August 31, 2010

August 30, 2010

HIV-positive women who are breastfeeding should not be given vitamin A supplements because it increases the risk of transmitting the AIDS virus to their infants, researchers said Thursday. Mother-to-child transmission of HIV has been largely controlled in the United States and other developed countries through the use of antiretroviral drugs, but is a major problem in the developing world. In 2008, there were 430,000 new HIV infections in infants, most of them in sub-Saharan Africa, and breast feeding accounted for more than 95% of them. Vitamin A supplements are commonly given to pregnant women in such countries, but physicians generally do not take into account the women's HIV status.

In one study reported in the American Journal of Clinical Nutrition, epidemiologist Eduardo Villamor of the University of Michigan School of Public Health and his colleagues studied 1,078 HIV-positive women who were pregnant. Half received 5,000 international units of vitamin A and 30 milligrams of beta-carotene every day during gestation and lactation and half received a placebo. The combination of supplements increased the risk of passing the virus to the infants, and it appeared that each supplement had an effect individually, Villamor said.

In a second study in the same journal, Villamor and his colleagues found that the supplements increase the risk of subclinical mastitis in HIV-positive women. Subclinical mastitis is an inflammatory condition that causes blood plasma to leak into the mammary gland, carrying virus particles with it.

"The takeaway is that daily supplementation of HIV-infected pregnant or lactating women with vitamin A and beta-carotene at the doses tested is probably not safe and efforts need to be strengthened on preventing mother-to-child transmission through other interventions, such as antiretroviral agents," Villamor said in a statement.

-- Thomas H. Maugh II / Los Angeles Times

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Bethesda, MD (Aug. 26, 2010) — Compliance with practice guideline-recommended treatment for cirrhosis is associated with a reduction in first esophageal variceal hemorrhage (EVH; bleeding), according to a new study in Clinical Gastroenterology and Hepatology, the official journal of the American Gastroenterological Association (AGA) Institute. Cirrhosis is a condition in which the liver is permanently scarred or injured.

“Esophageal variceal hemorrhage is a serious complication of cirrhosis, and the mortality rate associated with it is high at 20 percent,” said Jayavani Moodley, MD, of the Cleveland Clinic Foundation and lead author of the study. “This high mortality rate makes primary prevention of bleeding the best approach to improving outcomes for these patients.”

In this study, doctors conducted an Institutional Review Board-approved retrospective chart review on 179 adult patients selected by computerized randomization, newly evaluated for cirrhosis at the Cleveland Clinic from 2003 to 2006. These patients were followed for 23 months; doctors assessed actual compliance rates of gastroenterologists with current practice guidelines, which recommend screening and intervention for high-risk esophageal varices. Subsequent bleeding rates were also determined.

The study authors reported that 94 percent of the patients had a screening endoscopy (EGD), with 80 percent having one within six months of the initial visit. Varices were present in half of the patients. In addition, 68 percent of all patients screened and 91 percent with large varices received a practice guideline-recommended treatment. Seven percent had an episode of EVH; 82 percent of patients without bleeding had their screening EGD within six months versus 50 percent of those with bleeding. The likelihood of bleeding at two years, as predicted by the North Italian Endoscopy Club model, was 13 percent versus 27 percent.

“Our study suggests that the significant reduction in observed bleeding rates may be related to adherence to practice guideline-recommended care. Patients who did not bleed were more likely to have received their screening EGD within the six-month window as compared to those who bled, demonstrating the effectiveness of early variceal screening,” added Dr. Moodley.

The risk of developing gastroesophageal varices in patients with cirrhosis is between 50 percent and 66 percent, and 30 percent to 40 percent of patients with varices suffer a variceal hemorrhage. If untreated, variceal hemorrhage portends a 70 percent risk of death within one year.

About Cirrhosis

Cirrhosis occurs when the liver is permanently scarred or injured by chronic conditions and diseases. The scar tissue that forms in cirrhosis harms the structure of the liver, blocking the flow of blood through the organ.

To learn more about cirrhosis, visit the patient center on the AGA Web site at www.gastro.org/patient-center.

About the AGA Institute

The American Gastroenterological Association is the trusted voice of the GI community. Founded in 1897, the AGA has grown to include 17,000 members from around the globe who are involved in all aspects of the science, practice and advancement of gastroenterology. The AGA Institute administers the practice, research and educational programs of the organization. http://www.gastro.org/.

About Clinical Gastroenterology and Hepatology

The mission of Clinical Gastroenterology and Hepatology is to provide readers with a broad spectrum of themes in clinical gastroenterology and hepatology. This monthly peer-reviewed journal includes original articles as well as scholarly reviews, with the goal that all articles published will be immediately relevant to the practice of gastroenterology and hepatology. For more information, visit http://www.cghjournal.org/.
 
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2010-08-30, Source: Bionor Pharma  

Bionor Pharma (OSLO: BIONOR) today reported preliminary findings of its Phase 2 trial that served to re-immunize, or "re-vaccinate" twenty five study volunteers from its original Phase 2a study conducted in 2002/2003. Previously, at the XVIII International AIDS Conference in Vienna in July 2010, the Company reported that about half of the study volunteers retained memory to Vacc-4x seven years after their initial immunization. Bionor Pharma researchers now report that this memory can be safely reactivated following re-immunization/re-vaccination resulting in improved anti-viral responses.
 
Two thirds of study volunteers responded to Vacc-4x, and these responses were found to be cross-reactive with the virus itself. The study also showed that Vacc-4x is capable of triggering the specific T-cells of the immune system that function to seek out and kill infected cells (CD8+ killer T-cells) which is the objective of a successful T-cell vaccine. The complete study results are being prepared for publication in an international peer reviewed journal.

'It is promising that Vacc-4x has been able to induce such durable memory in patients and that this can be re-boosted many years later even after long periods of treatment interruption,' says Prof. Dag Kvale from Oslo University Hospital, Norway, who has led the study. 'This therapeutic vaccination technique demonstrates clearly a potential to achieve sustained immune responses which can be boosted while on antiretroviral therapy.'

Vacc-4x is composed of four modified peptides corresponding to conserved regions of the HIV core protein (p24) that are injected intradermally beneath the skin. This method of immunization is relatively simple and suited to a regime involving periodic boosting. A phase IIa study carried out in 2002/2003 showed that Vacc-4x could support prolonged periods free of antiretroviral therapy (average 31 months). Twenty five of the study volunteers who participated in the original phase IIa study have now been successfully given a voluntary 're-vaccination' with Vacc-4x and followed while on antiretroviral therapy.

About Bionor Pharma

Bionor Pharma is an innovative biotech company developing synthetic peptide vaccines that stimulate cell-mediated immunity using T-cell stimulation.

Bionor Pharma carefully designs synthetic peptides from low-mutating parts of the virus with improved immunogenicity, resulting in improved efficacy and safety profiles. HIV is the first disease targeted, with the most advanced vaccine candidate about to finish clinical phase IIb. However, Bionor Pharma's platform technology is broadly applicable, and the company has vaccine candidates also for chronic infections such as Hepatitis C (HCV), Human Papilloma Virus (HPV) and Influenza. Bionor Pharma ASA is listed on the Oslo Stock Exchange under the ticker symbol [BIONOR].

Contact information:

Trond Syvertsen
CEO
+47 23 01 09 60
+47 91 72 14 57
Email Contact

Rolf Henning Lem
CFO
+47 23 01 09 60
+47 97 74 88 45
Email Contact

Birger Sorensen
EVP Head of Vaccines
+47 404 07 565
+47 23 01 09 60
Email Contact

Washington DC, USA
David Sheon
Investor Relations
+1 202 547-2880
+1 202 422-6999
Email Contact
 
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Update to Hepatitis C Infection Control Investigation

JACKSONVILLE, Fla. — Mayo Clinic is working closely with the Florida Department of Health and in consultation with the Centers for Disease Control and Prevention to determine which patients should undergo follow-up testing after the Clinic last week discovered that a now, former employee put patients at risk for exposure to hepatitis C.

Mayo Clinic terminated the radiology technologist’s employment after he admitted stealing injectable fentanyl for personal use. His admission came after he was questioned about why his strain of hepatitis C infection was found to be similar to the strain of hepatitis C in three patients who underwent interventional radiology procedures over the last four years. For more details, see Mayo Clinic’s news blog at http://newsblog.mayoclinic.org/2010/08/24/employee-terminated-after-confessing-to-drug-diversion/.

“We find it heartbreaking that the actions of this single individual may have impacted some of our patients,” said William C. Rupp, M.D., CEO of Mayo Clinic in Florida. “We are devoted to meeting patient needs as we respond to this situation. We pride ourselves on offering safe, high-quality patient care. Patients have my firm commitment and the commitment of our entire team that Mayo Clinic will do everything possible to maintain the trust they have placed in us.”

The number of patients who might be affected is still being determined. Mayo Clinic will send letters to these patients and will make hepatitis C testing available at no charge to them. Specific details about testing options for patients who are at risk will be released later this week.

Patients who have questions or may be concerned that they may be at risk of infection can call the toll-free hotline at 877-956-1768 or 904-956-1768. Mayo Clinic nurses staffing the hotline can answer questions or concerns from patients about hepatitis C. Approximately 725 people have called the hotline since it was established last Wednesday.

Further information about hepatitis C is available on the Mayo Clinic website at http://www.mayoclinic.com/health/hepatitis-c/DS00097 or the Centers for Disease Control and Prevention website at http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf.

Mayo Clinic will provide additional information about this situation as it becomes available.

This entry was written by Newsletter Editor, posted on August 30, 2010 at 2:55 pm
 
Source
World J Gastroenterol 2010 August;16(32):4061-4065

Nash KL, Woodall T, Brown AS, Davies SE, Alexander GJ.

Department of Hepatology, Mailpoint 255, Southampton General Hospital, Tremona Road, Southampton, Hampshire SO16 6YD, United Kingdom. klnash11@yahoo.co.uk

AIM: To investigate and characterise patients with chronic hepatitis C virus (HCV) infection presenting with hepatocellular carcinoma (HCC) in the absence of cirrhosis. METHODS: Patients with chronic hepatitis C infection without cirrhosis presenting with HCC over a 2-year period were identified. The clinical case notes, blood test results and histological specimens were reviewed to identify whether additional risk factors for the development of HCC were present. RESULTS: Six patients (five male, one female) with chronic hepatitis C infection without cirrhosis presented to a single centre with HCC over a 2-year period. Five patients were treated by surgical resection and one patient underwent liver transplantation. Evaluation of generous histological specimens confirmed the presence of HCC and the absence of cirrhosis in all cases. The degree of fibrosis of the background liver was staged as mild (n = 1), moderate (n = 4) or bridging fibrosis (n = 1). Review of the clinical case notes revealed that all cases had an additional risk factor for the development of HCC (four had evidence of past hepatitis B virus infection; two had a history of excessive alcohol consumption; a further patient had prolonged exposure to immune suppression). CONCLUSION: HCC does occur in patients with non-cirrhotic HCV infection who have other risk factors for hepatocarcinogenesis.
 
Source
Articles in Press

Silvia Fargion, Luca Valenti, Anna Ludovica Fracanzani

Received 14 May 2010; accepted 22 July 2010. published online 27 August 2010.
Corrected Proof

Abstract

Following the model of hereditary hemochromatosis, the possible role of iron overload as a cofactor for disease progression in acquired liver diseases has been investigated with controversial results. In recent years, progress has been made in understanding the regulation of iron metabolism, thereby allowing the evaluation of the mechanisms linking liver diseases to excessive iron accumulation. Indeed, deregulation of the transcription of hepcidin, emerging as the master regulator of systemic iron metabolism, has been implicated in the pathogenesis of hepatic iron overload in chronic liver diseases. Whatever the cause, hepatocellular iron deposition promotes liver fibrogenesis, while an emerging possible aggravating factor is represented by the strong link between iron stores and insulin resistance, a recently recognized risk factor for the progression of liver diseases. Overall, these pathogenic mechanisms, together with the known proliferative and mutagenic effect of excess iron, converge in determining an increased susceptibility to hepatocellular carcinoma. Finally, an association between serum ferritin levels and mortality in patients with end-stage liver disease has recently been reported.

Prospective, randomized studies are required to evaluate whether iron depletion may reduce fibrosis progression, hepatocellular carcinoma development, and eventually mortality in patients with chronic liver diseases.

Keywords: Chronic hepatitis C, Hepatocarcinoma, Hepcidin, Nonalcoholic steatohepatitis

The Department of Internal Medicine, Università degli Studi, Fondazione IRCCS Ospedale Maggiore Policlinico “Ca’ Granda” IRCCS, Milan, Italy

Corresponding author. Tel.: +39 02 55033301; fax: +39 02 50320296.
PII: S1590-8658(10)00257-4
doi:10.1016/j.dld.2010.07.006
© 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Inc All rights reserved.

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Natural history and treatment of chronic delta hepatitis

J Viral Hepat. 2010 Aug 15.
Yurdaydın C, Idilman R, Bozkaya H, Bozdayi AM.
Gastroenterology Department, University of Ankara Medical School, Ankara, Turkey.

Abstract

Summary. Chronic delta hepatitis (CDH) represents a severe form of chronic viral hepatitis, induced by the hepatitis delta virus (HDV) in conjunction with the hepatitis B virus (HBV). Delta hepatitis may lead to disease in humans through co-infection. The former leads to acute hepatitis which clinically can range from mild hepatitis to fulminant hepatitis and death. Severe or fulminant hepatitis is more often observed with HBV-HDV co-infection compared to HBV mono-infection. Chronic infection after acute hepatitis B + D co-infection is infrequent and similar to the rate in mono-infected patients. CDH develops in 70-90% of patients with superinfection. CDH runs a more progressive course than chronic hepatitis B and may lead to cirrhosis within 2 years in 10-15% of patients. However, as with any immune-mediated disease, different patterns of progression, ranging from mild to severe progressive disease, are observed. Active replication of both HBV and HDV may be associated with a more progressive disease pattern. Further, different HDV and HBV genotypes may contribute to various disease outcomes. CDH may be frequently associated with hepatocellular carcinoma development although recent studies provided conflicting results. The only established therapy for CDH is treatment with interferons for a duration of at least 1 year. On treatment, 6 month HDV RNA assessment may give clues as to whether to stop treatment at 1 year or continue beyond 1 year. New approaches to treatment of CDH are an urgent need of which the use of prenylation inhibitors appears the most promising.

