Injection behaviors among injection drug users in treatment: The role of hepatitis C awareness - Does HCV+ Awareness Among IDUs Reduce Needle Sharing

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Does HCV+ Awareness Among IDUs Reduce Needle Sharing? This study found NO - ."In adjusted analysis (Table 2), recent syringe/needle sharing was more likely among those who reported they were HCV-positive compared with those who were HCV negative/unaware (aOR 2.37 [95% CI 1.15, 4.88]), and among IDUs obtaining needles from the street, using any opioids, marijuana, or injected crack cocaine; sharing was less likely among males and participants with some college education......More HCV-positive IDUs reported recent syringe/needle sharing compared with those with HCV negative/unknown status (44.6% vs. 38.5%, p = .131), though this was not statistically significant"

from Jules: with the advent & revolution of new HCV oral & interferon-free therapy it will be important to provide education to at-risk patients about the risks for-re-infection with HCV. It is important to provide treatment to IDUs as persons but also for society. All too often now treatment for IDUs is withheld for a number of reasons including because IDUs are at risk for continuing risky behavior, sharing unclean needles & getting re-infected. Instead treatment for IDUs should be viewed as important for the patient, for prevention, ad for society & treatment should be viewed as an opportunity to provide education about preventing re-infection, why & how the patient should not be re-infected. Often this means addressing the patient's risky behavior, which could be sharing used/unclean syringes for the IDU or continued risky sexual & drug behavior for MSM. In recent studies in NYC & in London re-infection was cited among MSM due to continued unsafe drug & sex behavior, in fact re-infection was reported to occur 2-3 times after successful treatment for some individuals. In recent studies re-infection among IDUs has been found often. With treatment & cure of HCV comes a responsibility that these at-risk individuals, IDUs or a history of IDU, are educated not to be re-infected. Resources are scarce and should not be wasted particularly in the developing & undeveloped world but also in Europe, the USA & the Western world, its possible that retreatment may be denied by government or payers.

High incidence of hepatitis C virus reinfection within a cohort of injecting drug users - (10/13/13)

HCV Reinfection - (10/11/13)

HCV superinfection and reinfection - Review - (10/10/13)

HCV reinfection incidence and treatment outcome among HIV-positive MSM in London - (06/17/13)

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Injection behaviors among injection drug users in treatment: The role of hepatitis C awareness

Highlights

->38.5% of 244 IDUs seeking treatment reported sharing needles/syringes. ->Only 46.9% of IDUs always used a sterile needle/syringe. ->37.7% of IDUs reported being HCV positive. ->HCV awareness was associated with increased risky injection behaviors. ->New HCV prevention interventions are needed for IDUs seeking treatment.

"one's belief about one's HCV status is conceptually more closely related to injection behaviors than biologically confirmed HCV status......IDUs may adopt more of a fatalistic attitude toward risky injection practices. Indeed, a recent synthesis of qualitative studies of HCV risk among IDUs identified risk ubiquity as a common theme, supporting a perception of HCV as "a risk accepted rather than avoided.....The observed multivariable association between knowledge of HCV status and syringe/needle sharing may reflect overall greater drug use severity among those who become HCV-infected rather than a causal pathway toward increased risky behaviors. Regardless, the association highlights the role of HCV awareness as a marker for IDUs in particular need of harm reduction interventions.....The observed association between HCV-awareness and increased needle/syringe sharing may reflect a complex cluster of characteristics among HCV-aware IDUs in this cross-sectional study. Our data support that HCV awareness is likely a marker for IDUs with greater addiction severity (e.g., increased heroin injection and methadone maintenance among HCV-aware), addiction duration (older age among HCV-aware), and increased opportunities for HCV testing (e.g., increased needle exchange program use among HCV-aware, many of which offer HCV testing)."

"Risky injection practices persist among IDUs, with rates in the current study consistent with those of other recent studies (Booth et al., 2011 and Centers for Disease Control and Prevention, 2009) and may partially explain persistently high HCV incidence among IDUs.......In adjusted analysis (Table 2), recent syringe/needle sharing was more likely among those who reported they were HCV-positive compared with those who were HCV negative/unaware (aOR 2.37 [95% CI 1.15, 4.88]), and among IDUs obtaining needles from the street, using any opioids, marijuana, or injected crack cocaine; sharing was less likely among males and participants with some college education......More HCV-positive IDUs reported recent syringe/needle sharing compared with those with HCV negative/unknown status (44.6% vs. 38.5%, p = .131), though this was not statistically significant......The majority of IDUs in the present study obtained needles from safe sources, including pharmacies and syringe exchange programs, as corroborated in surveys of IDUs in other U.S. cities with policies that increase availability of sterile needles and syringes......Despite this, fewer than half of IDUs reported always using a clean needle or consistently cleaning needles, indicating that needle re-use and lack of needle cleaning are common. Even among the minority of IDUs reporting consistent needle cleaning, sterilization techniques other than use of bleach were frequently employed, suggesting that renewed efforts are needed to promote harm reduction techniques among IDUs.......Participants who reported they were HCV positive differed in several important behaviors compared with their counterparts. HCV positive IDUs more frequently exhibited harm reduction behaviors such as obtaining needles from a syringe exchange program, cleaning needles with bleach, and avoiding drinking alcohol to intoxication, suggesting that awareness of HCV status may confer increased adoption of some protective behaviors. HCV positive IDUs, however, were also more likely to inject heroin and, in multivariable analysis, to share needles."

"This finding contrasts with a sero-survey of street-recruited IDUs in Denver from 1998 to 1999, where those with a previous HCV positive test reported less receptive syringe/needle sharing, sharing of drug paraphernalia, and safer injecting practices compared with those with unknown status who tested HCV-positive during the study (Kwiatkowski et al., 2002). It is possible that in populations where higher proportions of IDUs are aware they are HCV-positive, IDUs may adopt more of a fatalistic attitude toward risky injection practices. Indeed, a recent synthesis of qualitative studies of HCV risk among IDUs identified risk ubiquity as a common theme, supporting a perception of HCV as "a risk accepted rather than avoided" (Rhodes, Singer, Bourgois, Friedman, & Strathdee, 2005). This is consistent with findings from a multicenter study of Swedish IDUs, in which 74% of those HCV-aware shared needles compared with 68% of those with unknown status (Norden et al., 2009)."

Author's CONCLUSIONS: This study highlights the need for broadly implemented HCV prevention interventions for all IDUs seeking addiction treatment, and suggests such interventions might particularly decrease transmission behaviors by those aware of their HCV infection and prevent HCV infection in those HCV-negative/unaware. Research which prospectively studies the effect of HCV testing and notification on risk behavior could help further clarify the association between HCV awareness and risk behaviors. Interventions that could improve services for IDUs include those that explicitly and repeatedly educate IDUs about safer injection practices and the treatability of HCV, and those that integrate HCV testing and treatment with addiction treatment services. As HCV screening and treatment options advance, community based treatment programs have a greater opportunity to play a central role in reducing HCV transmission and engaging HCV-infected IDUs in treatment.

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Injection behaviors among injection drug users in treatment: The role of hepatitis C awareness

Addictive Behaviors April 2012

P. Todd Korthuis a,, Daniel J. Feaster b, Zoilyn L. Gomez b, Moupali Das c,d, Susan Tross e, Katharina Wiest f, Antoine Douaihy g, Raul N. Mandler h, James L. Sorensen c, Grant Colfax d, Dennis McCarty a, Stephanie E. Cohen d, Patricia E. Penn i, Diane Lape a, Lisa R. Metsch b
a Department of Medicine and Department of Public Health and Preventive Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
b Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, 1425 Northwest 10th Ave, 3rd floor, Miami, FL 33136, USA c University of California, San Francisco, 1001 Potero Ave., San Francisco, CA 94110, USA
d San Francisco Department of Public Health, 356 7th St., San Francisco, CA 94103, USA
e HIV Center For Clinical and Behavioral Studies, NYS Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA
f CODA, 1027 East Burnside St., Portland, OR 97214, USA
g University of Pittsburgh School of Medicine, 3811 O'Hara St # 1059, Pittsburgh, PA 15213, USA
h National Institute on Drug Abuse, National Institutes of Health, 6001 Executive Blvd., Bethesda, MD 20892, USA
i La Frontera Arizona, 504 W. 29th St., Tucson, AZ 85713, USA

Abstract

Background

Injection drug use (IDU) is a primary vector for blood-borne infections. Awareness of Hepatitis C virus (HCV) infection status may affect risky injection behaviors. This study determines the prevalence of risky injection practices and examines associations between awareness of positive HCV status and risky injection behaviors.

Methods

We surveyed individuals seeking treatment for substance use at 12 community treatment programs as part of a national HIV screening trial conducted within the National Drug Abuse Treatment Clinical Trials Network. Participants reported socio-demographic characteristics, substance use, risk behaviors, and HCV status. We used multivariable logistic regression to test associations between participant characteristics and syringe/needle sharing.

Results

The 1281 participants included 244 (19.0%) individuals who reported injecting drugs in the past 6 months and 37.7% of IDUs reported being HCV positive. During the six months preceding baseline assessment, the majority of IDUs reported obtaining sterile syringes from pharmacies (51.6%) or syringe exchange programs (25.0%), but fewer than half of IDUs always used a sterile syringe (46.9%). More than one-third (38.5%) shared syringe/needles with another injector in the past 6 months. Awareness of positive HCV vs. negative/unknown status was associated with increased recent syringe/needle sharing (aOR 2.37, 95% CI 1.15, 4.88) in multivariable analysis.

Conclusions

Risky injection behaviors remain prevalent and awareness of HCV infection was associated with increased risky injection behaviors. New approaches are needed to broadly implement HCV prevention interventions for IDUs seeking addiction treatment.

