have advanced fibrosis/compensated cirrhosis or decompensated cirrhosis. Results in the former group can be found in analyses of clinical studies with a low number of patients with advanced fibrosis/cirrhosis, and one study that was specifically designed to evaluate the effectiveness of IFN-free regimens in patients with compensated cirrhosis. The ION-1 and ION 2 trials are phase III clinical studies assessing the effectiveness of SOF/LED for 12- or 24-weeks with and without RBV in HCV-1 treatment-naïve (ION-1)^[12,13] or experienced (ION-2)^[14] patients. The studies included 865 and 440 patients, respectively, 16% with cirrhosis in the ION-1 and 20% with cirrhosis in the ION-2 study. Even if the low number of patients with cirrhosis included in the studies is taken into account, results showed that there was no significant difference in SVR12 rates among treatment-naïve patients with cirrhosis in any of the different arms (94–100%) and compared to patients without cirrhosis (97–99%). Cure rates in the 12-week arms were slightly lower in treatment-experienced patients with cirrhosis (86% without and 82% with RBV), while all patients with cirrhosis treated for 24 weeks achieved an SVR whatever the regimen. Similar promising results were reported in the COSMOS study assessing the effectiveness of SOF/SIM for 12–24 weeks with and without RBV.^[24] In the small subgroup of treatment-naïve/experienced F3-F4 patients (n = 41) the SVR rate ranged from 85% in the 12-week arm to 100% in the 24-week arm, with no obvious impact of the addition of RBV. Overall, these studies showed that oral, IFN-free regimens were effective in patients with cirrhosis, and even suggested an improvement in some cases with longer duration regimens, even if they did not have enough power to identify subgroups of patients with lower SVR rates. The TURQUOISE-II study^[16] was designed to assess the effectiveness of PAR/DAS/OMB plus RBV for 12 or 24 weeks in a large cohort of 380 treatment naïve or experienced patients with HCV-1 infection and cirrhosis with/without portal hypertension. This study was discussed recently.^[25] SVR rates were 92% (97.5% CI 88–96%) at 12 weeks compared to 96% (CI 93–99%) at 24 weeks. Interestingly HCV-1a non-responder patients were identified as difficult to treat and achieved an SVR of 80% in the 12-week arm compared to 93% in the 24-week arm. This study further confirms that the results of IFN-free regimens are generally good in compensated patients with cirrhosis even if further clinical development is necessary in certain groups to improve SVR rates.

The real challenge of IFN-free regimes is treating patients with decompensated cirrhosis. This issue creates interesting avenues of research on antiviral effectiveness and clinical outcomes. At present there is no conclusive evidence on the effectiveness of antivirals in this difficult clinical setting. The only available recent data reported an SVR rate of 65% in 20 patients with HCV-1 decompensated Child B cirrhosis who received LED/SOF. The remaining 7 patients experienced a virological relapse.^[26] These preliminary results must be confirmed and validated, even if they support the notion that the greater the severity of liver disease the lower the SVR rate in IFN-free regimens, probably because cirrhotic livers are less able to clear or cure infected cells. However, the other key issue in patients with decompensated cirrhosis is whether virological eradication can result in clinical improvement and compensated liver disease with possible removal from liver transplantation waiting lists, as observed in other clinical settings such as alcoholic hepatitis and HBV-related cirrhosis. Data are not available in this clinical setting where IFN is contraindicated, and where RBV can be a risk, and huge clinical advances are expected.

Existing evidence suggests that available and soon-to-be available IFN-free regimens are effective in patients with compensated cirrhosis, even if further clinical studies are necessary to identify difficult to treat patients (HCV-1a cirrhosis? cirrhotic non-responders?) requiring longer treatment and/or the addition of another DAA with/without RBV. On the other hand, data are needed in patients with decompensated cirrhosis, where the history of DAA-based regimens has barely begun.

Other areas of research in patients with cirrhosis are the use of RBV, and in particular, identifying clinical settings where RBV improves SVR, and finally, safety issues. Data on the safety of IFN-free regimens in patients with cirrhosis are only available for certain combinations and in patients with well-compensated disease. However, the impact of these drugs in patients with compensated cirrhosis – with older disease and co-morbidities – as well as in patients with decompensated liver disease must be evaluated.

Backup Strategies for Failure of DAAs: New Generation DAAs or IFN/RBV ?
The high number of HCV-1 patients treated with TVR or BOC-based TT in phase II and III clinical trials and then in clinical practice, has generated a corresponding proportion of patients with HCV variants resistant to NS3–4A protease inhibitors. With the introduction of IFN-based or IFN-free regimens with new generation DAAs the presence of patients with multidrug resistant viral populations is expected. Thus, the clinical relevance of response to other antiviral strategies has not been sufficiently studied and data are limited. However, the lower SVR rates observed in HCV-1a patients with the Q80K substitution treated with SIM-based therapy suggests that this issue must be carefully evaluated.^[9,10]

