March 19, 2011

Digestive and Liver Disease

Articles in Press

Rolf Teschkea, Samuel X. Qiub, Vincent Lebotc

Received 2 December 2010; accepted 25 January 2011. published online 07 March 2011.
Corrected Proof

Abstract

Herbal hepatotoxicity by the anxiolytic kava (Piper methysticum Forst. f.) emerged unexpectedly and was observed in a few patients worldwide. Liver injury occurred after the use of traditional aqueous kava extracts in the South Pacific region and of acetonic and ethanolic extracts in Western countries in rare cases, suggesting that the solvents used play no major causative role. In this review, we discuss actual pathogenetic issues of kava hepatotoxicity with special focus on developments regarding pipermethystine, flavokavain B, and mould hepatotoxins as possible culprits. There is abundant data of in vitro cytotoxicity including apoptosis by pipermethystine and flavokavain B added to the incubation media, yet evidence is lacking of in vivo hepatotoxicity in experimental animals under conditions similar to human kava use. Furthermore, in commercial Western kava extracts, pipermethystine was not detectable and flavokavain B was present as a natural compound in amounts much too low to cause experimental liver injury. There is concern, however, that due to high temperature and humidity in the South Pacific area, kava raw material might have been contaminated by mould hepatotoxins such as aflatoxins after harvest and during storage. Whether kava hepatotoxicity may be due to aflatoxicosis or other mould hepatotoxins, requires further studies.

Keywords: Drug induced liver injury, Herbal hepatotoxicity, Herbs induced liver injury, Kava, Kava hepatotoxicity, Piper methysticum

a Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Goethe University of Frankfurt/Main, Germany
b Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou, China
c CIRAD, Port-Vila, Vanuatu

Corresponding author at: Department of Internal Medicine II, Klinikum Hanau, Teaching Hospital of the Goethe University of Frankfurt/Main, Leimenstrasse 20, D-63450 Hanau, Germany. Tel.: +49 6181 2964200; fax: +49 6181 2964211.

PII: S1590-8658(11)00048-X
doi:10.1016/j.dld.2011.01.018
© 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Inc All rights reserved.

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Effects of silybum marianum on patients with chronic hepatitis C

Journal of Research in Medical Sciences, Vol 16, No 3 (2011)

Hamid Kalantari, Zahra Shahshahan, Mehdi Hejazi, Taghi Ghafghazi, Vahid Sebghatolahi

Abstract

BACKGROUND: Silymarin derived from silybum marianum (milk thistle), a flowering member of the daisy family, may benefit liver function in people infected with the hepatitis C virus. The aims of this pilot study were to assess the efficacy and safety of silymarin on serum hepatitis C virus (HCV) RNA, serum aminotransferases (ALT, AST) levels, liver fibrosis and well-being in patients with chronic hepatitis C (CHC).

METHODS: This prospective self-controlled trial study was conducted from March to September 2006 at Department of Gastroenterology, Isfahan University of Medical Sciences, Isfahan, Iran. 55 patients with HCV (10 female and 45 male) with a mean age of 31.8 ± 6.4 years (10-67 years) were participated in the study. Patients received 24 weeks of silymarin (630 mg/day). Baseline virological biochemical, liver fibrosis (by a serum fibrosis markers, including YKL–40 and Hyaluronic acid), and SF-36 questionnaire were performed with biochemical tests repeated at the end of the treatment period.

RESULTS: There was statistically difference in mean of ALT (108.7 ± 86.6 vs 70.3 ± 57.7) before and after the treatment (p < 0.001). The means of AST were 99.4 ± 139.7 and 59.7 ± 64.32 before and after the treatment with statistically differences (p = 0.004). After the treatment, nine patients were found with negative HCV-RNA (p = 0.004) and statistically significant improvement in results of liver fibrosis markers were found only in fibrosis group (p = 0.015). Quality of life was improved significantly (p < 0.001).

CONCLUSIONS: This study indicated that in patients with CHC performing silymarin (650 mg/day) for 6 months, improved serum HCV-RNA titer, serum aminotransferases (ALT, AST), hepatic fibrosis and patient’s quality of life. More future studies are warranted.

• KEYWORDS: Hepatitis C Virus (HCV), Quality of life, Serum Aminotransferases.

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Clinical Gastroenterology and Hepatology
Volume 9, Issue 3 , Pages 242-248, March 2011

Markus Peck–Radosavljevic, John Boletis, Fatih Besisik, Maria Lúcia Ferraz, Laurent Alric, Didier Samuel, Diethelm Messinger, Andreas Tietz, Hugo Cheinquer

published online 09 November 2010.

Abstract

Background & Aims
Chronic hepatitis C increases mortality of patients with end-stage renal disease (ESRD). Ribavirin is not recommended for patients with renal dysfunction; peginterferon monotherapy is the most appropriate treatment for chronic hepatitis C in such patients. We evaluated the efficacy and safety of 2 dosages of peginterferon alfa-2a (40 kDa) in patients with chronic hepatitis C and ESRD on hemodialysis.

Methods
We performed a randomized, multicenter, open-label clinical study of 85 patients with chronic hepatitis C and ESRD who were receiving hemodialysis at specialist outpatient hepatology clinics. Patients were treated with subcutaneous peginterferon alfa-2a (40 kDa) at dosages of 135 or 90 μg/wk for 48 weeks.

Results
The incidences of overall sustained virologic responses (SVRs) (undetectable hepatitis C virus [HCV] RNA [<50 IU/mL] after 24 weeks of untreated follow-up) were 39.5% (15/38) in the 135 μg/wk group and 34.9% (15/43) in the 90 μg/wk group (odds ratio, 1.22; 95% confidence interval, 0.49–3.06; P = .67). Among patients with undetectable HCV RNA at week 12, 60.9% (14/23) of those in the 135 μg/wk group and 87.5% (14/16) of those in the 90 μg/wk group achieved an SVR. Therapy was well-tolerated with no new safety concerns. The most common adverse events (>10% of patients in at least 1 treatment group) included conditions associated with ESRD (anemia and hypertension) and with interferon treatment.

Conclusions
Forty-eight weeks of treatment with low-dose peginterferon alfa-2a (40 kDa) is safe and produces an SVR in 35%–40% of patients with chronic hepatitis C and ESRD on hemodialysis.

Keywords: Chronic Hepatitis C, End-Stage Renal Disease, Hemodialysis, Hepatitis C Virus, Peginterferon, Sustained Virologic Response

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HIV Treatment Gap Widening

Jim Kling

March 18, 2011 — There is a growing gap between the number of individuals living with HIV and the number of healthcare providers required to meet their needs, according to a new report from the Institute of Medicine entitled "HIV Screening and Access to Care: Health Care System Capacity for Increased HIV Testing and Provision of Care." The report was published online March 17 by the Institute of Medicine's Committee on HIV Screening and Access to Care.

There are believed to be 1.1 million people living with HIV in the United States, and an estimated 21% of them are not aware that they are infected. About 56,000 individuals contract new infections each year. Individuals are also living longer with HIV, further increasing demand for services. However, there are currently more providers retiring from the HIV/AIDS field than there are new providers entering the field.

In 2006, the Centers for Disease Control and Prevention recommended routine HIV testing for individuals between the ages of 13 and 64 years. After those recommendations were issued, state health departments and other organizations received additional financial support for screening, but there is some debate as to whether the support is sufficient and whether the programs will be sustainable once outside funding ceases.

Expanded screening is also resulting in the identification of more individuals with HIV, which in turn will lead to a greater demand for service providers to meet their needs.

There are few data on patterns of care for patients with HIV/AIDS, but the committee concluded that most medical care for HIV-positive individuals is provided by primary care physicians, infectious disease specialists, advanced practice registered nurses, and physician assistants. Other needed providers include registered nurses, dentists, pharmacists, and social workers.

HIV-positive patients are well served by primary care providers who can address their other health needs, but there is a lack of adequate training and experience in HIV care among this group. This is especially true in outpatient clinics, which currently provide the majority of current HIV care.

The committee recommends that medical schools and residency training incorporate exposure to outpatient HIV care, and that continuing medical education programs also be developed to address the needs for the growing population of HIV-positive individuals.

In addition to the overall number of providers, it is important to have an adequate racial, ethnic, and cultural diversity among providers because many HIV-positive individuals are racial/ethnic minorities.

Another strategy in addition to increasing providers is to maximize the capacity of the current healthcare system to absorb increased demand. One approach is to implement delivery system strategies such as task shifting, comanagement, and care coordination models.

"Pathway" strategies can expose more trainees to HIV care, and financial and other incentives can be implemented to encourage more providers to enter the field. The committee also highlighted the current Ryan White model of care, in which patients receive a variety of medical and nonmedical services, and which incorporates task shifting. The Institute of Medicine recommends that this sort of integrated delivery system serve as a model for future care systems.

No matter what approach is used, it is imperative that there be an increase in HIV/AIDS care capacity. Each new detection of an HIV infection creates the need to counsel, refer, treat, and monitor an additional patient, at an average annual cost of $19,912.

If service is interrupted, patients suffer and become less productive, and the likelihood of new transmissions rises.

The report is the third and final in a series examining policy and capacity issues related to carrying out the National HIV/AIDS Strategy for the United States, which is designed to reduce the number of new HIV infections and improve access to care. Previous reports included "HIV Screening and Access to Care: Exploring Barriers and Facilitators to Expanded HIV Testing and HIV Screening" and "Access to Care: Exploring the Impact of Policies on Access to and Provision of HIV Care."

The study was supported by the National Academy of Sciences and the White House Office of National AIDS Policy. The report topic was approved by the Governing Board of the National Research Council. The members of the committee were drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The authors have disclosed no relevant financial relationships.

Institute of Medicine. Published online March 17, 2011.
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Report Highlights Shortage of HIV Care Providers in U.S.

Gap widening between number infected and those trained to treat these patients, experts say

Posted: March 18, 2011

FRIDAY, March 18 (HealthDay News) -- The U.S. medical system is ill-prepared to cope with the number of Americans now infected with HIV, a new report suggests.

Specifically, too few health care providers are adequately trained and experienced in providing the care these patients need, the report authors indicate.