1. Introduction

Injection drug use (IDU) is the primary driver for Hepatitis C virus (HCV) transmission, accounting for the majority of chronic HCV infections in the U.S. (Alter, 1999 and Armstrong et al., 2006). Across multiple U.S. studies, 35-65% of current IDUs report risky injection behaviors such as syringe/needle sharing (Bailey et al., 2007, Booth et al., 1998, Centers for Disease Control and Prevention, 2009 and Golub et al., 2007).

Knowledge of harboring a transmissible infection such as HCV may influence risky behaviors. Prior studies of the effects of HCV-infection awareness on risky behaviors demonstrate mixed results. In a serosurvey of out-of-treatment IDUs, those who reported awareness of HCV-infection engaged in fewer risky behaviors compared with those who were unaware (Kwiatkowski, Fortuin Corsi, & Booth, 2002). HCV-aware IDUs may also "sero-sort," or preferentially engage in risky injection behaviors with others they know to be similarly HCV-infected (Burt, Thiede, & Hagan, 2009). Other studies, however, suggest that HCV awareness is insufficient to change injection risk behaviors (Norden et al., 2009). Little is known about the influence of HCV awareness on IDUs engaged in substance use treatment-information that might improve HCV prevention services in addiction treatment settings.

The purpose of this analysis was to 1) assess the prevalence and correlates of drug use practices among patients presenting for addiction treatment and 2) compare risky behaviors in those reporting HCV-infection with those who reported negative or unknown HCV status.

2. Methods

2.1. Design and setting

The primary study was a National Drug Abuse Treatment Clinical Trials Network (CTN) trial comparing the effectiveness of strategies to increase HIV testing (Metsch et al., in press). Between January and May 2009, the trial randomized 1281 individuals receiving addiction treatment at 12 geographically diverse, community-based addiction treatment programs. After providing informed consent, participants completed an audio computer assisted self interview recording substance use behaviors.

2.2. Participants

Participants receiving addiction treatment were eligible for enrollment if they were 1) ³ 18 years old, 2) reported unknown or negative HIV status, and 3) had not been tested and received results for HIV within the last 12 months. The current analysis was restricted to the 244 participants who reported IDU in the six months preceding the study baseline assessment.

2.3. Measures

Participants were asked about injection risk behaviors over the prior six months using items from Project Inspire (Purcell et al., 2004) and the NIDA Risk Behavior Assessment survey (Needle et al., 1995) including source of syringes, needle cleaning practices, how they cleaned their needles, and recent syringe/needle sharing (the main dependent variable). Participants reported injection and non-injection drug use and drinking alcohol to intoxication in the past 6 months (Colfax et al., 2004).

The independent variable was self-reported HCV infection awareness. Patients were asked, "Have you ever been diagnosed with hepatitis C (yes, no, don't know)?" Because there was no difference in syringe/needle sharing between participants who reported they were HCV-negative and those who did not know their HCV status, we dichotomized this variable as HCV-positive vs.

HCV-negative/unknown. Covariates included age, gender, race/ethnicity, employment, education, court-mandated treatment, opioid replacement treatment, and whether or not the patient had been jailed in the last 6 months.

2.4. Analysis

Descriptive statistics characterized participant socio-demographics, and substance use behaviors. We assessed bivariate and multivariable associations between participant characteristics and any syringe/needle sharing using logistic regression. Variables were included in the multivariable logistic regression model if associated with syringe/needle sharing in univariate analyses (p < .20), or on the basis of a priori hypotheses. Potential interactions were assessed.

3. Results

3.1. Participant characteristics

Of 244 recent IDUs, 60.7% were men, 66.0% white, 14.3% Hispanic, and 10.2% Black race/ethnicity, with a mean age of 39.3 (SD = 11.0) years. Twenty percent were employed, 36.2% had attained at least some college education, 30.3% had been recently incarcerated, 20.1% were receiving court-mandated treatment and 46.7% opioid replacement therapy. Ninety-two IDU (37.7%) reported being positive for HCV, 55 (22.5%) HCV-negative, and 97 (39.8%) unknown HCV status. Compared with those who were HCV negative/unaware, HCV positive IDUs were older (45.3 vs. 35.6 years, p < .001), more likely to be women (52.2% vs. 31.6%, p = .001) or enrolled in opioid replacement programs (68.5% vs. 33.6%, p < .001) and less likely to be recently incarcerated (21.7% vs. 35.5%, p = .023).

The most commonly used substances were injected opioids (71.17%), drinking alcohol to intoxication (70.9%), non-injection opioids (66.4%), marijuana (48.8%), crack cocaine (45.1%), and cocaine (30.7%). The majority of IDUs (81.1%) injected more than one substance at a time. HCV positive IDUs were less likely to drink alcohol to intoxication (57.6% vs. 78.9%, p < .001) but more likely to inject heroin (68.5% vs. 55.3%, p = .041) compared with HCV negative/unaware.

3.2. Injection risk behaviors

More than one third (38.5%) of IDUs reported syringe/needles sharing in the past 6 months (Table 1). IDUs obtained needles mostly from pharmacies, syringe exchange programs, and diabetic supplies. Less than half always used a clean needle. Among IDUs who cleaned their needles, cleaning with bleach was the most common method, but many used more ineffective sterilization methods including soap and water. More HCV-positive IDUs reported recent syringe/needle sharing compared with those with HCV negative/unknown status (44.6% vs. 38.5%, p = .131), though this was not statistically significant. There was no difference in recent syringe/needle sharing between those who reported being HCV negative vs. unknown status (36.4% vs. 34.0%, p = .771). HCV positive IDUs more frequently obtained needles from a syringe exchange program and used bleach if they cleaned needles.

In adjusted analysis (Table 2), recent syringe/needle sharing was more likely among those who reported they were HCV-positive compared with those who were HCV negative/unaware (aOR 2.37 [95% CI 1.15, 4.88]), and among IDUs obtaining needles from the street, using any opioids, marijuana, or injected crack cocaine; sharing was less likely among males and participants with some college education.

4. Discussion

Risky injection practices persist among IDUs, with rates in the current study consistent with those of other recent studies (Booth et al., 2011 and Centers for Disease Control and Prevention, 2009) and may partially explain persistently high HCV incidence among IDUs (Mehta et al., 2011). In a survey of IDUs in 23 U.S. cities from 2005 to 2006, 31.8% of IDUs reported sharing needles (Centers for Disease Control & Prevention, 2009). Among IDUs enrolling in a behavioral intervention trial (2-session HIV/HCV counseling vs. therapeutic alliance vs. treatment as usual) at residential detoxification centers from 2004 to 2006, 61% reported sharing needles, works, or drug solution (Booth et al., 2011). More widespread adoption of interventions demonstrated to reduce risky injection practices, and development of new, more effective interventions, are urgently needed for patients enrolling in community-based treatment programs.

The majority of IDUs in the present study obtained needles from safe sources, including pharmacies and syringe exchange programs, as corroborated in surveys of IDUs in other U.S. cities with policies that increase availability of sterile needles and syringes (Golub et al., 2005 and Khoshnood et al., 2000) - policies that decrease HIV transmission and likely decrease HCV transmission, as well (Des Jarlais et al., 1996 and Des Jarlais et al., 2000). Despite this, fewer than half of IDUs reported always using a clean needle or consistently cleaning needles, indicating that needle re-use and lack of needle cleaning are common. Even among the minority of IDUs reporting consistent needle cleaning, sterilization techniques other than use of bleach were frequently employed, suggesting that renewed efforts are needed to promote harm reduction techniques among IDUs. Interventions that promote needle cleaning such as peer-based (Hawkins et al., 1999 and Rietmeijer et al., 1996), pharmacy-based (Romanelli, Smith, & Pomeroy, 2000), and provider-based (Carlson, Wang, Siegal, & Falck, 1998) interventions, continue to be relevant for IDUs engaged in community-based treatment. At the same time, renewed efforts to increase availability of clean syringe/needles are urgently needed to decrease HCV transmission.

Participants who reported they were HCV positive differed in several important behaviors compared with their counterparts. HCV positive IDUs more frequently exhibited harm reduction behaviors such as obtaining needles from a syringe exchange program, cleaning needles with bleach, and avoiding drinking alcohol to intoxication, suggesting that awareness of HCV status may confer increased adoption of some protective behaviors. HCV positive IDUs, however, were also more likely to inject heroin and, in multivariable analysis, to share needles. The observed association between HCV-awareness and increased needle/syringe sharing may reflect a complex cluster of characteristics among HCV-aware IDUs in this cross-sectional study. Our data support that HCV awareness is likely a marker for IDUs with greater addiction severity (e.g., increased heroin injection and methadone maintenance among HCV-aware), addiction duration (older age among HCV-aware), and increased opportunities for HCV testing (e.g., increased needle exchange program use among HCV-aware, many of which offer HCV testing).

This finding contrasts with a sero-survey of street-recruited IDUs in Denver from 1998 to 1999, where those with a previous HCV positive test reported less receptive syringe/needle sharing, sharing of drug paraphernalia, and safer injecting practices compared with those with unknown status who tested HCV-positive during the study (Kwiatkowski et al., 2002). It is possible that in populations where higher proportions of IDUs are aware they are HCV-positive, IDUs may adopt more of a fatalistic attitude toward risky injection practices. Indeed, a recent synthesis of qualitative studies of HCV risk among IDUs identified risk ubiquity as a common theme, supporting a perception of HCV as "a risk accepted rather than avoided" (Rhodes, Singer, Bourgois, Friedman, & Strathdee, 2005). This is consistent with findings from a multicenter study of Swedish IDUs, in which 74% of those HCV-aware shared needles compared with 68% of those with unknown status (Norden et al., 2009).

