September 29, 2012

Common HIV drug may cause memory loss

Washington, Sept 29, 2012 PTI:

A commonly prescribed drug for HIV patients may lead to memory decline by increasing the risk of damage to nerve cells, a new study by Johns Hopkins has claimed.

Nearly 50 per cent of people infected with HIV will eventually develop some form of brain damage that, while mild, can affect the ability to drive, work or participate in many daily activities, the researchers said.

It has long been assumed that the disease was causing the damage, but Johns Hopkins researchers say the drug ‘efavirenz’ may play a key role.People infected with HIV typically take a cocktail of medications to suppress the virus, and many will take the drugs for decades.

Efavirenz is known to be very good at controlling the virus and is one of the few that crosses the blood-brain barrier and can target potential reservoirs of virus in the brain.

Researchers say more caution is needed because there may be long-term effects of these drugs on the brain.

“People with HIV infections can’t stop taking anti-retroviral drugs. We know what happens then and it’s not good,” said Norman J Haughey, associate professor of neurology at Johns Hopkins University School of Medicine.

“But we need to be very careful about the types of anti-retrovirals we prescribe, and take a closer look at their long-term effects. Drug toxicities could be a major contributing factor to cognitive impairment in patients with HIV,” he said.

Investigators examined the effects of 8-hydroxyefavirenz and other metabolites and found major structural changes when using low levels of the drug, including loss of the important spines of the cells. Haughey and his colleagues found that 8-hydroxyefavirenz is 10 times more toxic to brain cells than the drug itself and, even in low concentrations, causes damage to the dendritic spines of neurons.

In the case of efavirenz, a minor modification in the drug’s structure may be able block its toxic effects but not alter its ability to suppress the virus.

Source

Map of key target brings hope of blocking HIV attack

Saturday, Sep. 29, 2012

Kyodo

NAGOYA — A team of Japanese researchers has identified the structure of an immune-cell protein targeted by HIV, increasing hope for the development of new medicines that could block attacks by the virus.

The discovery by researchers at the National Hospital Organization Nagoya Medical Center and at Nagoya University was published Sept. 23 in the online edition of the U.S. journal Nature Structural & Molecular Biology.

A central part of the human immune system is lymphocyte cells that have virus-fighting proteins on their surface. But an HIV protein called Vif (viral infectivity factor) is able to bind to and destroy these proteins, allowing the AIDS-causing virus to enter the cells and multiply.

The researchers analyzed the molecular structure of an antivirus protein called APOBEC3C, and found that it contains a cavity that Vif can bind to. They confirmed the process through which this phenomenon occurs, and found that the APOBEC3C protein disintegrates once the two combine, their report in Nature said.

While existing medicines to combat HIV often cause side effects or become less potent if used over a long period, the team's finding raises "the possibility for the development of a new AIDS treatment that taps into the human body's own defense mechanism," said Yasumasa Iwatani, who heads the medical center's laboratory of infectious diseases.

The team said it now plans to look for compounds that can fit into the protein cavity and block attacks by HIV to study the effectiveness of different candidate compounds.

Source

Ethicists question doctor’s pitch for a hepatitis C drug trial

WT106

An audience listened during a forum by doctors and attorneys about hepatitis C in Exeter, N.H., in August.

By Sarah Schweitzer

Globe Staff / September 25, 2012

Hepatitis C patients told of potential cure

EXETER, N.H. — They filed into the hotel conference room, faces pinched with worry, drawn by the prospect of an escape from hepatitis C.

It was a disease they never saw coming. They had gone to Exeter Hospital seeking treatment for other ailments, and wound up exposed to the hepatitis virus, allegedly by a technician now under federal indictment.

On this August evening, the patients had the opportunity, promotional materials from an advocacy group promised, to learn about “new wonder drugs” with a “75 percent cure rate in clinical trials” from a Harvard Medical School instructor and liver disease researcher at Massachusetts General Hospital.

As he took the microphone, Dr. Raymond T. Chung offered an authoritative message of deliverance: “We want to get about the business of helping these folks undo what’s been done unto them.”

But the drug combination that Chung hoped would undo hepatitis C’s damage had not been approved by the Food and Drug Administration, remained in clinical trials, and would not be approved for study by the committee that oversees Mass. General research until a month after Chung’s presentation.

Ethicists said in interviews that Chung’s comments appear to have breached ethics principles by potentially leaving his audience with outsize hope for drugs undergoing testing. Doing so, they said, was particularly striking at a moment when patients felt violated and vulnerable.

“I believe Dr. Chung is very well meaning, and it is possible that his study drug may be better than what is currently available,” said Dr. Brian O’Sullivan, director of the University of Massachusetts Medical School’s Bioethics Core. “But to sell it as such to a scared, desperate audience is not appropriate. He is misconstruing a promising but as yet unproven drug as a therapeutic alternative.”

Chung and hospital officials disputed the ethicists’ conclusions. In an interview, Chung said his comments reflected the promise of the drugs and his desire to make them available to patients who could benefit most — a presentation that, he said, conformed to ethical standards for clinical trials.

“We were very clear that this was a study,” Chung said in the telephone interview, “that this is a protocol and that patients would have to go through the next steps of private discussion and informed consent with a discussion of risks and benefits.

“That’s an absolute foundation of what we do with our clinical trials.”

For Jean Burke’s husband, who is among the infected and attended an earlier presentation by Chung in the summer, the doctor proved persuasive — so much so that her husband met privately with him and plans to enroll in the study, should it go forward.

“His reputation is nationally known. He’s a really excellent doctor and has been doing research on this for years,” said Burke, who said she and her husband understood Chung was talking about a drug trial. “He’s assured us that it’s probably going to be really successful.”

* * *

Human drug trials remain among the thorniest areas in medical ethics, poised between the need for scientific advancement and the mandate to protect patients. The revelation in the 1970s of the Tuskegee syphilis experiments, in which researchers deliberately withheld treatment from African-American men, spurred Congress to pass laws governing scientific trials.

A key area of oversight is recruitment, which can pose a hurdle for researchers. While patients stricken with life-ending illnesses, desperate for anything, sometimes seek out researchers and their trials, patients suffering diseases that do not pose an imminent threat may be less willing to submit to experimental interventions.

“Most people don’t want to be in research,” said George Annas, an ethics specialist at Boston University School of Public Health. “They want to be in treatment.”

Institutional review boards, composed of at least five members designated by the research institution, are charged with ensuring that researchers do not intentionally mislead patients about side effects and risks of an experimental drug. The review boards must also be on the lookout for well-meaning scientists who possess an exaggerated belief in their research and convey that to subjects — a phenomenon known as the therapeutic misconception.

“Researchers hope their drugs do well,” said Dr. Michael Grodin, a bioethicist at BU’s public health school. “There’s a bias on the investigator’s part. And that’s exactly why we want patients to know it’s research and not therapy.”

* * *

For months, the news out of Exeter sounded a steady drumbeat of despair. In May, word came that four cases of hepatitis C — a disease that over time can attack the liver and can ultimately lead to death — had been linked to the hospital’s cardiac department. That was only the start.

The numbers climbed, federal investigators arrived, and on July 19, with at least 30 people having tested positive, prosecutors announced they had identified the source of the infections: a former technician at the hospital.

Prosecutors allege that 33-year-old David Kwiatkowski stole syringes of a powerful anesthetic called fentanyl from the cardiac catheterization lab, injected himself, and then returned the tainted needles, which were reused on patients. Kwiatkowski worked in seven other states before New Hampshire, raising the specter that he infected others — possibly hundreds across the country, according to prosecutors.

For the patients in Exeter, the revelations heaped a new health problem onto old ones. Many had underlying conditions that had brought them to Exeter Hospital. Some had primary care doctors affiliated with the hospital — a place from which they no longer wished to receive care.

That led some two dozen of them to the “Hepatitis C Patient Information Night” in the conference room at the Georgian-styled Exeter Inn.

The evening was billed by its attorney-organizer, Domenic Paolini, as a chance to learn about advances in hepatitis C treatment and to hear attorneys explain the legal landscape for medical malpractice in New Hampshire and possible settlement options.