PMID: 20723036 [PubMed - as supplied by publisher]

Source
J Viral Hepat. 2010 Aug 17. [Epub ahead of print]
Chotiyaputta W, Degertekin B, McKenna BJ, Samala N, Fontana RJ, Lok AS.
Division of Gastroenterology, Department of Internal Medicine Ann Arbor, MI, USA.

Abstract

Summary. Significant liver disease has been reported in chronic hepatitis B patients with normal alanine aminotransferase (ALT) but most studies performed biopsies on selected patients only. The aims of this study were to determine the rate of liver biopsy, characteristics of patients who underwent a biopsy and factors associated with significant liver disease in a cohort of such patients. Records of patients with chronic hepatitis B during a 10-year period were reviewed. Significant liver disease was defined as Knodell HAI >/= 7 and/or Ishak fibrosis >/= 3. Of 743 patients, 55.7% were Asian, 56.4% were men, and the mean age was 43.1 years. One hundred and ninety-three (26%) had undergone a biopsy. Biopsied patients were more likely to be men, HBeAg positive, and had lower platelet and higher alkaline phosphatase, bilirubin, ALT and hepatitis B virus (HBV) DNA. Significant liver disease was observed in 20% of patients who had normal ALT at presentation, 14% of those with normal ALT at the time of biopsy and in none of the patients with persistently normal ALT. Patients with normal ALT who were biopsied had higher HBV DNA and higher ALT than those not biopsied. Multivariate analysis showed that low albumin at the time of biopsy and HBV DNA >5 log(10) copies/mL were predictors of significant liver disease. Significant liver disease is rare in patients with chronic HBV and persistently normal ALT and liver histology of chronic HBV infected patients with normal ALT cannot be generalized to other patients with normal ALT that were not biopsied.

PMID: 20726947 [PubMed - as supplied by publisher]

Source
Clinical Infectious Diseases 2010;51:000–000
© 2010 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2010/5107-00XX$15.00
DOI: 10.1086/656235

MAJOR ARTICLE

Juan A. Pineda, 1 Antonio Caruz, 3 Antonio Rivero, 4 Karin Neukam, 1 Irene Salas, 3 Ángela Camacho, 4 José C. Palomares, 2 José A. Mira, 1 Antonio Martínez, 5 Carmen Roldán, 1 Julián de la Torre, 4 and Juan Macías 1

Units of 1 Infectious Diseases and 2 Microbiology, Hospital Universitario de Valme, Seville, 3 Immunogenetics Unit, Faculty of Sciences, Universidad de Jaen, Jaen, and 4 Unit of Infectious Diseases and 5 Molecular Genetics Laboratory, Unit of Clinical Analysis, Hospital Universitario Reina Sofía, Cordoba, Spain

Background. Variation in the IL28B gene is associated with sustained virologic response (SVR) to pegylated interferon plus ribavirin in hepatitis C virus (HCV)–monoinfected patients with genotype 1. Data on other genotypes and on patients coinfected with human immunodeficiency virus (HIV) and HCV are more limited. We aimed to assess the predictive ability of variations in the single‐nucleotide polymorphism rs12979860 for SVR in HIV/HCV‐coinfected patients, regardless of HCV genotype.

Methods. The rs12979860 genotype was determined by polymerase chain reaction in 154 patients who had received therapy against HCV with pegylated interferon plus ribavirin.

Results. rs12979860 genotype was TT in 20 patients (13%), TC in 66 patients (43%), and CC in 68 patients (44%). Rates of SVR in patients with genotype CC and in those with genotype TC or TT, according to HCV genotype, were, respectively, 50% and 17% ( ) in patients with genotype 1, 80% and 25% ( ) in patients with genotype 4, and 93% and 77% ( ) in patients with genotype 3. The median (interquartile range) low‐density lipoprotein cholesterol level in patients with rs12979860 CC was 89 mg/dL (73–120 mg/dL) versus 75 mg/dL (55–91 mg/dL) ( ) in those with TC or TT. Independent predictors of SVR were HCV genotype 2–3 (odds ratio [OR], 13.98; 95% confidence interval [CI], 4.87–40.1; ), rs12979860 CC (OR, 5.05; 95% CI, 2.04–12.5; ), baseline plasma HCV RNA load of 600,000 IU/mL (OR, 1.99; 95% CI, 1.18–3.34; ), and female sex (OR, 4.28; 95% CI, 1.08–16.96; ).

Conclusions. IL28B gene variations independently predict SVR in HIV/HCV‐coinfected patients with HCV genotype 1 and non–genotype 1 HCV infection. The association between rs12979860 and plasma low‐density lipoprotein cholesterol suggests that the system low‐density lipoprotein ligand/receptor might be involved in the effect of this genotype.

Received 20 February 2010; accepted 9 June 2010; electronically published 30 August 2010.

Reprints or correspondence: Dr Juan A. Pineda, Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Avda de Bellavista, 41014 Sevilla, Spain (japineda@telefonica.net); or Dr Karin Neukam, Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Avda de Bellavista, 41014 Sevilla, Spain (keule165@gmail.com).
 
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From AIDS Clinical Care
Dan H. Barouch, MD, PhD
Posted: 08/30/2010; AIDS Clinical Care © 2010 Massachusetts Medical Society

Abstract and Introduction

Abstract

One monoclonal antibody neutralizes >90% of worldwide circulating HIV-1 isolates.

Introduction

One of the major roadblocks in the development of an HIV-1 vaccine has been the inability of vaccine immunogens to elicit broadly reactive HIV-1 Env–specific neutralizing antibodies. Some investigators have questioned whether the human immune system is even capable of generating such broadly reactive antibodies, given the extent of virus variability worldwide and the immune evasion tactics employed by the virus.

Researchers now describe the isolation and structural analysis of a new broadly reactive HIV-1 Env–specific monoclonal antibody (mAb) called VRC01, which was derived from an HIV-1–infected individual with broadly reactive serum neutralizing antibodies. Prior work from these investigators and others identified the CD4 binding site as a largely conserved site on HIV-1 Env that was the target of a different mAb (b12). VRC01 also targets the CD4 binding site, but it exhibits greater breadth, neutralizing >90% of HIV-1 isolates circulating worldwide. Moreover, it neutralizes these isolates with substantial potency. Interestingly, VRC01 partially mimics CD4 binding to HIV-1 Env, but the crystal structure shows that its orientation differs slightly from that of CD4, allowing it to target the vulnerable site of initial CD4 binding very precisely. Molecular sequence analysis also reveals that the variable loops of VRC01 have undergone extensive somatic hypermutation and affinity maturation — factors that likely contribute to the breadth and potency of this mAb.

Comment
 
Another study published last year described the isolation and characterization of two other new broadly reactive mAbs, PG9 and PG16, which were also derived from an HIV-1–infected individual with broadly reactive serum neutralizing antibodies (Science 2009; 326:285). These mAbs exhibit substantial breadth and potency, and they have been shown to bind to conserved portions of the variable V2 and V3 loops on the intact HIV-1 Env trimer — a previously undescribed epitope that could represent a potential new HIV-1 vaccine target.

Taken together, these studies demonstrate that exceptionally broadly reactive neutralizing antibodies with substantial potency can indeed be generated in HIV-1–infected humans, probably at higher frequencies than previously recognized. As basic research tools, these new mAbs will prove invaluable. Moreover, their identification and characterization may lead to insights into HIV-1 vaccine design by identifying new targets and defining mechanisms of action. A major challenge now is to use this knowledge to improve HIV-1 vaccine immunogens — a daunting task, given how difficult it has been in the past to translate increased understanding of mAbs into improved vaccine immunogens. Nevertheless, these recent advances offer increased hope that an HIV-1 vaccine may indeed be possible.

References

• Wu X et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 2010 Jul 8.

• Zhou T et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 2010 Jul 8.
 
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DEA Heads First-Ever Nationwide Prescription Drug Take-Back Day

News Release
FOR IMMEDIATE RELEASE
August 19, 2010
Contact: DEA Public Affairs
Number: 202-307-7977

DEA Heads First-Ever Nationwide Prescription Drug Take-Back Day

AUG 19 -- WASHINGTON, D.C. – The Drug Enforcement Administration and government, community, public health and law enforcement partners today announced a nationwide prescription drug “Take-Back” initiative that seeks to prevent increased pill abuse and theft. DEA will be collecting potentially dangerous expired, unused, and unwanted prescription drugs for destruction at sites nationwide o n Saturday, September 25 th from 10 a.m. to 2 p.m. local time. The service is free and anonymous, no questions asked.

This initiative addresses a vital public safety and public health issue. Many Americans are not aware that medicines that languish in home cabinets are highly susceptible to diversion, misuse, and abuse. Rates of prescription drug abuse in the U.S. are increasing at alarming rates, as are the number of accidental poisonings and overdoses due to these drugs. Studies show that a majority of abused prescription drugs are obtained from family and friends, including from the home medicine cabinet. In addition, many Americans do not know how to properly dispose of their unused medicine, often flushing them down the toilet or throwing them away – both potential safety and health hazards.

“Today we are launching a first-ever National Prescription Drug Take-Back campaign that will provide a safe way for Americans to dispose of their unwanted prescription drugs,” said Michele M. Leonhart, Acting Administrator of the Drug Enforcement Administration. “This effort symbolizes DEA’s commitment to halting the disturbing rise in addiction caused by their misuse and abuse. Working together with our state and local partners, the medical community, anti-drug coalitions, and a concerned public, we will eliminate a major source of abused prescription drugs, and reduce the hazard they pose to our families and communities in a safe, legal, and environmentally sound way.”

“With this National Prescription Drug Take-Back campaign, we are aggressively reaching out to individuals to encourage them to rid their households of unused prescription drugs that pose a safety hazard and can contribute to prescription drug abuse,” said Acting Deputy Attorney General Gary G. Grindler. “The Department of Justice is committed to doing everything we can to make our communities safer, and this initiative represents a new front in our efforts.”

“Prescription drug abuse is the Nation’s fastest-growing drug problem, and take-back events like this one are an indispensable tool for reducing the threat that the diversion and abuse of these drugs pose to public health,” said Director of National Drug Control Policy Gil Kerlikowske. “The Federal/state/and local collaboration represented in this initiative is key in our national efforts to reduce pharmaceutical drug diversion and abuse.”

Collection sites in every local community can be found by going to www.dea.gov . This site will be continuously updated with new take-back locations. Other participants in this initiative include the White House Office of National Drug Control Policy; the Partnership for a Drug-Free America; the International Association of Chiefs of Police; the National Association of Attorneys General; the National Association of Boards of Pharmacy; the Federation of State Medical Boards; and the National District Attorneys Association.

Source
SUMMARY: People with hepatitis C virus (HCV) who spontaneously clear the infection without treatment have a low risk of death, less than 10% over 5 years, according to a Danish study published in the July 2010 Journal of Hepatology. Individuals who develop chronic hepatitis C, however, have an elevated risk of overall and liver-related mortality, including deaths due to primary liver cancer.

By Liz Highleyman

Most experts estimate that approximately one-quarter to one-third of people initially infected with HCV will naturally clear the virus without treatment thanks to an effective immune response. Among those with persistent infection, however, HCV can over years or decades cause serious liver disease including cirrhosis and hepatocellular carcinoma, a form of primary liver cancer.

Research has shown that people with chronic hepatitis C have a higher risk of liver-related death, but outcomes among people who were once infected but naturally cleared the virus have not been extensively studied.

In the present analysis, Lars Haukali Omland and fellow investigators with the DANVIR Cohort Study examined the association between chronic HCV replication and mortality among Danish patients who tested positive for HCV antibodies.

This nationwide cohort study looked at more than 6000 patients with at least 1 HCV RNA (genetic material) viral load measurement available after testing positive for HCV antibodies between 1996 and 2005. To capture long-term outcomes, eligible participants needed to be alive for at least 1 year after HCV RNA assessment.

The researchers estimated mortality rate ratios (MRRs) for overall mortality and sub-distribution hazard ratios (SDHRs) for cause-specific mortality, after controlling for patient sex, age, co-existing conditions, heavy alcohol use, injection drug use, and income.

Results
  • Of the 6292 patients in the study, 37% spontaneously cleared HCV, while 63% developed chronic infection.
  • Overall 5-year survival rates were 92% for participants who cleared the virus, compared with 86% for those with chronic infection.
  • Chronic HCV infection was associated with higher overall mortality compared with viral clearance (MRR 1.55).
  • Chronic infection was also associated with a more than a 2-fold greater risk of liver-related death (SDHR 2.42).
  • In particular, chronic HCV infection greatly increased -- by more than 16-fold -- the risk of death due to primary liver cancer (SDHR 16.47). 
Based on these findings, the study authors concluded, "Patients with chronic HCV infection are at higher risk of death than patients who cleared the infection."

"The substantial association found between chronic HCV infection and death from primary liver cancer supports early initiation of antiviral treatment in chronically HCV-infected patients," they recommended.

Investigator affiliations: Department of Infectious Diseases, Rigshospitalet, Copenhagen; Department of Clinical Biochemistry, Aalborg Hospital; Department of Clinical Epidemiology, Aarhus University Hospital; Department of Clinical Immunology, Odense University Hospital; Department of Clinical Immunology and Blood Bank, Rigshospitalet, Copenhagen; Department of Clinical Immunology, Viborg Region Hospital; Department of Clinical Immunology, Hospital of Southern Jutland, Region of Southern Denmark; Department of Clinical Microbiology, Vejle Hospital; Department of Infectious Diseases, Odense University Hospital, Denmark; Department of Epidemiology, Boston University School of Public Health, Boston, MA.

8/31/10

Reference
LH Omland, H Krarup, P Jepsen, and others (DANVIR Cohort Study). Mortality in patients with chronic and cleared hepatitis C viral infection: a nationwide cohort study. Journal of Hepatology 53(1): 36-42 (Abstract). July 2010.