The current study confirms the importance of certain demographic and drug use characteristics previously associated with syringe/needle sharing including younger age, female gender, lower educational attainment, and use of opiates, and crack cocaine. While greater addiction severity is associated with riskier injection behaviors, the current study is among the first to identify an association between marijuana use and risky injection behaviors. Marijuana use in IDUs may be a marker of risk-taking personality or chronically decreased motivation to protect oneself, as hypothesized to explain similar findings in a study of Russian IDUs (Walley et al., 2008). Further research is required to assess the nature of this association.

This study has limitations. First, our study population was recruited from individuals seeking or actively engaged in treatment in community-based treatment programs. Findings may not be generalizable to IDUs in other settings. Second, HCV status was assessed by self-report and likely underestimates the actual prevalence of HCV. However, one's belief about one's HCV status is conceptually more closely related to injection behaviors than biologically confirmed HCV status. Third, we were unable to assess sero-sorting in the current study, so increased sharing among HCV may have been with other known HCV-positive IDU, as was observed in one prior study (Burt et al., 2009). Finally, the current study's cross-sectional design limits our ability to infer causality. The observed multivariable association between knowledge of HCV status and syringe/needle sharing may reflect overall greater drug use severity among those who become HCV-infected rather than a causal pathway toward increased risky behaviors. Regardless, the association highlights the role of HCV awareness as a marker for IDUs in particular need of harm reduction interventions.

5. Conclusions

This study highlights the need for broadly implemented HCV prevention interventions for all IDUs seeking addiction treatment, and suggests such interventions might particularly decrease transmission behaviors by those aware of their HCV infection and prevent HCV infection in those HCV-negative/unaware. Research which prospectively studies the effect of HCV testing and notification on risk behavior could help further clarify the association between HCV awareness and risk behaviors. Interventions that could improve services for IDUs include those that explicitly and repeatedly educate IDUs about safer injection practices and the treatability of HCV, and those that integrate HCV testing and treatment with addiction treatment services. As HCV screening and treatment options advance, community based treatment programs have a greater opportunity to play a central role in reducing HCV transmission and engaging HCV-infected IDUs in treatment.

Role of funding source

This work was supported by the National Institute on Drug Abuse which supported the design, distribution, collection and analysis of the clinical trial. The final version of the manuscript was reviewed and approved by the NIDA Clinical Trials Network publications committee.

Source

Patient Advocate Foundation Announces Co-Pay Relief (CPR) Support for Patients Living with Hepatitis C

The launch of the CPR Silo for Hepatitis C Patients Will Provide Financial Assistance to Patients in Need

HAMPTON, Va., Feb. 5, 2014 /PRNewswire-USNewswire/ -- Patient Advocate Foundation (PAF) announced today the expansion of its Co-Pay Relief (CPR) program with the opening of the Hepatitis C disease silo. Supported through a generous donation of5 million dollars, this CPR program silo providers financial support for pharmaceutical co-payments for insured patients who are facing financial distress and are unable to afford their costs associated with treatment for the virus. "Management of Hepatitis C is extremely challenging for patients as most need ongoing medication to reduce their chance of liver damage or liver cancer.  It is in these cases that a patient's survival and overall health can be jeopardized if he or she is unable to access pharmaceutical treatment and therapies required to control the virus," said Alan Balch, PhD,  CEO of PAF. "We are grateful for the significant support we have received for the Hepatitis C silo which allows us to expand our Co-Pay Relief Program in such a meaningful way."  The donation allows PAF to provide financial support to Hepatitis C patients ensuring their access to the treatments that can restore balance to their health and markedly improve their quality of life.  Qualified patients whose applications are approved, are eligible for up to $3,000 per year in copayment assistance through the program.

PAF is a pioneer in the field of copayment support programs, providing more than $190 million in financial assistance to more than 95,000 patients who would have been otherwise unable to afford their pharmaceutical co-payments since 2004. The program provides this support to insured patients who financially and medically qualify including those covered by government sponsored insurance programs such as Medicare, Medicaid or Tricare.  

For more information about PAF's Co-Pay Relief program and the options for assistance for Hepatitis C patients, visit http://www.copays.org/diseases/hepatitis-c or call 866-512-3861.

About the Patient Advocate Foundation (PAF) Co-Pay Relief Program (CPR)

The Co-Pay Relief Program, a division of Patient Advocate Foundation, provides direct financial support for pharmaceutical co-payments to insured patients who financially and medically qualify.

The program offers innovative technology tools for patients, providers and pharmacy representatives including 24 hour web based application portals, electronic signature, document upload and bar code fax routing capabilities, increasing the speed with which an approval can be granted and expenditure can be paid.  Keeping with Patient Advocate Foundation's emphasis on patient-centric service, the program also offers individualized assistance to all patients through trained, professional staff who personally guide them through the enrollment process. 

For more information or to contact Patient Advocate Foundation's Co-Pay Relief program visit www.copays.org or 1-866-512-3861

SOURCE Patient Advocate Foundation

Source

Gilead Sciences' CEO Discusses Q4 2013 Results - Earnings Call Transcript

These are two very interesting excerpts from todays Earnings Conference Call. There was a lot of talk about Sovaldi as well other HCV drugs in trials. I have pulled 2 very interestiong quoted pieces from the call, the first concerning European pricing and the second concerning new Research and Development (R&D). I would encourage everyone to go to read the entire transcript which is available at Seeking Alpha. It is very informative as well as enlightening.

“I would like to talk a little bit about the rest of the pricing for Europe. We have now listed our price in the U.K. The price in the U.K. is almost UK35,000, so that’s about $57,000. And I think, as a benchmark for the majority of Europe, that would be a good price point for you going forward. So I’ll say that again. About UK35,000, this is the 12-week course of treatment, or about $57,000.

And I also mentioned the German pricing. The German pricing is almost EUR49,000, or $66,000. So Germany typically is a little bit higher. And my final comment on European pricing is just to say that these are significant differences to the telaprevir pricing. And the [unintelligible] that we’ve taken for Sovaldi, we believe, is very justified according to cost effectiveness data, and the premium is very comparable to the premium that we took on Sovaldi versus the original price of telaprevir in the United States.”

---------------------------------

“Thanks for asking an R&D question. I thought I was going to escape this call without having been asked one single question. So thank you very much. As you know, we have now succeeded with our ledipasvir/sofosbuvir fixed dose combination to actually incredibly shorten treatment duration to 8 weeks and 12 weeks and Sovaldi treatment experience with response rates that go up to 95% or higher.

But we’re not stopping there. This is, of course, for genotype 1. We have another fixed dose combination in development, 5816 combined with sofosbuvir. You will see some of those early data at EASL, and we’re still waiting for the treatment experienced cirrhotic genotype 3 cohort to make a decision or to feel really comfortable going into Phase III.

And then finally, as you know, we have efforts underway to shorten the treatment duration even further, to six weeks, by adding a third drug. So you know, all of those things are ongoing, and I think we will be competitive with our, you know, you can’t really do much more than having one single pill, once daily. Very safe, very well tolerated tablet, given for eight weeks and achieving response rates of 95%.”

Source Seeking Alpha

Read full transcript here …….

Alcohol-linked deaths a problem for the Americas

Elizabeth DeVita-Raebrun
Reuters
3:05 p.m. CST, February 4, 2014

NEW YORK (Reuters Health) - Liver disease and brain disorders due to alcohol abuse are important causes of premature death in the Americas, a new study concludes.

The toll of too much drinking is especially high among men and among middle-aged people, according to the report, whose authors say it's the first to tabulate deaths resulting solely from alcohol.

"This provides direct evidence of the impact of alcohol on the health of countries in the region," said one of the study's authors, Dr. Vilma Pinheiro Gawryszewski, an advisor on health information and analysis for the Pan American Health Organization(PAHO).

In the 16 North, Central, and South American countries studied, alcohol was the sole cause of 79,456 deaths a year, the researchers say. That represented 1.4 percent of deaths from all causes, and alcohol-related liver disease alone accounted for 0.6 percent of all-cause mortality.

The study was based on data collected between 2007 and 2009 for countries in the PAHO mortality database.

The researchers excluded deaths from vehicle accidents and other fatal situations where alcohol might have been involved but there could also have been other causes.

Looking just at deaths due directly to alcohol, they found 63 percent were from liver disease and 32 percent were from neurological and psychiatric conditions grouped under "degeneration of the brain and nervous system."

Other listed causes of death included alcohol poisoning, alcohol-linked heart and gastric problems and fetal alcohol syndrome.

The death toll is the "tip of the iceberg," meaning that there are probably many more alcohol-related deaths that the researchers were not able to identify, said another of the study's authors, Dr. Maristela Monteiro, regional advisor on alcohol and substance abuse at PAHO.

Monteiro said that raising the price of alcohol and increasing taxes would help to prevent some of these deaths. Many countries have found these steps effective in controlling tobacco use, but such measures have not been used to control alcohol consumption, she said.

Even the U.S., which was included in the study, has not done as much as it could, said David Jernigan, director of the Center on Alcohol Marketing and Youth at Johns Hopkins Bloomberg School of Public Health.

"The single most efficient thing you can do is to raise taxes," Jernigan told Reuters Health. "Many states haven't raised it in decades. That means the price doesn't go up with inflation, and alcohol gets cheaper every year."

And while the U.S. and other countries have limited tobacco advertising, alcohol advertising "is virtually everywhere," he said.

Mortality due to alcohol was highest in El Salvador, Guatemala and Nicaragua, with death rates of 27.4, 22.3 and 21.3 per 100,000 people, respectively. These were also the countries with the highest consumption of hard liquor, the authors noted.

Colombia, Argentina and Canada had the lowest death rates attributable to alcohol at 1.8, 4.0 and 5.7 per 100,000, respectively. The alcohol death rate in the United States was "intermediate," at 6.7 per 100,000, Monteiro said.