The observation is outlined in the third and final report of a series focused on the state of HIV health care in the United States that was put together by the Institute of Medicine (IOM), an independent, nonprofit organization.

"There will be numerous challenges as the nation begins implementing the [Obama administration's] new National HIV/AIDS Strategy," Paul Cleary, dean of the Yale School of Public Health in New Haven, Conn., said in a news release from the National Academy of Sciences.

Cleary, chair of the committee that wrote the series, said that the reports set out to articulate "many practical suggestions from the research literature and experts about how to address and overcome the obstacles to a more effective and efficient HIV/AIDS strategy."

Given the widening gap between HIV-care supply and demand, the report emphasizes the need for health-care provider flexibility, in order to overcome the constraints under which many providers labor.

For example, the report authors say that collaboration across facilities should be encouraged, in order to better allocate and share sparse resources among multiple providers. However, at times such task-sharing may run afoul of state regulations, which can limit the ability of providers to share caseload responsibilities.

Released online March 17, the report -- entitled HIV Screening and Access to Care: Health Care System Capacity for Increased HIV Testing and Provision of Care -- also highlights the need for more training to provide caregivers with greater exposure to the demands of HIV care.

Two earlier reports in the series examined barriers to expanded HIV testing and the impact of policies on access and provision of care. The aim of the series is to facilitate the goals of the new National HIV/AIDS Strategy, which the White House has described as a roadmap for policy makers and the public.

That strategy aims to bring about a drop in the rate of HIV infection while at the same boosting access to care among those already infected.

The report series as a whole has highlighted a range of problems and issues that need addressing, according to the news release. Those include the lack of a clear federal policy regarding HIV testing, statewide differences regarding how testing is implemented, obstacles to the provision of rapid HIV testing and discrimination against HIV-positive individuals. Current prison practices are also a concern, the authors say.

The series was sponsored by the White House Office of National AIDS Policy.

More information

For more on HIV care, visit the New York State Department of Health AIDS Institute.

Source
European Journal of Internal Medicine
Volume 22, Issue 2 , Pages 187-190, April 2011

Heba S. Selim, Hadia A. Abou-Donia, Hossam A. Taha, Gasser I. El Azab, Ahmed F. Bakry

Received 16 August 2010; received in revised form 28 October 2010; accepted 1 December 2010. published online 18 January 2011

Abstract

Background
Occult HBV infection is defined by detection of HBV DNA in the serum or liver tissue of patients who test negative for HBsAg. The prevalence of occult HBV is higher in hepatitis C virus (HCV) positive patients than HCV negative patients and may have an impact on their clinical outcome. In this study, we evaluated the role of occult hepatitis B virus infection in chronic hepatitis C patients with ALT flare.

Methods
Sixty HBsAg negative patients with chronic hepatitis C virus infection were included. Patients were divided into 2 groups according to their ALT level: 30 patients with normal or slightly high ALT and 30 patients with ALT flare (≥5 times normal values). Patients in both groups were examined for the detection of anti-HBs, anti-HBc IgM, and anti-HBc IgG. HBV DNA was detected using semi-nested PCR technique.

Results
In patients with normal or slightly high ALT, HBV DNA was detected in 4 (13.3%) patients, while in those with ALT flare, HBV DNA was detected in 19 (63.3%) patients (p<0.001). No association was found between the presence of HBV DNA and various serology markers of HBV infection.

Conclusion
Presence of occult hepatitis B, with its added deleterious effect, must always be considered in chronic hepatitis C patients especially those with flare in liver enzymes; HBsAg should not be used alone for the diagnosis of HBV infection.

Keywords: Hepatitis C, Flare of liver enzyme, Elevated aminotransferases, Occult hepatitis B

Source
HIV Medicine
Early View (Articles online in advance of print)

P Trimoulet 1,†, C Belzunce 2,†, M Faure 1, L Wittkop 3, S Reigadas 1, M Dupon 2, J-M Ragnaud 2, H Fleury 1, D Neau 2

Article first published online: 16 MAR 2011
DOI: 10.1111/j.1468-1293.2011.00913.x
© 2011 British HIV Association

Author Information

1 Virology Laboratory, Bordeaux University Hospital, Bordeaux, France
2 Department of Tropical and Infectious Diseases, Bordeaux University Hospital, Bordeaux, France
3 INSERM U897 Center of Epidemiology and Biostatistics, ISPED Bordeaux School of Public Health, University of Bordeaux 2, Bordeaux, France

* Correspondence: Dr Pascale Trimoulet, Laboratoire de Virologie, Hôpital Pellegrin Tripode, Place Amélie Raba-Léon, EA 2968, Bordeaux University Hospital, Bordeaux Cedex 33076, France. Tel: +33 5 56 79 55 10; fax: +33 5 56 79 56 73; e-mail: pascale.trimoulet@chu-bordeaux.fr

†† The first two authors contributed equally to the study

Abstract

Keywords: HCV protease inhibitor resistance; HCV protease; HIV/HCV-coinfected patients

Objectives

Data on the natural selection of isolates harbouring mutations within the NS3 protease, conferring resistance to hepatitis C virus (HCV) protease inhibitors (PIs), are limited for HIV/HCV-coinfected patients. The aim of this study was to describe the natural prevalence of mutations conferring resistance to HCV PIs in HIV/HCV-coinfected patients compared with HCV-monoinfected patients.

Methods

The natural prevalences of HCV PI resistance mutations in 120 sequences from HIV/HCV-coinfected patients (58 genotype 1a, 18 genotype 1b and 44 genotype 4) and 501 sequences from HCV-monoinfected patients (476 genotype 1 and 25 genotype 4), retrieved from GenBank as a control group, were compared.

Results

Of 76 sequences from HIV/HCV genotype 1-coinfected patients, six (7.9%) showed amino acid substitutions associated with HCV PI resistance (V36L, n=1; V36M, n=2; T54S, n=2; R155K, n=1). In 31 of 476 (6.5%) HCV genotype 1 sequences retrieved from the GenBank database, HCV PI resistance mutations were found. The difference was not statistically significant (P=0.6). All of the sequences from HIV/HCV genotype 4-coinfected patients and those retrieved from the GenBank database had amino acid changes at position 36 (V36L).

Conclusion

Our study suggests that the natural prevalence of strains resistant to HCV PIs does not differ between HCV-monoinfected and HIV/HCV-coinfected patients. Further studies on larger cohorts are needed to confirm these findings and to evaluate the impact of these mutations in clinical practice.

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Experts Propose Transmissible Gene Therapy to Halt the HIV Epidemic

March 18, 2011

Researchers have outlined an intriguing model that could help slow the spread of HIV better than test-and-treat models or a modestly effective HIV vaccine. Their theory, published online March 17 in the journal PLoS Computational Biology and reported by aidsmap, details how a gene therapy that curbs HIV production could be given to people with HIV. If these people were to have unsafe sex with someone else, they would pass along the gene therapy, essentially limiting the effects of HIV if the virus were to take hold in their sex partner.

The new gene therapy technology uses tiny pieces of genetic code called therapeutic interfering particles (TIPs) packaged inside of a lentivirus. The TIPs can’t reproduce on their own. They depend on genes produced by HIV. In the body of someone who is HIV-positive, the TIPs essentially steal HIV’s genetic material and, because they reproduce faster than the virus, outcompete HIV in the body and prevent it from replicating at its normally high rate.

If a person with both HIV and TIPs in the body were to have unprotected sex or share injection equipment with an HIV-negative person, they would theoretically be less likely to pass on HIV—because the TIPs have caused HIV levels to drop—but they would be likely to pass on the TIPs. The person infected with the TIPs would have the TIPs genes sitting dormant inside of them until they did acquire HIV. When that happens, the TIPs would hopefully keep their HIV levels low enough that they wouldn’t easily pass on HIV to others. What makes the technology so exciting is that giving the gene therapy to just one HIV-positive partner could spread TIPs throughout their entire sexual or drug-using network, thus substantially lowering HIV transmission rates for all involved.

“TIPs are molecular parasites that ‘piggyback’ on HIV [transmission networks] to spread between individuals,” said Leor Weinberger, PhD, from the University of California at San Diego, the senior scientist on the team.

Weinberger and his colleagues devised their model based on a desire to reach a critical juncture of high-risk individuals whom experts call “super spreaders.” Such individuals, who typically make up less than 20 percent of a sexual or drug-using network, are actually responsible for 80 percent or more of all new infections. Because such individuals are often not in care and are undiagnosed, they are incredibly difficult to reach.

Using data from several real world databases from areas in Africa with the most out-of-control HIV epidemics, Weinberger’s team conducted computer simulations that modeled the effect of five scenarios on the rate of new infections and overall prevalence of HIV over a 30- to 50-year period. Those scenarios included: aggressively testing all HIV-negative people and placing those found to be positive on treatment (test and treat), offering a 30 percent effective vaccine in a community, offering a 50 percent effective vaccine, using TIPs that reduce HIV levels by 0.5 logs in those infected and using TIPs that could reduce HIV levels by 1.5 logs.

The team found that either TIPs scenario cut HIV infections and prevalence by 30 to 50 times more than the test and treat approach or either vaccine. They estimate that that this huge difference in efficacy was due to the fact that TIPs spread quickly and easily throughout an entire sexual network, while test and treat and vaccine approaches rely on the laborious process of finding such individuals, usually long after they have acquired HIV and spread it to others.

The authors caution that there is a lot of laboratory and clinical work that must first be done before TIPs can be judged feasible enough to continue study. For one thing, the specific TIPs must be tested in animals first to ensure that they don’t actually amplify HIV replication rather than slow it down. Scientists will also need to judge how long the TIPs last in the body.

Weinberger said that his team will be working with medical ethicists to determine if it would be ethical to introduce a transmissible new therapy, such as TIPs, into a population of people.

Nevertheless, the authors comment that a single injection of TIPs into a relatively small number of HIV-positive people has the potential to far outstrip either test and treat or a vaccine in cutting new infections—and at a fraction of the cost.

Source

Hepatitis B: Top 10 Treatment Centers

Thursday, 17 Mar 2011 02:45 PM

Here are the top treatment centers for Hepatitis B, a liver disorder:

1. The Johns Hopkins Hospital, Baltimore, Maryland: It is not only one of the best hospitals in the U.S., but also ranks among the best hepatitis B treatment centers in the country. The hospital combines medical technologies such as epidemiology, host immune response, viral pathogenesis, and viral evolution studies to gain insight into the treatment and prevention of hepatitis B.

