Roche's Pegasys gets EU backing for chronic hepatitis C in children aged five years and older

The European Medicines Agency has expanded the approval of Swiss drug major Roche’s (ROG: SIX) Pegasys (peginterferon alfa-2a) plus ribavirin for the treatment of chronic hepatitis C virus (HCV) to include children and adolescents five years of age and older, who have not received treatment and who have tested positive for the virus.

Pegasys in combination with the antiviral ribavirin is the foundation of treatment for chronic HCV in adults. The drug was first approved in the European Union over 10 years ago.

“Hepatitis C can ultimately lead to the development of advanced liver disease if left untreated. This approval provides doctors and parents of children as young as five with a treatment combination for this infection,” said Hal Barron, Roche’s head of global product development and chief medical officer.

Mother-to-child transmission of HCV is the most common route of acquiring the infection in children, with approximately 65,000 children estimated to live with chronic HCV in Europe. While the minority of children (4%-10%) born to infected mothers become infected, 80% of these children will develop chronic disease. Most children infected with chronic HCV do not have any symptoms, but the disease is progressive and can lead to advanced liver damage (cirrhosis), liver cancer and end-stage liver disease. The approval of Pegasys plus ribavirin provides an important additional treatment option for these children.

Clinical backing

The expanded EMA approval is based on a randomized controlled trial involving 114 children between the ages of five and 17 years with chronic HCV. The study assessed the efficacy of Pegasys in combination with ribavirin, as compared to treatment with Pegasys alone. The study showed that treatment with Pegasys plus ribavirin achieved sustained viral response (undetectable HCV ribonucleic acid [RNA] in the blood 24 weeks after completion of treatment) in over half of the children treated (53%), compared with 21% of children who received Pegasys alone. The majority of patients were infected with HCV genotype 1, a difficult-to-treat genotype. These results in children and adolescents are consistent with the pattern of response rates seen in adults infected with HCV genotype 1 treated with this combination of medicines

Source

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India revokes patent on Roche's Pegasys

November 02, 2012

India revokes patent on Roche's Pegasys

Last Updated:November 02, 2012 10:43

India's Intellectual Property Appellate Board (IPAB) revoked a patent Friday on Roche's hepatitis C drug Pegasys (peginterferon alfa-2a) on the grounds that it didn’t demonstrate inventiveness. The patent had been issued in 2006 and was the first to be granted under reforms introduced in the country a year earlier.

The original patent was challenged by patient group Sankalp Rehabilitation Trust in 2007 on the grounds that the pegylation process was known. Both Sankalp Rehabilitation Trust's post-grant opposition challenge and another made by Wockhardt were rejected by the Indian Patent Office, although the patient group appealed the decision.

In its ruling, the IPAB determined that "in the end, the invention is held to be obvious. The appeal is allowed and the grant of Patent No.198952 is set aside." The IPAB added that the technology involved in producing the drug could be easily replicated by anyone skilled in the process.

Pegasys costs around 360 000 rupees ($6700) for six months of treatment. Eldred Tellis, director of Sankalp Rehabilitation Trust, said "we hope that the absence of [a] patent barrier will spur generic competition to bring down the price of this much-needed drug."

This is the second patent setback that Roche has faced in India recently, after the Delhi High Court in September dismissed a patent infringement lawsuit filed by the company against Cipla over a generic version of Tarceva (erlotinib).

Reference Articles
Patent on Roche Hepatitis C drug revoked - (Business Line)
IPAB sets aside Indian patent for Roche's Pegasys - (Business Standard)
Board revokes patent on Roche hepatitis drug - (NDTV)
Intellectual Property Appellate Board revokes patent on Roche's Pegasys; victory for Hepatitis-C patients - (The Times of India)
IPAB invalidates patent on Roche hepatitis C drug Pegasys - (livemint.com)

http://www.firstwordplus.com/Fws.do?src=corp_site&articleid=5886A58FDCB94FB8AEFEC25BA5743EA9

FDA Pediatric indication;Pegasys and Copegus

Pegasys and Copegus - pediatric indication for patients 5 -17 years of age

Title: FDA Hepatitis Update - Pegasys and Copegus - pediatric indication for patients 5 -17 years of age

On August 22, 2011, the FDA approved the combination of Pegasys and Copegus for the treatment of chronic hepatitis C virus (HCV) infection in pediatric patients 5 through 17 years of age with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha.. Pegasys/Copegus combination treatment for HCV in adults was approved in December, 2002, and that original approval included a postmarketing requirement to evaluate the drugs in pediatric patients.

Hoffmann-La Roche Inc submitted the results of Study NV17424 to support the use of Pegasys/Copegus in pediatric patients. Subjects participating in the study received Pegasys at a dose of BSA x 180 mcg/1.73 m2 once weekly plus Copegus at a dose of approximately 15 mg/kg/day in two divided doses. Study participants received 24 weeks of blinded treatment and were determined to be responding or not responding based on undetectable HCV RNA (< 50 IU/mL). Responders continued their assigned treatment to 48 weeks regardless of HCV genotype. Nonresponders were unblinded and either stopped treatment (if they were in the Pegasys/Copegus group) or rolled into a “compassionate” Pegasys/Copegus combination group to continue 48 weeks of treatment (if they were in the Pegasys/placebo group). Subjects were followed off-treatment for an additional 24 weeks after the completion of 48 weeks of treatment to assess the primary efficacy endpoint, the proportion of subjects achieving sustained virologic response (SVR), defined as undetectable HCV RNA at 24 weeks post-treatment. Any subject switching from randomized Pegasys/placebo to the compassionate combination Pegasys/Copegus was counted as a treatment failure.

The trial enrolled 114 previously untreated pediatric subjects 5 through 17 years of age (of whom 55% were less than 12 years old who were randomized to receive either combination treatment of Pegasys/Copegus or Pegasys/placebo. The initial randomized arms were balanced for demographic factors: 55 subjects received initial combination treatment of Pegasys/Copegus and 59 received Pegasys/placebo. In the overall study population, 45% were female, 80% were Caucasian, and 81% were infected with HCV genotype 1. As previously shown in adults, the combination of Pegasys/Copegus provided significantly better response rates as measured by SVR compared to treatment with Pegasys alone. The SVR rate for study subjects receiving Pegasys/Copegus was 53% (29/55) compared to 20% (12/59) in the group receiving Pegasys. Subjects with the more difficult to treat genotype 1 receiving Pegasys/Copegus demonstrated SVR of 47% (21/45) while the smaller subgroup with non-genotype 1 had higher SVR (80%, 8/10).

The safety profile of Pegasys with or without Copegus in pediatric subjects in the clinical trial was similar to that observed in adults receiving similar treatment. Seven subjects receiving combination Pegasys/Copegus treatment for 48 weeks discontinued therapy for safety reasons (depression, psychiatric evaluation abnormal, transient blindness, retinal exudates, hyperglycemia, type 1 diabetes mellitus, and anemia). Dose modifications because of adverse events and laboratory abnormalities occurred commonly in the pediatric trial, about 35% during the randomized treatment period in both arms. The most common reason for modification of Pegasys was neutropenia and the most common reason for dose reduction of Copegus was anemia. The most common non-serious treatment related adverse events reported among subjects receiving Pegasys/Copegus included influenza-like illness (91 %), headache (62%), gastrointestinal disorders (56%), injection site reactions (45%), irritability (31%), fatigue (27%), rash (20%), pruritis (15%), and insomnia and decreased appetite (13% each).

The most important pediatric-specific safety issue related to Pegasys/Copegus was growth delay. Pediatric subjects treated with Pegasys/Copegus combination therapy experienced a delay in gaining weight and height after 48 weeks of therapy compared with baseline. Both weight and height for age z-scores as well as the percentiles of the normative population for subject weight and height decreased during treatment. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative growth curve percentiles for weight and height. At 2 years post-treatment, 16% of subjects remained 15 percentiles or more below their baseline weight curve and 11% remained 15 percentiles or more below their baseline height curve.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Linda Lewis
Division of Antiviral Products
Food and Drug Administration

Peginterferon Alfa-2a/PEGASYS Is Superior to Peginterferon Alfa-2b/Peg-Intron in the Treatment of Naïve Patients with Hepatitis C Virus Infection

Dig Dis Sci. 2011 Jun 4. [Epub ahead of print]

Peginterferon Alfa-2a Is Superior to Peginterferon Alfa-2b in the Treatment of Naïve Patients with Hepatitis C Virus Infection: Meta-Analysis of Randomized Controlled Trials.

Singal AK, Jampana SC, Anand BS.

Source

Department of Internal Medicine, University of Texas Medical Branch, Galveston, 77555-0764, TX, USA, aksingal@utmb.edu.

Abstract

BACKGROUND:

Pegylated interferon (PEGIFN) and ribavirin combination is the standard of care for the treatment of chronic hepatitis C virus (HCV) infection. Studies comparing the efficacy and safety of PEGIFN alfa-2a and PEGIFN alfa-2b in treatment-naïve HCV-infected patients have shown conflicting results.

AIM:
We performed a systematic review and meta-analysis of studies comparing the efficacy and safety of PEGIFN alfa-2a and PEGIFN alfa-2b in HCV-infected patients naïve to treatment.

METHODS:
Nine studies (five abstracts) with 3,546 patients (1,771 treated with PEGIFN alfa-2a) comparing PEGIFN alfa-2a and PEGIFN alfa-2b in treatment-naïve HCV patients were analyzed. Efficacy outcomes were sustained virologic response (SVR) and treatment discontinuation rates due to serious adverse effects (SAE).

RESULTS:
Pooled data on outcomes (reported as odds ratios [ORs] with 95% confidence intervals [CIs]: [OR (95% CI)]) showed higher SVR in patients treated with PEGIFN alfa-2a - PEGASYS as compared to treatment with PEGIFN alfa-2b/Peg-Intron  [1.36 (1.07-1.73); P = 0.01]. Subgroup analysis of good quality studies on SVR in genotypes 2 and 3 also favored PEGIFN alfa-2a over PEGIFN alfa-2b (1.91 [1.09-3.37]; P = 0.02). SVR results obtained with the two types of IFN showed no impact of viral load and the presence or absence of cirrhosis. Treatment discontinuation rates due to SAE, reported in six studies (two abstracts) on 3,211 patients (1,604 treated with PEGIFN alfa-2a), were similar in the two types of PEGIFN [0.66 (0.37-1.16); P = 0.15].

CONCLUSIONS:
PEGIFN alfa-2a has superior efficacy with higher SVR as compared to PEGIFN alfa-2b in treatment-naïve HCV-infected patients. The safety profile of the two types of PEGIFN was similar.

Doctors surveyed found peg-IFN-alpha-2a/ribavirin as the Most Efficacious Therapy for Hepatitis C Virus

The Majority of Surveyed Gastroenterologists and Surveyed MCO Pharmacy Directors Identified peg-IFN-alpha-2a/ribavirin as the Most Efficacious Therapy for Hepatitis C Virus, When Compared to Other Available Therapies Decision Resources
Posted on:24 Mar 11

Decision Resources, one of the world’s leading research and advisory firms for pharmaceutical and healthcare issues, finds that the majority of surveyed U.S. gastroenterologists (68 percent) and surveyed managed care organizations’ (MCOs) pharmacy directors (60 percent) identified the market and patient share leading regimen, peg-IFN-alpha-2a (Roche’s Pegasys)/ribavirin (Roche’s Copegus, Merck & Co.’s Rebetol, generics), as the most efficacious therapy for hepatitis C virus (HCV), when compared to other available therapies.

The findings from Decision Resources’ analysis of the HCV drug market reveal that interviewed thought leaders and data from several large clinical trials do not support the perception that peg-IFN-alpha-2a/ribavirin is more efficacious than the other marketed therapy, peg-IFN-alpha-2b/ribavirin (Merck’s PegIntron), but instead demonstrate that there is no significant difference between the two regimens. However, practical experience and greater familiarity with peg-IFN-alpha-2a/ribavirin may drive surveyed gastroenterologists’ perception of its superiority over peg-IFN-alpha-2b/ribavirin. For both peg-IFN-alpha-2a/ribavirin and peg-IFN-alpha-2b/ribavirin, surveyed gastroenterologists were most satisfied with sustained virological response rates of treatment-naive genotype 2- or 3-infected patients. Data from clinical trials in this population demonstrate much higher efficacy for both regimens compared with efficacy in genotype 1 patients. Also, specialists were least satisfied with sustained virological response rates in treatment-nonresponder genotype 1-infected patients, for both interferon-based therapies.

