August 18, 2010

Radiology: 31P MR spectroscopy depicts extent of nonalcoholic fatty liver disease

Author: Manjula Puthenedam
Wednesday, August 18 2010

Proton-decoupled phosphorus 31 (31P) MR spectroscopy shows promise in grading of nonalcoholic fatty liver disease and may be useful in detecting treatment response in patients with nonalcoholic steatohepatitis (NASH), according to a study published in this month’s Radiology.

The study was conducted by Ksenia Sevastianova, MD, from the department of medicine, division of diabetes and colleagues from University of Helsinki and Minerva Medical Research Institute, Helsinki, Finland.

Sevastianova and colleagues found that 31P MR spectroscopy showed promise in differentiating stages of nonalcoholic fatty liver disease by detecting an increase in signal of nicotinamide adenine dinucleotide phosphate (NADPH), a marker of inflammation and fibrogenesis in the liver.

A 3.0-T clinical imager was used by the researchers to obtain proton-decoupled 31P MR spectra in the liver of 12 control subjects, 13 patients with biopsy-proved simple steatosis due to nonalcoholic fatty liver, nine patients with NASH, and nine patients with cirrhosis.

Liver fat was determined with hydrogen1 MR spectroscopy and the content was found to be higher in patients with nonalcoholic fatty liver disease and NASH than in patients with cirrhosis or in control subjects, noted Sevastianova and colleagues.

The 31 P spectra from the patients were analyzed for phosphormonoester, phosphodiester , phosphoethanolamine , phosphocholine, glycerophosphocholine, glycerophosphoryl ethanolamine, uridine diphosphoglucose, NADPH, inorganic phosphate, phosphoenolpyruvate, and alpha-, beta- and gamma-nucleotide triphosphate levels.

Proton-decoupled 31P MR spectroscopy revealed an elevated level of NADPH in patients with NASH and those with cirrhosis and can be used as an in vivo marker metabolite with which to detect NASH, according to Sevastianova and colleagues.

NADPH may have value as an additional tool with which to define and grade liver injury, and it should be tested in further studies that include patients with liver disease not caused by nonalcoholic fatty liver disease, added Sevastianova and colleagues.

The researchers concluded that 31P MR spectroscopy could help to select patients for invasive liver biopsy and possibly replace biopsy in some patients.

Last Updated ( Wednesday, August 18 2010 )

Fast Cancer Growth In Poorer Countries -- Much Can Be Done, With Inexpensive Medications And Equipment

August 18, 2010

Eminent cancer and public health experts are urging governments and agencies to focus seriously on cancer care and prevention in poorer nations, according to a study published in the Lancet. A great deal could be done using generic, off-patent medications, educating people, and training physicians and community workers, conclude the authors.
  • In 1970 lower- and middle-income countries (LMICs) accounted for 15 percent of global cancer cases.
  • In 2008 the figure rose to 56 percent; experts estimate that by 2030 the percentage will reach 70 percent.
  • With nearly two-thirds of global annual cancer cases occurring in LMICs, it is today a leading cause of death.
  • The case fatality from cancer - estimated incidence to mortality ratio -- is 75 percent in low-income countries, compared to 46 percent in developed nations.
"Our focus is on fixing the harsh inequity and disparity that exists with cancer treatment between the developed and the developing world. Having the chance to live should not be an accident of geography," says Princess Dina Mired of Jordan, Honorary Co-President of the Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries (GTF.CCC) and co-author of the paper.

Cancer is a significant cause of premature death in most parts of the world. Unfortunately, it is a neglected health problem in poorer nations, says Dr. Julio Frenk.

"To correct this situation we must address the staggering 5/80 cancer disequilibrium (referring to the fact that LMIC account for almost 80 percent of the burden of disease due to cancer, yet receive only 5 percent of global resources devoted to deal with this emerging challenge)," says Frenk.

The following initiatives could help address the disparities which currently exist worldwide, without having to use high-priced on-patent medications or other equipment:
  • Anti-tobacco campaigns; smoking is a huge risk factor for cancer but it is still rising in many LMICs, while it is dropping in developed nations.
  • Education about early detection and screening.
  • HPV (human papillomavirus) vaccination programs to prevent cervical cancer.
  • Hepatitis B virus vaccination programs to prevent liver cancer.
Source: Christian Nordqvist, "Fast Cancer Growth In Poorer Countries - Much Can Be Done, With Inexpensive Medications And Equipment," Medical News Today, August 18, 2010; based upon: Paul Farmer et al., "Expansion of cancer care and control in countries of low and middle income: a call to action," The Lancet, August 16, 2010.

For text:

For study:


Also See: Tackling cancer among poor doesn't have to cost dear

Late Conversion to Sirolimus in Liver Transplant Recipients is a Safe Clinical Strategy: Presented at ICTS

By Claire Sowerbutt

VANCOUVER -- August 18, 2010 -- Converting patients who have undergone liver transplantation to calcineurin inhibitor (CNI)-free immunosuppression with sirolimus at 5 years or more post transplant is a safe clinical strategy, as it does not increase the risk for acute rejection (ACR) or steroid resistant rejection, researchers said here at the 23rd International Congress of the Transplant Society (ICTS).

While sirolimus-based CNI-free immunosuppression is useful in managing long-term complications in liver transplant recipients, information regarding this strategy is limited.

"Concerns of potential complications and risk for late ACR in a patient with otherwise stable immunosuppression cause many clinicians to avoid late conversion, since late ACR can negatively impact survival in liver transplant," reported Greg McKenna, MD, Transplant Services Department, Baylor Regional Transplant Institute, Dallas, Texas, and colleagues. "By avoiding later conversions, these co-morbidities and complications can progress, even to the patient's detriment."

Dr. McKenna and colleagues presented findings from what is the largest experience of conversion to sirolimus-based CNI-free immunosuppression.

The single centre, retrospective analysis utilised a prospectively identified database of 2,218 orthotopic liver transplant (OLT) recipients of Baylor Transplant Institute seen from January 1985 to December 2005.

The sirolimus cohort included all patients converted to sirolimus at >=5 years (late conversion. The control group (n = 1636) consisted of all surviving patients at >=5 years post transplant who had never received sirolimus either as de novo immunosuppression or as conversion therapy. The rates of ACR and patient survival were compared between the 2 groups.

The total number of patients converted to sirolimus was 476/2218 (21.5%), with 140 (29.4%) of 476 undergoing late conversion. The leading cause of conversion was nephrotoxicity (91.6%), followed by malignancy (2.1%), neurotoxicity (1.4%), and hepatitis C virus progression (1.4%).

The median time to late conversion was 8.8 years, the median duration 4.2 years, and the number of patients currently on sirolimus is 53.3%.

Patient death occurred in 13.6% of the 140 patients who underwent late sirolimus conversion, and was the leading reason for treatment cessation. The second leading reason was pending surgical procedures (8.6%).

Compared with the control group, fewer patients who underwent late sirolimus conversion experienced ACR (2.1% vs 3.5 %, respectively) -- the difference was not significant. The 3 episodes of ACR in the late conversion cohort occurred on days 115, 175, and 986 post conversion. Steroid resistant rejection did not occur at all in the sirolimus cohort, whereas there was a 0.5% incidence in the control group.

With respect to complications, there were no incidences of hepatic artery thrombosis, cytomegalovirus, and Epstein Barr virus or bilary complications in the late conversion group. However, a 2.9% incidence of hernia (4/140), and a 0.7% (1/140) incidence of Herpes simplex virus was reported.

"There was no significant difference in patient survival between the sirolimus cohort and the control group," the authors reported. "This is in itself significant, since 90% of the patients in the sirolimus cohort were converted for renal dysfunction and would be expected to have worse patient survival."

"Late conversion to sirolimus should not be deterred by concerns of complications or risks of rejection, even in patients on long-term stable immunosuppression, and should be done if the clinical situation warrants it," they concluded.

[Presentation title: The Safety of Late Conversion to Sirolimus in Liver Transplantation. Abstract MO12.05]


Evidence of intense ongoing endemic transmission of hepatitis C virus in Egypt

F. DeWolfe Miller a,1 and Laith J. Abu-Raddad b,c,d

a Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813;
b Infectious Disease Epidemiology Group, Weill Cornell Medical College–Qatar, Cornell University, Qatar Foundation–Education City, Doha, Qatar;
c Department of Public Health, Weill Cornell Medical College, Cornell University, New York, NY 10065; and
d Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, WA 98109

Communicated by Kirk R. Smith, University of California, Berkeley, CA, June 22, 2010 (received for review December 24, 2009)


Egypt has the highest prevalence of antibodies to hepatitis C virus (HCV) in the world, estimated nationally at 14.7%. An estimated 9.8% are chronically infected. Numerous HCV prevalence studies in Egypt have published various estimates from different Egyptian communities, suggesting that Egypt, relative to the other nations of the world, might be experiencing intense ongoing HCV transmission. More importantly, a new national study provided an opportunity to apply established epidemiologic models to estimate incidence. Validated mathematical models for estimating incidence from age-specific prevalence were used. All previous prevalence studies of HCV in Egypt were reviewed and used to estimate incidence provided that there was sufficient age-specific data required by the models. All reports of anti-HCV antibody prevalence were much higher than any single other national estimate. Age was the strongest and most consistently associated factor to HCV prevalence and HCV RNA positivity. It was not possible to establish a prior reference point for HCV prevalence or incidence to compare with the 2009 incidence estimates. The modeled incidence from the national study and collectively from the modeled incidence from the previous community studies was 6.9/1,000 [95% confidence interval (CI), 5.5–7.4] per person per year and 6.6/1,000 (95% CI, 5.1–7.0) per person per year, respectively. Projected to the age structure of the Egyptian population, more than 500,000 new HCV infections per year were estimated. Iatrogenic transmission is the most likely, underlining exposure to the ongoing transmission. The study demonstrates the urgency to reduce HCV transmission in Egypt.


1 To whom correspondence should be addressed. E-mail: Author contributions: F.D.M. designed research; F.D.M. and L.J.A-R. performed research; F.D.M. contributed new reagents/analytic tools; F.D.M. and L.J.A-R. analyzed data; and F.D.M. and L.J.A-R. wrote the paper.

