December 3, 2013

Liver disease: pump provides relief

3 December 2013 Last updated at 20:40 ET

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The rechargeable pump sits underneath the skin and can be switched off at night

Patients at the Royal Free Hospital in London are testing a device that provides relief from a common side-effect of liver disease.

The pump siphons off excess fluid that can build up in the abdomen after liver failure and diverts it to the bladder so it can be urinated out.

A liver transplant may be the only option for patients with cirrhosis.

Doctors say the pump could buy time and may even allow the liver to recover, avoiding the need for a transplant.

“It can improve quality of life for patients and keep them out of hospital for longer”

Prof Rajiv Jalan

So far eight patients at the Royal Free have had one fitted.

The Alphapump sits beneath the skin of the abdomen and is connected to two small tubes that do the siphoning.

Ascites

When patients have cirrhosis, the liver and kidneys stop working properly and fluid, known as ascites, can accumulate.

Litres of fluid can gather inside the abdominal cavity, making the patient appear pregnant as well as being painful.

Patients may have to make weekly or monthly trips to hospital to have the fluid drained.

Rajiv Jalan, professor of hepatology at University College London's institute for liver and digestive health at the Royal Free, is the doctor running the trial.

He said: "With cirrhosis, patients can accumulate litres and litres of fluid. They might need to come to hospital fortnightly to have up to 20 litres drained from their tummy.

"The pump can avoid this by draining about 15 millilitres every 15 minutes. It means they'll pass a little bit more urine but they can turn the pump off at night.

"It can improve quality of life for patients and keep them out of hospital for longer."

Source

Acceleron to start trial in liver cancer patients early next year

Dec 3, 2013, 1:45pm EST

Don Seiffert
BioFlash Editor-Boston Business Journal
Email

Newly-public biotech Acceleron Pharma says that it’s planning to start a trial of its cancer drug in patients with liver cancer early next year, based on promising early results of the same drug in kidney cancer patients.

The Cambridge company (Nasdaq: XLRN) gave on update Tuesday on its drug, dalantercept, which inhibits the formation of new blood vessels from existing ones, at the Piper Jaffray health care conference in New York. The drug is aimed primarily at patients with advanced cancer who have not responded to other drugs. That drug is currently in mid-stage trials to test its effectiveness against renal cell carcinoma, ovarian cancer and cancers of the head and neck.

The drug is also the only one now in human trials that is being developed solely by Acceleron. The biotech’s two other clinical-stage drugs (sotatercept and ACE-536) are both anemia drugs which are in trials in collaboration with Acceleron’s partner, Celgene.

In today’s presentation, Acceleron said that its on track to start the placebo-controlled portion of the dalantercept trial against renal cell carcinoma by the end of March 2014. But it also said that “based on the activity and tolerability” seen in that trial, it has decided to start a combination study in hepatocellular cancer patients in which dalantercept would be administered along with the existing drug for that kind of cancer, Nexavar (marketed by by Bayer and Onyx Pharmaceuticals).

Acceleron had previously planned to start its next clinical trial of dalantercept in the late summer or early fall of next year, but now expects to start the Phase 2 trial in HCC by next spring.

The company also said it will report data from a Phase 2 trial of sotatercept in patients with beta-thalassemia on Dec. 9 at the American Society of Hematology annual meeting in New Orleans.

In an interview earlier this year, Steve Ertel, chief business officer for Acceleron, said the company’s strategy is to run several concurrent trials against various diseases rather than focus on bringing a single drug to market quickly.

Source

J Hepatol. 2013 Dec;59(6):1271-7. doi: 10.1016/j.jhep.2013.07.029. Epub 2013 Aug 6.

Finn RS, Poon RT, Yau T, Klümpen HJ, Chen LT, Kang YK, Kim TY, Gomez-Martin C, Rodriguez-Lope C, Kunz T, Paquet T, Brandt U, Sellami D, Bruix J.

University of California Los Angeles, Los Angeles, CA, United States. Electronic address: rfinn@mednet.ucla.edu.

Abstract

BACKGROUND & AIMS: Sorafenib is the only therapy shown to improve overall survival in advanced hepatocellular carcinoma (HCC). Combination therapy targeting multiple signaling pathways may improve outcomes. This phase I study was designed to determine the maximum tolerated dose (MTD) of everolimus given with sorafenib 400mg twice daily in patients with advanced HCC of Child-Pugh class A liver function who were naive to systemic therapy.

METHODS: Everolimus was initiated at 2.5mg once daily and increased per a Bayesian sequential dose-escalation scheme based on the dose-limiting toxicities experienced within the first 28days of treatment. Adverse events were assessed continuously. Efficacy was evaluated using the best overall response rate per RECIST.

RESULTS: Thirty patients were enrolled; 25 were evaluable for MTD determination. One out of 12 patients treated with everolimus 2.5mg once daily and 6 out of 13 patients treated with everolimus 5.0mg once daily experienced a dose-limiting toxicity, most commonly thrombocytopenia (n=5). All patients experienced ⩾1 adverse event, most commonly diarrhea (66.7%), hand-foot skin reaction (66.7%), and thrombocytopenia (50.0%). Best overall response was stable disease (62.5% and 42.9% in the 2.5-mg and 5.0-mg cohorts, respectively). Median time to progression and overall survival in the 2.5-mg cohort were 4.5months and 7.4months, respectively, and 1.8months and 11.7months, respectively, in the 5.0-mg cohort.

