DO YOU KNOW A HERO? I DO!

DO YOU KNOW A HERO? I DO!
By Kathie Beach
In 1988, my husband Kurt, a Smithfield Police Officer, responded to an emergency call and tried to save a child's life who had been born with spina bifida and had a trachometry in her throat to be able to breathe. On this day, the child was not breathing and her heart had stopped. Kurt proceeded mouth to trach breaths and CPR on her having to suck the blood and mucous out of the airwaves to try to give her oxygen. It was to no avail, the child, sadly died. The mother of that precious child knew Kurt did everything within his power to save her. She considers Kurt a hero. So do I.
In 1988 the police department was not trained on blood pathogens and Hepatitis C had not even been classified yet, being called Non A and Non B Hepatitis. Kurt's attempt to save a life put his life in jeopardy. Later, he found out the terrible news that he had contracted this disease when he came in contact with the child's infected blood due to multiple blood transfusions her condition had demanded.
All these years God has kept His hand on Kurt. Although he was diagnosed with Hepatitis C and aggressive chronic liver disease, he was able to work and go about his life. He worked hard and gave tirelessly of whatever was required of him. He endured countless tests, procedures and experimental therapies to try to rid his body of the disease. The doctors were amazed by his stamina, his faith and his encouraging ways. He bounced back again and again and I suppose we always thought he would. Then in May of this year he ended up at Obici hospital for a five day stay. From there he went to MCV where his team of doctors did extensive tests and evaluations. Another stay at Obici and another round at MCV and then finally this week we are told by his team of doctors that Kurt needs a new liver and we need to prepare him for a live donor as a wait for a DD (deceased donor) is in the 100,000s. They did not mince words that Kurt could die waiting for a liver donor.
Kurt needs a living donor liver transplant.
This is a procedure that involves the removal of the recipient's (Kurt) native liver and replacing it with a potion of the living donor's liver. Both Kurt's and the donor's livers will regenerate to normal functional volume within weeks. AMAZING!
Kurt has a wonderful team of doctors who have monitored him over the years and when they convened they said he is a perfect candidate for this operation. The doctor went so far as to say 'Kurt, you will feel like a new man. Able to work, play and live and you will feel better than you have in years.'
My hero needs a hero, he needs a living donor.
(Just to clarify...this was an email petition sent out to friends and family in 2008. Kurt received a living liver donor in 2009 after 3 failed deceased donor attempts.)

Treatment of chronic hepatitis C genotype 1 with triple therapy comprising telaprevir or boceprevir

Review article | Published 24 February 2012, doi:10.4414/smw.2012.13516
Cite this as: Swiss Med Wkly. 2012;142:w13516

Swiss Association for the Study of the Liver¹

¹ Current Council Members of the Swiss Association for the Study of the Liver are listed in www.sasl.ch.

Abbreviations: AASLD, American Association for the Study of Liver Diseases; BOC, boceprevir; CHC, chronic hepatitis C; EASL, European Association for the Study of the Liver; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PEG-IFN-α, pegylated interferon-α; RBV, ribavirin; SVR, sustained virological response; SASL, Swiss Association for the Study of the Liver; TPV, telaprevir.

Summary

Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. Two first-generation protease inhibitors, telaprevir and boceprevir, have recently been approved for the treatment of chronic hepatitis C genotype 1. Triple therapy comprising pegylated interferon-α, ribavirin and telaprevir or boceprevir increases sustained virological response rates to ~70% and allows to shorten treatment duration in ~½ of treatment-naïve patients with chronic hepatitis C genotype 1. Sustained virological response rates in treatment-experienced patients depend on the response to previous treatment, ranging from >80% in previous relapsers to ~30% in previous null responders. These advances come at the expense of new adverse effects and increased cost. In addition, treatment of chronic hepatitis C will become more complex. In these times of changing medical practice, the present expert opinion statement by the Swiss Association for the Study of the Liver shall provide guidance on the treatment of chronic hepatitis C with triple therapy comprising telaprevir or boceprevir.

Key words: boceprevir; chronic hepatitis C; HCV; hepatitis C virus; interferon; protease inhibitor; ribavirin; telaprevir

Introduction

Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC) [1–3]. An estimated 120–200 million individuals worldwide and about 1% of the general population in Switzerland are chronically infected with HCV. About 50% of the chronic HCV infections in Switzerland are due to genotype 1 [4]. While the incidence of acute hepatitis C has declined significantly since the introduction of anti-HCV screening of blood and blood products in 1990, the number of patients presenting with decompensated cirrhosis and HCC is expected to increase further, attaining a peak around 2020 [1, 5]. More than 50% of the individuals at risk may currently be unaware of their infection. Strategies to increase testing and detection rates are currently being explored (e.g., screening of populations at risk vs. birth cohort screening) [6, 7].

Fifty to 80% of acutely infected individuals develop persistent infection. Of these, 2–20% will develop liver cirrhosis within the first 20 years, and accumulating evidence suggests that disease progression may increase in a nonlinear fashion thereafter [8]. Once cirrhosis is established, the rate of HCC development is 1–6% per year. Factors associated with more frequent and rapid progression to cirrhosis are, among others, higher age at the time of infection, male sex, alcohol consumption, coinfections with the human immunodeficiency virus (HIV) or hepatitis B virus (HBV), nonalcoholic fatty liver disease and smoking. Comprehensive management of chronic hepatitis C (CHC) takes these factors into consideration and aims at improving the ones that can be modified (alcohol abstinence; weight loss, regular physical activity and other measures to control the metabolic syndrome; vaccination against HBV [and hepatitis A virus]; smoking cessation including cannabis) [9].

While non-invasive methods for fibrosis assessment are actively being pursued [10], liver biopsy remains the reference for grading and staging of CHC. The Metavir and Ishak scoring systems are most often applied. Fibrosis stages are classified from 0 (absence of fibrosis) to 4 (cirrhosis) in the Metavir system [11], and from 0 to 6 in the Ishak system [12].

The decision to treat CHC is based on the analysis of numerous variables and should take into account the specific situation of each patient. Treatment is clearly recommended for patients with Metavir fibrosis stage ≥2 who do not have any contraindications. For other patients, decisions will have to be made on an individual basis. Additional factors that come into consideration are, among others, the (biological) age and general condition of the patient, the patient’s personal and professional plans, the duration of HCV infection, the risk of developing cirrhosis, the likelihood of response to therapy, and comorbidity.

For the last 10 years, standard therapy of CHC consisted of pegylated interferon-α (PEG-IFN-α) combined with ribavirin (RBV) for (16-)24-48(-72) weeks, yielding sustained virological response (SVR) rates of 40–50% in patients infected with HCV genotype 1 and ~80% in patients infected with genotypes 2 and 3. Definitions of virological response patterns are provided in table 1.

Polymorphisms near the IL28B gene have recently been identified as strong predictors of the outcome of IFN-α-based antiviral therapy (reviewed in [13, 14]). A number of laboratories offer IL28B genetic testing, but its role in clinical practice and decision making, if any, remains to be defined.

A first generation of directly acting antivirals, the NS3-4A protease inhibitors telaprevir (TPV; Incivo^®) and boceprevir (BOC; Victrelis^®), has recently been approved for the treatment of CHC genotype 1. TPV and BOC have to be combined with PEG-IFN-α and RBV in order to avoid the rapid selection of HCV strains resistant to antiviral therapy [15, 16]. Triple therapy comprising TPV or BOC increases SVR rates to ~70% in treatment-naïve patients with CHC genotype 1 [17–19]. In treatment-experienced patients, SVR rates depend on the virological response to previous therapy with PEG-IFN-α and RBV, ranging from >80% in patients with previous relapse to ~50% in patients with previous partial response and ~30% in patients with previous null response [20–22]. Treatment schedules comprising TPV or BOC have more side effects than PEG-IFN-α and RBV, and should be managed carefully.

A significant increase in the number of patients with CHC to be treated is expected for 2012, with triple therapy regimens that are more complex, as discussed below [23]. These expected developments represent a significant challenge and will stretch current resources.

The present Swiss Association for the Study of the Liver (SASL) expert opinion statement is not intended as guideline but shall provide some guidance on the management of CHC genotype 1 and the use of TPV and BOC. It is based on the results of recently published phase III clinical trials performed in treatment-naïve and treatment-experienced patients (ADVANCE [17], ILLUMINATE [19] and REALIZE [20] for TPV as well as SPRINT-2 [18], RESPOND-2 [21] and PROVIDE [22] for BOC), and take into account the recently updated American Association for the Study of Liver Diseases (AASLD) Practice Guidelines [3] as well as the labels approved by the US Food and Drug Administration, the European Medicinal Agency, and Swissmedic. Current European Association for the Study of the Liver (EASL) Clinical Practice Guidelines [2] are expected to be updated shortly. In addition, different national guidelines are in preparation. Therefore, as recommendations are emerging and as real-life data and practical experience on the use of TPV and BOC are still limited, it is strongly recommended to initiate and pursue triple therapy comprising TPV or BOC only in close collaboration with an expert centre.

Click to enlarge

Practical use of telaprevir and boceprevir

TPV is available in the form of 375-mg film-coated tablets and has to be taken at a dose of 750 mg every 8 hours (i.e., two tablets every 8 hours), with a meal or a snack containing ~20 g of fat to increase bioavailability. BOC is available in the form of 200-mg capsules and has to be taken at a dose of 800 mg every 8 hours (i.e., 4 capsules every 8 hours), with a meal or a snack. Dosing every 8 ± 1 hour rather than 3 times per day is important to maintain inhibitory drug serum concentrations and to avoid antiviral resistance development. TPV and BOC should never be used alone, and doses should never be reduced. When used alone, these drugs will not be effective and will cause emergence of HCV strains with resistance to antiviral therapy that could be difficult to treat subsequently. RBV can be taken with the first dose of TPV or BOC in the morning and with the last dose of TPV or BOC in the evening.