The authors declare no conflict of interest.

Freely available online through the PNAS open access option.


Campaign for Hepatitis Tests in Pharmacies as Deaths Rise


Testing in retail pharmacies is more likely to identify hepatitis than comparable screening in doctors’ offices, suggest the results of a pilot study in the UK. In response, health officials are urging the National Health Service to fund the outreach permanently. “We desperately need new approaches to testing that will find the undiagnosed patients,” said Charles Gore, CEO of the Hepatitis C Trust. “This pilot study shows pharmacy testing could be just what is needed.” Of the 236 tests run at pharmacies, 35 people were positive for hepatitis C and four were positive for hepatitis B. The testing took place in five areas at 19 pharmacies throughout the UK. Officials in the Isle of Wight added screening for HIV and syphilis to the pilot. “Pharmacies see a different cohort of people to [those who visit general practitioners] and therefore we can access and diagnose people who otherwise would not have been tested,” said Gary Warner, of the Isle of Wight’s Regent Pharmacy. “This scheme has woken a lot of people up to the problem of viral hepatitis, and we are now working with local drug and addiction services in a more integrated way than before,” Warner said.


Date of Publication

Sarah Boseley


Time to Restart the Battle Against HIV/AIDS

There’s a decided lack of energy on AIDS coming from the gay and lesbian community today

By Tom Sheridan
Posted: August 18, 2010

Tom Sheridan is president of the Sheridan Group, which serves public interest advocacy efforts and designs socially responsible public policy initiatives. His client portfolio includes Bono's ONE Campaign, One Voice Against Cancer, Catholic Charities USA, and the America Forward coalition, and several AIDS-related charities and causes.

Today marks two major events in this country's history. Twenty years ago, the Ryan White CARE Act became law. And one year ago, Sen. Edward Kennedy passed away, having seen the bill he championed save hundreds of thousands of lives.

In 1990, as I huddled with the senator and his staff to write the nation's first response to the HIV/AIDS epidemic, we were interrupted and told that Ryan White—the brave 19-year-old who challenged our presumptions and prejudices—was losing his battle with AIDS. Kennedy picked up the phone and asked Ryan's mother, Jeanne White, if it would be appropriate to name the bill for her dying son. I've always admired the grace and courage that enabled Mrs. White to see beyond her grief. Her support helped us pass a disaster assistance bill in response to an urgent national crisis.

We now have fewer deaths, more available drugs and treatments, more systems able to respond. But the initial response, repair, and recovery process has come to an end. Today's new HIV/AIDS challenges require the same kind of innovation and boldness that we, as a nation, demonstrated two decades ago. So, on this milestone anniversary, I'm compelled to offer this challenge: Let's honor Senator Kennedy and Ryan White by writing and passing the Ryan White CARE Act 2.0.

Ryan White was written when virtually no drug or pharmaceutical interventions were available, but drug access has nevertheless become the bill's primary focus. It was written for an epidemic that raged within the gay community, but HIV/AIDS is now a leading cause of death for African Americans, those with substance abuse issues, and for men who have sex with men but don't identify as gay. The bill couldn't mention education—in 1990, that was a political hot button. But half of today's new infections are among those under age 25 who clearly aren't getting enough HIV/AIDS education. And Ryan White never mentions preventive medicine, but huge strides have been made in that area. A new microbicide gel reduces a women's risk of infection by almost 40 percent. In five or 10 years, we'll probably have the equivalent of a "morning after pill" for HIV.

Clearly, it's time for an updated battle plan that is just as innovative as its predecessor. We need a bill that nationalizes the purchase of AIDS drugs similar to the Veterans Administration's approach, which could save 74 percent over open-market prices. With those savings, we could give greater numbers of Americans with HIV access to life-saving treatments. We need to merge care and prevention strategies so that the current wave of scientific discoveries has an express lane into the new at-risk communities. And we need to remove silos in the federal government that prevent agencies from coordinating care. The Centers for Disease Control, for example, could work much more closely with the Health Resources and Service Administration to develop innovative ideas for leveraging resources.

President Barack Obama's new plan essentially maintains the status quo, but doesn't bring forward any new ideas or offer much money. Twenty years ago, led by Senator Kennedy, our thinking was bolder and demanded more. Why not now?

Is part of the reason that we're just not holding the president's feet to the fire? There's a decided lack of energy on AIDS coming from the gay and lesbian community today, raising uncomfortable questions about who cares (and doesn't) about the new face of this disease. Why have no other groups stepped forward to address the new risks to their communities?

In 20 years things go stale, stakeholders become complacent; for-profit interests embed; innovation stops; creativity becomes lethargic. Edward Kennedy and Ryan White would demand that we honor the 20th anniversary of this bill and, indeed, their memory by committing ourselves to the Ryan White CARE Act 2.0. Let's get to it!


Newly Recognized Factor in Mother-to-Child Transmission of Hepatitis C

August 18, 2010

In general, the children of women infected with Hepatitis C have a low risk of being born with the virus. In addition to what was previously known about this type of Hepatitis C transmission, new research finds a genetic link that can aid - or prevent - this from occurring.

by Nicole Cutler, L.Ac.

Many women with a chronic viral infection are weary of procreating, because of the chance they may pass their illness on during pregnancy or birth. For those infected with Hepatitis C, this fear is especially pronounced.

There are a handful of reasonable causes supporting a fear of carrying a baby and giving birth with Hepatitis C. They include:

· Hepatitis C is rampant in our society - affecting approximately four million Americans.
· Hepatitis C often leads to chronic liver disease.
· There is currently no guaranteed cure for Hepatitis C.
· Nearly half of those with Hepatitis C are unsure as to how they originally became infected.

Known as vertical transmission, the risk of infants acquiring Hepatitis C from their mother during pregnancy or childbirth is surprisingly low. There have been quite a few studies examining what the likelihood is of vertical transmission and what increases or decreases the risk of infecting a newborn with Hepatitis C.

Although the statistics determining the rate of vertical transmission is not uniform among these studies, experts believe the most accurate estimate of vertical transmission from mothers with Hepatitis C is five percent. Based upon a comprehensive review of trials investigating Hepatitis C vertical transmission, the following appear to represent the two largest risks for bearing a child with Hepatitis C:

1. The mother is co-infected with Hepatitis C and HIV.

2. The mother has a high Hepatitis C viral load during birth.

In addition, physicians typically relay the following information to pregnant women with Hepatitis C:

· The presence of Hepatitis C infection does not appear to result in a higher risk pregnancy or a higher incidence of poor obstetric outcome.

· Testing for the presence of Hepatitis C in infants born to infected mothers should not begin until at least one year following delivery. The natural history of Hepatitis C infected infants is poorly understood at this time.

· Prophylactic caesarian section is not recommended in Hepatitis C infected mothers. The role of cesarean delivery in mothers co-infected with Hepatitis C and HIV remains controversial.

· Breastfeeding presents a negligible risk of Hepatitis C transmission. Given the well-documented benefits of breastfeeding, it is highly recommended.

It has been a while since there were any additional factors recognized to affect the likelihood of vertical transmission. However, researchers from Italy have recently identified a genetic component that reliably foretells this possibility.

As published in the July 2009 edition of the journal Virology, a mismatch between genes carried by a mother and her infant appear to confer protection against Hepatitis C transmission. Elena Bevilacqua and colleagues from Italy investigated the role of several genes known to play a role in Hepatitis C infection. These researchers found that a specific gene, HLA-DRB1, could predict whether or not the infant acquires Hepatitis C infection from its mother. Based on this research:

1. When a mother and child have the same genetic variant of HLA-DRB1, there is no guarantee that vertical transmission will occur; it just increases the likelihood.

2. When a mother and child have different variations of HLA-DRB1, there appears to be guaranteed protection from vertical transmission.

Unfortunately, a mother cannot control the similarity or dissimilarity of her infant's genetic construction. However, whenever a trial reveals a definitive link for Hepatitis C transmission, we gain some ground in understanding this virus. Undoubtedly, the more information gathered on how Hepatitis C is transmitted, infects people, replicates and dies, the closer we are - as a whole - to putting an end to this source of chronic liver disease.

References:, HLA-DR, Retrieved September 17, 2009, Wikimedia Foundation Inc., 2009., Mother-to-Child Transmission of HCV, Steven K. Herrine, MD, Retrieved September 15, 2009, Hepatitis C Support Project, 2009., Genetic Factors Influence Risk of Mother-to-child Hepatitis C Virus Transmission, Retrieved September 15, 2009,, 2009., Diagnostic and prognostic value of virologic tests in vertical transmission of hepatitis C virus infection: results of a large prospective study in pregnant women, Saez, A, et al, Retrieved September 16, 2009, Hepato-Gastroenterology, July-August 2004., Genetic factors in mother-to-child transmission of HCV infection, Bevilacqua E, et al, Retrieved September 16, 2009, Virology, July 2009.


Viral entry and escape from antibody-mediated neutralization influence hepatitis C virus reinfection in liver transplantation

Published August 16, 2010
The Rockefeller University Press, doi: 10.1084/jem.20090766
© 2010 Fafi-Kremer et al.