CONCLUSIONS: In patients with advanced HCC, the everolimus MTD in combination with standard-dose sorafenib was 2.5mg once daily. The inability to achieve a biologically effective everolimus concentration at the MTD precluded phase II study of this combination.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: AE, AST, BCLC, BID, Barcelona Clinic Liver Cancer, C(max), C(min), CI, DCR, DLT, Dose-finding, ECOG, Eastern Cooperative Oncology Group, Everolimus, HBV, HCC, Hepatocellular carcinoma, MTD, Mammalian target of rapamycin, OS, PDGFR, QD, RCC, RDI, RECIST, Response Evaluation Criteria in Solid Tumors, SD, SHAR, Sorafenib, Sorafenib HCC Assessment Randomized Protocol, TTP, ULN, VEGFR, adverse event, aspartate aminotransferase, confidence interval, disease control rate, dose-limiting toxicity, hepatitis B virus, hepatocellular carcinoma, mTOR, mammalian target of rapamycin, maximum blood concentration, maximum tolerated dose, minimum blood concentration, once daily, overall survival, platelet-derived growth factor receptor, relative dose intensity, renal cell carcinoma, standard deviation, time to progression, twice daily, upper limit of normal, vascular endothelial growth factor receptor

PMID: 23928403 [PubMed - in process]

Source

J Hepatol. 2013 Dec;59(6):1323-30. doi: 10.1016/j.jhep.2013.07.014. Epub 2013 Jul 15.

Romero-Gómez M, Berenguer M, Molina E, Calleja JL.

Source

UCM Digestive Diseases and CIBERHD, Hospital Universitario de Valme, Universidad de Sevilla, Sevilla, Spain.

Abstract

The addition of protease inhibitors, boceprevir or telaprevir, to peginterferon+ribavirin (PegIFN/RBV) increases the frequency as well as the severity, and hence, clinical relevance of anemia, which has now become one of the major complications associated with triple therapy. Most significant factors associated with anemia in patients receiving triple therapy include older age, lower body mass index (BMI), advanced fibrosis, and lower baseline hemoglobin. The variability in inosine triphosphate pyrophosphatase (ITPA) gene, which encodes a protein that hydrolyses inosine triphosphate (ITP), has been identified as an essential genetic factor for anemia both in dual and triple therapy. The correct management of anemia is based on anticipation, characterization and therapeutic management. Basically, anemia can be characterized in 3 types: ferropenic (mostly in fertile women), thalassemic type hemolytic anemia, and anemia from chronic processes. Functional deficit of iron should also be excluded in patients with normal ferritin and lower saturation of transferrin. Ribavirin dose reduction and epoetin, sequentially, are indicated in the management of anemia. Epoetin non-response can be caused by lack of time, type of anemia, functional iron deficit or erythropoietin resistance. In the transplantation setting, adding a protease inhibitor to PegIFN/RBV results in a significant increase in the incidence and severity of anemia and, as a consequence, a greater need for epoetin, transfusions, and ribavirin dose reductions. Packed red cell transfusions are utilized when hemoglobin decreases to less than 7.5g/dl and/or there are clinical symptoms and/or there is no response to other therapeutic measures.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: Anemia, BMI, Boceprevir, EPO, Epoietin, GWAS, HCV, Hepatitis C virus, ITPA, Pegylated interferon, Protease inhibitor, Ribavirin, SNP, Telaprevir, body mass index, erythropoietin, genome-wide association study, hepatitis C virus, inosine triphosphate pyrophosphatase, sRfT, single nucleotide polymorphisms, transferrin soluble receptor

PMID: 23867320 [PubMed - in process]

Source

Sofosbuvir for Hepatitis C: Simpler, Shorter, Safer?

William F. Balistreri, MD
December 03, 2013

Aiming for the Ideal Strategy

In 2011, the American Association for the Study of Liver Diseases (AASLD) issued an updated version of its practice guidelines for the treatment of chronic genotype 1 hepatitis C virus (HCV) infection.[1] The current standard-of-care regimens include a protease inhibitor -- telaprevir or boceprevir -- in combination with pegylated interferon (PEG-IFN) and ribavirin. Protease inhibitor-based strategies for patients with genotype 1 HCV have led to high rates of sustained virologic response (SVR); however, there are several recurring concerns.

The disadvantages of IFN treatment are well known. Moreover, this strategy presents a complex and prolonged therapeutic course (24-48 weeks), low tolerability, a low barrier to resistance, and reduced efficacy in prior null responders or cirrhotic patients. These regimens are not an option for many patients because of contraindications or intolerability to IFN.[2-7]

To address these concerns, there has been a massive effort to create the ideal agent or strategy for use in updated therapeutic efforts. The pace of discovery has been unprecedented, and several agents are in the later phases of development. The approach has been to discover drugs that directly target various aspects of the HCV life cycle -- hopefully leading to combinations of agents that will more effectively treat patients, while minimizing intolerable side effects or adverse events.

Sofosbuvir Enters the Fray

A recent article discussed simeprevir, an HCV NS3/4A protease inhibitor. [Editor's note: The US Food and Drug Administration (FDA) approved simeprevir (Olysio™) on November 22, 2013.]

The latest drug to emerge from this effort is sofosbuvir. In late October, an FDA advisory panel recommended the approval of sofosbuvir for the treatment of 2 groups of patients with chronic HCV: previously untreated adults with genotypes 1 and 4 infections (in combination with PEG-IFN and ribavirin) and adults with genotype 2 and 3 infections (in combination with ribavirin alone), which would allow an all-oral, IFN-free treatment for these 2 genotypes.

Sofosbuvir, an orally administered nucleotide analogue inhibitor of the HCV NS5B polymerase, exerts potent antiviral activity against HCV genotypes 1 through 6. This drug is meant to be taken once daily at a dose of 400 mg. Sofosbuvir has been extensively studied in various patient populations in combination with PEG-IFN/ribavirin, as well as with other direct-acting antiviral agents in treatment-naive patients with genotype 1 HCV infection.[8-12]

The FDA advisory committee reviewed primary efficacy and safety data from a series of clinical trials. The data supported the possibility of effectively treating HCV infection with a brief, well-tolerated, all-oral, once-daily regimen that has no known safety issues and no resistance development. Phase 3 trials of sofosbuvir in treatment-naive patients with hepatitis C virus genotypes 1 through 6 demonstrated that patients with genotype 1 infection have excellent treatment response that is superior overall to published response rates for combination therapy and currently available triple therapies. For patients with genotypes 2 and 3, efficacy was similar between an IFN-free sofosbuvir regimen and a standard PEG-IFN/ribavirin regimen.