2. The Mayo Clinic, Rochester, Minnesota: This hepatitis B treatment center plays a pivotal role in spreading awareness among the public and vaccinating people. With high-tech facilities and proficient medical personnel, Mayo Clinic is certainly one of the best picks for patients combating this disease.

3. The Massachusetts General Hospital, Boston, Massachusetts: A member of the extensive hepatitis B research network, the viral hepatitis department here is one of the best when it comes to treating the disease. This hepatitis B treatment center has phlebotomy, diagnostic labs, and radiographic facilities on site. The microbial and histopathological evaluations of the hepatitis B treatment center are world-class. The clinical trials done at the treatment center are highly competent.

4. The Cleveland Clinic, Cleveland, Ohio: This treatment center places importance on educating the public on hepatitis B. With some of the best doctors and specialists in the country on board, the treatment center has some of the best practices for the treatment of hepatitis B.

5. The UCLA Medical Center, Los Angeles, California: The medical center is known for its liver programs and advanced treatment methods. The center also has a remarkable pediatric center for hepatic complications. Their "Asian Liver Program" is one of the best known hepatitis programs in the country.

6. The New York-Presbyterian University Hospital of Columbia: The hospital has remarkable statistics on curing patients with hepatitis B. The Center for Liver Disease and Transplantation at the center is one of the best of its kind in the U.S.

7. The University of California, San Francisco Medical Center: The center does not charge a fee for testing and charges a nominal fee for vaccination. It has done work in treating patients with hepatitis B disease. The treatment center has also been doing commendable work in spreading public awareness about the disease. The San Francisco Hepatitis B Collaborative, established in 2004, is one such example of the initiative.

8. The Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania: This hospital is one of the best hepatitis B treatment centers in the country according to The U.S. News and World Report. This center, with its dedicated team of doctors, has treated numerous patients with hepatitis B. It has adopted a thorough vaccination strategy.

9. The Duke University Medical Center, Durham, North Carolina: The medical center is a part of the "Hepatitis B Research Network," which brings together leading clinics with excellent hepatitis departments to combat the disease globally.

10. The University of Washington Medical Center, Seattle, Washington: The medical center in Washington has high-tech treatment methods and is part of the "Hepatitis B Research Network," one of the biggest such initiatives in the world.

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Test All Chemo Patients for Hepatitis B, Says NCCN Presenter

Nick Mulcahy

March 17, 2011 (Hollywood, Florida) — Every cancer patient undergoing chemotherapy should be tested for hepatitis B virus (HBV) infection, said a presenter here at the National Comprehensive Cancer Network (NCCN) 16th Annual Conference.

Chemotherapy and its related immunosuppression can cause a reactivation of HBV – "a potentially fatal and preventable disease," said Emmy Ludwig, MD, from Memorial Sloan-Kettering Cancer Center in New York City.

"Reactivation may complicate cancer therapy," said Dr. Ludwig, explaining that delays in treatment can result.

Testing allows infected patients — those with chronic infection or past exposure — to be treated with prophylactic antiviral oral therapy, which is an "extremely effective" means of preventing reactivation, she said. Dr. Ludwig also told the NCCN audience that 5% to 40% of reactivation cases will die of liver failure.

Currently, cancer patients treated with rituximab are routinely screened for HBV, said Dr. Ludwig. In 2004, the US Food and Drug Administration issued a warning that there was a risk for HBV-reactivation-related fatal fulminant hepatitis with rituximab.

However, the need to screen for HBV is often associated only with "high-risk" groups, said Dr. Ludwig, especially natives of Asia. But "profiling patients by country of birth misses patients — about half of them," she said.

Furthermore, she said that the HBV problem is "enormous" and that an estimated one third of the world has been "exposed" to HBV, meaning that they have a core antibody (HBcAb+), and that about 350 million people have chronic infection, meaning that they have a surface antigen (HBsAg+).

In the United States, an estimated 15 million people (5% of population) have been exposed and about 1 million have chronic infection.

Interestingly, the NCCN does not recommend universal testing for patients undergoing chemotherapy.

Instead, the NCCN says in its Prevention and Treatment of Cancer-Related Infections guideline, that, "in patients undergoing intensive immunosuppressive therapy, evaluation of HBV surface antigen, core antibody, and surface antibody should be considered at baseline." Patients with a surface antibody only (HBsAb+) are effectively immunized against HBV, noted Dr. Ludwig.

The NCCN also recommends evaluation in hematopoietic stem cell transplantation recipients and donors.

However, at least 2 NCCN institutions routinely test all chemotherapy patients for HBV. Memorial Sloan-Kettering does, said Dr. Ludwig. Their testing protocol was outlined at the American Society of Clinical Oncology (ASCO) 2010 Annual Meeting.

Stanford Comprehensive Cancer Center in Palo Alto, California, also tests for HBV, Robert Carlson, MD, told Medscape Medical News. Dr. Carlson is a breast cancer expert from Stanford who attended the NCCN meeting.

Another meeting attendee, Suzanne Cole, MD, from Charleston, West Virginia, was inspired by Dr. Ludwig's presentation. "I plan to personally screen all patients I am placing on chemotherapy for hepatitis B," she told Medscape Medical News.

"It is not difficult or expensive to screen for patients at risk for reactivation — I currently screen everyone who receives rituximab chemotherapy for hepatitis B," she added.

Dr. Cole also said that her group at the Charleston Area Medical Center might perform an observational study "to see how many patients we identify at risk for hep B reactivation."

"I hope we see more data emerge on the true risk of hepatitis B reactivation during chemotherapy," she said.

Dr. Ludwig said that the hepatitis C virus (HCV) is not comparable to the B virus with regard to activation. Immunosuppression from chemotherapy can increase HCV RNA levels, but related flares are "rare" and are "not preventable," she said.

Limited Data

The NCCN guideline says that the data are "limited" in support of antiviral therapy for active HBV infection in the context of cancer treatment.

Dr. Ludwig said that the data in support of prophylaxis have "major limitations." She cited a systematic review of 14 studies (2 randomized controlled trials, 8 prospective cohort studies, 4 retrospective cohort studies). Despite various shortcomings, the data collectively indicated that none of the patients in the studies receiving prophylactic lamivudine developed HBV‐related hepatic failure (0 of 108 patients vs 21 of 162 patients who received placebo).

The options for HBV treatment include lamivudine (which is no longer in favor because of drug-resistant viral mutations that occur with long-term therapy), entecavir (which is used at Memorial Sloan-Kettering), adefovir, tenofovir, and telbivudine.

Also, prevention is better than treatment after reactivation, according to the results of one study, said Dr. Ludwig.

In that study, 30 HBsAg+ lymphoma patients were randomized to either lamivudine treatment before chemotherapy (prophylaxis) or lamivudine treatment during chemotherapy if HBV DNA polymerase chain reaction levels increased. There was no HBV reactivation in the prophylaxis group, but in the delayed treatment group, 53% reactivated. Furthermore, there was no HBV acute hepatitis or liver failure in the prophylaxis group, whereas there was 47% in the delayed treatment group.

"Screening and prophylaxis appear to work," said Dr. Ludwig.

A number of organizations endorse universal screening for immunosuppressive therapy. The list includes the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, the American Gastroenterology Association, the World Gastroenterology Organization, the Asian‐Pacific Association for the Study of the Liver, the American College of Rheumatology, the Infectious Disease Society of America, the French Society of Rheumatology, and the Centers for Disease Control and Prevention.

ASCO does not recommend universal screening and says that randomized controlled trials are needed to establish reactivation rates and HBV-related complications, said Dr. Ludwig.

Dr. Ludwig argued that such trials might not be possible, that "other evidence of effectiveness is good," and that the potential benefits are "large."

"There are no randomized controlled trials to show that parachutes work," she argued.

Since instituting screening at Memorial Sloan-Kettering in 2006, the center has had only 3 reactivations, all of which were related to a failure to adhere to the treatment, said Dr. Ludwig.

National Comprehensive Cancer Network (NCCN) 16th Annual Conference. Presented March 10, 2011.

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In focus : Hepatitis B virus and co-infections

Mike Oyahkire 19/03/2011 00:00:00

HEPATITIS C virus (HCV):

According to the World Health Organization, there are at present 170 million people infected with the hepatitis C virus(HCV), equivalent to 3 percent of the total world population. Inc prd 40 to 50 days.

In some countries there are three to four times more patients living with HCV than with HIV/AIDS.

Commonly associated with homosexuals seropositive for HIV, tribes who practice body and ear piercing, for cultural or religious reasons, dangerous living-those having many sexual partners in a short time, and intranasal/intravenous drug users.

Liver damage and progression to liver failure is far worse and faster with HBV/HCV co infection.

Laboratory tests may not show HBsAg , but high mutation rate leaves surplus protein particles that can be assembled by other viruses for further invasion .

Alcohol even in small doses increase HCV replication and quickens onset of liver failure, particularly for patients in the age group 40 to 50 yrs.

Use of steroids has similar effects though through different mechanisms.

Heterosexual transmission is lower for HCV than for HBV

Progression to cancer is worse when cirrhosis develops.

Mother-to-child transfusion occurs in 5 percent of cases and this increases when there is coinfection with HIV I& II. At the moment, prevention of mother to child transmission for HCV is fruitless.

Hepatitis E virus( HEV)Incubation period is 14 to 65 days.

Genotype 2 is prevalent in Nigeria and it is strongly ssociated with immune depression.

Source - usually cytologist monkeys, pigs, deer, and humans.

Mother-to-child transmission is common but not through breast milk.

Obstetric complications are common and include DIC APH, IUD, with severe life-threatening bleeding, preterm birth and stillbirth. Fulminate hepatitis with jaundice constitute bad prognosis in pregnant women.

No treatment options are currently available other than close monitoring. Data for vaccine is inconclusive. Complication may also include kidney disease, lymphoma,- cancer of the blood other and, poly viral infection as earlier stated.