The findings also reveal that the cost of an all-oral, interferon-free regimen consisting of two HCV-specific antivirals in combination with ribavirin generally plays an important role in the efficacy, safety and tolerability, and delivery expectations of surveyed gastroenterologists.

“However, regardless of cost, gastroenterologists are not willing to compromise on efficacy in certain subpopulations,” said Decision Resources Analyst Courtney Stanton, Ph.D. “If an all-oral, interferon-free regimen priced the same as the current gold standard—peg-IFN-alpha-2a/ribavirin—were available, surveyed gastroenterologists indicate that such a regimen would have to provide considerable improvement in efficacy for treatment-naive HCV genotype 1-infected patients.”

The findings also reveal that surveyed gastroenterologists and MCO pharmacy directors agree that the ability to achieve sustained virological response in treatment-naive HCV genotype 1-infected patients is one of the attributes that most influences their decisions regarding prescribing and tier placement decisions, respectively, in HCV. Clinical data and the opinions of interviewed thought leaders indicate that regimens combining a pegylated interferon and ribavirin plus Vertex/Johnson & Johnson/Mitsubishi Tanabe’s telaprevir, Merck’s boceprevir, Roche/Pharmasset’s RG-7128, Johnson & Johnson/Medivir’s TMC-435 or Bristol-Myers Squibb’s BMS-650032 and BMS-790052 in a quadruple regimen have advantages over sales-leading peg-IFN-alpha-2a on this attribute.

Through 2019, the launch of novel HCV-specific agents will increase the size of the drug-treated population due mainly to re-treatment of prior nonresponders as well as increased referral and drug-treatment rates. As a result, Decision Resources forecasts that the HCV drug market will more than triple from approximately $2 billion in 2009 to nearly $6.4 billion in 2014 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan. Thereafter, the market will decrease to $4.6 billion in 2019 due to a decline in the size of the treatment-eligible population, decreasing disease prevalence and the high efficacy of new treatment regimens.

Decision Resources’ Robust Market Forecast and Opportunities Analysis

Decision Resources provides a comprehensive view of what is happening in a specific drug market now and in the decade ahead. The research includes analysis of the unmet need and near-term drug development opportunities that exist within a drug market powered by primary research from physicians and payers. The robust market forecast and opportunities analysisis comprised of the Pharmacor 2011 advisory service and the DecisionBase 2011 report series.

About Decision Resources

Decision Resources (www.decisionresources.com) is a world leader in market research publications, advisory services and consulting designed to help clients shape strategy, allocate resources and master their chosen markets. Decision Resources is a Decision Resources, Inc. company.

About Decision Resources, Inc.

Decision Resources, Inc. is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources, Inc. at www.DecisionResourcesInc.com.

All company, brand, or product names contained in this document may be trademarks orregistered trademarks of their respective holders.

Business Wire
http://www.businesswire.com /

Last updated on: 24/03/2011 14:00:39


Read more: http://www.pharmiweb.com/pressreleases/pressrel.asp?ROW_ID=38155#ixzz1HWgkUvx1

Hepatitis C News; The Race is On for New Hepatitis C Drugs

From Dr. Joe Galati

Telaprevir and FDA Approval: The Race is On for New Hepatitis C Drugs

by Dr. Joe Galati on February 28, 2011

For those of us that are involved in the care of patients with chronic hepatitis C, the “never too soon” announcement that we will finally have new drugs to treat our hepatitis C patients with cannot come soon enough. There is a real possibility that one and possibly two new agents for hepatitis C will be granted approval by the FDA in the months to come. When that day will be is unknown to me, but I anticipate later this summer at the latest.

There is a frenzy of discussion in the press, as well as the blogosphere on the new drugs, namely Telaprevir, manufactured by Vertex, and Boceprevir, manufactured by Merck. I have had the opportunity to use both of these drugs in clinical studies over the past several years, and understand how they both work, and what patients can expect. Much to everyone’s surprise, patients will still need to take one of the pegylated interferons once weekly, and ribavirin twice daily. The new drugs are added to this backbone of therapy. Besides the expected interferon and ribavirin side effects, the protease inhibitors do add some additional problems, but for the most part, in experienced hands, they can be managed fine. Once these drugs are approved, I anticipate a mad-dash of patients, wanting to get their hands on these therapies.
My advise is to start requesting your old records now if you were previously treated. Knowing exactly how many weeks you were treated, what your response was, and what complications developed, will be important information prior to commencing any sort of new therapy, regardless of which protease inhibitor you are started on. It can take weeks to get these records, so start asking now.

There are hundreds of thousands of patients with hepatitis C that are either naive to therapy (never treated), or previously treated with a partial response (null responder, non-responder, or responder-relapser). All of these individuals should be considered for these new therapies, but you need to be sure you are being seen by a practice that can handle these patients. With the new protease inhibitor drugs, resistance can become an issue, and discontinuing the therapy in a timely fashion is important. The treatment protocols are different from prior therapies, with a lead-in phase with interferon. All of these steps requires careful monitoring and communication with the patient. An experienced staff of nurses will be needed. Prior to being evaluated for these new exciting drugs, you, as a consumer, need to ask these questions to see if your care provider has the necessary experience, as well as a dedicated team to support them once patients are started on therapy.

Besides the two contenders for FDA approval later this summer, the pipeline for additional drugs is incredibly long. We are conducting research studies on an additional 12 drugs, all of which look promising. Some of the protocols are free of the hated interferon. Imagine, HCV therapy without interferon? That day will be here, allbeit several more years. I am currently in Chicago with the HCV team from Abbott, who also has a number of exciting compounds we will start studying soon with our patients in Houston.

So, when will the new hepatitis C drugs be available? My best educated guess will be by Labor Day, but we may all be surprised sooner, based on the chatter in the press and FDA hallways.
I am eager to hear what you think? Comment on your prior experience with hepatitis C therapy.,

,

In The News APASL

,,

From NATAP
. ,
The 21st Conference of the Asian Pacific Association for the Study of the Liver
APASL Feb 17-20, 2011 Bangkok, Thailand

APASL: Associations between two SNPs (rs12979860, rs12980275) and complete early virological response for peginterferon alfa-2a (40KD) - based treatment in naive patients and previous non-responders - (02/28/11)

APASL: Retrospective pooled safety analysis of standard- versus high-dose peginterferon alfa-2a (40KD) (PEGASYS) in chronic hepatitis C genotype 1 or 4 patients - (02/28/11)

Hepatitis Associated Aplastic Anemia: A review

Hepatitis-associated aplastic anemia (HAAA) is an uncommon but distinct variant of aplastic anemia in which pancytopenia appears two to three months after an acute attack of hepatitis. HAAA occurs most frequently in young male children and is lethal if leave untreated.The etiology of this syndrome is proposed to be attributed to various hepatitis and non hepatitis viruses. Several hepatitis viruses such as HAV, HBV, HCV, HDV, HEV and HGV have been associated with this set of symptoms.Viruses other than the hepatitis viruses such as parvovirus B19, Cytomegalovirus, Epstein bar virus, Transfusion Transmitted virus (TTV) and non-A-E hepatitis virus (unknown viruses) has also been documented to develop the syndrome. Considerable evidences including the clinical features, severe imbalance of the T cell immune system and effective response to immunosuppressive therapy strongly present HAAA as an immune mediated mechanism.

However, no association of HAAA has been found with blood transfusions, drugs and toxins. Besides hepatitis and non hepatitis viruses and immunopathogenesis phenomenon as causative agents of the disorder, telomerase mutation, a genetic factor has also been predisposed for the development of aplastic anemia.Diagnosis includes clinical manifestations, blood profiling, viral serological markers testing, immune functioning and bone marrow hypocellularity examination. Patients presenting the features of HAAA have been mostly treated with bone marrow or hematopoietic cell transplantation from HLA matched donor, and if not available then by immunosuppressive therapy.New therapeutic approaches involve the administration of steroids especially the glucocorticoids to augment the immunosuppressive therapy response. Pancytopenia following an episode of acute hepatitis response better to hematopoietic cell transplantation than immunosuppressive therapy.Author: Bisma RauffMuhammad IdreesShahida ShahSadia ButtAzeem ButtLiaqat AliAbrar HussainIrshad RehmanMuhammad AliCredits/Source: Virology Journal 2011, 8:87

CROI: HIV-Resistant T Cells on Horizon
BOSTON -- Researchers are cautiously excited about preliminary data showing HIV-resistant T cells can be created in the lab and returned to patients, possibly offering a new approach to therapy.




People With HIV And Hepatitis C May Have Higher Rates Of Osteoporosis Than People With HIV Alone
By Mariana Torrente

Published: Mar 1, 2011 10:40 am
A new study of patients with both HIV and hepatitis C found they had a higher rate of osteoporosis than people in previous studies who had HIV but not hepatitis C. The researchers also found that controlled HIV replication, but not the severity of liver disease, was associated with increased risk of osteoporosis in people with both HIV and hepatitis C.
The study investigators noted that the primarily African-American study participants had a higher rate of osteoporosis than patients in a similar study of Caucasians in Italy. While factors other than race may be involved, the researchers suggested that African-Americans with HIV and hepatitis C virus (HCV) co-infection may be at higher risk of osteoporosis than expected.

Hepatitis B Rates Drop Among Kids Due To Effective Vaccination Programs, More Efforts Needed For Adults
28 February 2011Approximately 5.1% of the American population had been exposed to HBV (Hepatitis B virus) between 1988 and 1994, researchers wrote in Annals of Internal Medicine. Since that date, extensive vaccination campaigns for...

Breast Milk Ice Cream Confiscated Over Hepatitis Fears
Published March 01, 2011
FoxNews.com

LONDON -- A London borough council confiscated breast milk ice cream being sold in a shop in the city's tourist district over fears it could contain hepatitis viruses and sent it for testing.
"Following two complaints from members of the public and concerns from the Health Protection Agency and Food Standards Agency, our officers visited the premises and removed all ice cream being sold as containing breast milk," council officer Brian Connell told the London Evening Standard newspaper Tuesday. "Selling foodstuffs made from another person's bodily fluids can lead to viruses being passed on and in this case, potentially hepatitis."

Woman Gets New Liver From Church Parishioner
March 1, 2011 7:52 AM
CHICAGO (WBBM) – A 68-year-old local woman has received a liver donation from a member of her Northwest Side church.
Roberta Sturgill contracted hepatitis C from a blood transfusion in 1995. She was in need of a liver transplant, but thought all hope may be lost when her niece’s liver was rejected for being too small.

Wellness

Açaí Juice

In the nutraceutical or nutritional supplements market, there is never any shortage of bandwagons. One of the loudest and largest these days is the açaí bandwagon. Harvested from a Brazilian palm, açaí (ah-SAH-ee) berries are a dietary staple in Brazil and have also been used medicinally by Amazonian tribes. Açaí juice was introduced in the U.S. in 2001, and there are now more than 50 new food and drink products containing açaí. As a juice, pulp, powder, or capsule, it is marketed as a magic path to weight loss, a wrinkle remover, a way to cleanse the body of "toxins," and indeed just a plain old miracle cure. It is often combined with other ingredients, such as glucosamine, so that the claims for benefits multiply exponentially.
Offers for açaí have flooded the nation’s email boxes.

On the Internet you’ll find a bouquet of endorsements from such celebrities as Oprah, Nicholas Perricone (the TV "skin doctor"), and Rachael Ray (the TV chef), plus statements by these same celebrities denying any such endorsement, or at least any endorsement of a particular brand, except that Dr. Perricone sells a brand of his own. You will also find a war of words among makers of açaí products, each one claiming safety and effectiveness for its particular formulation, and warning of scams by others.
Since açaí came on the market there have been a few studies pointing to potential benefits. Like many other fruits, açaí berries are high in antioxidants (molecules that quell cell-damaging free radicals) and other interesting compounds. But these were lab studies, and the results may not apply to humans. There is no scientific basis for weight-loss claims or any other health claims for açaí. The term "antioxidant" has become a sales tool.