TPV and BOC are only approved for use in patients with HCV genotype 1 infection. The development of antiviral resistance is more frequent in subtype 1a than 1b but this should not influence therapeutic decision making.

Both TPV and BOC have a strong potential for drug-drug interactions, as they affect the metabolism of other drugs metabolised through cytochrome P450 3A4 (CYP3A4) and other pathways [24]. See package inserts, continuously updated online databases (e.g., http://www.hep-druginteractions.org, Epocrates, Medscape) and Leise et al. [25] for known drug-drug interactions and contraindicated drugs. Commonly used drugs that are contraindicated in combination with TPV or BOC include, among others, atorvastatin, lovastatin, simvastatin, sildenafil, alfuzosin, carbamazepin, phenytoin, oral midazolam, and St. John’s wort. Among the drugs commonly used to manage adverse effects of therapy, paracetamol and metoclopramide (but not domperidone) are allowed. TPV and BOC may decrease citalopram levels and efficacy.

Main adverse effects of TPV include anemia, nausea and diarrhea, skin rashes and pruritus as well as anorectal disorders. Rash should be managed in collaboration with an experienced dermatologist and should follow recommendations that have recently been summarised [26]. TPV has to be discontinued if rash progresses and becomes severe. Rare cases of DRESS (drug-related eosinophilia with systemic symptoms) and Stevens Johnson syndrome/toxic epidermal necrolysis have been observed. If either one is suspected, all drugs have to be stopped immediately, followed by emergency dermatological consultation.

Main adverse effects of BOC include anemia, with a significant number of patients requiring concomitant erythropoietin treatment in phase II and III clinical trials, as well as dysgeusia.

Anemia can develop rapidly and become very pronounced with both TPV and BOC, especially in patients with cirrhosis. Therefore, close monitoring is recommended. Anemia should be managed by timely RBV dose reduction and, if needed, blood transfusions and/or erythropoetin.

Data on the safety and efficacy of TPV and BOC in patients with HIV coinfection are emerging. TPV and BOC should be used only in close collaboration with an expert in these patients.

There is no data in liver transplant recipients, hemodialysis patients and children, and the use of TPV and BOC in these situations is currently proscribed.

In registration trials, TPV was used with PEG-IFN-α2a 180 µg per week plus RBV 1000–1200 mg per day and BOC was used with PEG-IFN-α2b 1.5 µg/kg per week plus RBV 600–1400 mg per day. However, both forms of PEG-IFN-α may be used with RBV and either TPV or BOC.

PEG-IFN-α is contraindicated in decompensated cirrhosis.

Strict contraception must be followed during and for 6 months after the end of triple therapy because of the potential teratogenicity of RBV.

Who should be treated with triple therapy comprising TPV or BOC?

Triple therapy will represent a new standard for most treatment-naïve patients with CHC genotype 1 as well as treatment-experienced patients with a relapse or partial response to previous therapy with PEG-IFN-α and RBV (table 2).

Treatment of CHC is expected to change significantly within the next few years, with the arrival of better tolerated and even more efficacious new drugs as well as the advent of IFN-free/sparing regimens [27–30]. These developments shall significantly improve the outlook for our patients. Therefore, deferring treatment may be considered in patients who’s treatment can be safely postponed.

Treatment-naïve patients with favourable baseline predictors (HCV RNA <4 x 10⁵ IU/ml, absence of advanced fibrosis or cirrhosis) who achieve a rapid virological response (RVR; see table 1) have excellent chances to achieve SVR with 24 weeks of therapy with PEG-IFN-α and RBV alone [31]. Therefore, a 4-week lead-in with PEG-IFN-α and RBV may be considered in patients with the above-mentioned favourable baseline predictors and treatment continued without adding TPV or BOC for a total of 24 weeks in those who achieve RVR.

Lead-in with PEG-IFN-α and RBV may also be considered if there are doubts concerning the tolerance or adherence to PEG-IFN-α and RBV backbone therapy.

There is currently only limited data on the use of BOC in patients with previous null response. In general, retreatment of previous null responders has to be considered carefully, as SVR rates remain limited, especially in patients with cirrhosis. Inclusion of such patients into clinical trials involving quadruple therapy or IFN-sparing regimens may be considered. Lead-in with PEG-IFN-α and RBV may be considered in previous null responders, especially in cirrhotics, with the addition of TPV or BOC only in case of ≥1 log decline of HCV RNA at week 4. Subanalysis of the REALIZE trial revealed that 54% of the patients with ≥1 log decline after 4 weeks of lead-in with PEG-IFN-α and RBV achieved SVR with triple therapy comprising TPV, compared to only 15% of those with a decline of HCV RNA <1 log [32].

Careful monitoring and stopping rules, as detailed below, shall reduce the risk of selecting HCV strains resistant to antiviral therapy. While long-term consequences of the selection of such strains are presently unknown, antiviral resistance is likely to affect future treatment options [15, 16].

Figure 1 Telaprevir-based triple therapy. (A) Treatment-naïve patients with CHC genotype 1 and treatment-experienced patients with previous relapse. (B) Treatment-experienced patients with CHC genotype 1 and previous partial or null response. eRVR, extended rapid virological response (see table 1 for definitions of virological response patterns); P, pegylated interferon-α; R, ribavirin; T, telaprevir; wks, weeks.

Figure 2 Boceprevir-based triple therapy. (A) Treatment-naïve patients with CHC of genotype 1 without cirrhosis. (B) Treatment-experienced patients with CHC genotype 1 and previous relapse or partial response without cirrhosis. (C) All cirrhotic patients and prior null responders. B, boceprevir; BPR = B + P + R; P, pegylated interferon-α; R, ribavirin; RVR8, rapid virological response at week 8 (see table 1 for definitions of virological response patterns); wks, weeks.

Click to enlarge

Specific treatment algorithms

Telaprevir-based triple therapy

• Treatment-naïve patients and previous relapsers with CHC genotype 1 (fig. 1A)

Non-cirrhotic patients who achieve eRVR

12 weeks TPV + PEG-IFN-α + RBV

+ 12 weeks PEG-IFN-α + RBV

Non-cirrhotic patients who do not achieve eRVR and all cirrhotic patients

12 weeks TPV + PEG-IFN-α + RBV

+ 36 weeks PEG-IFN-α + RBV

• Previous partial and null responders with CHC genotype 1 (fig. 1B)

• 12 weeks TPV + PEG-IFN-α + RBV
• + 36 weeks PEG-IFN-α + RBV

Lead-in with PEG-IFN-α and RBV may be considered in previous null responders, especially in cirrhotics, with the addition of TPV only in case of ≥1 log decline of HCV RNA at week 4.

Stopping rules:

• Stop all therapy if HCV RNA >1000 IU/ml at either week 4 or 12 of triple therapy.
• Stop all therapy if HCV RNA detectable at wk 24.
• Stop all therapy if previously negative HCV RNA becomes confirmed positive again under treatment.

Boceprevir-based triple therapy

• Treatment-naïve patients with CHC genotype 1 (fig. 2A and 2C)

Non-cirrhotic patients who achieve RVR8

4 weeks PEG-IFN-α + RBV lead-in

+ 24 weeks BOC + PEG-IFN-α + RBV

Non-cirrhotic patients who do not achieve RVR8

4 weeks PEG-IFN-α + RBV lead-in

+ 24 weeks BOC + PEG-IFN-α + RBV

+ 20 weeks PEG-IFN-α + RBV

Cirrhotic patients

4 weeks PEG-IFN-α + RBV lead-in

+ 44 weeks BOC + PEG-IFN-α + RBV

• Previous relapsers or partial responders with CHC genotype 1* (fig. 2B and 2C)

Non-cirrhotic patients who achieve RVR8

4 weeks PEG-IFN-α + RBV lead-in

+ 32 weeks BOC + PEG-IFN-α + RBV

Non-cirrhotic patients who do not achieve RVR8

4 weeks PEG-IFN-α + RBV lead-in

+ 32 weeks BOC + PEG-IFN-α + RBV

+ 12 weeks PEG-IFN-α + RBV*

Cirrhotic patients

4 weeks PEG-IFN-α + RBV lead-in

+ 44 weeks BOC + PEG-IFN-α + RBV

* For patients with prior null response, 4 weeks of lead-in with PEG-IFN-α + RBV, followed by 44 weeks of triple therapy with BOC + PEG-IFN-α + RBV is recommended.

Stopping rules:

• Consider stopping therapy in patients with cirrhosis and <1 log drop of HCV RNA after lead-in (chances of achieving SVR being 13–25% only [33]).
• Stop all therapy if HCV RNA ≥100 IU/ml at week 12.
• Stop all therapy if HCV RNA detectable at week 24.
• Stop all therapy if previously negative HCV RNA becomes confirmed positive again under treatment.

Conclusions

Key points are summarised in table 3.

Funding / potential competing interests: SASL or the SASL Council Members have not received any financial support in relation with the writing of this article. DM and BM as corresponding authors assume responsibility for the integrity of this article. Both have received research support from MSD and Roche and have acted as advisors to Janssen, MSD and Roche.

Correspondence: Professor Darius Moradpour, MD, Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Rue du Bugnon 44, CH-1011 Lausanne, Switzerland, darius.moradpour[at]chuv.ch
or
Professor Beat Müllhaupt, MD, Division of Gastroenterology and Hepatology, University Hospital Zürich, Rämistrasse 100, CH-8091 Zürich, Switzerland, beat.muellhaupt[at]usz.ch

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13 Rauch A, Rohrbach J, Bochud PY. The recent breakthroughs in the understanding of host genomics in hepatitis C. Eur J Clin Invest. 2010;40:950–9.

