January 3, 2012

Mayo Clinic Studies Identify Risk Factors in Rising Trend of Liver Cancer

Jan. 3, 2012, 3:55 p.m. EST

ROCHESTER, Minn., Jan 03, 2012 (BUSINESS WIRE) -- Doctors have known for years that the incidence of deadly liver cancer is on the rise, but what is causing that trend has remained a mystery. Two recent Mayo Clinic studies published in the January issue of Mayo Clinic Proceedings offer a clearer picture of the rise of hepatocellular carcinoma (HCC), or liver cancer, which has tripled in the U.S. in the last three decades and has a 10 to 12 percent five-year survival rate when detected in later stages.

"The studies illuminate the importance of identifying people with risk factors in certain populations to help catch the disease in its early, treatable stages," said W. Ray Kim, M.D., a specialist in Gastroenterology and Hepatology and principal investigator of one study.

Dr. Kim's research group looked at several decades of records in the Rochester Epidemiology Project, a database that accounts for an entire county's inpatient and outpatient care. The study found the overall incidence of HCC in the population (6.9 per 100,000) is higher than has been estimated for the nation based on data from the National Cancer Institute (5.1 per 100,000). The study also found that HCC, which two decades ago tended to be caused by liver-scarring diseases such as cirrhosis from alcohol consumption, is now occurring as a consequence of hepatitis C infection.

"The liver scarring from hepatitis C can take 20 to 30 years to develop into cancer," Dr. Kim says. "We're now seeing cancer patients in their 50s and 60s who contracted hepatitis C 30 years ago and didn't even know they were infected."

Eleven percent of cases were linked to obesity, in particular fatty liver disease.

"It's a small percentage of cases overall," Dr. Kim says. "But with the nationwide obesity epidemic, we believe the rates of liver cancer may dramatically increase in the foreseeable future."

Another study looked exclusively at the Somali population, which is growing in the U.S., particularly in Minnesota, where as many as 50,000 Somalis have settled in the last two decades. The East African country is known to have a high prevalence of hepatitis B, a risk factor for HCC.

Researchers investigating records in the Mayo Clinic Life Sciences System confirmed that hepatitis B remains a risk factor, but they were surprised to find that a significant percentage of liver cancer cases in the population are attributable to hepatitis C, which had not been known to be significantly prevalent.

"The study suggests that screening for hepatitis C would be helpful for the Somali population and would enable close surveillance of liver cancer among those at risk," says lead author Abdirashid Shire, Ph.D., a Mayo Clinic researcher. "That would greatly improve treatment and survival of Somalis with this type of cancer."

The studies were funded by the National Institute of Health and the Mayo Clinic Center for Translational Science Activities.

About Mayo Clinic Mayo Clinic is a nonprofit worldwide leader in medical care, research and education for people from all walks of life. For more information, visit www.mayoclinic.com and www.mayoclinic.org/news.

SOURCE: Mayo Clinic


AASLD: Sustained Response is Durable among Hepatitis C Patients Treated with Telaprevir

Provided by HIVandHepatitis.com

Published on Tuesday, 03 January 2012 00:00

Written by Liz Highleyman

Almost all chronic hepatitis C patients who achieved sustained virological response (SVR) using the recently approved HCV protease inhibitor telaprevir (Incivek) plus pegylated interferon and ribavirin continued to have undetectable viral load nearly 2 years later, according to data presented at the recent American Association for the Study of Liver Disease (AASLD) Liver Meeting in San Francisco.

The ADVANCE, REALIZE, and ILLUMINATE trials demonstrated that adding telaprevir to standard therapy significantly increased the rate of sustained response, or continued undetectable HCV RNA at 24 weeks after the completion of therapy.

Investigators with the EXTEND Study Team looked at whether treatment response was durable with longer follow-up. EXTEND is a 3-year study of participants who received at least 1 dose of telaprevir in selected Phase 2 and 3 trials including ADVANCE (genotype 1 treatment-naive) and REALIZE (genotype 1 previously treated).

Kenneth Sherman presented findings from the second interim analysis at the Liver Meeting. This analysis included 223 patients who achieved SVR (followed for a median 21 months) and 185 non-responders who did not achieve SVR (followed for a median of 29 months). A total of 228 were originally in Phase 2 studies and 180 were in Phase 3 trials; 162 were treatment-naive and 246 were treatment-experienced.


  • > 99% of patients -- all but 1 -- maintained SVR during follow-up.
  • 1 individual experienced late relapse 48 weeks after prematurely discontinuing therapy (after 10 weeks total treatment time).
  • The recurring virus matched the prior strain, indicating relapse rather than reinfection.
  • Among 162 patients who did not achieve SVR and had available genetic sequencing data, 85% no longer had detectable telaprevir-resistant HCV variants, which had been replaced by wild-type virus.
  • More people with HCV subtype 1b had wild-type virus at their last study visit compared to those with subtype 1a (95% vs 77%, respectively).
  • Looking at specific resistance mutations, replacement with wild-type virus ranged from 82% to 100%.
  • No patients with long-term SVR experienced liver-related clinical events, compared with 4 non-responders (2 with transplants due to liver cancer, 1 with hepatic encephalopathy, 1 with ascites).

"In this interim analysis, SVR after telaprevir-based therapy was durable," the researchers concluded. "In patients who did not achieve SVR during telaprevir-based therapy, resistant variants were replaced by wild-type."



KE Sherman, MS Sulkowski, F Zoulim, et al. (EXTEND Study Team). Follow-up of SVR Durability and Viral Resistance in Patients with Chronic Hepatitis C Treated with Telaprevir-Based Regimens: Interim Analysis of the EXTEND Study. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 248.


Experts Issue Early Guide for Hep C Protease Inhibitor Therapy in People Living with HIV

Provided by Hep Magazine

January 3, 2012

A small but influential group of hepatitis C virus (HCV) experts has published provisional guidelines on the use of HCV protease inhibitors (PIs) in people living with HIV. The guidelines, published ahead of print by Clinical Infectious Diseases, are based in part on recommendations made to the Maryland AIDS Drug Assistance Program (ADAP) to help guide the use of these drugs in people coinfected with both viruses in the absence of official approvals from the U.S. Food and Drug Administration (FDA) and complete clinical trial results.

“Until additional data or alternative treatments are available,” David Thomas, MD, of the Johns Hopkins Schoolf Medicine and his colleagues write, “some experts believe that HCV PIs should be used in combination with peginterferon and ribavirin in certain HIV/HCV-coinfected persons.”

Merck’s Victrelis (boceprevir) and Vertex’s Incivek (telaprevir) were approved by the FDA in May 2011 for use in combination with pegylated interferon and ribavirin in people with genotype 1 HCV infection. These approvals were based on clinical trial data indicating improved sustained virologic response (SVR) responses—viral cures—by 25 to 31 percent, over pegylated interferon and ribavirin alone, in HIV-negative people living with chronic HCV infection.

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Maternal liver grafts more tolerable for children with rare disease

Public release date: 3-Jan-2012

Contact: Juliana Bunim
University of California - San Francisco

Results may have important implications for counseling parents on organ donation

Children with a rare, life-threatening disease that is the most common cause of neonatal liver failure – biliary atresia – better tolerate liver transplants from their mothers than from their fathers, according to a UCSF-led study.

In the study, researchers reviewed all pediatric liver transplants nationwide from 1996 to 2010, and compared the outcomes for patients who received liver grafts from their mothers with those for patients who received livers from their fathers.

Researchers believe the improved outcomes for children receiving a maternal liver graft may be due to higher levels of maternal cells in the patients' livers. The presence of these cells may establish tolerance to maternal antigens – substances that induce an immune response – and therefore greater acceptance of maternal organs in these biliary atresia patients.

"This result is exciting because it supports the concept that trafficking of cells between the mother and the fetus has functional significance long after the pregnancy is over," said senior author Tippi MacKenzie, MD, assistant professor of pediatric surgery at UCSF and a fetal surgeon at UCSF Benioff Children's Hospital. "This is a topic we are actively studying both in animal models and in patients who have fetal surgery. Practically speaking, this study may allow us to counsel families in which both the mother and father are willing and able to be a donor."

