July 27, 2010

Vienna Declaration Urges Global Decriminalization of Drug Use

Norra MacReady and Martha Kerr

July 27, 2010 (Vienna, Austria) — More than 13,000 clinicians, researchers, and public policy experts have signed a declaration calling for the global decriminalization of drug use and the implementation of evidence-based policies to halt the rampant spread of HIV infection among injecting drug users (IDUs).

Released here at AIDS 2010: XVIII International AIDS Conference, the document, known as the Vienna Declaration, states that in parts of Eastern Europe and Central Asia, where the spread of HIV is most rapid, infection "can be as high as 70% among people who inject drugs, and in some areas more than 80% of all HIV cases are among this group." Yet these countries have some of the most punitive antidrug laws in the world.

"The International AIDS Conference is a unique mix of advocacy, activism, and science that you don't see at other conferences," Evan Wood, MD, director of the Urban Health Research Initiative at the BC Centre for Excellence in HIV/AIDS in Vancouver, British Columbia, told Medscape Medical News. Dr. Wood was a coauthor of the Vienna Declaration.

The Vienna Declaration calls drug policy reform "a matter of urgent international significance" and states that the epidemic will continue to spread if more-effective policies are not adopted, said Stephen Rolles, MSc, senior policy analyst at the Transform Drug Policy Foundation, a think tank based in London, England.

"The conference...was shaped by the outpouring of support for the Vienna Declaration and the need for scientists to stand together to support illicit drug policies based on evidence instead of ideology," Dr. Wood observed.

In the 50 years since countries around the world have outlawed the manufacture and possession of certain types of drugs, "the situation in terms of any indicators you might choose — public health, human rights, criminal justice — has deteriorated," Mr. Rolles added.

"For a policy that specifically aims to create a drug-free world, to eradicate drug production, prevent drug supply, and eliminate drug use from the world, it's been a staggering failure. Every year since this policy was begun, we've moved further and further away from that goal," he continued.

"Using drugs in a certain way and in a certain environment criminalizes the lifestyle that tends to lead to the spread of HIV, and that's what the Vienna Declaration is focusing on," Mr. Rolles stated. "It's calling for a shift away from this get-tough criminal justice populism that has tended to define the debate, and move it towards a more pragmatic, evidence-based, public health, scientifically driven model."

The best evidence to date suggests that HIV-positive IDUs benefit most from a triple-pronged approach to treatment, consisting of opioid substitution therapy, needle and syringe programs, and antiretroviral therapy. These are the key elements of a harm-reduction approach, Mr. Rolles said, which acknowledges that some people may be unwilling or unable to abstain from use drugs and instead "focuses on reducing the harm associated with the use itself."

Outside of sub-Saharan Africa, IDUs account for about one third of HIV disease internationally. To stem the epidemic, countries and clinicians around the world must grant HIV-infected drug users access to adequate healthcare services without turning them into criminals, forced laborers, or pariahs.

Despite clear evidence that opioid substitution therapy works, it is not available in many of the countries in which the epidemic is worst. Worldwide, only 8 of every 100 IDUs have access to it.

"The science has really moved forward, but that there is either a lack of political will or worse when it comes to addiction," Dr. Wood added.

"Methadone is on the World Health Organizations List of Essential Medicines but is illegal in places like Russia, where other harm-reduction tools are also scarce. Not surprisingly, it is now estimated that more than 1 in 100 adult Russians is HIV infected," Dr. Wood pointed out.

"The health impacts of the war on drugs obviously go beyond HIV.... Incarceration is a huge problem, with 1 in 100 Americans now in prison, and obviously there is an intersection with HIV," Dr. Wood said. "One in 9 African-American males ages 25 - 35 is incarcerated in the United States on any given day, and obviously this is the population where HIV is spreading most rapidly in the United States.

"The Obama administration's lifting of the needle exchange ban federally and the announcement about allowing [the President's Emergency Plan for AIDS Relief] funding for needle exchange in advance of the meeting were obviously welcome," he added.