Hepatitis D

This variant is common amongst heroine addicts and homosexuals. With an incubation period of 14 to 85 days, Hepatitis delta (depend virus) is considered the most severe form of viral hepatitis in humans. The hepatitis delta virus (HDV) is a defective RNA virus which requires the hepatitis B virus (HBV) surface antigen (HBsAg) for complete replication and transmission. Hence, it is common in HBsAg-positive individuals either as acute co infection or as super infection in patients with chronic hepatitis B in 90 percent of cases.

Several studies have shown that chronic HDV infection leads to more severe liver disease than chronic HBV mono-infection. Course of fibrosis is accelerated as well as marked disease progression, an increased risk of hepatocellular carcinoma and early decompensation.

Animal experiments have shown that simultaneous HBV and HDV infection is more severe than infection with HBV alone in chimpanzees.

Acute HBV and HDV co-infection tends to be more severe than acute HBV infection alone, and super infection with HBV often occurs.

Hepatitis A virus ( HAV)

WHO estimates about 10 to 30 persons/10,000/year get their infection from unsafe drinking water.

Incubation period is 15 to 49 days, and major route of transmission is from faeces to mouth but also via anal sex and fisting sexual intercourse

Child-to-child transmission very important. Children may be asymptomatic, so, excrete the virus in daycare centers, nursery and primary schools.

Co-infection with HBV can change the immunological profile of the patient and in the setting of poor sanitation, inadequate water supply, children are at risk at home and in the nursery schools.

In one study, it was found that two years old children placed their hands in their mouth every two (2) minutes . Infected parents can therefore transmit the disease to the communities through their children.

A severe fulminant course of HAV with hepatic failure is found more often in patients with underlying liver disease. Patients with chronic hepatitis C have a greatly increased risk of hepatic failure, while HBV co-infection is less dangerous.

Pathogenesis and virulence

Commonalties exist; most of them prefer the liver of humans to organs of other animals.

Nearly all elements regulating virus transcription have building sites for liver specific transcription factors.

The three laboratory specific surface proteins of HBV are believed to function as activators of transcription, but the presence of HBsAg may indicate less tendency to chronic liver disease meaning that in cases of co-morbidity with HIV, we need to check what antiretroviral agents the patient is getting.

HCV is cytolytic and can accelerate the progression of HBV down hill.

90 percent of cases of HIV co-infection with HIV leads to chronic hepatitis with very poor prognosis.

Cancer of the liver in HCV infection is probably due to prolonged immune reaction and the resultant chronic inflammation.

Several different virus induced immune escape mechanisms

Co infection with HSI & II promotes rapid CD4 depletion giving rise to opportunistic and other infections.

Reverse transcription - errors leading to mutations repair system overload.

Transcription as cellular genes

Together with proliferation – act as transforming genes and hence to cancer.

Faulty proof reading of the RNA dependent RNA polymerase leads to the production of large quantities HBV and HCV mutations every day.

A cellular protein, cyclophilin B expressed in many human tissues is involved in HCV replication.

- Ethnically - Duffy gene variants in Nigerian Africans.

- Obesity – the Leptin/C D 4 relationship or ratio – High cholesterol HDL, LDL & VDL may promote HCV replication

A fat matured lady is less likely to contract HIV compared with a slim young lady swhereas the opposite is the case if it is HCV.

Source

Antioxidant supplements for liver diseases

Bjelakovic G, Gluud LL, Nikolova D, Bjelakovic M, Nagorni A, Gluud C

Summary

Antioxidant supplements for liver disease

Beta-carotene, vitamin A, vitamin C, and vitamin E cannot be recommended for treatment of liver diseases.

An imbalance between too much oxidative stress and too little antioxidative defence has been suggested to cause a variety of liver diseases. Therefore, antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) could have a potential role in patients with liver disease. The evidence on whether antioxidant supplements are effective in treatment of liver diseases is contradictory.

In this review treatment with antioxidant supplements of alcoholic, autoimmune, hepatitis B or hepatitis C virus liver diseases, or liver cirrhosis is assessed. The review includes 20 randomised clinical trials. In total, 1225 participants were randomised to antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention. The low number of randomised participants increases the risk of random errors ('play of chance'). Trial quality was low and accordingly the risk of systematic errors ('bias') was high.

Based on the conducted randomised clinical trials, convincing evidence that beta-carotene, vitamin A, vitamin C, and vitamin E or their combinations are beneficial for treatment of alcoholic, autoimmune, hepatitis B or hepatitis C virus liver diseases, or liver cirrhosis could not be found.

This is a Cochrane review abstract and plain language summary, prepared and maintained by The Cochrane Collaboration, currently published in The Cochrane Database of Systematic Reviews 2011 Issue 3, Copyright © 2011 The Cochrane Collaboration. Published by John Wiley and Sons, Ltd.. The full text of the review is available in The Cochrane Library (ISSN 1464-780X).

This record should be cited as: Bjelakovic G, Gluud LL, Nikolova D, Bjelakovic M, Nagorni A, Gluud C. Antioxidant supplements for liver diseases. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD007749. DOI: 10.1002/14651858.CD007749.pub2

Editorial Group: Hepato-Biliary Group

This version first published online: March 16. 2011
Last assessed as up-to-date: February 2. 2011

Abstract

Background

Several liver diseases have been associated with oxidative stress. Accordingly, antioxidants have been suggested as potential therapeutics for various liver diseases. The evidence supporting these suggestions is equivocal.

Objectives

To assess the benefits and harms of antioxidant supplements for patients with liver diseases.

Search strategy

We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science to January 2011. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials.

Selection criteria

We considered for inclusion randomised trials that compared antioxidant supplements (beta-carotene, vitamin A, C, E, and selenium) versus placebo or no intervention for autoimmune liver diseases, viral hepatitis, alcoholic liver disease, and cirrhosis (any aetiology).

Data collection and analysis

Four authors independently selected trials for inclusion and extracted data. Outcome measures were all-cause mortality, liver-related mortality, liver-related morbidity, biochemical indices at maximum follow-up in the individual trials as well as adverse events, quality-of-life measures, and cost-effectiveness. For patients with hepatitis B or C we also considered end of treatment and sustained virological response. We conducted random-effects and fixed-effect meta-analyses. Results were presented as relative risks (RR) or mean differences (MD), both with 95% confidence intervals (CI).

Main results

Twenty randomised trials with 1225 participants were included. The trials assessed beta-carotene (3 trials), vitamin A (2 trials), vitamin C (9 trials), vitamin E (15 trials), and selenium (8 trials). The majority of the trials had high risk of bias and showed heterogeneity. Overall, the assessed antioxidant supplements had no significant effect on all-cause mortality (relative risk [RR] 0.84, 95% confidence interval [CI] 0.60 to 1.19, I2 = 0%), or liver-related mortality (RR 0.89, 95% CI 0.39 to 2.05, I2 = 37%). Stratification according to the type of liver disease did not affect noticeably the results. Antioxidant supplements significantly increased activity of gamma glutamyl transpeptidase (MD 24.21 IU/l, 95% CI 6.67 to 41.75, I2 = 0%).

Authors' conclusions

We found no evidence to support or refute antioxidant supplements in patients with liver disease. Antioxidant supplements may increase liver enzyme activity.

Source

March 17, 2011

REVIEW ARTICLE

By Richard Kim, MD 1, Michael T. Byrne, DO 2, Ann Tan, MD 3, Federico Aucejo, MD 2

March 17, 2011

1 H. Lee Moffitt Cancer Center, Tampa, Florida
2 Cleveland Clinic, Cleveland, Ohio
3 British Columbia Cancer Agency, Vancouver, British Columbia, Canada

ABSTRACT: The incidence of hepatocellular carcinoma is rising in many countries, including the United States. Approval of sorafenib(Drug information on sorafenib) (Nexavar) as the first targeted therapy for treatment of advanced hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. The approval was based on two large randomized phase III trials from the Western and Eastern hemispheres that showed an overall survival benefit compared with placebo in patients with well-preserved liver function. The exact indication for sorafenib is unclear, however. The US Food and Drug Administration (FDA) authorized use of sorafenib for “unresectable HCC,” an indication which is very broad, vague, and confusing. Less is known about the effects of sorafenib in patients with decompensated liver disease, or of sorafenib in combination with local therapy or in a transplant setting. Prospective trials are lacking in these areas. We will review current data on use of sorafenib in HCC.

Hepatocellular carcinoma (HCC) in the United States accounts for approximately 23,000 new cases annually.[1] The incidence of HCC continues to increase, partly as a result of the unsolved problem of hepatitis C and deficient screening in high-risk patients. Globally, HCC is the fifth most common cancer worldwide and the third most common cause of cancer mortality.[2] The only potentially curative options for patients with HCC are liver resection, radiofrequency ablation (RFA), and liver transplantation (LT). Patients who are fortunate enough to undergo LT have a 4-year survival rate of 85% if the tumors are within the Milan criteria. Recurrence rates in this patient population range from about 8% to 12%.[3] However, among patients undergoing hepatic resection in whom the procarcinogenic liver is not replaced, the disease recurrence rate can exceed 70% at 5 years.[4] Other noncurative options include local therapies such as transarterial chemoembolization (TACE), radioembolization, RFA, and systemic therapy.[5] Advanced HCC carries a very poor prognosis, and use of cytotoxic agents has provided only marginal benefit.[6,7]

In 2007, sorafenib was approved in United States and Europe for ad- vanced HCC based on results from the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial.[8] Sorafenib is an oral multikinase inhibitor that blocks tumor cell proliferation by targeting multiple pathways including the Raf/mitogen-activated protein kinase/extracellular signal–regulated kinase (Raf/MEK/ERK) signaling pathway, along with tyrosine kinases (TKs), VEGF receptor 2 (VEGFR-2), VEGFR-3, and the platelet-derived growth factor receptor β (PDGFR-β) pathway.[9] In the landmark SHARP trial, 602 patients with advanced HCC were randomized to either sorafenib at 400 mg twice a day or to placebo.[8] The final result showed that sorafenib had overall survival (OS) and time to tumor progression (TTP) benefits in patients with advanced HCC, compared with placebo. Median OS was 10.7 months in the sorafenib group and 7.9 months in the placebo group. In Asia, a similar phase III trial was being conducted simultaneously. This trial also showed a similar magnitude of benefit in the sorafenib arm compared with the placebo arm.[8,10] Based on these two phase III trials, sorafenib became the first molecularly targeted therapy to show an OS benefit, establishing it as the first new standard treatment for advanced HCC.