Observational data on the failure of first generation PI have shown that viral populations resistant to NS3-4A protease inhibitors progressively decline, replaced by wild-type viruses within a few months after treatment withdrawal. These encouraging experimental results were confirmed clinically in a preliminary study showing high SVR rates in patients who did not respond to TVR or BOC TT when there were retreated with IFN-free regimens. Specifically, a 24-week course of SOF/DAC with/without RBV resulted in an SVR in 40/41 patients who failed TVR-based TT.^[23] The LONESTAR-1 study^[27] tested the effectiveness of 12 weeks of SOF/LED with/without RBV in 40 HCV-1 CHC patients who did not respond to first generation PI, 22 of them with cirrhosis. The authors reported SVR rates of 95% and 100% in the arms without and with RBV respectively.
Results in patients who did respond to IFN plus new generation DAAs vary. Nineteen HCV-1 patients from the ELECTRON-1 study who relapsed after SOF TT were retreated with 12 weeks of SOF/LED and all of them achieved an SVR.^[26] On the other hand, HCV-1 patients who did not respond to PEG-IFN/RBV + an investigational PI with/without LED or tegobuvir, achieved an SVR rate of 74%.^[28] Most of these patients (90%) carried at least 1 resistance associated variant.
Finally, clinical trials have shown that IFN-free regimens combining more DAAs are highly effective, and that virological failures because of breakthrough or relapse with resistant viruses are rare due to the high resistance barriers. Nevertheless, it should be remembered that: (i) viral populations harbouring resistance to NS5A protease inhibitors may persist for many years after treatment is discontinued and that the clinical significance of this is unknown for new combinations; (ii) the development of viral strains resistant to DAAs is expected to increase in clinical practice because of cases of suboptimal adherence to therapy; and (iii) until now studies evaluating escape strategies for unsuccessful IFN-free regimens have not been performed.

Although results are encouraging and suggest that IFN-free regimens are highly effective in cases of failure with BOC or TVR, further efforts are needed to identify standardized or personalized approaches in patients who do not achieve an SVR even with IFN-based or IFN-free new generation DAA combinations. For this, different approaches should be tested, such as careful assessment of virological strains, extending therapy, and/or adding PEG-IFN and/or RBV to modulate the immune system.

The issue of the cost: careful cost-effectiveness analyses needed
The rapid change in the landscape of antiviral therapy has resulted in an increase in the number of available molecules and significantly better results as well as a significant increase in the cost of drugs. Specifically, the cost of one course of antiviral therapy increased from approximately €10 000–15 000 for DT, to €30 000 for IFN-based first-generation PI therapy and €60 000 with SOF TT. In particular pricing of IFN-free regimens is not yet available, but the cost of the combination of SOF with SIM is approximately €120 000. This raises the key question of whether the application of a universal IFN-free strategy by national healthcare systems is viable in all HCV-1 CHC patients. To answer this question, assessment of the price of a course of antiviral therapy must take into account the cost of drugs, the effectiveness of the treatment strategy, and both direct and indirect costs of the management of side-effects related to drugs. In this way, we can accurately calculate the real cost of achieving an SVR. However, to assess the cost-effectiveness of a therapeutic strategy, its impact on the natural history of the disease and on the costs of managing the disease over time must also be evaluated. For this, the incremental cost-effectiveness ratio for life-years gained or for quality adjusted life years are the markers used. Two recent cost-effectiveness analyses of IFN-free regimens were published for CHC patients with contrasting results.^[29,30] Differences in the results of these analyses were due to the estimated pricing of IFN-free regimens and the different comparison arms. Younossi et al.^[29] simulated an unrealistic scenario in which the price of the IFN-free regimen was the same as IFN-based first-generation PI which generated a universal cost-effectiveness of IFN-free therapy. On the other hand, Deuffic-Burban et al.^[30] developed a more realistic model in which IFN-free treatment was twice as expensive as IFN-based second generation DAAs. This model resulted in the lack of cost-effectiveness of a full IFN-free scenario. However, although the proposed analyses are useful for decision-making and for negotiation of the price of newer IFN-free regimens, the clinical value and ethical impact of treatment should not be unduly influenced by an economic analysis. In other words, availability of highly effective, short duration well tolerated treatment regimens, make them preferable for all patients, from those with advanced disease to those with mild liver damage. Although pricing and cost-effectiveness analyses provide information on IFN-free cost-effectiveness in all clinical scenarios, they cannot determine which patients should receive IFN-free and IFN-based strategies. In resource-limited settings a priority-based treatment plan must be designed where patients at high risk of the complications of liver disease are treated first while those with milder disease can be deferred while undergoing periodic re-evaluation of liver damage.

Conclusions
The availability of short duration, safe and highly effective regimens has created new challenges in the treatment of patients with HCV infection, and especially in groups in which the SVR was low with prior therapies, or in which IFN-based strategies were contraindicated. Despite the optimism for the near future, certain areas require further evaluation to make IFN-free regimens effective in all patients. Finally, efforts should be made to make IFN-free cost-effective in all clinical scenarios and accessible to all patients.

Source-Medscape