Evidence for Sofosbuvir

Numerous studies have emerged; a brief overview of a few representative studies of sofosbuvir in combination with other direct-acting antiviral agents is offered here:

  • Sofosbuvir was combined with simeprevir with and without ribavirin; SVR rates of 93%-96% were reported.[11]
  • Sofosbuvir plus the NS5A inhibitor daclatasvir led to SVR at 12 weeks (SVR12) rates of 86%-100%.[13]
  • Ledipasvir is a novel HCV NS5A inhibitor that has shown potent antiviral activity against genotypes 1a and 1b HCV infection.[14,15] It is active against HCV with the S282T mutation, the only variant known to reduce susceptibility to sofosbuvir.[16] All treatment-naive patients and prior null responders (noncirrhotic) who received 12 weeks of sofosbuvir and ledipasvir plus ribavirin achieved high SVR12 rates (95%-100%). Patients treated for 12 weeks had a similar response to patients who received 8 weeks of therapy, suggesting that this shorter treatment strategy might be sufficient for noncirrhotic patients who have not previously been treated for HCV.

In all of these studies, sofosbuvir was well tolerated, with a low incidence of adverse events. In conjunction with the suggested brief duration of this regimen, this indicates that drug combinations should improve treatment adherence compared with IFN-based treatment. Traditional predictors of response, such as IL28B genotype and baseline viral load, do not seem to affect response rates. Other large multicenter trials are under way, designed to address the optimal treatment combination and duration, the need for ribavirin, and the efficacy in patients with compensated cirrhosis in both treatment-naive and previously treated patients.

Data on the Drug

Presentations offered at the AASLD's Liver Meeting 2013 abetted the data submitted to the FDA. Several studies reported pan-genotypic efficacy and safety of sofosbuvir, as well as other potential uses for this agent in various drug combinations and in various populations, including the following:

  • In a phase 3 trial, 12 weeks of sofosbuvir plus ribavirin demonstrated high SVR rates in a predominantly treatment-experienced patient population with genotypes 2 and 3 HCV infection, with higher response rates in patients infected with genotype 2 than in those infected with genotype 3 HCV.[17]
  • In a phase 2, randomized, open-label study, the combination of sofosbuvir plus simeprevir plus ribavirin for 12 or 24 weeks in patients with HCV genotype 1 infection resulted in high SVRs. This study included null responders and patients with cirrhosis.[18]
  • Sofosbuvir plus ledipasvir given in a fixed combination elicited a rapid decline in HCV RNA levels in all patient populations, with no viral breakthrough. In treatment-naive patients with genotype 1 infection and without cirrhosis, a reduction in duration of therapy from 12 to 6 weeks increased the rate of relapse.[19]In genotype 1-infected patients who were prior null responders and had cirrhosis, the addition of ribavirin to sofosbuvir and ledipasvir reduced the rate of relapse.
  • Treatment-naive patients with HCV genotype 2 and 3 who were coinfected with HIV achieved high SVR12 rates with an IFN-free, oral regimen of sofosbuvir plus ribavirin.[20] The SVR12 rates were 76% among patients with HCV genotype 1, 88% among those with genotype 2, and 67% among those with genotype 3; these are similar to the rates observed for patients infected with HCV only. These preliminary data suggest that sofosbuvir plus ribavirin treatment was well tolerated and safe, even with the coadministration of multiple antiretroviral drugs.

A Markov model, developed to evaluate the long-term outcomes of sofosbuvir-based therapy for HCV infection, indicated that regimens incorporating this agent are highly effective in preventing progression to advanced liver disease.[21]

New Opportunities Bring New Challenges

Recurrence of HCV infection is the most common cause of graft loss and mortality in HCV-infected liver transplant recipients. IFN-based post-transplantation antiviral regimens, including those using protease inhibitors, are poorly tolerated and achieve SVRs that are lower than those in nontransplant patients.

Administration of sofosbuvir plus ribavirin after liver transplantation in the setting of established HCV recurrence was well tolerated, and approximately 80% of patients achieved an early SVR at 4 weeks. There were no episodes of rejection or drug interaction, and there was no apparent effect of sofosbuvir on serum levels of immunosuppressive medications, offering the potential for an all-oral therapy for treatment of HCV infection after liver transplantation.[22] Sofosbuvir and ribavirin may, in fact, be used in the pretransplant phase to prevent recurrence of HCV infection after transplantation.[23]

In summary, 2 novel direct-acting antiviral agents -- sofosbuvir and simeprevir -- target various components of the HCV genome. Advantages of these drugs include a high barrier to viral resistance, a shorter duration of treatment, once-daily dosing, absence of food restrictions, few clinically significant drug interactions, and similar efficacy in all genotypes. This will offer clinicians new options as well as new challenges. A recent review addressed some of these anticipated issues, such as the off-label use of HCV medications and the roles of the FDA, consumer pressure, medical society guidelines, and third-party payers.[24]

The availability of these agents will provide unprecedented opportunities for off-label use of these therapies in many patients, including those with decompensated cirrhosis or chronic kidney disease, pediatric populations, and those with HIV coinfection. Because many of these populations represent relatively small numbers of patients with HCV, it may be difficult to accumulate the requisite data and possibly cost-prohibitive for manufacturers to apply for FDA approval.

The bottom line is that simpler, shorter, and safer strategies for treatment of patients infected with HCV are at hand.