Men accounted for 84 percent of the deaths overall, but that proportion was not the same in all countries. The risk of a man dying from alcohol in El Salvador was nearly 30 times higher than that of a woman, but only about three times higher in Canada and the U.S.

People in the mid-to-late 50s and 60s age range were at the highest risk. This later in life risk, Jernigan said, points to the long-term impact of heavy drinking.

"Mostly in this country, we talk about alcohol and the risk for the young," in whom drunk driving, violence, and accidents are important causes of death, Jernigan said. "This really shows the impact over the life course."

Despite the grim statistics, Jernigan says studies like this one are a positive sign.

"On one hand, you could say, 'this is a huge problem, and not enough is being done.' On the other," he said, "you could say, 'we're getting better at documenting it and showing that, until we take meaningful action, it's not going to go away.'"

In poorer countries, other factors contributing to the deaths could include infectious diseases that hasten the course of liver disease, as well as poor nutrition and limited access to health services.

"In the U.S., people wouldn't wait until they were too sick for help to seek out services, because treatment is available," said Monteiro. That is not always the case, she said, in other countries.

Source: http://bit.ly/1enwJIT Addiction, online January 14, 2014.

Source

The Risk of Long-term Morbidity and Mortality in Patients With Chronic Hepatitis C

JAMA Internal Medicine

February 2014, Vol 174, No. 2

Original Investigation | February 2014

Results From an Analysis of Data From a Department of Veterans Affairs Clinical Registry

Jeffrey McCombs, PhD¹; Tara Matsuda, BA^1,2; Ivy Tonnu-Mihara, PharmD²; Sammy Saab, MD³; Patricia Hines, BA⁴; Gilbert L’Italien, PhD⁴; Timothy Juday, PhD⁴; Yong Yuan, PhD⁴

[+] Author Affiliations

JAMA Intern Med. 2014;174(2):204-212. doi:10.1001/jamainternmed.2013.12505.

Abstract

Importance The impact of viral load suppression, genotype, race, and other factors on the risk of late-stage liver-related events in patients with hepatitis C (HCV) has been assessed previously using data from small observational cohorts or clinical trials. Data from large real-world practice samples are needed to improve risk factor estimates for late-stage liver events and death in HCV.

Objective To describe the natural history of HCV in real-world clinical practice.

Design, Setting, and Participants Observational cohort study. Patients with a detectable viral load (>25 IU/mL) and a recorded baseline genotype were selected from the Veterans Affairs (VA) HCV clinical registry (CCR), which compiles electronic medical records data from 1999 to present.

Exposures Risk factors included genotype, race, age, sex, and time to achieving an observed undetected viral load.

Main Outcomes and Measures The primary outcomes were time to death and time to a composite of liver-related clinical events. Secondary outcomes included the components of the composite clinical outcome. Outcomes were measured using a time-to-event format and were analyzed using Cox proportional hazards models.

Results A total of 28 769 of 360 857 unique HCV CCR patients met all study criteria. Only 24.3% of patients received treatment, and 16.4% of treated patients (4.0% of all patients) achieved an undetectable viral load. The unadjusted death rates were 6.8 (95% CI, 6.0-7.7) per 1000 person-years for patients who achieved viral load suppression vs 21.8 (95% CI, 21.5-22.2) deaths per 1000 person-years in patients who did not achieve this goal. Cox model results found that achieving viral suppression reduced risk of the composite clinical end point by 27% (hazard ratio [HR], 0.73 [95% CI, 0.66-0.82]) and the risk of death by 45% (HR, 0.55 [95% CI, 0.47-0.64]). Genotype 2 patients were at significantly lower risk, and genotype 3 patients were at higher risk for all study outcomes relative to genotype 1. Black patients were at lower risk for all liver events than white patients.

Conclusion and Relevance Achieving an undetectable viral load was associated with decreased hepatic morbidity and mortality. It remains to be determined whether newer treatment regimens can offer higher response rates with fewer adverse effects in real-world settings.

Source

CIHR Canadian HIV Trials Network Coinfection and Concurrent Diseases Core: Canadian guidelines for management and treatment of HIV/hepatitis C coinfection in adults

Can J Infect Dis Med Microbiol. 2013 Winter;24(4):217-38.

Hull M¹, Klein M², Shafran S³, Tseng A⁴, Giguère P⁵, Côté P⁶, Poliquin M⁶, Cooper C⁷.

Abstract

BACKGROUND: Hepatitis C virus (HCV) coinfection occurs in 20% to 30% of Canadians living with HIV, and is responsible for a heavy burden of morbidity and mortality. HIV-HCV management is more complex due to the accelerated progression of liver disease, the timing and nature of antiretroviral and HCV therapy, mental health and addictions management, socioeconomic obstacles and drug-drug interactions between new HCV direct-acting antiviral therapies and antiretroviral regimens.

OBJECTIVE: To develop national standards for the management of HCV-HIV coinfected adults in the Canadian context.

METHODS: A panel with specific clinical expertise in HIV-HCV co-infection was convened by The CIHR HIV Trials Network to review current literature, existing guidelines and protocols. Following broad solicitation for input, consensus recommendations were approved by the working group, and were characterized using a Class (benefit verses harm) and Level (strength of certainty) quality-of-evidence scale.

RESULTS: All HIV-HCV coinfected individuals should be assessed for HCV therapy. Individuals unable to initiate HCV therapy should initiate antiretroviral therapy to slow liver disease progression. Standard of care for genotype 1 is pegylated interferon and weight-based ribavirin dosing plus an HCV protease inhibitor; traditional dual therapy for 24 weeks (for genotype 2/3 with virological clearance at week 4); or 48 weeks (for genotypes 2-6). Therapy deferral for individuals with mild liver disease may be considered. HIV should not be considered a barrier to liver transplantation in coinfected patients.

DISCUSSION: Recommendations may not supersede individual clinical judgement.

KEYWORDS: Antivirals, Direct-acting antivirals, HCV, HIV, Pharmacokinetics

PMID: 24489565 [PubMed]

Source

How heroin kills you

By Jen Christensen, CNN
updated 11:05 AM EST, Tue February 4, 2014

(CNN) -- The autopsy results aren't in yet, but police believe heroin played a role in the death of Academy Award winning actor Philip Seymour Hoffman -- if not the primary role.

Using heroin can kill you, but it may not be in the way you think. If Hoffman did die from using heroin, his death was atypical in some aspects. Here's how heroin kills.

The numbers

Drug overdose deaths in the United States have risen steadily since 1970. Painkillers actually kill more Americans than heroin and cocaine combined, according to the Centers for Disease Control, but heroin is still one of the No. 1 killers of illegal drug users. Only one in 10 heroin overdoses ends in death.

Overdose deaths from heroin have increased recently, and heroin use is also on the rise. In 2011, 4.2 million Americans over the age of 11 had tried heroin at least once, according to the National Institute on Drug Abuse.

An estimated 23% of them will become addicts. And it's addicts who die more frequently than new users, studies show.

How heroin works

Heroin is most often mixed with water and injected. Injecting it minimizes the lag time between when the drug is taken and effects are felt -- with injection, the effects are almost immediate.

It can also be smoked, snorted or eaten, but smoking or eating destroys some of the drug and mutes its effects.

When someone takes heroin there is an immediate rush. Then the body feels an extreme form of relaxation and a decreased sense of pain.

What's happening inside the body is the heroin is turning into morphine. Morphine has a chemical structure similar to endorphins -- the chemicals your brain makes when you feel stressed out or are in pain. Endorphins inhibit your neurons from firing, so they halt pain and create a good feeling.

Morphine, acting like your endorphins, binds to molecules in your brain called opioid receptors. When those receptors are blocked, that creates a high.

Why you die

Most people die from heroin overdoses when their bodies forget to breathe.

"Heroin makes someone calm and a little bit sleepy, but if you take too much then you can fall asleep, and when you are asleep your respiratory drive shuts down," said Dr. Karen Drexler, director of the addiction psychiatry residency training program and an associate professor in Emory University's psychiatry and behavioral sciences department.

"Usually when you are sleeping, your body naturally remembers to breathe. In the case of a heroin overdose, you fall asleep and essentially your body forgets."

A heroin overdose can also cause your blood pressure to dip significantly and cause your heart to fail.

Studies show intravenous heroin users are 300 times more likely to die from infectious endocarditis, an infection of the surface of the heart.

Heroin use can also cause an arrhythmia -- a problem with the rate or rhythm of the heartbeat. During an arrhythmia, the heart may not be able to pump enough blood to the body, and lack of blood flow affects your brain, heart and other organs.

Heroin use can also cause pulmonary edema. That's when the heart can't pump blood to the body well. The blood can back up into your veins, taking that blood through your lungs and to the left side of the heart.

As pressure in the blood vessels increases and fluid goes into the alveoli, the air spaces in the lungs, this reduces the normal flow of oxygen through your lungs, making it hard to breathe. This too can give you a heart attack or lead to kidney failure.

Heroin can also come with other toxic contaminants that can harm a user -- although deaths from such instances, while not unheard of, are thought to be rare.

Studies suggest instantaneous death -- like what may have happened in Hoffman's case -- is unusual. The actor was found dead on his bathroom floor with a needle sticking out of his left arm, authorities have said.

Such deaths, where a needle and syringe are still in place, would be considered instant by scientists. One study showed this accounts for only 14% of heroin-related deaths.

Heroin deaths increase when...

There are some common social characteristics in heroin deaths that would make Hoffman more of a typical case. Most fatalities involve men, particularly those who have struggled with other drugs or alcohol (he admitted to this in the past) and other drugs or alcohol are often present.

While many are single (Hoffman had a partner), most users die in their homes and/or in the company of another person.