Source
SUMMARY: Children with hepatitis C virus (HCV) infection who were treated with pegylated interferon plus ribavirin showed a high rate of sustained virological response, greater than that seen in most adult studies, according to a report in the June 2010 Journal of Hepatology. Nearly 60% of children with hard-to-treat HCV genotypes including 1 and 4 -- and more than 90% of those with easier-to-treat genotypes 2 or 3 -- achieved a cure.

By Liz Highleyman

Studies of combination interferon-based therapy for chronic hepatitis C usually focus on adults, who typically demonstrate sustained virological response (SVR) rates of just under 50% for HCV genotype 1 and 70%-80% for genotypes 2 or 3 using a standard regimen of pegylated interferon plus ribavirin for 48 or 24 weeks, respectively. Treatment of children with hepatitis C has not been as extensively studied.

In the present study, Etienne Sokal from Catholic University Louvain in Belgium and an international team of colleagues evaluated the safety and efficacy of pegylated interferon alfa-2a (Pegasys) plus ribavirin in previously untreated HCV antibody positive children with detectable HCV RNA viral load.

This prospective analysis included 18 children with HCV genotypes 2 or 3, who were treated for 24 weeks, and 47 children with harder-to-treat genotypes 1, 4, 5, or 6, who were treated for 48 weeks.

Results
  • 83% of the genotype 2/3 children and 57% of the genotype 1/4/5/6 children achieved early virological response at week 12.
  • End-of-treatment response rates were 94% (at week 24) and 57% (at week 48), respectively.
  • Relapse rates were low, with 89% of easier-to-treat participants and 57% of hard-to-treat children achieving sustained response at 24 weeks after completion of therapy.
  • 10 participants overall (15%) stopped treatment prematurely -- 2 due to serious adverse events and 8 due to lack of virological response at week 24.
  • 15 children overall (23%) had their pegylated interferon or ribavirin doses adjusted -- 11 (17%) due to neutropenia and 3 (5%) due to anemia.
  • The most common treatment-related adverse events included:
          --Fever and flu-like symptoms (54%);
          --Abdominal pain (38%);
          --Irritability, depression, or mood changes (34%);
          --Dermatitis (29%);
          --Vomiting (23%);
          --Loss of appetite (22%).
  • Interferon-based treatment had no observed effect on the children's growth in height.
These results, the researchers concluded, show that children have an improved rate of sustained virological response compared with reference studies of adult chronic C patients treated with similar regimens.

Investigator affiliations: Université Catholique de Louvain, Cliniques universitaires St Luc, Bruxelles, Belgium; Paediatric Gastroenterology, Hospital de clinicas de Porto Alegre, Porto Alegre, Brazil; Unidade de Hepatologica Pediatrica, Hospital das clinicas da faculdade de medicina da universidade de Sao Paulo, Sao Paulo, Brazil; Department of Pediatrics, Stradinš University, Riga, Latvia; Department of Paediatrics, CLINTEC, Karolinska University Hospital, Huddinge, Stockholm, Sweden; Liver Unit, Birmingham Children's Hospital, Birmingham, UK.

8/31/10

Reference
EM Sokal, A Bourgois, X Stéphenne, and others. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in children and adolescents. Journal of Hepatology 52(6): 827-831 (Abstract). June 2010.

Source

August 29, 2010

Hepatitis C and End-stage Liver Disease

Current Hepatitis Reports
DOI: 10.1007/s11901-010-0056-0
 
Diane M. Settles and Rakesh Vinayek
 
Online First™, 27 August 2010
 
Abstract
 
Cirrhosis secondary to infection with hepatitis C virus (HCV) is one of the leading causes of end-stage liver disease worldwide. The World Health Organization estimates that about 3% of the world population is chronically infected with HCV, with about 4 million infected individuals in the United States. Despite the declining US incidence of HCV, the complications of chronic HCV infection are rising rapidly. The cirrhosis can be classified as compensated or decompensated based on clinical complications. Compensated HCV-related cirrhosis can be treated safely per American Association for the Study of Liver Diseases guidelines. Treatment of decompensated HCV-related cirrhosis is challenging secondary to increased risk of complications and adverse effects during the course of antiviral therapy. The recommended treatment is the low, but accelerating dose regimen. HCV-related cirrhosis is associated with complications including ascites, variceal bleeding, renal insufficiency, hepatic encephalopathy, and hepatocellular carcinoma. Because of its poor prognosis, liver transplantation is the only definitive therapy for decompensated cirrhosis.

Keywords Hepatitis C - Cirrhosis - Portal hypertension - Complications of cirrhosis - Hepatocellular carcinoma - Variceal bleeding

Source
 
(Reprinted with kind permission from Springer Science+Business Media)
The Journal of Infectious Diseases 2010 Sept Early publication

Josiah D. Rich and Lynn E. Taylor

Brown Medical School and Miriam Hospital Immunology Center, Brown University, Providence, Rhode Island

"This group is the first to our knowledge to develop a microculture assay to detect viable HCV in small volumes of blood found in syringes. This work suggests that the duration of survival of HCV in used syringes and the amount of residual blood inside the syringe are important parameters for understanding transmission. The ability to use cultured virus to explore transmission mechanisms and develop prevention interventions has the potential to revolutionize the field. There has already been an improved understanding of the role played by biocides for HCV treatment [20].

Heimer's earlier work employed similar methods to illuminate the transmission dynamics of HIV during injection drug use [21, 22]. His group demonstrated that HIV can survive in a syringe for months. This finding, along with his team's elegant mathematical modeling studies, proved that reducing syringe circulation time could lead to reduced HIV transmission. This provided critical early evidence in support of needle exchange programs (NEPs). NEPs have had a huge impact on the reduction of HIV transmission. However, NEPs do not seem to have had as dramatic an effect on the reduction of HCV transmission among IDUs; Heimer's HCV transmission model may facilitate understanding of why this is so. It is estimated that an individual IDU injects 1000 times a year. HCV transmission remains unrestrained among IDUs, with incidence rates ranging from 16% to 42% per year [25]. This novel investigation provides robust evidence about the dynamics of viral transmission with syringes, using simulated injecting practices. More importantly, the ability to culture HCV heralds a new era in which the combination of basic laboratory, epidemiologic, and ethnographic research should allow a much more precise understanding of HCV transmission and pave the way for designing and targeting future public health interventions to prevent HCV infection."

Hepatitis C virus (HCV) infection is a staggering problem in the United States and worldwide. In the United States, HCV is responsible for 12,000 deaths each year, is the most common bloodborne pathogen, and is a leading cause of liver transplantation. Although more than 4 million people in the Unites States and 180 million worldwide (about 3%) are chronically infected, most are not aware of their diagnosis. The disease burden and mortality from HCV infection are predicted to increase in the United States 2-fold to 3-fold over the next 10-20 years as the number of persons with long duration of infection grows. This will greatly affect individual and public health and will lead to a substantial economic burden as well. Most HCV-related mortality is occurring in men <60 years of age (and disproportionately among non-Hispanic black men [1]), which makes HCV a leading infectious cause of years of potential life lost. Death due to HCV infection is the most frequent cause of non-AIDS-related death for human immunodeficiency virus (HIV)-infected persons with access to highly active antiretroviral therapy [2].

Since the discovery of a reliable test for HCV antibodies in 1990 [3], we have learned a great deal about the virus-that it leads to chronic infection in about 85% of exposures, that those who are infected have an average chance of 20% of developing cirrhosis after 20 years, and that those who consume alcohol, as well as those who are coinfected with HIV, are much more likely to progress to cirrhosis and death than others. Although HCV is curable, and antiviral HCV treatment leading to viral eradication reduces liver-related morbidity and mortality, treatment with pegylated interferon plus ribavirin is burdensome, toxic, expensive, and ineffective for half of those who attempt therapy [4-6]. Treatment initiation rates are low across varied settings [7-11]. Most patients diagnosed with chronic HCV infection have not received antiviral therapy. This is due, in part, to restrictive treatment criteria excluding patients with concomitant substance use that led to the infection in the first place [12]. The treatment landscape is on the verge of a paradigm shift with the impending launch of specifically targeted antiviral therapy for HCV (STAT-C) to inhibit HCV-specific enzymes. Along with higher anticipated cure rates will come higher costs of therapy, increased toxicity, thrice daily pill dosing, and the introduction of resistance. The lack of an HCV vaccine and limitations of treatment highlight the imperative of developing strategies to prevent HCV transmission.

Although perinatal and sexual transmission occur (including sexual transmission among HIV-infected men who have sex with men [13]), the HCV epidemic is predominantly driven by the injection of illicit drugs [14]. Before 1992, when widespread screening of the blood supply began in the United States, HCV was also commonly spread through blood transfusions and organ transplants. Testing of blood donors for HCV RNA by means of nucleic acid amplification was introduced in the United States as an investigational screening test in mid-1999 to identify donations made during the window period before seroconversion [15]. In the United States, iatrogenic transmission has been almost completely eliminated with screening of the blood supply. However, there are still incidents of transmission, such as the 2007 HCV outbreak at a freestanding private endoscopy clinic in Nevada, resulting from reuse of syringes and use of single-use medication vials on multiple patients [16, 17].

Outside of the Unites States, one of the worst iatrogenic outbreaks of HCV infection occurred in Egypt where, from the 1960s to the 1980s, a mass campaign to eradicate schistosomiasis using repeated intravenous antischistosomal therapy inadvertently infected a generation. Decades later, the overall prevalence of HCV antibody is 15%-20% of the general population [18]. Clearly, the intravenous aspect of this campaign markedly increased the transmission rate. In the absence of mass treatment campaigns using intravenous medication, similar outbreaks are not anticipated. However, acute HCV infection is typically clinically silent, and routine screening for HCV is not recommended or done, so iatrogenic transmission of HCV may be more common than we know.

During intravenous injection by injection drug users (IDUs), blood (and any bloodborne virus such as HCV) is typically drawn up into the syringe to locate the vein, thus contaminating the inside of the syringe and creating an effective tool for transmission of whatever bloodborne pathogen is then lining the syringe. IDUs often lack knowledge about safe injection practices and the need for sterility and also often lack the necessary tools (ie, sterile syringes, diluent, mixing containers [cookers], and filters [cotton]) to prevent viral transmission.

Injection drug use remains a hidden and stigmatized behavior. Addiction is a chronic relapsing disease that is highly treatable, although most people do not get the treatment that they need. Preventive efforts should focus on IDUs, but this has not transpired on the massive scale required. IDUs have been overlooked in part because of the challenges involved in working with this population, the difficulty in finding IDUs, and the underlying stigma. In the United States, society's major response to addiction in terms of resources has been to criminalize and further drive underground the behavior, often alienating people from treatment, which then leads to negative health and social consequences. Most IDUs are incarcerated at some point, and this has contributed to an unprecedented rate of incarceration. This "intervention" is expensive and ultimately ineffective. However, while we work to redirect policies and resources toward evidence-based prevention, treatment, and harm reduction, mass incarceration allows us to find IDUs and provides opportunities to address prevention, diagnosis, and treatment of addiction and HCV infection in the correctional setting.

HCV is much more prevalent than HIV among IDUs, and yet the reason for this has not been fully elucidated. Are key determinants the differences in viral viability in syringes, the concentration of the virus, the volume of blood remaining in the syringes, or other factors? The increased prevalence of HCV among IDUs certainly contributes to the difference (with a higher prevalence of HCV, a given syringe is more likely to have been used by someone infected with HCV than someone with HIV) but probably does not explain it completely. Answering these questions has, until very recently, been hampered by the inability to culture HCV and the lack of a small animal model of HCV transmission.

In this issue of the Journal, Paintsil et al [19] have contributed to our understanding of the biological mechanisms of HCV transmission by developing an experimental model of injection drug use by using cultured virus from HCV-contaminated syringes. This group is the first to our knowledge to develop a microculture assay to detect viable HCV in small volumes of blood found in syringes. This work suggests that the duration of survival of HCV in used syringes and the amount of residual blood inside the syringe are important parameters for understanding transmission. The ability to use cultured virus to explore transmission mechanisms and develop prevention interventions has the potential to revolutionize the field. There has already been an improved understanding of the role played by biocides for HCV treatment [20].

Heimer's earlier work employed similar methods to illuminate the transmission dynamics of HIV during injection drug use [21, 22]. His group demonstrated that HIV can survive in a syringe for months. This finding, along with his team's elegant mathematical modeling studies, proved that reducing syringe circulation time could lead to reduced HIV transmission. This provided critical early evidence in support of needle exchange programs (NEPs). NEPs have had a huge impact on the reduction of HIV transmission. However, NEPs do not seem to have had as dramatic an effect on the reduction of HCV transmission among IDUs; Heimer's HCV transmission model may facilitate understanding of why this is so. Furthermore, although noninjection drug use has been epidemiologically linked to HCV transmission (perhaps through the use of contaminated drug-sniffing implements [23, 24]), it is possible that noninjection drug use is really just a marker for illicit, undetected injection drug use. Using simulated laboratory studies with cultured virus should contribute to understanding the mechanism(s) and relative contribution of noninjection drug use to HCV transmission.

It is estimated that an individual IDU injects about 1000 times a year. HCV transmission remains unrestrained among IDUs, with incidence rates ranging from 16% to 42% per year [25]. This novel investigation provides robust evidence about the dynamics of viral transmission with syringes, using simulated injecting practices. More importantly, the ability to culture HCV heralds a new era in which the combination of basic laboratory, epidemiologic, and ethnographic research should allow a much more precise understanding of HCV transmission and pave the way for designing and targeting future public health interventions to prevent HCV infection.