14 Lange CM, Zeuzem S. IL28B single nucleotide polymorphisms in the treatment of hepatitis C. J Hepatol. 2011;55:692–701.

15 Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology. 2010;138:447–62.

16 Halfon P, Locarnini S. Hepatitis C virus resistance to protease inhibitors. J Hepatol. 2011;55:192–206.

17 Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–16.

18 Poordad F, McCone J, Jr., Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195–206.

19 Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365:1014–24.

20 Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417–28.

21 Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207–17.

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27 Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2010;376:1476–5.

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29 Gane EJ, Stedman CA, Hyland RH, et al. Once daily PSI-7977 plus RBV: pegylated interferon-alfa not required for complete rapid viral response in treatment-naïve patients with HCV gt 2 or gt 3. Hepatology. 2011;54(Suppl 1):377A.

30 Lok ASF, Gardiner D, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med. 2012;366:216–24.

31 Di Martino V, Richou C, Cervoni JP, et al. Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: Meta-analyses of randomized, controlled trials and implications for the future. Hepatology. 2011;54:789–800.

32 Foster GR, Zeuzem S, Andreone P, et al. Subanalyses of the telaprevir lead-in arm in the REALIZE study: response at week 4 is not a substitute for prior null response categorization. J Hepatol. 2011;54(Suppl 1):S3.

33 Bruno S, Vierling JM, Esteban R, et al. Boceprevir in addition to standard of care enhanced SVR in hepatitis C virus genotype 1 with advanced fibrosis/cirrhosis: subgroup analysis of SPRINT-2 and RESPOND-2 studies. J Hepatol. 2011;54(Suppl 1):S4.

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Medicyte and PRIMACYT Receive Grant to Develop Human Liver Cells for Cell-based Therapies

Monday, 05 March 2012 11:15 (UTC + 1)

Heidelberg and Schwerin, Germany, March 5, 2012 / B3C newswire / - Medicyte, specializing in the generation of human primary cells based on the upcyte^® technology, and PRIMACYT, specializing in long-term culturing of primary human hepatocytes, have received a 300k Euro grant from the BMBF to develop culturing methods of human hepatocytes for use in cell-based therapies.

Cell-based therapies and the development of transplantable bioartificial livers to treat severe liver diseases still fail due to the limited availability of appropriate cells in large numbers and clinical quality. These failures are often related to the complex and difficult culturing of liver cells.

Medicyte’s upcyte^® technology enables the expansion of human primary liver cells to large amounts and with consistent quality. Upcyte^® hepatocytes are functionally equivalent to human primary liver cells and therefore suitable for use in cell-based bioartificial liver systems. PRIMACYT’s main expertise lies in the serum-free, long-term culturing of primary human hepatocytes and the development of cell culture media. Both companies now combine their knowledge to develop modified liver cells in large amounts for use in cell-based therapies.

Dr. Braspenning, Managing Director and CSO of Medicyte stated: “We are enthusiastic about working together with well-known German experts. I am sure that this collaboration will result in a vast pool of scientific data that support upcyte^® as enabling technology of great value.”

Dr. Runge, Managing Director of PRIMACYT added: “The application and development of improved in-vitro systems for the treatment of severe liver disease is a key area of focus of our research and we believe the partnership with Medicyte and the University of Tübingen creates an ideal opportunity for our two companies to improve bioartificial liver devices.”

The three-year project is supported by a team from the University of Tübingen lead by Prof. Andreas Nüssler, a well-known liver cell expert. The Federal Ministry of Education and Research (BMBF) is supporting the joint effort out of the grant program “KMU-innovativ”.

Background
Chronic liver disease is the fifth common cause of death in Europe. In Germany approximately 70.000 patients suffer from an inpatient treated severe liver disease e.g. fatty liver, cirrhosis or acute liver failure. These diseases can result in temporary to permanent liver failure. At present liver transplant is the only hope for patients with end stage liver diseases. The Number of patients waiting for a donor liver is many times higher than available organs.

About Medicyte
Medicyte is specialised in the controlled generation and standardisation of human primary cell products in virtually unlimited quantities and of highest quality for cell therapy and cell- based R&D. Medicytes proprietary technologies upcyte^® and vericyte^® enable to expand human hepatocytes from different donors and other cells in a standardized way, thereby making these cells for the first time commercially available in high numbers and consistent quality. Increasingly pharmaceutical companies consider using upcyte^® hepatocytes for in vitro ADMET testing.

About PRIMACYT
PRIMACYT Cell Culture Technology GmbH (www.primacyt.eu), located in the technology- and business park in Schwerin, is a GLP certified company that provides services in the area of in vitro technologies for pharmaceutical and biotech industry. Human and animal hepatocytes are offered as biosensoric assay systems for pharmacologic-toxicological analyses of drugs and for analysis of chemicals and environmental substances.
With HEPAC², the human hepatocyte cell culture system developed by PRIMACYT, clinical functional liver parameters in patients should be better predetermined than by animal studies.

Contacts

Medicyte GmbH
Stefan Holder
Im Neuenheimer Feld 581
69120 Heidelberg
Tel.: +49-6221-72925-30
bd@medicyte.com This e-mail address is being protected from spambots. You need JavaScript enabled to view it

PRIMACYT Cell Culture Technology Gmbh
Dieter Runge
Hagenower Str. 73
D-19061 Schwerin
Tel.: +49-385-3993-600
dieter.runge@primacyt.de

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Nuron Biotech Expands Portfolio With License of Therapeutic and Prophylactic Hepatitis Vaccine Candidates

PRESS RELEASE

March 5, 2012, 8:05 a.m. EST

EXTON, Pa., Mar 05, 2012 (BUSINESS WIRE) -- Nuron Biotech Inc. today announced it has acquired an exclusive license of technology and product rights relating to Chimigen(R) multi-antigen vaccines from Akshaya Bio Inc., of Edmonton, Alberta, Canada, for the hepatitis B virus (HBV). Nuron Biotech has also acquired an exclusive option to license prophylactic and therapeutic products for the hepatitis C virus (HCV). Currently, no therapeutic vaccine for HBV and no prophylactic vaccine for HCV exist on the market. Financial terms were not disclosed.

"These licenses and options fit incredibly well with Nuron Biotech's strategy of identifying and in-licensing life-saving and life extending product candidates in the areas of vaccines and biologics," said Shankar Musunuri, Ph.D., MBA, Chief Executive Officer of Nuron Biotech. "This chimeric vaccine platform (Chimigen(R) technology), which is used in generating both therapeutic and prophylactic vaccines, is advanced to the point where we can expect to transition our first candidate into a Phase 1 clinical trial in 2013."

"This unique technology provides Nuron Biotech with the capability to develop a highly efficient vaccine for the treatment and prevention of HBV and HCV by inducing both cellular (T cell) and humoral (B cell, antibody) immune responses to clear disease," said Robert G. Gish, M.D., Chief of Clinical Hepatology and Professor of Clinical Medicine, University of California, San Diego. Dr. Gish is also a member of the Scientific Advisory Board for Nuron Biotech. "HBV and HCV are life-altering and potentially fatal diseases, and this technology may offer a break-through for a new generation of novel therapies and preventative vaccines for patients around the world."

Currently, 380 million people worldwide are infected with chronic HBV, which is not curable by any known therapy. More than 170 million people are infected by HCV, which is one of the leading causes of chronic liver disease, cirrhosis, liver transplantation and hepatocellular carcinoma.

About Chimigen(R) Vaccine Technology

The bifunctional nature of the chimeric multi-antigen vaccine technology represents a unique and direct approach in the therapy of chronic infectious diseases by specifically targeting antigen-presenting cell receptors with the most effective combination of viral antigen(s) and novel antibody tail fragment, the chimeric antigen. This technology offers to induce a balanced cellular as well as humoral immune response to attack chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) and may offer protection from infection.

About Nuron Biotech

Nuron Biotech is developing novel biologics and vaccines for the prevention and treatment of chronic neurodegenerative and infectious diseases. Our team of industry veterans is advancing products to meet unmet medical needs in the areas of multiple sclerosis, Alzheimer's, hepatitis B and hepatitis C for patients across the globe. Our lead drug candidate, NU100 (interferon beta-1b), is a new chemical entity currently in Phase 3 for patients with multiple sclerosis. www.nuronbiotech.com .

SOURCE: Nuron Biotech Inc.

Source

QUAL research - stage 4 liver cancer

Find A Cure Panel is looking for people with Stage IV liver cancer or the caregivers of people with Stage IV liver cancer to participate in anonymous and qualitative research that will take an estimated 60 minutes of your time.

This is opinion based, experiential research and is NOT a drug trial.
Note that Stage IV is also known as “advance disease” or metastatic liver cancer.

If you participate, FACP will donate $100 to a non-profit of your choice.

If you are interested in participating, please email FACP at: info@findacurepanel.com

Boosting cell production could help treat liver disease

Public release date: 4-Mar-2012

Contact: Catriona Kelly
Catriona.Kelly@ed.ac.uk
44-131-651-4401
University of Edinburgh

Scientists have shed light on how the liver repairs itself with research that could help develop drugs to treat liver disease

Scientists have shed light on how the liver repairs itself with research that could help develop drugs to treat liver disease.

Researchers at the Medical Research Council (MRC) Centre for Regenerative Medicine at the University of Edinburgh have discovered how to enhance the production of key cells needed to repair damaged liver tissue.

The study, published in the journal Nature Medicine, could help heal livers affected by diseases such as cirrhosis or chronic hepatitis.

Scientists were able to unpick the process of how different cells in the liver are formed.

When the liver is damaged it produces too many bile duct cells and not enough cells called hepatocytes, which the liver needs to repair damaged tissue.