Consumer protection groups such as the Center for Science in the Public Interest (CSPI) and the Better Business Bureau (BBB) have now come out against açaí marketers. "If Bernard Madoff were in the food business," said a CSPI nutritionist, "he’d be offering ‘free’ trials of açaí-based weight-loss products." Online ads regularly promise a free trial, saying that all you have to pay is shipping and handling. The catch is that you must supply your credit card number, and you’ll automatically be signed up for $50 monthly shipments that will prove hard to cancel.
We urge you not to give your credit card number to anybody selling açaí products. Hundreds of complaints have been registered, and you may never get your money back. Beware of web-sites warning you of açaí scams—far from helping you get your money back, most turn out to be just sales pitches for more açaí.

There is no magic berry for weight loss or good health. Açaí berries are no doubt a good food, like other berries, but why pay a fortune for them or supplements containing them?

Liver Cancer

Announcing 510(k) Clearance of a New Microfluidic-based IVD Test System, the uTASWako® i30 Immunoanalyzer, and AFP-L3 and DCP Assays for Liver Cancer Risk Assessment.

RICHMOND, Va., March 1, 2011 /PRNewswire/ -- Wako Diagnostics, a division of Wako Chemicals USA, has received 510(k) clearance from the U.S. Food and Drug Administration (FDA) to market the uTASWako i30 instrument with alpha-fetoprotein L3 (AFP-L3) and des-gamma-carboxy prothrombin (DCP) in vitro diagnostic (IVD) tests in the USA. The AFP-L3 and DCP assays are intended for use by healthcare professionals as an aid in the risk assessment of patients with chronic liver disease for development of hepatocellular carcinoma (HCC).

"Wako is very pleased to receive 510(k) clearance for these assays using microfluidic technology," said Peter Panfili Ph.D., General Manager, Wako Diagnostics. "We expect that the adoption of these biomarkers into HCC surveillance programs will complement the use of imaging technologies to bring about the desired earlier detection and treatment of liver cancer."

HCC, primary liver cancer, is currently the fastest growing cause of cancer-related death in the USA. It has been demonstrated that HCC surveillance programs for at-risk patients improves applicability of curative therapies. Incorporating these biomarkers as additional surveillance tools will improve the chance of detecting early stage HCC and improve patient outcomes.
Microfluidics has enabled miniaturization and integration of key analyzer processes for the uTASWako i30: sampling, mixing, separation, and detection on microfluidic chips. The system uses immunochemical and electrophoretic techniques to achieve rapid, accurate, precise and sensitive assay results.
As a bench top automated instrument, the uTASWako i30 is designed for efficiency and ease of use in a clinical chemistry setting. Up to six analytes may be selected per patient sample with the first result reported in nine minutes. With automated calibration and quality control, the uTASWako i30 requires minimal setup time. Reagent usage is tracked using radio frequency identification (RFID) tags.
The uTASWako i30 reports AFP-L3%, total AFP, and DCP values using Wako's unique reagents. This IVD test system is available to hospital laboratories, reference laboratories and tertiary care centers. Wako is the only company that offers 510(k)-cleared AFP-L3 and DCP assays for IVD use.

Hepatitis Awareness: 10 Liver Cancer Risks
Liver cancer rates doubled in the United States between 1976 and 2002, and is one of the most deadly cancers worldwide. A recent review article reported on the risk factors:

1. Hepatitis B or C virus infection. Worldwide, viral liver infections are the most common cause of liver cancer. Rates of hepatitis C infection are on the rise in the United States, and this is one contributing factor to the rising rates of liver cancer.

2. Alcohol. Liver damage is the most familiar hazard of excessive alcohol consumption. Cirrhosis is a common step on the way to liver cancer..............


Pharmaceuticals

Pharma jobs outlook bleak as European sites axed

Tue Mar 1, 2011 5:50am EST
* Pfizer, Merck, AstraZeneca sites in Europe face closure

Drug industry moving to "fragmented" model of research
* 6,000 pharmaceutical jobs gone in UK in last 12 months
By Ben Hirschler

LONDON, March 1 (Reuters) - Drug companies are pulling down the shutters on major European research laboratories, posing a serious challenge to the region's ambitions for creating new high-tech jobs.

Nowhere is the problem more acute than in Britain, where Prime Minister David Cameron named pharmaceuticals as one of five "industries of the future" in early January -- only to have the rug pulled from under his feet two weeks later.
Pfizer's (PFE.N) new CEO Ian Read told Cameron on Jan. 24 the world's biggest drugmaker's was closing its Sandwich site in southern England with the loss of up to 2,400 jobs.
Company executives said on Monday they had been discussing the possibility of shutting Sandwich as early as last November, when site head Ruth McKernan started to wind down recruitment for the flagship research centre.
Pfizer, facing massive revenue losses from drugs whose patents are expiring, is exiting Sandwich as part of a drive to cut 2012 research and development (R&D) spending by as much as $2 billion from an originally planned $8.0-8.5 billion.
The group is talking to a number of companies interested in using part of Sandwich, and McKernan said it was encouraging staff hoping to form spin-outs or management buy-outs.
But she acknowledged finding a single occupier for the 3 million square feet available at Sandwich "would be a real challenge".
"This is really an evolution of the industry to a more fragmented model," McKernan told a parliamentary committee probing Pfizer's plans to quit Sandwich within 18-24 months.
NEW TENANTS?
Pfizer's site is the biggest casualty of the current round of drug industry retrenchment but it is not alone -- and the flood of specialist lab-equipped real estate now hitting the market makes it doubly tough to find new occupiers.

From Pharmalot

Abbott & Glaxo Go To Court Over AIDS Drug Price
By Ed Silverman // March 1st, 2011 /
8:39 am
Abbott sells a combo pill called Kaletra that includes Norvir and its own protease inhibitor. The lawsuit claims Abbott raised Norvir’s price - but not the Kaletra price - in order to boost Kaletra sales at the expense of other protease inhibitors that require Norvir as a booster. In other words, Abbott allegedly tried to use Norvir to create an illegal monopoly over the market for protease inhibitors. The stakes are high, though, because the damages can be tripled


Off The Cuff

From Celebrity Dianosis;

Celebrity "Mental Cases": Charlie Sheen, Dr. Drew and the Goldwater Rule

Recently, radio/TV personality, internist and host of Celebrity Rehab Dr. Drew Pinsky was asked to comment on one of Charlie Sheen's recent public statements and said, "He's in an acute manic state now ... whether it's drug-induced or drug-withdrawal or he has bipolar disorder, I don't know but right now he's manic and that's an acute psychiatric emergency. Bipolar patients who are manic are more likely to kill themselves or hurt themselves than when they're depressed. So this is somebody ...........

21st Century Medicine, 19th Century Practices
8:19 AM Friday February 25, 2011

Editor's note: This post is part of a three-week series examining innovation in health care, published in partnership with the Advanced Leadership Initiative at Harvard University.

By the time I saw Mr. Johnson (not his real name), he had received three CT scans in less than 24 hours — and we had done nothing to make him feel better or cure his clinical problem. The day prior, he had seen his primary care physician in rural Maine for fever and belly pain, and had a CT scan which showed an abscess in his abdomen. At the nearby emergency room, where he went next, another physician, unable to obtain the original films, reordered the CT scan. The ER physician was about to hospitalize the patient when Mr. Johnson reported being a veteran and was promptly transferred to the Boston VA. The films were misplaced during his transfer to Boston and after arriving, he had — you guessed it — yet another CT scan confirming the abscess. All that diagnosing and still no treatment! Although this true story is alarming, it's hardly atypical for our $2.5 trillion healthcare system.........

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Hepatitis C: 12wk Rule in Standard Therapy SOC

Even with all the excitement of telaprevir and boceprevir the fact remains there are numerous people treating right now with standard therapy; peginterferon alfa plus ribavirin. This blog has not posted information on standard therapy in sometime. With this entry I hope to remind everyone of the 12 week stopping rule.

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This information isn't new, however, until its brought out into the spotlight it could be easily forgotten, or overlooked. During the 2010 AASLD meeting we were slammed with new information, with a lot of attention focused on the new drugs.

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Presented at the AASLD meeting was this abstract on SOC therapy; "High Correlation Between Week 4 and Week 12 as the Definition for Null Response to Peginterferon alfa (PEG) Plus Ribavirin (R) Therapy: Results From the IDEAL Trial"

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Predictive SVR In Viral Load Testing At 4 and 12 weeks

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This was powerful information with results showing a "less" then 1 log drop in viral load at week 4, equates to a "less" then 2 log drop in viral load at week 12. Both are an earlier predictor of "null response".

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Fact; 97% to 100% of genotype 1 patients in the study who failed to attain an early virologic response (less then a 2-log drop at week 12 of treatment) failed to attain a sustained virologic response (SVR)

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What is null response ?

"Null response means that hepatitis C viral load drops by "less" than one log (10%) after four weeks of treatment, and drops by less than two logs (99%) drop after 12 weeks of treatment."

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What is a two log drop ?
Example; 2 log drop = 15,000,000 IU/Ml with a drop to 150,000 IU/mL
Or a viral load that starts at 15,000,000 IU/mL and does not decrease to 150,000 IU/mL or lower.

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12 week stopping rule

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In 2009 the FDA Approved an Expanded Indication for Peginterferon-based Combination Therapy for Patients with Chronic Hepatitis C

Excerpted from the press release see full info here;

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This new expanded indication covered patients with compensated liver disease who did not achieve sustained response to prior treatment. Patients less likely to benefit from retreatment after failing a course of therapy include those with previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, or HCV genotype 1 infection.

Data from the clinical study supporting the approval helped to define those patient groups most likely to respond to retreatment as well as those unlikely to respond.

In the clinical study supporting the approval, achievement of undetectable virus (HCV RNA) at treatment week 12 was a strong predictor of SVR. Patients who still had detectable virus at week 12 of therapy were highly unlikely to achieve SVR.

A quote from Dr. Schiff ;

"Patients with "undetectable" virus at week 12 have a better chance for success and can be motivated to continue treatment," Schiff added, "and those patients who fail to achieve an early response can have their therapy stopped with confidence, thus avoiding unnecessary treatment and potential adverse events."

With this data made readily available to the public it brings to light the importance of understanding your own particular treatment protocol. Knowing the protocol will be especially important in the future when telaprevir and boceprevir make its way into clinical practice.

A quick review of the terminology;

Terms for HCV treatment response

Relapse means that HCV became—and remained—undetectable during treatment, but reappeared within weeks to months after finishing it.

Viral breakthrough means that HCV reemerged after becoming undetectable during treatment.

Non-response means that the hepatitis C viral load drops by "two logs (99%) but does not ever become undetectable during treatment".

Null response means that hepatitis C viral load drops by less than one log (10%) after four weeks of treatment, and drops by less than two logs (99%) drop after 12 weeks of treatment.

Time point

Very rapid virological response (vRVR) is a new term, used to indicate that HCV RNA has become undetectable after 14 days of treatment.

Rapid virological response (RVR) means that HCV cannot be detected in the blood after four weeks of treatment. RVR is a significant milestone in response-guided therapy because it predicts sustained virological response (see below) in ~90% of cases—regardless of HIV status, but a person can still be cured in the absence of RVR.

Sustained virological response (SVR) means that no HCV is detectable in a person’s bloodstream six months after completion of treatment. SVR is durable, and linked to reductions in liver-related morbidity and mortailty; HCV is cured.

Extended rapid virlogic response (eRVR) is a newly coined term indicating that HCV RNA has becomes undetectable after 4 weeks of treatment and remains undetectable at week 12.

Partial early virological response (pEVR) means that HCV RNA has dropped by at least two logs (99%).

Complete early virological response (cEVR) means that HCV RNA is undetectable after 12 weeks of treatment. SVR is more likely for people who have a cEVR than people who have a pEVR.

Although an early virological response cannot predict who will be cured, it does indicate who will not be cured if they remain on treatment.

Since SVR is extremely unlikely in people who don’t have a pEVR or cEVR, HCV treatment is usually discontinued at this point. Sometimes this is called an early stopping rule.