References

Source

Journal of Viral Hepatitis

Early View (Online Version of Record published before inclusion in an issue)

Original Article

C. Treloar1,*, J. Rance1, G. J. Dore2, J. Grebely2 the ETHOS Study Group

Article first published online: 3 DEC 2013

DOI: 10.1111/jvh.12183

© 2013 John Wiley & Sons Ltd

Abstract

Keywords: hepatitis C;  opiate substitution treatment;  qualitative research;  treatment

Summary

Provision of hepatitis C virus (HCV) assessment and treatment via opioid substitution treatment (OST) clinics has been posed as an effective means of engaging populations with high HCV prevalence. This study explores OST client and health professional reports concerning barriers and facilitators affecting the delivery and uptake of HCV care and treatment within OST settings. In-depth interviews were conducted with 57 clients, 16 staff from four NSW clinics participating in the Australian ETHOS study and three peer workers. Client participants included those who had not had HCV assessment; those who had HCV assessment only; and those who were awaiting or undertaking HCV treatment. A clear difference in decisions about HCV treatment emerged between participant groups. For those who have not been assessed, barriers to engaging with HCV care included the perception that they were physically well, were not experiencing HCV symptoms, had other life priorities and were concerned about the side effects and tolerability of treatment. Those who had engaged with care expressed motivations stemming from seeing friends becoming unwell, wanting to live longer and hearing positive stories of treatment. For those interested in HCV treatment, issues related to both provider and setting were important, such as presence of an engaged clinician, an accessible treatment pathway and availability of support. In this integrated care model, some barriers to HCV care and treatment (particularly those relating to health provider and the system) are minimized. In this setting, HCV treatment remained an unattractive option for a significant number of clients. Providing ways for those without HCV symptoms to be assessed for liver damage may be important to open up alternative conversations about HCV care. Further, the importance of a changing discourse of treatment is apparent from these data and could be enhanced by peer communication that provides information about successful treatment experiences.

Source

BURLINGTON, N.C.--(BUSINESS WIRE)--December 03, 2013--

Laboratory Corporation of America(R) Holdings (LabCorp(R) ) (NYSE: LH) announced today the immediate availability of an enhanced version of its HCV GenoSure(R) NS3/4, a drug resistance test that screens for the Q80K polymorphism. Q80K is a naturally occurring polymorphism that develops in certain strains of HCV, making the virus less susceptible to Janssen Therapeutics' OLYSIO(TM) (simeprevir), which was recently approved by the U.S. Food and Drug Administration for the treatment of certain adult patients diagnosed with genotype 1chronic hepatitis C (HCV). In clinical trials, patients with HCV genotype 1 containing the Q80K polymorphism demonstrated significantly lower response rates to treatment with OLYSIO. Approximately one-third of HCV patients have virus with Q80K polymorphism. Given the high frequency of the Q80K polymorphism and its significant impact on OLYSIO's success rate, it is recommended that patients be screened for the Q80K polymorphism prior to treatment.

LabCorp and Monogram Biosciences, Inc., a member of the LabCorp Specialty Testing Group, were the first to launch an HCV drug resistance test for NS3/4A protease inhibitors. In addition to OLYSIO, LabCorp's HCVGenoSure NS3/4A test also provides resistance information for the drugs VICTRELIS(R) (boceprevir) and INCIVEK(R) (telaprevir). With the inclusion of all three FDA approved protease inhibitors, HCV GenoSure NS3/4A enables healthcare providers to select the most appropriate therapy regimen for their patients.

An estimated 3.2 million people in the U.S. (and 170 million worldwide) are chronically infected with HCV, which if left undiagnosed and untreated can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. The Centers for Disease Control and Prevention (CDC) estimates that nearly half of the U.S. HCV population is currently undiagnosed, and the slow and often silent onset of HCV disease presentation has prompted more aggressive efforts to proactively diagnose and treat HCV infection. "We are proud to be a leader in the growing effort to screen and monitor individuals with HCV and to support physicians in treatment decisions to improve patient outcomes," said David P. King, Chairman and CEO.

About LabCorp(R)

Laboratory Corporation of America(R) Holdings, an S&P 500 company, is a pioneer in commercializing new diagnostic technologies and the first in its industry to embrace genomic testing. With annual revenues of $5.7 billion in 2012, over 34,000 employees worldwide, and more than 220,000 clients, LabCorp offers more than 4,000 tests ranging from routine blood analyses to reproductive genetics to companion diagnostics. LabCorp furthers its scientific expertise and innovative clinical testing technology through its LabCorp Specialty Testing Group: The Center for Molecular Biology and Pathology, National Genetics Institute, ViroMed Laboratories, Inc, The Center for Esoteric Testing, Litholink Corporation, Integrated Genetics, Integrated Oncology, Dianon Pathology, Monogram Biosciences, Inc, Colorado Coagulation, Cellmark Forensics, MedTox, and Endocrine Sciences. LabCorp conducts clinical trials testing through its LabCorp Clinical Trials division. LabCorp clients include physicians, government agencies, managed care organizations, hospitals, clinical labs, and pharmaceutical companies. To learn more about our organization, visit our website at: www.labcorp.com.

OLYSIO is a trademark of Janssen Therapeutics, Division of Janssen Products, LP.

VICTRELIS is a registered trademark of Schering Corp., a subsidiary of Merck & Co., Inc.

INCIVEK is a registered trademark of Vertex Pharmaceuticals Incorporated.

This press release contains forward-looking statements. Each of the forward-looking statements is subject to change based on various important factors, including without limitation, competitive actions in the marketplace and adverse actions of governmental and other third-party payors. Actual results could differ materially from those suggested by these forward-looking statements. Further information on potential factors that could affect LabCorp's financial results is included in the Company's Form 10-K for the year ended December 31, 2012, and subsequent SEC filings.