Daniel Wolfe, MPH, from the International Harm Reduction Program of the Open Society Institute in New York City, noted at the conference that 5 countries in particular — China, Vietnam, Russia, Ukraine, and Malaysia — claim 47% of all HIV-infected IDUs in low- and middle-income nations. In Russia, IDUs account for 83% of all HIV cases, and in Malaysia, they account for 70%. Yet only about 25% of the patients most in need are receiving antiretroviral therapy, and less than 2% have access to opioid substitution therapy.

Draconian policies against drugs and drug users often are motivated by the idea that adoption of harm-reduction policies is tantamount to approving of, or at least tolerating, drug use, said Mr. Rolles, who was not involved in the Lancet symposium.

"In some circles there's a saying that 'harm reduction equals harm facilitation.' Often this can be traced back to a moralistic, almost quasi-religious view of drugs as inherently evil that has not been closely scrutinized until recently," Mr. Rolles said. "And anyone who challenges this policy was seen as being on the side of evil, or at least on the side of [using] drugs."

The problem with prohibitionist policies is that they ignore the overwhelming evidence that the war on drugs has failed, Mr. Rolles added. As the Vienna Declaration states, "the international scientific community calls for an acknowledgement of the limits and harms of drug prohibition, and for drug policy reform to remove barriers to effective HIV prevention, treatment and care."

"There was a strong sentiment [at the conference] that WHO and UNAIDS have been largely marginalized within the UN system with respect to the problems of drug addiction and a hope that the declaration will help to change this," Dr. Wood said.

He continued, "My colleague and president of the International AIDS Society, Julio Montaner [professor of medicine and chair in AIDS Research at the University of British Columbia] announced that the declaration and all the endorsements would be delivered to Ban Ki-moon [secretary-general of the United Nations], although we are keep the timeline open on this because the declaration process is going to culminate when the meeting is in Washington, DC, at AIDS 2012.

"Certainly, the focus on drug addiction and drug policy was welcome by those working in this area, given how it has not received much attention in the past," said Dr. Wood. "However, the problems in Africa and elsewhere are obviously huge issues, [and] so certainly must be acknowledged. It was interesting how the different groups (eg, gay men, sex workers, those with HIV, drug users, etc) united under the banner of the need for a human rights approach [to HIV], and hopefully this will strengthen the overall effort to address the epidemic."

The Vienna Declaration can be viewed on its own Web site.

Dr. Wood is the brother of an editor at theheart.org, a Web site owned by WebMD, which also owns Medscape. None of the speakers have disclosed any other relevant financial relationships.

AIDS 2010: XVIII International AIDS Conference: Symposium TUSY07. Presented July 20, 2010.

Lancet. Published online July 20, 2010.


Merck Grants License to LabCorp for Development of Test To Potentially Identify Patients Likely to Respond to Hepatitis C Therapy

IL-28B Genetic Polymorphism May Help Predict Patient Response to Peginterferon Alpha-Based Hepatitis C Treatment

LabCorp has developed an in vitro genetic test designed to identify the presence of the IL-28B polymorphism in patients, which studies suggest may be associated with successful response to peginterferon alpha-based therapy, the current standard-of-care in HCV treatment.

“The discovery of a link between the IL-28B polymorphism and response to peginterferon alpha is a scientific finding that may potentially help identify a patient's genetic predisposition for successful response to HCV therapy," said Roger J. Pomerantz, M.D., F.A.C.P., global franchise lead for Infectious Diseases and senior vice president, Merck Research Laboratories. "Viral hepatitis remains a key focus at Merck, and we are committed to seeking solutions that advance patient care, including treatment approaches that are tailored to patient response."

The association of IL-28B polymorphism with peginterferon alpha response was identified by Merck in collaboration with other researchers through a genome-wide association study of nearly 1,700 individuals with HCV genotype 1 who participated in the IDEAL study (Individualized Dosing Efficacy vs. Flat Dosing to Assess OptimaL pegylated interferon therapy), which was sponsored by Merck. The IL-28B association was first reported in a paper published in the journal Nature (September 2009), and the full study manuscript was published in Gastroenterology (May 2010). HCV genotype 1 is the most common form of the virus, accounting for approximately 70 percent of HCV cases in the United States, and is the most difficult to treat.