End-of-treatment response (EOT) means that HCV viral load is undetectable at the end of HCV treatment.

SVR-12 means that HCV remains undetectable 12 weeks after completion of treatment. Although it has not been prospectively validated (meaning that researchers have found this to be true by looking back at trial results rather than planning in advance to see if it is true), SVR-12 is a good predictor of SVR because relapse usually occurs within a few weeks after treatment completion.

Source For Terms

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The Data

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High Correlation Between Week 4 and Week 12 as the Definition for Null Response to Peginterferon alfa (PEG) Plus Ribavirin (R) Therapy: Results From the IDEAL Trial

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. Detailed Information can be found here; Recent Advances in Hepatitis C: Entitled "Highlights from the 2010 AASLD Meeting"

In the IDEAL study, 3,070 treatment-naive patients with genotype 1 HCV infection received up to 48 weeks of treatment with 1 of 3 regimens:

Peginterferon a-2b (1.0or 1.5 μg/kg/week) plus ribavirin (800–,400 mg/day) or peginterferon α-2a (180 μg/week) plus ribavirin(1,000–,200 mg/day).

In the current analysis, Poordad and colleagues evaluated data from patients enrolled in the IDEAL study to determine the concordance between virologic response at Weeks 4 and 12.

A null response was defined as a failure to achieve an HCV RNA decline of at least 1 log IU/mL at Week 4 or a decline of at least 2 log IU/mL at Week 12.

The investigators found high positive correlations between the change in HCV RNA levels at Weeks 4 and12 for all peginterferon and ribavirin regimens.

A null response at Week 12 corresponded to an HCV RNA decline of 0.7–1.1 log IU/mL at Week 4 in patients receiving peginterferon α-2b (1.5 μg/kg/week) plus ribavirin. The concordance rate for attaining a null or non-null response at both time points was 89% overall, with similarly high rates across the study’s 3 treatment arms (Table 1).

In a pooled analysis of patients in all 3 treatment arms, concordance rates at Weeks 4 and 12 according to IL-28B genotype were 98% in patients with CC alleles and 83% in patients with CT/TT alleles.

The more unfavorable allele was present in almost all patients with a null response at Week 4 or 12.

The investigators concluded that a viral load decline of less than 1 log IU/mL at Week 4 is roughly similar to a decline of less than 2 log IU/mL at Week 12. Therefore, Week 4 null response may provide an early method of predicting "null response", which could help guide early treatment decisions.

The Bottom Line

Patient is given a PCR/viral load test at four weeks, results are.... "less" then a 1 log drop.

This equates with "less" then two log drop at 12 weeks, which is an earlier predictor of "null reponse".

The Stats...

97% to 100% of genotype 1 patients in the study who failed to attain an early virologic response (less then a 2-log drop at week 12 of treatment) failed to attain a sustained virologic response (SVR)

Patients with an "undetectable" virus at week 12 in the study had an SVR rate of 79% .

This stopping rule can save the patient adverse effects, time, money and emotional/physical pain. Should a patient stop at week 4 if they had less then a 1 log drop? What if the patient had the IL-28B genotype test and had the good allele "CC"? What if the patient had very little liver damage ? What if the patient is under 30 and just contracted HCV? What if the patient has time to wait ? What if ? What if? When should you stop treatment ?

If I were treating today, I would be asking my physician all these questions.

What do we know for sure ? The 12 week stopping rule remains in place.

2011/Current Therapies for Chronic Hepatitis C

From Pharmacotherapy

Current Therapies for Chronic Hepatitis C

McKenzie C. Ferguson, Pharm.D.
Authors and Disclosures

Posted: 01/11/2011; Pharmacotherapy. 2011;31(1):92-111. © 2011 Pharmacotherapy Publications

Abstract

Hepatitis C virus affects more than 180 million people worldwide and as many as 4 million people in the United States. Given that most patients are asymptomatic until late in the disease progression, diagnostic screening and evaluation should be performed in patients who display high-risk behaviors associated with acquisition of hepatitis C. Chronic hepatitis C is associated with cirrhosis, hepatic failure, and death; therefore, treatment is aimed at reducing these complications, as well as improving quality of life and minimizing adverse effects.

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The American Association for the Study of Liver Diseases Practice Guidelines on the Diagnosis, Management, and Treatment of Hepatitis C represent the gold standard for guidance on the management of hepatitis C. Standard treatment for hepatitis C is peginterferon alfa in combination with ribavirin. Currently, two pegylated interferon products are approved by the U.S. Food and Drug Administration for the treatment of hepatitis C. The duration of therapy with peginterferon and ribavirin is dictated by viral genotype and virologic response. Additional therapies are under investigation for treatment of chronic hepatitis C and show early promise of comparative efficacy and fewer adverse effects. Special considerations in certain populations, including patients coinfected with human immunodeficiency virus, those with end-stage renal disease, injection drug users, pregnant women, and pediatric patients, should guide treatment decisions.

Introduction

Hepatitis C virus (HCV), a single-stranded RNA virus, is the most common chronic blood-borne illness in the United States. Approximately 4 million people in the United States have chronic infection. Although reported surveillance data likely reflect accurate trends, they also likely underestimate the true burden of disease.[1] Hepatitis C virus was officially recognized in 1989 and had previously been referred to as non-A, non-B hepatitis.[2] Most patients who develop acute hepatitis C will develop chronic infection, and as many as 30% of chronic HCV infections are from unknown causes.[3]

The incidence of acute hepatitis C has declined since the 1980s and 1990s and has stabilized since 2003 (Figure 1), possibly as a result of increased education and public awareness of transmissible risk factors.[1, 4, 5] Routine blood screening, implemented in 1992, has also contributed to the declining frequency. The HCV rates in people aged 25–39 years, typically those with the highest rates of infection, have decreased 90% from 1990 to 2007. In addition, the historically higher frequency in men is declining, with similar rates now reported for both sexes. Currently, the prevalence of chronic infection is highest in persons aged 40–49 years. Rates during 2004–2007 were similar among racial-ethnic groups except for American Indians and Alaskan Natives, in which the incidence increased. Previous prevalence data showed higher rates in non-Hispanic blacks.[1]

Figure 1.
Incidence of acute hepatitis C infection in the United States between 1982 and 2007.5

Complications and Economic Burden

Given that most patients living with chronic hepatitis C are relatively young and often asymptomatic, the future economic impact of associated complications is likely to be substantial. Cirrhosis, liver failure, and hepatocellular carcinoma are possible complications of chronic HCV. As many as 20–30% of patients with chronic HCV will progress to cirrhosis within 20 years. Chronic viral hepatitis is a leading cause of hepatocellular carcinoma and one of the most common reasons for liver transplantation in the United States.[1] It is estimated that 12,000 deaths/year are a result of chronic liver disease due to HCV infection.[5]

One group of authors analyzed U.S. hospitalization and prescription data over an 8-year period (1994–2001) to understand outcomes associated with hepatitis C.[6] Hospitalization trends were analyzed by using the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project where a 20% stratified sample of U.S. community hospitals was collected for data extrapolation. Outpatient data were obtained through the National Ambulatory Medical Care Survey and prescription data from Verispan Source Prescription Audit. International Classification of Diseases, Ninth Revision, codes were used for diagnoses. Although the average length of stay for liver-related hospitalizations associated with HCV decreased from 8.5 in 1994 to 6.9 in 2001, the number of hospitalizations more than doubled (111 vs 244). Additional findings included that for every $100,000 spent in nationwide hospitalizations in 2001, $427 was due to liver-related complications from hepatitis C, compared with $145 in 1994. Patients aged 40–49 years accounted for more hospitalizations, greater expenditures, and a higher rate of death than other age groups. Physician office visits by patients with HCV and prescription drug expenditures also greatly increased.

Diagnosis

The American Association for the Study of Liver Diseases (AASLD) Practice Guidelines on the Diagnosis, Management, and Treatment of Hepatitis C represent the gold standard for guidance on the management of hepatitis C(Table 1).[7] These guidelines were approved and are supported by the AASLD, the Infectious Diseases Society of America, and the American College of Gastroenterology.[7]

A laboratory diagnosis of HCV is determined after screening for possible risk factors and evaluation of signs and symptoms. Acute illness manifests symptomatically in 20–30% of patients. Many patients with chronic HCV infection are asymptomatic or may exhibit only mild symptoms.[8] Possible symptoms include abdominal pain, fever, fatigue, loss of appetite, nausea, and vomiting.[3, 8, 9]

Risk Factors

Hepatitis C virus is transmitted by exposure to infected blood or blood products (Table 2).[1–3, 7, 9, 10] Injection drug use is the most common route of exposure to hepatitis C.[1, 7] All persons who report illicit drug use, including intranasal cocaine use, should be screened for HCV.[2, 7] The prevalence of HCV reported in injection drug users is extremely high, with a proportional relationship to the duration of drug use. Within 5 years of beginning injection drug use, one in three persons will become infected with HCV.[11]

Other populations at risk for HCV infection include individuals who received a blood or blood component transfusion before 1992, individuals who provide health care to infected patients, individuals who receive long-term hemodialysis, persons with human immunodeficiency virus (HIV), children of HCV-infected mothers, and persons with multiple sexual partners, although transmission between monogamous partners is uncommon (Table 2).[1–3, 7, 9, 10] The risk of HCV transmission between monogamous sexual partners is less than 1%.[3]

Persons who have been receiving long-term hemodialysis, those with unexplained abnormal aminotransferase levels, or those infected with HIV are considered at risk because of the higher prevalence of infection in these patient populations.[7] Less than 5% of infants born to HCV-infected mothers will acquire the infection.[3]

In addition, breastfeeding has not been linked to transmission of HCV.[3, 7]

Although HCV exposure through tattooing, acupuncture, and body piercing is possible, each has rarely been reported as the sole possible mode of transmission.[2, 3, 7, 9]

Several risk factors are associated with progression to chronic disease. Nonmodifiable risk factors include advanced age at the time of initial infection, male sex, Hispanic ethnicity, and genetic factors linked to polymorphisms of specific genes involved in the rate of fibrosis and hepatocellular carcinoma.[10]

Whereas African-American patients display a higher rate of development of hepatocellular carcinoma, a lower response to therapy, and higher liver-related mortality compared with Caucasian patients, studies have shown that they are actually less likely to progress to cirrhosis.[10] Limited evidence shows that Hispanic patients, on the other hand, progress faster to cirrhosis compared with Caucasian patients.[10] Potentially modifiable risk factors include elevated alanine aminotransferase (ALT) levels, alcohol intake, smoking, and coinfection with HIV or hepatitis B virus.[10]

Clinical features of disease progression to cirrhosis

Clinical features of disease progression to cirrhosis may include jaundice, enlarged liver and/or spleen, muscle wasting, and ascites. Elevated levels of alkaline phosphatase, γ-glutamyl transferase, and aspartate aminotransferase (AST) may also be seen. Low platelet and white blood cell counts may be observed. Extra-hepatic manifestations, such as cryoglobulinemia, glomerulonephritis, and porphyria cutanea tarda, are uncommon.[3]

The diagnosis of chronic HCV infection is established when anti-HCV is present and serum aminotransferase levels remain elevated for 6 months or longer.[3, 7] Polymerase chain reaction (PCR) testing for HCV RNA will establish the diagnosis, and a positive result is indicative of current and active infection.