Source
 
Also See: Survival of Hepatitis C Virus in Syringes: Implication for Transmission among Injection Drug Users
Download the PDF Here

(from Jules: again, the 2nd recent study providing I think good evidence to consider early HCV treatment)

Hepatology Sept 2010 Timothy R. Morgan1,2,*, Marc G. Ghany3, Hae-Young Kim4, Kristin K. Snow4, Mitchell L. Shiffman5, Jennifer L. De Santo6, William M. Lee7, Adrian M. Di Bisceglie8, Herbert L. Bonkovsky9, Jules L. Dienstag10, Chihiro Morishima11, Karen L. Lindsay12, Anna S. F. Lok13

"Durability of SVR: Ninety-one SVR patients had follow-up HCV R NA testing performed an average of 78.6 ± 15.9 months (range: 22.1-99.6 months) after achieving SVR, and 90 of the 91 (99%) had undetectable HCV RNA in serum"

"In summary, we found that patients with advanced chronic hepatitis C who achieved SVR had significantly lower rates of death from any cause or liver transplantation, and of liver-related morbidity and mortality, compared to patients who failed to eliminate HCV with treatment (NR). Still, patients who achieved SVR remained at risk of HCC for at least 6 years after achieving SVR. Our study also showed that patients who had temporary, but complete viral suppression (BT/R) were less likely to die or undergo liver transplantation, or to experience liver-related complications than patients in the NR group, indicating that the duration of clinical benefit may outlast the period of actual viral suppression. Importantly, laboratory tests associated with liver-disease severity (e.g., platelet count, albumin) continued to improve after patients achieved SVR. Overall, our data indicate that patients with chronic hepatitis C and advanced hepatic fibrosis who achieve SVR have a marked reduction in the risk for death or liver transplantation, or of liver-related complications, and continued improvement in laboratory markers of liver function in the 5-6 years following successful viral eradication."

"An interesting and heretofore unreported finding was the intermediate risk of clinical outcomes in the BT/R group, between the risk of that for the NR and the SVR groups. In particular, the adjusted risk of death from any cause/liver transplantation or of any liver-related outcome was significantly lower in the BT/R group than in the NR group. The risks of decompensated liver disease, HCC, and liver-related death or liver transplantation were also lower in the BT/R group than in the NR group, although these differences did not reach statistical significance. These findings suggest that complete viral suppression is associated with a reduced risk of clinical outcomes and that the benefits may outlast the period in which HCV RNA is undetectable.16"


Abstract

Retrospective studies suggest that subjects with chronic hepatitis C and advanced fibrosis who achieve a sustained virological response (SVR) have a lower risk of hepatic decompensation and hepatocellular carcinoma (HCC). In this prospective analysis, we compared the rate of death from any cause or liver transplantation, and of liver-related morbidity and mortality, after antiviral therapy among patients who achieved SVR, virologic nonresponders (NR), and those with initial viral clearance but subsequent breakthrough or relapse (BT/R) in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) Trial. Laboratory and/or clinical outcome data were available for 140 of the 180 patients who achieved SVR. Patients with nonresponse (NR; n = 309) or who experienced breakthrough or relapse (BT/R; n = 77) were evaluated every 3 months for 3.5 years and then every 6 months thereafter. Outcomes included death, liver-related death, liver transplantation, decompensated liver disease, and HCC. Median follow-up for the SVR, BT/R, and NR groups of patients was 86, 85, and 79 months, respectively. At 7.5 years, the adjusted cumulative rate of death/liver transplantation and of liver-related morbidity/mortality in the SVR group (2.2% and 2.7%, respectively) was significantly lower than that of the NR group (21.3% and 27.2%, P < 0.001 for both) but not the BT/R group (4.4% and 8.7%). The adjusted hazard ratio (HR) for time to death/liver transplantation (HR = 0.17, 95% confidence interval [CI] = 0.06-0.46) or development of liver-related morbidity/mortality (HR = 0.15, 95% CI = 0.06-0.38) or HCC (HR = 0.19, 95% CI = 0.04-0.80) was significant for SVR compared to NR. Laboratory tests related to liver disease severity improved following SVR. Conclusion: Patients with advanced chronic hepatitis C who achieved SVR had a marked reduction in death/li ver transplantation, and in liver-related morbidity/mortality, altho ugh they remain at risk for HCC.

Clinical Outcomes of SVR Patients.

Five patients who achieved SVR (3.6%) had six liver-related clinical outcomes (Table 2). One patient (patient A) had a 3-cm lesion detected on ultrasound performed for his amended study clinic visit, 7.3 years after his baseline visit and 5.8 years after achieving SVR. At entry into the HALT-C Trial, he had a liver biopsy with an Ishak fibrosis score of 4 and his platelet count was 112,000/mm3. The resected specimen revealed a well-differentiated HCC; cirrhosis was present in the nontumor liver. Another patient (patient B) who had an Ishak fibrosis score of 3 on his baseline liver biopsy was found to have a 15-cm lesion on magnetic resonance imaging performed to evaluate an elevated AFP during a routine follow-up visit 5.8 years after his baseline visit and 4.4 years after achieving SVR. Biopsy of the lesion confirmed the presence of HCC and cirrhosis in the adjacent liver. This patient died of progressive HCC 4 months later. After magnetic resonance imaging was performed, a third patient (patient G) was found to have a 1.3-cm liver mass and underwent transarterial chemoembolization twice, followed by liver transplantation, but no tumor was found in the liver explant. This patient did not meet the HALT-C Trial criteria for presumed or definite HCC. Two patients with SVR experienced variceal hemorrhage (patients E and F).

Chronic hepatitis C virus (HCV) infection is a common cause of cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation. Follow-up studies of patients who achieved a sustained virological response (SVR) after antiviral therapy have demonstrated that the majority of patients continue to have undetectable serum HCV RNA, improvement in liver fibrosis, including reversal of cirrhosis, and a reduction in the incidence of decompensated liver disease and HCC compared with subjects who did not achieve an SVR.1-3 These studies notwithstanding, the beneficial effect of achieving an SVR on the outcome of patients with advanced chronic hepatitis C remains incompletely defined because prior studies were retrospective4-7 and included a small number of patients with cirrhosis2 and a relatively limited period of follow-up.8 In addition , few data are available on patients in the United States, because most of these studies were conducted in Japan or Europe.4-8 Furthermore, the beneficial effect of interferon and ribavirin treatment on the outcomes of patients with advanced hepatitis C who achieved viral clearance during treatment and who relapsed after discontinuation of treatment has not been established clearly.6

The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial was a multicenter study involving more than 1000 patients in the United States with advanced chronic hepatitis C and nonresponse to previous treatment with interferon-based therapy.9 During the lead-in phase of the HALT-C Trial, 1145 patients were treated with a combination of pegylated interferon and ribavirin; of these, 180 achieved SVR. Patients who did not achieve SVR entered the randomized phase of the HALT-C Trial and were followed prospectively for the development of fibrosis progression, decompensated liver disease, HCC, and death. The aim of the current study was to evaluate the effect of achieving SVR on overall mortality and on liver-related morbidity and mortality in this large, prospectively followed cohort of patients from the United States with advanced chronic hepatitis C.

DISCUSSION

We report here the results of a prospective, long-term follow-up study to evaluate the effect of achieving SVR with pegylated interferon and ribavirin treat ment on death from any cause or liver transplantation, and on liver- related morbidity and mortality, in a large cohort of patients in the United States with chronic hepatitis C and bridging fibrosis or cirrhosis. Patients who achieved SVR were compared with two groups of patients who were enrolled into the HALT-C Trial at the same time: (1) patients who failed to respond to peginterferon and ribavirin (NR) and (2) patients with virologic clearance at Week 20 but subsequent virologic breakthrough during combination antiviral therapy or relapse after completion of therapy (BT/R). In this cohort of patients with advanced chronic hepatitis C, we found that those who achieved SVR after peginterferon and ribavirin treatment had a significantly reduced risk of death from any cause/liver transplantation, and of liver-related morbidity and mortality, when compared with patients in the NR group. Importantly, achieving SVR significantly reduced the risk of developing each component of liver-related morbidity and mortality (i.e., hepatic decompensation, HCC, and liver-related death or liver transplantation) when compared with NR patients.

A strength of this study was the long duration of prospective follow-up. Patients were identified at entry into the HALT-C Trial and were followed for a median of 79 (NR) to 86 (SVR) months after starting their final course of peginterferon/ribavirin. Our findings on the effect of SVR on liver-related clinical outcomes are similar to those of retrospective, and often smaller, studies from Japan5, 7, 13-15 and Europe,6 the results of which supported an approximately 70%-90% reduction in the risk of liver-related clinical outcomes over a follow-up period of 2-6 years in patients achieving an SVR. An interesting observation in our study was the relative rapidity of the effect of achieving an SVR on hepatic decompensation; within 1 year, rates of decompensation among patients with an SVR and those with NR began to diverge. Both SVR patients in whom HCC developed had no discernable cause for ongoing liver damage . These data underscore the continued risk of HCC in patients with advanced chronic hepatitis C, even in those who achieved SVR, as has been noted previously.2, 4, 7-8, 13 Because both SVR patients in whom HCC developed were diagnosed more than 4 years (4.4 and 5.9) after achieving SVR, HCC surveillance should continue for more than 5 years after SVR, and probably for life.

Based on Cox proportional hazard analyses, we found that baseline platelet count was associated independently with all five outcomes, whereas albumin level was associated independently with four outcomes (not with HCC). Age and alkaline phosphatase were associated with the risk of HCC but not with any other outcome. This observation could suggest that the development of HCC follows a different pathway than, and is temporally independent of, the development of other complications of liver disease. In prior studies, age and sex have been associated with risk of HCC, and we reported previously that alkaline phosphatase is associated with the risk of HCC in the HALT-C Trial cohort.11

An interesting and heretofore unreported finding was the intermediate risk of clinical outcomes in the BT/R group, between the risk of that for the NR and the SVR groups. In particular, the adjusted risk of death from any cause/liver transplantation or of any liver-related outcome was significantly lower in the BT/R group than in the NR group. The risks of decompensated liver disease, HCC, and liver-related death or liver transplantation were also lower in the BT/R group than in the NR group, although these differences did not reach statistical significance. These findings suggest that complete viral suppression is associated with a reduced risk of clinical outcomes and that the benefits may outlast the period in which HCV RNA is undetectable.16

Laboratory tests commonly associated with liver disease severity, such as albumin and platelet count, improved in patients achieving an SVR but worsened in patients not achieving SVR. Of particular interest, in these patients with advanced fibrosis who achieved SVR, platelet count and albumin continued to improve between Week 72 and the final visit approximately 5.5 years later. In the only prior report of laboratory tests among SVR patients followed for 5 years, George et al.2 were unable to demonstrate improvement in laboratory tests. Therefore, improvement in liver-related blood tests after achieving an SVR in patients with advanced fibrosis is an original finding. One possible explanation for the difference between the prior report and ours is that the majority of patients followed by George and colleagues2 had mild liver fibrosis, with minimal changes in albumin and platelets that would not be expected to improve during follow-up monitoring. Overall, our data demonstrating improvement in liver-related blood tests, when combined with prior studies demonstrating reduction in liver fibrosis,1-3 suggest that liver function continues to recover in the years following an SVR in patients with advanced fibrosis/cirrhosis.

This study has several limitations. A total of 17% of patients who achieved SVR were lost to follow-up and an additional 6% declined to participate. Potentially, decompensated liver disease or HCC may have developed in these patients; therefore, our results may be an underestimate of the rate of clinical outcomes in patients who achieved SVR. We were able to determine, however, that none of the 30 patients who were lost to follow-up died according to a search of the SSDI performed at the end of amended study. Another potential limitation was the fact that the patients who achieved SVR were not monitored as closely as the BT/R and NR patients and that not all SVR patients were evaluated in person. Nevertheless, medical records with physical examination, blood tests, and/or liver imaging of the patients who were interviewed by phone were reviewed and added reliability to the ascertainment of the occurrence of decompensated liver disease or HCC as of the time of their last follow-up assessment.

In summary, we found that patients with advanced chronic hepatitis C who achieved SVR had significantly lower rates of death from any cause or liver transplantation, and of liver-related morbidity and mortality, compared to patients who failed to eliminate HCV with treatment (NR). Still, patients who achieved SVR remained at risk of HCC for at least 6 years after achieving SVR. Our study also showed that patients who had temporary, but complete viral suppression (BT/R) were less likely to die or undergo liver transplantation, or to experience liver-related complications than patients in the NR group, indicating that the duration of clinical benefit may outlast the period of actual viral suppression. Importantly, laboratory tests associated with liver-disease severity (e.g., platelet count, albumin) continued to improve after patients achieved SVR. Overall, our data indicate that patients with chronic hepati tis C and advanced hepatic fibrosis who achieve SVR have a marked reduction in the risk for death or liver transplantation, or of liver-related complications, and continued improvement in laboratory markers of liver function in the 5-6 years following successful viral eradication.

RESULTS

Demographic and Clinical Data.

Data were obtained on 140 (78%) of the 180 HALT-C Trial patients who achieved SVR. Thirty patients could not be located, and 10 declined to participate. The 40 patients who did not participate did not differ from the 140 who did at baseline or at Week 72 in demographic characteristics, baseline Ishak fibrosis score, or routine blood tests. Specifically, at Week 72 no difference was found between the SVR nonparticipants (n = 40) and participants (n = 140) for key predictors of clinical outcome such as age (49.8 ± 8.02 years versus 50.0 ± 6.12 years for nonparticipants and participants, respectively; P = 0.87), albumin (4.3 ± 0.4 versus 4.2 ± 0.4 g/dL; P = 0.26), platelet count (191 ± 56 versus 191 ± 59 x 1000/mm3; P = 0.97), AFP (3.3 ± 1.5 versus 3.3 ± 1.7 ng/mL; P = 0.88) or alkaline phosphatase (72 ± 20 versus 78 ± 20 IU/mL; P = 0 .27). Three of the 140 SVR patients had died, and copies of death certificates for two of the three were obtained. Of the 137 surviving participants, 70 were seen in clinic whereas 67 were evaluated by telephone interviews supplemented by examination of external medical records. None of the 30 patients with SVR who could not be located were listed as deceased in the online SSDI.

Baseline demographic data as well as clinical and laboratory data on the SVR group and the two comparison groups (BT/R and NR) are shown in Table 1. The three groups differed significantly in race/ethnicity, presence of cirrhosis, hepatitis C genotype, and laboratory values associated with advanced liver disease. SVR patients were more likely to be Caucasian, infected with HCV genotypes other than 1, to have fibrosis (rather than cirrhosis) on baseline biopsy and less likely to have laboratory values associated with advanced liver disease (e.g., low blood counts and albumin, or high INR and AFP) compared with patients in the BT/R and NR groups.

Durability of SVR.