They found they could increase the number of hepatocyte cells – which detoxify the liver – by encouraging these cells to be produced instead of bile duct cells.

Understanding how liver cells are formed could help to develop drugs to encourage the production of hepatocytes to repair liver tissue. This could eventually ease the pressure on waiting lists for liver transplants.

Professor Stuart Forbes, Associate Director at the MRC Centre for Regenerative Medicine at the University of Edinburgh, who is a consultant hepatologist and was the academic leader of the study, said: "Liver disease is on the increase in the UK and is one of the top five killers. Increasing numbers of patients are in need of liver transplants, but the supply of donated organs is not keeping pace with the demand. If we can find ways to encourage the liver to heal itself then we could ease the pressure on waiting lists for liver transplants."

Liver disease is the fifth biggest killer in the UK. There are almost 500 people waiting for a liver transplant, compared to just over 300 five years ago.

The production of hepatocyte cells was increased by altering the expression of certain genes in early stage liver cells.

Dr Luke Boulter, of the University of Edinburgh's MRC Centre for Regenerative Medicine and first author on the paper, said: "This research helps us know how to increase numbers of cells that are needed for healthy liver function and could pave the way for finding drugs that help liver repair. Understanding the process in which cells in the liver are formed is key in looking at ways to repair damaged liver tissue."

Dr Rob Buckle, Head of Regenerative Medicine at the MRC, said: "Liver transplants have saved countless lives over the years, but demand will inevitably outstrip supply and in the long term we need to look beyond replacing damaged tissues to exploiting the regenerative potential of the human body. The MRC continues to invest heavily across the breadth of approaches that might deliver the promise of regenerative medicine, and this study opens up the possibility of applying our increasing knowledge of stem cell biology to stimulate the body's own dormant repair processes as a basis for future therapy."

###

The study was carried out in collaboration with the University's MRC Centre for Inflammation Research, the Beatson Institute for Cancer Research in Glasgow and the K.U. Leuven in Belgium.

Source

HIV Rate Among U.S. Injection Drug Users Falls: CDC

From Reuters Health Information

By Julie Steenhuysen

CHICAGO (Reuters) Mar 01 - HIV infections among injection drug users in the United States have fallen by half in the past decade, but HIV testing is also down and risky behaviors such as needle-sharing persist, raising worries that progress may be short-lived, U.S. health experts said on Thursday.

A study by researchers at the U.S. Centers for Disease Control and Prevention based on a 2009 survey of 10,000 people from 20 urban areas found that 9% of IV drug users were infected with HIV.

That compared with a rate of 18% in the 1990s.

"Despite the fact that we've seen declines in new HIV infections, a substantial number of IDUs (injection drug users) in major US cities are HIV-infected and their risk behavior remains fairly high," said Dr. Cyprian Wejnert, an epidemiologist at the CDC whose study appeared online today in the CDC's Morbidity and Mortality Weekly Report.

"We found 9% of IDUs were HIV-positive and nearly half of those were unaware of their infection," Dr. Wejnert said in a telephone interview.

HIV rates have been falling in the United States, but pockets of infection continue to persist, especially in high-risk groups such as young people and men who have sex with men.

The latest survey tested individuals for HIV and asked questions about their risk behaviors and use of HIV prevention services.

About one third of injection drug users said they shared syringes, most said they had unprotected sex in the past year and more than half said they had more than one sexual partner.

The study also found that rates of HIV testing in this at-risk population are falling.

"While CDC recommends that individuals are tested for HIV at least annually, only 49%, less than half of those interviewed, reported being tested in the last 12 months," Dr. Wejnert said.

That represents a significant drop from a survey done in 2005-2006, he said.

Dr. Amy Lansky, deputy director in the Division of HIV/AIDS Prevention at CDC, said the findings will be used as CDC focuses its prevention efforts on high risk populations.

"It's a really important part of understanding the leading edge of the epidemic," she said.

"What the data from this report shows is we really do need to continue our efforts to expand HIV testing and improve testing," she said, adding that the CDC also needs to focus its prevention efforts on reaching more drug users. Such efforts include offering new sterile syringes, condoms, and substance abuse treatment.

According to the CDC, 1.2 million Americans have HIV, and 1 in 5 U.S. adults with HIV do not know they are infected.

SOURCE: http://1.usa.gov/ygj7iP

MMWR 2012.

Source

Ultrasound Dx of HCV Effective in Liver Transplant

By Michael Smith, North American Correspondent, MedPage Today

Published: March 04, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

Action Points

• A non-invasive diagnostic method, ultrasound-based transient elastography, can accurately pick up fibrosis and cirrhosis in patients with recurrent hepatitis C after a liver transplant.
• Note that the major limitation of the technique lies in interpreting results that correspond to intermediate stages of fibrosis.

A non-invasive diagnostic method can accurately pick up fibrosis and cirrhosis in patients with recurrent hepatitis C after a liver transplant, researchers reported.

In a meta-analysis, ultrasound-based transient elastography had excellent diagnostic accuracy in detecting cirrhosis, according to Jayant Talwalkar, MD, and colleagues at the Mayo Clinic in Rochester, Minn.

The major limitation of the technique lies in interpreting results that correspond to intermediate stages of fibrosis, Talwalkar and colleagues reported in the March issue of Liver Transplantation.

"Further studies that confirm our results could highlight the importance of [transient elastography] as a diagnostic tool for liver transplant recipients" with recurrent hepatitis C, Talwalkar said in a statement.

Hepatitis recurrence is common among transplant patients and is "universal" among those who are positive for hepatitis C RNA at the time of transplant, the researchers noted.

And the development of fibrosis is faster in the transplanted organ than in the native liver, resulting in rapid cirrhosis and graft failure. The "only practical approach for improving ... clinical outcomes" is early recognition of patients with progressive recurrent disease, Talwalkar and colleagues argued.

The gold standard for diagnosing fibrosis and cirrhosis is the liver biopsy, they noted, since the degree of inflammation and the stage of fibrosis can be directly measured.

And the stage of fibrosis is needed for the timing of antiviral therapy if patients are eligible, they added.

But there is evidence that liver biopsies -- as well as having the risk associated with an invasive procedure -- may actually understage fibrosis up to 30% of the time, Talwalkar and colleagues said.

To see how well transient elastography performs, they conducted a systematic literature review that turned up six high-quality studies of the issue, five with data on fibrosis and five with data on cirrhosis.

The studies included 470 patients, with a range from 50 to 124. Diagnostic cut-offs for significant fibrosis ranged from 7.1 to 10.1 kilopascals; the values for cirrhosis ranged from 10.5 to 26.5.

Analysis showed that transient elastography had a sensitivity and specificity of 83%, respectively, for detecting fibrosis. The diagnostic odds ratio was 30.5.

For cirrhosis, the sensitivity was 98% and specificity was 84%. The diagnostic odds ratio was 130.

The analysis "yielded excellent summary estimates of the sensitivity and specificity for detecting cirrhosis and good estimates for detecting significant fibrosis," the researchers concluded.

They cautioned that, for both patient subgroups, the results demonstrated varying degrees of statistical heterogeneity, probably owing to such things as differences in study design and "subtle variations in the technical performances" of the two diagnostic methods between studies.

The researchers did not report external support for the study or any potential conflicts.

Primary source: Liver Transplantation
Source reference:
Adebajo CO, et al "Ultrasound-based transient elastography for the detection of hepatic fibrosis in patients with recurrent hepatitis C virus after liver transplantation: a systematic review and meta-analysis" Liver Transpl 2012; 18: 323-331.

Source

HIV Main Focus of Retrovirus Conference

By Michael Smith, North American Correspondent, MedPage Today

Published: March 02, 2012

SEATTLE -- HIV is usually the main focus -- as the name suggests -- of the Conference on Retroviruses and Opportunistic Infections.

And this year will be no exception, according to Scott Hammer, MD, of Columbia University in New York City, co-chair of the scientific program committee.

"Other retroviruses come into play," he told MedPage Today, "but the bulk of the meeting is HIV and its related complications, both opportunistic and non-opportunistic."

But if the overall focus is not much changed, this year's meeting will narrow its gaze to three main areas, Hammer said:

• Preventing HIV infection, a topic that has included both good news and bad in the past year
• Treating the major co-infections, tuberculosis and hepatitis C
• Examining the potential for curing the infection

That last is "not fantasy, it's good science," Hammer said, although for years researchers and clinicians thought the best they could do was make HIV a chronic disease.

Now, though, many leading scientists think it may soon be possible to reach into the reservoirs where HIV hides in the body and eradicate the virus, although exactly how remains a matter of active investigation.

It's unlikely that this meeting will see any reports of a breakthrough in the area – "there aren't going to be any show-stoppers," as Hammer puts it – but he's expecting some incremental progress.

On the other hand, meeting-goers are likely to get more information on using anti-retroviral drugs to prevent HIV infection in the first place, Hammer said.

That field has been spurred by results from several trials, showing that treating people at risk of infection and also treating partners of infected people reduces the risk of infection.

But other trials – some looking at using anti-retroviral drugs in vaginal gels, for instance – have reported disappointing results, so that the overall picture remains unclear, Hammer noted.

"There's a lot of excitement, but also a lot of discussion points," he said.

For instance, the annual N'Galy-Mann lecture, which recognizes important epidemiological or clinical research, will be given this year by the husband-and-wife team of Quarraisha Abdool Karim, PhD, of the Centre for the AIDS Program of Research in South Africa (CAPRISA) and Salim Abdool Karim, MBChB, PhD, of the University of KwaZulu-Natal in Durban, South Africa.

The pair were investigators on the CAPRISA 004 trial, which showed for the first time that a microbicide gel could reduce the risk of infection for women.