The new data are now being met with cautious optimism, but there are several unanswered questions. The US Food and Drug Administration (FDA) authorized use of sorafenib for patients with “unresectable hepatocellular carcinoma,” a very vague and broad indication. In Europe, the indication is even broader, as sorafenib is indicated for “hepatocellular carcinoma.” Therefore, the exact indication for sorafenib in advanced HCC is confusing and gives rise to many uncertainties, including use of sorafenib in patients with decompensated liver disease, use in conjunction with local therapy, or use in a transplant setting.

Most of the patients enrolled in these large phase III trials had well-compensated liver function (Child-Pugh A cirrhosis); therefore the utility of sorafenib in Child-Pugh class B or C cirrhotic patients remains unknown. Also unclear is the potential role of sorafenib in combination with locoregional therapies, as well as its potential use in liver-transplant settings. The safety and feasibility of the implementation of sorafenib as a pretransplant neoadjuvant agent, or as an adjuvant therapy for posttransplant HCC recurrence, are uncertain. These practical questions have to be addressed as we deal with a complex disease in which an oncologic state evolves from conditions of liver dysfunction or immunosuppression. In this review article we will discuss the current data on, and future role of, sorafenib in the treatment of HCC beyond Child-Pugh A cirrhosis, in conjunction with local therapy, and in a transplant setting. The role of sorafenib in combination with other targeted therapies or other promising agents in the treatment of advanced HCC is beyond the scope of this article and will not be discussed.

Sorafenib in Child-Pugh B or C Cirrhosis

The safety and efficacy of sorafenib have been proven in patients with Child-Pugh A cirrhosis based on the aforementioned two large phase III trials. Little is known about the safety and efficacy of sorafenib in patients with Child-Pugh class B or C cirrhosis. Nevertheless, since there are no other effective treatments for cirrhotic patients with advanced disease, many single institutions have used sorafenib in these patients.

Prior to the SHARP study, a phase II trial by Abou-Alfa et al analyzed use of sorafenib in both Child-Pugh A and B cirrhotic patients.[11,12] In this trial, out of 137 patients, 38 had Child-Pugh B cirrhosis and 99 had Child-Pugh A cirrhosis. In the analysis of the study, toxicity profiles for Child-Pugh A and B cirrhosis, drug discontinuation rates, and dose reduction rates were similar in both groups. Nevertheless, overall outcome was much worse in the Child-Pugh B group, with an overall survival (OS) outcome of 3.5 months and time to tumor progression (TTP) of 3.3 months. Another large retrospective study from the Western Hemisphere, by Pinter et al, included 23 patients with Child-Pugh B cirrhosis and 10 with Child-Pugh-C cirrhosis.[13] Results revealed an OS of 4.3 months and a TTP of 2.9 months in the Child-Pugh B group, similar to findings from the phase II trial by Abou-Alfa et al. In the Child-Pugh C group, however, OS was only 1.5 months, and the authors concluded that sorafenib should not be used in patients with advanced-stage cirrhosis.

Two of the largest Asian experiences in patients with Child-Pugh B cirrhosis are described in studies from Korea, where hepatitis B is the number one risk factor for HCC. Lee et al reported on 29 patients with Child-Pugh B cirrhosis who received sorafenib and exhibited an OS of 3.7 months.[14] Another series included 23 patients with Child-Pugh B cirrhosis; TTP was 2 months but OS was not reported.[15] Results of other small series that included patients with Child-Pugh B cirrhosis are listed in Table 1.

In terms of drug-related toxicity profiles, most of these retrospective analyses did not distinguish between Child-Pugh A and B cirrhosis. Four of the studies did attempt to make a distinction, however, and the toxicities are outlined in Table 2.

There are data showing no statistically significant difference in the pharmacokinetics (PK) of sorafenib in Child-Pugh A versus Child-Pugh B patients.[11] A phase I trial conducted in Japan also showed no substantial differences in the incidence of adverse events or clinically relevant differences in PK between the Child-Pugh A and B groups.[16] Overall, toxicity profiles for Child-Pugh B patients seem to be similar to or slightly worse than those for Child-Pugh A patients (see Table 2). However, toxicity reflecting worsening hepatic dysfunction, such as hyperbilirubinemia, encephalopathy, and ascites, appears to be to be greater in Child-Pugh B patients. Notably worsening bilirubin levels were reported in 40% of Child-Pugh B patients, compared with 18% of Child-Pugh A patients.[11] Nevertheless, because direct bilirubin levels were not reported, it is unclear if the rise in total bilirubin was related to sorafenib as a result of decreased bilirubin glucuronidation; this can increase indirect bilirubin or cause pre-existing hepatic dysfunction to worsen, which usually increases direct bilirubin levels. Interestingly, it seems that patients with hepatitis B may have a higher chance of developing liver toxicity from treatment with sorafenib. A phase II trial by Yao et al did not break down all of the toxicity findings by Child-Pugh class, but it did report a 73% rate of grade 3 or 4 liver toxicity among patients with Child-Pugh B or C cirrhosis.[17] Even though this finding was not statically significant compared with the high rate of liver toxicity seen in Child-Pugh A patients, it does raise an eyebrow. One of the hypotheses that may explain this result is that administration of targeted therapy can lead to reactivation of the underlying hepatitis B infection and, consequently, can worsen liver function.[18,19]

Efficacy of sorafenib in Child-Pugh B patients in the small series reported in the medical literature seems to be very modest, with OS ranging from 2–5 months. Difficulty in evaluating survival in Child-Pugh B patients has to do with the coexistence of HCC and advanced-stage liver disease. Patients who have Child-Pugh B cirrhosis without HCC have a 1-year survival rate of about 80%.[20] Therefore, deaths from cirrhosis could potentially mask treatment-related antitumor efficacy. The potential for a clinically meaningful gain in OS with use of sorafenib in Child-Pugh B patients can only be evaluated in a prospective, randomized, placebo-controlled trial. However, placebo-controlled trials in Child-Pugh B patients will be very difficult in an era in which drug regulatory agencies allow sorafenib to be used to treat patients with HCC and any degree of liver failure.

These retrospective analyses, therefore, give us important insights into use of sorafenib in Child-Pugh B patients, despite their obvious limitations. It is hoped that, as more institutions publish their experiences with incorporating sorafenib into the treatment of patients with advanced cirrhosis, we will gain further knowledge about its efficacy and toxicity profiles in a variety of patient settings.

In the future, instead of lumping all Child-Pugh B cirrhosis patients together in the outcomes analysis, we should consider categorizing them into subgroups. For example, Child-Pugh B patients with a Child-Pugh score of 7 may have a better outcome with sorafenib than those with a score of 8 or 9. Unfortunately, HCC patients who are classified as having Child-Pugh C disease will most likely not benefit from any therapeutic options except for LT secondary to liver cirrhosis. Quality of life also should be part of the assessment, given that OS in most patients with HCC and Child-Pugh C disease is measured in months.

GIDEON (Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and Of its Treatment with Sorafenib) is an ongoing global, prospective, noninterventional study of patients with unresectable HCC and for whom the decision has been taken to treat with sorafenib under real-life practice conditions.[21] The purpose of this study is to evaluate the safety and efficacy of sorafenib in different subgroups, especially in patients with Child-Pugh B disease, or in conjunction with local therapy, a treatment option for which data are limited. The plan is to accrue more than 3,000 patients, and the findings are likely to provide us with valuable information about certain HCC patient subgroups.

Meanwhile, until more definitive data become available, it is imperative that clinicians employ caution and their best judgment when using sorafenib in patients with Child-Pugh B cirrhosis. As expected, patients with Child-Pugh C cirrhosis had a very poor outcome despite being on sorafenib, with median survival times between 2 and 3 months.[13,22] The poor outcome is most likely related to underlying liver cirrhosis, so it is highly unlikely that sorafenib or any other therapy will provide those patients with clinically meaningful benefits. Biomarker development or new information about tumor characteristics that identify subgroups of patients who may respond to sorafenib independent of Child-Pugh stage may be helpful in the future.

Sorafenib Plus Local Therapy

There is a good rationale for using sorafenib(Drug information on sorafenib) in conjunction with local therapy such as transarterial chemoembolization (TACE) or radioembolization. A study from China showed that TACE before hepatic resection enhances angiogenesis in HCC cells by upregulating the expression of vascular endothelial growth factor (VEGF).[23] Importantly, however, it has been shown that after the TACE procedure there is a rise in serum VEGF levels, which can feed the residual cancerous tissue and allow tumor cell proliferation.[24] Because of this, it might be beneficial to add an antiangiogenic agent to repress tumor angiogenesis after the patient has received therapies to induce tissue ischemia, such as TACE. Another potential advantage of these combinations is that use of an antiangiogenic systemic agent might enable control of systemic tumor cell spread. In the SHARP study, about 50% of patients did receive some form of local therapy prior to treatment with sorafenib.[8]

TACE is the most common local therapy used in patients with HCC. Transarterial radioembolization has been implemented in recent years, and even more recently, drug-eluting beads loaded with doxorubicin(Drug information on doxorubicin) (Adriamycin) have been used. TACE involves the injection of chemotherapeutic agents into the artery feeding the tumor, using lipiodol (Ethiodol) as a carrier. It is traditionally used for treatment of large unresectable HCCs that are not eligible for other treatments such as resection, RFA, or liver transplantation. Although data on TACE are controversial, there are two randomized controlled trials and a meta-analysis that support use of TACE in patients with advanced HCC.[25-27] Drug-eluting beads loaded with doxorubicin have an advantage over standard TACE in that they can deliver higher levels of chemotherapy released to the target over time, thereby decreasing potential systemic side effects. A recent randomized phase II trial comparing conventional TACE versus drug-eluting-bead (DEB) embolization showed that DEB embolization was associated with better response and better patient tolerance than standard TACE.[28]

Another local mode of therapy that is gaining popularity is radioembolization using intrahepatic arterial administration of yttrium 90 (Y90)-tagged glass (TheraSphere) or resin (SIR-Spheres) microspheres. Because HCC is a hypervascular tumor, micropsheres injected intraarterially will preferentially deliver to the tumor-bearing area and selectively emit high energy, high-penetrating-power radiation to the tumor. One of the advantages of radioembolization is that it can be used safely in patients with portal vein thrombosis, because it is less embolic and spares the arterial blood flow to the treated liver parenchyma. While multiple trials show that radioembolization has some antitumor activity, there are no prospective data showing improved survival benefits compared with placebo or TACE.[29,30]

Table 3 provides currently available information about the combination of sorafenib with local therapy. As one can see, most of the trials are small retrospective or prospective studies in only abstract forms, with the exception of one phase III trial. This trial was presented at the 2010 Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology.[31] Investigators randomized patients with advanced HCC to TACE alone versus TACE plus sorafenib. In this trial, sorafenib was started a mean of 9.1 weeks after TACE. The primary endpoint was TTP. Despite the sound rationale for administering combination therapy, the trial did not meet its primary endpoint. There were several study limitations, however: Most patients only received one course of TACE despite the fact that most had bilobar disease; the rationale for this is unclear. The duration of treatment with sorafenib was relatively short, with a high rate of discontinuation (45%) secondary to adverse events. Inclusion criteria in this study were very heterogeneous, with patients having fewer than 3 lesions or up to 10 lesions. In addition, definitions of complete response and progression were unclear in the study. It is hoped that the investigators will answer some of these questions in the published manuscript.