The researchers found that patients with biliary atresia who received a transplanted maternal portion of liver had a failure rate of 3.7 percent, compared to the failure rate of 10.5 percent observed in recipients of paternal livers. In children who had liver transplantation for other diseases, there were no differences in the transplant outcome between maternal or paternal grafts.

The results will be published in the January issue of the American Journal of Transplantation and can be found online at http://onlinelibrary.wiley.com/doi/10.1111/j.1600-6143.2011.03895.x/full

Biliary atresia, which affects one in 10,000 newborn infants, occurs when the common bile duct between the liver and the small intestine is blocked or absent. While early surgical intervention to treat biliary atresia is critical to prevent irreversible liver damage, once the liver fails, a liver transplant is required.

"We were testing the idea that if cells from the mother travel into the fetus during pregnancy and are involved in maternal-fetal tolerance, this phenomenon may have a long-lasting effect for transplantation tolerance when the mother donates an organ to the child," MacKenzie said.


Co-authors of the study are Amar Nijagal, MD, Shannon Fleck, BS, Nancy Hills, PhD, Sandy Feng, Md, PhD, Qizhi Tang, PhD, Sang-mo Kang, MD, and Phil Rosenthal, MD, all of UCSF. It was funded by the Irene Perstein Award and a grant from the California Institute for Regenerative Medicine.

About UCSF Benioff Children's Hospital

UCSF Benioff Children's Hospital creates an environment where children and their families find compassionate care at the forefront of scientific discovery, with more than 150 experts in 50 medical specialties serving patients throughout Northern California and beyond. The hospital admits about 5,000 children each year, including 2,000 babies born in the UCSF Medical Center. For more information, visit http://www.ucsfbenioffchildrens.org/.

About UCSF

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. For further information, please visit http://www.ucsf.edu/.


Understanding Patient Acceptance and Refusal of HIV Testing in the Emergency Department

Published on: 2012-01-03

Despite high rates of patient satisfaction with emergency department (ED) HIV testing, acceptance varies widely. It is thought that patients who decline may be at higher risk for HIV infection, thus we sought to better understand patient acceptance and refusal of ED HIV testing.

Methods: In-depth interviews with fifty ED patients (28 accepters and 22 decliners of HIV testing) in three ED HIV testing programs that serve vulnerable urban populations in northern California.

Results: Many factors influenced the decision to accept ED HIV testing, including curiosity, reassurance of negative status, convenience, and opportunity.

Similarly, a number of factors influenced the decision to decline HIV testing, including having been tested recently, the perception of being at low risk for HIV infection due to monogamy, abstinence or condom use, and wanting to focus on the medical reason for the ED visit. Both accepters and decliners viewed ED HIV testing favorably and nearly all participants felt comfortable with the testing experience, including the absence of counseling.

While many participants who declined an ED HIV test had logical reasons, some participants also made clear that they would prefer not to know their HIV status rather than face psychosocial consequences such as loss of trust in a relationship or disclosure of status in hospital or public health records.

Conclusions: Testing for HIV in the ED as for any other health problem reduces barriers to testing for some but not all patients. Patients who decline ED HIV testing may have rational reasons, but there are some patients who avoid HIV testing because of psychosocial ramifications.

While ED HIV testing is generally acceptable, more targeted approaches to testing are necessary for this subgroup.

Author: Katerina A ChristopoulosSheri D WeiserKimberly A KoesterJanet J MyersDouglas AE WhiteBeth KaplanStephen F Morin
Credits/Source: BMC Public Health 2012, 12:3


Silymarin Flops in Treatment of Chronic Hepatitis C

By: SUSAN LONDON, Family Practice News Digital Network

SAN FRANCISCO – Oral silymarin, an extract of milk thistle, is well tolerated but not efficacious for treating chronic hepatitis C virus infection, according to results from a randomized phase II trial reported at the annual meeting of the American Association for the Study of Liver Diseases.

After 24 weeks, patients taking high doses of the botanical agent – which is known to have anti-inflammatory, immunomodulatory, and antiviral activity in vitro – did not show improvement in serum levels of alanine aminotransferase (ALT) compared with their counterparts taking placebo.

A botanical agent – and milk thistle extract – has been proven ineffective for treating chronic hepatitis C.

There were also no significant differences between groups in a variety of measures of symptoms and quality of life.

"We must conclude that oral silymarin used at higher-than-customary doses did not significantly alter biochemical or virological markers of disease activity in hepatitis C patients previously treated with interferon-based regimens," said first author Dr. Michael W. Fried, director of hepatology at the University of North Carolina at Chapel Hill. But he added that "this was a fairly difficult group – these were nonresponders [to conventional therapy] – they were older."

The study is noteworthy for its many strengths, such as its use of a well characterized silymarin product, prolonged treatment, excellent adherence, and focus on a specific liver disease, he said.

Recent studies finding a benefit of silymarin in treating HCV infection used a different, intravenous formulation, according to Dr. Fried. That formulation contains a succinate moiety that may be important and likely achieves blood levels of silybin A, a major active component, higher than can be achieved with the oral formulation.

The oral doses used in the trial were probably not sufficient to inhibit the virus’ replicative enzymes, but giving higher doses was not practical. "We had to balance that with the pill burden: These were five capsules given three times a day, so we were not able to push the dose currently," he explained. "There may be attempts to try higher[-dose] formulations. There is also some way, interestingly, that’s being investigated to try to boost the silymarin levels with other botanical products ... because of their interactions on metabolism."

Dr. T. Jake Liang, president of the AASLD and chief of the liver diseases branch at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md., noted that the market for herbal and related products "is a big business in this country, about $30 billion, and it’s really not that well regulated, and there are a lot of unsubstantiated claims."

He pointed out that the trial focused on a more modest disease outcome. "The goal was not so much to see whether silymarin can eradicate the hepatitis C virus; the goal was really to see whether it could improve the damage to the liver," he explained in a press conference.

"I think this study clearly shows that the use of milk thistle is not effective in treating patients with hepatitis C. It’s a very important negative study – I think that’s key. We really want to make sure that we prevent any unwarranted use of herbal products despite the [health claims]," Dr. Liang concluded.

The trial, known as SyNCH and funded by the National Institutes of Health, enrolled 154 adult patients from four U.S. centers with chronic HCV who had not had a sustained virologic response to prior interferon-based therapy, had quantifiable HCV RNA, and had an ALT level of at least 65 IU/L.

Patients who had decompensated cirrhosis or moderate to severe steatosis or steatohepatitis were excluded, as were those who were positive for HIV or hepatitis B surface antigen, or who had used silymarin in the past month.

The patients were assigned to double-blind treatment in three groups: silymarin 420 mg three times daily, silymarin 700 mg three times daily, or matching placebo three times daily. The silymarin product used was a standardized preparation (Legalon, manufactured and supplied by Rottapharm Madaus in Monza, Italy, and Cologne, Germany) that is approved as a prescription drug in some European and Asian countries. Doses three- to fivefold higher than the customary one were chosen to achieve the highest likelihood of finding a benefit, according to Dr. Fried.

The patients studied were about 55 years old, on average, and three-fourths were white. Their mean ALT was 125 IU/L. Forty-four percent had used silymarin previously.

"Adherence throughout the treatment trial was quite excellent," he reported; across groups, 92%-98% of participants took more than 80% of planned doses. And random testing confirmed that patients in the silymarin group had silybin A in plasma while those in the placebo group did not.

However, final intent-to-treat analyses showed no significant difference between groups at 24 weeks in the primary end point, defined as achievement of a serum ALT level of 45 IU/L or lower (approximately the upper limit of normal) or a drop in serum ALT level of at least 50% to less than 65 IU/L (approximately 1.5 times the upper limit of normal).

Just 3.8% of patients in the placebo group met this end point, as did 4% in the silymarin 420-mg group and 3.8% in the silymarin 700-mg group.

"We really looked at many different subpopulations, and we could not find any signal at all," Dr. Fried said; additionally, the findings were much the same in per-protocol analyses.

The treatment groups were also statistically indistinguishable with respect to the changes from baseline in ALT levels and in HCV RNA levels, and with respect to changes from baseline in scores on questionnaires assessing depression, physical and mental health, and quality of life specific to chronic liver disease.

"Silymarin was well tolerated with an adverse event profile similar to placebo," Dr. Fried said. The three treatment groups did not differ significantly with respect to rates of adverse events (most of which were mild or moderate) or serious adverse events.