Ninety-one SVR patients had follow-up HCV RNA testing performed an average of 78.6 ± 15.9 months (range: 22.1-99.6 months) after achieving SVR, and 90 of the 91 (99%) had undetectable HCV RNA in serum. The patient with reappearance of HCV RNA was presumed to have a relapse because there were no risk factors for reinfection and genotype 1b was detected at enrollment and at HCV reappearance 15 months following discontinuation of combination treatment. This patient had persistently detectable HCV RNA but no evidence of hepatic decompensation or HCC when last seen 108 months after enrollment in the lead-in phase of the HALT-C Trial.

Clinical Outcomes of SVR Patients.

Five patients who achieved SVR (3.6%) had six liver-related clinical outcomes (Table 2). One patient (patient A) had a 3-cm lesion detected on ultrasound performed for his amended study clinic visit, 7.3 years after his baseline visit and 5.8 years after achieving SVR. At entry into the HALT-C Trial, he had a liver biopsy with an Ishak fibrosis score of 4 and his platelet count was 112,000/mm3. The resected specimen revealed a well-differentiated HCC; cirrhosis was present in the nontumor liver. Another patient (patient B) who had an Ishak fibrosis score of 3 on his baseline liver biopsy was found to have a 15-cm lesion on magnetic resonance imaging performed to evaluate an elevated AFP during a routine follow-up visit 5.8 years after his baseline visit and 4.4 years after achieving SVR. Biopsy of the lesion confirmed the presence of HCC and cirrhosis in the adjacent liver. This patient died of progressive HCC 4 months later. After magnetic resonance imaging was performed, a third patient (patient G) was found to have a 1.3-cm liver mass and underwent transarterial chemoembolization twice, followed by liver transplantation, but no tumor was found in the liver explant. This patient did not meet the HALT-C Trial criteria for presumed or definite HCC. Two patients with SVR experienced variceal hemorrhage (patients E and F).

Two additional SVR patients died, one from alcohol toxicity (patient D) and the other from an unconfi rmed cause, although a family member reported that the death had occ urred after spinal surgery (patient C). These two deaths were not considered to be liver-related.

Models to Predict Clinical Outcomes.

The numbers of patients with death from any cause/liver transplantation and with liver-related outcomes in the SVR, BT/R, and NR groups are presented in Table 3. SVR patients had fewer deaths from any cause/liver transplantation (four or 2.9%) and liver-related outcomes (six outcomes in five [3.6%] patients) compared to BT/R (four or 5.2%) death from any cause/transplant; 15 liver-related outcomes in eight (10.4%) patients and NR (64 or 20.7%) death from any cause/transplant; 148 liver-related outcomes in 78 (25.2%) patients. Because the three patient groups differed in baseline severity of liver disease (e.g., Ishak fibrosis score, platelet count, albumin level; Table 1), we performed a Cox proportional hazard regression analysis (Table 4), adjusting for histological stratum (fibrosis or cirrhosis), age, race, platelet count, AST/ALT ratio, albumin, alkaline phosphatase, AFP, and treatment response (SVR, B T/R, and NR). These variables were selected because they have been associated with liver disease severity or clinical outcomes in prior HALT-C Trial analyses.11, 12 Separate multivariate models were developed to assess risk factors associated with the five outcomes analyzed in this study.

A low baseline platelet count was significantly associated with all five outcomes, whereas a low baseline albumin was a significant risk factor for all outcomes except HCC (Model 4). Age and baseline alkaline phosphatase were also sig nificant risk factors for the development of HCC (Model 4). Achievin g an SVR, when compared with nonresponders, was associated with a significantly lower hazard ratio for each of the five clinical outcomes. Patients with BT/R had a significantly lower hazard ratio for death from any cause/liver transplantation (hazard ratio [HR] = 0.29; 95% confidence interval [CI] = 0.10-0.79) and for any liver-related outcome (HR = 0.46; 95%CI = 0.22-0.96) when compared with NR. Fibrosis stage, race, and baseline AST/ALT ratio were not statistically significant risk factors in any multivariate model.

Adjusted Rates of Clinical Outcomes in SVR, BT/R, and NR Patients.

The cumulative rates of death from any cause/liver transplantation, and of liver-related morbidity and mortality, adjusted for the significant risk factors identified in the Cox models, are shown in Fig. 2 and Supporting Information Table 1. At year 7.5 from enrollment, the adjusted cumulative incidence of outcomes for the SVR, BT/R, and NR patients was, respectively, 2.2%, 4.4%, and 21.3% for death from any cause or liver transplantation (P = 0.0002); 2.7%, 8.7%, and 27.2% for any liver-related outcome (P < 0.0001); 0.9%, 4.7%, and 11.7% for decompensated liver disease (P = 0.012); 1.1%, 5.5%, and 8.8% for HCC (P = 0.077); and 0.99%, 4.1%, and 14.7% for liver-related death or liver transplantation (P = 0.005). For each of the five outcomes, the adjusted cumulative proportion of patients with outcomes was lowest for the SVR group, intermediate for the BT/R group, and highest for the NR group of patients. Although the SVR patients had fewer outcomes than the BT/R patients, the adjusted cumulative incidence was not significantly different between the SVR and the BT/R groups for any of the five outcomes (SVR versus BT/R: P = 0.44 for death or liver transplantation, P = 0.05 for any liver-related outcome, P = 0.07 for decompensated liver disease, P = 0.05 for HCC, and P = 0.13 for liver-related death or liver transplantation). The adjusted cumulative proportion with death or liver transplantation (P = 0.02) or any liver-related outcome (P = 0.04) was significantly lower for the BT/R group when compared with patients from the NR group, but the difference between these two groups was not statistically significant when decompensated liver disease (P = 0.24), HCC (P = 0.93), or liver-related death or liver transplantation (P = 0.11) were analyzed individually.

Because there was no effect of long-term peginterferon treatment on the rate of clinical outcomes,9 the Cox proportional hazard analysis and the adjusted cumulative survival analysis were repeated after including 400 patients who were randomized to the peginterferon alfa-2a (90 µg/week) arm of the HALT-C Trial and who were followed after randomization. Including these patients increased the NR group to 638 and the BT/R group to 148 individuals. All HRs and cumulative outcome analyses were essentially unchanged, except that statistical significance for SVR versus NR was stronger, the HR and adjusted survival analyses for SVR versus BT/R were significant for any liver-related outcome (P < 0.05), and the HR and adjusted survival analyses for BT/R versus NR were significant for liver-related death or liver transplantation (P < 0.05) (data not shown).

Changes in Laboratory Test Results.

Figure 3 shows changes in selected blood tests over time among patients who had blood tests performed at each of the three time points. Among the SVR patients, platelet count and albumin (shown in Fig. 3) as well as AST, ALT, and AFP (data not shown) significantly improved from baseline to the most recent values. A significant improvement in platelet count and albumin was also observed between Week 72 (Month 18), when SVR was attained, and the time of the amended study visit. In contrast, patients from the BT/R and NR groups had a significant worsening of platelet count and bilirubin between baseline and Month 72 visits, and NR patients also had deterioration in albumin and INR during the same time period.
 
Source
HCV is a leading cause of liver chronic diseases all over the world. In developed countries the highest prevalence of infection is reported among intravenous drug users and haemodialysis (HD) patients.

The present report is to identify the pathway of HCV transmission during an outbreak of HCV infection in a privately run haemodialysis (HD) unit in Italy in 2005.

Methods: Dynamics of the outbreak and infection clinical outcomes were defined through an ambi-directional cohort study. Molecular epidemiology techniques were used to define the relationships between the viral variants infecting the patients and confirm the outbreak.

Risk analysis and auditing procedures were carried out to define the transmission pathways.

Results: Of the 50 patients treated in the HD unit 5 were already anti-HCV positive and 13 became positive during the study period (AR= 28.9%). Phylogenic analysis identified that, all the molecularly characterized incident cases (10 out of 13), were infected with the same viral variant of one of the prevalent cases.

The multivariate analysis and the auditing procedure disclosed a single event of multi-dose vials heparin contamination as the cause of transmission of the infection in 11 out of the13 incident cases; 2 additional incident cases occurred possibly as a result of inappropriate risk management.DiscussionMore than 30% of all HCV infections in developed countries results from poor application of standard precautions during percutaneous procedures. Comprehensive strategy which included: educational programmes, periodical auditing on standard precaution, use of single-dose vials whenever possible, prospective surveillance for blood-borne infections (including a system of prompt notification) and risk assessment/management dedicated staff are the cornerstone to contain and prevent outbreaks in HD

Conclusions: The outbreak described should serve as a reminder to HD providers that patients undergoing dialysis are at risk for HCV infection and that HCV may be easily transmitted whenever standard precautions are not strictly applied.

Author: Simone LaniniIsabella AbbateVincenzo PuroFabrizio SosciaFrancesco AlbertoniWalter BattistiAmilcare RutaMaria CapobianchiGiuseppe Ippolito

Credits/Source: BMC Infectious Diseases 2010, 10:257

Published on: 2010-08-27
 
Source
Hepatitis C virus (HCV) infection is a global public health problem. Long-distance truck drivers live apart from their family for long periods of time, a lifestyle that favors at-risk behaviors such as unprotected sex with multiple partners and illicit drug use.

As data concerning HCV infection in this population are still rare, this paper aims to investigate the prevalence, genotypes/subtypes, and the factors associated with HCV infection in long-distance truck drivers in Brazil. A cross-sectional survey was carried out with 641 Brazilian long-truck drivers who were recruited at a major truck stop located at kilometer 1,296 of the BR-153 highway, which is considered to be one of the longest roads in Brazil.

All individuals were interviewed, and their serum samples were tested for the presence of antibodies to HCV (anti-HCV) by ELISA and immunoblot. Anti-HCV positive samples were tested for HCV RNA by PCR amplification of the 5'NC and NS5B regions and were genotyped using the LiPA assay and nucleotide sequencing, respectively.

Factors associated with HCV infection were identified with logistic regression. The prevalence of HCV infection was 1.4% (95% CI: 0.7-2.8).

History of blood transfusion, sharing of personal hygiene tools, illicit drug use and HBV status were factors independently associated with HCV infection in the study population. HCV RNA was detected in 8/9 anti-HCV positive samples, in which genotypes 1 (n = 3), 2 (n = 2), and 3 (n = 3) were determined by LiPA.

Using phylogenetic tree analysis of the NS5B region, subtypes 1a (n = 1), 1b (n = 2), 2b (n = 2) and 3a (n = 3) were identified. These data show that the prevalence of HCV infection among Brazilian truck drivers was similar to that observed for the general population.

History of blood transfusion, sharing of personal hygiene tools, illicit drug use and HBV status were predictors of HCV infection. The HCV genotypes/subtypes identified in the study population are consistent with those circulating in Brazil.

Author: Nara FreitasSheila TelesMarcos MatosCarmen LopesNadia ReisMarcia Espirito-SantoElisabeth LampeRegina Martins

Credits/Source: Virology Journal 2010, 7:205

Published on: 2010-08-27
 
Source
Therapure Biopharma Inc. (Therapure) today announced receipt of a financial contribution from the National Research Council’s Industrial Research Assistance Program (NRC-IRAP). The funding is to support Therapure’s drug delivery program for the treatment of liver cancer and hepatitis C infection.
 
Toronto, ON (Vocus) August 27, 2010

Therapure Biopharma Inc. (Therapure) today announced receipt of a financial contribution from the National Research Council’s Industrial Research Assistance Program (NRC-IRAP). The funding is to support Therapure’s drug delivery program for the treatment of liver cancer and hepatitis C infection.

Therapure’s lead product for infectious disease is a stable protein-drug conjugate of hemoglobin and ribavirin designed to selectively target the delivery of ribavirin to the liver for the treatment of hepatitis C virus (HCV) infection. Therapure’s lead cancer product is a similar conjugate of hemoglobin and floxuridine, which delivers the powerful chemotherapy drug floxuridine directly to the liver as treatment for primary liver cancer. Both products are based on a core expertise in protein chemistry and cell biology that Therapure scientists have pioneered and applied to the natural and highly specific pathway for hemoglobin metabolism as a means of treating chronic and acute liver diseases with high unmet medical need.

Both drug delivery products are in the pre-clinical stage of development. Therapure has recently completed pre-IND and pre-CTA submissions to the US FDA and Health Canada, respectively, as a key step in defining the clinical and regulatory paths for both products and advancing them products to the clinic and the treatment of patients sooner.

In addition to technical and business advisory services, the financial assistance provided by NRC-IRAP will support funding for continued pre-clinical safety and efficacy studies, and bioanalytical method development.

“Therapure is very proud to have been chosen by NRC-IRAP” said Thomas Wellner, President and CEO of Therapure. “This demonstrates the breadth of Therapure’s capabilities in Product and Method Development.”

About Therapure Biopharma Inc.:

Therapure Biopharma Inc. is an integrated biopharmaceutical company that develops, manufactures, purifies and packages therapeutic proteins. As a contract development and manufacturing organization (CDMO) Therapure Biopharma applies scientific, manufacturing, and downstream purification expertise with an intimate understanding of advanced biology, complex proteins, and regulatory processes to develop effective and innovative solutions to advance products from discovery to market for its clients. Therapure’s Health Canada licensed 130,000 sq. ft. facility, includes manufacturing, research and quality control laboratories and a cGMP warehouse, and is built to U.S. FDA, EMEA, MHRA and Health Canada standards for the aseptic handling and purification of proteins.

For more information, please visit: http://www.therapurebio.com/

Company Contacts:
Thomas Wellner, President and CEO
Therapure Biopharma Inc.
+1 905 286-6204
ceo(at)therapurebio(dot)com

Source
Many diagnostic and treatment options have been developed for chronic liver disease during the last 40 years, yet their influence on survival remain unclear. A new study of the prognosis for patients hospitalized for liver diseases between 1969 and 2006, and of differences in mortality and complications between patients with alcoholic and non-alcoholic liver diseases, has found that the general prognosis for patients hospitalized with chronic liver diseases has not improved.

Results will be published in the November 2010 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

"The most effective changes in treatment for chronic liver disease during the last 40 years are, in my opinion, combination treatment for hepatitis C and treatment with prednisolone and azathioprine for autoimmune hepatitis," said Knut Stokkeland, an instructor in the department of medicine at Visby Hospital in Sweden and corresponding author for the study. "In addition, new diagnostic tools such as endoscopic examinations, computed tomography, MRI, and ultrasound have probably increased our possibilities to detect early disease and the development of cirrhosis."