Hammer also said he expects to learn more about the prospects for a vaccine, as researchers report on the so-called correlates of risk associated with protection during the RV-144 vaccine trial conducted in Thailand.

That trial, again for the first time, showed a small but significant benefit for a vaccine candidate and researchers want to know why, in the hope that they can tweak some factors and get a better result.

Hammer said he also expects to get some data on new agents and new combinations of agents that are in the clinical trials process, including the so-called quad pill and the integrase inhibitor dolutegravir.

The other major theme will be ways of dealing with some of the major diseases that march in step with HIV – tuberculosis (TB) and hepatitis C.

Hammer said he's looking forward to hearing more about new direct-acting agents against hepatitis C, which present their own challenges when they are used in people with an HIV co-infection.

But the novel agents – two of which have already been approved – have the potential to increase hepatitis cure rates, while reducing the toxicity that complicates therapy and the time it takes to treat the virus.

TB remains a major challenge, especially in resource-poor regions where appropriate treatment of people with co-infection is often difficult to obtain. Meeting attendees will hear about community-based approaches to treatment in Africa.

Source

HCV therapeutics: Times are changing

Infectious Disease News February 2012

by Robert T Schooley, MD

There are few areas in medicine in which the therapeutic landscape is poised to change more rapidly than in that for the therapy of hepatitis C infection. The 20 years after the introduction of interferon-alpha therapy witnessed only two advances in hepatitis C therapy.

First, ribavirin, an agent that had previously been pitched at more viruses than are included in most medical school curricula, was found to reduce the rate of relapse after a course of interferon-alpha therapy. Secondly, conjugation of interferon-alpha to polyethylene glycol was demonstrated to increase the chance of treatment and the tolerability of interferon therapy.

When these two modifications to classical interferon-alpha therapy were combined, a patient with HCV genotype-1 could look forward to a difficult year that resulted in a cure less than half of the time. In this situation, it would be expected that most patents reluctantly accepted therapy when they (and their physicians) came to the conclusion that therapy was required as a last effort to avoid end-stage liver disease or hepatocellular carcinoma.

In these circumstances, patients usually avoided therapy until their liver disease resulted in referral to a hepatologist who generally viewed their problem as a liver rather than a viral disease. We are now entering a new era in which therapeutic advances for HCV will completely change the treatment paradigm. This will be accompanied by much better outcomes for patients and will require a major expansion of the treating community in which HIV physicians will play a much greater role. These shifts will be driven by three major factors.

Success rates will increase

The addition of either of the newly approved HCV protease inhibitors — boceprevir (Victrelis, Schering) or telaprevir (Incivek, Vertex Pharmaceuticals) — to polyethylene glycol-interferon and ribavirin therapy has already increased the prospect of treatment success to about 70% in genotype-1 infection.

With the increased potency of three-agent antiviral regimens, treatment duration has decreased from 1 year to 6 months in most patients, and early assessment of the antiviral response can provide patients with prognostic information that is reliable as to whether a course of therapy is likely to be successful. Taken together, patients can expect treatment to be successful more frequently, and they will likely be inconvenienced for only half as long as before.

Furthermore, clinical trials with newer agents provide strong evidence that treatment success rates are poised to go higher and that courses of therapy will be shorter for many patients — and perhaps, most importantly, will ultimately include neither interferon nor ribavirin. These factors have already increased interest in testing for and treatment of HCV infection.

Initiation not driven by liver biopsy findings

As current therapies are limited in appeal, most patients seek therapy (and most physicians recommend therapy) only when liver disease has progressed to the point that cirrhosis is at hand or established. Although noninvasive approaches are emerging that serum markers or ultrasound are reasonably good at identifying patients with very little liver damage or substantial cirrhosis, liver biopsy is generally needed to provide sufficiently precise information in the middle spectrum of HCV-induced liver disease to make good therapeutic recommendations in most patients.

In addition, if therapy is delayed too long and decompensated cirrhosis has developed, interferon therapy can lead to liver failure and death. These factors have generally drawn hepatologists into the dialogue about whether therapy is indicated and usually keep them involved after therapy is started, if it is started later in the course of HCV-induced liver disease.

Decisions more complicated

Although art and science were involved in deciding when treatment should be recommended and when a patient should go through a course of polyethylene glycol-interferon/ribavirin therapy, the therapeutic landscape was reasonably straightforward once therapy was recommended.

Ribavirin was included in both regimens, and the two interferons differed from each other only in nuance. Thus, the treatment decision was a dichotomous one, and once therapy was started, side effects (though they were often substantial) were well delineated and predictable. In many treatment settings, a physician (usually a hepatologist) gathered the data and made recommendations about whether treatment was recommended, and care was actually delivered by physicians and nurse practitioners who were able to follow relatively simple toxicity management algorithms and manage most serious side effects with dose reduction and referrals to mental health workers for management of depression.

More than 20 directly acting anti-HCV agents are currently in various phases of development. These drugs have different molecular targets, resistance profiles, metabolic profiles, drug interactions and treatment durations — and it is clear that every regimen will require two to four of these new agents. As it becomes easier to decide who to treat, it is likely that more complex decisions will be required once therapy is started.

Decisions, not unlike those that the HIV-treating community has confronted for years, will be brought into the process, and “laminated-card driven” decision-making of the polyethylene glycol-interferon/ribavirin era will be a thing of the past. Decisions about overlapping resistance pathways and about interactions among anti-HCV agents (and between HCV agents and other drugs that patients must take) will be required. Because decisions about treatment duration and futility will be driven by close monitoring of antiviral response, multiple decisions will be required throughout the course of therapy. Although it is clear that these sorts of decisions can be made by hepatologists if they are heavily engaged in HCV therapy, it is likely that the hepatology community will see a further division into a subset of hepatologists who take care of hepatitis most of the time and a much larger subset who focus on transplantation and/or procedures.

Care models in new HCV therapy era

At present, there are approximately 4 million HCV-infected people in the United States, and it is estimated that fewer than 2,000 physicians are responsible for more than 80% of the currently administered antiviral therapy. As the number of those interested in HCV therapy increases and as the threshold to recommend therapy increasingly shifts to earlier stages of liver disease, current HCV treatment communities will become increasingly overrun. With a likely constriction in the number of hepatologists who are actively engaged in HCV therapy, it is clear that physicians from other disciplines will be drawn into HCV therapy.

Due to the complexity of HCV therapy, it will neither be good for patients nor an efficient use of resources to have thousands of generalists provide care to a few patients each. When HIV-1 emerged in the 1980s, AIDS “specialists” initially came from multiple training backgrounds, including internal medicine, infectious diseases, oncology, dermatology and family medicine.

As the field matured, most de novo training eventually became centered on infectious disease training programs. Most of the “primary” care for HIV (and many of us would also argue the best care) is now provided by multidisciplinary teams that are usually coordinated by physicians with infectious disease specialty training. These multidisciplinary teams optimally include those with complementary specialized expertise in the complications of the disease, including oncologists, hepatologists, psychiatrists, neurologists and clinical pharmacologists.

This shift occurred over time and with little explicit coordination or pre-cognition, but it has proved to be an extremely efficient model of care in which outcomes are better than in settings in which HIV care is provided by those with limited experience and expertise.

Rather than to stumble into an analogous model for HCV therapy during the next decade, it is attractive to think that the HIV experience could provide yet another window on the best approach to HCV care. Optimal HCV care will require interactive multidisciplinary teams with specialized expertise. Developing centers of excellence in HCV care should be a priority for the infectious disease community that should occur in anticipation of, rather than in response to, radically changing treatment paradigms.

These centers of excellence should also include hepatologists interested in viral hepatitis in their direction and operation and will need to include translational virologists, liver transplant surgeons, psychiatrists, radiologists with expertise in noninvasive imaging of the liver and clinical pharmacologists. Based on our experience in the medical and operational aspects of HIV infection, the infectious disease community must play a major role in the initial development of these centers, and most of the leaders in this exciting area of medicine should emerge from our training programs.

We’ve applied a lot of what we learned about RNA viruses from antiretroviral drug development to HCV drug discovery. Although it has been a bit slower, some of the lessons of the benefits of closely aligning clinical and translational science in drug development have been introduced into HCV drug development. There is no reason not to apply what we learned about optimal HIV care models to the very similar multidisciplinary landscape of HCV care.

Tremendous benefits will accrue to patients, and what could be more appealing to those of us in infectious diseases than a viral disease that we can actually eradicate — all that remains is to develop a billing code for “virectomy.”

Robert T. Schooley, MD, professor and head in the division of infectious diseases, and vice-chair of the department of medicine at the University of California, San Diego. Disclosure: Dr. Schooley is a member of scientific advisory boards for Gilead Sciences, GlobeImmune, Inhibitex, Johnson & Johnson, Monogram Biosciences, and Santaris. He has consulted for Merck. Research support is provided by Boehringer Ingelheim and Bristol-Myers Squibb.

Source

Is HCV Infection a Neurologic Disorder?

Download the PDF here

Gastroenterology March 2012
CYRILLE FERAY
Service d'HEpatogastroentErologie
Hotel-Dieu Hospital
Nantes, France

Hepatitis: Brain endothelial cells support HCV entry and replication - (01/27/12)

HCV SVR Improves Quality of Life & Brain Function - (01/27/12)

from Jules of NATAP: this topic of does HCV have a neurological effect & cause neurological symptoms has been controversial with many clinicians over the years doubting that this is true and with conflicting research, for example in HIV researchers have reported from studies not finding HCV caused cognitive impairment in HIV+ coinfected individuals. In the recent year or so there have been a number of research papers just like this finding that HCV enters the brain & can cause damage. There was research years ago from Pegasys studies showing improvement in neurological symptoms in patients achieving SVR. It is clear to me this is true. After achieving an SVR about 10 yrs ago I realized how much fatigue & cognitive impairment I had previously but before achieving the SVR I had no idea how much fatigue & cognitive impairment I had & I certainly did not appreciate it could be associated with HCV. After finishing HCV therapy & achieving an SVR the I started to feel improved energy & improved cognitive abilities. And over the next several years I experienced ongoing continuing further improvements. So there is no doubt that HCV can be associated neurological impairment and that it can improve. Now I had cirrhosis before achieving SVR so having a more severe stage of HCV disease may be more associated with experiencing cognitive impairment but I think earlier HCV disease can also be associated with fatigue, depression and cognitive impairment.