Paolini organized the evening under the umbrella of the Patients Speak, a not-for-profit advocacy group that he formed with Elenore Casey Crane, a public relations consultant, after the outbreak. The group held an initial meeting in June, at which Chung also spoke, assuring patients that hepatitis C was not a death sentence and could be treated.

On this August evening, sandwiched between Paolini and another medical malpractice lawyer, Chung waited his turn to make a pitch — his latest foray in the fierce race to conquer hepatitis C, which affects an estimated 3.2 million people in the United States.

* * *

The standard treatment for hepatitis C for years has been weekly injections with interferon, a regimen that, on average, cures fewer than half of patients with the most common form of the virus and sometimes spawns flu-like side effects.

The terrain shifted dramatically last year when the FDA approved two new drugs, Vertex Pharmaceuticals’s telaprevir and Merck & Co.’s boceprevir, which, when taken in combination with interferon, increased cure rates to roughly 80 percent and 65 percent, respectively. Chung was an investigator for trials of both drugs.

Now, Chung is seeking to be at the forefront of the next frontier: identifying a combination of oral medications that would not require interferon.

“We are on the threshold of a treatment revolution,” Chung wrote in the New England Journal of Medicine in January.

But in late August, Bristol-Myers Squibb announced it was discontinuing development of an oral hepatitis C drug after nine patients in a clinical trial were hospitalized and one died. The FDA that month put a hold on trials of a drug in the same class being tested by Idenix Pharmaceuticals.

The oral combination that Chung hopes to test in Exeter is made by Gilead Sciences, according to Dr. Elizabeth Hohmann, director of Partners Human Research Committee, charged with overseeing Mass. General’s clinical trials. Chung, who said he does not have a financial stake in the research, said the combination had already been tested in phase one trials to establish safety, phase two trials to assess efficacy, and has entered phase three trials, often the last step before submission for FDA approval.

The Exeter patients, who would be in a phase 2 trial, represent a singular research opportunity because they contracted the disease in the same recent time span, potentially providing a window into how the infection plays out in its early stages — a vital piece of knowledge in tackling the disease.

At the Exeter Inn, Chung introduced that drug combination as a “strand of hope.”

“We were able to approach a company that was developing these newfangled drugs,” he told the audience. “And this isn’t just any set of compounds. This is a set of compounds that have already been in trials . . . that have demonstrated not just safety, but as well, effectiveness against hepatitis C. And effectiveness here means not only the clearance of virus during the administration of the medications but a permanent clearance.

“You can essentially equate that with a cure, a cure of the infection.” These drugs, he said, were accomplishing in as little as three months what an interferon-based regimen took six months or longer to achieve. The new drugs were doing so “in a manner that does not disrupt or interrupt quality of life to anywhere near the extent that interferon might,” Chung said.

“That’s way over the top,” said Arthur Caplan, head of the division of medical ethics at NYU Langone Medical Center. “When you are doing research, you have to make sure that people understand it’s promising, that you’re making no guarantee of benefit. That’s getting very close to guaranteeing a benefit. That language is irresponsible.”

* * *

Five ethicists and researchers who reviewed Chung’s comments at the Globe’s request said they appeared to violate ethical standards requiring that researchers convey a balanced message about clinical trials to possible research subjects.

“It’s inappropriate, and I would argue unethical, to approach people about a research study that hasn’t been approved and to say the potential benefits outweigh the risks,” Grodin said.

“That was definitely overselling,” O’Sullivan said. “There needed to be, ‘We hope there will be fewer side effects. We hope it will be more effective, but we don’t know that.’ ”

Chung made little mention of side effects. After prompting by an audience member’s question, he said, “The important point to make about this combination therapy is that it has been very well tolerated . . . and we believe that the side effect profile described in those [earlier] trials will be something we will be able to manage effectively in this group of patients.”

Hohmann said Chung’s comments were not “hyperbolic.”

“I think it’s enthusiastic but justified based on these drugs, which are really looking very good,” she said.

Chung, too, defended his comments. “This is not a hard sell. This is simply a restatement of facts in an informational setting.”

Indeed, he said, he felt it was his responsibility to alert the patients to the drug combination’s promise so they could, if they wished, access it before approval, which he said could come as early as next year.

He also noted that the evening’s promotional materials — which called the combination he hopes to test “wonder drugs” — were the work of the Patients Speak; neither he nor Mass. General officials reviewed the materials.

The FDA, which enforces laws governing clinical research trials, declined to comment on Chung’s presentation. But agency spokeswoman Michelle Bolek pointed to laws that bar investigators from representing “in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug.”

Some ethicists questioned Chung’s timing, saying he should have held off on taking names and contact information of interested patients until he had secured approval from the Partners Human Research Committee. That panel did not approve Chung’s study until a month after the Exeter presentation.

FDA guidelines note that institutional review boards — widely known by the acronym IRB — should review the “methods and material that investigators propose to use to recruit subjects.”

“In his capacity as an educator and a doctor, he may want to educate people broadly about what’s going on in hepatitis C and how there is a sea change afoot in hepatitis C drug treatment options,” said Dr. Timothy Lahey, cochairman of the Dartmouth-Hitchcock Medical Center Ethics Committee.

“But he would have to be very careful not to actively recruit anyone to a specific study without IRB approval or to overstate the expected potency of an experimental regimen.”

And taking names, some ethicists said, clearly constituted recruitment.

“If you are taking names so you can contact them, that’s recruiting,” said Lisa Bero, a University of California, San Francisco specialist in clinical trial ethics.

Chung and Hohmann disagreed. “This is simply collecting names and contact information for when [the study] is ready to rock,” Hohmann said.

She compared Chung’s presentation to notices about upcoming trials placed by researchers and institutions on the Internet. Those are permitted, under FDA guidelines, so long as they are restricted to basic information, such as the study’s title, purpose, protocol, eligibility criteria, and study site.

Chung said he notified Hohmann before the meeting in Exeter and advised her that he planned to discuss the upcoming trial.

Some ethicists said Chung’s recruitment methods reflected real-world pressures and demands on researchers.

“I have a little sympathy,” Annas said. “It’s hard to recruit people for a study. The key thing is, did he tell people clearly that this is research?”

At root, Chung said, “I was responding to what I perceived and I felt was a very strong, intense need for information on behalf of an aggrieved group of patients who were confused and had nowhere to turn.”

For Jean Burke and her 61-year-old husband, whose work days have been marked by fatigue and other symptoms they attribute to hepatitis C, Chung offered an infusion of good news.

“It was very exciting for us to hear because we are in such a bad situation,” Jean Burke said.

Sarah Schweitzer can be reached at schweitzer@globe.com.

Source

Reduction in Hepatic Inflammation Is Associated With Less Fibrosis Progression and Fewer Clinical Outcomes in Advanced Hepatitis C

Subject Category: Liver

Am J Gastroenterol 2012; 107:1388–1398; doi:10.1038/ajg.2012.137; published online 12 June 2012

Chihiro Morishima MD1, Mitchell L Shiffman MD2, Jules L Dienstag MD3,4, Karen L Lindsay MD, MMM5, Gyongyi Szabo MD, PhD6, Gregory T Everson MD7, Anna S Lok MD8, Adrian M Di Bisceglie MD9, Marc G Ghany MD, MHSc10, Deepa Naishadham MA, MS11, Timothy R Morgan MD12,13 and Elizabeth C Wright PhD10,14 for the HALT-C Trial Group15

  1. 1Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA
  2. 2Liver Institute of Virginia, Bon Secours Health System, Newport News, Virginia, USA
  3. 3Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
  4. 4Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
  5. 5Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  6. 6Department of Medicine, Division of Gastroenterology, Hepatology and Liver Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  7. 7Section of Hepatology, Division of Gastroenterology and Hepatology, University of Colorado Denver School of Medicine, Aurora, Colorado, USA
  8. 8Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA
  9. 9Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
  10. 10Department of Health and Human Services, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
  11. 11New England Research Institutes, Watertown, Massachusetts, USA
  12. 12Division of Gastroenterology, University of California—Irvine, Irvine, California, USA
  13. 13Gastroenterology Service, VA Long Beach Healthcare System, Long Beach, California, USA
  14. 14Department of Health and Human Services, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA

Correspondence: Chihiro Morishima, MD, Research Associate Professor, Department of Laboratory Medicine, University of Washington, Box 358050, 850 Republican Street, Seattle, Washington 98109, USA. E-mail: chihiro@u.washington.edu

15The HALT-C Trial was registered with clinicaltrials.gov (#NCT00006164).