An addict does have a much higher chance of dying if he or she leaves treatment. The risk of death is higher for newly clean heroin addicts. A number of fatalities appear to happen after periods of reduced use, one 2000 study showed.

In fact, long-term users who die from overdoses are likely to have heroin levels no higher than those who survive.

That may be in part because those who are newly clean don't know how much of the drug to give themselves any more, Drexler said. They won't need the same amount to get high as when they were using more regularly.

There are also some studies that show tolerance to the respiratory depressive effects of opiates increases at a slower rate than tolerance to the euphoric and analgesic effects. As your tolerance to the drug develops, you typically need more of it to produce the high you are used to getting. This may be why long-term users are potentially at greater risk of overdose than novices.

Statistics suggest that newer heroin users aren't the ones most likely to die. One study showed only 17% of the deaths studied were in new heroin users.

However, Drexler said newer users can overdose because they don't know how much drug to take, compared to experienced users. "I think it is misleading to say you would not die if you only use it once or twice," she said.

A person's chances of dying from heroin use increase dramatically after 20 years of use. Studies show that after 30 years of use, 16% of heroin users have died, compared with 6.5% of cocaine users and 1.5% of meth users.

Source

AbbVie hep. C combo wows in hard-to-treat

Provided by MM&M

KEVIN MCCAFFREY

FEBRUARY 03, 2014

AbbVie unveiled Phase-III trial results for its multi-drug hep. C regimen Friday, and the all-oral regimen looks impressive. Up to 99% of genotype-1b, treatment-naive patients taking the cocktail achieved SVR12 (sustained virologic response, or cure, at 12 weeks). And up to 96% of cirrhotic patients, or those with liver scarring and poor liver function, reached SVR after a three-month course of the regimen, which consists of ABT-450/r + -267 + -333.

Some specialists might find value in using a regimen like AbbVie's for their cirrhotic patients, but the question is how they compare against those offered up last December by Gilead for its HCV fixed-dose oral therapy. Gilead's two-drug all-oral regimen, which pairs recently approved antiviral Sovaldi with the experimental drug ledipasvir and ribavirin (RBV), saw 97% SVR12 in the treatment-naïve, while 94% of those in the same population got to SVR12 taking a RBV-free regimen.

Gilead has yet to break down how effective its regimen is in cirrhotic patients, but ISI Group analyst Mark Schoenebaum, in an investor note Friday, estimated the lower boundary to be around 95% SVR12 rate with and without ribavirin, based on other trial data.

While AbbVie's regimen showed strong efficacy, and demonstrated it in what has been the largest Phase-III program of an all-oral, interferon-free therapy for HCV GT1 patients to date, Schoenebaum—in another investor note from Friday—shared concerns that it may fall short when compared to Gilead's fixed-dose combo and that AbbVie's results were “right in-line with Street expectations.”

“Gilead's regimen continues to have potential commercial advantages on multiple points,” he wrote. Of those competitive advantages, Schoenebaum cited the Gilead regimen's lower pill burden (one pill daily vs. AbbVie's expected four to six), a potential for shorter duration (8 weeks vs. 12 weeks) and a possibly larger population to cater to that includes GT1-naïve patients, as well as a lack of ribavirin, which can lead to anemia.

Gilead's combo also stands to hit pharmacy shelves before the competition. The Foster City, CA, drugmaker said it will file within the first quarter of this year. AbbVie confirmed, along with Friday's data, that it won't file its regimen with regulators until the early part of the second quarter of this year.

Source

Also See: Abbvie completes largest phase III program of an all-oral, interferon-free therapy for the treatment of hepatitis C genotype 1

Video: Efficacy of an Interferon- and Ribavirin-Free Regimen of Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With HCV Genotype 1 Infection

Published on Jan 15, 2014

Dr. Gregory T. Everson discusses his manuscript "Efficacy of an Interferon- and Ribavirin-Free Regimen of Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With HCV Genotype 1 Infection." To view abstract http://bit.ly/1astcIL.

Also See: Efficacy of an Interferon- and Ribavirin-Free Regimen of Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With HCV Genotype 1 Infection – Full Text

---------------------------------

BPA Exposure in Womb Linked with Liver Tumors

Provided by Nature World News

By Staff Reporter Feb 03, 2014 06:13 AM EST

mice exposed to BPA have high risk of liver tumors. (not pictured) (Photo : REUTERS/Asmaa Waguih)

University of Michigan School of Public Health researchers found liver tumors in mice whose mothers were exposed to the chemical BPA.

Bisphenol A or BPA is a chemical used in plastics and epoxy resins. The chemical is found in many products including water bottles, cups and impact resistant material. Compact discs Epoxy resin is used to coat metal products such as food cans, bottles and cup.

Previous research has shown that BPA can affect fertility in animals. A related study on mice had linked the chemical with prostate cancer in the rodents.

The study shows a direct link between BPA and cancer. The mice in the study were exposed to the chemical during gestation and nursing.

For the study, researchers fed female mice with food containing BPA. These mice were then allowed to mate and were given one of three chemical doses (50 µg, or 50 mg of BPA per kg diet) during gestation and nursing.

The scientists then followed one male and female mouse from each litter and tracked their growth for ten months.

They found that mice whose mothers were exposed to 50 mg of BPA per kg diet had seven times higher risk of developing liver tumor than other non-exposed mice.

"We found that 27 percent of the mice exposed to one of three different doses of BPA through their mother's diet developed liver tumors and some precancerous lesions. The higher the dosage, the more likely they were to present with tumors," said Caren Weinhouse, U-M doctoral student in the School of Public Health's Department of Environmental Health Sciences and first author of the paper, according to a news release.

Also, researchers found that BPA didn't discriminate between male and female. "In general, females are at lower risk of spontaneous development of liver cancer," she said in a news release. "That distinction was erased in this study, with both males and females showing tumors."

The study is published in the journal Environmental Health Perspectives.

Source

Liver disease and diabetes: Association, pathophysiology, and management

Diabetes Res Clin Pract. 2014 Jan 14. pii: S0168-8227(14)00005-9. doi: 10.1016/j.diabres.2014.01.003. [Epub ahead of print]

Ahmadieh H¹, Azar ST².

Abstract

Diabetes is associated with a spectrum of liver diseases including nonalcoholic liver disease, steatohepatitis, and liver cirrhosis with their increased complications and mortality. Hepatitis C virus (HCV) and its associated liver cirrhosis has been associated with diabetes through insulin resistance. Cryptogenic diabetes occurs as a consequence of liver cirrhosis with the pathophysiology being complex, but mostly attributed to the increased insulin resistance in muscle, liver, and adipose tissue. As for the management of diabetes in patients with liver disease, lifestyle modification plays an important role. Oral diabetic medications are contraindicated in patients with advanced liver diseases with associated cirrhosis, ascites, or encephalopathy. As for stable liver disease, metformin and thiazolenediones have shown mixed results, with some showing them to be effective in improving liver transaminases in addition to histological improvement in steatosis and inflammation. α-glucosidase inhibitors may be helpful in decreasing hepatic encephalopathy. Upregulation of Dipeptidyl peptidase-4 (DPP-4) has been suggested as a possible pathogenetic mechanism for HCV-related insulin resistance, and treatment with DPP-4 inhibitors could improve insulin sensitivity in diabetic patients with liver disease. Patients with impaired liver function with associated insulin resistance may need increased insulin requirements. On the other hand patients with altered liver metabolism might need decreased insulin requirements.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

KEYWORDS: Diabetes mellitus, liver disease, liver transaminases, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis

PMID: 24485856 [PubMed - as supplied by publisher]

Source

Medical therapies for hepatocellular carcinoma: a critical view of the evidence

Nature Reviews Gastroenterology and Hepatology 10, 34-42 (January 2013) |doi:10.1038/nrgastro.2012.199

Augusto Villanueva, Virginia Hernandez-Gea & Josep M. Llovet  About the authors

The management of hepatocellular carcinoma (HCC) has substantially changed in the past few decades. Improvements in patient stratification (for example, using the Barcelona Clinic Liver Cancer staging system) and the introduction of novel therapies (such as sorafenib) have improved patient survival. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. Decision-making largely relies on evidence-based criteria, as depicted in the US and European clinical practice guidelines, which endorse five therapeutic recommendations: resection; transplantation; radiofrequency ablation; chemoembolization; and sorafenib. However, areas still exist in which uncertainty precludes a strong recommendation, such as the role of adjuvant therapies after resection, radioembolization with yttrium-90 or second-line therapies for advanced HCC. Many clinical trials that are currently ongoing aim to answer these questions. The first reported studies, however, failed to identify novel therapeutic alternatives (that is, sunitinib, erlotinib or brivanib). Moreover, genomic profiling has enabled patient classification on the basis of molecular parameters, and has facilitated the development of new effective drugs. However, no oncogene addiction loops have been identified so far, as has been the case with other cancers such as melanoma, lung or breast cancer. Efforts that focus on the implementation of personalized medicine approaches in HCC will probably dominate research in the next decade.