Under the terms of the agreement, LabCorp will pay a Merck affiliate, a one-time payment and royalties for tests covered under the agreement in exchange for a license to the Merck affiliate’s patent rights covering the detection and use of the IL-28B polymorphism.

Merck intends to provide a limited number of non-exclusive licenses to established diagnostics companies.

Merck's commitment to advancing hepatitis therapy

Merck is committed to building on its strong legacy in the hepatitis field by continuing to discover, develop and deliver vaccines and medicines that prevent and treat viral hepatitis. Extensive research efforts are underway to develop differentiated compounds that bring innovation to hepatitis care.

About PEGINTRON ® (peginterferon alfa-2b)

PEGINTRON is indicated for use in combination with REBETOL® (ribavirin, USP) for the treatment of chronic hepatitis C in patients three years of age and older with compensated liver disease.

The following points should be considered when initiating therapy with PEGINTRON in combination with REBETOL: (1) These indications are based on achieving undetectable HCV RNA after treatment for 24 or 48 weeks and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose. (2) Patients with the following characteristics are less likely to benefit from re-treatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection. (3) No safety and efficacy data are available for treatment of longer than one year.

PEGINTRON is also indicated for use alone for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with interferon alpha and who are at least 18 years of age.

The following points should be considered when initiating therapy with PEGINTRON alone: Combination therapy with REBETOL is preferred over PEGINTRON monotherapy unless there are contraindications to, or significant intolerance of, REBETOL. Combination therapy provides substantially better response rates than monotherapy.

Selected Safety Information on PEGINTRON


Alpha interferons, including PEGINTRON, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many, but not all cases, these disorders resolve after stopping PEGINTRON therapy.

Use with Ribavirin: Ribavirin may cause birth defects and death of the unborn child. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with REBETOL therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen.


PEGINTRON is contraindicated in patients with known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction, anaphylaxis, Stevens-Johnson syndrome and toxic epidermal necrolysis to interferon alpha or any other component of the product, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score >6 [class B and C]) in cirrhotic CHC patients before or during treatment. PEGINTRON/REBETOL combination therapy is additionally contraindicated in women who are pregnant or may become pregnant, men whose female partners are pregnant, patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia), and patients with creatinine clearance < 50 mL per min.


REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Patients should use at least two effective forms of contraception and have monthly pregnancy tests during therapy and for 6 months after completion of therapy. If this drug is used during pregnancy, or if a patient becomes pregnant, the patient should be apprised of the potential hazard to a fetus. A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment, and for 6 months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.

Patients with the following conditions should be closely monitored and may require dose reduction or discontinuation of therapy:

•Hemolytic anemia with ribavirin
•Neuropsychiatric events
•History of significant or unstable cardiac disease
•Hypothyroidism, hyperthyroidism, hyperglycemia, diabetes mellitus that cannot be effectively treated by medication
•New or worsening ophthalmologic disorders
•Ischemic and hemorrhagic cerebrovascular events
•Severe decreases in neutrophil or platelet counts
•History of autoimmune disorders
•Pancreatitis and ulcerative or hemorrhagic/ischemic colitis and pancreatitis
•Pulmonary infiltrates or pulmonary function impairment
•Child-Pugh score >6 (Class B and C)
•Increased creatinine levels in patients with renal insufficiency
•Serious, acute hypersensitivity reactions and cutaneous eruptions
•Dental/periodontal disorders reported with combination therapy
•Hypertriglyceridemia may result in pancreatitis (eg, triglycerides >1000 mg/dL)
•Weight loss and growth inhibition reported with combination therapy in pediatric patients.

Life-threatening or fatal neuropsychiatric events, including suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior, sometimes directed towards others, have occurred in patients with and without a previous psychiatric disorder during PEGINTRON treatment and follow-up.

Adverse Events

Serious adverse reactions have occurred in approximately 12 percent of subjects in clinical trials. The most common serious events occurring in subjects treated with PEGINTRON and REBETOL were depression and suicidal ideation, each occurring at a frequency of less than one percent. The most common fatal events occurring in subjects treated with PEGINTRON and REBETOL were cardiac arrest, suicidal ideation and suicide attempt, all occurring in less than one percent of subjects.