Laboratory Testing

Both qualitative and quantitative tests are used in the diagnosis of HCV. Enzyme immunoassay–confirmed anti-HCV is the initial serologic test used to establish exposure to HCV but is not necessarily indicative of current infection. The available enzyme immunoassays have specificity greater than 99%. Current infection can be established with quantitative analysis of HCV RNA through PCR or transcription-mediated amplification. Currently available PCR assays have excellent specificity (98–99%) and will detect HCV RNA in the serum to a lower limit of 50–100 copies/ml. Most patients with chronic HCV will have levels of HCV RNA (viral load) between 100,000 (105) and 10,000,000 (107) copies/ml (or 50,000–5 million IU/ml). Interpretation of anti-HCV and HCV RNA results is given in(Table 3).3, 7]

Confirmatory testing is essential in high-risk patients who test negative for anti-HCV. Immuno-compromised patients, including those with HIV, solid-organ transplant recipients, or those receiving hemodialysis, may have false-negative test results due to the inability to mount a sufficient immune response. Likewise, persons with acute HCV infection may require up to 1 month or more for adequate antibody detection. Follow-up and/or confirmatory testing of HCV RNA for these patients may be warranted Table 3.[).[3, 7] Retesting for both anti-HCV and HCV RNA in 4–6 months may help to resolve issues with false-positive and false-negative results.[3, 7]

In June 2010, the U.S. Food and Drug Administration (FDA) approved the first rapid blood test for antibodies to HCV (OraQuick HCV Rapid Antibody Test; OraSure Technologies, Bethlehem, PA). It is approved for use in patients aged 15 years or older. The test is approved for screening persons who are considered at risk for HCV infection and works from a sample of venous blood, with readable results in about 20 minutes.[12, 13]

In patients with chronic HCV infection, ALT and AST levels may appear either normal or elevated. Elevations in ALT level are more frequently seen, usually less than 5 times but may be as high as 20 times the upper limit of normal.[3]

Liver biopsy is not needed to diagnose HCV but is useful in determining the grade and stage of liver disease.

The grade of disease is determined by evidence of necrosis and inflammation in liver tissue, whereas the stage is determined by the extent and presence of fibrosis and cirrhosis. At this time, the decision to perform liver biopsy for prognostic purposes or to guide a treatment decision should be individualized, taking into consideration the probability of disease progression, patient willingness to undergo the procedure, and patient genotype.[3, 7]

Genetic Variations

Six different genotypes and more than 50 subtypes exist for HCV.

Genotype denotes nucleotide variation and is typically represented geographically by location for HCV. Genotype 1 is the most common in the United States, followed by genotypes 2 and 3. Genotype 4 is most represented in the Middle East, including Egypt and Africa, whereas genotype 5 is seen in South Africa and genotype 6 in Southeast Asia.[14, 15] Genotypic variations aid in identifying patients likely to respond to treatment and guide the duration of therapy, both of which are critical to therapeutic decision making.[3, 7]

Therapeutic Management

The management of chronic HCV infection should be individualized. Methods to prevent transmission and the importance of adherence to treatment should be addressed. Treatment is strongly recommended and should be considered in patients with chronic HCV and detectable levels of HCV RNA, elevated aminotransferase levels, and histologic evidence of progressive liver disease.[7, 16]

The primary goals of therapy are to prevent complications and death from HCV while reducing adverse events and maintaining quality of life. The difficulty in achieving these goals is complicated by the slow progression of chronic disease and treatment responses that are based on surrogate virologic parameters versus long-term clinical outcomes. Normalization of serum aminotransferase levels, virologic response, and histologic improvement are several short-term outcomes commonly assessed.[7]

SVR sustained virologic response

Virologic cure is established by a sustained virologic response (SVR), defined as the absence of serum HCV RNA by PCR assay 24 weeks after cessation of therapy.[7] The SVR offers the best prediction of long-term response. Lack of an early virologic response (EVR) can be used to predict nonresponders and a lack of SVR. Evaluation of rapid virologic response (RVR) can be used to assess durations of treatment based on genotype. All virologic responses are defined in Table 4.7]

α-Interferon or interferon alfa-2b was the first therapy approved for the treatment of HCV.[17] The limitations with conventional, nonpegylated interferon include rapid absorption in subcutaneous tissue, large volume of distribution, rapid renal elimination, short half-life, and variable peak-trough concentrations.[16] These unfavorable characteristics necessitated dosing 3 times/week. The later addition of a polyethylene glycol (pegylated) moiety resolved many of these issues.

Ribavirin, an oral synthetic nucleoside analog, acts synergistically with pegylated interferon and is administered in divided doses. Ribavirin is not effective or indicated as monotherapy for treatment of HCV.[18] The combination of pegylated interferon and ribavirin represents the recommended treatment for HCV.

Safety

Treatment-limiting adverse effects are a common complication of HCV treatment and are experienced by most patients.

Treatment-limiting adverse effects are a common complication of HCV treatment and are experienced by most patients. Adverse events may lead to dosage reductions or treatment discontinuation. The most common adverse effects (occurring in 20–40% of patients) include flu-like symptoms (fatigue, headache, fever), gastrointestinal effects (nausea, anorexia, diarrhea), and psychiatric effects (irritability, depression, insomnia).

Psychiatric effects can be managed with frequent assessment and counseling. Selective serotonin reuptake inhibitors can be used to treat depression. Agent selection should address hepatic dysfunction and drug interactions.

Laboratory abnormalities such as neutropenia (absolute neutrophil count less then 1500 cells/mm3) and anemia also frequently lead to dosage reductions and/or treatment discontinuation. The use of granulocyte colony-stimulating factors is usually not necessary except in cases of advanced cirrhosis. Likewise, growth factors such as erythropoietin and darbepoetin should be used cautiously in light of the potential for serious cardiac and thromboembolic events and increased costs. Their use has not been associated with better clinical outcomes, including attainment of SVR, in patients with HCV.[7, 18–20]

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Interferon

Significant safety concerns exist with all interferon products.

A black-box warning highlights the potential for causing or aggravating fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients require careful monitoring and observation while receiving these therapies.

Therapy should be discontinued in patients with persistently severe or worsening signs or symptoms of any of the mentioned conditions.

Contraindications to the use of interferon include hepatic decompensation as evidenced by a Child-Pugh score greater than 6 (class B or C) in patients with cirrhosis before or during treatment.

Routine monitoring of complete blood cell count and liver function tests, including before treatment and routinely thereafter, is necessary.

Dose reductions should be considered in patients with hematologic abnormalities, moderate depression, or renal dysfunction, or if transaminase levels flare.

Severe depression warrants discontinuation of therapy.

Individual prescribing information should be consulted for specific recommendations for dosage reductions associated with each interferon product.[19, 20]

Ribavirin

Ribavirin carries a black-box warning regarding its potential to cause birth defects and fetal death. It is rated as pregnancy category X and is contraindicated in pregnant women and men whose female partners are pregnant.

Women of childbearing age and men must use two effective forms of contraception during the treatment period and for 6 months after treatment. Routine monthly monitoring of pregnancy tests is also required.

A toll-free hotline to the Ribavirin Pregnancy Registry was established to monitor maternal and fetal outcomes of pregnant women exposed to ribavirin.

[19, 20] Other serious effects with ribavirin highlighted in a black-box warning are the risk of hemolytic anemia, which may result in worsening cardiac disease.

Because of this risk, a complete blood cell count should be obtained before treatment and, at a minimum, at weeks 2 and 4 of therapy.

Patients with preexisting cardiac disease need to have an echocardiogram before treatment and should be closely monitored.

The need for dosage reductions is determined by laboratory values, specifically those showing anemia in the presence or absence of cardiac history.

Ribavirin is also contraindicated in patients with a history of hypersensitivity to ribavirin or any component of the formulation and should not be used in patients with a creatinine clearance less than 50 ml/minute.[18]

Treatment Regimens

All patients with chronic HCV infection should be evaluated for treatment with peginterferon and ribavirin.

The duration of therapy will be determined depending on HCV genotype.

Genotype 1

Patients with genotype 1 infection typically have an SVR rate of 40–55%, whereas those with genotype 2 or 3 have higher rates at 70–90%.

Genotype 1 or 4

[21, 22] Patients with genotype 1 or 4 require treatment for 48 weeks, whereas those with

Genotype 2 or 3

genotype 2 or 3 can receive 24 weeks of therapy.

[7] Given the complexity and breadth of the literature in patients receiving retreatment of HCV after liver transplantation, studies focused in that area of practice are not included in the scope of this review.

Recent clinical studies evaluating various treatment strategies are summarized in Table 5 and Table 6 .[23–38] Most studies were conducted in treatment-naïve patients with detectable HCV RNA, histologic findings consistent with chronic HCV, and elevated ALT levels. Study analyses were conducted as intent to treat unless otherwise noted.

Comparative Efficacy of Pegylated Interferons

Two pegylated interferons are FDA approved for treatment of HCV, peginterferon alfa-2a and peginterferon alfa-2b.[17] Although both agents are routinely prescribed for treatment, their dosing regimens and pharmacokinetics differ. Peginterferon alfa-2b is dosed according to body weight, whereas peginterferon alfa-2a is a fixed dose. Both agents are dosed subcutaneously once/week; however, their half-lives are different.

Peginterferon alfa-2b has a 40-hour mean elimination half-life, and peginterferon alfa-2a has a plasma half-life of 80–160 hours.[19, 20] These differences in half-lives have corresponded to reduced or absent plasma concentrations at 7 days and variable peak:trough ratios with peginterferon alfa-2b.[23] Until the results of recent studies were available, it was uncertain whether these differences significantly impacted treatment outcomes.

The efficacy and safety of both pegylated interferons have been studied in several recent prospective, randomized, clinical trials ( Table 5 23–33] Standard dosages of peginterferon alfa-2a at 180 μg and peginterferon alfa-2b at 1.5 μg/kg subcutaneously once/week were used in all studies unless otherwise noted. A prospective, randomized, open-label study was conducted to compare viral pharmacokinetics and HCV RNA response at 12 weeks between peginterferon alfa-2a and peginterferon alfa-2b, both in combination with ribavirin.[23] Patients with genotype 1 and a viral load of 800,000 IU/ml or greater were evaluated.

Ribavirin was dosed according to weight, 1000 mg/day for patients weighing 75 kg or less and 1200 mg/day for those weighing greater than 75 kg. Standard dosing of peginterferon alfa-2a and peginterferon alfa-2b was used.

The primary end point, HCV RNA over time, was comparable between both groups at all time points. Similarly, the proportion of patients who achieved RVR was similar. More patients discontinued treatment in the peginterferon alfa-2b group (5.7% vs 1% in the peginterferon alfa-2a group) due to adverse events, such as rash, anemia, suicidal ideation, depression, influenza-like symptoms. However, no significant differences in overall safety outcomes were noted.

The peginterferon alfa-2b group experienced more influenza-like illness, chills, fever, rash, and vomiting, whereas the peginterferon alfa-2a group had more dyspnea reported. Neutropenia (≥ grade 3) occurred in 43.4% of patients in the peginterferon alfa-2a group versus 34.8% in the peginterferon alfa-2b group. Another prospective, randomized, open-label study compared peginterferon alfa-2a and peginterferon alfa-2b, both with ribavirin, for differences in SVR in treatment-naïve patients with chronic HCV.[24]

Dosing of ribavirin was based on patient weight: 800 mg/day if less than 65 kg, 1000 mg/day if 65–75 kg, and 1200 mg/day if greater than 75 kg. Duration of treatment was 24 weeks for patients with genotypes 2 or 3 and 48 weeks for those with genotypes 1 or 4. Results showed that SVR rates were similar between groups: 66% in the peginterferon alfa-2a group and 62% with peginterferon alfa-2b (p=0.64).

Differences among genotypes according to treatment group were also not significant, with more than 45% of patients with genotype 1 and more than 80% of those with genotypes 2, 3, or 4 achieving SVR.

(IDEAL) study

A third arm of the Individualized Dosing Efficacy vs Flat Dosing to Assess Optimal Pegylated Interferon Therapy

(IDEAL) study was undertaken to evaluate the safety and efficacy of standard-dose peginterferon alfa-2a, standard-dose peginterferon alfa-2b, and low-dose peginterferon alfa-2b (1.0 μg/kg/wk) in 3070 treatment-naïve patients with genotype 1 HCV.[25] All regimens included weight-based ribavirin; however, the dose differed according to which interferon product was used.

For the peginterferon alfa-2b group, ribavirin was dosed based on patient weight: 800 mg/day if 40–65 kg, 1000 mg/day if more than 65 kg but less than 85 kg, 1200 mg/day if more than 85 kg but less than 105 kg, and 1400 mg/day if more than 105 kg but less than 125 kg, . The peginterferon alfa-2a group received ribavirin 1000 mg/day for weight less than 75 kg, and 1200 mg/day for weight of 75 kg or more.