Samira Fafi-Kremer 1,2,3, Isabel Fofana 1,2, Eric Soulier 1,2, Patric Carolla 1,2, Philip Meuleman 6, Geert Leroux-Roels 6, Arvind H. Patel 7, François-Loïc Cosset 8, Patrick Pessaux 2,4, Michel Doffoël 1,2,5, Philippe Wolf 1,2,4, Françoise Stoll-Keller 1,2,3, and Thomas F. Baumert 1,2,3,5

+ Author Affiliations

1 Institut National de la Santé et de la Recherche Médicale, Unité 748, F-67000 Strasbourg, France
2 Université de Strasbourg, F-67000 Strasbourg, France
3 Laboratoire de Virologie,
4 Pôle des Pathologies Digestives, Hépatiques et Transplantation, and
5 Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France
6 Center for Vaccinology, Ghent University and Hospital, 9000 Ghent, Belgium
7 Medical Research Council Centre for Virus Research, University of Glasgow, Glasgow G11 5JR, Scotland, UK

8Institut National de la Santé et de la Recherche Médicale, Unité 758, Institut Fédératif de Recherche 128, Ecole Normale Supérieure, Université Claude Bernard Lyon 1, Université de Lyon, F-69007 Lyon, France

CORRESPONDENCE Thomas F. Baumert: OR Françoise Stoll-Keller:


End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is a leading cause for liver transplantation (LT). Due to viral evasion from host immune responses and the absence of preventive antiviral strategies, reinfection of the graft is universal. The mechanisms by which the virus evades host immunity to reinfect the liver graft are unknown. In a longitudinal analysis of six HCV-infected patients undergoing LT, we demonstrate that HCV variants reinfecting the liver graft were characterized by efficient entry and poor neutralization by antibodies present in pretransplant serum compared with variants not detected after transplantation. Monoclonal antibodies directed against HCV envelope glycoproteins or a cellular entry factor efficiently cross-neutralized infection of human hepatocytes by patient-derived viral isolates that were resistant to autologous host-neutralizing responses. These findings provide significant insights into the molecular mechanisms of viral evasion during HCV reinfection and suggest that viral entry is a viable target for prevention of HCV reinfection of the liver graft.


Abbreviations used:

ANOV Aanalysis of variance
HCV hepatitis C virus
HCVpp HCV pseudoparticle
LT liver transplantationu
PA-SCID urokinase-type plasminogen activator/severe combined immunodeficient

Submitted: 7 April 2009
Accepted: 8 July 2010

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at


HIV/AIDS: The Best of Times and the Worst of Times

David Mixner
Posted: August 18, 2010 10:20 AM

Over the past three decades, HIV/AIDS has had a way of taunting us with progress and then reminding us of its immense devastation. Even in the early years, we had a parade of promising therapies that gave us hope, only to find out they did not contain the answer. Not until the advent of AZT, although far from perfect, were we allowed real hope for the future. Unfortunately until the development of antiretrovirals, those small steps forward were too late for so many of our brothers and sisters.

In the last few months, the media has been filled with encouraging, and even exciting, news about the progress in treating this horrendous epidemic. At the very same time, we have been dealt some real setbacks in the care and treatment of people with HIV/AIDS. The lesson is the same as it always has been to the HIV/AIDS community: embrace and celebrate the progress while not letting up the pressure until there is a cure.

The good news is indeed reason to celebrate. Real progress is being made in fighting this disease. From the International AIDS Conference in Vienna comes word that promising new gels have been developed that could dramatically lower the infection rate among at risk women. The progress toward ending mother to child transmission has been just short of a miracle. In addition, the Wall Street Journal published a story indicating that scientists have discovered three powerful antibodies which can neutralize 91% of HIV strains.

The bad news is that the economic situation is wrecking havoc with HIV/AIDS budgets, international funds to fight HIV, research and treatment and care. Many states are freezing the ability of people with HIV/AIDS to receive antiretrovirals and treatment. AIDS Drug Assistance Program (ADAP) funds have either been cut way back or frozen making it impossible for new clients to have access to them. Unless this situation is totally corrected, it could mean a death sentence for some people with HIV/AIDS.

This brings us to the need to keep up the pressure, seek new funds and most importantly hold people in government accountable for their actions. Given the uncertainty with the economy and ADAP, it makes Medicare funds for treating HIV/AIDS even more critical in assisting people with the disease.

Medicare provides a vital source of health coverage for around 100,000 people with the disease. In 2006, Medicare became the single largest source of federal financing for HIV care. The number of people with HIV receiving Medicare benefits has grown over time, reflecting growth in the size of the of the HIV positive population in the U.S. but also an increased lifespan for people with HIV due to antiretroviral medicines and other treatment advances.

When you get to accountability, we face an enormous problem with Medicare with the passage of the new health care law. Thrilled as I was with this major step forward, there is one part that is extremely disturbing to me. Especially since my journey over the years has taught me the urgent need to hold our public officials accountable for their actions in this battle for a cure.

Quite simply, with the creation of an entity called the Independent Payment Advisory Board (IPAB), we could lose our ability to put pressure for change. This new board is simply not accountable to anyone.

While the IPAB is tasked with cutting Medicare spending, it is exempt from any judicial or administrative review of its decisions and is barred from probing the government's spending patterns on specific health care providers, such as hospitals where large chunks of federal health care dollars are spent.

Shackled by such restraints and yet dangerously unaccountable to Congress, the people or the courts, this board could turn its attention to successful programs in Medicare to carry out its cost cutting mission.

The mere existence of an unchecked, powerful agency making life-determining decisions should be worrisome to all Medicare beneficiaries. Draconian decisions by IPAB to limit access to medicines to treat HIV will be free from judicial review, the need for advance public notice, or even appeals from patients.

The fact of the matter is that the IPAB, like any other agency of government, can make bad and disastrous decisions which could dramatically impact our ability to treat, fight and win the battle against HIV/AIDS. And if they do, we have absolutely no recourse to change them.....none....nada.

Yes, we can assume that the appointees would be 'enlightened people." However anyone in government knows the bizarre process of selecting appointments. We cannot count on the basic good nature of human beings and can only count on our ability to hold them accountable in a democratic and open process.

Personally, I can't think of a worse scenario than for our research leaders to be on the cusp of a cure, only to be denied the necessary resources because a government panel has blown research and development into the stone ages.

We must not be shortsighted in our zeal to bring down health care costs by thwarting future research and reversing already achieved progress. Stated simply, if we go this route, we would only blunt the more laudable and courageous goal of saving lives and one day eliminating this horrific disease once and for all.


HBV Damage Disappears With Long-Term Therapy

By Crystal Phend, Senior Staff Writer, MedPage Today
Published: August 18, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Long-term treatment with entecavir (Baraclude) at least partially reverses cirrhosis and fibrosis in most chronic hepatitis B patients, according to extended follow-up of a clinical trial.

In nucleoside-naive patients, liver biopsies taken at least six years after starting on three or more years of entecavir treatment revealed histologic improvement in 96% of patients.

Fibrosis score improved by at least one point in 88% of patients as well, found Ting-Tsung Chang, MD, of National Cheng Kung University Hospital in Tainan, Taiwan, and colleagues.

All 10 patients with advanced disease at baseline saw improvements in fibrosis and cirrhosis long term, the researchers reported in the September issue of Hepatology.

These results add to evidence challenging the idea that fibrosis is an irreversible and relentlessly progressive process, they noted.

The researchers analyzed outcomes from 69 patients who provided a long-term biopsy sample after having received entecavir for a total of at least three years as part of one of two identical phase III randomized trials, followed by rollover into an open-label study in which all patients got 1.0 mg entecavir daily.

The randomized phase of the trials showed entecavir superior to lamivudine (Epivir) for both patients with chronic e antigen-negative hepatitis B and those with e antigen-positive infections. All patients were nucleoside-naive before the trial.

Among the 57 patients who met criteria for the long-term efficacy analysis, the median time on entecavir was approximately six years (range three to seven).

The rate of histologic improvement compared with baseline rose to 96% at the long-term assessment, compared with 73% after just 48 weeks of therapy.

The same was true for the proportion with at least a one-point improvement in Ishak fibrosis score, rising from 32% at 48 weeks to 88% at the long-term assessment.

For those with necroinflammation by the Knodell classification at baseline, 75% dropped down to no or minimal necroinflammation long term. Among those with fibrosis at baseline, 72% had no or minimal fibrosis long term.

Only one of the 57 patients showed an increase in Ishak fibrosis score (1 at baseline versus 2 at long-term biopsy) despite undetectable HBV DNA, normal liver enzymes, and an improvement in necroinflammatory score long term.

Virologic suppression -- HBV DNA under 300 copies/mL -- was maintained for all patients at the time of long-term biopsy, while 86% had normalized alanine transaminase (ALT).

As expected from the sustained virologic response, there was no evidence of virologic rebound or development of antiviral drug resistance, the researchers noted.

Although 55% of patients lost e antigen and 33% had seroconversion during long-term treatment, those who didn't also showed improved liver histology and reversal of fibrosis, which Chang's group pointed to as evidence that "these outcomes are more closely associated with HBV DNA suppression than with immunologic response to therapy."

Moreover, the results confirm the value of long-term treatment for chronic hepatitis B, they concluded.

"The safety profile, potent suppression of HBV replication, and low potential for antiviral drug resistance in nucleoside-naive patients make long-term treatment of chronic hepatitis B with entecavir monotherapy possible," they wrote in the paper.

The study was sponsored by the Bristol-Myers Squibb Pharmaceutical Research Institute.

Chang reported having research funding from Gilead Sciences, Bristol-Myers Squibb, GlaxoSmithKline, Schering-Plough, and Pfizer, as well as receiving speech honoraria from Bristol-Myers Squibb and Schering-Plough.

Several co-authors reported being employees of Bristol-Myers Squibb.

Primary source: Hepatology

Source reference:
Chang T-T, et al "Long-term entecavir therapy results in reversal of fibrosis/cirrhosis and continued histologic improvement in chronic hepatitis B patients" Hepatology 2010; DOI: 10.1002/hep.23785.


Potential HIV drug keeps virus out of cells

Public release date: 18-Aug-2010

Contact: Phil Sahm
University of Utah Health Sciences

University of Utah biochemist hopes to begin human clinical trials in two to three years

SALT LAKE CITY—Following up a pioneering 2007 proof-of-concept study, a University of Utah biochemist and colleagues have developed a promising new anti-HIV drug candidate, PIE12-trimer, that prevents HIV from attacking human cells.

Michael S. Kay, M.D., Ph.D., associate professor of biochemistry in the University of Utah School of Medicine and senior author of the study published Wednesday, Aug. 18, 2010, online by the Journal of Virology, is raising funds to begin animal safety studies, followed by human clinical trials in two to three years. Kay believes PIE12-trimer is ideally suited for use as a vaginal microbicide (topically applied drug) to prevent HIV infection. His research group is particularly focused on preventing the spread of HIV in Africa, which has an estimated two-thirds of the world's 33 million HIV patients according to the World Health Organization.