Key points

• Epidemiological data indicate that the disease burden of hepatocellular carcinoma (HCC) is increasing worldwide, both in terms of incidence and mortality
• The Barcelona Clinic Liver Cancer staging system provides a general framework for decision-making in patients with HCC, and facilitates stage-based unified selection criteria for clinical trials
• Evidence-based criteria dominate recommendations for HCC management, enabling stratification of evidence according to scientific standards and providing a hierarchy of medical recommendations
• Five treatments are strongly recommended in HCC on the basis of evidence-based data: resection; liver transplantation; radiofrequency ablation; chemoembolization; and sorafenib
• Sorafenib, a molecular targeted agent, prolongs survival in patients with advanced HCC and is the sole systemic drug that is proved to be effective in this disease
• No oncogenic addiction loops have so far been identified in HCC; research initiatives should aim to identify subgroups of patients with targetable dominant molecular alterations

Introduction

Disease burden owing to hepatocellular carcinoma (HCC) is increasing markedly worldwide.¹ In the USA, epidemiological data published in 2009 show a substantial increase in HCC mortality in the past few decades²—a trend that underscores the importance of this disease in upcoming years.³ Nonetheless, major improvements have been made in HCC management during the past 30 years. Traditionally, HCC was considered a deadly disease without curative options, with an overall survival of <6 months.⁴ Advances in early detection, imaging techniques and novel therapies have improved patient selection and enabled evidence-based treatment approaches.⁵Consequently, prognostic algorithms, such as the Barcelona Clinic Liver Cancer (BCLC) classification, have been introduced in routine clinical care.⁴ The BCLC approach classifies patients according to tumour burden, underlying liver dysfunction and patient symptoms (Figure 1); it additionally links each stage to specific therapeutic interventions.⁵ The BCLC system is widely accepted, being currently endorsed by US and European associations for the study of liver diseases and oncology.^{5, 6} Better patient selection has resulted in improvements in patient outcomes for almost every approved therapeutic intervention in HCC, including curative (for example, resection, transplantation, local ablation) and palliative (for example, transarterial chemoembolization [TACE]) approaches. In addition, the molecular-targeted agent sorafenib has shown antitumour activity in patients with advanced HCC, improving 3 months overall survival and delaying tumour progression.⁷

Figure 1 | BCLC staging system and therapeutic strategy according to EASL–EORTC guidelines.

Staging classification comprises five stages that select the best candidates for the best therapies currently available. Patients with asymptomatic early tumours (stage 0–A) are candidates for radical therapies (resection, transplantation or local ablation). Asymptomatic patients with multinodular HCC (stage B) are suitable for chemoembolization (TACE), whereas patients with advanced symptomatic tumours and/or an invasive tumoural pattern (stage C) are candidates to receive sorafenib. End-stage disease (stage D) includes patients with grim prognosis that should be treated by best supportive care. Abbreviations: BCLC, Barcelona Clinic Liver Cancer; DDLT, deceased donor liver transplantation; EASL, European Association for the Study of Liver Disease; EORTC, European Organisation for Research and Treatment of Cancer; GRADE, grading of recommendations assessment, development and evaluation; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; PEI, percutaneous ethanol injection; RF, radiofrequency ablation; TACE, transcatheter arterial chemoembolization; OS, overall survival; PST, performance status. Permission obtained from Elsevier © European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer. J. Hepatol. 56, 908–943 (2012).

HCC frequently occurs in a damaged organ; liver cirrhosis owing to viral hepatitis (HBV or HCV infection) and alcohol abuse are the main risk factors.⁸ However, the rapid development of potent antiviral agents and the increasing incidence of cirrhosis owing to NASH and overweight will modify the aetiological landscape of chronic liver disease in the next decades.⁹ The unique coexistence of two diseases—cirrhosis and HCC—in the same patient complicates the prognostic prediction and therapeutic strategies. This coexistence was observed in a phase III trial assessing sunitinib versus sorafenib in patients with advanced HCC, which was prematurely halted owing to toxicity and futility in the sunitinib arm.¹⁰

This finding emphasizes the fact that patients with cirrhosis, even at early stages of liver failure, are more susceptible to toxicities associated with drugs that are otherwise harmless in individuals without liver disease (sunitinib is approved for renal cell carcinoma). This issue, in addition to the fact that conventional chemotherapy was proven ineffective for this malignancy,¹¹ makes HCC management particularly challenging. This Review will dissect the evidence behind medical interventions in HCC, and discuss some relevant areas of controversy in disease management.

Milestones in research and management

Evidence-based approaches are progressively governing decision-making in medicine. This development is particularly relevant in oncology, in which the disease is frequently lethal and medical interventions can have major adverse effects. Hence, changes in the standard of care need to be supported by robust data. In fact, clinical practice guidelines tend to follow evidence-based criteria to select and grade clinical recommendations, as is the case for HCC.⁵ This approach enables the establishment of a hierarchy of recommendations based on levels of evidence, and identifies those 'grey areas' in which more research is required to provide clear recommendations. When considering HCC management, only five interventions reach the highest level of evidence, being worldwide accepted recommendations for the treatment of HCC:⁵ resection for patients with solitary tumours and well-preserved liver function; liver transplantation for patients with tumours within Milan criteria (single nodules <5 cm or three nodules <3 cm);¹² percutaneous ablation with radiofrequency in early tumours not suitable for surgical treatment; TACE for patients with multinodular asymptomatic tumours without vascular invasion or extrahepatic spread (BCLC B); and sorafenib for patients at advanced stage (Figure 1). Beyond this framework, all other interventions require additional research to prove survival advantages when confronted with the above-mentioned standards of care. Such is the case for internal radioembolization with ytrrium-90 or the role of adjuvant therapies after resection.⁵ Herein, we discuss some of the areas of HCC management that require improvement and summarize the evidence currently available.

The most relevant advances in HCC management have resulted from randomized studies, meta-analysis and cohort studies providing different levels of evidence and strength of recommendations in guidelines of clinical practice (Figure 2). Some of these pivotal studies have been widely cited, and represent scientific milestones in liver cancer research (Table 1); even though clinical decision-making should rely on recommendations based on levels of evidence, showing how frequently these recommendations reflect the importance of published research when evaluating the total number of citations is interesting. Table 1 summarizes the most relevant achievements and milestones in HCC research during the past 30 years, represented in hierarchical order according to number of citations and topic. These milestone studies in HCC address different aspects of clinical management such as epidemiology (association between viral hepatitis and HCC development), surgery (Milan criteria for liver transplantation, intention-to-treat analysis for resection), locoregional therapies (percutaneous ablation in small tumours, randomized trials and meta-analyses of TACE), chemoprevention (HBV vaccination or interferon therapy and decreased HCC risk) and systemic therapies (such as sorafenib). Besides clinically oriented studies, few other studies represent true breakthroughs in the understanding of the pathogenesis of HCC, such as TP53 mutations and HCC in aflatoxin endemic areas, or the oncogenic role of HBV and core proteins in transgenic mice.¹³ With respect to HCC management, to date, the highest cited paper (Table 1; n = 2,331 citations) is the landmark study published in 1996 by Mazzaferro et al.¹² that introduced the Milan criteria for selection of optimal HCC candidates for liver transplantation. When analysing the manuscripts according to number of citations per year, the sorafenib study ranks first with an average of 325 citations per year. Not surprisingly, both studies provide the rationale for strong clinical practice recommendations in HCC management.^{5, 6} In fact, substantial overlap exists between findings from the top cited papers and the clinical recommendations made in guidelines.⁵

Figure 2 | Therapeutic interventions in HCC according to level of evidence and grade of recommendation.

Level of evidence (based on NCI classification and grade of recommendation based on GRADE criteria. Abbreviations: GRADE, grading of recommendations assessment, development and evaluation; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; OLT, orthotopic liver transplantation; NCI, National Cancer Institute; PEI, percutaneous ethanol injection; RF, radiofrequency ablation. Permission obtained from Elsevier © European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer. J. Hepatol. 56, 908–943 (2012).

Table 1 | Milestones in HCC research reported during the past 30 years^*

Citations	Reference	Title	Thematic area	Direct influence on CPG	Citations per year
Data accessed on Web of Science® (Thomson Reuters, New York, USA), using the search terms “hepatocellular carcinoma” or “liver cancer” on 20 September 2012.
*Sorted by number of citations.
Abbreviations: CPG, clinical practice guidelines; HCC, hepatocellular carcinoma.
Molecular pathogenesis
1,640	Knowles et al. (1980)83	Human HCC cell lines secrete the major plasma proteins and hepatitis B surface antigen	Basic science	No	49
1,285	Hsu et al. (1991)84	Mutational hotspot in the p53 gene in human HCCs	Basic science	No	56
1,085	Bressac et al. (1991)85	Selective G-mutation to T-mutation of p53 gene in HCC from Southern Africa	Basic science	No	48
788	Kim et al. (1991)86	HBx gene of HBV induces liver cancer in transgenic mice	Basic science	No	34
736	Moriya et al. (1998)87	The core protein of HCV induces HCC in transgenic mice	Basic science	No	46
Epidemiology and natural history
1,867	Beasley et al. (1981)88	HCC and HBV: a prospective study of 22,707 men in Taiwan	Epidemiology	No	57
1,661	El-Serag et al. (1999)89	Rising incidence of HCC in the US	Epidemiology	No	116
1,215	Okuda et al. (1985)90	Natural history of HCC and prognosis in relation to treatment: study of 850 patients	Prognosis	No	42
978	Kiyosawa et al. (1990)91	Interrelationship of blood transfusion, non-A, non-B hepatitis and HCC: analysis by detection of antibody to HCV	Epidemiology	No	42
943	Saito et al. (1990)92	HCV infection is associated with the development of HCC	Epidemiology	No	40
881	Chang et al. (1997)23	Universal HBV vaccination in Taiwan and the incidence of HCC in children	Chemoprevention	Yes	54
899	Chen et al. (2006)25	Risk of HCC across a biological gradient of serum HBV DNA level	Epidemiology	No	118
720	Tsukuma et al. (1993)93	Risk factors for HCC among patients with chronic liver disease	Epidemiology	No	35
683	Nishiguchi et al. (1995)94	Randomized trial of effects of IFN-α on incidence of HCC in chronic active hepatitis C with cirrhosis	Chemoprevention	No	37
668	Bruix et al. (1989)95	Prevalence of antibodies to HCV in Spanish patients with HCC and hepatic cirrhosis	Epidemiology	No	28
Treatment
2,331	Mazzaferro et al. (1996)12	Liver transplantation for the treatment of small HCC in patients with cirrhosis	Surgery	Yes	129
1,777	Llovet et al. (2008)7	Sorafenib in advanced HCC	Systemic therapy	Yes	325
984	Llovet et al. (2002)96	Arterial embolization or chemoembolization vs symptomatic treatment in patients with unresectable HCC: a randomized controlled trial	Locoregional	Yes	84
831	Llovet et al. (2003)11	Systematic review of randomized trials for unresectable HCC: chemoembolization improves survival	Locoregional	Yes	78
791	Livraghi et al. (1999)97	Small HCC: treatment with radiofrequency ablation vs ethanol injection	Locoregional	Yes	56
791	Lo et al. (2002)98	Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable HCC	Locoregional	Yes	59
722	Llovet et al. (1999)99	Intention-to-treat analysis of surgical treatment for early HCC: resection vs transplantation	Surgery	Yes	50
730	Curley et al. (1999)100	Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients	Locoregional	No	49
663	Livraghi et al. (1995)101	HCC and cirrhosis in 146 patients: long-term results of percutaneous ethanol injection	Locoregional	Yes	36