Dr. Fried reported that he is a consultant to Genentech, Tibotec, Vertex, Merck, Abbott, and Pharmasset; receives grant or research support from Genentech, Tibotec, Vertex, Merck, Anadys, Abbott, and Bristol-Myers Squibb; is an adviser or reviewer for GlaxoSmithKline; and has stock in Pharmasset. Dr. Liang reported that he had no relevant conflicts of interest.


Influence of interferon-based therapy on liver fibrosis progression in HIV/HCV coinfected patients: A retrospective repeated liver biopsy analysis

Journal of Hepatology
Volume 56, Issue 1 , Pages 49-54, January 2012

Patrick Ingiliz, Marc-Antoine Valantin, Paul Preziosi, Laetitia Finzi, Raluka Pais, Larysa Fedchuk, Stéphanie Dominguez, Christine Katlama, Thierry Poynard, Yves Benhamou

Received 1 October 2010; received in revised form 26 May 2011; accepted 31 May 2011. published online 20 July 2011.


Background & Aims

Hepatitis C virus (HCV) coinfection is one of the leading causes of mortality in human immunodeficiency virus-infected patients. The current standard of care leads to cure only in a part of these patients. The course of the disease is determined by the rapidity of liver fibrosis progression (LFP). The influence of interferon on LFP in coinfected patients has yet not been evaluated by comparative liver biopsies.


We extracted data of patients who had serial liver biopsies from a hospital database. Histopathological findings were compared to factors possibly linked to fibrosis progression. Furthermore, we studied the impact of response to interferon treatment on fibrosis progression.


Hundred and twenty-six patients were included, 68 had received anti-HCV treatment, and 58 had not. The median time between the first and the last biopsy was 4years. Worsened fibrosis was observed in 35 of 58 (60%) untreated patients, and 22 of 50 (44%) patients in the nonresponder/relapser group, and in 5 out of 18 (28%) in the SVR group. Liver fibrosis evolution was significantly better in patients achieving a SVR than in untreated and NR/R patients (p<0.02, odds-ratio [95% CI] for improvement vs. stability vs. worsening=3.16 [1.24–8.07]). This result persisted after adjustment for known predictors of liver fibrosis progression, HBsAg, CD4, and alcohol consumption: adjusted odds ratio=2.89 [1.09–7.68], p=0.03.


HCV treatment can stop fibrosis progression and induce its regression. Nonresponders to treatment may even have a fast fibrosis progression. It remains to be clarified if the same factors that induce nonresponse to treatment may also induce faster fibrosis progression.


Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: The ANRS HCEP-23 study

Journal of Hepatology
Volume 56, Issue 1 , Pages 55-62, January 2012

Jean-Pierre Zarski, Nathalie Sturm, Jérôme Guechot, Adeline Paris, Elie-Serge Zafrani, Tarik Asselah, Renée-Claude Boisson, Jean-Luc Bosson, Dominique Guyader, Jean-Charles Renversez, Jean-Pierre Bronowicki, Marie-Christine Gelineau, Albert Tran, Candice Trocme, Victor De Ledinghen, Elisabeth Lasnier, Armelle Poujol-Robert, Frédéric Ziegler, Marc Bourliere, Hélène Voitot, Dominique Larrey, Maria Alessandra Rosenthal-Allieri, Isabelle Fouchard Hubert, François Bailly, Michel Vaubourdolle, The ANRS HCEP 23 Fibrostar Group

Received 21 October 2010; received in revised form 13 April 2011; accepted 3 May 2011. published online 20 July 2011.


Background & Aims

Blood tests and transient elastography (Fibroscan™) have been developed as alternatives to liver biopsy. This ANRS HCEP-23 study compared the diagnostic accuracy of nine blood tests and transient elastography (Fibroscan™) to assess liver fibrosis, vs. liver biopsy, in untreated patients with chronic hepatitis C (CHC).


This was a multicentre prospective independent study in 19 French University hospitals of consecutive adult patients having simultaneous liver biopsy, biochemical blood tests (performed in a centralized laboratory) and Fibroscan™. Two experienced pathologists independently reviewed the liver biopsies (mean length=25±8.4mm). Performance was assessed using ROC curves corrected by Obuchowski’s method.


Fibroscan™ was not interpretable in 113 (22%) patients. In the 382 patients having both blood tests and interpretable Fibroscan™, Fibroscan™ performed similarly to the best blood tests for the diagnosis of significant fibrosis and cirrhosis. Obuchowski’s measure showed Fibrometer® (0.86), Fibrotest® (0.84), Hepascore® (0.84), and interpretable Fibroscan™ (0.84) to be the most accurate tests. The combination of Fibrotest®, Fibrometer®, or Hepascore® with Fibroscan™ or Apri increases the percentage of well classified patients from 70–73% to 80–83% for significant fibrosis, but for cirrhosis a combination offers no improvement. For the 436 patients having all the blood tests, AUROC’s ranged from 0.82 (Fibrometer®) to 0.75 (Hyaluronate) for significant fibrosis, and from 0.89 (Fibrometer® and Hepascore®) to 0.83 (FIB-4) for cirrhosis.


Contrarily to blood tests, performance of Fibroscan™ was reduced due to uninterpretable results. Fibrotest®, interpretable Fibroscan™, Fibrometer®, and Hepascore® perform best and similarly for diagnosis of significant fibrosis and cirrhosis.


Can-Fite BioPharma Announces Successful Results of its Phase I/II Liver Cancer Study with its CF102 Drug; the Study Achieved the Primary and Secondary Endpoints

Jan.3, 2012, 11:00 am

PETAH-TIKVA, Israel, Jan 03, 2012 (BUSINESS WIRE) -- Can-Fite BioPharma Ltd (tase:CFBI), a biotechnology company developing small molecule drugs for the treatment of inflammatory, and liver diseases, traded on the Tel Aviv Stock Exchange announced today the successful results of the Phase 1/2 study of its drug candidate CF102 in the treatment of hepatocellular carcinoma (HCC).

The company also announced today that a separate phase 1/2 study in patients with Hepatitis C (HCV) reached the study's main objectives of safety and pharmacokinetic behavior.

The HCC study which was conducted under the supervision of Dr. Salomon M. Stemmer, Institute of Oncology, Davidoff Center, Rabin Medical Center, included 18 patients with HCC, most of them had failed prior treatment with Sorafenib (Nexavar), the only currently approved drug for this indication. The primary study objectives were to evaluate the safety profile of long-term administration of CF102 at 3 different dose levels in patients with HCC, and to determine the pharmacokinetic behavior of CF102 in this patient population. The secondary objective of the trial was to document evidence of clinical efficacy and to look at the correlation between A3 adenosine receptor expression levels at base line and patients' response to CF102.

The study data demonstrate that the trial objectives were successfully achieved, showing a very favorable safety profile for CF102 in a patient population with hepatocellular carcinoma and Child-Pugh cirrhosis classes A and B. In addition, the median overall survival time was 7.8 months, which is very encouraging data given that most patients were treated in the second-line setting and some were Child-Pugh class B. Remarkably, the median overall survival time of the Child-Pugh B patients was 9.4 months, the longest overall survival time that has been reported in the literature for this patient population.

Out of the 18 patients, 9 were infected with Hepatitis C. In 7 patients treated with the high CF102 dosages, a reduction in HCV load was observed.

According to Dr. Keith Stuart, MD, Chairman, Department of Hematology and Oncology, Lahey Clinic Medical Center, Professor of Medicine, Tufts University School of Medicine: "The safety and efficacy data of the CF102 Liver Cancer study are impressive and encouraging in the context of other investigational drugs. Therefore, I would recommend further clinical development of this drug for the treatment of patients with hepatocellular carcinoma. I hope that the present data will be reproducible and that patients could benefit from this drug."

In parallel, the company also announced today that a separate phase 1/2 study in patients with Hepatitis C (HCV) reached the study's primary objectives of safety and pharmacokinetic behavior. However, a reduction in the HCV viral load was not observed. It should be noted that patients on this study were treated for several months only with the low dose of CF102.

According to Dr. Pnina Fishman, the company CEO, "We are very pleased that the study achieved all of its objectives in patients with HCC, most of whom had failed prior treatment with Nexavar. The impressive results in the HCC study encourage us to continue development of CF102 in patients with Liver Cancer. We will focus on this disease and will continue to observe the viral load of HCC patients who also suffer from HCV."