Hepatitis C is known to induce chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The absence of symptoms is common even when the disease has reached the stage of cirrhosis or hepatocellular carcinoma. For this reason, infection with hepatitis C virus (HCV) is frequently called a "silent killer." Fatigue is the most frequent complaint in infected subjects. HCV infection has also been associated with cognitive dysfunction and depression, which are not correlated with the severity of liver disease and cannot be explained by hepatic encephalopathy or drug abuse.

Numerous extrahepatic disorders have been attributed to or are more frequent during HCV infection. The most common mechanism underlying these disorders is autoimmunity. Thyroiditis, arthropathies, lymphocytic sialadenitis with or without sicca syndrome, and diabetes have long been known to be more frequent with HCV.1, 2 The second most frequent disorder associated with HCV infection is type II or III cryoglobulinemia. Cryoglobulins contain immune complexes made of HCV virions and anti-HCV antibodies and are highly prevalent in infected subjects. This can lead to symptomatic vasculitis with purpura, arthralgias, and asthenia, as well as peripheral nervous system and kidney involvement. Cryoglobulins are considered to be the result of B-cell proliferation owing to chronic antigenic stimulation, and B-cell lymphomas have been reported to be slightly more common in this population.3 A direct role of HCV is suggested by the fact that antiviral therapies have an antitumoral effect.4 The third group of extrahepatic symptoms associated with HCV infection could be a direct consequence of HCV infection of components of the central nervous system. Indeed, HCV RNA has been detected at autopsy in brain tissues.5, 6, 7, 8 Recently, an elegant study using microdissection in brain tissues from HCV-positive patients obtained at autopsy combined with measurement of cytokine mRNA in cells that were positive for the HCV nonstructural 3 protein suggested that brain macrophages/microglia cells were activated in HCV-infected patients.

The purpose of the paper by Fletcher et al,9 published in this issue of Gastroenterology, was to explore the original hypothesis that HCV could infect and alter the function of blood-brain barrier (BBB) endothelial cells. The authors first demonstrated that all of the known viral receptor molecules (CD81, claudin-1, occludin, LDLR, and scavenger receptor-B1) are expressed at the surface of BBB endothelial cells. It is important to note that scavenger receptor-BI expression was restricted to the microvascular endothelium, whereas other receptors were expressed by astrocytes. In a second step, the authors convincingly showed that HCV replicates in 2 distinct cell lines derived from these BBB endothelial cells. Hepatitis C is known to infect nonhepatocyte cells. There are numerous reports in the literature describing the presence of HCV RNA in immune cells10 as well as in the brain.11 In immune cells (mainly B-cells)12 and in the central nervous system,13, 14 the detection of viral sequences different from those found in the blood or the liver illustrates the compartmentalization of viral quasispecies and supports the idea that replication takes place in these extrahepatic sites. Indeed, in the absence of local replication, the presence of HCV RNA would be because of the adsorption or internalization of circulating viral particles produced in the liver; thus, no phylogenetic differences would exist with majority variants present in the serum (unless selection of liver-generated viral variants takes place at the cell receptor level). In almost all studies, the level of extrahepatic replication of HCV has been reported to be low, so that the contribution of these sites to circulating virions is limited. The HCV genome is positively stranded, meaning that it is directly translated into the viral polyprotein in the cell cytoplasm. The detection of negatively stranded HCV RNA in tissues or cells demonstrates that viral proteins have been translated and the HCV replication complex is functional, at least for the synthesis of negatively stranded HCV RNA. This intermediate of replication has frequently been detected in extrahepatic sites. There are, however, numerous technical issues that challenge the specificity of such detection. The detection of viral proteins in tissues or cells is also difficult because of their low level of expression. However, their presence has been convincingly reported recently in lymph nodes from the liver pedicle15 and in the brain.16

The most important information in the article by Fletcher et al9 is that human cell lines derived from BBB endothelial cells can be infected by HCV. The authors first tested HCV binding using HCV pseudoparticles (HCVpp) formed by the incorporation of the envelope glycoproteins E1 and E2 into lentiviral core particles. HCVpp closely mimic the functionality of wild-type viruses during the early steps of the viral lifecycle. HCVpp binding to endothelial cells was quantitatively similar to that observed with hepatocyte cell lines. The authors then used the JFH1 strain, the only HCV strain that effectively infects and replicates in primary human hepatocytes and in the hepatocyte cell line Huh7.5.17 Not surprisingly, HCV replicated at much lower levels in endothelial cells than in hepatocytes. Definitive confirmation of viral replication in endothelial cells was provided by using specific HCV protease inhibitors, which decreased the amount of HCV RNA in these cells. Micro-RNA (miR)-122 is hepatocyte specific and its fixation at 2 sites in the 5' untranslated region of the virus genome is required for efficient HCV replication. As expected, miR-122 was not detected in endothelial cell lines. The transfection of these cells to express functionally active miR-122 RNA duplexes failed to promote HCV replication, demonstrating that replication is miR-122 independent in endothelial cells. Indirectly, this result also suggested that liver-specific factors are required for the action of miR-122 on HCV replication in hepatocytes.

Another important group of findings in this paper was the observation of functional consequences of HCV infection of endothelial cells. Indeed, HCV increased endothelial cell permeability and this effect was reversed when replication was inhibited by antiviral molecules. Neutralization of HCV infection with pooled anti-HCV immunoglobulins also restored endothelial cell permeability, demonstrating the direct effect of HCV on this parameter. Furthermore, the authors noted that HCV-infected endothelial cell lines expressing nonstructural protein NS5A were TUNEL positive, suggesting an effect of infection on brain endothelial cell apoptosis. Altogether, these findings suggest that the infection of endothelial cells by HCV and HCV replication in these cells in vivo are highly plausible.

These findings raise the important question of the impact of HCV replication in BBB endothelial cells on neurocognitive and psychological symptoms frequently reported by subjects infected by this virus. This issue has been evaluated in case-control and in longitudinal studies assessing patients before and after a sustained virologic response to antiviral therapy. In these works, neurologic involvement was evaluated by means of neurocognitive tests combined with quality-of-life questionnaires or by measuring magnetic resonance spectroscopy (MRS) signals. Such case-control studies raise the issue of matching patients with HCV infection who know their status and have past or present addictive behaviors and HCV-negative controls. Despite these limitations, most studies reported more fatigue, more depression, and less effectiveness in HCV-infected patients than in controls. The longitudinal approach also has drawbacks. Subjects know the results of therapy and have experienced the adverse effects of antiviral drugs for many months. Although numerous studies have reported an improvement of the quality of life after achieving a sustained virologic response,18 only a few recent papers investigated changes in neurocognitive functions and MRS in relation to the response to therapy. The results of these studies are conflicting. In 1 study, the authors concluded that HCV eradication had a beneficial effect on cerebral metabolism and selective aspects of neurocognitive functions, especially in patients with mild disease.19 In contrast, another comparable study concluded that HCV had a measurable effect on brain integrity in patients screened for other medical and/or psychiatric comorbidities, but that these abnormalities did not improve after viral eradication.20 Both studies were based on a very small number of patients and the evaluation of neurocognitive functions and MRS were performed early after viral clearance. The second study20 questioned the reversibility of brain involvement once HCV infection is cured. Indeed, because brain cells have a very low rate of regeneration, the effect of HCV infection could be prolonged by months or years after the virus has been cured.

The main interest of the article by Fletcher et al9 is to show that the brain is a likely target for HCV. More important, the results with BBB endothelial cells suggest that other endothelial cells could be targeted and altered by HCV. For example, a study in an Egyptian population showed higher carotid intimal media thickness in HCV-infected than in noninfected patients.21 If this is confirmed, the possibility that HCV infection could induce brain or vascular disorders could modify the current indications for therapy, which are essentially based on the severity of liver disease or the presence of extrahepatic manifestations of immune origin, such as symptomatic cryoglobulinemia or B-cell lymphoma. Further studies are thus needed in the field of HCV neuroinvasion to better define the actual consequences of infection and their reversibility if infection is eradicated. However, it must be emphasized that the effects of HCV on neurocognitive functions, depression, or fatigue are generally mild. Many HCV-infected patients are highly successful and creative. Because stigmatization of HCV infected people exists, the notion of a brain involvement in these patients could have devastating consequences. The results of the present study should therefore be interpreted as what they are, certainly not overinterpreted as the demonstration that HCV infection leads to severe brain disease (Figure 1).

Source

TMC435-TiDP16-C212 - Trial of TMC435 in Genotype 1 Hepatitis C and Human Immunodeficiency Virus Co-Infected Patients

Provided by NATAP

This study is currently recruiting participants.