Combination of radioembolization using Y-90 SIR-Spheres or DEB embolization and sorafenib also has been studied (seeTable 3). The largest series using radioembolization with sorafenib was done in Asia.[32] The trial included 35 patients with Barcelona Clinic Liver Cancer (BCLC) stage B and C disease. Results were a cause for optimism, with 33% of patients achieving a complete or partial response. The combination was well tolerated, as there were only three treatment-related adverse events of grade 3 and above reported. The largest series assessing combination of sorafenib with DEB was presented by a group from Johns Hopkins.[33] Preliminary analysis reveals that the combination appears to be safe, as it did not result in any greater toxicities than were seen with either therapy alone. The outcomes of this trial have not been reported.

In conclusion, trials evaluating local therapy with and without sorafenib are very small and too premature. Most have been communicated only in the form of study abstracts, leaving many questions unanswered. Primary endpoints and response criteria were not well defined in most of these studies. Because of these factors, no robust conclusion can be drawn in regard to the combined therapies investigated thus far. The critical question that needs to be answered is whether the addition of sorafenib to local therapy induces a better outcome than local therapy alone. Okita et al attempted to answer this question in a phase III trial,[31] but failed to do so because of several limitations.

There are other lingering questions as well. For example, when should we initiate treatment with sorafenib? Maybe it makes sense to start sorafenib prior to TACE in order to block upregulation of VEGF in the tumor as well as in serum. Should we stop sorafenib 1 to 2 days prior to initiating local therapy, given the concerns about toxicity? As one can see in Table 3, the schedule of sorafenib administration is different in each trial. Another major problem is the lack of consistency regarding the frequency of scheduling TACE procedures and the type of chemotherapy agent or embolic material used. In the past, TACE has been given as frequently as two courses per month, but under this schedule it has induced hepatic decompensation in 7.5% of patients.[26,34] Clearly, the toxicity profile needs to be closely looked at with these combinations. Large phase II and III studies underway are using a combination of local therapy plus sorafenib; the outcomes of these trials are eagerly awaited. It is hoped that, as these data become more mature and as these studies are developed into full manuscripts, we will have better insights into these trials. In oncology, we have learned from the past that one plus one does not always equal two, and sometimes can equal zero. Therefore, careful consideration must be given prior to combining sorafenib with local therapy in patients with HCC.

Sorafenib and Liver Transplantation

The neoadjuvant setting

If disease is caught at an early stage, then LT is a potential curative option. However, the shortage of donor organs leaves waitlisted patients at risk for disease progression beyond transplant criteria. Prevention of waitlist dropout has fueled investigation into a wide array of locoregional therapies as “bridging therapy” or neoadjuvant therapy prior to LT. The purpose of these therapies would be to decrease the dropout rate, to prevent tumor progression, and possibly to increase overall survival. Currently most of the transplant institutions are implementing some form of neoadjuvant therapy despite the lack of randomized prospective data.[35]

Sorafenib potentially can be used as a neoadjuvant therapy in patients awaiting LT, since the drug can extend the time to disease progression. Another possible use of sorafenib would be in patients who are not candidates for local therapy secondary to elevated bilirubin levels. There is a phase I trial showing that sorafenib can be used in patients with bilirubin levels > 1.5 times but < 3 times the upper limit of normal (ULN) with dose reduction.[36] Using sorafenib in patients with bilirubin levels > 3 times the ULN may be problematic, however, as patients in the phase I trial could not even tolerate a dosage of 200 mg every other day.

One analysis by Vitale et al, using the Markov model, showed that sorafenib given as neoadjuvant therapy can be cost-effective in comparison with no therapy for Milan criteria HCC patients waiting for LT, particularly for median times to LT that are < 6 months.[37] There is concern associated with the use of sorafenib in pretransplant patients, however.

Because sorafenib is a VEGF inhibitor, there is an associated risk of bleeding and/or wound healing complications. Bevacizumab (Avastin), a monoclonal antibody to VEGF, has been used as neoadjuavnt therapy prior to liver resection for advanced colorectal cancer.[38] Yet the antiangiogenic effects of bevacizumab(Drug information on bevacizumab), coupled with its long half-life (approximately 21 days), have led to concern that preoperative bevacizumab may affect liver regeneration and wound healing, requiring a waiting period of at least 6 weeks after the last dose of bevacizumab before performing surgical resection.[38-40] Sorafenib has an advantage over bevacizumab in that it has a much shorter half-life, but safety data prior to surgery are sorely lacking. The only prospective data that we have are in renal cell carcinoma patients who received sorafenib prior to nephrectomy; sorafenib was held at 24–48 hours prior to surgery, and no surgical complications were seen.[41] In a transplant setting, waiting 24 hours after sorafenib intake is not feasible, as a donor liver can become available at any time.

Therefore, the treatment safety profile is of the utmost importance. Currently there are no prospective trials reported, but several case reports have been published in which sorafenib has been used as a neoadjuvant agent in the pretransplant setting.[42,43] In those small case reports, there were no unforeseen surgical complications. Currently there is a small pilot study ongoing at the Cleveland Clinic to investigate the safety and feasibility of using sorafenib in HCC pretransplant patients.

The adjuvant setting

Patients whose HCC falls within the Milan criteria and who undergo LT tend to have a favorable outcome, but patients with high-risk tumor features (HCC beyond the Milan criteria, poorly differentiated tumors, presence of microvascular spread or satellite lesions) have a significantly higher rate of posttransplant tumor relapse.[44] Naturally, therefore, it will make sense to conduct a trial using an effective systemic agent in an adjuvant setting to prevent tumor recurrences. An ongoing multicenter international trial (STORM: Sorafenib as Adjuvant Treatment in the Prevention of Recurrence of Hepatocellular Carcinoma) is evaluating the efficacy of sorafenib in preventing tumor recurrence after liver resection or RFA. This trial does not include transplant patients, however, owing to safety concerns associated with the interaction with immunosuppressive agents. There is an ongoing pilot study assessing the safety of sorafenib as an adjuvant therapy in patients with high-risk features of recurrence after LT. The main concern would be the short-term and long-term toxicities associated with the use of sorafenib in immunosuppressed patients.

Sorafenib for post-transplant recurrent HCC

Another area of interest is the use of sorafenib in patients with recurrence of HCC after LT. Currently no standard therapy is available for these patients. In the large phase III SHARP and Asia Pacific trials, patients who experienced a recurrence after transplant were excluded. The use of this drug in recurrent HCC after LT has therefore never been studied prospectively. Similar to the adjuvant setting after LT, a concern in transplant patients with recurrent HCC is the potential interaction between immunosuppressive medications and sorafenib. Even though there are no prospective trials in this setting, many institutions have reported their experience with the use of sorafenib in posttransplant patients who have tumor recurrences. Table 4 describes those findings. So far, only a few published reports exist, with little detailed information. In terms of its safety profile, however, it definitely seems feasible to use sorafenib concomitantly with immunosuppressive medications. The largest series, which have been published by investigators from Korea, the University of Miami, and the Cleveland Clinic, show that toxicities of sorafenib were quite manageable with dose reduction.[45-47] The main difference was that the data from Korea only included patients who had HCC recurrence after living donor transplantation; this reflects a difference in the practice pattern in Korea, as most of the transplants in the United States are from cadaveric livers. Overall results seem to be promising, but based on the small sample sizes of these studies, conclusions cannot be made regarding efficacy in this setting. It would be ideal, then, to conduct a randomized prospective trial to determine the efficacy of sorafenib versus placebo in patients who have disease recurrence after LT, since there is no standard therapy.

For a variety of reasons, however, it will be difficult to conduct a randomized prospective trial of sorafenib against placebo. First, the number of recurrences after transplant is quite small compared with advanced HCC patients in the pretransplant setting; thus, a much longer time would be required for the trial to accrue patients, which might not be feasible. Second, there is the issue of randomizing patients to a placebo arm when sorafenib is already available in the market. To begin, it would be reasonable to conduct a phase I trial to find out the correct dose of sorafenib to use in this setting, since most of the retrospective studies have required dose reduction secondary to toxicity. Then, a small phase II trial could be conducted with a single arm of sorafenib and comparing OS data against historical data, or a randomized phase II study could compare sorafenib against placebo, with patients on the placebo arm allowed to cross over upon progression. These trials would still require collaboration from many institutions in order to accrue in a timely fashion, and PK studies would be helpful as well.

Conclusion

In summary, the approval of sorafenib marks a major advance in the treatment of advanced HCC. Even though the indication for sorafenib is for patients with unresectable HCC, the published data and clinical experience thus far do not provide definitive conclusions about the use of sorafenib in advanced HCC patients with cirrhosis beyond Child-Pugh A classification. Most of the data reviewed in this article were from small-scale prospective or retrospective studies, resulting in a low level of evidence.