CF102 is a small orally bioavailable drug which binds with high affinity and selectivity to the A3 adenosine receptor. The latter is highly expressed in tumor cells whereas low expression is found in normal cells. This differential effect accounts for the excellent safety profile of the drug. The drug induces a robust anti-tumor effect via de-regulation of the Wnt signaling pathway, resulting in apoptosis of liver cancer cells agonist at the A3 adenosine receptor.

About Can-Fite Biopharma Ltd.

Can-Fite Biopharma Ltd is a public company, trading on the Tel Aviv Stock Exchange. The company, which commenced business activity on 2000, was founded by Prof Pnina Fishman, researcher in the Rabin Medical Center, and Dr Ilan Cohen, patent attorney and senior partner at Reinhold Cohen Patent Attorneys. Prof Fishman serves as CEO of the company. The company was founded on the basis of Prof Fishman's scientific findings, and is focused on the development of small molecule drugs, ligands to the A3 adenosine receptor. The latter mediates anti-inflammatory and anti-cancer effects and is suggested as a biological predictive marker. The company's lead drug, CF101, is in advanced clinical development for the treatment of autoimmune inflammatory diseases. The CF102 drug candidate is being developed for the treatment of liver diseases. Can-Fite has a wealth of clinical experience: to date, more than 700 patients have participated in clinical trials conducted by the company. Can-Fite recently licensed its activity in the ophthalmic field to OphthaliX Inc.

About OphthaliX Inc (formerly Denali Concrete Management Inc).

OphthaliX Inc. /quotes/zigman/503466 DCMG 0.00% is an advanced clinical-stage biopharmaceutical company focused on developing therapeutic products for the treatment of ophthalmic disorders. Denali's product candidate, CF101, is being developed to treat three ophthalmic indications: dry eye syndrome; glaucoma and uveitis. Can-Fite holds 82.3% in OphthaliX Inc.

SOURCE: Can-Fite BioPharma Ltd


Risk Factors for Hepatocellular Carcinoma in a Cohort Infected With Hepatitis B or C

Scott R Walter; Hla-Hla Thein; Heather F Gidding; Janaki Amin; Matthew G Law; Jacob George; Gregory J Dore

Posted: 12/28/2011; J Gastroenterol Hepatol. 2011;26(12):1757-1764. © 2011 Blackwell Publishing

Abstract and Introduction


Background and Aim: The incidence of hepatocellular carcinoma (HCC) has increased in Australia in recent decades, a large and growing proportion of which occurs among a population chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). However, risk factors for HCC among these high-risk groups require further characterization.
Methods: We conducted a population-based cohort study using HBV and HCV cases notified to the New South Wales Health Department between 2000 and 2007. These were linked to cause of death data, HIV/AIDS notifications, and hospital records. Proportional hazards regression was used to identify significant risk factors for developing HCC.
Results: A total of 242 and 339 HCC cases were linked to HBV (n = 43 892) and HCV (n = 83 817) notifications, respectively. For both HBV and HCV groups, being male and increasing age were significantly associated with risk of HCC. Increasing comorbidity score indicated high risk, while living outside urban areas was associated with lower risk. Hazard ratios for males were two to three times those of females. For both HBV and HCV groups, cirrhosis, alcoholic liver disease, and the interaction between the two were associated with significantly and considerably elevated risk.
Conclusion: This large population-based study confirms known risk factors for HCC. The association with older age highlights the potential impact of HBV and HCV screening of at-risk groups and early clinical assessment. Additional research is required to evaluate the impact of improving antiviral therapy on HCC risk.


Hepatocellular carcinoma (HCC) is one of the leading causes of cancer incidence and mortality worldwide.[1–3] Although less common in Australia than other regions, there has been a marked increase in HCC incidence in recent decades.[4–6] Chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is the main risk factor for HCC,[7,8] with over 80% of cases worldwide developing in the presence of these infections.[9] The increasing prevalence of chronic viral hepatitis in Australia has been identified as a key driver behind the rising incidence of HCC.[10,11] Other known HCC risk factors include cirrhosis, alcoholic liver disease (ALD), aflatoxin B1,[12] hemochromatosis,[8] HIV,[13] diabetes,[14–16] and HBV/HCV co-infection.[17–20] Increasing age, being male,[21] and certain ethnicities[22] have also been identified as risks, along with lifestyle factors, such as high alcohol intake and smoking. The prevalence of risk factors can vary considerably between geographical regions.[21]

Many published studies have examined risk factors for HCC in various regions of the world,[8,21,23–26] some of which have looked at risk within HBV- or HCV-infected groups.[23–25] However, there are very few studies of HCC risks in the Australian context,[10] and none which quantify risk among HBV- or HCV-infected people at a population level. To this end, we conducted a population-based, retrospective cohort study to identify and quantify risk factors for HCC among an already high-risk group of HBV or HCV infected individuals in New South Wales (NSW), Australia's most populous state.


Data Sources

The study group consisted of all HBV and HCV notifications recorded in the NSW Notifiable Diseases Database between 1 January 1992 and 31 December 2007. Notification of HBV or HCV infection has been required by law since 1991 (NSW Public Health Act 1991). A notifiable HBV case requires detection of HBV surface antigen or HBV–DNA, while a notifiable HCV case requires detection of anti-HCV antibody and/or HCV-RNA.

The NSW Admitted Patient Data Collection contains information on all hospital admissions occurring in NSW hospitals, public psychiatric hospitals, public multipurpose services, and private day-only procedure centers. It also contains records of NSW residents who were admitted to interstate hospitals. The hospital data were only available for linkage from 1 July 2000. The NSW Central Cancer Registry contains information on all cancers diagnosed and mandatorily reported in NSW since 1972 (Public Health Act 1972). We obtained all HCC records, defined by ICD-O-3 topography code C22.0 and histology codes 81703–81753, which linked with a HBV or HCV record. HIV and AIDS are also legally notifiable conditions in Australia, and new diagnoses are recorded in the National HIV Database (NHD) and the National AIDS Registry (NAR), respectively. The NHD has recorded HIV diagnoses since 1985, and the NAR has recorded AIDS diagnoses since 1982. Both data sources record a four-letter name code in place of full name identifiers.


Records of viral hepatitis notifications were probabilistically linked to cancer and hospital records using full name, address, sex, and date of birth identifiers. Linkage of both the HIV and AIDS records to the hepatitis notifications was performed by deterministic linkage using name code, date of birth, and sex only. All linkage was carried out by the NSW Centre for Health Record Linkage[27] using ChoiceMaker software (ChoiceMaker Technologies, New York, NY, USA).

Statistical Methods

Where multiple HBV or HCV records were matched to one individual, the earliest record was used to define date of diagnosis. When defining HBV/HCV co-infection, diagnosis date was defined by the date of the second infection. Since hospital admission data were only available from 1 July 2000, the analysis was restricted to HBV or HCV cases still alive at this date and without any record of HCC diagnosis prior to this date. Although cases with a viral hepatitis notification prior to 1 July 2000 did not have hospital data for the initial period of follow up, the conditions of interest were all chronic and were expected to be recorded in later hospital records as either principal diagnoses or comorbidities. These cases were treated as left truncated, when defining analysis time. Given that a primary objective was to identify factors associated with HCC that could guide chronic viral hepatitis therapeutic intervention and HCC screening, cases diagnosed with HCC within 6 months of their viral hepatitis diagnosis were excluded. Inclusion of "late HCC" diagnoses would also have potentially biased the estimation of HCC incidence. Therefore, follow-up time commenced 6 months after viral hepatitis diagnosis, and ended at the earliest of date of HCC diagnosis or the end of the study period: 31 December 2007.