Received 14 December 2011; Accepted 17 April 2012
Advance online publication 12 June 2012

Abstract
OBJECTIVES:

During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 previous interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation.

METHODS:

Relationships between change in hepatic inflammation (Ishak hepatic activity index, (HAI)) and serum alanine aminotransferase level, fibrosis progression and clinical outcomes after randomization, and hepatitis C virus (HCV) RNA decline before and after randomization were evaluated. Histological change was defined as a ≥2-point difference in HAI or Ishak fibrosis score between biopsies.

RESULTS:

Among 657 patients who received full-dose peginterferon/ribavirin “lead-in” therapy before randomization, year-1.5 HAI improvement was associated with lead-in HCV RNA suppression in both the randomized treated (P<0.0001) and control (P=0.0001) groups, even in the presence of recurrent viremia. This relationship persisted at year 3.5 in both the treated (P=0.001) and control (P=0.01) groups. Among 834 patients followed for a median of 6 years, fewer clinical outcomes occurred in patients with improved HAI at year 1.5 compared with those without such improvement in both the treated (P=0.03) and control (P=0.05) groups. Among patients with Ishak 3–4 fibrosis at baseline, those with improved HAI at year 1.5 had less fibrosis progression at year 1.5 in both the treated (P=0.0003) and control (P=0.02) groups.

CONCLUSIONS:

Reduced hepatic inflammation (measured 1.5 and 3.5 years after randomization) was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized treatment.

Source

High-dose ribavirin induction shows no benefit in HIV/HCV coinfection

Labarga P. J Infect Dis. 2012;206:961-968.

September 24, 2012

Researchers from Spain have found that high ribavirin induction did not improve sustained virological response rates among patients with HIV and hepatitis C virus coinfection.

The Peginterferon Ribavirin in Coinfection (PERICO) trial was a randomized prospective trial of the safety and efficacy of peginterferon alpha-2a with two different doses of ribavirin in coinfected patients. Patients received the standard dose or ribavirin according to weight, or a high fixed dose of 2,000 mg/day during the first 4 weeks of therapy. Those who received the high dose also received erythropoietin beta.

“Whereas the use of higher dosing of peginterferon alpha has not shown any benefit in terms of treatment success, the use of higher ribavirin exposure has led to improvements in the rate of HCV clearance, although the development of anemia is a major limitation of this approach,” the researchers wrote.

The study included 357 patients, of whom 160 attained a sustained virological response. There were no differences found in the rate of sustained virological response between the two groups. The level of undetectable HCV RNA and the mean ribavirin trough concentration were similar in both groups at week 4.

Ninety-one patients discontinued treatment due to nonresponse and 29 discontinued due to adverse effects. HCV genotypes 2 and 3, IL28B CC variants, nonadvanced liver fibrosis and rapid virological response were predictors of sustained virological response.

“The use of preemptive erythropoietin may have blunted the increased disposition of free ribavirin by promoting erythrocyte sequestration,” the researchers wrote. “While awaiting the arrival of new direct acting antivirals against HCV, it seems worthwhile to ensure maximal ribavirin exposure when treating HIV/HCV-coinfected patients, limiting the indication of erythropoietin only to patients who develop severe anemia on therapy.”

Disclosure: The researchers report no relevant financial disclosures.

Source

Hepatitis B vs. Hepatitis C Infection on Viral Hepatitis-Associated Hepatocellular Carcinoma

From BMC Gastroenterology

Spiros P Hiotis; Nuh N Rahbari; Gerald A Villanueva; Eunjie Klegar; Wei Luan; Qin Wang; Herman T Yee

Posted: 09/18/2012; BMC Gastroenterol. 2012;12(64) © 2012 BioMed Central, Ltd.

Abstract and Introduction
Abstract

Background To determine clinical-pathologic variables in patients with a new diagnosis of hepatocellular carcinoma (HCC) and underlying hepatitis B vs. C infection.
Methods Patients presenting to a single urban hospital with a new diagnosis of HCC were entered into a clinical database. Variables including number and size of tumors, presence of metastases, serum alpha-Fetoprotein, hepatitis serologies, severity of hepatic dysfunction, and presence of cirrhosis were evaluated in 127 patients.
Results Patients with hepatitis B (HBV) were more likely to develop HCC at a younger age than patients with hepatitis C (HCV) (HBV-26% under age 40, HCV-0% under age 40; p < 0.001), with greater serum alpha-Fetoprotein production (median level: HBV-1000 ng/ml vs. HCV-37 ng/ml; p = 0.002), with larger tumors (HBV-78% >5 cm, HCV-28% >5 cm; p < 0.001), in the absence of cirrhosis (HBV-40%, HCV-0%; p < 0.001), and a decreased eligibility for curative treatment (HBV-14%, HCV-34%; p < 0.05). Conversely, patients with HCV were more likely to develop HCC in association with multiple co-morbidities, cirrhosis, and older age.
Conclusions Significant clinical-pathologic differences exist among HCC patients with underlying HBV vs. HCV. These differences impact eligibility for potentially-curative therapy and prognosis.

Background

Hepatocellular Carcinoma (HCC) is the third leading cause of cancer related mortality worldwide.[1] The global prevalence and mortality resulting from HCC is directly related to underlying risk factors for primary liver cancer in at-risk populations. Although several chronic liver diseases are associated with HCC, Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) statistically are the most commonly implicated risk factors. Combined they are responsible for 85% of total new HCC cases worldwide; 54% occurring as a result of HBV, and 31% as a result of HCV.[2,3] HBV, which is endemic in developing geographic regions such as Eastern Asia and Sub-Saharan Africa, is responsible for up to 90% of new HCC cases in such areas.[4]

Epidemiologic analyses and clinical series which lead to our understanding of the behavior and natural history of HCC do not usually subset results according the underlying viral risk factors for the disease.[5] Most survival analyses from institutions with broad experience in surgical resection, transplantation, ablation, transarterial chemoembolization, or other treatments usually combine patients, irrespective of their underlying viral hepatitis status or association to other risk factors.[6,7] Therefore variations in patterns of presentation, tumor biology, or treatment outcomes for HCC according to underlying association to viral hepatitis B or C remain unclear.

Despite histologic similarities in end-organ damage and eventual carcinomas, adequate scientific rationale supports a proposed hypothesis that distinct pathophysiologic mechanisms may be responsible for hepatocarcinogenesis due to either HBV or HCV. This is based in part on marked virologic differences seen among the 2 pathogens. Hepatitis B is a DNA virus belonging to the Hepadna virus family, which persists in the hepatocyte nucleus predominantly in the form of covalently closed circular DNA (cccDNA), the functional template for viral transcription and replication.[8] Conversely, Hepatitis C is an RNA virus belonging to the flavivirus family which replicates in the hepatocyte cytoplasm, with a completely distinct life cycle and pattern of viral replication.[9,10] Differences in natural history of resulting benign liver disease is well-described among the 2 viruses.[11]

In this study, an attempt has been made to evaluate potentially significant clinical-pathologic differences in HCC's that develop in association with chronic HBV vs. HCV. Comparisons have been made among two otherwise comparable groups according to data collected upon initial cancer diagnosis at a single, urban hospital. Demographic data and widely accepted relevant clinical-pathologic features of newly diagnosed HCC's have been collected with the intended purpose of delineating potentially significant differences in cancers which arise in HBV vs. HCV infected patients.

Methods
Database Enrollment

Patients were enrolled into a clinical database based upon a diagnosis of HCC at a single New York City public hospital (Bellevue Hospital Center). The database was approved by the IRB of New York University Medical Center and was in compliance with the Helsinki Declaration. The overall period of enrolment spanned the years of 1993 to 2005. Data for patients diagnosed between 1993 and 2001 was collected in a retrospective manner, while data collected between the years of 2001 and 2005 was entered prospectively. This study was exempt from IRB approval according to the institutional criteria at New York University Medical Center. Hence, informed consent was not required for this study.