Different ribavirin regimens were used based on the current prescribing information at the time of the study. The treatment duration was 48 weeks. The primary end point was SVR, and two superiority analyses were conducted to compare the two dosage regimens of peginterferon alfa-2b and standard-dose peginterferon alfa-2b versus peginterferon alfa-2a. Rates of SVR were similar among all three groups: 39.8% for standard-dose peginterferon alfa-2b versus 38% for low-dose peginterferon alfa-2b (p=0.20), and 40.9% for standard-dose peginterferon alfa-2a versus standard-dose peginterferon alfa-2b (p=0.57).

Adverse events were also similar in type and frequency among all groups.

Two deaths were considered to be possibly related to treatment, one with standard-dose peginterferon alfa-2b (suicide) and one with peginterferon alfa-2a (myocardial infarction).

Duration of Therapy According to Genotype

Given that peginterferon and ribavirin represent the established treatment for chronic HCV, much of the current research focuses on duration of therapy. Genetic differences have been heavily studied in relation to HCV.

The standard of evidence-based HCV care has been to treat patients with genotype 1 or 4 for 48 weeks and those with genotype 2 or 3 for 24 weeks.

More recently, studies have focused on individualizing the duration according to RVR or EVR. The following studies highlight some of these recent findings. Analysis of common predictors of SVR was conducted in several of these studies.

Factors such as age 45 years or younger, genotype 2, baseline HCV RNA level of 400,000 IU/ml or lower, weight of 80 kg or less, ALT levels, and degree of fibrosis were all predictive of SVR.[26, 28–30, 32]

It is important to note that with many of these studies, the overall SVR rates may not differ, but the relapse rates and rates of discontinuation may be balancing the results. This, in addition to differences in study design, may contribute to the lack of consistent results regarding the optimal durations of treatment according to genotype.

Genotype 1.

A prospective, open-label German study of patients with genotype 1 randomly assigned to standard-dose peginterferon alfa-2a in addition to ribavirin 800 mg/day for either 48 weeks (group A) or 72 weeks (group B) aimed to evaluate differences in SVR and relapse rates.[26] The primary efficacy measure, SVR, was similar in both groups (53% at 48 wks [group A] and 54% at 72 wks [group B], p=0.8), highlighting that duration of therapy did not translate into higher SVR rates. In addition, a significantly higher proportion of patients in group B prematurely discontinued therapy (p less then 0.001).>

Patients who had detectable HCV RNA levels at week 12 achieved significantly higher SVR rates with 72 weeks of treatment versus 48 weeks (29% vs 17%, p=0.04), whereas those who had undetectable levels at weeks 4 or 12 reached SVR rates as high as 84%, independent of treatment duration.

This demonstrated that patients considered "slow responders" to therapy may benefit from extended treatment. Benefits of extended treatment on relapse rates were also noted in patients who were considered slow responders (HCV RNA detectable at wks 4 or 12). Relapse rates were lower in patients with HCV RNA first undetectable at week 12 (group A 37% vs group B 23%, p=0.016) and at week 24 (64% vs 40%, p=0.021).

Rates of relapse were similar between groups (group A 29% vs group B 21%, p=0.13). The frequency of adverse events was not significantly different between treatment groups; however, a higher proportion of patients treated for 72 weeks discontinued therapy compared with those treated for 48 weeks. A similar study was conducted in the United States to evaluate extended treatment (48 vs 72 wks) in treatment-naïve patients with genotype 1 treated with peginterferon alfa-2b in combination with weight-based ribavirin (≤ 64 kg, 800 mg; 65–84 kg, 1000 mg; 85–104 kg, 1200 mg; ≥ 105 kg, 1400 mg).[27]

Before randomization, patients were determined to be slow responders, defined as at least a 2-log reduction in HCV RNA and undetectable levels at week 24. The primary end point, SVR, was statistically significantly higher in the extended treatment group receiving 72 weeks of treatment (38%) versus those treated for a total of 48 weeks (18%, p=0.03). A lower relapse rate was also found with the extended duration (20% vs 59%, p=0.004).

The rates of adverse effects and discontinuation did not differ significantly between groups. A noninferiority study conducted in Italy evaluated the efficacy of peginterferon alfa-2a or peginterferon alfa-2b combined with ribavirin for a standard treatment duration (48 wks) versus an extended treatment duration in patients with genotype 1.[28]

Weight-based ribavirin was dosed at 1000 mg/day for patients weighing 75 kg or less and 1200 mg/day if weight was more than 75 kg. Patients randomized to the extended-treatment group received the drugs for an individualized duration based on virologic response during the initial 12 weeks of therapy. Patients in this group who achieved undetectable HCV RNA levels (RVR) at 4 weeks were treated for 24 weeks, and those achieving RVR at 8 and 12 weeks were treated for 48 and 72 weeks, respectively. Sustained virologic response occurred in 45.1% of patients in the standard-duration group and 48.8% in the individualized group (p=0.37). This met the criteria for establishing noninferiority.

Patients who achieved RVR at 4 weeks had SVR rates of 87% after receiving therapy for the standard treatment duration (48 wks) and 77.2% after 24 weeks of treatment in the individualized group (p=0.12). Patients achieving undetectable HCV RNA levels at week 12 showed a greater overall SVR when randomized to the 72-week duration rather than 48 weeks (63.4% vs 38.1%). Relapse rates, adverse events, and virologic responses according to duration and peginterferon were also similar.

More patients in the individualized group discontinued therapy. The authors concluded that these findings warrant larger studies to determine the benefit of individualized therapy based on 12-week response. Finally, a study was conducted in Austria in patients with genotype 1 or 4; patients received peginterferon alfa-2a plus ribavirin 1000–1200 mg/day.[29] Patients who achieved RVR were assigned to 24 weeks of therapy.

Results showed an overall SVR rate of 76.7%. These results were the first reported of a larger study involving 516 patients that will also evaluate treatment durations of 48 and 72 weeks depending on virologic response. Cumulatively, the results of these recent studies recognize possible alternative durations of therapy in patients with HCV genotype 1, depending on virologic response, both RVR and EVR. For slow-responding patients, commonly determined by week 12 and 24, a longer duration of treatment, up to 72 weeks, may be beneficial.

Those patients with genotype 1 who achieve RVR may be candidates for 24 weeks of treatment. However, more conclusive evidence and larger studies need to be conducted to confirm these findings. Genotypes 2 and 3. Several small studies have found SVR rates of 80% or higher in patients with genotype 2 or 3 HCV after achieving RVR at 4 weeks and being treated with 12–16 weeks of therapy.[39–42]

Differences in these studies, including treatment duration, ribavirin dosage, population characteristics, and study design have made it difficult to use these findings as evidence to support a shortened duration of therapy for these patients. Although the concept of a shortened duration based on genotype and virologic response aims at reducing unnecessary treatment and adverse effects, some recent studies have shown attenuated efficacy when compared with the standard 24 weeks of therapy. A randomized, open-label, phase III, multicenter study sought to compare the efficacy of 12 or 24 weeks of therapy in patients with genotype 2 or 3.[31] Peginterferon alfa-2a and ribavirin 800 mg/day were administered.

Results showed that 12 weeks of therapy was inferior to 24 weeks in relation to SVR rates (59% vs 78%, p<0.0001).>

Another study randomly assigned patients with genotype 2 or 3 to receive peginterferon alfa-2b plus weight-based ribavirin (800 mg/day if <> 105 kg) for a treatment duration of 14 or 24 weeks dependent on virologic response.[32] Patients who achieved RVR were randomly assigned to either 14 weeks (group A) or 24 weeks (group B) of treatment, and patients not achieving RVR received 24 weeks (group C) of therapy.

This was an open-label, noninferiority study to evaluate SVR. Noninferiority could be established if the upper limit of the 95% confidence interval (CI) was below the margin of 10%. Most patients (80%) were infected with genotype 3. Results showed that group A had an SVR rate of 81.1% and group B achieved SVR in 90.7% (difference 9.6%, 95% CI 1.7–17.7%), not establishing noninferiority. Group C achieved SVR in 55% of patients. When adjusted to include only patients with an HCV RNA determination 24 weeks after the end of treatment, SVR rates were similar (86.3% in group A and 93.2% in group B). Patients in group A experienced higher relapse rates over group B (10.8% vs 5.3%), but group B had higher rates of discontinuation. The occurrence of adverse effects did not differ significantly between groups.

The ACCELERATE trial is the largest study to our knowledge that evaluated a shortened duration of treatment in patients with genotype 2 or 3.

[30] Efficacy was assessed in this large international study conducted in 1469 patients. Patients were randomly assigned to receive 16 or 24 weeks of therapy with peginterferon alfa-2a and ribavirin 400 mg twice/day.

The study was designed as a per-protocol, noninferiority analysis with a margin for noninferiority set at 6%. Overall results failed to demonstrate noninferiority. The SVR rates were 65% in the 16-week group versus 76% in the 24-week group (p<0.001). p="0.01).">

Although genotypes 1 and 4 are thought to be similar, a recent prospective, uncontrolled study in 30 patients from the Middle East with genotype 4 demonstrated that treatment with peginterferon alfa-2a in combination with weight-based ribavirin 1000 mg/day for patients weighing less than 75 kg and 1200 mg/day if weight was more than 75 kg, for 48 weeks resulted in an SVR in 63.6% of patients, which was slightly higher than normally observed SVR rates for patients with genotype 1.[15]

Genotype 5

A 2008 retrospective study conducted in Syrian patients with genotype 5 evaluated virologic response in 26 patients who received ribavirin 1000–1200 mg/day in combination with interferon alfa-2a 3 million units 3 times/week or peginterferon alfa-2a at standard dosages.[43] Patients were treated for 24 or 48 weeks. More patients received conventional interferon (65%) than pegylated interferon (35%).

Results showed SVR was attained in 47% of patients receiving interferon versus 67% receiving pegylated interferon (p=0.43). Higher rates were also achieved with 48 weeks of treatment. Genotype 6. Limited evidence exists regarding the appropriate duration of therapy for patients with genotype 6. One small, retrospective cohort study evaluated peginterferon plus ribavirin for 24 or 48 weeks in this population.[33]

Dosing was as follows: interferon alfa-2b 3 million units 3 times/week plus ribavirin 1000 mg/day; weight-based peginterferon alfa-2b 80–150 μg/day with weight-based ribavirin 800–1200 mg/day; or peginterferon alfa-2a 180 μg/week with ribavirin 1000–1200 mg/day. In total, 23 patients were treated for 24 weeks, and 12 patients completed 48 weeks. Most patients were Asian-American.

Results showed SVR rates of 39% versus 75% for those treated for 24 and 48 weeks, respectively (p=0.044). The results of this study need to be confirmed with larger, prospective studies in this population.

Overall the results of studies in patients with HCV genotype 2, 3, or 6 indicate that a treatment duration of 24 weeks remains the most appropriate. Shorter durations are associated with relapse and lower SVR rates.

Relapse and Nonresponse

Few studies have assessed patients who do not respond to the current standard of therapy. Early studies evaluated clinical response to peginterferon plus ribavirin in patients who failed treatment with interferon, and more recent studies aim to evaluate retreatment after treatment failure with pegylated interferon.[44]

Current U.S. guidelines do not strongly advocate retreatment of patients who previously fail to respond to initial therapy.[7]

Although consistent results are lacking and need to be confirmed with larger studies, potential situations for retreatment exist, including in those patients who previously failed therapy with nonpegylated interferon.

The Evaluation of PegIntron in Control of Hepatitis C (EPIC)

Sgnificant hepatic fibrosis or cirrhosis

(EPIC) study was a large, international, multicenter, open-label study conducted to evaluate the retreatment of patients with chronic HCV who previously failed therapy with peginterferon or nonpegylated interferon therapy in combination with ribavirin.[45]

Patients qualified for retreatment if they had significant hepatic fibrosis or cirrhosis at presentation and needed to receive at least 12 weeks of combination therapy without achieving SVR. Patients received standard-dose peginterferon alfa-2b plus weight-based ribavirin for 48 weeks.

Most patients were Caucasian men with genotype 1 HCV and viral loads greater than 600,000 IU/ml, and who did not respond to previous treatment with interferon therapy in combination with ribavirin.

Overall, 22% of patients achieved SVR, with a greater response observed in patients who relapsed versus those who did not respond (38% vs 14%) regardless of previous treatment. Furthermore, patients who previously received interferon therapy responded better than those who received pegylated interferon (25% vs 17%).