Summary counts, percentages, and crude person-time rates were generated to characterize the study cohort. Cox proportional hazards models were developed for those with HBV, including HCV co-infection, and separately for those with HCV, including HBV co-infection, where HCC diagnosis was the outcome of interest. Potential covariates considered were sex, remoteness, HBV/HCV co-infection, age group, time period, health insurance status, and Charlson–Deyo comorbidity score, the latter four being treated as time-varying covariates. Remoteness was calculated from postcode of residence at the time of hepatitis notification using concordances defined by the Australian Bureau of Statistics. Comorbidity score was calculated according to the methods described by Charlson et al.[28] and Deyo et al.[29] This involves assigning a severity value if any of a set of predetermined conditions appeared in any diagnosis field for a hospital episode. Based on the sum of these values for a given episode, it is then categorized into one of three groups representing different degrees of comorbidity. Thus, the score reflects both the number of comorbid conditions, as well as their severity. All variables with a univariate log–rank test significant at the 0.20 level were initially chosen for inclusion in each model. Non-significant covariates were then removed from the model until those remaining were significant at the 0.10 level. The removal of each successive covariate was assessed with a likelihood ratio test between successive models and by examining the percentage change in coefficients.[30] Finally, variables that were non-significant in the univariate test were added to see if they became significant when adjusted for other factors. The proportional hazards assumption was assessed via a residual-based test, as described by Grambsch and Therneau.[31] Overall model fit was examined by plotting the Nelson–Aalen cumulative hazards estimates against Cox–Snell residuals and assessing their approximate adherence to the line of equality.

As it was not possible to include hospitalization for specific conditions in the same model as the comorbidity score due to collinearlity, separate models were developed, which replaced the comorbidity score with specific chronic comorbid conditions of interest. These conditions were diabetes, ALD, cirrhosis, hemochromatosis, and HIV. For the first four, a person was flagged as having a certain condition if the diagnosis code appeared in any diagnosis field on any hospital record for that person, while HIV status was determined by the presence of a HIV or AIDS notification record. The same model-building process was followed with the addition of plausible two-way interaction terms involving the conditions of interest. A more relaxed inclusion criterion of 0.15 was used to determine the significance of interaction terms.

Ethics approval for the study was granted by the University of NSW Human Research Ethics Committee and the NSW Population and Health Services Research Ethics Committee.


Study Cohort

There were 43 892 people with HBV monoinfection, and 83 817 with HCV monoinfection in the final study cohort, of which 13 645 (31%) and 35 615 (43%), respectively, had a linked hospital record (Table 1). The median ages at viral hepatitis diagnosis were very similar between the two monoinfected groups, both being just under 35 years. A total of 242 (0.6%) people in the HBV monoinfected group, and 339 (0.4%) in the HCV group, had a linked HCC record, 71% and 80% of whom also had a linked hospital record, respectively. There were 3347 people co-infected with HBV and HCV; 1670 (50%) of these had a linked hospital record, and 23 (0.7%) had a linked HCC record. Those co-infected with HIV made up less than 1% of the cohort and accounted for less than five HCC cases.

The overall crude rate of HCC incidence was significantly higher among those with HBV monoinfection compared to those with HCV monoinfection (9.5 vs 6.9 cases per 10 000 person years, P < 0.001) (Table 2). For both groups, rates increased significantly with age category, were higher among males and among those living in metropolitan areas. People with a comorbidity score of three or more had rates over 15 times higher than people with a comorbidity score of one (HBV 187.0 vs 12.0, HCV 171.5 vs 5.5 per 10 000 person years). Having a hospital record for diabetes, ALD, or cirrhosis was associated with significantly higher crude rates of HCC incidence, particularly cirrhosis, which was associated with more than a 50-fold increase in crude rates for the HBV and HCV monoinfected groups, respectively.

HBV and HCV Proportional Hazards Models, Including Comorbidity Score

For those infected with HBV, including HBV/HCV co-infection, age, sex, time period, remoteness, comorbidity score, and insurance status, were all significant at the univariate level and were included in the initial model. Only age group, sex, remoteness, and comorbidity remained significant at the 0.10 level in the final model after following the model-building process described above. The risk of developing HCC increased with age, with those aged 75 or over having 14 times the risk of those aged under 45 (hazard ratio [HR]: 14.0, 95% confidence interval: 8.6–22.7) (Table 3). The risk for males was threefold that of females (HR: 3.1, 95% CI: 2.3–4.3). Risk increased with increasing comorbidity score, while those not hospitalized had significantly lower risk compared to those in the lowest comorbidity group (HR: 0.4, 95% CI: 0.3–0.5). Those living outside metropolitan areas had lower risk compared to city dwellers (HR: 0.5, 95% CI: 0.3–1.0), although there were only seven cases of HCC in the non-metropolitan group.
For the HCV cohort, the final model included the same four covariates as the HBV model, with the exception that HBV/HCV co-infection was also included. An increase in risk with age was also observed, although with a somewhat steeper gradient of risk than in the HBV model, and with a peak in the 65–74-year age group. Males had just over double the risk of females (HR: 2.3, 95% CI: 1.8–2.9), while the distribution in risk across comorbidity groups was similar to the HBV model. The 39 non-metropolitan HCC cases were also observed to have significantly lower risk (HR: 0.5, 95% CI: 0.4–0.8), and HBV/HCV co-infection was associated with increased risk (HR: 1.6, 95% CI: 1.1–2.5).

HBV and HCV Proportional Hazards Models, Including Chronic Conditions

The final model for both HBV and HCV groups retained the same variables, namely, age, sex, remoteness, health insurance status, ALD, and cirrhosis, as well as the interaction between these two chronic conditions. The only exception was that the HCV model also found HBV/HCV co-infection to be significant (HR: 1.6, 95% CI: 1.1–2.5). Despite crude rates of HCC being much higher among those with diabetes, this risk factor did not remain significant in the model when adjusted for other factors. For insurance status in both models, although most categories were non-significant, removing this variable made a significant difference to the model fit, so its deletion could not be justified. HIV co-infection and hemochromatosis were omitted from both models due to the very small numbers of HCC cases having been hospitalized with these conditions. Age, sex, and remoteness effects were similar to those seen in the models described above; however, the age-related HRs were somewhat amplified (Table 4). Compared to those without hospitalization for major liver disease, those hospitalized with ALD without cirrhosis had a significantly elevated risk (HBV HR: 6.4, 95% CI: 2.6–15.9; HCV HR: 10.8, 95% CI: 7.3–16.1), while those hospitalized with cirrhosis, but not ALD, had even higher risk of HCC (HBV HR: 24.1, 95% CI: 17.8–32.7; HCV HR: 17.9, 95% CI: 13.7–23.4). Among those with HBV, having been hospitalized with both cirrhosis and ALD was associated with further increase in risk (HR: 28.2, 95% CI: 11.3–70.5), but this interaction was slightly less than additive. For those with HCV, the combined effect was somewhat greater (HR: 36.4, 95% CI: 10.8–122.5), which showed that the interaction was more than additive, but less than multiplicative.

This study identifies sociodemographic and health factors predictive of developing HCC among a cohort of people with chronic HBV or HCV infection in NSW. The incidence of HCC increased with age and comorbidity score, and was higher among males, metropolitan residents, and those with ALD, and particularly cirrhosis. Older age, being male, and having a high comorbidity score were significantly and independently associated with the risk of HCC. Co-infection with HBV and HCV was associated with increased HCC risk in the HCV cohort, and of all risk factors considered, cirrhosis conferred the greatest additional risk, regardless of infection type.

The risk of HCC was observed to increase significantly with age for both HBV- and HCV-infected groups. Such an increase in risk with age has been widely observed,[32] but in some countries, age-specific incidence peaks in the 60s, rather than late 70 s or beyond, possibly due to variation in the prevalence of certain risk factors between regions.[17,21]

Being male is another well-known risk factor for HCC, although there is considerable regional variation in the relative risk compared to females.[21] While relative risks of males compared to females for HCC among the general population range from close to one to almost nine, in most regions in the world, males have two to four times the risk of females,[21] consistent with our results.

A clear increase in the risk of HCC with comorbidity score was observed for both infection groups. Few studies have assessed the association between comorbidity score and HCC risk, as it is often more informative to examine individual health conditions. Each comorbid condition influences the risk of HCC by varying degrees, and multiple conditions might interact in complex ways. However, in terms of identifying high-risk individuals, the comorbidity score quantifies the combined effect of multiple conditions, without the need to interpret risks associated with multiple factors and their interactions.

A number of papers have reported a twofold to threefold increase in HCC risk due to diabetes,[14–16,26] some of which also found an interaction between viral hepatitis and diabetes.[14,16] While including diabetes in the models suggested an increase in the risk of comparable magnitude, the difference was not sufficiently significant to remain in the final model, suggesting that in our cohort, this is a low-risk condition relative to other factors considered.