Demographic data including age, sex, race, and ethnicity were collected. Several clinical-pathologic features were also recorded upon initial HCC diagnosis including the following: tumor size, tumor number, presence of synchronous distant metastases, macro-vascular invasion (tumor thrombus), viral hepatitis serologies, serum biochemistries including liver function tests, serum alpha-fetoprotein, presence and severity (according to Childs-Pugh classification) of coexisting cirrhosis, and underlying co morbidities.

In subsequent retrospective analysis of database variables, patients were stratified according to underlying risk factors for HCC. In order to facilitate a cohort comparison of HBV vs. HCV as risk factors for cancer, patients with either HBV or HCV only were included for analysis. Those co-infected both with HBV and HCV, or neither hepatitis virus were excluded from this analysis.

Diagnosis of HCC

The diagnosis of HCC was based upon histology or cytology, when tissue was available following surgical resection or biopsy. For cases in which no tissue was available, patients were diagnosed with HCC if dynamic imaging findings (CT with intravenous contrast or MRI only) of a hypervascular solid liver mass with features characteristic for HCC were present in a setting of underlying risk factors, along with a clearly elevated serum alpha-fetoprotein (>100 ng/ml). A diagnosis of HCC for all patients that presented with non-AFP-producing tumors was confirmed by biopsy. Of all 127 patients, 76 (60%) were diagnosed based upon histology or cytology, while 51 (40%) were diagnosed with imaging along with other features.

Diagnosis of Cirrhosis

A diagnosis of cirrhosis was made based on a combination of clinical parameters. For patients in whom tissue (from biopsy of resection specimens) was available from the non-neoplastic liver, a diagnosis of cirrhosis was made if histologic findings of hepatic fibrosis were observed in conjunction with clinical evidence of severe hepatic dysfunction (such as hypoalbuminemia). Patients with available histologic specimens demonstrating no evidence of hepatic fibrosis were deemed non-cirrhotic. For patients in whom non-neoplastic liver tissue was unavailable, a diagnosis of cirrhosis was based upon a combination of axial imaging features (including hepatic macronodularity and ascites), serum biochemistries indicative of severe hepatic dysfunction (such as hypoalbuminemia), and physical exam findings such as documented ascites.

Statistical Analyses

Comparisons of patient cohorts were performed using Fisher's exact test. A p value of <0.05 was used to designate a statistically significant difference among observed vs. expected outcomes.

Results
Demographics, Age Distribution, and Underlying Comorbidities

A total of 149 HCC patients were enrolled during the study period: 89 (59.7%) with HBV-associated cancers, 38 (25.5%) with HCV-associated cancers, 4 (2.7%) with cancers associated with both HBV and HCV, and 18 patients (12.1%) with cancers not associated with either hepatitis virus (Figure 1). HCC patients with HBV and HCV co-infection, as well as those without underlying viral hepatitis were excluded from the present analysis. HCC developed more commonly among males in both groups, however the association to male gender was stronger in the HBV group. Only 5% of HBV-associated HCC's developed in female patients compared with 21% of HCV-associated HCC's (p = 0.007, Table 1). The majority of HBV-associated HCC patients were of Asian race (90%), compared with only 5% in HCV-associated HCC patients (p < 0.001, Table 1).

769907-fig1

Figure 1. HCC incidence according to underlying etiology (current series). Underlying risk factors for HCC in current series closely resembles global demographic: worldwide epidemiologic data estimate HCC due to HBV in 53-54% of total cases, and due to HCV in 25%-31% of cases

The median age upon initial diagnosis for patients with either HBV or HCV-associated HCC's was similar (HBV, 50 years; HCV, 58 years); however, the age distribution in the two groups differed considerably. Approximately one fourth (26%) of all HBV-associated HCC's occurred in patients aged 40 years or younger, while no cancers developed in patients under the age of 40 in the HCV group (p < 0.001, Table 1). In fact, only 2 HCC's (5%) occurred in the HCV group at 50 years of age or less. This contrasted with the HBV group, in whom nearly half (49%) of cancers had already occurred by the age of 50 (Table 1).

As a group, patients who developed HCC associated with underlying HBV had fewer systemic comorbidities than those with underlying HCV. A mean of 1.0 underlying systemic comorbidity was present in HBV patients at the time of initial cancer diagnosis, compared with a mean of 2.9 associated systemic comorbidities in HCV patients (Table 1, p < 0.001). A coincident history of alcohol abuse was also less frequent in the HBV group (7% in HBV vs. 32% in HCV, p < 0.001), as was the frequency of HIV co-infection (1% in HBV vs. 13% HCV, p < 0.001).

Co-existence of Cirrhosis in the Non-neoplastic Liver

Patients with underlying HBV were less likely to have developed cirrhosis at the time of progression to cancer compared with patients with underlying HCV (p < 0.001, Table 1). Without exception, all patients who developed HCC in a setting of chronic HCV had established cirrhosis at the time of initial cancer diagnosis. However, 40% of patients with underlying HBV developed HCC in the absence of cirrhosis. When HCC patients with established cirrhosis due to either HBV or HCV were compared, the severity of cirrhosis as determined by the Childs-Pugh classification, was similarly distributed in both viral hepatitis groups.

Alpha-fetoprotein Production

A significant difference in serum alpha-fetoprotein (AFP)-production was observed in HCC's associated with underlying HBV as opposed to those associated with HCV (Table 1). The median level of serum AFP in HBV-associated HCC was greater than HCV-associated HCC (1000 ng/ml vs. 37 ng/ml, p = 0.002). While the proportion of patients with normal level of serum AFP (<20 ng/ml) was similar between HBV- and HCV-associated HCC, the proportion of HCC producing higher amount of AFP (>100 ng/ml) was greater in HBV-associated HCC. Sixty five percent of HBV-associated HCC, in contrast to only 27% of HCV-associated HCC, produced AFP greater than 100 ng/ml (p < 0.001). Similarly, the proportion of HBV-associated HCC producing AFP greater than 1,000 ng/ml or 10,000 ng/ml was higher compared with HCV-associated HCC (52% vs. 16%, and 25% vs. 5%, respectively, Table 1).

Oncologic Prognostic Variables

The presence upon initial cancer diagnosis of several well established oncologic variables associated with a poor cancer specific prognosis was assessed according to underlying viral hepatitis status. These include tumor size, tumor number, macrovascular invasion, and the presence of synchronous distant metastases.

Patients with HBV-associated HCC were significantly more likely to be diagnosed with larger tumors, than those with HCV-associated HCC. Seventy eight percent of HBV-associated tumors exceeded 5 cm in greatest cross-sectional diameter, as compared with only 28% of those associated with HCV (p < 0.001, Table 2). Analysis of all other selected variables failed to demonstrate a significant difference according to viral hepatitis status. Multifocal tumors and macrovascular invasion occurred with similar frequency in both the HBV and HCV groups (HBV-49% vs. HCV-54% and HBV-31% vs. HCV-24%, respectively). The incidence of synchronous distant metastases was observed with double the frequency in HBV patients, when compared to those with HCV (HBV-15% vs. HCV-6%). However, this trend did not achieve statistical significance, likely due to statistical underpowering of the study at the current sample size.

Eligibility for Treatment With Curative Intent

Eligibility for liver transplantation and surgical resection with expected favorable long-term survival, according to underlying viral hepatitis status, was determined by application of the Milan criteria.[12,13] Patients with HBV-associated cancers were far less likely to meet these criteria upon initial HCC diagnosis than were those with HCV-associated cancers (14% vs. 34%, respectively, p < 0.05). This more commonly precluded treatment with expectation for cure in patients with HBV-associated HCC, when compared to patients with HCV.