The incidence of serious adverse reactions was comparable between PEGINTRON monotherapy (~12 percent) and PEGINTRON/REBETOL combination therapy weight-based (12 percent) or flat-dose (17 percent). In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy. Some patients experienced ongoing or new serious adverse reactions during the six-month follow-up period. In a study with PEGINTRON/REBETOL (weight-based) combination therapy in adult patients, anemia with weight-based dosing occurred at an increased rate (29 percent vs. 19 percent); however, the majority of these cases were mild and responded to dose reductions. The incidence of serious adverse reactions reported for the weight-based REBETOL group was 12 percent. There were 31 deaths in clinical trials which occurred during treatment or during follow-up. Of the deaths, 19 were patients on either PEGINTRON or PEGINTRON/REBETOL combination therapy and three occurred during the follow-up period but had been on PEGINTRON/REBETOL combination therapy.

Additional serious adverse reactions seen in clinical trials at a frequency of less than or equal to one percent included psychosis, aggressive reaction, relapse of drug addiction/overdose; nerve palsy (facial, oculomotor); cardiomyopathy, angina, pericardial effusion, retinal ischemia, retinal artery or vein thrombosis, blindness, decreased visual acuity, optic neuritis, transient ischemic attack, supraventricular arrhythmias, loss of consciousness; neutropenia, infection (sepsis, pneumonia, abscess, cellulitis); emphysema, bronchiolitis obliterans, pleural effusion, gastroenteritis, pancreatitis, gout, hyperglycemia, hyperthyroidism and hypothyroidism, autoimmune thrombocytopenia with or without purpura, rheumatoid arthritis, interstitial nephritis, lupus-like syndrome, sarcoidosis, aggravated psoriasis, urticaria, injection site necrosis, vasculitis, and phototoxicity.

Greater than 96 percent of all subjects in clinical trials experienced one or more adverse events. Most common adverse reactions (>40 percent) in adult patients receiving either PEGINTRON or PEGINTRON/REBETOL are injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and anxiety/emotional lability/irritability.

The adverse reaction profile was similar between weight-based and flat-dose PEGINTRON/REBETOL therapies. Weight-based PEGINTRON/REBETOL dosing resulted in increased rates of anemia. Most common adverse reactions with PEGINTRON/REBETOL (weight-based) therapy were psychiatric, which occurred among 68-69 percent of patients and included depression, irritability, and insomnia, each reported by approximately 30-40 percent of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and suicides) occurred in two percent of all patients during treatment or during follow-up after treatment cessation. Other common reactions included injection site reactions, fatigue/ asthenia, headache, rigors, fever, nausea, myalgia, anxiety/emotional lability/irritability. The severity of some of these systemic symptoms tends to decrease as treatment continues.

Subjects receiving PEGINTRON /REBETOL as re-treatment after failing a previous interferon combination regimen reported adverse reactions similar to previous treatment-naïve patients receiving this regimen.

In general, the adverse reaction profile in the pediatric population was similar to that observed in adults. Most common adverse reactions (>25 percent) in pediatric patients receiving PEGINTRON/REBETOL are pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, abdominal pain, and vomiting.

Please see full prescribing information at http://www.spfiles.com/pipeg-intron.pdf.

About Merck

Today's Merck is a global healthcare leader. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit http://www.merck.com/.

Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2009 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (http://www.sec.gov/).

Please see attached Prescribing Information and Medication Guide including Boxed Warning for PEGINTRON® and REBETOL®. Full Prescribing Information and Medication Guide is also available at http://www.spfiles.com/pipeg-intron.pdf.

PEGINTRON® and REBETOL® are registered trademarks of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.

F- 33538820T


These highlights do not include all the information needed to use PegIntron safely and effectively. See full prescribing information for PegIntron.