Breakthroughs in the management of human cancers have been dominated by the discovery and selective blockade of so-called oncogenic addiction loops.^{14, 15} The concept of oncogene addiction describes the selective dependence of cancer cell proliferation to certain molecular aberrations. Tumoural cells become dependent on and/or addicted to a specific molecular alteration responsible for its own controlled proliferation.¹⁶ Many of these loops have been therapeutically exploited and some have substantially improved patient survival.¹⁴ Examples include BRAF-mutated metastatic melanoma and response to vemurafenib,¹⁷ or ALK rearrangements in lung cancer and response to crizotinib.¹⁸ Strikingly, ALK oncogenic addiction in lung tumours was discovered after a fairly short timeframe: 3 years passed between the identification of ALK rearrangement¹⁹ and publication of the phase II trial.¹⁸ Unfortunately, not a single oncogenic addiction loop has thus far been identified in HCC.¹⁵ However, several efforts aimed at improving patient selection for novel therapies in HCC, such as deep sequencing and genomic profiling,²⁰ are ongoing and could elucidate oncogenic addiction loops in the setting of HCC.

Evidence-based management of HCC

Chemoprevention

Identification of patients at risk of HCC development has become a public health priority. Assuming that close to 1% of the global population has cirrhosis²¹ and one-third of patients develop HCC in their lifespan,⁵ the expected number of lives saved following successful prevention of HCC is substantial. Cirrhosis of any aetiology is, by itself, a risk factor for the development of HCC.²² In terms of primary prevention, studies from Taiwan clearly demonstrated that prevention of HBV-related liver disease with universal vaccination is highly effective at diminishing HCC rates.²³ Consequently, since 1991, the WHO has recommended vaccination of all newborn babies and high-risk individuals.²⁴ In the setting of chronic hepatitis B or C, the main risk factors for the development of HCC are the presence of advanced hepatic fibrosis or cirrhosis, and high viral load.²⁵ In fact, current guidelines recommend antiviral treatment to suppress virus replication and prevent the progression of fibrosis.²⁶ Few randomized controlled trials (RCTs) are available that evaluate the role of HBV treatment for HCC prevention as a primary end point. The only two RCTs designed to measure the importance of treatment on HCC development showed that both interferon²⁷ and lamivudine²⁸ are effective in increasing HBV clearance, decreasing cirrhosis progression and subsequently reducing HCC risk. Studies with PEG-IFN-α are limited and restricted to the demonstration of improvement of surrogate markers (for example, viral DNA suppression, hepatitis B e antigen seroconversion and hepatitis B surface antigen loss),²⁹ although the clinical benefits are expected to be at least similar to those with conventional IFN-α. Regarding chronic HCV infection, achievement of sustained virologic response has been shown to decrease the risk of HCC in patients with chronic hepatitis C.³⁰ However, once cirrhosis is established, the benefit of antiviral treatment for HCV infection in terms of HCC prevention remains unclear.³¹ Moreover, maintenance treatment in nonresponders with IFN-α was neither beneficial for fibrosis progression nor for HCC development.³²

As previously mentioned, the vast majority of HCC occurs in cirrhotic livers and increasing evidence suggests that fibrosis per se confers carcinogenic risk.³³ Molecular data also point towards a major pathogenic role for diseased liver microenvironment ('field effect') in HCC development.³⁴ Hence, reversal of fibrosis regardless of primary aetiology could theoretically prevent HCC development. However, studies targeting fibrosis as a chemopreventive strategy are scarce. Only two large, prospective, placebo-controlled studies have tested antifibrotic agents and showed no effects on fibrosis after 1 year of therapy.^{35, 36} Overall, besides primary prevention efforts aimed at avoiding known environmental risks for liver disease (including, HBV vaccination and withdrawal of alcohol intake), or antiviral therapy to suppress viral load in chronic hepatitis, no clear measures to decrease HCC incidence in patients with cirrhosis are available. In addition, little is known about the predictors that confer higher risk among individuals with cirrhosis, which justifies the recommendation of surveillance with abdominal ultrasonography every 6 months in all patients with cirrhosis.⁵ Preliminary evidence at the molecular level in experimental studies has identified different signalling pathways as potential targets for chemoprevention (for example, EGFR and PDGFR^{37, 38}). However, there are two major drawbacks to developing effective drugs in the chemoprevention setting: first, the expected long duration of these trials requires the inclusion of enrichment strategies to increase feasibility by selecting those patients at very high risk of HCC development; second, a pressing need exists to identify accurate and noninvasive biomarkers for diagnosis and monitoring of fibrosis progression.

Treatment

Stage-oriented HCC management based on the BCLC algorithm (Figure 1) classifies medical interventions as potentially curative (for example, surgical resection, liver transplantation or percutaneous ablation) or palliative (for example, TACE and sorafenib).⁵ Treatment allocation is based on levels of evidence as defined by the National Cancer Institute, which rely on strengths of study design and end points. Herein, we summarized the different therapeutic interventions for HCC according to these evidence-based parameters (Figure 2).

Surgical treatments

Surgical resection and liver transplantation are first-line options for patients with early stage HCC (BCLC)0–A), as they confer 5-year survival rates of 70%.³⁹ Improvements in surgical approaches and refined selection of candidates for surgery (single nodule without liver dysfunction of portal hypertension⁴⁰) have contributed to increased patient survival, minimization of complications and reduced recurrence.⁴¹ Overall, recurrence after resection reaches 70% at 5 years, either because of true metastases or de novo HCC,⁴²and no adjuvant therapies able to reduce recurrence are currently approved. Local ablation has been suggested as a competitive alternative to resection in patients with a single tumour <2 cm.⁴³ As no RCT has been designed ad hoc to address this issue, the role of local ablation as a first-line option in this setting remains controversial. Patients within Milan criteria (that is, single tumour <5 cm or three nodules <3 cm), without vascular invasion (BCLC A) should be evaluated for liver transplantation.⁵ These criteria have been independently validated by several groups and are widely adopted in transplant centres in Europe and the USA.³⁹ Despite their utility, Milan criteria might be too restrictive and preliminary evidence indicates that some patients with tumours exceeding Milan criteria are potentially curable by liver transplantation.^{44, 45} Studies using clinical or pathological variables to expand Milan criteria have a number of methodological limitations, such as small sample size⁴⁶ and their retrospective nature,⁴⁷which prevents providing any recommendation owing to lack of robust data. A retrospective study suggested that microvascular invasion was a limiting factor to discriminate good and poor outcome among patients with HCC who underwent liver transplantation within and beyond Milan criteria (under the so-called up-to-seven rule).⁴⁵These data emphasize the need to unravel molecular readouts of tumour biology to enable proper decision-making.⁴⁸

Locoregional therapies

Local ablation is the standard of care for patients with early stage tumours who are not suitable for surgery; survival rates are 50–70% at 5 years with this approach.⁵Radiofrequency is the first option, and percutaneous ethanol injection is only reserved as a complementary treatment in cases of difficult tumour location.⁵ Patients with multinodular disease, preserved liver function, without tumour-related symptoms and absence of vascular invasion or extrahepatic spread (BCLC B, intermediate stage) are candidates for TACE, with the goal of delaying tumour progression and extension of patient survival.^{5, 6} Evidence to support this recommendation comes from a meta-analysis of pooled data.¹¹ Improvements in embolization devices (for example, drug-eluting beads) provide median survival rates beyond 30–40 months, at least in referral centres.⁴⁹ Findings from a Cochrane Review have challenged the role of TACE as the standard of care for patients with intermediate stage HCC,⁵⁰ but the inclusion of studies using inadequate control arms and suboptimal patient selection might bias this conclusion.⁵¹ Regarding other embolization approaches (such as radioembolization with microspheres loaded with yttrium-90), data suggest it has a favourable safety profile,⁵²but only well-designed, properly powered RCTs will determine the therapeutic niche, if any, of this intervention.