Discussion

Viral Hepatitis B and Hepatitis C are the most commonly implicated risk factors for HCC, with HBV responsible for the majority of cases worldwide. The epidemiologic predominance of HBV-associated HCC worldwide is largely due to the endemic nature of HBV infection in East Asian and subsaharan African populations.[14] Given the broad ethnic and racial diversity of patients seen at the single New York institution from which data was collected (Bellevue Hospital Center), patients included in the current analysis closely resemble the global demographic for HCC.[2,3] Sixty percent of all HCC cases were due to underlying HBV, and 25% were due to HCV. The majority of patients in the HBV group were of East Asian race (90%), compared to only 5% in the HCV group. This statistic potentially explains the significant disparity in age at initial cancer diagnosis among HBV vs. HCV-infected patients. HBV transmission in East Asian populations predominantly follows vertical (maternal-fetal) patterns of transmission.[15] In contrast, HBV in non-Asian populations, and HCV are more frequently transmitted in horizontal patterns as a result of exposure to infected body fluids.[16–18] Thus HCV exposure usually occurs later in life compared to HBV in the largest worldwide at risk populations. This finding from our study is consistent with previous studies in Japan showing younger detection age in HBV HCC patients compared with HCV HCC patients.[19,20] Although the mechanistic sequence of events required for progression from chronic viral hepatitis infection to HCC are poorly understood, a reasonable conclusion based on the current data could imply that the young age associated with HBV-HCC occurs as a direct result of vertical HBV transmission. Thus screening for HCC in patient populations known to be at risk for vertically-transmitted HCC should begin at an early age, no later than early adulthood.

Another important difference in the progression to HCC among HBV vs. HCV infected patients is the association to pre-existing cirrhosis at the time of initial cancer diagnosis. The occurrence of HCC in the absence of cirrhosis in a substantial percentage of HBV-HCC patients (40%), compared to the invariable association to established cirrhosis in those with HCV-HCC, suggests a potential cirrhosis-independent pathway to cancer unique (among viral hepatitis-associated cancers) to HBV-HCC. Much of the literature suggests a generally accepted common pathway to hepatocarcinogenesis, proposed in both HBV and HCV patients, based on: active viral replication, chronic hepatocellular necroinflammatory activity, hepatic parenchymal fibrosis, cirrhosis, and eventually cancer.[21–23] Although this model appears valid for patients with HCV, some with HBV do not experience such a predictable sequence of events prior to developing liver cancer.[24–26]

Considerations relevant to the care of patients who are subject to a cirrhosis-independent pathway to HCC should lead to proposed changes in current widely-adopted practices of screening for HCC in patients with chronic HBV.[27–29] Proposed changes in surveillance practices, particularly in those suspected of perinatal infection, should include a high level of vigilance for cancer even in the absence of cirrhosis. Several levels of evidence, in addition to the current data, reinforce that HBV patients are at risk for HCC even prior to the development of cirrhosis. Thus HCC screening should not be withheld until evidence of active hepatocellular necroinflammation or cirrhosis are observed.

Several additional significant clinical-pathologic differences in HCC were also observed according to underlying viral hepatitis status, including AFP production. This observation is particularly interesting, given that the utility of serum AFP as a cancer screening tool has been the subject of considerable recent debate, leading some experts in the field to not advocate its use as a tumor marker.[30] In the current study, median AFP level in HCV-associated HCC was 37 ng/ml, compared with 1000 ng/ml in HBV-associated HCC, and only 27% among HCV-associated cancers produced serum AFP greater than 100 ng/ml, compared with 65% in of HBV-associated HCC. This result suggests a higher sensitivity of serum AFP as a tumor marker when used in patients with HBV, but maybe less so in screening patients with HCV for cancer.

Oncologic variables with established prognostic significance were evaluated according to viral hepatitis status. Both macrovascular invasion and synchronous metastases occurred with greater frequency in the HBV-HCC group, although these observations did not achieve statistical significance. Only tumor size on initial HCC diagnosis, an important prognostic indicator, was statistically different among HBV vs. HCV patients.[31–33] This tumor size discrepancy may be explainable by less rigorous cancer screening recommendations for patients with chronic HBV, compared to more uniform and frequent screening programs for patients with HCV.[34,35] Many of the accrued HBV-HCC patients would not have met current American Association for the Study of Liver Diseases (AASLD) guidelines for HCC screening due to their young age, absence of cirrhosis or other variables.[30] Thus a relatively delayed cancer diagnosis may be attributable in part to under screening of HBV patients for HCC, when compared to those with chronic HCV.

Often due to initial presentation with large tumors, patients in the HBV-HCC group were less likely to meet Milan eligibility criteria for liver transplantation (single tumor <5 cm in greatest diameter or multiple tumor each <3 cm in greatest diameter).[12] Due to the similar prognostic importance of applying Milan criteria to surgical resection series, this association to larger tumors also predicted a lower likelihood of surgical resection with expected favorable long term survival.[13,36,37] Overall a staggeringly small fraction of all patients with HCC associated with either hepatitis virus met Milan criteria, underscoring the fact that most patients (80%) cannot be treated with the two most effective treatments or an expectation for favorable long term outcome. However, despite this observation in both viral hepatitis patients, inoperable or poor prognosis cancers were significantly more common in patients with HBV. Whether HBV or HCV viral etiology is an independent prognostic factor in patients with HCC following surgical resection or liver transplantation remains controversial and requires further investigation.[38–42]

Conclusions

In summary, patients with HBV-associated HCC were more likely to present with poor-prognosis cancers, often at a young age, and in the absence of cirrhosis. In contrast, patients with HCV-associated HCC often were diagnosed in a setting of pre-existing cirrhosis, with multiple comorbidities, but with more favorable oncologic features. These data suggest a role for more aggressive screening and management of chronic HBV patients, particularly those subjected to maternal-fetal viral transmission. The importance of earlier screening and more aggressive treatment is especially emphasized by the advanced oncologic nature of HCC associated with HBV on typical initial diagnosis.

References
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  12. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996, 334:693–699.
  13. Cha CH, Ruo L, Fong Y, Jarnagin WR, Shia J, Blumgart LH, DeMatteo RP: Resection of hepatocellular carcinoma in patients otherwise eligible for transplantation. Ann Surg 2003, 238:315–321.
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  16. Deuffic-Burban S, Abiteboul D, Lot F, Branger M, Bouvet E, Yazdanpanah Y: Costs and cost-effectiveness of different follow-up schedules for detection of occupational hepatitis C virus infection. Gut 2009, 58(1):105–110.
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  20. Shiratori Y, Shiina S, Imamura M, Kato N, Kanai F, Okudaira T, Teratani T, Tohgo G, Toda N, Ohashi M, Ogura K, Niwa Y, Kawabe T, Omata M: Characteristic difference of hepatocellular carcinoma between hepatitis B- and C- viral infection in Japan. Hepatology 1995, 22(4 Pt 1):1027–1033.
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  31. Martins A, Cortez-Pinto H, Marques-Vidal P, Mendes N, Silva S, Fatela N, Gloria H, Marinho R, Tavora I, Ramalho F, de Moura MC: Treatment and prognostic factors in patients with hepatocellular carcinoma. Liver Int 2006, 26(6):680–687.
  32. Llovet JM, Bru C, Bruix J: Prognosis of hepatocellular carcinoma: The BCLC staging classification. Seminars in Liver Disease 1999, 19(3):329–338.
  33. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M, Rodes J: Clinical angement of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. J Hepatol 2001, 35(3):421–430.
  34. Chalasani N, Horlander JC, Said A, Hoen H, Kopecky KK, Stockberger SM, Manam R, Now PY, Lumeng L: Screening for hepatocellular carcinoma in patients with advanced cirrhosis. Am J Gastroenterol 1999, 94(10):2988–2993.
  35. Patel D, Terrault NA, Yao FY, Bass NM, Ladabaum U: Cost-effectiveness of hepatocellular carcinoma surveillance in patients with hepatitis C virus-related cirrhosis. Clin Gastroenterol Hepatol 2006, 3(1):75–84.
  36. Morioka D, Tanaka K, Matsuo K, Takeda K, Ueda M, Sugita M, Nagano Y, Endo I, Sekido H, Togo S, Shimada H: Applicability of the Milan criteria for determining liver transplantation as a first-line treatment for hepatocellular carcinoma. Ann Surg Oncol 2006, 13:1500–1510.
  37. Margarit C, Escartin A, Castells L, Vargas V, Allende E, Bilbao I: Resection for hepatocellular carcinoma is a good option in Child-Turcotte-Pugh class A patients with cirrhosis who are eligible for liver transplantation. Liver Transpl 2005, 11:1242–1251.
  38. Roayaie S, Haim MB, Emre S, Fishbein TM, Sheiner PA, Miller CM, Schwartz ME: Comparison of surgical outcomes for hepatocellular carcinoma in patients with hepatitis B versus hepatitis C: a western experience. Ann Surg Oncol 2000, 7(10):764–770.
  39. Huang YH, Wu JC, Chen CH, Chang TT, Lee PC, Chau GY, Lui WY, Chang FY, Lee SD: Comparison of recurrence after hepatic resection in patients with hepatitis B vs. hepatitis C-related small hepatocellular carcinoma in hepatitis B virus endemic area. Liver Int 2005, 25(2):236–241.
  40. Li Q, Li H, Qin Y, Wang PP, Hao X: Comparison of surgical outcomes for small hepatocellular carcinoma in patients with hepatitis B versus hepatitis C: a Chinese experience. J Gastroenterol Hepatol 2007, 22(11):1936–1941.
  41. Ahmad SA, Bilimoria MM, Wang X, Izzo F, Delrio P, Marra P, Baker TP, Porter GA, Ellis LM, Vauthey JN, Dhamotharan S, Curley SA: Hepatitis B or C virus serology as a prognostic factor in patients with hepatocellular carcinoma. J Gastrointest Surg 2001, 5(5):468–476.
  42. Kao WY, Su CW, Chau GY, Lui WY, Wu CW, Wu JC: A Comparison of Prognosis between Patients with Hepatitis B and C Virus-related Hepatocellular Carcinoma Undergoing Resection Surgery. World J Surg. 2011, 35(4):858–867.