Alcohol consumption has been identified as a key risk factor for HCC, interacting synergistically with chronic viral hepatitis infection,[16,33] but relatively few studies have examined the risk associated with ALD.[34] We observed significant risk associated with hospitalization with this condition, possibly through the combined effects of alcohol-related and hepatitis-related liver injury. The observed increased risk of HCC among those with HBV/HCV co-infection is consistent with other studies, which found that the combined effect of the two infections is more than additive, but less than multiplicative.[17,18,20,35]

Cirrhosis is well known as the precursor for the vast majority of chronic viral hepatitis-related HCC cases.[19,36,37] Not surprisingly, our study identified cirrhosis as the strongest predictor of HCC for both HBV and HCV cohorts. Two studies based in Taiwan found a 12-fold and 50-fold increase in risk due to cirrhosis among a HBV-infected cohort.[25,38] Sherman reports a more than 20-fold increase in HCC incidence in people with HCV and cirrhosis, compared to those with HCV alone.[36] The magnitude of these estimates approximately agrees with the very high risk identified in our study. The combined effects of cirrhosis and ALD indicated further amplified risk of HCC, particularly among those with HCV. Having a hospital record for both conditions likely indicates advanced or rapidly-progressing liver disease.

A limitation of this study was the incompleteness of country of birth information in the viral hepatitis notification data, which inhibited analysis of the differential risk of developing HCC between people born in different regions. This is particularly pertinent, given that more than half of the HBV-infected group have immigrated from HBV-endemic countries, such as China and Vietnam,[39,40] while the majority of those with HCV are Australian born.[41] Region of birth might also confound the association between remoteness and HCC, since there are much higher proportions of Asian born people in metropolitan areas than non-metropolitan areas.[42] This is particularly likely to be a factor among the HBV-infected cohort. More limited access to specific HCC diagnostic services in non-metropolitan areas might also be a factor in producing an apparently lower incidence of HCC.

A further limitation was the availability of cirrhosis data only through hospitalization codes, particularly as liver biopsy and hepatic elastography diagnosis are generally undertaken through outpatient services. Also, linked treatment data were not available for this study, which eliminated the possibility of examining the extent to which antiviral therapy reduces HCC risk; however, this might form the basis of future studies when additional data permit.

HCC screening and surveillance among at-risk groups have only relatively recently been shown to improve survival.[43,44] Cases only presenting when symptomatic often have a poorer prognosis and fewer treatment options than those detected in the asymptomatic stage of disease.[24,45] In light of its ability to detect tumors early and improve treatment eligibility and survival, screening and surveillance play a key role in reducing the burden of HCC. However, it is only practiced by some groups in NSW, with less than 20% of HCC cases being identified via surveillance.[45,46] Identifying and quantifying risk factors specific to a population, as we have done, forms an integral part of targeting cost-effective surveillance and provides motivation for more widespread screening of high-risk groups.

Antiviral therapy has been shown to limit the progression of liver disease, and in some HBV cases, can reverse decompensated cirrhosis, considerably reducing the risk of HCC.[37,47] Thus, antiviral therapy of chronic viral hepatitis represents a pivotal pathway for reducing the burden of HCC. This also bolsters the case for increasing treatment uptake in general among those with chronic viral hepatitis infection, given that currently, approximately 5% of HBV-infected people[48] and 1–2% of HCV-infected people[41] receive antiviral therapy. A combination of surveillance and treatment has been shown to be a more cost-effective way to reduce the burden of liver cancer than surveillance alone.[46]

In summary, this study has identified and quantified important risk factors for HCC within a high-risk, population-based cohort. Several key factors emerged as independent and significant risks for HCC. Although some previously-reported risk factors were not significant in our analysis, those that were identified were largely consistent with studies conducted in other regions of the world. The association with older age highlights the potential impact of HBV and HCV screening of at-risk groups and early clinical assessment. Antiviral therapy for chronic viral hepatitis is an important strategy for preventing HCC, and further research is required to quantify its mitigation of HCC risk at a population level in the Australian context.


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The authors thank Dr Lee Taylor, Ms Kate Ward, Ms Kim Lim, Ms Narelle Grayson, Ms Hui You, and the staff at the Centre for Health Record Linkage, and Ms Katie Irvine and Ms Anita Bobba for their advice and conducting the data linkage.

SW is supported by the NSW Health Biostatistical Officer Training Program. HHT is currently supported by the Ontario Institute for Cancer Research Health Services Research Program New Investigator Award. JG is supported in part by the Robert W. Storr bequest to the Sydney Medical School Foundation. GD is supported by a NHMRC Practitioner Fellowship. This publication was funded by the Australian Government Department of Health and Ageing and the NSW Cancer Council STREP Grant (SRP08-03).

J Gastroenterol Hepatol. 2011;26(12):1757-1764. © 2011 Blackwell Publishing


The invaders and the barrier

Journal of Hepatology
Volume 56, Issue 1 , Pages 11-13, January 2012

Jean-Michel Pawlotsky

published online 19 September 2011.

See Article, pages 41–48

Barriers exist to protect. The first images of World War II show the invaders breaking a barrier at the border of Poland, signifying the end of a peaceful world and the beginning of chaos… This is analogous to viral resistance to antiviral drugs. The invader is the drug-resistant virus; this virus preexists as poorly fit, minority viral populations. The “barrier to resistance” of a drug or a drug combination prevents their outgrowth in the presence of the drug(s), thus preventing virological breakthrough, disease progression, and eventually severe complications. If the barrier to resistance is high enough, resistant viral variants are not selected and do not grow; if it is not, they rapidly fill in the replication space and become the dominant (or exclusive) viral population associated with high-level replication.

The main components of the barrier to resistance in vivo are: (i) the “genetic barrier to resistance”, defined as the number of amino acid substitutions needed for a viral variant to acquire full resistance to the drug in question. If a single substitution is sufficient to confer high-level resistance, then the drug is considered to have a low genetic barrier to resistance, while the need for three or more substitutions represents a high genetic barrier; (ii) the “in vivo fitness” of the resistant viral variant population, defined as its ability to survive and grow in the replicative environment; (iii) drug exposure, defined as the drug concentration achieved in vivo relative to the 50% and 90% inhibitory concentrations (IC) and efficient concentrations (EC) [1].

A number of direct acting antiviral (DAA) drugs are in development for the treatment of chronic hepatitis C virus (HCV) infection. Two NS3/4A protease inhibitors, telaprevir and boceprevir, have been recently approved in combination with pegylated interferon (IFN)-α and ribavirin for the treatment of genotype 1 chronic hepatitis C [2], [3], [4], [5]. Other DAAs are at various stages of preclinical to late clinical development. They can be schematically classified into two groups, according to their barrier to resistance. Drugs with a low barrier to resistance include first-generation NS3/4A protease inhibitors (e.g. telaprevir and boceprevir and numerous other molecules in development), NS5A inhibitors, and non-nucleoside inhibitors (NNI) of HCV RNA-dependent RNA polymerase (RdRp) [6]. Their administration as monotherapies has been reported to be associated with early virological breakthroughs due to the selection and subsequent outgrowth of fit resistant viral populations carrying one or several substitutions that confer resistance to the drug [7], [8], [9]. Drugs with a high barrier to resistance include nucleoside/nucleotide analogue inhibitors of HCV RdRp, cyclophylin inhibitors (drugs that target a host cell protein involved in viral replication), and potential second-generation NS3/4A protease inhibitors. They can be administered alone for weeks without any virological breakthrough due to resistance in the majority of cases [10], [11].

Prevention of resistance, particularly when drugs with a low barrier to resistance are used, is based on the combination of several molecules that are potent and have no cross-resistance. No cross-resistance means that each member of the combination is fully active on viruses that are resistant to the others. This concept was the basis for combining NS3/4A protease inhibitors (or other DAAs with a low barrier to resistance) with pegylated IFN-α and ribavirin. Unfortunately, in patients who do not respond adequately to IFN-α and ribavirin, treatment fails and as a result DAA-resistant variant populations grow [1]. In order to cure infection without selecting for resistance, it is also possible to combine potent DAAs without cross-resistance, with the double goal of achieving better antiviral efficacy and substantially increasing the barrier to resistance. Attempts with combinations of drugs with low barriers to resistance, such as an NS3/4A protease inhibitor with an NS5A inhibitor, or an NS3/4A protease inhibitor with an NNI, have been disappointing [12], [13]. Although cure was achieved in a few patients receiving the former combination [14], the rates of failure due to selection of viral variants bearing substitutions at both drug target sites were frequent in these studies, suggesting that the barrier to resistance of a combination of two HCV drugs with low barriers to resistance is not dramatically greater than that of each drug alone.