Verified February 2012 by Tibotec Pharmaceuticals, Ireland

Estimated Enrollment: 100

Drug: TMC435

150 mg capsule once daily for 12 weeks in addition to peginterferon alfa-2a and ribavirin for 24 or 48 weeks

First Received on October 18, 2011. Last Updated on February 27, 2012

Recruiting TMC435-TiDP16-C212 - Trial of TMC435 in Genotype 1 Hepatitis C and Human Immunodeficiency Virus Co-Infected Patients

This is an open-label (all people know the identity of the intervention) study of TMC435 in patients who are infected with genotype 1 hepatitis C virus and co-infected with human immunodeficiency virus (HIV). Patients in this study will also receive two other drugs for their hepatitis C infection called peginterferon alfa-2a and ribavirin. The purpose of the study is to investigate the safety, tolerability, and efficacy of TMC435 against hepatitis C virus in this patient population. For the first 12 weeks all patients will receive TMC435 plus peginterferon alfa-2a and ribavirin. For the subsequent 12 weeks, patients will take peginterferon alfa-2a and ribavirin only. After that, based on prior HCV treatment experience and prespecified on-treatment response criteria, some patients will continue to take peginterferon alfa-2a and ribavirin for total treatment duration of 48 weeks. The study doctor will inform each patient about how to take their study medication and when they should stop taking it. Patients will take their own regimen of HIV medication(s) throughout the study, according to the instructions of the study doctor. After a patient stops taking study medication, they will continue to come to the study doctor's office for study visits for up to 72 weeks after they received the first dose of treatment in the study. The maximum duration of the study is 81 weeks (including screening). Patients will be monitored for safety throughout the study. Study assessments at each study visit may include, but are not limited to: blood and urine collection for testing and physical examinations.

Importance of Pharmacokinetics and Adherence to Avoid Emergence of Resistant HCV Variants

Jean-Michel Pawlotsky, MD, PhD
Professor, Department of Virology
Henri Mondor Hospital
Université Paris Est
Créteil, France

Introduction

Hepatitis C virus (HCV) resistance to a direct-acting antiviral (DAA) agent corresponds to the selection during treatment of viral variants that bear amino acid substitutions that alter the drug target; therefore, they are less susceptible to the inhibitory activity of the drug. These drug-resistant variants preexist as minor populations within the patient’s HCV quasispecies. Drug exposure profoundly inhibits replication of the dominant “wild-type” drug-sensitive viral population, and the resistant variants gradually occupy the vacant replication space. Moreover, viruses with low-level or partial resistance that can continue to replicate in the presence of drug, often favored by suboptimal drug exposure, may accumulate further mutations, leading to stepwise decreases in drug susceptibility, albeit often at a cost of reduced replicative capacity. If insufficient antiviral activity is provided because of suboptimal dosing or adherence, inadequate virologic suppression and the selection of resistance is inevitable. Therefore, to reduce the development of resistance, it is essential to achieve optimal drug concentrations through proper dosing and maximal adherence.

Factors That Influence Viral Resistance in vivo

In vivo, viral resistance is influenced by 3 major related factors: the genetic barrier to resistance, the in vivo fitness of the resistant viral population, and drug exposure.^[1]

The genetic barrier to resistance is defined as the number of amino acid substitutions needed for a viral variant to acquire full resistance to the drug in question. If a single substitution is sufficient to confer high-level resistance to a specific drug, the drug is considered to have a low genetic barrier to resistance, whereas 3 or more substitutions are required to confer resistance to a drug with a high genetic barrier. There is a low likelihood that variants bearing a large number of resistance substitutions will preexist in a given patient and be fit enough to replicate at high levels when an antiviral drug is administered. Therefore, drugs with a high genetic barrier to resistance are less likely to be associated with clinically meaningful resistance.

The in vivo fitness of the viral variant is defined as its ability to survive and grow in the replicative environment. A selected resistant variant must have the capacity to propagate to fill in the replication space left vacant by the elimination of a susceptible wild-type virus during drug exposure. Thus, a highly resistant but poorly “fit” virus will be less clinically significant than a less resistant but “fitter” virus that can replicate efficiently in the presence of the drug. The acquisition of compensatory mutations may restore the fitness of a resistant variant and allow it to replicate efficiently in the presence of the drug, possibly allowing it to persist after drug withdrawal.

Finally, drug exposure affects the development of drug resistance. The degree of drug resistance of a variant can be measured in vitro as the fold increase in the 50% and 90% inhibitory concentrations (IC₅₀ and IC₉₀ in cell-free assays) or the 50% and 90% effective concentrations (EC₅₀ and EC₉₀ in cell-culture systems), that is, the drug concentrations that inhibit the tested enzyme function or viral replication by 50% and 90%, respectively. Drug exposure is defined as the drug concentration achieved in vivo relative to the IC₅₀, IC₉₀, EC₅₀, or EC₉₀ of resistant variants. This measurement is a key determinant of the development of resistance in vivo. Indeed, if drug levels achieved in vivo are far above these IC/EC values, then resistant variants will be effectively inhibited even if they are far less susceptible than the wild-type virus in vitro. Therefore, the pharmacokinetics of the antiviral drugs and adherence to therapy are key in preventing treatment failure due to viral resistance.

Importance of Pharmacodynamics/Adherence to Interferon-Containing DAA Regimens

The importance of achieving high blood DAA concentrations to prevent the emergence of resistance was demonstrated in the first phase Ib trial with telaprevir, an NS3/4A protease inhibitor (PI) with a low genetic barrier to resistance, administered as monotherapy for 14 days.^[2] In this trial, patients were more likely to achieve either an HCV RNA plateau or virologic breakthrough during the dosing period due to selection of telaprevir-resistant variants if they received lower telaprevir doses (450 mg every 8 hours or 1250 mg every 12 hours) than if they received the higher dose (750 mg every 8 hours).^[2] However, outgrowth of resistant viral populations was only delayed in the latter group. In vivo fitness assessments showed that less resistant, but “fitter” variants were more likely to become the dominant species than more resistant, less “fit” HCV variants.^[2] These findings led the American and European regulatory agencies to limit monotherapy studies involving DAAs with low genetic barriers to resistance to only a few days. Therefore, no other studies provided sufficiently long administration to accurately assess the effect of drug exposure on the emergence of resistance.

Resistance to antiviral drugs is classically prevented by combining several drugs with potent antiviral activity and no cross-resistance. Indeed, HCV resistance to DAAs is observed significantly less frequently when one of these drugs is administered in combination with peginterferon and ribavirin.^[3,4] Therefore, the triple combination of peginterferon, ribavirin, and a PI—telaprevir or boceprevir—has become the new standard-of-care therapy for both treatment-naive and treatment-experienced patients with genotype 1 HCV infection.^[5-8] For the reasons defined above, it is crucial that optimal exposure to all 3 drugs in the regimen be achieved for these patients. Telaprevir must be taken at a dose of 750 mg every 8 hours with fatty food, whereas boceprevir must be taken at the dose of 800 mg every 8 hours with food. Patients must fully adhere to the regimen for the entire treatment period because any prolonged interruption in PI administration would inevitably result in a resurgence of wild-type viruses and the opportunity for resistant variants to acquire fitness, especially if the antiviral pressure exerted by peginterferon and ribavirin is only modest. However, if the patient does miss a dose of telaprevir or boceprevir, the package inserts provide guidance on how to manage these short interruptions. For telaprevir, the prescribing information recommends that a missed dose should be skipped if more than 4 hours have passed since the time it is usually taken; however, if it is within 4 hours of the time that it is usually taken, the missed dose should be taken immediately with high-fat food.^[5,6] The recommendation for boceprevir is similar, but the timing is different. A missed boceprevir dose should be skipped if it is fewer than 2 hours before the next dose is scheduled; if it is more than 2 hours before the next scheduled dose, the missed dose should be taken immediately with food.^[7,8]

The importance of adherence to peginterferon and ribavirin has been demonstrated in the absence of DAAs; these data showed that optimal response rates were observed in patients who achieved more than 80% of their prescribed peginterferon and ribavirin doses for more than 80% of the time.^[9] The impact of poor adherence to, or dose reductions of, peginterferon, ribavirin, or both has not been extensively studied in clinical trials with the triple combination of peginterferon, ribavirin, and telaprevir or boceprevir. Nevertheless, maintaining the dose of peginterferon is likely to be key in interferon-responsive patients treated with triple therapy because treatment failure primarily results from an inadequate response to peginterferon, leading to the uncontrolled outgrowth of resistant variants selected by the PI.^[1,10-12] By contrast, a retrospective analysis of patients completing 48 weeks of peginterferon/ribavirin therapy suggested that reducing the dose of ribavirin has a negative impact on the outcome of therapy only before HCV RNA becomes undetectable, whereas the impact is modest after HCV replication is controlled.^[13] More recent studies in patients receiving PI-based therapy have shown that modest ribavirin dose reductions do not impair the likelihood of treatment success.^[14,15] Finally, a recent study showed that the cost effectiveness of triple therapy is dependent on optimal adherence.^[16]

There are several strategies that can be used to optimize adherence rates in patients receiving DAA-based therapy, some of which are under investigation. Current strategies include patient education on the importance of adherence, interventions to reduce the adverse effects of therapy, addressing comorbidities that may affect adherence to therapy, and using a multidisciplinary team to help physicians implement all of the aforementioned strategies. Regarding patient education, a prospective, multicenter study was conducted to determine the influence of patient education on adherence to peginterferon plus ribavirin therapy in patients infected with HCV.^[17] Investigators showed that patient education can significantly influence adherence to treatment as evidenced by adherence rates to ribavirin of 56% at 6 months in 175 patients not receiving education vs 70% in 208 patients receiving education (P = .006).^[17] Therapeutic education included intervention by healthcare professionals other than the prescribing physician as well as the distribution of support documents and educational materials. Another study found that physician’s treatment experience and patient motivation were associated with improved adherence to HCV therapy, indicating that empowering patients to take charge of their own treatment can impact adherence.^[18] It should be noted, however, that no data are yet available on how these strategies may affect adherence to triple combinations with the HCV PIs.