Source

Silymarin Is Ineffective for Chronic Hepatitis C Virus Infection

From Journal Watch > Journal Watch Gastroenterology

Atif Zaman, MD, MPH

Posted: 09/21/2012; Journal Watch © 2012 Massachusetts Medical Society

Abstract and Introduction
Abstract

In the most rigorous trial to date, oral silymarin was not superior to placebo in decreasing disease activity.

Introduction

Silymarin is a botanical extract of milk thistle commonly used by patients with liver disease. In vitro studies have demonstrated antiviral, anti-inflammatory properties of silymarin in hepatitis C virus (HCV) replicon systems. However, the few efficacy studies conducted in patients with chronic HCV infection have produced mixed results.

In a new multicenter, double-blind, placebo-controlled efficacy trial, investigators randomized 154 patients (median age, 54; 71% men) with chronic HCV infection who previously failed interferon-based therapy to receive 420 mg of silymarin, 700 mg of silymarin, or placebo three times daily for 24 weeks. The two oral doses of pure silymarin were determined by earlier dose finding studies and were three to five times higher than concentrations used in previous studies. The primary endpoint was a serum alanine aminotransferase (ALT) level of ≤45 U/L or a 50% reduction from baseline ALT to a level <65 U/L. Secondary endpoints included HCV RNA levels and quality-of-life indicators.

After 24 weeks of treatment, only two patients in each group achieved the primary endpoint. The mean decline in ALT levels at the end of treatment, the mean change in HCV RNA levels, and the quality-of-life indicators did not differ among the three groups.

Comment

This trial definitively demonstrates that silymarin, even at three to five times the typical dose, is ineffective in treating patients with chronic HCV infection. Unlike previous trials, this study used a pure, quantifiable formulation of silymarin and well-defined outcomes, its cohort was large and representative of the patient population, the treatment period was sufficiently long, and both medication and visit adherence rates were high. Clinicians should quote this study when addressing patients' questions regarding the use of milk thistle for treating HCV infection.

References
  1. Fried MW et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: A randomized controlled trial. JAMA 2012 Jul 18; 308:274.

Source

Despite Poor Interferon Response in Advanced Hepatitis C Virus Infection, Models of Protease Inhibitor Treatment Predict Maximum Treatment Benefit

From Alimentary Pharmacology & Therapeutics

I. A. Rowe; D. D. Houlihan; D. J. Mutimer

Posted: 09/28/2012; Aliment Pharmacol Ther. 2012;36(7):670-679. © 2012 Blackwell Publishing

Abstract and Introduction
Abstract

Background Protease inhibitors have improved sustained virological response (SVR) rates for subjects with genotype 1 hepatitis C virus infection (HCV). There is however uncertainty regarding how, and in whom, these agents should be used. In previously treated subjects, prior response to interferon has a major effect on SVR rates with protease inhibitor therapy.
Aim To assess the benefits of treatment and to understand the utility of a stopping rule for subjects with a poor interferon response following a 4-week lead-in with pegylated interferon and ribavirin.
Methods Treatment responses and long-term outcomes were modelled using hypothetical 1000 subject cohorts with 5 years of follow-up. Treatment strategies were compared with number needed to treat (NNT) and comparative effectiveness approaches.
Results Over 5 years of follow-up the NNT to prevent liver-related mortality for subjects with advanced fibrosis was substantially lower than that for subjects with all fibrosis stages (18 vs. 60) indicating particular benefit in this high-risk population. The use of a stopping rule for subjects with advanced fibrosis and a poor interferon response after a 4-week lead-in reduces the number of subjects exposed to a protease inhibitor by 55%. However, 33% fewer liver-related deaths are prevented using this strategy, indicating that there is unacceptable harm associated with this approach over a 5-year follow-up period.
Conclusions Subjects with advanced fibrosis should be prioritised for triple therapy on the basis of need. Treatment should be continued regardless of initial interferon response to maximise the early prevention of hepatitis C virus-related mortality.

Introduction

Hepatitis C virus (HCV) infection affects up to 200 million individuals worldwide and is an important cause of both morbidity and mortality.[1] Indeed up to 30% will develop cirrhosis with the attendant risks of liver failure and the development of hepatocellular cancer (HCC).[2, 3] Antiviral treatment has improved during the last two decades, but sustained virological response (SVR) rates remained below 50% for individuals infected with genotype 1 HCV who were treated with pegylated interferon and ribavirin. Since these were until recently the only available treatments many patients have been treated and not cured. Many of these individuals have cirrhosis, are at significant risk from liver related mortality and are prime candidates for more efficacious treatments that will reduce this mortality risk. To estimate this risk reduction it is crucial to understand the impact of the surrogate outcome of SVR on liver-related morbidity and mortality. This understanding permits well-informed discussion with patients who are considering retreatment.[4]

In the last year, the first generation of directly acting antiviral (DAA) agents has been licensed for treatment of patients with genotype 1 HCV infection. These are NS3 serine protease inhibitors that, when used with pegylated interferon and ribavirin, substantially improve response rates and have the potential to cure many individuals who would not have been cured with the previous standard of care.[5, 6] This increased cure rate comes at the expense of increased adverse events and an increased pill burden. Furthermore, DAAs have the potential to cause drug resistance, analogous to that seen with antiviral treatment for human immunodeficiency virus and hepatitis B virus (reviewed in).[7] Resistant species are associated with antiviral treatment failure, but the long-term ramifications of resistance are not known. It is possible that resistance to these agents will compromise the chance of treatment success with regimens that contain similar agents in the future. To limit the development of resistance, all of the phase II and III studies employed strict stopping rules to prevent futile drug exposure. Despite this up to 50% of those treated and who were not cured still developed drug resistant variants although these were frequently short-lived in the plasma.[8]

In the boceprevir development programme and in the phase III study of previously treated subjects with telaprevir, a 4-week lead-in phase with pegylated interferon and ribavirin was employed.[8–10] This strategy confirmed that interferon responsiveness was a key determinant of successful treatment. It has been suggested that the lead-in could be used to identify individuals with poor interferon response where treatment with first-generation protease inhibitors should be avoided, thus eliminating the risk of drug resistance and reducing the frequency and severity of treatment-associated adverse events.[11–13] Indeed, some experts would use the 4-week lead-in with both telaprevir and boceprevir where poor interferon response might be expected to aid decision making.[14] This approach is the subject of intense debate as some patients with poor response during the lead-in phase are subsequently cured with DAA containing treatment.

The aims of this study were therefore twofold: first to quantify the benefit associated with protease inhibitor treatment in previously treated subjects to aid patient selection for treatment, and second to evaluate the benefits and risks of using a lead-in phase with interferon and ribavirin dual therapy to identify patients who will benefit from addition of a protease inhibitor. The comparative effectiveness of treatment strategies was assessed using hypothetical patient cohorts over a clinically relevant 5-year follow-up period.