"We believe that PIE12-trimer could provide a major new weapon in the arsenal against HIV/AIDS. Because of its ability to block the virus from infecting new cells, PIE12-trimer has the potential to work as a microbicide to prevent people from contracting HIV and as a treatment for HIV infected people. HIV can develop resistance rapidly to existing drugs, so there is a constant need to develop new drugs in hopes of staying ahead of the virus." Kay said.

PIE12-trimer was designed with a unique "resistance capacitor" that provides it with a strong defense against the emergence of drug-resistant viruses.

Peptide drugs have great therapeutic potential, but are often hampered by their rapid degradation in the body. D-peptides are mirror-image versions of natural peptides that cannot be broken down, potentially leading to higher potency and longevity in the body. Despite these potential advantages, no D-peptides have yet been developed.

PIE12-trimer consists of three D-peptides (PIE12) linked together that block a "pocket" on the surface of HIV critical for HIV's gaining entry into the cell. "Clinical trials will determine if PIE12-trimer is as effective in humans as it is in the lab," Kay said.

Across the world, HIV occurs in many different strains and has the ability to mutate to resist drugs aimed at stopping it. Due to the high conservation of the pocket region across strains, PIE12-trimer worked against all major HIV strains worldwide, from Southeast Asia and South America to the United States and Africa.

To help advance toward human clinical trials, Kay and co-authors Brett D. Welch, Ph.D., and Debra M. Eckert, Ph.D., research assistant professor of biochemistry, formed a company, Kayak Biosciences, which is owned by the University of Utah Research Foundation. If PIE12-trimer proves to be an effective and safe drug against HIV, the same D-Peptide drug design principles can be applied against other viruses, according to Kay. Approval of the first D-peptide drug would also greatly stimulate development of other D-peptide drugs.


The study's first authors are Welch, and U of U graduate student J. Nicholas Francis. Also contributing were U graduate students Joseph Redman and Matthew Weinstock, as well as Eckert. Images of how PIE12 binds to the HIV pocket were obtained using X-ray crystallography, a technology that provides high-resolution analysis of atomic structures, and were provided by Frank Whitby, Ph.D., research assistant professor of biochemistry, and Christopher P. Hill, Ph.D., professor and co-chair of the Department of Biochemistry. The study includes colleagues from Thomas Jefferson University in Philadelphia and Monogram Biosciences, South San Francisco, Calif.

This research was funded by the National Institutes of Health and the University of Utah Research Foundation.


Healthcare Quality in HCV Is Suboptimum, Based on Medicare Criteria

Laurie Barclay, MD

August 18, 2010 — Healthcare quality in chronic hepatitis C virus (HCV) infection is suboptimum based on Medicare criteria, according to the results of a retrospective cohort study reported in the August 17 issue of the Annals of Internal Medicine.

"Medicare has proposed quality-of-care indicators for chronic [HCV] infection," write Fasiha Kanwal, MD, MSHS, from the John Cochran Veterans Affairs Medical Center and Saint Louis University School of Medicine, Missouri, and colleagues. "The extent to which these standards are met in practice is largely unknown."

Using a nationwide US health insurance company research database, the investigators aimed to assess the quality of healthcare received by patients with HCV, as well as factors linked to receipt of quality care. Between 2003 and 2006, 10,385 patients with HCV were enrolled in the database. Those patients eligible for at least 1 of 7 explicit quality indicators included in Medicare's 2009 Physician Quality Reporting Initiative were included in the analysis.

All recommended care was received by only 18.5% of patients (95% confidence interval [CI], 18% - 19%). The proportions of patients who met quality indicators varied considerably, from 21.5% for vaccination to 79% for the HCV genotype testing indicator.

Factors associated with lower quality of care were older age and presence of comorbid conditions, whereas elevated liver enzyme levels, cirrhosis, and HIV infection predicted higher quality of care. The best care was received by patients who saw both generalists and specialists. Compared with collaborative care (ie, from both specialist and primary care physician), the odds ratio of receiving care for which a patient was eligible was 0.79 (95% CI, 0.66 - 0.95) when specialists alone were involved in the patient's care, and 0.44 (95% CI, 0.40 - 0.48) when the primary care physician alone was involved in the patient's healthcare.

Limitations of this study include observational retrospective design, use of a convenience sample, lack of data on patient ethnicity, and the possibility that the indicators or the reporting of the indicators of HCV care are suboptimal, rather than the care itself. In addition, some of the findings may reflect differential ascertainment and coding.

"Healthcare quality, based on Medicare criteria, is suboptimum for HCV," the study authors write. "Care that included both specialists and generalists is associated with the best quality. Our results support the development of specialist and primary care collaboration to improve the quality of HCV care."

The Saint Louis University Liver Center supported this study. Some of the study authors report various financial relationships with Veterans Affairs Health Services, Saint Louis University Liver Center, Merck/Schering-Plough, Valeant, Gilead Sciences, Three Rivers Pharma, Vertex, Human Genome Sciences, and/or Up-To-Date.

Ann Intern Med. 2010;153:231-239.

Also See: Quality of Care in Patients With Chronic Hepatitis C Virus Infection

Live donors not an option for some waiting for liver transplants

Ginger Delgado KDVR Denver
10:11 PM MDT, August 17, 2010

GOLDEN, Colo. - There are currently 524 people in Colorado waiting for a deceased liver donor. With the average wait time about three to five years, many of them will die waiting. Some have the option of a live donor liver transplant but won't take the risk.

One of those women is Pamela Meadows, 57, of Golden. Three years ago, she was diagnosed with Stage 4 liver disease. Only 15% of her liver is still functioning. She's been on the waiting list in Colorado for three years for a deceased liver donor, but for her, a live liver donor is simply not an option.

Meadows reached out to us here at Fox 31, shortly after we aired a story about Chad and Ryan Arnold, two brothers who underwent a live donor liver transplant in which Ryan died shortly after the procedure. Meadows told us, "My heart goes out to Chad more than ever now because not only does he have the physical recovery to face but he has the emotional struggle now."

While the Arnold's story touched her heart, Meadows says a live liver transplant is not for her, "I think it would be an extremely difficult thing for me. It's just not an option. Do I want to die anytime soon? No. Do any of us? But I'm OK with whatever the plan is."

A bloated stomach and swollen feet were just a few of her symptoms when doctors told her she had Hepatitis C. Today, Meadows is weak but better and still waiting patiently for a deceased liver donor. She told FOX31, "It has been a huge hurdle for me to think about the fact that someone has to die in order for me to live. And while I know they're not technically dying for me to live, it still feels that way." Despite the emotional struggle though, and her very serious condition, Meadows is still in good spirits. She says, "I have yet to get depressed about it. I have yet to feel like woe is me."

She is now focusing on her family and living for the present with no fears about whether she gets a new liver or not. She says, "If I could possibly live a number of years more in the kind of condition I'm in now, I would be happy with that. I'm at peace with it. I really am."

For more information on how you can become an organ donor, visit

Copyright © 2010, KDVR-TV

Related Links:
Donor dies after live liver transplant at CU Hospital


Study Says, Many People Unknowingly Carry One of the Hepatitis Viruses

Submitted by Barinder Khatra on Wed, 08/18/2010 - 14:36

NHS has been told to provide free-of-cost tests for hepatitis B and C in pharmacies. Hepatitis B and C cause severe damage to liver and can lead to liver cancer.

The study shows that one out of every six people is the carrier of either hepatitis C or hepatitis B virus. Both the viruses can be transmitted by infected blood.

When a pilot study was done in 19 pharmacies in five regions in the United Kingdom, it was found that more than expected people had the viruses.

The pharmacies conducted 236 tests, out of which 35 people (15%) had hepatitis C and 4 people (2%) were suffering from hepatitis B. The GP screening rate was 4% for hepatitis C and 2% for hepatitis B, respectively.

The Royal Pharmaceutical Society and the Hepatitis C Trust want that more screenings should be done on a national scale. It is worth mentioning that lot of people carry the disease for a long time without showing any symptoms.

Charles Gore, the Chief Executive of the Hepatitis C Trust says that death rates from hepatitis are increasing significantly. He also said that it is very unfortunate that the number is increasing in those people who would have otherwise survived, if they were treated properly at the right time.

Gore also mentioned that, “we desperately need new approaches to testing that will find the undiagnosed patients. This pilot study shows pharmacy testing could be just what is needed”.

Also See:

Aethlon Medical Announces Expansion of Hepatitis C Virus (HCV) Treatment Programs

(PRNewsFoto/Aethlon Medical, Inc.) SAN DIEGO, CA UNITED STATES

SAN DIEGO, Aug. 18 /PRNewswire-FirstCall/ -- Aethlon Medical, Inc. (OTC Bulletin Board: AEMD), the pioneer in developing therapeutic filtration devices to address infectious disease and cancer, today announced that it has entered into an agreement with GVK Biosciences (GVK BIO) to expand the opportunity for Aethlon to commercialize its Hemopurifier® treatment technology at three to five new clinical centers in India. The therapeutic focus at each center will be the implementation of the Hemopurifier® as an adjunct therapy to accelerate the benefit of HCV standard of care (SOC) drug regimens. Therapeutic filtration at the outset of SOC improves early virus reduction kinetics to levels associated with patients most likely to achieve a sustained viral response, which is the goal of HCV therapy. GVK BIO is Asia's leading Discovery Research and Development organization.


Aethlon further disclosed that the Ethics Review Board (ERB) at Medanta, The Medicity Institute (Medicity) met on August 14th, 2010 to discuss the potential approval for Aethlon to initiate HCV treatment programs at the Medicity. Aethlon has been advised that a formal response should be expected from the Medicity ERB in the coming weeks. The Medicity is a $360 million facility recently established on a 43-acre campus to be a premier center of medical tourism in India.

About GVK Biosciences

GVK Biosciences (GVK BIO) is Asia's leading Discovery Research and Development organization. GVK BIO provides a broad spectrum of services, stand-alone and integrated, across the R&D value chain. GVK BIO's diverse portfolio of more than 100 customers includes Big Pharma, Agri & Life-sciences companies, leading biotechs and academic institutions. Spread across five locations in India and headquartered in Hyderabad, GVK BIO assists clients accelerate their research. Additional information can be accessed at

About Aethlon Medical

At Aethlon Medical, we create revolutionary devices to address infectious disease and cancer. Our devices are designed to be novel platform solutions that fill therapeutic voids or aid in disease diagnosis and monitoring.