It is important that clinicians continue to exercise caution and their best judgment when treating patients with HCC beyond Child-Pugh A, until more definitive data become available. Ideally we would like to have prospective data for each Child-Pugh classification. While there are ongoing prospective trials—for example, those investigating sorafenib in combination with local regional treatment, as previously noted—for various reasons there are certain circumstances in which prospective trials will not be conducted. Indeed, there are many limitations to the current retrospective data, including lack of randomization to specific treatment arms and the lack of a placebo-control arm. These factors limit robust evaluation of the efficacy of any treatments received by these patients. Despite the limitations of retrospectively designed studies, information from retrospective/single-institution studies provides us with important insights to aid in decision-making when treating patients with end-stage liver disease complicated by HCC. In the future, as more retrospective and prospective data become available, we will be able to determine the best treatment options in a variety of settings and stages of liver disease, in order to maximize the outcome and benefits for our patients.

Financial Disclosure: Dr. Kim receives an honorarium from Bayer/Onyx. Dr. Byrne, Dr. Tan, and Dr. Aucejo have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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10. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25-34.

11. Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24:4293-300.

12. Abou-Alfa GK, Amadori D, Santoro A, et al. Is sorafenib (S) safe and effective in patients (pts) with hepatocellular carcinoma (HCC) and Child-Pugh B (CPB) cirrhosis? (Abstract 4518) J Clin Oncol. 2008(May 20 suppl)

13. Pinter M, Sieghart W, Graziadei I, et al. Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist. 2009;14:70-6.

14. Lee S, Kang Y, Chang H, et al. Sorafenib in patients with advanced hepatocellular carcinoma: experience in a single institute (abstract 256). Presented at the 2009 Gastrointestinal Cancers Symposium, San Francisco, CA, Jan 15-17, 2009.

15. Shim JH, Park JW, Choi JI, et al. Practical efficacy of sorafenib monotherapy for advanced hepatocellular carcinoma patients in a hepatitis B virus-endemic area. J Cancer Res Clin Oncol. 2009;135:617-25.

16. Furuse J, Ishii H, Nakachi K, et al. Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma. Cancer Sci. 2008;99:159-65.

17. Yau T, Chan P, Ng KK, et al. Phase 2 open-label study of single-agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B-endemic Asian population: presence of lung metastasis predicts poor response. Cancer. 2009;115:428-36.

18. Sera T, Hiasa Y, Michitaka K, et al. Anti-HBs-positive liver failure due to hepatitis B virus reactivation induced by rituximab. Intern Med. 2006;45:721-4.

19. Ikeda K, Shiga Y, Takahashi A, et al. Fatal hepatitis B virus reactivation in a chronic myeloid leukemia patient during imatinib mesylate treatment. Leuk Lymphoma. 2006;47:155-7.

20. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44:217-31.

21. Lencioni R, Marrero J, Venook A, et al. Design and rationale for the non-interventional Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and Of its Treatment with Sorafenib (GIDEON) study. Int J Clin Pract. 2010;64:1034-41.

22. Wörns MA, Weinmann A, Pfingst K, et al. Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma in consideration of concomitant stage of liver cirrhosis. J Clin Gastroenterol. 2009;43:489-95.

23. Xiao EH, Guo D, Bian DJ. Effect of preoperative transcatheter arterial chemoembolization on angiogenesis of hepatocellular carcinoma cells. World J Gastroenterol. 2009;15:4582-6.

24. Wang B, Xu H, Gao ZQ, et al. Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization. Acta Radiol. 2008;49:523-9.

25. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35:1164-71.

26. Marelli L, Stigliano R, Triantos C, et al. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol. 2007;30:6-25.

27. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003;37:429-42.

28. Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33:41-52.

29. Kulik LM, Carr BI, Mulcahy MF, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology. 2008;47:71-81.

30. Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology. 2010;138:52-64.

31. Okita K, Imanaka N, Chida N, et al. Phase III study of sorafenib in patients in Japan and Korea with advanced hepatocellular carcinoma (HCC) treated after transarterial chemoembolization (TACE) (Abstract LBA 128). Presented at the 2010 ASCO Gastrointestinal Cancers Symposium, Orlando, FL, Jan 22-24, 2010.

32. Chow PK, Poon D, Win KM, et al. Multicenter phase II study of SIR-sphere plus sorafenib as first-line treatment in patients with nonresectable hepatocellular carcinoma: the Asia-Pacific Hepatocellular Carcinoma Trials Group Protocol 05 (AHCC05) (Abstract 4072). J Clin Oncol. 2010;28:15s.

33. Reyes DK, Azad NS, Koteish A, et al. Phase II trial of sorafenib combined with doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) for patients with unresectable hepatocellular carcinoma (HCC): Interim safety and efficacy analysis (Abstract 254). Presented at the 2010 ASCO Gastrointestinal Cancers Symposium, Orlando, FL, Jan 22-24, 2010.

34. A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire. N Engl J Med. 1995; 332:1256-61.

35. Almhanna K, Kalmadi S, Pelley R, Kim R. Neoadjuvant therapy for hepatocellular carcinoma: is there an optimal approach? Oncology (Williston Park). 2007;21:1116-22.

36. Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol. 2009;27:1800-5.

37. Vitale A, Volk ML, Pastorelli D, et al. Use of sorafenib in patients with hepatocellular carcinoma before liver transplantation: a cost-benefit analysis while awaiting data on sorafenib safety. Hepatology. 2010;51:165-73.

38. Kesmodel SB, Ellis LM, Lin E, et al. Preoperative bevacizumab does not significantly increase postoperative complication rates in patients undergoing hepatic surgery for colorectal cancer liver metastases. J Clin Oncol. 2008;26:5254-60.

39. Karoui M, Penna C, Amin-Hashem M, et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006;243:1-7.

40. Ellis LM, Curley SA, Grothey A. Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J Clin Oncol. 2005;23:4853-5.

41. Cowey CL, Amin C, Pruthi RS, et al. Neoadjuvant clinical trial with sorafenib for patients with stage II or higher renal cell carcinoma. J Clin Oncol. 2010;28:1502-7.

42. Vagefi PA, Hirose R. Downstaging of hepatocellular carcinoma prior to liver transplant: is there a role for adjuvant sorafenib in locoregional therapy? J Gastrointest Cancer. 2010;41:217-20.

43. Kim R, Menon N, Aucejo F. Safe use of sorafenib in a patient undergoing salvage liver transplantation for recurrent hepatocellular carcinoma after hepatic resection. Med Oncol. 2010; Jul 16. [Epub ahead of print]

44. Molmenti EP, Klintmalm GB. Liver transplantation in association with hepatocellular carcinoma: an update of the international tumor registry. Liver Transpl. 2002;8:736-48.

45. Feun LG, Levi D, Moon J, et al. Sorafenib in hepatocellular carcinoma (HCC) patients after liver transplantation (Abstract e15579).. J Clin Oncol. 2009;27.

46. Yoon DH, Ryoo BY, Ryu MH, et al. Sorafenib for recurrent hepatocellular carcinoma after liver transplantation. Jpn J Clin Oncol. 2010;40:768-73.

47. Kim R, El-Gazzaz G, Tan A, et alet al. Safety and feasibility of using sorafenib in recurrent hepatocellular carcinoma after orthotopic liver transplantation. Oncology (Williston Park). 2010. 25:XXXX-XXXX.

48. Del Prete S, Montella L, Addeo R, et al. Sorafenib plus long-acting octreotide in advanced hepatocellular carcinoma. Preliminary results of a multicenter ongoing study (Abstract 15624). J Clin Oncol. 2008;26(15 May 20 Suppl).

49. Schuette K, Zimmermann L, Bornschein J, et al. Tolerability of sorafenib in the treatment of hepatocellular carcinoma (HCC) in patients with Child A and B liver cirrhosis (Abstract e15593). J Clin Oncol. 2009;27 Suppl)

50. Balsom SM, Li X, Trolli E, et al. A single-institute experience with sorafenib in untreated and previously treated patients with advanced hepatocellular carcinoma. Oncology. 2010;78:210-2.

51. Ozenne V, Paradis V, Pernot S, et al. Tolerance and outcome of patients with unresectable hepatocellular carcinoma treated with sorafenib. Eur J Gastroenterol Hepatol. 2010;22:1106-10.

52. Xu L, Li P, Lin XJ, et al. Clinical observation of sorafenib monotherapy in Chinese patients with advanced hepatocellular carcinoma. Zhonghua Zhong Liu Za Zhi. 2009;31:58-61.

53. Sinakos E, Dedes I, Papalavrentios L, et al. Safety of transarterial chemoembolization plus sorafenib combination treatment in unresectable hepatocellular carcinoma. Scand J Gastroenterol. 2010;45:511-2.

54. Duan F, Wang MQ, Liu FY, et al. Clinical observation of the treatment with combination of transcatheter arterial chemoembolization and sorafenib for hepatocellular carcinoma with lung metastasis. Zhonghua Zhong Liu Za Zhi. 2009;31:716-8.

55. Cabrera R, George T, Soldevila-Pico C, et al. Safety of sorafenib alone or in combination with locoregional therapy in patients with advanced hepatocellular carcinoma (HCC) and decompensated cirrhosis (Abstract 147). Presented at the 2008 ASCO Gastrointestinal Cancers Symposium, Orlando, FL, Jan 25-27, 2008.

56. Martin II RC, Keck G, Robbins K, et al. Evaluation of sorafenib in combination with doxorubicin-loaded DC bead as a combination treatment option for HCC (Abstract 216). Presented at the 2010 ASCO Gastrointestinal Cancers Symposium, Orlando, FL, Jan 22-24, 2010.

57. Chung Y, Kim B, Chen C, et al. Study in Asia of the combination of transcatheter arterial chemoembolization (TACE) with sorafenib in patients with hepatocellular carcinoma (HCC) trial (START): second interim safety and efficacy analysis (Abstract 4026). J Clin Oncol. 2010;28(15 May 20 Suppl).

58. Valdivieso A, Bustamante J, Gastaca M, et al. Management of hepatocellular carcinoma recurrence after liver transplantation. Transplant Proc. 2010;42:660-2.

59. Yeganeh M, Finn RS, Saab S. Apparent remission of a solitary metastatic pulmonary lesion in a liver transplant recipient treated with sorafenib. Am J Transplant. 2009;9:2851-4.