Importance of Pharmacodynamics/Adherence to Interferon-Free DAA Regimens

Maintaining optimal adherence has been shown to be an extremely effective way of minimizing the development of resistance in the HIV field.^[19] Strategies under investigation that may help optimize adherence rates to interferon-free DAA therapy include less frequent dosing and ritonavir boosting. Many DAA agents in development have half-lives that may allow for twice- or even once-daily dosing, which is encouraging.

In HIV therapy, the use of low-dose ritonavir to improve the pharmacokinetics of HIV PIs (so-called ritonavir boosting) has become standard practice. NS3/4A PIs are cytochrome P450 3A substrates; therefore, their plasma concentrations can also be substantially improved when coadministered with low-dose ritonavir, which may allow for prolonged dosing intervals and subsequent increased adherence rates. Boosting has been studied with 3 PIs—danoprevir, narlaprevir, and ABT-450—with encouraging results that suggest such strategies may support once-daily dosing, reduce adverse events (by lowering the required dose of the HCV PI), and reduce the risk of resistance.^[20-23] Results with ABT-450 showed that higher plasma trough levels were associated with a lower likelihood of selecting resistant HCV variants over a short course of administration of 3 days.^[23] However, a number of first-generation PIs can achieve high and well-tolerated plasma concentrations with once- or twice-daily dosing without ritonavir boosting.

Interferon-free regimens will reduce toxicity and adverse effects associated with peginterferon and ribavirin therapy, possibly improving adherence rates. The results of a short-term study combining the NS3/4A PI GS-9256 and the nonnucleoside RNA-dependent RNA polymerase inhibitor tegobuvir has been disappointing because this combination of agents has a low genetic barrier to resistance and frequent early virologic breakthroughs were observed.^[24] Additional studies which have combined agents with low genetic barriers to resistance include the SOUND-C1 and SOUND-C2 studies. These trials combined the NS3/4A protease inhibitor BI 201335 and nonnucleoside polymerase inhibitor BI 207127, with or without ribavirin.^[25,26] The ZENITH study combined the NS5B polymerase inhibitor VX-222 plus telaprevir.^[27] In the SOUND-C2 study, treatment response rates, and likely the selection of resistant HCV variants, appeared to be influenced by the genetic background of the host (IL28B genotype).^[26] Regimens comprising agents with higher barriers to resistance, such as the cyclophilin inhibitor alisporivir,^[28] the combination of the nucleoside analogue inhibitor mericitabine and the PI danoprevir,^[29] and the combination of the nucleotide inhibitor PSI-7977 with ribavirin have shown more promising results.^[30] Indeed, the latter combination resulted in undetectable HCV RNA at 12 weeks post-therapy (SVR12) for 10 out of 10 genotype 2/3 HCV–infected treatment-naive patients receiving this regimen for 12 weeks.

Another interferon-free regimen comprising agents with low barriers to resistance—the first-generation NS3/4A PI asunaprevir and the NS5A inhibitor daclatasvir—has provided valuable information on the importance of drug exposure and how this differs depending on HCV subtype.^[31,32] Protease inhibitors have a low genetic barrier to resistance; they can select fit variants that are poorly controlled at the drug concentrations achieved by doses used in clinical trials and practice. This is also true for NS5A inhibitors in genotype 1a HCV, as suggested by in vitro by studies showing a major shift in the IC₅₀s induced by single amino acid substitutions in the NS5A sequence.^[33] As a result, virologic breakthrough due to the selection of HCV variants resistant to both drugs was observed within a few days to weeks in 6 of the 9 patients infected with genotype 1a HCV.^[31] By contrast, in genotype 1b HCV models in vitro, daclatasvir retains subnanomolar potency against all variants with single amino acid substitutions; the fold-change in IC₅₀s conferred by these substitutions in the presence of the inhibitor was substantially lower than in genotype 1a.^[33] Consequently, the drug concentrations achieved in vivo in genotype 1b HCV–infected patients were able to control NS5A variants carrying these substitutions, both in the absence or presence of associated substitutions conferring resistance to the PI. As a result, the combination of asunaprevir and daclatasvir was shown to lead to high sustained viral eradication rates (~ 90%) in patients infected with genotype 1b HCV.^[31,32] To date, the available data on interferon-free regimens are more informative regarding pharmacodynamics and exposure than adherence. Additional data are awaited.

Conclusions

Although data are scarce regarding drug exposure and adherence in the context of HCV treatment with new DAA-based therapies, preliminary data and lessons learned from the HIV field suggest that optimal drug exposure and maximal adherence will be crucial to success with DAA-based therapies. In addition, the data from interferon-free regimens emphasize the importance of drug exposure, through optimal dosing and strict adherence to the prescribed regimen, when using combinations of drugs with a low to moderate barrier to resistance. Drugs with a higher barrier to resistance, such as nucleos(t)ide analogues, cyclophilin inhibitors, or second-generation PIs may theoretically be more tolerant to weaker adherence, but data are lacking thus far. When these therapies are available in clinical practice, virologic failures may be observed more often than in strictly controlled clinical trials. Vigilance and thorough patient education will be required to ensure high cure rates.

References

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2. Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology. 2007;132:1767-1777.

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14. Sulkowski MS, Poordad F, Manns MP, et al. Peginterferon alfa-2b/ribavirin with or without boceprevir is associated with higher SVR rates: analysis of previously untreated and previous treatment-failure patients. Program and abstracts of the 46th Annual Meeting of the European Association for the Study of the Liver; March 30 - April 3, 2011; Berlin, Germany. Poster 476.

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18. Tanioka D, Iwasaki Y, Araki Y, et al. Factors associated with adherence to combination therapy of interferon and ribavirin for patients with chronic hepatitis C: importance of patient's motivation and physician's treatment experience. Liver Int. 2009;29:721-729.

19. Mocroft A, Phillips AN, Soriano V, et al. Reasons for stopping antiretrovirals used in an initial highly active antiretroviral regimen: increased incidence of stopping due to toxicity or patient/physician choice in patients with hepatitis C coinfection. AIDS Res Hum Retroviruses. 2005;21:743-752.

20. Gane E, Rouzier R, Stedman C, et al. Ritonavir boosting of low dose RG7227/ITMN-191, HCV NS3/4A protease inhibitor, results in robust reduction in HCV RNA at lower exposures than provided by unboosted regimens. Program and abstracts of the 45th Annual Meeting of the European Association for the Study of the Liver; April 14-18, 2010; Vienna, Austria. Abstract 38.

21. Rouzier R, Larrey D, Gane EJ, et al. Activity of danoprevir plus low-dose ritonavir (DNV/R) in combination with peginterferon alfa-2a (40KD) plus ribavirin (PEGIFNα-2A/RBV) in previous null responders. Program and abstracts of the 46th Annual Meeting of the European Association for the Study of the Liver; March 30 - April 3, 2011; Berlin, Germany. Abstract 62.

22. de Bruijne J, Bergmann JF, Reesink HW, et al. Antiviral activity of narlaprevir combined with ritonavir and pegylated interferon in chronic hepatitis C patients. Hepatology. 2010;52:1590-1599.

23. Pilot-Matias T, Tripathi R, Dekhtyar T, et al. Genotypic and phenotypic characterization of NS3 variants selected in HCV-infected patients treated with ABT-450. Program and abstracts of the 46th Annual Meeting of the European Association for the Study of the Liver; March 30 - April 3, 2011; Berlin, Germany. Abstract 1229.

24. Zeuzem S, Buggisch P, Agarwal K, et al. The protease inhibitor GS-9256 and non-nucleoside polymerase inhibitor tegobuvir alone, with RBV or peginterferon plus RBV in hepatitis C. Hepatology. 2011;[Epub ahead of print].

25. Zeuzem S, Asselah T, Angus PW, et al. High sustained virologic response following interferon-free treatment of chronic HCV GT1 infection for 4 weeks with HCV protease inhibitor BI201335, polymerase inhibitor BI207127 and ribavirin, followed by BI201335 and pegIFN/ribavirin—the SOUND-C1 study. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 249.

26. Zeuzem S, Soriano V. Asselah T, et al. Virologic response to an interferon-free regimen of BI 201335 and BI 207127, with and without ribavirin, in treatment-naive patients with chronic genotype-1 HCV infection: Week 12 interim analysis of the SOUND-C2 study. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract LB15.

27. Nelson DR, Gane EJ, Jacobson IM, et al. VX-222/telaprevir in combination with peginterferon-alfa and ribavirin in treatment-naive genotype 1 HCV patients treated for 12 weeks: ZENITH study, SVR12 interim analysis. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract LB14.

28. Pawlotsky JM, Flisiak R, Rasenack J, et al. Once-daily alisporivir interferon (IFN)-free regimens achieve high rates of early HCV clearance in previously untreated patients with HCV genotype (G) 2 or 3. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract LB11.

29. Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2010;376:1467-1475.

30. Gane EJ, Stedman CA, Hyland RH, et al. PSI-7977: ELECTRON. Interferon is not required for sustained virologic response in treatment-naive patients with HCV GT2 or GT3. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 34.

31. Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med. 2012;366:216-224.

32. Chayama K, Takahashi S, Kawakami Y, et al. Dual oral combination therapy with the NS5A inhibitor daclatasvir (DCV; BMS-790052) and the NS3 protease inhibitor asunaprevir (ASV; BMS-650032) achieved 90% sustained virologic response (SVR12) in Japanese HCV genotype 1b–infected null responders. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract LB4.

33. Fridell RA, Qiu D, Wang C, Valera L, Gao M. Resistance analysis of the hepatitis C virus NS5A inhibitor BMS-790052 in an in vitro replicon system. Antimicrob Agents Chemother. 2010;54:3641-3650.

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