Our Hemopurifier® is the first medical device to selectively target the removal of infectious viruses and immunosuppressive proteins from the entire circulatory system. We recently discovered that our Hemopurifier® captures tumor-secreted exosomes that suppress the immune system of those afflicted with cancer. Prior to this discovery, a therapeutic strategy to directly inhibit or reverse the immunosuppressive destruction caused by exosomes did not exist in cancer care. By eliminating this mechanism, we believe our Hemopurifier® can fill an unmet clinical need and provide the benefit of an immune-based therapy without adding drug toxicity or interaction risks to established and emerging treatment strategies.

Human studies have documented the ability of our Hemopurifier® to safely reduce viral load in both Hepatitis-C virus (HCV) and Human Immunodeficiency Virus (HIV) infected patients without the administration of antiviral drugs. However, our initial clinical and commercialization focus is to establish our Hemopurifier® as an adjunct therapy to enhance the benefit of both infectious disease and cancer treatment regimens. In this regard, we plan to commercialize our Hemopurifier® in India as we advance our clinical strategies in the United States and the European Union. In vitro studies conducted by government and non-government research institutes have also verified that our Hemopurifier® has broad-spectrum capabilities against bioterror and emerging pandemic threats. These studies have confirmed the capture of Dengue Hemorrhagic Virus, Ebola Hemorrhagic Virus, Lassa Hemorrhagic Virus, West Nile Virus, H5N1 Avian Influenza Virus, 2009 H1N1 Influenza Virus, the reconstructed Spanish Flu of 1918 Virus, and Monkeypox Virus, which serves as a model for human Smallpox infection.

As a therapeutic device, the Hemopurifier® provides us with a pipeline into four significant market opportunities:
  1. Cancer: A treatment candidate to improve patient responsiveness to established cancer therapies by removing immunosuppressive exosomes from circulation.
  2. Hepatitis-C Virus (HCV): As an adjunct therapy to accelerate viral load reduction at the outset of standard of care drug regimens.
  3. Human Immunodeficiency Virus (HIV): Provides a potential therapeutic option for HIV-infected individuals to manage disease progression once they become resistant to antiviral drug regimens.
  4. Bioterror and Pandemic Threats: Represents the most advanced broad-spectrum strategy to address untreatable bioterror and emerging pandemic threats.
The Hemopurifier® is an expansive multi-patented platform technology whose mechanism of action can be leveraged to provide therapeutic, diagnostic, and biomarker discovery solutions. As a therapeutic, the Hemopurifier® is a single-use disposable cartridge designed for implementation within the established infrastructure of dialysis machines and other blood circulatory pumps already located in hospitals and clinics worldwide.

In design, our Hemopurifier® is a selective filtration device containing affinity agents that tightly bind to high-mannose structures unique to the surface of exosomes produced by cancer and glycoproteins residing on the envelope of viruses. These agents are immobilized around approximately 2800 porous hollow fibers that run the interior length of our device. The resulting design provides us the novel ability to separate both exosome and viral targets away from blood cells so they can then be selectively and permanently removed from the circulatory system. In application, blood circulation is established into the Hemopurifier® via a catheter or other blood access device. Once blood flow has been established, treatment benefit is immediate as the entire circulatory system can pass through the Hemopurifier® in as little as 15 minutes.

Our wholly owned subsidiary, Exosome Sciences, Inc. (ESI) is focused on the development of exosome-targeted products and services that improve cancer diagnosis, provide post-treatment cancer surveillance, and aid in the discovery of biomarkers that allow doctors to optimize patient therapy. Additional information regarding Aethlon Medical and Exosome Sciences can be accessed online at

Certain of the statements herein may be forward-looking and involve risks and uncertainties. Such forward-looking statements involve assumptions, known and unknown risks, uncertainties and other factors which may cause the actual results, performance or achievements of Aethlon Medical, Inc. to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. Such potential risks and uncertainties include, without limitation, the capability of the Hemopurifier® to reduce viral loads and other disease conditions or to identify or treat disease conditions such as cancer, including the ability to capture exosomes and the impact that potential ability may have on disease conditions, the Company's ability to raise capital when needed, the Company's ability to complete the development of its planned products, the ability of the Company to obtain FDA and other regulatory approvals permitting the sale of its products, the Company's ability to manufacture its products either internally or through outside companies and provide its services, the impact of government regulations, patent protection on the Company's proprietary technology, product liability exposure, uncertainty of market acceptance, competition, technological change, and other risk factors. In such instances, actual results could differ materially as a result of a variety of factors, including the risks associated with the effect of changing economic conditions and other risk factors detailed in the Company's Securities and Exchange Commission filings.


James A. Joyce
Chairman, CEO
858.459.7800 x301

John P. Salvador
Director, Communications & Investor Relations
858.459.7800 x307

Jon Cunningham
RedChip Companies, Inc.
800.733.2447 x107

SOURCE Aethlon Medical, Inc.



What is Hepatitis C?

This Hackney pharmacy has been pilot testing Hep C screening

Page last updated at 12:48 GMT, Wednesday, 18 August 2010 13:48 UK

More than 45,000 Londoners are believed to have Hepatitis C without knowing it.

Latest figures by the Hepatitis C Trust suggest 53,145 suffer from the disease in the capital - 7,386 have been diagnosed but a further 45,759 are estimated to be undiagnosed.

What is Hepatitis C?

Hepatitis C is an infection with the hepatitis C virus. Although there is no vaccine to protect against infection, there is effective treatment available.

Hepatitis C is a blood-borne virus that predominantly infects the cells of the liver. This can cause inflammation of and sometimes significant damage to the liver and affect its ability to perform its many, varied and essential functions.

According to the Hepatitis C Trust, although it has always been regarded as a liver disease (hepatitis means inflammation of the liver), recent research has shown that Hepatitis C affects a number of other areas of the body including the digestive system, the lymphatic system, the immune system and the brain.

Many do not realise they have it because they have no symptoms - it can take decades for symptoms to appear and by then serious damage can be caused.


Possible symptoms of Hepatitis C infection include:

• Fatigue
• Weight loss
• Loss of appetite
• Joint pains
• Nausea
• Flu-like symptoms (fever, headaches, sweats)
• Anxiety
• Difficulty concentrating
• Alcohol intolerance and pain in the liver area

How is it contracted?

-- Regularly sharing razors or toothbrushes (with a person who has Hepatitis C or B)
--Tattoos/piercings/acupuncture (in unregistered premises or with possibly unsterile equipment or with needles that were not new)
-- Unprotected sex - Hepatitis B (not C)
-- Sniffing/snorting cocaine (sharing pipes, notes or straws with a person with Hepatitis B or C
-- Receiving a blood transfusion/blood products /organ transplantation prior to 1991
-- Intravenous drug use - sharing needles with someone with Hepatitis B or C

Hepatitis B

Hepatitis B can be transmitted through blood and some body fluid contact and sexually transmitted. A vaccine and treatment is available which can manage but not clear the virus.


The Role of Rapid Virological Response in Determining Treatment Duration for Chronic Hepatitis C

F. F. Poordad
Posted: 08/18/2010; Alimentary Pharmacology & Therapeutics. 2010;31(12):1251-1257.
© 2010 Blackwell Publishing

Abstract and Introduction


Background For patients with chronic hepatitis C, attaining rapid virological response (RVR) is highly predictive of attaining SVR.

Aim To consider the predictive value of RVR in terms of SVR and relapse.

Methods Data were collected from published clinical trials to define the predictive value of RVR for SVR and evaluate the proposed continuum linking RVR to relapse.

Results These data support a 24-week regimen among genotype (G)1 patients who attain RVR with positive predictive values (PPVs) of 77.8% and 85.7% in patients with G1 infection treated for 24 and 48 weeks. Conversely, failure to attain RVR among G1 patients should not be viewed as a criterion for extending treatment duration beyond 48 weeks: negative predictive values (NPVs) were 60.9% and 52.7% in G1 patients without RVR treated for 48 and 72 weeks. Among G2/3 patients, RVR has a high PPV; however, the NPV varied with treatment duration indicating that a 24-week treatment regimen is warranted in G2/3 patients who fail to attain RVR.

Conclusions The present analysis confirms RVR as a strong predictor of SVR that can be used to tailor treatment duration, but which also should be appreciated in the context of treatment duration and regimen.


Sustained virological response (SVR), the goal of therapy for patients with chronic hepatitis C, is attained by 54–56% of patients who receive pegylated interferon (PEG-IFN) alfa plus ribavirin.[1, 2] Unfortunately, patients with chronic hepatitis C do not represent a homogeneous population with uniform responses to therapy. Therefore, developing an optimized therapeutic regimen suited to all patients has proved difficult. To optimize treatment outcomes and health care resources, research efforts have focused on an individualized approach to treatment in which therapeutic regimens are developed to suit the particular host and viral characteristics of each patient.[3]

The essence of individualized treatment is to apply the minimum possible therapeutic burden on each patient without compromising the likelihood of attaining SVR. Thus, the individualized approach allows shorter treatment durations and lower dose regimens in patients who respond quickly to therapy, longer treatment durations and higher dose regimens in patients who respond slowly and early discontinuation of treatment in patients who do not respond at all. In principle, this approach is straightforward. However, identifying patients who fall into each category with a high degree of accuracy is important for its success.