CONTACT: Laboratory Corporation of America(R) Holdings
Stephen Anderson, 336-436-5076
www.labcorp.com

SOURCE: Laboratory Corporation of America Holdings
Copyright Business Wire 2013

Source

Provided by NATAP

Summary from AASLD 2013 for Hepatitis C Washington 1-5 November 2013

Jurgen K. Rockstroh M.D., Professor of Medicine
University of Bonn, Germany

Correspondence:
Prof. Dr. J.K. Rockstroh
Department of Medicine I
University of Bonn
Sigmund-Freud-Str. 25
53105 Bonn
Germany
Tel.: +49-228-287 16558
FAX: +49-228-287 15034
e-mail: juergen.rockstroh@ukb.uni-bonn.de

Introduction

\Although the introduction of the first DAA based triple therapy (telaprevir or boceprevir in combination with IFN/RBV) has already considerably improved outcome of HCV therapy and changed HCV treatment paradigms for HCV therapy, it became rapidly clear that patient populations exist which will remain difficult to treat including previous non-responders, particularly with concomitant cirrhosis, as well as patients pre and post liver transplantation with HCV recurrence. Also genotype 3 patients have emerged as a new difficult to treat patient group with IFN-free HCV regimens, again particularly in patients with cirrhosis. Moreover, with sofosbuvir achieving positive FDA panel approval and simeprevir just being approved in the USA and Canada at the end of November, the question remains how these drugs will be best used in the future after final approval in the next months. Will combinations of DAA from different companies on the basis of promising results from early pilot trials be sufficient to warrant their use outside of clinical trials? Will the various DAA combinations from a number of different companies be able to offer interferon-free HCV treatment regimens for all even for cirrhotic genotype 3 patients? This AASLD was able to create a great buzz around the fast moving and exciting HCV treatment story, which attracted over 10.000 delegates to attend AASLD in Washington and to experience these new advances in an unparalleled medicine success story. With a constantly increasing number of DAAs in development from conference to conference it becomes increasingly difficult to foresee where and in whom the individual drugs will be used eventually. Clearly pricing of the new drugs will also impact the use of the respective drug accordingly. The conference closed with a hepatitis C debrief by Mark Sulkowski which was simply excellent and everyone interested in HCV drug development should be encouraged to listen in into Marks wonderful summary through the AASLD website (1). The following conference report aims at covering the main HCV DAA trials and clinical relevant HCV management issues presented at AASLD in Washington from 1-5 November 2013.

Ending the silent epidemic

In an introduction to the hepatitis debrief towards the end of the conference Ronald Valdiserri summarized the best way forward to end the the HCV epidemic (2). He emphasized that improved HCV treatment outcomes will require timely diagnosis and linkage to care. He reported that during 2005-2011 at 8 US surveillance sites 217,755 persons were identified as newly HCV positive, whereby 49% lacked HCV-RNA testing (3). In a phone survey of 53,896 minority adults from 28 communities only 19% reported HCV testing despite 60% having a risk factor for HCV transmission (4). Of those tested 8,3% were HCV positive but only 44% were subsequently followed by a doctor. Readdressing the American HCV treatment cascade he highlighted that of the 3,2 Mllion Americans believed to have HCV only 50% (1,6 Million) know their diagnosis. 32-38% of these patients are presumed to be referred to care with only 7-11% being treated and eventually only 5-6% (170,000 - 200,000) being cured from their HCV infection (5). The corresponding American HCV treatment cascade he presented is depicted in Figure 1. Clearly these findings highlight that improved treatments with high cure rates also need to be implemented in a sector of medicine where up to now acess to diagnostics and subsequent linkage to hepatitis mangement have been more than challenging.

AASLD1

Efficacy and safety of boceprevir and telaprevir: the real-life experience

HCV-TARGET is an ongoing longitudinal observational study at 44 academic and 59 community centers (6). Demographic, clinical and virologic data and adverse events are collected throughout treatment and follow-up on sequentially enrolled patients, together with information on adherence to treatment futility rules at key time points. 61% of the included patients are already treatment experienced. 137/678 treatment experienced patients showed prior null response, most patients were relapsers (302/678). Virological results and baseline characteristics of the cohort are summarized in table 1. Indeed, overall response rates in this real-life cohort become lower with prior null response. However cure rates in the treatment naïve patients are reassuringly high. With regard to safety there appears to be a higher rate of SAEs than seen on the registrational trials but overall manageable.

Table 1: Experience with boceprevir or telaprevir + PEG-IFN/RBV in an observational cohort at academic and community sites: HCV-TARGET

AASLD2

Data from the French CUPIC study (7) and an Austrian cohort (8) have previously demonstrated that patients with F3 or F4 stage fibrosis had a modest treatment outcome and a high rate of severe events, particularly in patients with low platelet counts <100,000/mm3 and serum albumin <35 g/L. In a German cohort, initiated by the Association of German Gastroenterologists in Private Practice (bng) and Roche, the impact of these baseline factors on treatment efficacy was analysed in this noninterventional "PAN" cohort (9). Only patients infected with HCV genotype 1, initiating treatment with BOC or TVR from October 2011 to March 2012 with an APRI score >1.5 were included into this analyses (see Figure 2).

Figure 2: Study design of the PAN cohort.

AASLD3

A total of 204 patients were analysed, 45 with boceprevir (BOC) and 159 with telaprevir (TVR) triple therapy. 47.1% of patients had liver cirrhosis (at least one result of sonography, histology, elastography or clinical appearance). 56.4% male, mean age 53.6 years, BMI 27.1 kg/m2. 65.2% of patients had ALT >3xULN, 33.3% platelets <100,000/μl and 17.1% albumin <35 g/L. Genotype-subtypes distribution was 1a 29.9%, 1b 52.0%, unknown/other 18.1%; High viral load (HCV-RNA>400,000 IU/ml) 74,4%. 147/204 patients (72.1%) were pretreated with 61 relapsers, 86 non-responders. Treatment discontinuation rate increased over time with 33.3% discontinuing before week 48. Preliminary data of 88 patients having reached an observational period of 60 of 72 weeks reveal 65.9 % treatment discontinuation and 25.0% SVR. The risk of SAE increased to 28.6% with platelet count <100,000/mm3 and serum albumin <35g/L (see Figure 3). These findings are clinically extremely relevant as they underline that patients with low albumin and platelet levels indeed are high risk for SAE development. It also suggests that outside of clinical trials far more patients are discontinued under first wave HCV-protease inhibitor based therapy.