Stokkeland added that the key difference between alcoholic and non-alcoholic liver disease is alcohol dependence (AD), which almost all patients with alcoholic liver disease have. "AD increases the risks of social problems, being a smoker, and severe psychiatric diseases," he said. "It also inhibits staying sober, which may stop disease progression."

Stokkeland and his colleagues used data from the Swedish Hospital Discharge Register and Cause of Death Register between 1969 and 2006 to both identify and follow up with a cohort of 36,462 patients hospitalized with alcoholic liver diseases and 95,842 patients hospitalized with non-alcoholic liver diseases.

"The main finding of Dr. Stokkeland's study is the much increased mortality risk of having an alcohol- versus a non-alcohol-related liver disease," observed Johan Franck, a professor of clinical addiction research at Karolinska Institutet in Sweden. "Thus, patients with alcohol-induced liver diseases should receive more attention, and they should routinely be offered treatment for their alcohol-use disorder. Presumably, the various treatment systems involved – such as hepatology versus substance-abuse care – may not be very well coordinated and this may present an area for improvement."

Stokkeland agreed. "This may be caused by the fact that hospitalized patients with [alcoholic] liver disease have such a severe liver disease that no effort may change their prognosis," he said. "I hope this study will motivate clinicians and scientists in the field of hepatology and gastroenterology to design clinical studies to see if any changes in care-taking of our patients with alcoholic liver disease may change their severe prognosis. We must also focus on treating their AD so that they may stop drinking."

"Given that alcohol doubles the risk of having a serious liver disease," added Franck, "efforts to reduce alcohol drinking will likely have a positive impact on the disease's outcome."

###

Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper, "Increased Risk of Esophageal Varices, Liver Cancer and Death in Patients with Alcoholic Liver Disease," were Fereshte Ebrahim of the National Board of Health and Welfare, and Anders Ekbom of the Department of Medicine at the Karolinksa Institutet, both of Stockholm, Sweden. The study was funded by the Bengt Ihre Foundation, the Karolinksa Institutet, and Visby Hospital. This release is supported by the Addiction Technology Transfer Center Network at http://www.attcnetwork.org/
 
Published on: 2010-08-29
 
Source

August 26, 2010

From Alimentary Pharmacology & Therapeutics

C. M. Lange; C. Sarrazin; S. Zeuzem

Posted: 08/25/2010; Alimentary Pharmacology & Therapeutics. 2010;32(1):14-28. © 2010 Blackwell Publishing

Abstract and Introduction

Abstract

Background Novel, directly acting anti-viral agents, also named 'specifically targeted anti-viral therapy for hepatitis C' (STAT-C) compounds, are currently under development.

Aim To review the potential of STAT-C agents which are currently under clinical development, with a focus on agents that target HCV proteins.

Methods Studies evaluating STAT-C compounds were identified by systematic literature search using PubMed as well as databases of abstracts presented in English at recent liver and gastroenterology congresses.

Results Numerous directly-acting anti-viral agents are currently under clinical phase I–III evaluation. Final results of phase II clinical trials evaluating the most advanced compounds telaprevir and boceprevir indicate that the addition of these NS3/4A protease inhibitors to pegylated interferon-alfa and ribavirin strongly improves the chance to achieve a SVR in treatment-naive HCV genotype 1 patient as well as in prior nonresponders and relapsers to standard therapy. Monotherapy with directly acting anti-virals is not suitable. NS5B polymerase inhibitors in general have a lower anti-viral efficacy than protease inhibitors.

Conclusions STAT-C compounds in addition to pegylated interferon-alfa and ribavirin can improve SVR rates at least in HCV genotype 1 patients. Future research needs to evaluate whether a SVR can be achieved by combination therapies of STAT-C compounds in interferon-free regimens.

Introduction

With the current standard of care, a combination therapy of pegylated interferon-alfa plus weight based ribavirin for 24 to 72 weeks, only half of all patients with chronic hepatitis C can be cured.[1–4] The chance to achieve a sustained virologic reponse (SVR) by such regimens differs significantly between HCV genotypes with SVR rates of 40–50% in patients infected with genotype 1, contrasted by SVR rates of approximately 80% in those infected with genotypes 2 or 3.[1–5] In addition, treatment with pegylated interferon-alfa and ribavirin is long (up to 72 weeks) and associated with numerous side effects like anaemia, flu-like symptoms or depression. In view of these facts, there is an urgent need for improved treatment strategies. The exploding knowledge of the HCV life cycle and of structural features of the HCV proteins has supported the development of many promising directly acting anti-viral agents, also named 'specifically targeted anti-viral therapy for hepatitis C' (STAT-C) compounds.[6–13] Figure 1 summarizes the HCV life cycle and potential targets for STAT-C.[11, 12] Many of these direct anti-virals are currently in phase I–III development and will significantly change treatment options for HCV infection in the near future. The most advanced compounds are telaprevir and boceprevir that are both inhibitors of the HCV NS3 protease and that have been shown to significantly enhance SVR rates in HCV genotype 1 patients, when applied in addition to pegylated interferon-alfa and ribavirin.[14–16] These and other STAT-C compounds will be described in this review with a focus on agents that were already evaluated in clinical trials (Table 1). Anti-virals targeting host proteins which are mandatory for HCV replication (e.g. nitazoxanide, celgosivir or DEBIO-025) are reviewed elsewhere.[17–21]


Figure 1.
The HCV replication complex. After clathrin-mediated endocytosis, fusion of HCV with cellular membranes, and uncoating the viral nucleocapsid, the single-stranded positive-sense RNA genome of the virus of approximately 9600 nucleotides is released into the cytoplasm to serve as a messenger RNA for the HCV polyprotein precursor. The HCV genome contains a single large open reading frame encoding for a polyprotein of approximately 3100 amino acids. The translated section of the HCV genome is flanked by the strongly conserved HCV 3′ and 5′ untranslated regions (UTR). The 5′ UTR is comprised of four highly structured domains forming the internal ribosome entry site (IRES), which is a virus-specific structure to initiate HCV mRNA translation. From the initially translated polyprotein, the structural HCV protein core (C) and envelope 1 and 2 (E1, E2); p7; and the six nonstructural HCV proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B, are processed by both viral and host proteases. The core protein forms the viral nucleocapsid carrying E1 and E2, which are receptors for viral attachment and host cell entry. The tetraspanin protein CD81, claudin-1, occludine, scavenger receptor class B type 1 (SR-B1), the low-density lipoprotein (LDL) receptor, glycosaminoglycans and the dendritic cell-/lymph node-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN/L-SIGN) have been identified as putative ligands for E1 and E2.[83–86] The nonstructural proteins are mainly enzymes essential for the HCV life cycle. P7 is a small hydrophobic protein that oligomerises into a circular hexamer, most probably serving as an ion channel through the viral lipid membrane.[7, 87–91] NS2 and NS3 are viral proteases required for the procession of the HCV polyprotein. NS2 is a metalloproteinase that cleaves itself from the NS2/NS3 protein, leading to its own loss of function and to the release of the NS3 protein.[7, 90, 91] NS3 provides a serine protease activity and a helicase/NTPase activity. The serine protease domain comprises two β-barrels and four α-helices. The serine protease catalytic triad – histidine 57, asparagine 81 and serine 139 – is located in a small groove between the two β-barrels. NS3 forms a tight, noncovalent complex with its obligatory cofactor and enhancer NS4A, which is essential for proper protein folding. The NS3/4A protease cleaves the junctions between NS3/NS4A, NS4A/NS4B, NS4B/NS5A and NS5A/NS5B. Besides its essential role in protein processing, NS3 is integrated into the HCV RNA replication complex, supporting the unwinding of viral RNA by its helicase activity. NS4B and NS5B are involved in the organization of the HCV replication complex by interactions with lipid membranes, which lead to the formation of the so called membranous web.[11, 12, 69, 92] The membranous web comprises of rearranged intracellular lipid membranes derived from the endoplasmic reticulum. It provides the basis for the highly structured association of viral proteins and RNA, and of cellular proteins and cofactors within the replication complex. In addition, NS4B and NS5B are involved in transport of viral RNA within the replication complex.[11, 12, 69, 92] NS5B is an RNA-dependent RNA-polymerase which catalyses the synthesis of a complementary negative-strand RNA by using the positive-strand RNA genome as a template.[11, 12, 69] From this newly synthesized negative-strand RNA, numerous RNA strands of positive polarity are produced by NS5B activity which serve as templates for further replication and polyprotein translation. As a result of its poor fidelity leading to a high rate of errors in its RNA sequencing, numerous different isolates are generated during HCV replication in a given patient, termed HCV quasispecies. It is thought that as a result of the lack of proof-reading of the NS5B polymerase together with the high replication rate of HCV every possible mutation will be generated each day. Thus, NS5B is one key factor in the development of viral resistance during STAT-C therapies.
 
Compounds Targeting HCV Polyprotein Procession
 
NS3/4A Protease Inhibitors

The design of NS3/4A inhibitors is relatively difficult because the active site of the NS3/4A protease is located in a shallow groove between two β-barrels of the protease.[6, 7] Nevertheless, many NS3/4A protease inhibitors are under development, which in general provide a high anti-viral efficacy but a low genetic barrier to resistance. Protease inhibitors can be divided into two chemical classes, macrocyclic inhibitors and linear tetra-peptide α-ketoamid derivatives. NS3/4A protease inhibitors of both classes strongly inhibit HCV replication during monotherapy, but also frequently cause the selection of resistant mutants which may be followed by viral breakthrough.[13, 22] However, it was shown that the frequency of resistance development against protease inhibitors can be vastly reduced by the additional administration of pegylated interferon and ribavirin. The most advanced compounds are telaprevir and boceprevir that are currently under phase III evaluation and are expected to be approved in 2011/2012.

Ciluprevir (BILN 2061)

The first NS3/4A inhibitor applied in clinical studies was ciluprevir (BILN 2061), an orally bioavailable, peptidomimetic, macrocyclic drug binding noncovalently to the active centre of the enzyme.[23] Ciluprevir monotherapy was evaluated in a double-blind, placebo-controlled pilot study in treatment-naïve genotype 1 patients with compensated liver disease.[24] In this study, ciluprevir, administered twice daily for 2 days at doses ranging from 25 to 500 mg, led to a mean 2–3 log10 decrease of HCV RNA serum levels in most patients. Another study with equivalent design assessed the influence of the HCV genotype on treatment with this protease inhibitor. Compared with genotype 1 patients, the anti-viral activity of ciluprevir was less pronounced and more variable in patients infected with genotypes 2 or 3.[25] Although the development of ciluprevir was stopped because of serious cardiotoxicity observed in an animal model, these studies provided the proof-of-principle for successful suppression of HCV replication by NS3/4A inhibitors in patients with chronic hepatitis C.

Viral Resistance to Ciluprevir. As a result of the high replication rate of HCV and the poor fidelity of its RNA-dependent RNA polymerase, numerous variants (quasispecies) are continuously produced during HCV replication. Amongst them, variants carrying mutations altering the conformation of the binding sites of STAT-C compounds can develop. During treatment with specific anti-virals, these pre-existing drug-resistant variants have a fitness advantage and can be selected to become the dominant viral quasispecies. Many of these resistant mutants exhibit an attenuated replication fitness with the consequence that, after termination of exposure to specific anti-virals, the wild-type may again replace the resistant variants.[22, 26] Nevertheless, HCV quasispecies resistant to NS3/4A protease inhibitors or non-nucleoside polymerase inhibitors can be detected at very low levels in some patients who were never treated with specific anti-virals before.[27–29] The clinical relevance of these pre-existing mutants is not completely understood, although there is evidence that they may reduce the chance to achieve a SVR by therapies based on HCV protease or non-nucleoside polymerase inhibitors.

Exposure of genotype 1 replicon cells to ciluprevir and subsequent sequence analyses of the NS3 region have led to the identification of several mutations conferring ciluprevir-resistance: A156T, R155Q and D168V/A. These mutations result in a 357-fold, 24-fold and 144-fold reduced susceptibility to ciluprevir, respectively, compared with wild-type.[30–32] The A156T mutant confers varying levels of cross-resistance to ciluprevir, telaprevir and boceprevir. The A156T mutation causes a significantly reduced enzymatic function attenuating the HCV life cycle, which, however, can be overcome by additional mutations at P89L, Q86R or G162R.[30–32] No data are available on clinically selected resistance mutations after administration of ciluprevir in patients with chronic hepatitis C.

Telaprevir (VX-950)

Telaprevir is an orally bioavailable NS3 protease inhibitor which belongs to the α-ketoamids and binds the enzyme covalently but reversibly, with a half-life of 58 min of the enzyme-inhibitor complex. Currently, telaprevir is under phase III evaluation (ADVANCE- and ILLUMINATE-Study for treatment-naïve patients, REALIZE study for nonresponders).

Phase I Studies. Telaprevir Monotherapy Study A double-blind, randomized placebo-controlled phase Ib clinical trial evaluating telaprevir monotherapy over 14 days was performed in patients with chronic HCV genotype 1 infection.[33] In this study, anti-viral activity, safety, optimal dosage and pharmacokinetics were assessed in treatment-naïve patients, relapsers or nonresponders to standard treatment. Doses of telaprevir were 450 mg or 750 mg every 8 h or 1250 mg every 12 h. Telaprevir was well tolerated and led to a rapid decline of HCV RNA serum levels in all groups. The best results were obtained in the 750 mg telaprevir q8h dose group with a median reduction of HCV RNA of 4.4 log10 after 14 days of treatment, which is the basis for telaprevir-dosage in most of the following clinical trials. However, viral rebound because of selected mutants occurred in all patients after treatment completion and in some patients even during therapy. The selection of resistant mutants was more frequent in patients who received suboptimal doses.[22

Telaprevir/pegylated (peg) Interferon α-2a/ribavirin Combination Studies A second phase I study investigated the safety, viral kinetics and the development of telaprevir-resistant mutants of telaprevir monotherapy and in combination with pegIFN-α 2a in treatment-naïve genotype 1 patients.[34] Telaprevir dosage was 750 mg every 8 h after an initial loading dose of 1250 mg and it was administered either alone or in combination with pegIFN-α 2a in comparison to pegIFN-α 2a monotherapy. Treatment was given for 14 days and caused a median reduction of HCV RNA of 1.09 log10 in the pegIFN-α 2a/placebo group, of 3.99 log10 in the telaprevir/placebo group and of 5.49 log10 in the telaprevir/pegIFN-α 2a group at the end of therapy. As observed before, selection of telaprevir-resistant mutants occurred during telaprevir monotherapy. However, their frequency was significantly lower during combination therapy with pegIFN-α 2a and no viral breakthrough was seen during the combination therapy within 14 days.[34]

A parallel study evaluated the safety and efficacy of telaprevir (750 mg every 8 h) in combination with pegIFN-α 2a and weight-based ribavirin in treatment-naive genotype 1 patients for 28 days.[35] At the end of the 28-day treatment period, all patients had undetectable HCV RNA serum levels.