Host and viral factors such as hepatitis C virus (HCV) genotype, baseline viral load, fibrosis, body weight and age influence response to therapy and can help predict treatment outcomes.[4] Once treatment is initiated, on-treatment markers of response can further aid in predicting treatment outcomes. These markers include rapid virological response (RVR, undetectable HCV RNA at week 4 of therapy), partial early virological response (pEVR, ≤2 log10 decline in HCV RNA from baseline at week 12 of therapy) and complete EVR (cEVR, undetectable HCV RNA at week 12 of therapy).[5, 6]

Among patients who attain an end-of-treatment (EOT) response, two different clinical outcomes – SVR and relapse – are possible. Factors influencing attainment of SVR or relapse are becoming better defined. For example, the on-treatment period of undetectable HCV RNA is one of the most important factors influencing the ratio of SVR to relapse.[7, 8] In turn, two elements of the treatment regimen are critical: the time during treatment at which the patient first attains undetectable HCV RNA and the overall duration of treatment. For example, the standard duration of therapy for a patient infected with HCV genotype 1 (G1) is 48 weeks.[9] Thus, G1 patients who attain RVR will experience 44 weeks of undetectable HCV RNA while on treatment; the ratio of SVR to relapse in these patients favours SVR.[8] In contrast, G1 patients who do not attain undetectable HCV RNA until week 24 of therapy will experience only 24 weeks of undetectable HCV RNA while on treatment; the ratio of SVR to relapse in this case shifts dramatically to favour relapse.[8]

Rapid virological response is the earliest on-treatment predictor of treatment response investigated to date. Theoretically, a continuum should connect RVR, treatment duration and the ratio of SVR to relapse. The objective of this review was to consider the predictive value of RVR in terms of SVR and relapse.

Study Selection Criteria
Search Strategy. Bibliographic searches were performed in MEDLINE and through conference proceedings for clinical trials of PEG-IFN alfa plus ribavirin in the treatment of patients with chronic hepatitis C. Reference lists of the clinical trials identified during electronic searching were also hand searched to identify additional relevant trials for inclusion.

Selection of Studies. Studies were eligible for inclusion in this analysis if PEG-IFN alfa-2a (Pegasys; Hoffman-La Roche, Nutley, NJ, USA) or PEG-IFN alfa-2b (PegIntron; Schering-Plough Corp., Kenilworth, NJ, USA) plus ribavirin was used to treat patients with chronic hepatitis C. The presence of hepatitis C was defined by detectable HCV RNA [as indicated by polymerase chain reaction (PCR)–based assay] and most studies also required histological evidence of chronic hepatitis on liver biopsy before enrolment.

For inclusion, studies had to be conducted in treatment-naive patients with genotype 1, 2 or 3 infections, include an evaluation of HCV RNA levels at week 4 of therapy, include outcomes of treatment (EOT response, SVR, relapse rates) according to HCV RNA status at week 4 and designate SVR as the primary study outcome. Where stated, SVR was defined using a highly sensitive HCV RNA assay with a lower limit of detection (LLD) ≤50 IU/mL. For consideration in the final analysis, studies were required to provide data specific to genotype (studies providing data from populations of mixed genotypes were not considered in detail). Studies of patients treated with standard IFN alfa or co-infected with HCV and HIV and studies that were not written in English were excluded.

Assessment of Study Quality and Data Extraction. All studies were prospective clinical trials or retrospective analyses of primary clinical trial data if the study was conducted before the importance of week 4 HCV RNA levels was recognized. For each study, the following variables were extracted: treatment regimen, treatment duration, HCV genotype, number of patients treated, and HCV RNA status at week 4 of therapy. The sensitivity of assays used to define RVR ranged from 50 to 600 IU/mL. The following outcomes data were collected: rates of EOT response (undetectable HCV RNA at EOT), SVR, and relapse (undetectable HCV RNA at EOT and subsequent re-emergence of HCV RNA during follow-up). If relapse rates were not provided, but EOT response and SVR rates were available, relapse was calculated as follows:

Of note, actual relapse rates might differ because of patients lost during follow-up. The predictive value of RVR for SVR was calculated using positive and negative predictive values (PPV and NPV respectively). PPV was calculated as the percentage of patients who attained RVR and SVR. NPV was calculated as the percentage of non-RVR patients who did not attain SVR. If predictive values were not reported, but RVR and SVR rates were available, PPV and NPV were calculated as follows:

Outcome Measures. The primary outcome measure in this analysis was the predictive value of RVR for SVR, which was calculated according to genotype, treatment duration and ribavirin dosing (for G2 and G3 patients). A secondary analysis aimed to establish a disease continuum between RVR (an early marker of virological response) and SVR or relapse (markers of treatment outcome).


Predictive Value of RVR

Twenty-two studies were identified with PPV and NPV data; four[10–13] contained information on only mixed genotype populations and were not included in this analysis. In addition, one retrospective study[14] was not included because the data were derived from a patient group also used in a separate analysis ( Table 1 ).[3, 10–13, 15–30]

Genotype 1 Patients. Among G1 patients, the primary therapeutic value of RVR lies in defining patients who are suitable for a reduced, 24-week treatment duration rather than the recommended 48-week duration.[9] Alternatively, some research has focused on the benefit of extended 72-week treatment duration among G1 patients who do not attain RVR. In all, eight studies provided data regarding the outcome of therapy among G1 patients who attained RVR.[3, 15–21] Three studies provided data on the therapeutic outcomes of G1 patients who attained RVR and were treated for 24 weeks[3, 19, 21] and two studies provided data regarding 72-week treatment duration for patients without RVR.[17, 18]

24 vs. 48 Weeks of Therapy among G1 Patients who Attained RVR. Overall, 5270 G1 patients received PEG-IFN alfa plus ribavirin, were evaluated for RVR and received 24 or 48 weeks of therapy (Figure 1). Of these, 891 (16.9%) had undetectable HCV RNA at week 4 of therapy; 288 were treated for 24 weeks, and 603 were treated for 48 weeks. Of the 288 patients treated for 24 weeks, 224 attained SVR, yielding a PPV of RVR for SVR of 77.8%. Similarly, of the 603 patients who attained RVR and were treated for 48 weeks, 517 attained SVR yielding a PPV of RVR for SVR of 85.7%. Overall, these observations tend to support the use of a 24-week regimen among G1 patients who attain RVR; however, there appears to be a marginal benefit associated with the 48-week treatment duration (Δ = 8%). Our data do not permit comment on the clinical significance of this difference; however, we can speculate that G1 patients with RVR who are adherent to their treatment and tolerate therapy may be treated for 24 weeks, whereas patients who are less adherent may be treated for 48 weeks to augment the opportunity for SVR.

Figure 1.
Predictive value of RVR for SVR among genotype 1 patients with (24- vs. 48-week comparison) and without (48- vs. 72-week comparison) RVR. RVR, rapid virological response; SVR, sustained virological response.

Baseline viral load has been shown to influence whether a patient attains RVR; however, studies included in the present analysis did not take baseline viral load into account when stratifying patients to 24 or 48 weeks of treatment. For example, Jensen et al. [16] showed that 9.2% of patients with baseline viral loads >600 000 IU/mL attain RVR; however, the effectiveness of a 24-week treatment duration in these patients has not been prospectively studied. Zeuzem et al.,[31] in their investigation of a reduced treatment duration for G1 patients, found that SVR rates were comparable in G1 patients with baseline viral load ≤600 000 IU/mL who attained RVR when treated for 24 or 48 weeks (89% vs. 85%). Overall, the results of the present analysis indicate that therapeutic outcomes are broadly equivalent in G1 patients who attain RVR and are treated for 24 or 48 weeks. Whether a minority of G1 patients with high baseline viral loads who attain RVR may attain higher rates of SVR if treated for 48 vs. 24 weeks cannot be determined because data on baseline viral load are lacking in the evaluated studies.

48 vs. 72 Weeks of Therapy among G1 Patients who do not Attain RVR. Overall, 1550 G1 patients were evaluated for RVR and treated for 48 or 72 weeks (Figure 1). Of these, 1204 (77.7%) did not attain RVR, 872 were treated for 48 weeks and 332 were treated for 72 weeks. Among patients treated for 48 weeks, 531 of 872 did not attain SVR, yielding an NPV of RVR for SVR of 60.9%. However, of the 332 patients without RVR who were treated for 72 weeks, 175 did not attain SVR, yielding an NPV of RVR for SVR of 52.7%. Thus, among patients who do not attain RVR, 60.9% did not attain SVR when treated for 48 weeks and 52.7% did not attain SVR when treated for 72 weeks. These data indicate that 8.2% of G1 patients who did not attain RVR benefited from extended treatment. This minimal advantage, however, does not warrant treating all G1 patients who do not attain RVR for 72 weeks because many patients would be over-treated, unnecessarily exposed to adverse events and unnecessarily incur health care expenditures.

Genotype 2 and 3 Patients. Patients infected with HCV G2 or G3 are considered the easiest to treat, and current recommendations suggest treatment with PEG-IFN alfa and fixed-dose (800 mg/day) ribavirin for 24 weeks. For these patients, RVR is an important predictor of treatment outcome. Several studies have assessed whether G2/3 patients who attain RVR can be effectively treated for 12–16 weeks rather than 24 weeks.[23–26] A crucial element of these studies is the use of weight-based ribavirin, in contrast to the recommended fixed dose of 800 mg/day.[9] Studies show that reducing treatment duration to 12–16 weeks among G2/3 patients receiving PEG-IFN alfa and a fixed 800-mg/day ribavirin dose resulted in a significant decline in SVR rates, even among those who attained RVR.[25, 30] These studies emphasize the importance of both RVR status and ribavirin dose when considering reduced treatment duration for G2/3 patients.

In an initial analysis that did not account for varying ribavirin dosing regimens, NPVs and PPVs of RVR for SVR were defined according to treatment duration (24 weeks vs. 12–16 weeks) (Figure 2). Overall, RVR had a high PPV for SVR regardless of treatment duration. However, PPVs for a 24-week regimen were slightly higher (G2, 89.3%; G3, 86.4%) than a shortened treatment duration (G2, 83.2%; G3, 82.4%), suggesting that overall, the PPV of RVR for SVR remains fairly consistent regardless of treatment duration. In contrast, the NPV was clearly related to treatment duration. Among G2/3 patients who did not attain RVR, approximately half did not attain SVR when treated for 24 weeks (NPV was 44.3% for G2 and 58.2% for G3), and more than 70% did not attain SVR if treated for 16 weeks (NPV was 71.8% for G2 and 73.5% for G3). Therefore, in G2/3 patients with detectable HCV RNA at week 4, a minimum 24-week treatment regimen is warranted.
Figure 2.
Predictive value of RVR for SVR among genotype 2 (a, c) and genotype 3 (b, d) patients. RVR, rapid virological response; SVR, sustained virological response. (a, b) Top-line data do not include NORTH-C, in which all patients had RVR (i.e. probability of RVR was theoretically 100%). aSingle-study observation from ACCELERATE.