Figure 3: Real World: Significant Adverse Events (SAEs)

AASLD4

Treatment in special patient populations: HIV/HCV coinfection
At AASLD various trials were reported from DAA-based therapy in HIV/HCV coinfected individuals which included data from trials with telaprevir and boceprevir in more real-life treatment scenarios including considerable patient numbers with more advanced fibrosis as well as previous treatment failure to dual therapy (10, 11). In addition SVR4 results from the phase III trial investigating the second-wave HCV protease inhibitor faldaprevir in combination with PEG-IFN/RBV (12) as well as the results from the first IFN-free regimen with Sofosbuvir and ribavirin (PHOTON trial) were reported (13).

Studies with telaprevir or boceprevir in HIV-coinfection

n the hepatitis poster session an update on two ANRS studies were presented which looked at the efficacy and safety of triple HCV therapy (with either telaprevir or boceprevir) in previous non-responders to dual PEG-IFN/RBV therapy (10,11). In the two trials patients with previous null-response and cirrhosis however, were excluded because of the overall low probability of treatment response. At CROI interim results from week 16 had been presented, here at AASLD 48 week results were reported for the first time (14,15). In the telaprevir ANRS HC26 study overall 69 patients who received at least one dosage were included (10). Background HIV therapy contained ATV, ATV/r, EFV, RAL, TDF, FTC, or 3TC. The study design is depicted below (Figure 4):
Figure 4: Study design of the ANRS HC26 TelapreVIH Study.

AASLD5

Patients started with a 4 week lead-in of PEG-IFN/RBV. This approach, which is outside the labelling of telaprevir, was chosen to be able to compare the results to the study design wise similar boceprevir study and because data from telaprevir studies in HCV mono-infection in treatment experienced patients had potentially promised some benefit for this approach. After week 4 telaprevir was added for 12 weeks. Patients who achieved a complete rapid virological response at week 8 (RVR8) defined as HCV-RNA <15 IU/mL received 32 weeks of PEG-IFN/RBV after stopping telaprevir at week 16 after 12 weeks of triple therapy (full treatment: 48 weeks). Whereas patients who only obtained a partial RVR8 (15 IU/mL < HCV-RNA < 1000 IU/mL) received an additional 56 weeks of PEG-IFN/RBV (full treatment: 72 weeks). Telaprevir was administered as 750 mg q8h (1125 mg q8h with Efavirenz) and Peg-IFN α-2a as 180 μg sc / week. Ribavirin was dosed as 1000 mg / day (≤75 kg) and 1200 mg /day (>75 kg). EPO, G-CSF, and TPO-R agonists were allowed within the study. Futility rules for telaprevir were HCV-RNA > 1000 IU/mL at week 8 or week 12 or virological breakthrough at any time. For study inclusion patients needed to have CD4 ≥ 200 cells/mm³ and ≥ 15%, as well as plasma HIV-RNA levels < 50 copies/mL. At baseline median CD4-count was 630 cells/mm³ (range 459-736) and HIV-RNA was below 50 copies in 99% of patients. Interestingly, 11 (18%) patients had F3 fibrosis and 16 (23%) F4 fibrosis upon inclusion to the study, allowing studying safety and efficacy of telaprevir based triple therapy in this more difficult-to-treat patient population. 39% of patients were previous relapsers to dual therapy, 9% had previous viral breakthrough, 22% were partial responders and 30% null-responders. The week 48 efficacy results in an ITT-analysis are presented below in Figure 5.:

Figure 5: Results: Telaprevir + PegIFN + RBV in HIV/HCV co-infected patients with previous virologic failure on IFN +RBV: virologic response at week 48 (ITT, n=69)

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UTND= target not detected

With 83% being HCV-RNA negative at week 48 in this patient population with 30% previous null-responders and 40% F3/F4 fibrosis this study showed surprising high efficacy results at EOT for most patients. Most interestingly efficacy remained high throughout all sub analyses and was independent of prior fibrosis stage, previous HCV treatment response or background ART (see Figure 6). With regard to safety 20% of patients were reported to develop grade 4 adverse events. Most common grade 4 adverse events were haematological. 65% of patients received EPO, 23% blood transfusions. So although side effects were manageable complications under triple therapy with telaprevir in this more challenging patient population were frequent.

Figure 6: Virological response by baseline characteristic

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The second ANRS study looked at the efficacy and safety of a boceprevir containing triple therapy again in 64 previous IFN/RBV non-responders (11,15). The study design is depicted below in Figure 7:

Figure 7: Study design: Multi-center single arm open label Phase 2 Trial

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Following a lead-in with dual therapy boceprevir was added at week 4. Complex futility rules were in place during the study warranting discontinuation of boceprevir in all patients with a HCV viral load above 1000 IU/ml at week 8 as well as in week 12. All HCV drugs were discontinued if HCV viral load was >1000 IU/ml at week 16 or still detectable at week 28 and in case of virological breakthrough. Duration of therapy was dependent on initial response as shown above. Patients who achieved a rapid virological response and had an HCV-RNA <15 IU/ml at week 8 were treated for 48 weeks, patients with slower decline in HCV RNA were treated for 72 weeks. Patients recruited for the trial had to be on stable ART for at least 3 months, with at least three molecules among ATV (rtv boosted or not), RAL, TDF, ABC, FTC, or 3TC. Again only previous non-responders to dual therapy with HCV genotype 1 infection were included. Null-responders with cirrhosis were excluded from this trial. Overall, 17% of patients at baseline had F4 fibrosis, 33% were previous null-responders. Only patients who received ≥ 1 dose of treatment Interim week were included into this first interim week 16 efficacy analyses. The corresponding response rate (Patients (%) with HCV-RNA < 15UI/ mLs ) at 48 weeks are depicted below (Figure 8):