PegIntron (Peginterferon alfa-2b) Injection, Powder for Solution for Subcutaneous Use

Initial U.S. Approval: 2001

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Histologic outcomes in hepatitis C-infected patients with varying degrees of virologic response to interferon-based treatments


Early View (Articles online in advance of print)
Published Online: 16 Jun 2010
Copyright © 2010 American Association for the Study of Liver Diseases

Paul J. Pockros 1 *, Fayez M. Hamzeh 2, Paul Martin 3, Ellen Lentz 2, Xiaolei Zhou 4, Sugantha Govindarajan 5, Anna S. Lok 6

1 Scripps Clinic, La Jolla, CA
2 Genentech, Inc., South San Francisco, CA
3 Miller School of Medicine, University of Miami, Miami, FL
4 RTI Health Solutions, Research Triangle Park, NC
5 University of Southern California-Keck School of Medicine and Liver Research Laboratory, Downey, CA
6 University of Michigan Medical Center, Ann Arbor, MI

email: Paul J. Pockros (Pockros.Paul@scrippshealth.org)

*Correspondence to Paul J. Pockros, Division of Gastroenterology/Hepatology, Scripps Clinic, 10666, North Torrey Pines Road, La Jolla, CA 92037

Potential conflict of interest: Nothing to report.
fax: 858-554-8065
Funded by: Roche, Nutley, NJ


Patients with chronic hepatitis C with partial virologic response or nonresponse to interferon-based therapies can experience treatment-related improvements in liver histology. This retrospective analysis assessed the histologic response to treatment in patients with varying degrees of virologic response (sustained virologic response [SVR], breakthrough, relapse, or nonresponse), time to hepatitis C virus (HCV) RNA undetectability, and duration of viral suppression. Patients (HCV genotypes 1-6) with baseline and follow-up liver biopsies from eight phase 2 to phase 4 interferon-based trials were analyzed. Blinded biopsies were evaluated by a single pathologist. Improvements or worsening of METAVIR necroinflammatory activity and fibrosis were defined as increase or decrease of 1 grading category from baseline to 24 weeks after end of treatment. A majority of the 1571 patients with paired biopsy data were white, male, with HCV genotype 1/4, baseline HCV RNA levels >800,000 IU/mL, and baseline alanine aminotransferase levels 3 × upper limit of the normal range; mean baseline activity and fibrosis scores were 1.8 and 1.7, respectively. Overall, 80% of patients received peginterferon alfa-2a monotherapy or peginterferon alfa-2a/ribavirin combination therapy. Mean treatment duration was 46 weeks. There was a positive correlation between the degree of virologic response and improvements in METAVIR activity and fibrosis, and an inverse correlation with worsening activity and fibrosis (all comparisons, P < 0.0001). Patients with SVR had the greatest histologic benefit. As a combined group, relapsers and patients with breakthrough had significantly greater benefits than nonresponders (activity, P = 0.0001; fibrosis, P = 0.003). Consistent with these results, a better histologic response was correlated with a shorter time to undetectable HCV RNA and a longer duration of viral suppression (all comparisons, P < 0.0001). Conclusion: In patients with chronic hepatitis C who were treated with interferon-based therapies, histologic benefits may be observed even in the absence of an SVR. (HEPATOLOGY 2010;)

Received: 25 January 2010; Accepted: 7 June 2010

Digital Object Identifier (DOI)
10.1002/hep.23809 About DOI


2010 Annual Evidence Update on Hepatitis B and C

- Introduction

NHS Evidence Annual Evidence Updates (AEUs) attempt to draw together recently published, high quality evidence – focusing particularly on systematic reviews and published guidelines - which it is hoped will inform and enhance the decision making and planning of clinicians, commissioners and others involved in the process of health care.

For this Hepatitis B and C AEU updating last year's work, a detailed literature search from 2009-2010 identified 246 potential pieces of evidence (see methods for retrieving and evaluating the evidence for more information). Following a process of filtering and peer review (with thanks to the reviewers listed below) 61 of these form the basis of this AEU.

It is imperative that those involved in commissioning and delivering care are apprised of the best available evidence and guidelines against which to review their service. We hope that the AEU in Hepatitis B and C will provide a prime source of such evidence.

A summary of the methods used for retrieving and evaluating the evidence can be found here. The evidence has been split into sections as follows:


Adverse effects
Risk factors
Articles in foreign languages and on foreign populations

Click on the sections above to find links to critically appraised systematic reviews, expert commentaries and other information of interest, or download the PDF version.