There are four distinct groups of NNI inhibitors of HCV RdRp in development. Each targets a different allosteric site at the surface of the enzyme, and they have been reported to have different resistance profiles in vitro, without cross-resistance. Thus, although targeting the same viral enzyme, NNIs from different classes could theoretically be combined together. In this issue of the Journal of Hepatology, Delang et al. report their assessment of the antiviral potencies and resistance selection profiles of members of three of the four NNI groups [15]. These compounds were tested alone and in double or triple combination in replicon-harboring Huh7 cell lines, the usual model for this type of experiments. The authors confirmed the low barrier to resistance of each NNI alone and the lack of cross-resistance between them. They also showed that these drugs have additive antiviral effects in vitro.

When a stepwise, long-term procedure was used, the authors were able to select variants resistant to each pair-wise combination, which carried amino acid substitutions conferring high-level resistance to both tested NNIs on the same strain. Triple resistant replicons were also generated, starting from a replicon that was already resistant to two NNIs and was subsequently exposed to the third one. The triple-resistant replicons harbored substitutions conferring resistance to the three drugs tested. It was also cross-resistant with the fourth class of NNIs, not used in the experiments [15]. Whether such triple resistant variants naturally preexist in infected patients remains unknown. Short-term replication models, such as replicons in Huh7 cell lines, could underestimate the extent of HCV variability encountered in patients who have been infected for decades. Indeed, it has been recently suggested, based on mathematical modeling, that in HCV-infected patients, all possible single and double mutants are generated multiple times each day, all viable single and double mutants that confer drug resistance preexist and may compete with the wild-type virus during therapy, and triple mutants can be selected by sequential mutations when single or double mutants replicate [16]. It is therefore highly likely that HCV variants that are resistant to three drugs preexist at baseline in a substantial proportion of patients, or that they can be generated through replication of double-resistant viruses.

Resistance to DAAs is often feared as the main cause of treatment failure with new HCV therapies. This is not the case with the triple combination of a DAA with pegylated IFN-α and ribavirin, during which treatment failure results of an inadequate response to IFN-α that favors the outgrowth of resistant viral variants selected by the DAA [1], [2], [3], [4], [5]. In contrast, control of resistance will be key during the era of all-oral, IFN-free regimens. Indeed, antiviral potency and a high barrier to resistance are required to ensure that inhibition of HCV production is sustained for a sufficient amount of time in order for every infected cell to clear the remaining viruses. If any viral population is not controlled by the drug combination, it replicates, is produced, infects new cells and leads to treatment failure. Intuitively, the best way to prevent such failure is to include at least one drug with a high barrier to resistance, such as a nucleoside/nucleotide analogue or a cyclophylin inhibitor, in any combination of HCV DAAs. However, these drugs have not yet reached the market and the results of long-term combination studies including one or two nucleoside/nucleotide analogue(s) are awaited.

What will be the role of NNIs in this context? Recent results with the two most advanced in development NNIs, tegobuvir and filibuvir, have been disappointing: no difference was observed between the triple combination of different doses of the NNI with pegylated IFN-α and ribavirin vs. pegylated IFN-α and ribavirin alone [17], [18]. Nevertheless, this failure appears to be principally related to the lack of antiviral potency of these compounds rather than to their barrier to resistance, which is not fundamentally different from that of telaprevir or boceprevir. It is therefore possible that more potent NNIs could prove to be useful in combination with pegylated IFN-α and ribavirin.

What the study by Delang et al. teaches us is that combinations of NNIs are unlikely to be helpful, even if the molecules belong to different classes, have different target sites and no cross-resistance. In vitro results in the replicon system have proven to be accurate in predicting resistance in vivo; thus, single, double, and triple-resistant variants are likely to be selected early by NNI combinations in infected patients. How will we use NNIs in IFN-free regimens in the future? Ideally, in combinations including at least one drug with a high barrier to resistance (e.g. a nucleoside/nucleotide analogue, a cyclophylin inhibitor, or a second-generation NS3/4A protease inhibitor with an improved resistance profile compared to first-generation ones). Nevertheless, if these drugs are potent enough, they should, at least theoretically, be able to block virus production without resistance emergence for long enough for the virus to be cleared by host cells without the need for other drugs. If this is the case, drugs with a narrow genotype coverage and a low barrier to resistance, such as NNIs, may not be absolutely required in the HCV drug armamentarium. This question will be solved by ongoing and future clinical trials.

Overall, trial designers and clinicians should remember that, if resistance is not a major threat in patients treated with the triple combination of a DAA with pegylated IFN-α and ribavirin, since the final outcome depends mainly on the IFN response, its prevention will be key in the design of all-oral treatment strategies based on DAA combinations. Only combinations with a high enough barrier to resistance should be envisaged, as they are the only ones that can ensure sustained inhibition of viral production for the time needed for host cells to get rid of the virus. As in any war, the final victory depends on the allies you chose. Our mission is now to find the best alliance to keep the invaders out. This is the price to pay for a peaceful world, i.e. a world without hepatitis C.

Conflict of interest

The author has received research grants from Gilead and Roche. He has served as an advisor for Abbott, Anadys, Biotica, Boehringer-Ingelheim, Bristol-Myers Squibb, DebioPharm, Gilead, Glaxo-SmithKline, Idenix, Janssen-Cilag, Madaus-Rottapharm, Schering-Plough/Merck, Novartis, Pfizer, Pharmasset, Roche, Vertex and Virco.


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  2. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207–1217
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  8. Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010;465:96–100
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  12. Zeuzem S, Buggisch P, Agarwal K, Manns MP, Marcellin P, Foster GR, et al. Dual, triple, and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or PegIFN/RBV for up to 28 days in treatment-naïve, genotype 1 HCV subjects. Hepatology. 2010;52:400A
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  18. Lawitz E, Jacobson I, Godofsky E, Foster GR, Flisiak R, Bennett M, et al. A phase 2B trial comparing 24 to 48 weeks treatment with tegobuvir (GS-9190)/PEG/RBV to 48 weeks treatment with PEG/RBV for chronic genotype 1 HCV infection. J Hepatol. 2011;54:S181

PII: S0168-8278(11)00674-X


© 2011 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.


HCV Test & Treat

Written by Jules Levin of NATAP

'HCV Test & Treat' is different than HIV test & treat which clearly has limitations but HCV test & treat does not suffer from the limitations that HIV test & treat does. To begin with HCV therapy is short-term, it will be as little as 24 weeks or in the future perhaps 16 weeks for the hard to treat genotype 1 patients...cure rates will be 100% in the future...and HCV is curable as alluded to above so there will not be lifetime therapy as in HIV......the cost of HCV therapy is actually much less than the cost of HIV therapy which is lifetime....HAART costs $15,000 per year for a patient but 10 years of HAART costs $150,000 and it is still considered highly cost effective. With the aging of the HCV+ patient population rates of liver cancer (HCC) and decompensated or very advanced liver disease is causing increased rates of expensive sickness & hospitalizations & increasing death rates, all of which will continue on the uptrend unless we implement HCV test & care(or treat) in the future. ItÕs widely recognized that 80% of HCV-infected in the USA are untested & undiagnosed, and itÕs estimated that at least 5 million people in the USA have HCV but the prevalence I estimate might be higher. The goal of large-scale HCV testing is firstly to get patients diagnosed and into care, whether or not they should be treated is another question because 20 new drugs are in development now, the average cure or SVR (Sustained Viral Response) rates are 75-80% in the clinical studies for the 2 new HCV protease inhibitors approved this year boceprevir & telaprevir in combination with pegintereron+ribavirin. It is hoped and from proof-of-concept studies that we will be able to eventually eliminate peginterferon and ribavirin eventually from therapy, which we expect will consist of several, 2 or 3 or 4, orally administered HCV antiviral drugs, like in HIV, so this will overcome one of the key barriers to taking therapy for patients, having to take peginterferon. Before we will be able to eliminate both pegING & ribavirin, studies are now looking at therapy with ribavirin but without peginterferon, so we hope & expect that these new regimens without pegINF but including ribavirin will be successful. But ultimately not too far in the future, within 5 years I think, it is expected that for many if not for all patients, particularly genotype 1, but also for other genotypes, 100% cure or SVR rates will be the achievable for all treatable patients. So if we can start now HCV testing projects and put patients into care they can be treated at the appropriate time as deemed by their care provider, whether that is now, perhaps because they have advanced disease and shouldn't wait for more effective therapy, or at some later time when therapy is more effective. Jules Levin