Figure 8: HCV- Virological response at week 48: Patients (%) with HCV-RNA < 15UI/ mL

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Overall 56% achieved undetectability at week 48. Response rates at week 48 were best for previous relapsers (with 90% < 15 IU/ml) versus patients with previous partial response (61% < 15 IU/ml) and null-responders (33% < 15 IU/ml), respectively. Notably, none of the previous breakthroughs responded raising the question whether this group of patients may be more difficult to treat (patient numbers are very small though). No difference in response was seen according to fibrosis at baseline. Figure 9 summarizes the results of the corresponding subanalyses.

Figure 9: Virological response according to baseline characteristics

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In summary, these first two studies in previous non-responders to dual therapy with PEG-IFN/RBV and a considerable proportion of patients with more advanced fibrosis stages demonstrates very high on treatment response rates in this more challenging to treat patient population. Overall, it appears as if boceprevir works less well in the context of previous non-responders or breakthroughs. This should remind us not to postpone HCV therapy for all in hope of easier and less toxic HCV treatment regimens in the future but also to at least consider the improved treatment options we already have in our hands which preferably should be used in those patients where risk for development of HCC or progression to cirrhosis and eventually hepatic decompensation is a real threat. Cure rates are particularly promising in treatment-naïve and relapser patients. Safety appears manageable but haematological adverse events are common.

More data on HCV combination therapy with telaprevir was reported from the INSIGHT trial. This study evaluated the efficacy and safety of response guided telaprevir/PEG-IFN/RBV therapy in HCV treatment naïve and experienced patients (16). In the study patients who were on stable, suppressive HIV antiretroviral therapy (ARV) including atazanavir (ATZ)/ritonavir (r), efavirenz (EFV), darunavir (DRV)/r, raltegravir (RAL), etravirine (ETR) or rilpivirine received TVR 750mg q8h (1125mg q8h if on EFV) plus PEG-IFN (180μg once-weekly) and ribavirin (800mg/day) for 12 weeks, followed by an additional 12 weeks (HCV treatment-naïve and relapse patients with extended rapid viral response [eRVR]) or 36 weeks (all others) of PEG-IFN/RBV alone. Interim 12-week results in 162 patients were reported. At baseline 30% of patients had bridging fibrosis or cirrhosis. 64 patients were treatment-naïve, 29 prior relapsers, 18 prior partial responders, and 51 prior non-responders. The proportion of patients with undetectable HCV-RNA at week 12 was high with 72%, with almost half of the patients (49%) achieving eRVR. Again promising early response rates were obtained, but due to the short follow-up further conclusions cannot be drawn at this time-point.

Studies with new DAAs in HIV/HCV coinfection

The STARTVerso4 (SV4) study was set up to assess efficacy and safety of the second wave HCV protease inhibitor faldaprevir (FDV) plus PEG-IFN/RBV and evaluate a 24-week, shortened treatment duration in HIV patients coinfected with chronic HCV genotype (GT) 1 (12). SV4 is an open-label, sponsor-blinded study in HCV/HIV coinfected patients who were HCV treatment-naïve (TN) or relapsed after previous HCV therapy. In arm A patients received FDV 120 mg QD and PEG-IFN/RBV for 24 weeks; in arm B: patients received FDV 240 mg QD plus PEG-IFN/RBV for 12 weeks and were randomized at week12 to receive a further 12 weeks of FDV/PEG-IFN/RBV or PEG-IFN/RBV alone (see Figure 10). At week 24 all patients who achieved early treatment success (ETS, HCV RNA <25 IU/mL detected or undetected at W4 and undetected at W8) were re-randomized 1:1 to stop treatment at week 24 or continue PEG-IFN/RBV up to W48. Patients without ETS received PEG-IFN/RBV through 48 weeks. In order to correct for drug-drug interactions patients on HIV protease-based antiretroviral therapy (ART) or efavirenz were allocated to receive FDV 120 mg or 240 mg QD, respectively; those receiving other allowed ART (raltegravir or maraviroc) or no ART were randomized to either FDV dose. The primary endpoint was SVR12. In the AASLD interim analysis SVR4 rates were presented.

Figure 10: Study design of the STARTVerso4 Phase III open-label, sponsor-blinded study in treatment-naïve and relapser patients with chronic HCV GT-1 and HIV infection

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The red dot resembles patients with HCV RNA below LLoQ, at Week 4, and HCV RNA below LLoQ target not detected at Week 8 (=ETS). In total, 308 patients were treated (mean age 47 years, 81% male, 83% Caucasian, 14% Black/African American, 29% ≥F3 liver fibrosis, 79% GT1a, 66% IL28B non-CC rs12979860). ART was used by 96% of patients. A successful SVR 4 response was achieved by 220/308 (74%) of the total patient population being even higher in previous relapsers with 60/69 (87%) (Please see Figure xx). Most common AEs were nausea (37%), fatigue (34%), and diarrhea (27%). Study medication was discontinued due to AEs in 7% of patients in Arm A and 8% in Arm B. Serious AEs occurred in 14% and 8% of patients, respectively. Hemoglobin ≤8.5 g/dL occurred in 6% of patients.