We have also provided a list of treatment uncertainties, taken from the articles included in the AEU.

This year's update has been put together by the NHS Evidence - gastroenterology and liver diseases Project Team, with expert advice and commentaries provided by our liver disease topic leads. These are:

•Graeme Alexander, Consultant Hepatologist, Addenbrooke's Hospital, Cambridge
•Andrew Austin, Consultant Hepatologist, Royal Derby Hospital
•Jane Collier, Consultant Hepatologist, John Radcliffe Hospital, Oxford
•Jan Freeman, Consultant Hepatologist and Lead Clinician for Gastroenterology and Hepatology, Royal Derby Hospital
•Martin James, Consultant Hepatologist and Gastroenterologist, Queen's Medical Centre, Nottingham
•Lynda Greenslade, Clinical Nurse Specialist in Hepatology, Royal Free Hampstead NHS Trust, London
•Janice Main, Reader in Infectious Diseases and General Medicine, Imperial College at St Mary's Hospital, London
•Steven Ryder, Consultant Physician and Hepatologist, Queen's Medical Centre, Nottingham

- Economics

Reviewed by Graeme Alexander, Consultant Hepatologist, Addenbrooke's Hospital, Cambridge and Andrew Austin, Consultant Hepatologist, Royal Derby Hospital

Graeme Alexander: The paper by Sroczynski et al, which is pertinent to the UK, indicates that there is an economic benefit in screening for hepatitis C when the prevalence is sufficiently high. The only failing of this paper is that it doesn’t really define clearly what an adequate prevalence is to make studies cost effective, but it is one of the better papers in the field and the cost of screening and the cost of treatment are very important issues for the UK.

Andrew Austin: With the advent of a number of effective oral antiviral treatments for chronic hepatitis B, both clinical and cost-effectiveness need to be considered. The latest EASL guidelines recommend pegylated interferon, entecavir and tenofovir as first-line treatment for both HBeAg-positive and HBeAg-negative patients with chronic hepatitis B. Buti et al used a Markov model to project lifetime costs in cohorts of 40 year old HBeAg-positive and HBeAg-negative patients treated with six different first-line and two second-line management strategies. Costs were assessed using Spanish data. The analysis found that tenofovir is the most cost-effective oral therapy for both groups of patients. Entecavir was the second most effective strategy and the difference is determined primarily by the difference in purchase price in Spain. When the pricing is similar the two drugs are equally cost-effective and it would be important to check on the real drug cost in your area. Furthermore, longer term modelling (> 5 years) is based on scant data and may be effected by changing resistance patterns, local cost of managing complications of chronic liver disease and unforeseen treatment side effects.

Deuffic-Burban et al compare different approaches to the detection of occupational hepatitis C infection in healthcare workers using a decision-analysis model. In France in 2004, a staggering 41,276 accidental blood exposures occurred in hospitals, 58.7% of which were percutaneous injuries. Of these 6.2% occurred to anti-HCV antibody-positive source patients. The authors compared three existing follow-up strategies from Europe and USA using combinations of ALT and anti-HCV antibody tests with a strategy based on early HCV RNA testing one month after exposure. The study found that although the HCV RNA testing strategy is more expensive than the other strategies examined, it is reasonably cost-effective and the study recommends its use. Given the advantage of early treatment of acute hepatitis C and the likely quality of life benefits from an earlier “all clear”, such a bland conclusion is surprising. I suspect that most clinicians who have been able to confirm the donor is HCV-positive will recommend an early HCV RNA test at one month using a highly sensitive assay for HCV RNA.

Grishchenko et al have used similar methodology to estimate the lifetime cost per quality-adjusted life-year (QALY) of antiviral treatment compared to no treatment for chronic HCV infection. However, rather than using estimates of sustained virological response, costs and transitional probabilities from registration trials, they have drawn estimates from the Trent HCV database, a large representative sample of UK cases. The authors found that pegylated interferon and ribavirin is generally cost-effective when provided in routine clinical practice. Treatment appears cost saving for patients with non-1, and has low costs per QALY for most patients with genotype 1. However, treatment is less effective in older patients with genotype 1 and cirrhosis whose chance of achieving an SVR may be less than 10%. As a member of the Trent HCV cohort study I declare an interest in this paper.

