March 19, 2011

Herbal hepatotoxicity by kava: Update on pipermethystine, flavokavain B, and mould hepatotoxins as primarily assumed culprits

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


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
© 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Inc All rights reserved.


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


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.


Low-Dose Peginterferon Alfa-2a Is Safe and Produces a Sustained Virologic Response in Patients With Chronic Hepatitis C and End-Stage Renal Disease

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.


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.

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.

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.

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


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.

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.


Role of occult hepatitis B virus in chronic hepatitis C patients with flare of liver enzymes

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


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.

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.

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.

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


Hepatitis C virus (HCV) protease variability and anti-HCV protease inhibitor resistance in HIV/HCV-coinfected patients

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:

†† The first two authors contributed equally to the study


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


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.


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.


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).


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.


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.


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.


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.


In focus : Hepatitis B virus and co-infections

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


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.


Antioxidant supplements for liver diseases

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


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



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.


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.