Figure 11: SVR rates in Startvers4

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Overall, virological breakthrough was observed in 8% of patients, relapse occurred in 4% of patients. No difference in SVR4 rate was seen between GT 1a and 1b. Also no difference in outcome was observed by baseline cirrhosis (see Figure 12) or ART. Even more importantly, 80% of patients achieved early treatment success which qualified them for being randomized to shorter (24 weeks) or longer treatment duration (48 weeks). Interestingly, no difference in outcome was obtained for ETS patients irrespective of treatment duration or faldaprevir dose. Overall, this once daily second wave HCV protease inhibitors promises good efficacy for most patients with short treatment duration following response guided therapy. This is the first HCV PI which can be administered concomitantly with boosted darunavir.

Figure 12: SVR4 rate by baseline cirrhosis

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Clearly with regard to coinfection studies the results from the first interferon-free trial in coinfection were the most exciting study results presented at AASLD. The so called PHOTON 1 study evaluated the safety and efficacy of the oral HCV NS5B inhibitor sofosbuvir (SOF) with ribavirin (RBV) in HIV -seropositive patients coinfected with HCV genotypes 1, 2 or 3. Patients included into the study received SOF 400 mg QD and RBV 1000-1200mg/day; GT 1 patients received 24 weeks and GT 2/3 patients received 12 weeks of treatment. The study design is shown below in Figure 13. At the AASLD meeting only results from the treatment-naïve arms were reported.

Figure 13: Study design of the PHOTON-1 trial.

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Overall, 4% of the treatment -naïve GT1 patients (n=114), 4% of the GT2 patients (n=26) and 14% of the GT 3 patients (n=42), respectively had cirrhosis at baseline. 93-98% of patients were on ART and had stable HIV disease. Among patients with GT1, GT2 and GT3, SVR12 was achieved in 76% (87/114), 88% (23/26) and 67% (28/42), respectively (see Figure 14). Among the 27 GT 1 patients without SVR12, viral relapse was confirmed in 25 patients. In contrast no relapse occurred in the GT 2 patients but in 12 GT 3 patients without SVR12. Therefore it appears that treatment duration of 12 weeks is sufficient for GT2 treatment whereas for GT3 potentially longer treatment durations are required to prevent relapse (currently being investigated in PHOTON-2). For GT1 the majority of patients respond well to an interferon-free regimen of sofosbuvir and ribavirin but the high relapse rate suggests that there exists a subset of patients which will require DAA combination therapy. Overall, these results demonstrate that interferon-free treatment strategies are a very close reality for the majority of patients. As response rates are virtually superimposable to findings in monoinfected patients these findings also underline that probably HIV patients no longer should be treated as an independent patient population (other than for their potential for drug-drug interactions between HCV drugs and antiretroviral therapy) but on average can be treated like HCV mono-infected subjects. Figure 14: On-treatment and Sustained Virologic Response.

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Treatment discontinuations due to adverse events (AEs) were uncommon (3-4%) in the PHOTON trial and grade 3/4 AEs were reported in only 13% of the treatment-naïve GT1patients and 10% in the treatment-naïve GT2/3 patients. Most adverse events were typical side effects under ribavirin based therapy (see table 2).

Table 2: Safety findings from the PHOTON-1 trial

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Patients pre- and post-liver transplantation

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New wave of hepatitis C drugs hits US shore

3 December 2013 Phillip Broadwith

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The variability of hepatitis C viruses means there is room for several players with new drugs © Shutterstock

Johnson & Johnson’s hepatitis C drug Olysio (simeprevir) has been approved by the US Food and Drug Administration (FDA). While it has some advantages over currently available therapies, rivals from a new class that promise easier dosing and fewer side effects are advancing rapidly.

Olysio’s big selling point is that it can be taken once daily instead of three times as required for the current class-leaders, Vertex’s Incivek (telaprevir) and Merck & Co’s Victrelis (boceprevir). However, like Incivek and Victrelis, it has to be administered in combination with ribavirin and a weekly injection of interferon, which leads to unpleasant flu-like side effects.

Several companies are close to releasing all-oral combination drugs, which get rid of the interferon requirement. However, because the six different genotypes of the hepatitis C virus (HCV) don’t all respond equally to the different treatments, there is room for several drugs to carve out their own niches.

Approaching the final fence

Gilead’s Sovaldi (sofosbuvir) has been recommended for approval by both the European Committee for Medicinal Products for Human use and an FDA advisory panel, and just needs final approval from the European Commission and FDA. For some genotypes of HCV it is effective without interferon, for others it can be used with interferon, and clears the virus much more quickly than currently available drugs, reducing the side effect impact of the interferon significantly.

However, even if Sovaldi does make it as the first approved all-oral HCV treatment, it is not going to be plain sailing for Gilead.  The Initiative for Medicines, Access & Knowledge (I-MAK), an activist US lawyer group, has filed an opposition against Gilead’s patent in India. ‘India’s patent law doesn’t give monopolies for old science or for compounds that are already in the public domain,’ said Tahir Amin, director of I-MAK. ‘We believe this patent on sofosbuvir does not deserve to be granted in India and have the legal grounds to prove it.’ If the challenge is successful, it could allow Indian generics companies to manufacture and distribute cheap versions of the drug in india and other areas not covered by Gilead’s patents.

Big in Japan

Bristol-Myers Squibb (BMS) is aiming at the Japanese market, having filed for approval for its all-oral combination of daclatasvir and asunaprevir at the beginning of November. Neither ribavirin nor interferon is required with BMS’s combination, and it is effective against the HCV genotype most common in Japan, which often responds poorly to current treatments. Meanwhile, Merck & Co and Abbvie each have promising combinations of their own in late stage clinical trials. Abbvie has said it is aiming for regulatory submissions in the second quarter of 2014.

Roche is taking a similar tack for danoprevir, its interferon and ribavirin combination treatment. The company has signed a deal with Chinese firm Ascletis, which will complete the clinical development of the drug (currently in Phase II trials), then manufacture and distribute it for the Chinese market.

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