When treatment duration and ribavirin dosing regimen were considered as variables, the number of analysis groups increased to four, making a marked reduction in the number of patients available for analysis in each group a limitation of this approach. In particular, calculation of an NPV among G3 patients receiving weight-based ribavirin for 24 weeks was not possible. Several recurring themes within this analysis, however, deserve brief comment despite this limitation. The frequency of RVR was similar among G2/3 patients receiving weight-based ribavirin or a fixed 800-mg/day dose. Considering G2 and G3 patients collectively, our calculations suggest an estimated 68.8% of patients who received a weight-based ribavirin regimen and 65.5% of those who received a fixed 800-mg/day regimen attained RVR.

Weight-based ribavirin is important in optimizing treatment outcomes in G2 and G3 patients. The PPV of RVR for SVR is highest among patients receiving weight-based ribavirin for 24 weeks and lowest among those receiving fixed 800-mg/day ribavirin for 14–16 weeks (Figure 3). Observations regarding NPV are consistent with the relationship between treatment duration and ribavirin regimen. NPV is highest among patients treated for 16 weeks with fixed 800-mg/day ribavirin dosing; absence of RVR becomes a moderately reliable indicator of treatment failure in this cohort. NPV is lowest among patients treated with weight-based ribavirin for 24 weeks, indicating that many patients who do not attain RVR may eventually attain SVR using this treatment strategy.

Figure 3.
Positive (a) and negative (b) predictive values of RVR for SVR according to treatment duration (24 weeks vs. <14–16 weeks) and ribavirin (fixed 800 mg/day vs. weight-based) dosing. FD, fixed dose; RBV, ribavirin; RVR, rapid virological response; SVR, sustained virological response; WBD, weight-based dose.
Relationship between RVR and Relapse
Relapse risk is closely related to the period of continuously undetectable HCV RNA while on treatment.[7, 8] Therefore, patients who clear HCV early during therapy should theoretically have a lower likelihood of relapse than those who clear the virus later during treatment.[7, 8] RVR is the earliest clinical milestone during therapy and represents the best time at which to determine early HCV RNA clearance. Whether patients who attain RVR are at lower risk for relapse because of their longer on-treatment period of undetectable HCV RNA was evaluated ( Table 2 and Table 3 ).[2, 3, 10, 11, 15–20, 22–26, 28–32]

Genotype 1 Patients. Within the G1 cohort, a strong relationship exists between RVR and relapse. Among G1 patients who attained RVR, relapse rates were 19% or less regardless of treatment duration, even among those who were treated for fewer than 48 weeks ( Table 3 ). In contrast, at least 25% of patients who did not attain RVR experienced relapse. Relapse rates as high as 53% among G1 patients who did not attain RVR and were treated for the standard 48 weeks were reported in at least 1 study (note: this study used a fixed 800-mg/day ribavirin dose).[18]

Among G1 patients who attained RVR, little difference in treatment outcomes was apparent between 24- and 48-week treatment durations. Relapse rates were slightly higher among patients treated for 24 vs. 48 weeks (6–19% vs. 0–10%), but the differences in relapse rates fell within acceptable limits given the similarities in SVR rates (74–89% vs. 73–92%). Among G1 patients who did not attain RVR, relapse rates were also high, regardless of treatment duration. These data clearly reinforce the concept that patients who do not clear HCV RNA early are prone to relapse and that this relationship remains unaffected by extending treatment duration to 72 weeks. These data also support the current trend in clinical practice that leans towards the use of pEVR and not RVR for delineating the 'slow-responder' G1 population who derive most benefit from an extended, 72-week treatment duration.[33]

Genotype 2/3 Patients. For G2 and G3 patients, use of 12–16 weeks of treatment among patients who attain RVR was associated with a slightly elevated risk for relapse. Relapse rates were 0–9.5% among G2 patients treated for 12–16 weeks and 2.3–3.1% among G2 patients treated for 24 weeks. Similarly, relapse rates were 11–16% and 0–8% respectively among G3 patients. However, given the universally high SVR rates associated with 12- to 16-week (G2: 78–100%; G3: 77–89%) and 24-week (G2: 85–97%; G3: 75–100%) treatment durations, the potential for increased relapse risk in patients treated for less time may be clinically acceptable.

Conversely, G2/3 patients who do not attain RVR probably require 24 weeks of treatment to mitigate relapse. Although data are limited, results from a single study confirmed that shortened treatment duration is associated with very high relapse rates in patients who do not attain RVR. Yu et al. [28] treated 50 G2 patients with PEG-IFN alfa-2a (180 μg/week) plus ribavirin (1000–1200 mg/day) for 16 weeks. Forty-three patients attained RVR and SVR. The seven patients who did not attain RVR did attain EOT response; however, three (43%) of the seven experienced relapse off treatment.[28] In contrast, a 24-week treatment duration is more suitable for G2 and G3 patients who do not attain RVR; however, even within this cohort, relapse rates of up to 32% were reported.[22]

Rapid virological response is an important and accurate positive predictor of SVR. For this reason, treatment duration can be shortened among patients who attain RVR without discernible declines in SVR rates. Results of this literature analysis suggest that treatment may be shortened from 48 to 24 weeks among G1 patients who attain RVR. This observation is consistent with the recommended use of PEG-IFN alfa in Europe, where there is an optional 24-week treatment duration for G1 patients with baseline viral load <600 000 IU/mL (PEG-IFN alfa-2b) or ≤800 000 IU/mL (PEG-IFN alfa-2a) who have undetectable HCV RNA at week 4 and who remain virus-free at week 24 (Figure 4).[34, 35] RVR is a less reliable predictor of treatment failure. Approximately 60% of G1 patients who do not attain RVR will not attain SVR when treated for 48 weeks. Thus, lack of RVR represents a setback in treatment progress, but does not represent grounds for withdrawing patients from therapy because approximately 40% of G1 patients who do not attain RVR will go on to attain SVR. Furthermore, in the present analysis, the sensitivity of assays used to define RVR varied widely across the included studies, with LLDs ranging from 50 to 600 IU/mL. However, we strongly advise that wherever possible, an assay with a LLD ≤50 IU/mL be used to define RVR, thus avoiding the erroneous classification of very low levels of HCV RNA as undetectable.
Figure 4.
Predictive value of RVR in the treatment of (a) genotype 1 or (b) genotype 2/3 patients. PEG-IFN, pegylated interferon; REL, relapse; RBV, ribavirin; SVR, sustained virological response; WBD, weight-based dose. aThe decision to stop therapy at week 24 or to continue to week 48 might have been influenced by other disease characteristics, including baseline viral load, tolerability, adherence and patient preference.

Among G2 and G3 patients, the predictive value of RVR for SVR is dependent on treatment duration and ribavirin dosing. Treatment can be shortened from 24 weeks to 12–16 weeks in patients with RVR, but these data suggest it is preferable to use a weight-based ribavirin regimen alongside the reduced treatment duration. With a shortened treatment duration and a fixed 800-mg/day ribavirin dose, RVR is a weak predictor of SVR, but lack of RVR is a strong predictor of treatment failure. In contrast, RVR is a strong predictor of SVR, but lack of RVR is a weak predictor of treatment failure when a weight-based ribavirin dosing regimen is used for 24 weeks.
What ribavirin dosing schedule should be used in G2 and G3 patients? At the outset of therapy, physicians must consider whether to initiate a standard fixed-dose[9] or a weight-based dosing regimen of ribavirin. Results of the present analysis indicate that RVR rates are comparable among G2/3 patients receiving weight-based ribavirin (68.8%) and fixed-dose ribavirin (65.5%). However, beyond week 4, our data suggest that the type of dosing chosen affects SVR rates (Figure 4).

This pooled analysis suggests that for G2/3 patients who do not attain RVR, fixed-dose ribavirin can be continued for 24 weeks. However, these observations suggest that consideration may be given to adjusting ribavirin dose in G2/3 patients who are started on a fixed 800-mg/day dose and subsequently attain RVR and are thus selected for shortened treatment duration. For these patients, the clinician may elect to make no change to the fixed 800-mg/day dose, a strategy which, our data suggest, is associated with slightly lower PPV than if using weight-based ribavirin; or change to a weight-based ribavirin dosing, a strategy which would necessitate an increase in ribavirin dosing for some patients, but which is also associated with a high likelihood of SVR. In the event of ribavirin-related toxicity arising from the increase in dose, ribavirin could be safely reduced back to 800 mg/day and treatment duration returned to the original 24 weeks. Alternatively, G2/3 patients could start with a weight-based ribavirin regimen. This regimen would then be maintained for 12–16 weeks in patients who attain RVR. In patients who experience ribavirin-related toxicity, the dose could be reduced to 800 mg/day and treatment duration extended to the standard 24-week period. These approaches require prospective evaluation before any decisions can be made regarding the more effective regimen. PEG-IFN alfa-2a and PEG-IFN alfa-2b have different approved regimens for the treatment of G2/3 patients. In the United States and Europe, PEG-IFN alfa-2b is approved for the treatment of G2/3 patients when combined with a weight-based ribavirin schedule (800–1400 mg/day) for a period of 24 weeks.[34, 36] In contrast, in the United States and Europe, PEG-IFN alfa-2a is approved when combined with ribavirin at a fixed dose of 800 mg/day, also for 24 weeks.[35, 37] However, European recommendations also indicate that a treatment period of 16 weeks (without any adjustment of ribavirin dose) may be considered with PEG-IFN alfa-2a in G2/3 patients with baseline viral load ≤800 000 IU/mL who have undetectable HCV RNA at week 4 that remains undetectable at week 16.[35]

Several other questions remain to be prospectively evaluated. For example, prospective data are required to determine whether treatment duration can be shortened to 12 weeks[23] or whether more conservative 14-week[22] or 16-week[26] treatment durations offer improved outcomes. Furthermore, the relative merits of various weight-based ribavirin regimens also require assessment. Prospective comparison of the 'full' weight-based approach (800–1400 mg/day[22]) with less structured 800- to 1200-mg/day[26] or 1000- to 1200-mg/day[23] treatment is also of interest. Baseline viral load is also recognized as an important factor in determining appropriate treatment duration and studies have shown a close relationship between low baseline viral load and increasing likelihood of RVR, both in patients with G1 and with G2/3 infection.[16, 34] However, a proportion of patients with high baseline viral load also attain RVR, with data indicating that 9.2% of G1 patients with baseline viral load >600 000 IU/mL will attain RVR.[16] Clearly, there is a strong association between baseline viral load and RVR, and further study is required to establish the degree of accuracy with which baseline viral load can predict RVR.