Genotype, viral load at baseline, stage of fibrosis, previous treatment regimen, and previous response were found to be significant predictors of response. Extending the treatment duration of therapy may be a feasible option in patients with HCV who did not respond after treatment with peginterferon and ribavirin.

One study investigated the use of peginterferon alfa-2a with ribavirin to retreat nonresponders to peginterferon alfa-2b plus ribavirin.[46] This parallel-group, international study randomly assigned patients to one of four possible open-label treatment groups: peginterferon alfa-2a 360 μg/week for 12 weeks followed by 180 μg/week to complete 72 weeks of treatment (group A) or 48 weeks of treatment (group B), or peginterferon alfa-2a 180 μg/week for 72 weeks (group C) or 48 weeks (group D). All patients received ribavirin 1000 or 1200 mg/day. Most patients had genotype 1. The rate of SVR in group A was 16% versus 9% in group D (p=0.006). The SVR rates were 7% in group B and 16% in group C.

More patients in treatment groups A and C benefited from extended durations but withdrew from the study. In addition, the overall rate of serious adverse events was higher in patients assigned to 72 weeks of therapy.

The results of this study demonstrate the possibility of extended treatment in nonresponders to peginterferon therapy; however, the withdrawal rate and risk of adverse events need to be considered.

Patients who relapse or those who do not respond to initial peginterferon and ribavirin therapy need to be adequately assessed before starting retreatment. Previous response (non-response, relapse, and breakthrough) needs to be assessed. Also, modifiable risk factors affecting treatment should be identified, including adherence to treatment, body weight, and alcohol abuse.[44]

Alternative and Investigational Therapies

Several new therapies are in development for the treatment of HCV infection (Table 6).[34–38] In addition, targeted HCV inhibitors are promising agents for future treatment.[47]

Albinterferon A

Albinterferon A new interferon product, albinterferon, consists of interferon alfa-2b genetically fused to recombinant human albumin, allowing for a more convenient dosing schedule (once or twice/mo).[34, 47] Albinterferon alfa-2b is an 85.7-kilodalton protein with an estimated half-life of 150 hours.[34, 35]

Albinterferon is in phase I studies in the United States for the treatment of HCV infection in patients with HIV coinfection. No studies, to our knowledge, have evaluated the use of albinterferon in patients with renal dysfunction. Several other countries are in phase III of development for the use of albinterferon as combination therapy in treatment-naïve patients with HCV.[48]

An open-label, phase III, multicenter trial investigated dosing strategies, efficacy, safety, and patient-reported health-related quality of life with albinterferon alfa-2b compared with peginterferon alfa-2a in previously untreated patients with genotype 1.[34] Patients were randomly assigned to one of four treatment groups: albinterferon 900 μg subcutaneously once every 2 weeks, albinterferon 1200 μg once every 2 weeks, albinterferon 1200 μg once every 4 weeks, or peginterferon alfa-2a 180 μg subcutaneously once/week (active control). In addition, all patients received ribavirin 1000 mg/day if their weight was less than 75 kg or 1200 mg/day if their weight was 75 kg or more. The duration of treatment was 48 weeks.

Results of the primary and secondary efficacy end points, including SVR, relapse rate, and breakthrough rate, demonstrated no significant difference between the albinterferon groups and peginterferon alfa-2a. The SVR ranged from 55–58% in the intent-to-treat analysis of all groups (p=0.64). Rates of adverse events were similar among all groups with the exception of the albinterferon 1200 μg every 2 weeks group, which experienced a higher frequency and more severe adverse effects.

The rate of discontinuation was also higher in this group (p=0.04). Hematologic abnormalities were comparable across groups except for the albinterferon 1200 μg every 4 weeks group, which had a significantly lower rate of events (p<0.05).>

Another phase II, open-label, multicenter trial conducted in 43 treatment-naïve patients with genotype 2 or 3 evaluated different dosages of albinterferon alfa-2b in combination with ribavirin.[35] In contrast to the previous study, a higher dose of albinterferon of 1500 μg every 2 or 4 weeks was used. In addition to assessing efficacy and safety, this study sought to determine if an association exists between insulin resistance and antiviral response in patients with genotype 2 or 3.

The treatment duration was 24 weeks. Rates of SVR were 77.3% for the every 4 week treatment arm versus 61.9% for the every 2 week arm (p=0.27). The lower response in the every 2 week arm was attributed to a higher discontinuation rate unrelated to treatment. Insulin resistance, estimated by homeostasis model assessment of insulin resistance (HOMA-IR), was diagnosed when the HOMA-IR score was greater than 2. Patients who demonstrated insulin resistance according to these methods exhibited a lower SVR compared with those patients without insulin resistance (42.9% vs 88.2%, p=0.02).

No significant differences were found between dosage regimens in terms of safety and tolerability. Some of the most frequently reported moderate-to-severe adverse events were headache, fatigue, chills, myalgia, nausea, pyrexia, decreased weight, back pain, altered mood, and arthralgia; their rates of occurrence did not significantly differ between groups. In addition, the rate of hematologic abnormalities did not significantly differ; however, a higher frequency of low absolute neutrophil count (≤ 750 cells/mm3) was found in the 1500 μg every 2 weeks treatment group compared with the every 4 weeks group (23.8% vs 9.1%, p=0.24). No reductions in hemoglobin level less than 10 g/dl or platelet count less than 50 x 103/mm3 occurred.

In addition, no patients in the every 4 weeks treatment group required dosage reductions due to hematologic effects.

Taribavirin

Taribavirin (formerly known as viramidine), a prodrug of ribavirin, is also being studied for the treatment of chronic HCV with the benefit of a lower frequency of anemia.[47, 49] The major conversion site of taribavirin is in the liver, enabling this drug to concentrate in this location. Taribavirin contains a positively charged 3-carboxymide group, which prohibits its uptake in red blood cells and is thus associated with less hemolytic anemia.[36, 49, 50]

Taribavirin is in phase II testing in the United States for treatment of chronic HCV, in combination with peginterferon.[48, 50] A phase II noninferiority study evaluating the use of taribavirin 800–1600 mg/day versus ribavirin 1000–1200 mg/day, all in combination with peginterferon, resulted in lower SVR rates with taribavirin; however, it did prove to be noninferior to ribavirin (23–37% vs 44%, p=0.155).[36, 49]

Lower rates of severe anemia were noted with taribavirin versus ribavirin (4% vs 27%). Subsequent phase III studies (Viramidine's Safety and Efficacy versus Ribavirin [VISER] 1 and VISER 2) compared taribavirin 600 mg twice/day with ribavirin 1000–1200 mg/day (based on weight), both combined with peginterferon alfa-2a, in treatment-naïve patients with any genotype.[37, 49, 51] Results of these studies failed to demonstrate noninferiority of taribavirin to ribavirin in the intent-to-treat analysis.

The SVR rates were 38% with taribavirin and 52% with ribavirin in VISER 1 and 40% versus 55% in VISER 2, respectively. In both studies, taribavirin did have lower rates of anemia (5% vs 24% and 6% vs 22% in VISER 1 and 2, respectively); however, in VISER 2, more patients receiving taribavirin experienced moderate-to-severe diarrhea (29.5% vs 15.7%, p<0.0001).>

An unpublished phase IIb study was initiated based on post hoc findings that weight-based taribavirin may prove more effective than standard dosing.[49, 52] This study evaluated 275 treatment-naïve patients with genotype 1 HCV.

Taribavirin at dosages of 20, 25, or 30 mg/kg/day were compared with ribavirin in addition to peginterferon. End-of-treatment response rates after 48 weeks of treatment were reported as 43.4%, 32.9%, and 29.4% for taribavirin doses, respectively, and 32.9% for ribavirin. Rates of anemia were also lower in the taribavirin groups (13.4%, 15.7%, and 27.9% for taribavirin and 32.9% for ribavirin).

The results of this study are promising and need to be confirmed in larger, well-designed studies.

Protease Inhibitors

Boceprevir (SCH 503034) and telaprevir (VX-950)

Two protease inhibitors targeted against chronic HCV are in development.[47] Boceprevir (SCH 503034) and telaprevir (VX-950) are oral agents in phase III development in the United States.

Both antiviral therapies are reversible, selective NS3 protease inhibitors; NS3 is an enzyme responsible for viral replication.[53–55] Both agents have shown substantial reductions in viral load in phase I clinical studies. All studies thus far have been conducted in patients with genotype 1. More recent studies have evaluated the use of these agents as a retreatment option for patients previously unable to achieve or maintain SVR.[38, 56]

Additive and synergistic effects in viral reduction and SVR have been noted with the combination of peginterferon, ribavirin, and a protease inhibitor.

In addition, combination therapy has decreased the emergence of resistance with these agents.[53, 57, 58]

Adverse events telaprevir

Adverse events noted to be more common with telaprevir include rash and pruritis.[53, 55, 57, 58] A phase I clinical study conducted in 26 patients with genotype 1, who previously did not respond to therapy, evaluated the safety and tolerability of boceprevir in combination with peginterferon alfa-2b.[56]

This randomized, open-label, crossover study evaluated two dosages of boceprevir over three dosing periods. One week of boceprevir monotherapy was followed by monotherapy with peginterferon alfa-2b for 2 weeks and then combination therapy of both agents for 2 weeks. A minimum 2-week washout period was incorporated between each dosing period.

The two dosage regimens of boceprevir evaluated were 200 mg 3 times/day and 400 mg 3 times/day. Peginterferon alfa-2b was administered at standard dosing of 1.5 μg/kg once/week.

Results of this study showed that boceprevir was well tolerated.

Combination therapy was associated with a higher frequency of headache, rigor, and myalgia. Pharmacokinetic analyses showed only a slight increase in bioavailability for combination therapy as compared with low-dose boceprevir monotherapy, and no increase in area under the concentration-time curve was noted during combination therapy with high-dose boceprevir versus monotherapy.

Telaprevir in patients with genotype 1 who did not achieve or maintain SVR with previous therapy

A recently published international phase II study evaluated the use of telaprevir in patients with genotype 1 who did not achieve or maintain SVR with previous therapy (Table 6).[38] The study was a randomized, stratified study evaluating one of four possible treatment regimens on achievement of SVR.

Telaprevir was administered as a single initial oral dose of 1125 mg followed by 750 mg every 8 hours, peginterferon alfa-2a was dosed at 180 μg/week subcutaneously, and ribavirin was dosed according to weight (1000 mg/day for weight less than 75 kg and 1200 mg/day if weight was 75 kg or more). One group (T12PR24) received telaprevir in combination with peginterferon alfa-2a and ribavirin for 12 weeks followed by placebo, peginterferon alfa-2a, and ribavirin for an additional 12 weeks.

Another group (T24PR48) received telaprevir in combination with peginterferon alfa-2a with ribavirin for 24 weeks followed by peginterferon alfa-2a and ribavirin for an additional 24 weeks. The T24P24 group received telaprevir and peginterferon alfa-2a for 24 weeks, and the PR48 group received placebo plus peginterferon alfa-2a in combination with ribavirin for 24 weeks, followed by peginterferon alfa-2a and ribavirin for an additional 24 weeks (control group). Most patients were Caucasian men, aged 51 years, who had previously not responded to therapy. Results showed that SVR was statistically significantly higher in each telaprevir group than in the control group.[38]

In addition, SVR rates were higher among patients who previously experienced relapse versus nonresponders. Logistic regression analyses revealed SVR was associated with assignment to the shorter telaprevir courses combined with longer peginterferon-ribavirin courses, previously undetectable HCV RNA levels, and low baseline viral load.

Rash

Maculopapular rash and pruritis were more common in groups that received telaprevir.

The median time to rash appearance was 7–28 days, and 18 patients (5%) in the telaprevir group discontinued treatment due to rash.

Also, patients in the telaprevir group were more likely to discontinue treatment due to adverse effects, with skin disorders the most common reason for discontinuation.

A decrease in hemoglobin levels was observed more frequently in the telaprevir-based groups versus the control group.

Overall, protease inhibitors hold promise in treating patients with chronic HCV.

To our knowledge, all studies have focused on genotype 1, and more studies are beginning to evaluate the use of protease inhibitors as an option for retreatment versus initial therapy. Broader patient populations and larger studies in the future will help to clarify the exact role of these agents in the treatment of HCV.