Phase II Studies. Telaprevir and peg Interferon with and without Ribavirin

Studies in treatment naïve patients (PROVE 1 and 2, C208, C209, C210) Larger phase II clinical trials (PROVE 1 and 2) in treatment naïve genotype 1 patients assessed whether with additional telaprevir to pegIFN-α 2a and ribavirin, overall treatment duration can be reduced and/or SVR rates be improved (Figures 2 and 3). PROVE 1 was conducted in the USA whereas PROVE 2 was conducted in Europe. In addition, a study comparing two vs. three times daily administration of telaprevir in combination with either pegylated interferon alfa 2a or 2b (C208) and studies in genotype 2, 3 and 4 infected patients were performed (C209, C210).


Figure 2.
Results of PROVE 1 (USA). Combination therapy of telaprevir (TVR) and pegIFN-α 2a + ribavirin in treatment-naive genotype 1 patients.
 
 
Figure 3.
Results of PROVE 2 (Europe). Combination therapy of telaprevir (TVR) and pegIFN-α 2a ± ribavirin in treatment-naive genotype 1 patients
 
In PROVE 1, telaprevir, pegIFN-α 2a and ribavirin were administered for 12 weeks in combination, followed by pegIFN-α 2a and ribavirin alone for 0 (n = 17), 12 (n = 79) or 36 (n = 79) weeks in comparison to standard treatment. SVR rates were 35%, 61% and 67%, respectively, compared to 41% with standard treatment. According to the study protocol, treatment was only stopped after 12 or 24 weeks when a rapid virological response (RVR) was achieved. Serious adverse effects led to premature treatment termination in 18% of all subjects treated with telaprevir in contrast to 4% of patients with standard-therapy. Most common adverse events were skin rash, anaemia and gastrointestinal disorders.[15]
 
The study design of PROVE 2 was similar to PROVE 1 with the main difference being that treatment termination after 12 or 24 weeks was independent of achieving an RVR and one treatment arm was ribavirin-free. The recently published final results showed SVR rates of 36%, 60% and 69% for patients treated with telaprevir plus pegIFN alone for 12 weeks (n = 78), telaprevir and pegIFN and ribavirin for 12 weeks (n = 82), and with telaprevir, pegIFN and ribavirin for 12 weeks followed by 12 weeks of pegIFN plus ribavirin alone (n = 81) respectively. The SVR rate achieved by standard treatment was 46%. However, the rate of relapse in the groups treated for 12 weeks was relatively high with 30% and 48% of all patients who were treated with and without ribavirin respectively. Two patients who discontinued treatment at day 60 and 65 experienced a late relapse 36 and 48 weeks after the end of treatment respectively.[14]

The results of PROVE 1 and 2 indicate that 12 weeks of triple therapy was too short because of the high rate of relapse after treatment completion. Moreover, ribavirin is necessary in therapies with telaprevir to achieve high SVR rates. However, 24 to 48 weeks of total therapy including 12 weeks of triple therapy with telaprevir in addition to standard treatment greatly improved SVR rates in treatment-naïve genotype 1 patients compared with the standard of care. The RVR during triple therapy is an important predictor for treatment success and can be applied for defining individualized treatment durations.

The most important side effects of telaprevir are rash, gastrointestinal disorders and anaemia. Although severe rash may require treatment discontinuation, moderate forms can be treated successfully with topical steroids. The median decline of blood haemoglobin concentration related to telaprevir was approximately 1 g/dL. As telaprevir was administered in most trials for only 12 weeks, the use of erythropoietin-analogues was rarely necessary.

C208 was a small study (n = 161) comparing three times daily 750 mg with two times daily 1125mg telaprevir combined with pegylated interferon alfa 2a or 2b, respectively, and ribavirin.[36] In all four treatment arms comparable SVR rates were observed (81–85%). These high overall SVR rates underline the potential of the triple therapy approach. They are explained in part by experienced study centres with very low discontinuation rates (5%) in comparison with the PROVE studies. In addition, in this study the response-guided therapy approach was investigated. Treatment duration was shortened to 24 weeks in patients who achieved a RVR, while the remaining patients received 48 weeks therapy. Between 80–83% of all patients treated with pegIFN-α 2a, and 67–69% of all patients treated with pegIFN-α 2b achieved an RVR and could therefore be treated for 24 weeks.

As the amino acid sequence of the NS3 protease domain varies significantly between HCV genotypes, protease inhibitors may have a different anti-viral efficacy in patients infected with different genotypes. Like ciluprevir, telaprevir alone or in combination with pegIFN and ribavirin was less effective in treatment-naïve patients infected with other genotypes than genotype 1. For HCV genotype 2, a somewhat weaker anti-viral activity in comparison with HCV genotype 1 was observed with a mean viral decline of 3.9 log10 IU/mL during 14 days of monotherapy with telaprevir. In genotype 3 and 4 infected patients, no significant anti-viral activity was detectable (0.5–0.9 log10 decline).[37, 38]

Studies in Nonresponders and Relapsers (PROVE 3) The PROVE 3 trial was conducted to determine SVR rates of treatment with telaprevir in combination with pegIFN-α and ribavirin in treatment-experienced patients (Figure 4). Telaprevir was administered in combination with pegIFN-α 2a with and without ribavirin for 12 to 24 weeks followed by pegIFN-α 2a and ribavirin alone for up to 24 weeks. Retreatment of previous nonresponders with 12 weeks of triple therapy followed by 12 weeks of standard treatment led to a SVR rate of 51% (69% relapser, 39% nonresponder), which is significantly higher compared with SVR rates achieved with the standard of care (14%). Retreatment of nonresponders with 24 weeks of triple therapy followed by 24 weeks of standard treatment led to a SVR rate of 53% (76% relapser, 38% nonresponder) and retreatment of nonresponders with 24 weeks of telaprevir and pegIFN-α 2a without ribavirin followed by 24 weeks of pegIFN-α 2a alone led to a SVR rate of only 24% (42% relapser, 11% nonresponder). The latter result indicates that ribavirin is required for a successful treatment of nonresponders with telaprevir. As in the PROVE 1 and 2 studies viral breakthrough was observed more frequently in patients infected with genotype 1a than in patients infected with genotype 1b.[39]


Figure 4.
Results of PROVE 3. Combination therapy of telaprevir (TVR) and pegIFN-α 2a ± ribavirin in HCV genotype 1 patients with prior nonresponse or relapse to standard treatment.
 
Phase III Studies. Design of Phase III Clinical Trials: Telaprevir with Pegylated Interferon-alfa and Ribavirin Phase III clinical trials evaluating telaprevir in combination with pegIFN-α and ribavirin have been initiated. The ADVANCE trial enrolled more than 1000 treatment-naïve HCV genotype 1 patients to evaluate 24 weeks of telaprevir-based therapy. Telaprevir was dosed at 750 mg every 8 h and given for 8 or 12 weeks in combination with pegIFN-α 2a and ribavirin followed by pegIFN-α 2a and ribavirin alone until treatment week 24. Patients who did not achieve an RVR were treated with pegIFN-α 2a and ribavirin until week 48. In the ILLUMINATE trial, telaprevir was given for 12 weeks in combination with pegIFN-α 2a and ribavirin followed by pegIFN-α 2a and ribavirin alone until treatment week 24 or 28. The aim of the ILLUMINATE trial is to assess whether treatment extension beyond 24 weeks of total therapy improves SVR rates in patients with RVR or EVR. The REALIZE study enrolled more than 650 patients with prior failure to standard treatment. PegIFN-α 2a and ribavirin were given for 48 weeks including 12 weeks of telaprevir at a dose of 750 mg every 8 h. In one treatment arm, telaprevir treatment was initiated after a 4 week lead-in phase of pegIFN-α 2a and ribavirin alone. SVR data of the ADVANCE, ILLUMINATE and REALIZE study are expected to be published in 2010.
 
Viral Resistance to Telaprevir To date, mutations conferring telaprevir-resistance have been identified at four positions, V36A/M/L, T54A, R155K/M/S/T and A156S//T,[22, 30, 31, 40] see Table 2 and Table 3 . The A156 mutation was shown by in vitro analyses in the replicon assay while the other mutations could only be detected in vivo by a clonal sequencing approach during telaprevir administration in patients with chronic hepatitis C. A detailed kinetic analysis of telaprevir-resistant variants was performed in genotype 1 patients during 14 days of telaprevir monotherapy and combination therapy with pegIFN-α 2a.[41] Telaprevir monotherapy initially led to a rapid HCV RNA decline in all patients as a result of a strong reduction in wild-type virus. In patients who developed a viral rebound during telaprevir monotherapy, mainly the single mutation variants R155K/T and A156/T were uncovered by wild-type reduction and became dominant after day 8. These single mutation variants were selected from pre-existing quasispecies. During the viral rebound phase these variants typically were replaced by highly resistant double-mutation variants (e.g., V36M/A +R155K/T). The combination of telaprevir and pegIFN-α 2a was sufficient to inhibit the breakthrough of resistant mutations in a 14-day study. It is important to note that after up to 3 years after telaprevir treatment low to medium levels of V36 and R155 variants were still observed in single patients.[42] Another study modelling the dynamics of wild type HCV genotype 1 in patients treated with telaprevir with and without pegylated interferon-alfa and ribavirin showed a first and second phase reduction in virus decline which was up to 10-fold stronger than reported for the standard of care.[43]

As shown for other NS3/4A protease inhibitors as well (e.g. ITMN-191), the genetic barrier to telaprevir resistance differs significantly between HCV subtypes. In all clinical studies of telaprevir alone or in combination with pegIFN-α and ribavirin, viral resistance and breakthrough occurred much more frequently in patients infected with HCV genotype 1a compared with genotype 1b. This difference was shown to result from nucleotide differences at position 155 in HCV subtype 1a (aga, encodes R) vs. 1b (cga, also encodes R). The mutation most frequently associated with resistance to telaprevir is R155K; changing R to K at position 155 requires 1 nucleotide change in HCV subtype 1a and 2 nucleotide changes in subtype 1b isolates.[44]

Boceprevir (SCH 503034)

Boceprevir is another novel peptidomimetic orally bioavailable α-ketoamid HCV protease inhibitor that forms a covalent but reversible complex with the NS3 protein.[45] Like telaprevir, boceprevir is currently in phase III evaluation.

Phase I Studies. Boceprevir Monotherapy Study An initial phase I trial evaluated safety, tolerability and anti-viral efficacy of boceprevir monotherapy (100 to 400 mg daily) in HCV genotype 1 patients with prior failure to standard therapy.[46] After the 14-day treatment period, a mean log10 reduction in HCV RNA load of 2.06 was achieved in patients treated with 400 mg boceprevir daily. Boceprevir was well tolerated at all doses without significant adverse effects. However, viral breakthrough with selection of resistant variants occurred in some patients with a frequency depending on boceprevir dosage.[47]

Boceprevir/peg Interferon α-2b Combination Study A subsequent phase Ib study evaluated the combination of boceprevir and pegIFN-α 2b in HCV genotype 1-infected nonresponders to standard therapy.[48] In this randomized, double-blind crossover study, boceprevir was administered at doses of 200 or 400 mg every 8 h either alone for 7 days or in combination with pegIFN-α 2b for 14 days in comparison to 14 days of pegIFN-α 2b monotherapy. As HCV genotype 1 nonresponders to standard treatment are heterogeneous, the study design intended each patient to receive boceprevir alone, in combination with pegIFN-α 2b and pegIFN-α 2b alone with washout-periods in between in a randomized crossover sequence. Mean maximum reductions in HCV RNA load were 2.45 and 2.88 log10 for boceprevir 200 mg and 400 mg plus pegIFN-α 2b, 1.08 and 1.61 log10 for boceprevir monotherapy and 1.08 and 1.26 log10 for pegIFN-α 2b monotherapy. Boceprevir was well-tolerated alone and in combination with pegIFN-α 2b. Viral breakthrough resulting from selection of pre-existing resistant mutants was observed in some patients, in particular during boceprevir monotherapy.[49]

Phase II Studies. Boceprevir and peg Interferon with and without Ribavirin

Treatment Naïve Phase II Study (SPRINT-1) The aim of the SPRINT 1 trial was to investigate safety, tolerability and anti-viral efficacy of boceprevir (800 mg three times a day) in combination with pegIFN-α 2b and ribavirin in treatment-naïve HCV genotype 1 patients.[16] Treatment with boceprevir in combination with pegIFN-α 2b and ribavirin was either performed continuously for 28 or 48 weeks or for 24 or 44 weeks after a previous 4-week lead-in phase of pegIFN-α 2b and ribavirin alone. The lead-in design was chosen to determine a potential benefit of pre-treatment with pegIFN-α 2b and ribavirin on avoiding resistance development. The control group was treated with pegIFN-α 2b and ribavirin for 48 weeks. SVR rates after 28 weeks of triple treatment were 54% and 56% after 24 weeks with an additional 4 weeks of pre-treatment lead in with pegIFN-α2 and ribavirin (Figure 5). SVR rates after 48 weeks of triple treatment were 67% and 75% after 44 weeks with an additional 4 weeks of pre-treatment lead in with pegIFN-α 2b and ribavirin. After 4 weeks triple therapy with boceprevir, pegIFN and ribavirin 38% of patients achieved an RVR. The most common side-effects related to boceprevir were anaemia, nausea, vomiting and dysgeusia. In general, SPRINT-1 has proven a higher anti-viral efficacy of combination therapy with boceprevir in comparison to the standard of care with slightly better results after a 4 week lead-in phase. However, RVR rates of only 38% during boceprevir triple therapy indicate that boceprevir is potentially less potent than telaprevir which, during triple therapy with pegIFN-α 2b, lead to an RVR rate of approximately 70%.