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OraSure Makes Final FDA Submission for Approval of Over-the-Counter Rapid HIV Test

Jan. 3, 2012, 6:00 a.m. EST

BETHLEHEM, Pa., Jan 3, 2012 (GlobeNewswire via COMTEX) -- OraSure Technologies, Inc. /quotes/zigman/84183/quotes/nls/osur OSUR -0.02% , a market leader in rapid point-of-care infectious disease diagnostics and biological sample collection, stabilization and preparation products, announced today that it has submitted the final of three modules in its application to the U. S. Food and Drug Administration (FDA) for the approval of the Company's OraQuick(R) Rapid HIV-1/2 test for sale in the U.S. consumer or over-the-counter (OTC) market.

The third module contains the findings from the final phase of clinical testing, which involved the use of the OraQuick(R) Rapid HIV-1/2 test with subjects in an unobserved setting. Approximately 5,800 subjects were enrolled and tested in this phase across 20 sites nationwide, resulting in the identification of more than 100 previously undiagnosed individuals with HIV.

According to the Centers for Disease Control and Prevention (CDC), there are approximately 1.2 million people in the U.S. that have HIV and approximately 240,000 of them are unaware of their status, despite current HIV testing options. Not only is their own health at risk, they are also unknowingly responsible for up to 70 percent of the approximately 50,000 new HIV infections occurring each year in the U.S. The CDC recommends routine HIV screening for all people ages 13 to 64, with more frequent testing for people at higher risk.

"The latest CDC figures demonstrate the status quo for testing is inadequate and additional options to capture undiagnosed individuals infected with HIV must be brought to the market. We've been working closely with the community and FDA on the development of a powerful new HIV testing option for individuals. This submission was a major undertaking for OraSure and the culmination of years of hard work and financial commitment. An easy-to-use, private, and accurate in-home HIV test will enable more people to learn their presumptive HIV status so that they can receive necessary care and support," said Douglas A. Michels, President and Chief Executive Officer of OraSure Technologies. "The completion of our submission to the FDA is a critical milestone in our efforts to secure approval and expand the tools available to combat the spread of HIV."

The final phase of clinical testing consisted of a multi-visit, blinded, unobserved user study in which individuals conducted unsupervised oral fluid self-testing using an investigational OTC version of the OraQuick ADVANCE(R) Rapid HIV-1/2 test. Once all subject tests were complete and study results unblinded, the performance of the OraQuick HIV test in the unobserved OTC setting was compared with FDA-approved laboratory HIV test results.

The Company intends to provide the necessary resources to ensure optimal support for individuals who, pending approval, would then be able to use the OraQuick HIV test in an OTC setting. In addition to a highly informative website, OraSure will offer "live" support and comprehensive referral services 24 hours a day, seven days a week, every day of the year, through a highly trained specialized toll-free call center, which was functional as part of the clinical trials. Detailed, easy-to-understand information on HIV and HIV testing was part of the clinical studies as well and will also be included in every test kit.

The first module for FDA review was submitted to the agency in the third quarter of 2011 and contained data from all studies performed prior to the final phase of testing. The second module was submitted to the FDA several weeks ago and included information about manufacturing and the customer care call center.

In the professional market, OraSure manufactures and sells the OraQuick ADVANCE(R) Rapid HIV 1/2 Test which is the first and only FDA-approved and CLIA-waived rapid point-of-care test that can detect antibodies to both HIV-1 and HIV-2 in 20 minutes, using oral fluid, finger-stick or venipuncture whole blood or plasma specimens. As the market leading rapid HIV test with over 20 million tests sold, OraQuick ADVANCE(R) is used extensively throughout the country in public health settings, hospitals, community-based organizations, and physician offices where HIV testing is conducted.

About OraSure Technologies

OraSure Technologies is a leader in the development, manufacture and distribution of rapid point-of-care infectious disease tests, collection devices and other technologies designed to detect or diagnose critical medical conditions. Its innovative products include rapid tests for the detection of antibodies to HIV and HCV at the point of care and testing solutions for detecting various drugs of abuse. In addition, through its wholly-owned subsidiary, DNA Genotek Inc., the Company also is a leading provider of oral fluid sample collection, stabilization and preparation products for molecular diagnostic applications. OraSure's portfolio of products is sold globally to various clinical laboratories, hospitals, clinics, community-based organizations and other public health organizations, research and academic institutions, distributors, government agencies, physicians' offices, and commercial and industrial entities. The Company's products enable healthcare providers to deliver critical information to patients, empowering them to make decisions to improve and protect their health. For more information on OraSure Technologies, please visit www.orasure.com .

The OraSure Technologies, Inc. logo is available at http://www.globenewswire.com/newsroom/prs/?pkgid=6440

Important Information

This press release contains certain forward-looking statements, including with respect to products, clinical studies and regulatory submissions. Forward-looking statements are not guarantees of future performance or results. Known and unknown factors that could cause actual performance or results to be materially different from those expressed or implied in these statements include, but are not limited to: ability to market and sell products, whether through an internal, direct sales force or third parties; ability to manufacture products in accordance with applicable specifications, performance standards and quality requirements; ability to obtain, and timing and cost of obtaining, necessary regulatory approvals for new products or new indications or applications for existing products; ability to comply with applicable regulatory requirements; changes in relationships, including disputes or disagreements, with strategic partners or other parties and reliance on strategic partners for the performance of critical activities under collaborative arrangements; failure of distributors or other customers to meet purchase forecasts or minimum purchase requirements for the Company's products; impact of replacing distributors and success of direct sales efforts; inventory levels at distributors and other customers; ability to identify, complete, integrate, and realize the full benefits of potential future acquisitions, including the Company's acquisition of DNA Genotek; impact of competitors, competing products and technology changes; impact of the economic downturn, high unemployment and poor credit conditions; reduction or deferral of public funding available to customers; competition from new or better technology or lower cost products; ability to develop, commercialize and market new products; market acceptance of oral fluid testing or other products; changes in market acceptance of products based on product performance, extended shelf life or other factors; ability to fund research and development and other products and operations; ability to obtain and maintain new or existing product distribution channels; reliance on sole supply sources for critical product components; availability of related products produced by third parties or products required for use of our products; history of losses and ability to achieve sustained profitability; ability to utilize net operating loss carry forwards or other deferred tax assets; volatility of our stock price; uncertainty relating to patent protection and potential patent infringement claims; uncertainty and costs of litigation relating to patents and other intellectual property; availability of licenses to patents or other technology; ability to enter into international manufacturing agreements; obstacles to international marketing and manufacturing of products; ability to sell products internationally, including the impact of changes in international funding sources and testing algorithms; loss or impairment of sources of capital; ability to meet financial covenants in agreements with financial institutions; ability to refinance outstanding debt under expiring credit facilities on acceptable terms or at all; ability to retain qualified personnel; exposure to product liability and other types of litigation; changes in international, federal or state laws and regulations; customer consolidations and inventory practices; equipment failures and ability to obtain needed raw materials and components; the impact of terrorist attacks and civil unrest; and general political, business and economic conditions. These and other factors are discussed more fully in the Company's Securities and Exchange Commission filings, including its registration statements, Annual Report on Form 10-K for the year ended December 31, 2010, Quarterly Reports on Form 10-Q, and other filings with the SEC. Although forward-looking statements help to provide information about future prospects, readers should keep in mind that forward-looking statements may not be reliable. The forward-looking statements are made as of the date of this press release and OraSure Technologies undertakes no duty to update these statements.

This news release was distributed by GlobeNewswire, www.globenewswire.com 

SOURCE: OraSure Technologies, Inc.