The present analysis confirms the strong predictive value of RVR for SVR across the entire continuum of chronic hepatitis C disease and shows how the predictive value of RVR can fluctuate according to genotype, treatment duration and ribavirin regimen. However, SVR is not the only possible clinical outcome in patients who attain an EOT response. Relapse is also emerging as an important clinical end point. Patients who have relapses after full-course therapy experience emotional strain related to the late failure of therapy. Recent data from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) study showed significant declines in measures of physical and sexual functioning and general health (as assessed using the 36-item Short-Form Health Survey) in patients who experienced relapse compared with patients who attained SVR after re-treatment.[38] Furthermore, maximum health care expenditure (to deliver a full course of therapy and manage side effects for the entire treatment period) is lost when patients experience relapse.

Although not confirmed through statistical analysis, the results of the present analysis strongly indicate a close relationship between RVR and relapse. Across all genotypes, relapse rates are generally higher among patients who do not attain RVR than among those who do, an observation that is consistent with the theory of continuously undetectable HCV RNA. Further studies are urgently required to understand the full pathobiology of relapse. Clinical focus on EOT response rate as a marker of efficacy is misleading and can create false hope of SVR among patients who attain undetectable HCV RNA late in their treatment course. Of greater clinical value are early changes in HCV RNA, which can be used to tailor therapy according to each patient's response. Measures to mitigate relapse should begin early in therapy, when proactive control of influencing factors, such as ribavirin dosing and treatment duration, is possible. The belief that relapse occurs simply as a function of end-of-treatment viraemia represents a passive attitude to managing relapse and does not adequately take into account the on-treatment factors that can influence this treatment outcome.

Finally, while this analysis has focused on data regarding the role of RVR in the treatment of hepatitis C genotypes 1, 2 and 3 infections, there is also a limited amount of information available regarding the role of RVR in treating hepatitis C genotype 4. Ferenci et al. reported that 30 of 66 patients (45.5%) receiving PEG-IFN alfa-2a plus ribavirin attained RVR with a PPV of 86.7% when treated for 24 weeks.[19] Similarly, Kamal et al. found that 69 of 358 (19.3%) patients with G4 infection attained RVR when treated with PEG-IFN alfa-2b plus ribavirin and, as in the study by Ferenci et al., 86% of these patients attained SVR after a 24-week treatment duration.[39] This study also included a control population in which 50 patients with G4 infection were treated for a fixed 48-week period. Among these 50 patients, eight attained RVR (16%) of whom seven attained SVR (88%) after 48 weeks of therapy, suggesting that there is no incremental benefit in extending treatment duration from 24 to 48 weeks in G4 patients with RVR.[39]

In conclusion, the present analysis confirms the importance of RVR in the individualized approach to the treatment of patients with chronic hepatitis C. RVR is a strong predictor of SVR and, as such, can be used to tailor treatment duration. However, the results of this analysis confirm that RVR is a dynamic variable influenced by other factors. Therefore, the predictive value of RVR has to be appreciated in the context of treatment duration and treatment regimen. These findings confirm that a strong continuum exists throughout a course of treatment for chronic hepatitis C and the influence that an early event such as RVR can have on SVR and relapse rates. Controlled prospective studies are now warranted to evaluate these observations in a clinical setting.

1.Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958–65.

2.Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–82.

3.Mangia A, Minerva N, Bacca D, et al. Individualized treatment duration for hepatitis C genotype 1 patients: a randomized controlled trial. Hepatology 2008; 47: 43–50.

4.Lee SS, Heathcote EJ, Reddy KR, et al. Prognostic factors and early predictability of sustained viral response with peginterferon alfa-2a (40KD). J Hepatol 2002; 37: 500–6.

5.Poordad F, Reddy KR, Martin P. Rapid virologic response: a new milestone in the management of chronic hepatitis C. Clin Infect Dis 2008; 46: 78–84.

6.Marcellin P, Jensen DM, Hadziyannis SJ, Ferenci P. Differentiation of early virologic response (EVR) into RVR, complete EVR (CEVR) and partial EVR (PEVR) allows for a more precise prediction of SVR in HCV genotype 1 patients treated with peginterferon alfa-2a (40kd) (Pegasys) and ribavirin (Copegus). Hepatology 2007; 46: 818A. Abstract 1308.

7.Marcellin P, Heathcote EJ, Craxi A. Which patients with genotype 1 chronic hepatitis C can benefit from prolonged treatment with the 'accordion' regimen? J Hepatol 2007; 47: 580–7.

8.Drusano GL, Preston SL. A 48-week duration of therapy with pegylated interferon α2b plus ribavirin may be too short to maximize long-term response among patients infected with genotype-1 hepatitis C virus. J Infect Dis 2004; 189: 964–70.

9.Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49: 1335–74.

10.Ferenci P, Fried MW, Shiffman ML, et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. J Hepatol 2005; 43: 425–33.

11.Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003; 38: 645–52.

12.Shiffman ML, Rodriguez-Torres M, Gordon SC, et al. Rapid virologic response is enhanced by higher drug exposure among patients receiving taribavirin in combination with pegylated interferon alfa-2b for the treatment of HCV infection. Hepatology 2006; 44(4 suppl 1): 616A. Abstract 1146.

13.Wong JB, Davis GL, McHutchison JG, Manns MP, Albrecht JK, and the International Hepatitis Interventional Therapy Group. Clinical implications of testing viral response during ribavirin and peginterferon α-2b treatment for hepatitis C. Hepatology 2002; 36(suppl 1): 281A. Abstract 472.

14.Reddy KR, Rakela J, Lopez-Talavera JC, Pockros PJ. Correlations between rapid virologic response, early virologic response and sustained virologic response in HCV genotype 1 patients treated with pegylated interferon alfa-2a and ribavirin. Gastroenterology 2005; 128(4 suppl 2): A-716. Abstract S1540. Segadas-Soares JA, Villela-Nogueira CA, Perez RM, Nabuco LC, Brandao-Mello CE, Coelho HSM. Is the rapid virologic response a positive predictive factor of sustained virologic response in all pretreatment status genotype 1 hepatitis C patients treated with peginterferon-alpha2b and ribavirin? J Clin Gastroenterol 2009; 43: 362–6.

16.Jensen DM, Morgan TR, Marcellin P, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006; 43: 954–60.

17.Berg T, von Wagner M, Nasser S, et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 2006; 130: 1086–97.

18.Sanchez-Tapias JM, Diago M, Escartin P, et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology 2006; 131: 451–60.

19.Ferenci P, Laferl H, Scherzer TM, et al. Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 2008; 135: 451–8.

20.Sulkowski M, Lawitz E, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361: 580–93.

21.Yu ML, Dai CY, Huang JF, et al. Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial. Hepatology 2008; 47: 1884–93.

22.Dalgard O, Bjoro K, Hellum KB, et al. Treatment with pegylated interferon and ribavarin in HCV infection with genotype 2 or 3 for 14 weeks: a pilot study. Hepatology 2004; 40: 1260–5.

23.Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005; 352: 2609–17.

24.Dalgard O, Bjoro K, Ring-Larsen H, et al. Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response. Hepatology 2008; 47: 35–42.

25.Shiffman ML, Suter F, Bacon BR, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007; 357: 124–34.

26.von Wagner M, Huber M, Berg T, et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005; 129: 522–7.

27.Mecenate F, Barbaro G, Pellicelli A, et al. Comparison of interferon alfa-2a and ribavirin for 12 or 24 weeks in patients with HCV genotype 2 or 3: the CLEO trial. Presented at: 58th Annual Meeting of the American Association of the Study of Liver Diseases; November 2–6, 2007; Boston, MA.

28.Yu M-L, Dai C-Y, Huang J-F, et al. A randomised study of peginterferon and ribavirin for 16 vs 24 weeks in patients with genotype 2 chronic hepatitis C. Gut 2007; 56: 553–9.

29.Willems B, Hadziyannis SJ, Morgan TR, et al. Should treatment with peginterferon plus ribavirin be intensified in patients with HCV genotype 2/3 without a rapid virological response? Hepatology 2007; 46(suppl 1): S6. Abstract 8.

30.Lagging M, Langeland N, Pedersen C, et al. Randomized comparison of 12 or 24 weeks of peginterferon alpha-2a and ribavirin in chronic hepatitis C virus genotype 2/3 infection. Hepatology 2008; 47: 1837–45.

31.Zeuzem S, Buti M, Ferenci P, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006; 44: 97–103.

32.Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-α2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 346–55.

33.Pearlman BL, Ehleben C, Saifee S. Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis c genotype 1-infected slow responders. Hepatology 2007; 46: 1688–94.

34.SP Europe. PegIntron [Summary of Product Characteristics]. Bruxelles, Belgium: SP Europe, 2008.

35.Roche Registration Limited. Pegasys [Summary of Product Characteristics]. Welwyn Garden City, UK: Roche Registration Limited, 2008.

36.Schering Corporation. PegIntron (Peginterferon Alfa-2b) Injection. Kenilworth, NJ: Schering Corporation, 2008.

37.Hoffman-LaRoche, Inc. Pegasys (Peginterferon Alfa-2a). Nutley, NJ: Hoffmann-La Roche Inc., 2004.

38.Bonkovsky HL, Snow KK, Malet PF, et al. Health-related quality of life in patients with chronic hepatitis C and advanced fibrosis. J Hepatol 2007; 46: 420–31.

39.Kamal SM, El Kamary SS, Shardell MD, et al. Pegylated interferon alfa-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response. Hepatology 2007; 46: 1732–40