Systemic therapies

Until 2007, and despite substantial efforts, no single systemic agent had shown survival benefits in patients with HCC. This finding can be partially explained by the frequent coexistence of HCC and cirrhosis, its high molecular heterogeneity and a relative resistance to conventional chemotherapy.⁵³ The SHARP trial demonstrated that sorafenib, a tyrosine kinase inhibitor with a broad inhibitory profile (for example, BRAF, PDGFR and VEGFR), was able to substantially increase survival in patients with advanced HCC (stage C of the BCLC classification: patients with well-preserved liver function and extrahepatic spread or vascular invasion) from 7.9 months to 10.7 months (HR 0.69).^{5, 6}The effects of sorafenib in delaying tumour progression and improving survival were further validated in Asian HBV-infected patients.⁵⁴ Adverse events such as diarrhoea or hand–foot skin reaction associated with sorafenib were manageable. On the basis of these data, sorafenib (400 mg, twice daily) is the standard of care for patients at advanced stages of HCC, and it should be maintained at least until radiological progression with periodic monitoring of adverse effects (mostly cardiovascular, diarrhoea and skin reactions).¹⁵ Thus far, no strong biomarkers are available to accurately predict a patient's response to sorafenib.⁵⁰

Numerous targeted therapies are currently under evaluation in different developmental phases for the systemic treatment of HCC, both as first and second-line therapies (thoroughly reviewed elsewhere¹⁵). Regarding potential registration trials, initial results have been negative: the sunitinib trial was prematurely halted because of adverse events and futility in the sunitinib arm as a first-line therapy. Brivanib showed an antitumoural effect that did not markedly improve survival compared with placebo in second-line therapies,⁵⁵ and the phase III trial testing the multikinase inhibitor linifanib has therefore been halted.⁵⁶ Furthermore, the combination of sorafenib and EGFR inhibitors (erlotinib) failed in comparison to sorafenib alone as a first-line therapy.⁵⁷ The remaining ongoing phase III trials are testing monoclonal antibodies against VEGFR2 (ramucirumab) and mTOR (mammalian target of rapamycin) inhibitor (everolimus). In addition, >250 early phase clinical trials of HCC therapies are ongoing, testing 56 molecular therapies.¹⁵ If more trial results are negative, alternative approaches will be needed to improve on the results already achieved with sorafenib. Potential alternatives are, first, the identification of drugs that can be safely used in combination with sorafenib. Second, the discovery of oncogene addiction loops that restrict survival benefits in a subpopulation of patients with HCC (for example, MET-positive patients), and third, to develop drugs targeting novel signalling cascades (for example, WNT–β-catenin and Notch) or molecular mechanisms (for example, epigenetic aberrations). In any case, it will be necessary to implement changes to the current paradigm of trial design (Box 1). Progressively, enrolment criteria should include molecular information of the mechanisms responsible for tumour progression in each patient, following previous examples in other solid tumours.⁵⁸

Box 1 | Main issues for phase II/III trial design in patients with HCC^{102, 103}

To select the target population

• BCLC stage: include patients at specific BCLC stage (A–C)
• Child–Pugh classification: include Child–Pugh A

To choose the appropriate end points

• Overall survival (main end point in cancer research)
• Time to progression^*
• Objective response rate^*

To decide the adequate control arm

• TACE for intermediate stage
• Sorafenib for advanced stage (first-line therapy)
• Placebo plus best supportive care for advanced stages (second-line therapy)

To stratify factors before randomization

• ECOG performance status
• Tumour burden (extrahepatic spread and/or vascular invasion)
• AFP levels >200 ng/ml

^*Time to progression and overall response rate should be assessed according to modified RECIST criteria. Abbreviations: AFP, α-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; OS, overall survival; RECIST, response evaluation criteria in solid tumours; TACE, transarterial chemoembolization.

Adjuvant therapies as a first unmet need

Tumour recurrence is a major complication after resection, occurring in 70% of patients at 5 years after surgery.³⁹ Unlike most malignancies, two clear patterns of recurrence exist in HCC. Early recurrences (<2 years) are related to early dissemination of the primary tumour (that is, true metastasis) whereas late recurrences (>2 years) are a result of the carcinogenic cirrhotic milieu present in the remaining liver that promotes the progression of new malignant clones (that is, de novo tumours).^{42, 59} Feasibly, each type might have a different molecular background and therefore would require different therapeutic approaches for its prevention.⁶⁰ Unfortunately, despite the fact that several RCTs have been conducted to evaluate adjuvant therapy, no agent has shown robust efficacy in preventing or delaying tumour recurrence.⁵

The role of IFN-α as adjuvant therapy after resection has been frequently evaluated in different studies, including RCTs.^{61, 62} One of the largest trials analysed the use of IFN-αin 150 patients with HCC, finding a negative trend for the primary end point (recurrence-free survival), but a positive trend in terms of prevention of late recurrence of HCC in the patients tested.⁶³ Additionally, different meta-analyses have tried to provide a more comprehensive answer for the role of IFN-α in preventing HCC recurrence.^{64, 65, 66}Owing to conflicting data and issues related to study design (such as trial selection for meta-analysis and mixing end points), IFN-α is currently not recommended as an adjuvant therapy after resection.⁵ In HBV-related HCC, a systematic review including 230 patients with HCC treated with ablation or resection found no evidence to support the use lamivudine with or without adefovir as adjuvant therapy.⁶⁷

Besides IFN-α, other agents such as vitamin analogues have been evaluated in the adjuvant setting. Vitamin K was believed to have a beneficial effect in prolonging disease-free survival on the basis of findings from small studies.^{68, 69, 70} However, when tested in a large RCT including >500 patients, vitamin K was unable to prevent either HCC recurrence or death.⁷¹ Vitamin A analogues also have controversial results. Although the acyclic retinoid prevented the development of secondary HCC after resection and improved survival in one RCT,⁷² this result was not validated in an, as yet unpublished, large, multicentre RCT.⁷³ Regarding adoptive immunotherapy with IL-2-activated lymphocytes, despite initial encouraging results,⁷⁴ this strategy has not been subsequently validated and it is not recommended in HCC clinical management.⁵ Also, no survival benefits have been established with other immunotherapy regimens including cytokine-induced killer cells.⁷⁵ Currently, two large phase III RCTs are ongoing that are evaluating the role of sorafenib and rapamycin in preventing tumour recurrence after resection and/or ablation (STORM trial)⁷⁶ and after liver transplantation (SiLVER trial)⁷⁷in patients with HCC.

One of the main limitations of liver transplantation for HCC is donor shortage, which causes longer waiting times and increases drop-out rates as a result of tumour progression whilst waiting for a graft. Therefore, transplant groups are applying locoregional therapies upon listing to prevent drop out.⁷⁸ Evidence behind this approach comes from uncontrolled studies and cost–benefit analysis,⁷⁸ showing that when expected waiting time exceeds 6 months it is cost-effective to offer the patient neoadjuvant therapies. This approach has been incorporated in a consensus document on HCC and liver transplantation that recommends locoregional therapies in patients with HCC within Milan criteria or United Network for Organ Sharing stage T2 (one nodule 2–5 cm or ≤3 nodules each ≤3 cm), with an expected waiting time longer than 6 months.^{5, 79}Medical therapies, including sorafenib, have not been able to demonstrate a beneficial effect in this particular setting.

Towards molecular medicine in HCC

The future paradigm for treating patients with HCC includes customization of medical interventions on the basis of molecular alterations that govern tumour development and progression on an individual basis. In this regard, the most straightforward approach is to identify and validate oncogenic addiction loops, following the path opened in other solid tumours (for example, mutated BRAF melanoma, ALK rearrangements in lung cancer, and so on). Deep analysis of the HCC genome (such as exome and RNA sequencing) could provide new candidates. Several failures of systemic treatment in first-line therapy (brivanib versus placebo,⁸⁰ sorafenib plus erlotinib versus sorafenib,⁸¹ sorafenib versus linifanib⁵⁶ and sorafenib versus sunitinib)⁸² and second-line therapy (brivanib versus placebo)⁵⁵ alert us to several concerns: the heterogeneity of the disease; toxicity of multikinase inhibitors in patients with cirrhosis; complexity of the disease; and the need for a more stratified approach by using reliable biomarkers and drugs for specific molecular aberrations. Targeting oncogenic addiction loops is expected to add survival benefits to the existing HCC therapy that currently relies on sorafenib.

Besides trial enrichment, combination therapies can also improve the current standard of care. The wide inhibitory profile of sorafenib, in addition to an antiangiogenic effect and good safety profile confirms this drug as the benchmark for systemic management of HCC. The bottleneck of the combination approach will be drug toxicity. The trade-off between efficacy and adverse effects is pivotal in this scenario, as patients with cirrhosis are clearly more susceptible to adverse effects of drugs than patients without cirrhosis. When considering changing the standard of care for HCC management, any intervention should be evaluated in the context of well-designed, properly powered, high-level RCTs—only these types of studies can currently change accepted treatment recommendations in guidelines.

Conclusions

The management of HCC has changed substantially in the past few decades, and five treatment options are accepted in clinical guidelines. Decision-making relies on evidence-based criteria; however, despite the recent advance in the understanding of HCC pathophysiology and development of new therapies, several clinical areas lack strong recommendations. The approval of sorafenib changed the understanding of HCC and brought in a new era in the management of liver cancer, led by the effort in understanding the molecular regulation and the identification of new molecular targets. Efforts on the implementation of personalized medicine will probably dominate research in the next decade.

Review criteria

A search for original articles focusing on hepatocellular carcinoma was performed in MEDLINE and PubMed. The search terms used were “hepatocellular carcinoma”, “liver cancer”, “treatment”, “management”, “medical therapies”, “randomized” and “systemic review”, alone and in combination. All articles identified were English-language, full-text papers. We also searched the reference lists of identified articles for further relevant papers.

Author contributions

All authors contributed equally to all aspects of this manuscript.

Competing interests statement

The authors declare competing interests.

Author affiliations

A. Villanueva, V. Hernandez-Gea & J. M. Llovet
Hepatocellular Carcinoma Translational Research Laboratory, Barcelona Clinic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Liver Unit, Hospital Clínic, Villarroel 170, Barcelona 08036, Catalonia, Spain (A. Villanueva, V. Hernandez-Gea, J. M. Llovet).

Correspondence to: J. M. Llovet jmllovet@clinic.ub.es

Published online 13 November 2012

References

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