Figure 5.
Results of SPRINT-1. Combination therapy of boceprevir and pegIFN-α 2b + ribavirin (RBV) in treatment-naive genotype 1 patients.
 
Studies in Nonresponders and Relapsers In a complex study of HCV genotype 1 nonresponders, the addition of boceprevir to pegIFN-α 2b and ribavirin resulted in only slightly increased SVR rates compared with standard treatment (14% vs. 2%).[50]
 
Design of Phase III Studies. A phase III clinical trial (SPRINT-2) evaluating boceprevir in treatment-naïve patients was initiated recently and has enrolled more than 1000 patients. Equivalent to the SPRINT-1 study design, patients receive 800 mg boceprevir three times daily in combination with pegIFN-α 2b and weight based ribavirin for 28 or 48 weeks. RESPOND-2 evaluates boceprevir in combination with pegIFN-α 2b and ribavirin at the same doses but for 36 and 48 weeks in relapsers and nonresponders. In all investigational arms a lead-in strategy with pegIFN-α 2b and ribavirin is followed.

Viral Resistance to Boceprevir. In the replicon system, mutations at three positions conferring boceprevir resistance were discovered (Table 3). T54A, A156S and V170A confer low level resistance to boceprevir whereas A156T that also confers telaprevir and ciluprevir resistance exhibited greater levels of resistance.[26] In patients with chronic hepatitis C three additional mutations were detected during boceprevir monotherapy (V36G/M/A, V55A, R155K).[47] In a number of these patients one year and in single patients even 4 years after the end of boceprevir treatment still resistant variants were detected in the HCV quasispecies by clonal sequence analysis.[51] However, an additional study revealed that the anti-viral activity of boceprevir was not impaired in patients who were treated with boceprevir with and without pegIFN-α before.[49]

Other NS3 Protease Inhibitors

Other NS3 protease inhibitors are currently in phase 1–2 development (R7227/ITMN191, MK7009, BI201335, TMC435350, SCH900518, BMS-650032, PHX1766, ACH-1625).[13, 52, 53] In general, they exhibit a high anti-viral activity in HCV genotype 1 patients, comparable with telaprevir and boceprevir (Figure 6). Triple therapy studies for a number of compounds have been initiated and confirm that resistance development is significantly reduced by combination with pegylated interferon and ribavirin. Whereas linear tetrapeptide and macrocyclic inhibitors do not differ in general with respect to their anti-viral activity, their resistance profile differs significantly. However, R155 is an overlapping position for resistance and different mutations at this amino acid site within the NS3 protease confer resistance to all protease inhibitors which are currently in advanced clinical development.[13]


Figure 6.
Anti-viral activity of NS3/4A protease inhibitors during monotherapy for 3–14 days (modified from [13]).
 
NS4A Inhibitors
 
ACH-806. NS4A is a crucial cofactor of NS3, mandatory for proper folding of the protease and capable to enhance the enzymatic activity of NS3 manifold. ACH-806 targets NS4A and therefore inhibits the NS3/4A protease by a different mechanism than peptidomimetic NS3 inhibitors. ACH-806 binds to newly synthesized NS4A molecules, which leads to the blockade of their assembly with NS3 proteins. A phase Ib trial in HCV genotype 1-infected patients demonstrated that ACH-806 has a significant inhibitory impact on HCV replication.[54] Although the development of ACH-806 was halted as a result of reversible serum creatinine elevations, the concept of NS4A inhibition was proven. Importantly, no cross-resistance between ACH-806 and peptidomimetic NS3/4A protease inhibitors was observed in vitro.[55, 56] Novel NS4A inhibitors (e.g. ACH-1095) are currently under preclinical development.

Compounds Targeting HCV Replication
 
NS5B Polymerase Inhibitors

NS5B RNA polymerase inhibitors can be divided into two distinct categories. Nucleoside analogue inhibitors (NIs) like valopicitabine (NM283), R7128, R1626, PSI-7851 or IDX184 mimic the natural substrates of the polymerase and are incorporated into the growing RNA chain, thus causing direct chain termination by tackling the active site of NS5B.[29, 57–67] As the active centre of NS5B is a highly conserved region of the HCV genome, NIs are potentially effective against different genotypes, in contrast to NS3/4A inhibitors. Moreover, single amino acid substitutions in every position of the active centre may result in loss of function. Thus, there is a relatively high genetic barrier in the development of resistances to NIs.

In contrast to NIs, the heterogeneous class of non-nucleoside inhibitors (NNIs) bind to different allosteric enzyme sites, which results in conformational protein change before the elongation complex is formed.[68] To inhibit NS5B allostericaly, a high chemical affinity of the compound to the enzyme is required. NS5B is structurally organized in a characteristic 'right hand motif', containing finger, palm and thumb domains, and offers at least four NNI-binding sites, a benzimidazole-(thumb 1)-, thiophene-(thumb 2)-, benzothiadiazine-(palm 1)- and benzofuran-(palm 2)-binding site.[68, 69] Theoretically, NNIs targeting different binding sites can be used in combination or in sequence to manage the development of resistance. As NNIs bind distantly to the active centre of NS5B, their application results more frequently in resistance development than during treatment with NIs. In addition, mutations at the NNI-binding sites do not necessarily lead to impaired function of the enzyme.

Nucleoside Analogues

Valopicitabine (NM283, 2′-C-methylcytidine/NM107) was the first nucleoside inhibitor investigated in patients with chronic hepatitis C. Anti-viral activity of valopicitabine was low.[70] The clinical development of valopicitabine was stopped because of gastrointestinal side effects and an insufficient risk/benefit profile.

The second nucleoside inhibitor investigated in patients with chronic hepatitis C was R1626 (4′-azidocytidine/PSI-6130). A phase 1 study showed a high anti-viral activity at high doses of R1626 in patients infected with HCV genotype 1.[63–65] No viral breakthrough with selection of resistant variants was reported from monotherapy or combination studies with pegylated interferon ± ribavirin. However, severe lymphopenia and infectious disease adverse events led to the stop of R1626 development.

R7128 is another nucleoside polymerase inhibitor with potent anti-viral activity during monotherapy in HCV genotype 1 patients. Currently, R7128 is investigated in phase 2 clinical trials in HCV genotype 1, 2 and 3 infected patients in combination with pegylated interferon and ribavirin.[59] Both during monotherapy and combination therapy with pegylated interferon and ribavirin, no resistance development against R7128 was observed.

Other nucleoside analogue inhibitors of the NS5B polymerase (PSI-7851 and IDX184) are evaluated in phase 1 clinical trials in patients with chronic hepatitis C and many compounds are under preclinical development.[13] For a summary of anti-viral activities of nucleoside polymerase inhibitors see Figure 7.


Figure 7.
Anti-viral activity of nucleoside analogue NS5B polymerase inhibitors during monotherapy for 3–14 days (modified from [13]).
 
Non-nucleoside Analogues
 
NNI-site 1 Inhibitors (Thumb 1/benzimidazole Site). BILB1941, BI207127 and MK-3281 are NNI-site 1 inhibitors which have been investigated in clinical phase 1 trials and exhibit low to medium anti-viral activities.[13, 71, 72] No selection of resistant variants and viral breakthrough has been observed during 5 days of treatment with BILB1941 or BI207127.

NNI-site 2 Inhibitors (Thumb 2/thiophene Site). Filibuvir (PF-00868554) is a NNI-site 2 inhibitor with medium anti-viral activity in a phase 1 study. In a subsequent trial viral breakthrough was observed in 5 of 26 patients during combination therapy with pegIFN-α 2a and ribavirin for 4 weeks.[72]

Other NNI-site 2 inhibitors which were evaluated in phase 1 trials are VCH-759, VCH-916 and VCH-222, their anti-viral efficacy is shown in Figure 8.[13, 73] Like during treatment with filibuvir, VCH-759 and VCH-916 application resulted in viral breakthroughs with selection of resistant variants, indicating a low genetic barrier to resistance of these agents.


Figure 8.
Anti-viral activity of non-nucleoside analogue NS5B polymerase inhibitors during monotherapy for 3–14 days (modified from [13]).
 
NNI-site 3 Inhibitors (Palm 1/benzothiadiazine Site). ANA598 is a NNI-site 3 inhibitor which displayed anti-viral activity during treatment of HCV genotype 1 infected patients. No viral breakthrough was observed during a short term monotherapy trial.[74]
 
NNI-site 4 Inhibitors (Palm 2/benzofuran Site). Monotherapy with the NNI-site 4 inhibitor HCV-796 showed low anti-viral activity in HCV genotype 1 infected patients and resulted in selection of resistant variants and viral breakthrough in several patients.[75, 76] GS-9190 displays a low anti-viral activity in a clinical study and variants conferring resistance were identified in the beta-hairpin of the polymerase.

An overview of the anti-viral activities of non-nucleoside polymerase inhibitors in monotherapy studies is shown in Figure 8.

NS5A Inhibitors

In a single ascending dose study it was shown that inhibition of the NS5A protein with BMS-790052 leads to a sharp initial decline of HCV RNA concentrations.[77] BMS-790052 binds to domain I of the NS5A protein, which was shown to be important for regulation of HCV replication. No clinical data on resistance to this class of drugs have been presented yet and results of multiple dose and combination therapy studies have to be awaited.

NS4B Inhibitors

NS4B is a hydrophobic protein mandatory for the formation of the membranous web of the HCV replication complex. Moreover, NS4B displays RNA-binding properties which may be crucial in HCV RNA procession and replication. In vitro, inhibition of NS4B by small molecular compounds has been shown to compromise HCV replication significantly.[78]

Combination Therapies of Specific Anti-virals

It is a fundamental question whether SVR can be achieved by combination therapies of different STAT-C compounds without pegIFN-α and ribavirin. A first clinical trial (INFORM-1 study) evaluated the combination of a polymerase inhibitor (R7128) and a NS3 inhibitor (R7227/ITMN191). In this proof-of-principle study, patients were treated with both compounds for up to 2 weeks. HCV RNA concentrations decreased up to 5.2 log10 IU/mL, no viral break-through was observed, and HCV RNA was undetectable at the end of dosing in up to 63% of treatment-naïve patients.[79] Future clinical trials need to address whether a long-term suppression of HCV replication or even SVR can be achieved with such direct anti-viral combination therapies. Currently, combination studies with several compounds are conducted (R7128 + R7227, VX-950 + VCH222, BMS790052 + BMS650032, BI201335 + BI207127).

Conclusions
 
Numerous directly acting anti-viral agents are currently under clinical phase I-III evaluation. Results of phase II clinical trials evaluating the most advanced compounds telaprevir and boceprevir indicate that the addition of these NS3/4A protease inhibitors to pegylated interferon-alfa and ribavirin substantially improves the chance to achieve a SVR in treatment-naive HCV genotype 1 patients as well as in prior nonresponders and relapsers to standard therapy. In addition, at least during treatment with telaprevir-based regimens, overall treatment durations can be shortened significantly.

Results of the milestone studies PROVE 1 and 2 indicate that 12 weeks of telaprevir-based triple therapy is too short because of the high rate of relapse after treatment completion. Moreover, ribavirin is necessary in therapies with telaprevir to achieve high SVR rates. However, 24 to 48 weeks of total therapy including 12 weeks of triple therapy with telaprevir in addition to standard treatment greatly improved SVR rates in treatment-naïve genotype 1 patients compared with the standard of care. The RVR during triple therapy is an important predictor for treatment success and can be applied for defining individualized treatment durations. Important side effects of telaprevir are, as observed during treatment with other protease inhibitors as well, anaemia, rash and gastrointestinal disorders. The SPRINT-1 trial demonstrated that SVR rates in treatment-naïve HCV genotype 1 patients can be enhanced by the addition of boceprevir to standard treatment as well. However, the lower anti-viral efficacy of boceprevir compared with telaprevir may require longer durations of boceprevir application.

PROVE 3 has shown that telaprevir is also highly effective in the treatment of prior nonresponders or relapsers infected with HCV genotype 1. In contrast, addition of boceprevir to standard treatment only revealed a minor impact on SVR rates in nonresponders, but further trials are awaited. In addition to telaprevir and boceprevir, many NS3/4A inhibitors with promising anti-viral activities are currently investigated in phase I and II trials.

Compared with NS3/4A protease inhibitors, most HCV polymerase inhibitors display a lower anti-viral activity during monotherapy. SVR data of triple therapies containing NS5B inhibitors need to be awaited. However, some polymerase inhibitors are equally effective against different HCV genotypes whereas it was shown that protease inhibitors such as telaprevir are less potent in other genotypes than HCV genotype 1. In addition, NS5B inhibitors at least of the nucleoside analogue family display a high genetic barrier to resistance.

Although it can be vastly reduced by addition of pegylated interferon-alfa and ribavirin, resistance development to directly acting anti-viral agents has to be kept in mind. R155 is the overlapping mutation conferring resistance to all clinically yet evaluated protease inhibitors. Although resistance against polymerase inhibitors needs to be better characterized, it is evident that their resistance profiles differ from those of protease inhibitors. Combination of different classes of STAT-C agents may therefore help to overcome limitations of resistance development. The impact of recently discovered polymorphisms near the IL28B gene on resistance development and SVR rates during STAT-C regimens needs to be characterized in future studies.[80–82]

A pivotal trial evidenced an additive anti-viral efficacy of the polymerase inhibitor R7128 in combination with the protease inhibitor ITMN-191 in an interferon- and ribavirin-free regimen. Whether SVR can be achieved with such interferon-free regimens needs to be addressed in future trials.

In conclusion, STAT-C compounds in addition to pegylated interferon-alfa and ribavirin are capable to improve SVR rates at least in HCV genotype 1 patients and will therefore be included in future treatment recommendations and guidelines.

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