Special Considerations

Human Immunodeficiency Virus

Patients coinfected with HIV and HCV represent a unique challenge to the treatment of HCV. A large number of patients infected with HIV are also infected or become infected with HCV, leading to increased susceptibility to adverse treatment and disease effects, resulting in higher morbidity and mortality.[59] When patients with HIV are infected with HCV, they are less likely to spontaneously clear the virus, and the rate of liver disease progression may be accelerated.[59–62] Liver-related hospitalizations tripled for patients coinfected with HIV from 1994 to 2001.[6] Clinical judgment needs to be used regarding which coinfected patients to treat. Risk of serious liver disease should be weighed against the risk of morbidity from adverse events and anticipated treatment response.[7]

Peginterferon alfa plus ribavirin at standard dosages for 48 weeks is the recommended treatment for HIV-HCV–coinfected patients.[7, 59, 61, 62] Two meta-analyses of six and seven, respectively, randomized controlled trials found that peginterferon in combination with ribavirin was shown to produce a higher probability of achieving SVR compared with treatment with interferon or peginterferon monotherapy.[59, 62] Patients treated with peginterferon and ribavirin were less likely to withdraw from treatment and develop hepatic decompensation.[59] The SVR rate for patients with HIV and HCV genotypes 1 or 4 was 26%, versus 55% for genotypes 2 or 3.[62] A clinical outcome study of HIV-HCV–coinfected patients in Spain showed that patients who achieved SVR had a lower rate of all-cause mortality, liver-related death, and liver decompensation (p<0.05).[61]

Adverse effects and drug interactions with ribavirin are especially concerning in patients infected with both HIV and HCV.

Anemia and neutropenia are of particular concern and require careful monitoring, dosage adjustment, and supplemental therapy as appropriate. Drug interactions with antiretroviral therapy also require careful evaluation. Ribavirin can increase the activity and toxicity of didanosine and other nucleoside reverse transcriptase inhibitors (NRTIs), with the potential to cause mitochondrial toxicity and lactic acidosis.[63] Other NRTIs that may interact through this mechanism include abacavir, lamivudine, stavudine, zalcitabine, and zidovudine. For this reason, concomitant administration of didanosine and ribavirin is contraindicated, and the other NRTIs should be used cautiously and only if the benefit of treatment outweighs the risk. Ribavirin can also reduce the effectiveness of stavudine and zidovudine.[18] Additive pharmacodynamic drug interactions may also result in increased adverse effects, including the risk of anemia with coadministration of ribavirin and zidovudine, and the risk of hepatotoxicity with the administration of ribavirin and lamivudine or zidovudine. Reduced adherence due to drug interactions, adverse effects, and poor tolerability should be assessed in every patient. In patients infected with both HIV and HCV, reducing and/or extending treatment durations and appropriately managing nonresponders (treatment algorithms) need to be more adequately studied before strong recommendations can be made in this population.[64]

End-Stage Renal Disease

The rate of infection with HCV is high among patients with end-stage renal disease (ESRD). The approach to treatment in patients with ESRD is different from that in patients with normal renal function. Altered pharmacokinetics and drug-related toxicities are concerns.[65] Both interferon and ribavirin are renally eliminated. Because ribavirin is not recommended for use in patients with moderate renal function impairment (creatinine clearance < href="javascript:newshowcontent(">[18, 66] Ribavirin is not removed by hemodialysis. In renal dysfunction, the half-life of interferon and peginterferon is increased by as much as 40%, and the AUC is also increased by as much as 90% when compared with patients with normal renal function. For this reason, dosage reductions in patients with moderate-to-severe renal impairment are necessary. Important considerations for therapy in patients with ESRD include level of tolerance to adverse effects and the potential for increased toxicity, and reduced adherence.[65]

The AASLD guidelines do provide a class IIa recommendation for patients with severe kidney disease of careful monitoring and treatment at reduced dosages with peginterferon alfa-2a 135 μg/week or peginterferon alfa-2b 1 μg/kg/week, both with ribavirin 200–800 mg/day, and a class IIb recommendation for patients receiving dialysis that they be considered for treatment with conventional interferon or reduced-dose peginterferon.

The recommendation also states that ribavirin can be added at a markedly reduced dosage with careful monitoring for adverse effects. The limited number of studies cited in support of using low-dose ribavirin in any setting of renal dysfunction (creatinine clearance < href="javascript:newshowcontent(">[7]

Few prospective clinical studies have evaluated the treatment of chronic HCV in patients with ESRD. Studies of treatment with conventional interferon monotherapy often included a very small number of patients and poor study design (observational studies). The SVR rates were found to be lower in treatment-naïve patients with normal renal function (13–19%) versus patients with renal impairment (33–37%), which indicate that interferon monotherapy may be more effective in patients with ESRD.[65] Studies of peginterferon monotherapy in patients with ESRD have shown reduced tolerability and SVR rates ranging from 12–75%.[65-67]

Comparative studies are needed to determine which therapy is associated with better treatment response and better tolerability.[65, 66] A meta-analysis of 20 prospective studies of interferon-based (nonpegylated) treatment in patients with ESRD and HCV revealed several characteristics associated with a higher likelihood of achieving SVR, including patients receiving a larger dose of interferon, a longer duration of treatment, full completion of treatment, female sex, lower HCV RNA, and virologic response.[67] More recent studies have begun focusing on the use of low-dose ribavirin in patients with ESRD, often based on serum ribavirin concentrations; however, once again, stronger evidence is needed before implementing this therapeutic strategy into routine practice.[65, 66, 68]

Injection Drug Abuse

Special considerations are necessary before initiating treatment for chronic HCV in patients with a history of injection drug abuse. These considerations include evaluating the benefits of treatment, the risk of reinfection, comorbid psychiatric illness, and adherence to therapy and monitoring.[7, 69] Although some data indicate a lower rate of SVR is achieved in patients with injection drug abuse, the data are conflicting.[69, 70] A recent retrospective study showed no significant differences in efficacy in adherent patients with active injection drug abuse.[70] The pharmacokinetics of methadone are not significantly altered by peginterferon.[71] A study evaluating treatment of acute HCV in injection drug users has shown promising results on SVR and greater compliance with a short treatment regimen.[72] This was a prospective, open-label, nonrandomized study in 23 patients with injection drug abuse and acute HCV who received peginterferon alfa-2b for 12 weeks. Results showed an overall SVR in 17 patients (74%).

Pregnancy

Routine screening of all pregnant women for HCV infection is not recommended by AASLD or the American College of Obstetricians and Gynecologists.[7, 73] No evidence suggests that HCV infection will adversely affect pregnancy outcomes in terms of fetal or obstetric complications.[74] In addition, no specific agencies have guidelines for treatment or monitoring of HCV during pregnancy. Given that ribavirin is absolutely contraindicated in pregnant women, and strict precautions must be undertaken to prevent pregnancy in women of child-bearing age, treatment must occur well before conception or after delivery. Because ribavirin has a multiple-dose half-life of 12 days, it can persist for up to 6 months in nonplasma compartments. For this reason, pregnancy must be avoided both during treatment with ribavirin and for 6 months after treatment in female patients and female partners of male patients.[18]

From 2003–2009, 351 pregnancies have been tracked in the Ribavirin Pregnancy Registry, six of which described birth outcomes with defects. Three of these exposures were direct exposure, and three were as a result of indirect ribavirin exposure. Specific defects included one cardiac defect, two cases of torticollis, one case of glucose-6-phosphate dehydrogenase deficiency, one case of hypospadias, and one case of polydactyly. A larger sample of patients from the registry is planned in order to assess the relative risk of birth defects associated with ribavirin.[75] Interferon monotherapy has not been well studied in pregnant women, and interferons are classified as pregnancy category C. Peginterferon alfa-2a contains benzyl alcohol. Interferons should be considered to have abortifacient potential.[19, 20]

Pediatrics

In children with HCV, the focus is on promoting awareness, diagnosis, and initiating early treatment. Since the implementation of routine blood screening, vertical transmission has replaced transfusion-associated HCV as the most common mode of HCV transmission in the pediatric population in the United States.[7] Maternal viral load is the most important factor associated with vertical transmission.[76] Most children with HCV are asymptomatic, as in adults, and the standard therapy is peginterferon in combination with ribavirin. Peginterferon alfa-2b is FDA approved for patients aged 3 years or older and is dosed at 60 μg/m2/week subcutaneously in combination with ribavirin 15 mg/kg/day. A treatment duration of 48 weeks is recommended as a class I recommendation by AASLD regardless of genotype.[7] Treatment should be considered in the same manner as in adults, with additional consideration given to patient age and stress.

Most children who undergo treatment tolerate therapy well, but adverse effects are commonly reported such as flu-like symptoms, pyrexia, headache, vomiting, fatigue, and neutropenia.[18, 77–79] Studies have shown that pediatric patients, especially adolescents, who received ribavirin experienced suicidal ideation or attempted suicide more frequently than adults (2.4% vs 1%). This occurred both during treatment and follow-up. In addition, weight loss (mean percentile decrease of 13%) and decreased linear growth (mean percentile decrease of 9%) occurred in pediatric patients treated for 48 weeks, which was mostly reversible during the 6 months after treatment.[18]

One of the earliest pediatric studies on the use of peginterferon alfa for treatment of HCV was an open-label, noncontrolled study in 62 children, aged 2–17 years.[78] The children were administered peginterferon alfa-2b 1.5 μg/kg/week subcutaneously in combination with ribavirin 15 mg/kg/day in two divided doses for 48 weeks. Most patients (75.8%) had genotype 1. Overall rate of SVR was 59%, including 47.8% of patients with genotype 1 HCV and 100% of those with genotype 2 or 3 (p=0.0003). Adverse events frequently reported included leucopenia (75.4%), neutropenia (55.7%), flu-like symptoms (82%), and fever (51%). Other events included weight loss (19.7%) and temporary mood swings (14.8%).

A more recent open-label study was conducted in 30 children, aged 3–16 years, to evaluate peginterferon alfa-2b 1 μg/kg/week subcutaneously in combination with ribavirin 15 mg/kg/day.[79] In this study, children with genotype 1 were treated for 48 weeks and those with genotype 2 or 3 were treated for 24 weeks.

Most patients had genotype 1, were treatment naïve, and acquired HCV through vertical transmission. Overall, SVR was attained in 50% of patients. Adverse effects included flu-like symptoms, fever, fatigue, headache, decreased appetite, and weight loss.

Body weight decreased in 20% of children (> 5% weight loss occurred in 7%) but returned to baseline by week 48. Growth was reduced by 1.6 cm in 22 of 26 children compared with the growth velocity 50th percentile for age and sex but was entirely normal in the 6 months after treatment. Neutropenia (absolute neutrophil count <>

Further studies in children are needed to clarify treatment duration in those with genotype 2 or 3 and long-term clinical outcomes.

Conclusion

Treatment of patients with chronic HCV should be individualized, with consideration given to prevention of transmission, risk factor modification as appropriate, adverse events and tolerability, adherence, and avoidance of complications.

Current practice guidelines published by the AASLD represent the evidence-based standard for management of HCV.

Currently, peginterferon and ribavirin represent the standard of care for treatment of chronic HCV. A surrogate marker for clinical outcomes in HCV is SVR. Of the two available pegylated interferons, both are equally efficacious in attaining SVR.

Duration of therapy is guided by HCV genotype and virologic response. Because of the high rates of RVR and SVR, patients with genotype 2 or 3 can be treated for 24 weeks.

Those with genotype 1 or 4 require 48 weeks' duration of treatment.

In all patients undergoing treatment, appropriate monitoring for serious treatment-related adverse effects must be conducted. Hematologic abnormalities, including anemia and neutropenia, may require a reduction in dosage or withdrawal from treatment. New therapies in development for treatment of HCV have the potential to reduce adverse effects and improve outcomes.

Special populations, including patients coinfected with HIV, patients with severe chronic kidney disease, injection drug users, pregnant women, and pediatric patients should be closely monitored to prevent HCV-related morbidity and mortality.

Abstract and Introduction

Complications and Economic Burden

Diagnosis

Therapeutic Management

Special Considerations

Conclusion References