Methods
Treatment Strategy

All patients who had previously failed treatment with interferon and ribavirin were considered suitable for treatment. The proportions of subjects with previous null response (<2log10 decline in plasma HCV RNA during 12 weeks of dual therapy), partial response (>2log10 decline in plasma HCV RNA but without achieving plasma HCV RNA PCR negativity) and relapse (PCR negativity at end of antiviral treatment, but subsequent relapse) were estimated at 45%, 20%, 35% respectively.[15–17] There is no head-to-head comparison of boceprevir and telaprevir, and treatment responses appear comparable.[8–10, 18] As patients with prior null response to dual therapy were not included in the registration studies of boceprevir we planned treatment using a prototypic protease inhibitor modelled on telaprevir. Sustained virological response rates were estimated from studies in previously treated subjects and their subgroup analyses (Table 1, and supplementary information).[9, 19] The utility of treating subjects with advanced fibrosis (defined as METAVIR F3/F4) was first determined using these SVR estimates and by comparison with treatment of subjects with all stages of fibrosis.

Treatment regimens with and without a stopping rule after the 4-week pegylated interferon and ribavirin lead-in phase (<1log10 reduction in HCV RNA) in subjects with advanced fibrosis were then assessed. The variables included in this analysis are shown in Table 2 (and are summarised in Supplementary Figure S1). Standard stopping rules to avoid futile treatment were left in place (i.e. HCV RNA greater than 1000 IU/mL at either 4 weeks or 12 weeks after the start of triple therapy[20]) but were not explicitly modelled. In each case, analyses were done containing only those showing previous partial or null response since it was considered likely that previous relapsers would receive full treatment regardless of response to lead-in pegylated interferon and ribavirin (SVR rates in this population are very high regardless of baseline fibrosis stage).[9] Frequency of poor interferon response was extracted from a subgroup analysis of the REALIZE trial.[9, 19]

Outcomes After Treatment

Estimations of the rates of liver-related mortality, hepatic decompensation, and for the development of HCC were reported in a meta-analysis of previously treated patients,[21] and more recently in a prospective study of patients entered into clinical trials in a single centre.[22] These data allow the calculation of the absolute risk reduction (ARR) for each of these clinical events with successful treatment. For instance in the meta-analysis,[21] in previously treated subjects with advanced fibrosis and who do not achieve SVR the annual risk of liver-related mortality is estimated at 2.7%. For individuals with SVR the annual risk reduction is estimated at 0.19, or an annual mortality risk of 0.5% thus giving an ARR of liver-related mortality of 2.2% in those with SVR. The ARR for each outcome is given inTable 2. Adverse outcomes were calculated considering a follow-up duration of 5 years as it is unlikely that additional classes of DAAs will be licensed in that timeframe, and since it is interferon failure in this group that governs poor treatment response this is likely the minimum time until interferon-free regimens are licensed.

Comparison of Treatment Regimens

Calculations were based on hypothetical cohorts of 1000 subjects, and were compared using a decision analysis and comparative effectiveness approach.[23–25] These cohorts were assigned to receive treatment according to the regimens defined above. Treatment benefit was estimated using a number needed to treat (NNT) approach.[26] The NNT was calculated using the formula below accounting both for the ARR associated with successful treatment (i.e. the SVR) and also the relative probability of that success.

771286-eq1

Since the ARR is expressed per annum, to account for 5-year follow-up, the NNT was divided by 5 to give a 5-year NNT for each outcome.

The rate of clinical events in each cohort was then calculated using the NNT and compared by treatment regimen. The rate of the treatment related serious adverse events of hepatic decompensation (2%) and death (1%)[27–29] were also compared using this approach.

Sensitivity Analyses

Selected parameters in the base case analysis were varied within plausible limits (Table 2). For instance, rates of ARR for liver-related mortality and HCC varied from 2% to 4%, and 2% to 5%, respectively, in line with recently published data.[21, 22] As relatively few subjects with advanced fibrosis were included in the phase III studies, and those that were had well-preserved liver function, SVR rates varied from 10% to 20% in previous null responders and from 40% to 60% in partial responders. The proportion of subjects not achieving a 1log10 reduction at 4 weeks also varied from 32% to 45% in partial responders and from 55% to 70% in null responders. The relative proportion of null and partial responders included varied from 80/20 to 60/40 splits. Finally, the rate of treatment emergent adverse events varied between 1% and 3% for hepatic decompensation and 0.5% and 2% for treatment-related death.

Results
Mortality Reduction After Treatment

The effect of antiviral treatment on mortality has been assessed in relatively few studies due to the slowly progressive nature of HCV infection and the consequent use of SVR as a surrogate endpoint. To assess the treatment benefit of protease inhibitor containing triple therapy in previously treated subjects, we calculated the 5-year NNT for two groups: those with any stage of liver disease, and those with advanced fibrosis.[30] For those treated with a protease inhibitor, the 5-year NNT for those with any stage of liver disease is 60 to prevent one liver-related death whereas it is 18 when considering those with advanced fibrosis, despite a reduced SVR (Table 3). The impact of the NNT is highlighted when the number of deaths prevented in each treatment strategy is calculated in hypothetical patient cohorts: more than threefold more deaths are prevented when treating only subjects with advanced disease. These data highlight the importance of considering treatment in this high-risk group and indicate that this group should be prioritised for treatment on the basis of need.

Comparative Effectiveness of Including a Stopping Rule After the 4-week Lead-in

The outcomes of subjects treated with protease inhibitor containing triple therapy are shown in Figure 1. The strategy of treating all patients regardless of response after the 4-week lead-in with pegylated interferon and ribavirin results in the maximal prevention of death (Figure 1a). Employing the virological response to a 4-week lead-in with dual therapy as a stopping rule (Figure 1b) allows treatment to be stopped in the majority of this difficult-to-treat population thus reducing protease inhibitor exposure, and reducing the total number of treatment emergent adverse events. However, there is a notable increase in the efficacy of protease inhibitor containing therapy if treatment is stopped in subjects not achieving a >1log10 reduction in HCV RNA. As those with unfavourable responses are excluded from protease inhibitor containing treatment SVR rates for subjects treated with triple therapy are increased from 37.9% in the treat all strategy to 56.1% when the 4-week stopping rule is applied (Figure 1a,b).

771286-fig1

Figure 1. Flow diagram of the hypothetical 1000 subject cohort based on two strategies. (a) All 1000 subjects were treated with protease inhibitor containing triple therapy regardless of initial interferon response, and (b) after a 4-week lead-in treatment was stopped in subjects not achieving >1log10 reduction in HCV RNA. The number needed to treat for each scenario of completed treatment was calculated. After 5-year follow-up the number of deaths prevented was also assessed. F/U, follow-up; NNT, number needed to treat; P/R, pegylated interferon and ribavirin; SVR, sustained virological response.

There is however a significant reduction in overall clinical effectiveness associated with using the 4-week stopping rule. The number of patients achieving SVR is reduced by 37% as a result of excluding those subjects who would otherwise have been cured by continued treatment (SVR 'missed', Figure 1b). As this is a high-risk group and subjects who are not cured remain at significant risk of liver related morbidity and mortality we calculated the effects of the 4-week stopping rule on these parameters (Table 4). For subjects treated with triple therapy but without a stopping rule at week 4, 42 deaths are prevented over 5-year follow-up. However, only 28 deaths are prevented when the 4-week stopping rule is applied, a reduction of 33%. This indicates that by using the 4-week stopping rule 14 premature deaths occur that would have otherwise have been prevented by treating in the absence of the stopping rule.

The Impact of Treatment Emergent Adverse Effects on Outcome

This difficult to treat population is at risk of treatment emergent adverse effects that can negatively impact on the outcome of treatment. In similar studies of dual therapy hepatic decompensation occurs in approximately 2% of those treated and death occurs in approximately 1%.[28, 29] These data are supported by the initial safety data reported in the early expanded access to protease inhibitor programmes in France.[27] The impact on these episodes is summarised in Table 4. For instance, treatment emergent hepatic decompensation (i.e. decompensation precipitated by treatment) decreases overall treatment effectiveness. In effect there is an approximately 40% reduction in the net number of decopmensation episodes prevented by treatment in the treat-all strategy. When the 4-week stopping rule is employed there is a reduction in treatment-related decompensation episodes, but the advantage of treating all subjects regardless of response at week 4 of treatment remains. The impact on death is similar and these data indicate that the development of treatment emergent adverse effects does not significantly reduce the comparative benefit that is achieved by treating subjects regardless of virological response at treatment week 4.