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FDA hearing set for Vertex Hep C drug

Boston Business Journal - by Julie M. Donnelly

Date: Thursday, March 17, 2011, 4:26pm EDT - Last Modified: Thursday, March 17, 2011, 4:57pm EDT

Vertex Pharmaceuticals Inc. (Nasdaq: VRTX) will glean some important insight into the fate of its closely-watched potential treatment for hepatitis C on April 28. The U.S. Food and Drug Administration has announced it will hold an advisory panel meeting on the drug candidate, called telaprevir, on that date. A positive report from the panel would be a good indication that telaprevir is likely to gain approval from the regulatory agency as a whole on May 23.

The drug aims to treat chronic hepatitis C genotype 1 infection, in combination with two already-approved drugs, in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy.

Vertex executives, investors and analysts are waiting with bated breath, because the approval of telaprevir would likely catapult Vertex into the elite of profitable biotech companies. Also waiting anxiously for an FDA decision is the city of Boston, which currently has a non-binding agreement with the Cambridge, Mass.-based biotechnology company to move across the river to the South Boston waterfront — but only if the drug is approved.

Vertex faces stiff competition in the hepatitis C space. The FDA advisory committee will discuss another potential treatment for hepatitis C, developed by Whitehouse Station, N.J.-based Merck & Co Inc (NYSE: MRK), on April 27.

In addition, Vertex saw its stock fall almost 5 percent March 8, after Princeton, N.J.-based Pharmasset Inc. (Nasdaq: VRUS) released positive late-stage data for its potential rival to Vertex’s drug candidate

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Also See: FDA Hepatitis Update - FDA Advisory Committee meeting to consider boceprevir and telaprevir, April 27 and April 28, 2011

Hepatitis C transmission still high among injection drug users

Nicole Blazek
March 17, 2011

Efforts to control blood-borne infections have dramatically reduced HIV incidence among injection drug users (IDUs), but declines in hepatitis C virus (HCV) infection have been less substantial, prompting health officials to call for better prevention and treatment strategies.

Incidence of HIV infection decreased from 5.5 cases per 100 person-years in a cohort of injection drug users recruited from 1988 to 1989 to zero cases per 100 person-years in a cohort recruited between 2005 and 2008.

In contrast, HCV infections declined from 22 cases per 100 person-years in the 1988 to 1989 cohort, to 17.2 per 100 person-years in a cohort recruited in 1994 and 1995. A slight increase to 17.9 cases was reported in another group recruited in 1998, before infections rates declined to 7.8 cases per 100 person-years from 2005 to 2008 (P=0.07).

The disparity in HIV and HCV reduction rates may be due to the fact that HCV is 10-times more transmissible than HIV, according to study researcher Shruti H. Mehta, MD, of the Johns Hopkins Bloomberg School of Public Health, in Baltimore, and colleagues.

Because HCV can be acquired after just one instance of needle-sharing, hazard reduction interventions such as needle exchange and substance abuse treatment programs that have been effective at reducing HIV, may have less of an impact. CDC estimates indicate that approximately one-third of IUDs share needles.

“Efforts need to be intensified on both the prevention and treatment fronts to reduce the reservoir of HCV-infected IDUs,” the researchers wrote in the March 1 issue of the Journal of Infectious Diseases.

To get a better understanding of HCV incidence in IDUs, they analyzed data from four cohorts of IDUs during a 20-year period (1988-1989, n=2,946; 1994-1995, n=391; 1998, n=244; 2005-2008, n=875).

The researchers found that compared with the 1988-1989 cohort, HCV incidence significantly declined among patients younger than 39 years in each subsequent cohort (adjusted prevalence ration=0.73; 95% CI: 0.65-0.81).

However, the same decreases were not observed in patients older than 39 years — among that age group HCV infection rates only declined in the most recent cohort (adjusted prevalence ratio=0.87; 95% CI: 0.77 to 0.99).

“For many persons, the interval between initiation and injection simply remains too brief for prevention strategies to be successful,” the researchers wrote.

They emphasized the importance of targeting prevention efforts towards very young IDUs and drug users who have not yet begun injecting. The other strategy for reducing the HCV reservoir is treatment, the efficacy of HCV treatment regimens is often limited among certain subpopulations including blacks with genotype-1 HCV and those with HIV coinfection, the researchers noted.

“With new, more efficacious therapeutics on the horizon, it is critical that strategies to improve uptake and completion of HCV infection treatment of IDUs be implemented,” they wrote.

Jason Grebely, PhD, and Gregory J. Dore, MBBS, PhD, of the University of New South Wales in Sydney, Australia, offered several suggestions for improving treatment and prevention.

“The development and implmentation of national harm-reduction strategies including broader coverage, enhanced early access and intesnifcation and combination of interventions are probably all needed,” they wrote.

Grebely and Dore also emphasized the importance of conducting randomized clinical trials to evaluate new HCV interventions to ensure that they are successful.

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by Meg Heckman

Published Mar. 16, 2011 12:02 pm
Updated Mar. 17, 2011 12:20 pm

Nearly two years ago, my boss suggested that I turn myself into a story.

I was halfway through a grueling round of experimental treatment for hepatitis C, a potentially-fatal liver disease I contracted as an infant. My experience had all the trappings of compelling journalism. There was a simple central tension — girl versus virus — and a simple, central question: Will she be cured? Plus, HCV is a sweeping, under-reported epidemic with the potential to cost billions of dollars and millions of lives.

The journalist in me knew all this was newsworthy, but it was Concord Monitor Editor Felice Belman who urged me to use myself as a source.

Over lunch one day, she sketched out her idea: a heavily researched, first-person narrative told in short, serial installments. The piece would explore the epidemic, the idea of medical research on humans and the reasons why so few people know about a virus that affects four times as many Americans as AIDS.

It was an ambitious project for many reasons. For starters, I felt awful. Antiviral medication can cause brutal side effects, and keeping up with my normal workload was already a struggle. Plus, the Monitor’s newsroom is small, and the demands on our time seem to grow every day.

The research and writing took months longer than expected, but we finished the project, called “My Epidemic,” last December. Each day for a week, we published a new chapter in print and online, and used social media to promote the series and to invite feedback.

The result was a profound reminder of the power of storytelling and an illustration of the potential for new media to allow our stories to live on.

Lesson 1: Share your story in a way that works for both print and online.

Yes, journalism has changed, but narrative is still effective, especially if it’s structured to work in print and online. We picked a serial format for reasons both practical and organic. The ups and downs and cliffhangers inherent in serial narratives mimic the reality of living with a chronic disease.

In print, multiple chapters were also easier to place in a tight news hole, and we had multiple opportunities to find space for graphics and photos. Online, each chapter gave us another chance to invite readers into the story through Facebook and Twitter, and to promote HCV resources we’d assembled on our website.

The project was a boon for online traffic. Visits to our website shot up 12 percent compared to December 2009 — by far the largest month-to-month increase in recent memory.

Lesson 2: Find documents, include details for context.

Writing about myself demanded more research than writing about someone else.

When I’m writing about other people, I try to climb inside their heads, which means many hours of watching them just live their lives. In this case, I needed to do just the opposite and place myself in the context of the broader epidemic.

My brother, a doctor, directed me to medical journals and helped me decipher the articles. A database at the local public library supplied archival information about media coverage of HCV, and the Congressional record revealed how public health officials are — or are not — responding to the epidemic.

The most important documents were my own medical records. They included detailed doctors’ notes about all the tests I’d undergone as a teenager and a time-stamped transfusion report that revealed exactly when I’d contracted HCV.

One of the hardest parts was choosing what to include, particularly when it came to describing my birth. There were so many details: my hurried baptism, my father sleeping on the waiting room floor, my parents in their Jeep following the ambulance from one hospital to another, not knowing if I was dead or alive. Those are all important pieces of family lore, but they didn’t advance the story. Including them would have been indulgent, a disservice to the reader.

Lesson 3: Be honest about your fears, discomfort.

I was a crummy photo subject.

For more than a decade, I’ve been trained to collaborate, collaborate and collaborate some more with visual journalists. That’s what I planned to do with this story, but it didn’t quite work out that way.

Photographer Katie Barnes joined the Monitor newsroom a few months after I’d started working on the project and was soon assigned to my story. I was hesitant to drag Katie through my medical hell, and I (irrationally) didn’t trust anyone but myself to get it right.

There were logistical challenges, too. One of the side effects of antiviral medication is temporary absentmindedness. In my case, that meant showing up to work with mismatched shoes, getting lost in the grocery store and forgetting to tell Katie when something important was happening.

Finally, she made me a list of things I might do — walk the dog, cook dinner, visit the acupuncturist — that would help her tell the story.

I know now what it means, what it feels like, to be the subject of someone else’s journalism. Our sources have so much at stake: their reputations, their public images, the truth of how they view themselves. Building trust with the people we cover is everything, and that’s why honest storytelling requires so much time.

Katie ultimately made my discomfort a part of the story, producing a video focused on my feelings about the project. I was terrified when I sat down in front of that camera, but we’d been working together for almost a year, and I understood that this was part of the story only she could tell.

Lesson 4: Tend the seeds you sow.

The response to the series was overwhelming. By the time the last installment was published, I had Twitter followers from Russia and my e-mail and voicemail were full of messages from other people living with HCV.

My editors and I decided to turn some of those responses into an impromptu seventh installment. As I was writing, I found myself wondering if such a swift, multifaceted (and international) reader response would have been possible a decade ago.

The story continues to live on. I receive new e-mails every week from people who have discovered the series, often through Facebook or Twitter. More often than not, they have a personal connection to HCV. Take, for instance, the teenage girl in California who, like me, contracted the virus as a baby and who, like me, has faced cruel judgment from her peers.

As I read the e-mail, I was devastated that another young woman had endured such fear, shame and humiliation. Then she told me that she showed her family and friends my stories and, at last, people began to understand.

Meg Heckman splits her time at the Concord Monitor between writing and exploring digital storytelling. She is a 2001 Poynter summer fellow and a graduate of the University of New Hampshire, where she now works as an adjunct instructor in the journalism program

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Also See: My Epidemic.....Shared and Written by Meg Heckman of the Concord Monitor