Sensitivity Analyses

In sensitivity analyses, the overall benefit of continued treatment despite poor virological response at treatment week 4 was maintained despite variation in the proportion of null and partial responders, low SVR rates to protease inhibitor containing treatment, and also in cohorts containing an increased frequency of subjects not achieving >1log10 reductions at treatment week 4. However, in scenarios where there was greater mortality associated with treatment, and particularly where this was associated with low treatment efficacy, there was no difference in overall mortality between those treated regardless of virological response and those treated according to the 4-week stopping rule (Table 5). These analyses support not using the 4-week lead-in as a universal stopping rule but rather individualising treatment where subjects at high risk of on-treatment mortality due to the presence of advanced cirrhosis and portal hypertension[28, 29] should have interferon sensitivity considered in treatment planning.

Discussion

The development of novel DAA agents targeting HCV has the potential to significantly improve outcomes for subjects with HCV infection.[5, 6] There are however a number of questions regarding how, and in whom, these agents should be used.[13, 14, 31] This analysis provides a clear rationale for prioritising subjects with advanced fibrosis who are at significant risk of liver-related morbidity and mortality for treatment. This group represents at least 25% of infected subjects at current estimates[32] and targeted treatment offers the potential to reduce liver-related mortality in a relevant timeframe. Our modelling cautions against the use of the 4-week lead-in phase as a universal decision point in subjects with advanced fibrosis as this strategy will disadvantage as many as 37% of subjects who would otherwise ultimately have derived benefit from continued treatment.

Recent licensing of DAA agents has brought further complexity to the management of genotype 1 HCV infection. In addition, the rapid development of new agents has led to uncertainty regarding which subjects to treat now, and which patients might be deferred from treatment.[33] Using the analyses presented here we have illuminated this difficult topic, particularly highlighting the benefits of treating subjects with advanced fibrosis. This population is in need of effective treatment and the benefit of this analysis is that it clarifies the clinical outcome that results as a consequence of treatment vs. no treatment in a clinically relevant timeframe. There is clinical heterogeneity in a group containing all subjects with advanced fibrosis (METAVIR F3/F4), however, the data included in the model are supported by clinical data drawn directly from this population. For instance, treatment responses are from randomised controlled data, and long-term follow-up data are from a meta-analysis of more than 1400 subjects.[9, 21] Using these analyses to support clinical decision making and the prioritisation of subjects for treatment should allow clinicians to maximise treatment benefit through mortality reduction in the next 5 years despite relatively low SVR rates and whilst further developments in therapy occur. Furthermore, the analyses provide critical information in the explanation of the potential benefits (and risks) of treatment for clinicians to share with subjects with advanced fibrosis who are considering treatment.

The rationale for using the 4-week lead-in phase for decision making has been based on concerns regarding increased toxicity in subjects with advanced disease, and also concerns about the evolution and persistence of drug resistant variants.[11–13] The registration studies for both boceprevir and telaprevir included patients with advanced fibrosis, albeit at a relatively low frequency, and these patients had well compensated liver disease. In subjects treated with pegylated interferon and ribavirin dual therapy there is evidence that the treatment emergent adverse effects of hepatic decompensation and death are more common in those with advanced cirrhosis and portal hypertension.[28, 29] Our analysis indicates that allowing for treatment-associated decompensation at a rate of 1 in 50 treated patients and mortality at 1 in 100 (in keeping with reports from early access programs),[27] there remains a benefit in continuing treatment regardless of treatment response at treatment week 4. The development of resistant variants is more difficult to model since the consequences of these frequently short-lived variants are uncertain. Whilst there is the potential for these variants to persist and to impact on future protease inhibitor containing treatment[7] and candidacy for future clinical trials of perhaps more effective therapies, the likelihood is that for many of the subjects included in this analysis this would be the last opportunity for treatment (prior to liver transplantation or death). This is especially apparent as it is interferon sensitivity that governs the poor responses to treatment in this group and that pegylated interferon is likely to remain a component of standard of care therapy for the next 5 years at least.

This analysis is limited by several factors. The data are extracted from several studies, none of which were intended to address this particular question. Furthermore, none of the studies contained large numbers of patients with advanced fibrosis and indeed the boceprevir development programme did not address treatment responses in prior null responders. The treatment responses for boceprevir and telaprevir appear broadly similar and we therefore considered a prototypic protease inhibitor based on the published data that were available. In sensitivity analyses, we varied the proportions of prior null and partial responders, the SVR rates and the rates of treatment emergent adverse effects to address the areas where there were uncertainty in the primary reports. These analyses indicated that there was benefit of continued treatment regardless of virological response at treatment week 4. There were however important exceptions to this, and that is in scenarios where there are high rates of treatment emergent mortality. In these situation there was no benefit to continued treatment following a <1log10 reduction in HCV RNA when considering 5-year follow-up. These scenarios might be represented by subjects with advanced cirrhosis and significant portal hypertension where treatment is already risky and where a failure to respond to the 4-week lead-in could be considered an indication to stop treatment. The analyses presented here therefore provide important evidence to support individualised treatment decision making in this difficult population. Further studies addressing this population should be carefully designed to ensure that stopping rules are implemented both for virological failure and to protect those included from excessive treatment related morbidity and mortality.

This analysis contains a relatively crude assessment of benefit and harm. Whilst this is based on important clinical outcomes of death, hepatic decompensation and the development of HCC rather than the surrogate measure of SVR it is likely that the lasting benefits of SVR are underestimated. Whilst several investigators have studied the effects of SVR on more relevant outcomes, such as serum biochemistry[34] and fibrosis stage,[35, 36] the overall clinical outcomes of SVR are seldom reported. We therefore utilised a meta-analysis of clinical outcomes after SVR.[21] A more recent prospective report suggests that both the annual risk of liver-related mortality, and the ARR in mortality might be greater than we considered[22] suggesting that the mortality reductions in the base case analysis might underestimate the true effect of treatment. Furthermore considering follow-up of only 5 years duration will underestimate the overall benefit of treatment. This parameter was however set at 5 years to permit decisions to be made in this clinically relevant timeframe. Additional data indicating that productivity is decreased and absenteeism is increased in HCV infected subjects suggests significant additional benefit from successful treatment.[37, 38] Although these outcomes are difficult to model the benefit we have highlighted in continuing treatment regardless of response at treatment week 4 is likely increased when all factors are considered. Of course, additional treatment emergent adverse events will also be incurred through continued treatment of this population regardless of virological response at week 4, and some of these will be severe. In those subjects with advanced disease these are likely to be more frequent, and to contribute to treatment emergent decompensation and death. These events, however, do not negate the benefit of treatment. A decision to wait for further treatment developments in this high-risk group therefore has the potential to cause the greatest harm when compared with any of the treatment strategies presented here and the mortality reduction noted with treatment strongly cautions against that approach.

These analyses describe previously treated subjects with prior null and partial responses. As the absolute risk reduction in mortality associated with successful treatment in the untreated population is likely to be similar[39] these findings are generalisable to all subjects with advanced fibrosis undergoing treatment with protease inhibitor containing treatment. The findings are however not applicable to subjects with early fibrosis where the harms of treatment manifest through treatment emergent adverse effects, or the development of resistant variants, may outweigh the benefits of continued treatment in poor interferon responders. Whilst information on the significance of resistance is emerging there are concerns that the harms relating to resistant variants may be significant and individualised decision making is appropriate until such data are available.

In summary, this analysis indicates that subjects with advanced disease should be prioritised on the basis of need. Furthermore, when considering protease inhibitor treatment of previously treated subjects with advanced fibrosis, this should be done without consideration of interferon responsiveness following the 4-week lead-in. This analysis provides critical information regarding both selection and on-treatment decision making for previously treated subjects that should be included in guidance for physicians using protease inhibitors to treat subjects with HCV infection.

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