Saab et al use retrospective data to compare switching from HBIG to adefovir one year after successful liver transplantation versus continuing with HBIG/lamivudine. The authors report that the switching strategy leads to significant cost-savings. However, looking to the future it seems unlikely that many patients will come to transplantation who are treatment-naive with respect to either tenofovir or entecavir and the result may be of mainly historical interest.


Buti M, Brosa M, Casado MA, Rueda M, Esteban R. Modeling the cost-effectiveness of different oral antiviral therapies in patients with chronic hepatitis B. J Hepatol 2009;51(4):640-6.

Deuffic-Burban S, Abiteboul D, Lot F, Branger M, Bouvet E, Yazdanpanah Y. Costs and cost-effectiveness of different follow-up schedules for detection of occupational hepatitis C virus infection. Gut 2009;58(1):105-10.

Grishchenko M, Grieve RD, Sweeting MJ, De Angelis D, Thomson BJ, Ryder SD, Irving WL, Trent HCV Study Group. Cost-effectiveness of pegylated interferon and ribavirin for patients with chronic hepatitis C treated in routine clinical practice. Int J Technol Assess Health Care 2009;25(2):171-80.

Saab S, Ham MY, Stone MA, Holt C, Tong M. Decision analysis model for hepatitis B prophylaxis one year after liver transplantation. Liver Transpl 2009;15(4):413-20.

Sroczynski G, Esteban E, Conrads-Frank A, Schwarzer R, Mühlberger N, Wright D, Zeuzem S, Siebert U. Long-term effectiveness and cost-effectiveness of screening for hepatitis C virus infection. Eur J Public Health 2009;19(3):245-53.

- Prevention
Cochrane reviews
The following Cochrane reviews were released or updated this year:

Bar-On ES, Goldberg E, Fraser A, Vidal L, Hellmann S, Leibovici L. Combined DTP-HBV-HIB vaccine versus separately administered DTP-HBV and HIB vaccines for primary prevention of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae B (HIB). Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD005530. DOI: 10.1002/14651858.CD005530.pub2.

Katz LH, Tur-Kaspa R, Guy DG, Paul M. Lamivudine or adefovir dipivoxil alone or combined with immunoglobulin for preventing hepatitis B recurrence after liver transplantation. Cochrane Database of Systematic Reviews 2010, Issue 7. Art. No.: CD006005. DOI: 10.1002/14651858.CD006005.pub2.

McIntyre PG, Tosh K, McGuire W. Caesarean section versus vaginal delivery for preventing mother to infant hepatitis C virus transmission. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD005546. DOI: 10.1002/14651858.CD005546.pub2.

Other reviews

Reviewed by Janice Main, Reader in Infectious Diseases and General Medicine, Imperial College at St Mary's Hospital, London

The paper by Alavian and Tabatabaei reviews the problems of the reduced efficacy of hepatitis B vaccination in patients with end-stage renal disease. Various strategies have been suggested for this group of patients and the authors performed a meta-analysis of controlled clinical trials of levamisole, an immune modulator, in this setting. They identified four studies which suggest a beneficial response and highlight the need for larger randomized clinical trials.

Poorolajal et al have published two meta-analyses (1, 2) on the long term protection of HBV vaccination and the effects of booster doses. Their analyses suggest that although, with time, protective antibodies gradually decrease the risk of subsequent infection is low and, in healthy individuals with a good response to the initial vaccine course, booster doses of vaccine are not required.

Saab et al review 13 studies comparing lamivudine monotherapy with lamivudine/hepatitis B immune globulin (HBIG) after liver transplantation from a hepatitis B core antibody donor. Their analysis suggests that both strategies are effective and that lamivudine monotherapy is as effective as the combination approach.


Alavian SM, Tabatabaei SV. Effects of oral levamisole as an adjuvant to hepatitis B vaccine in adults with end-stage renal disease: a meta-analysis of controlled clinical trials. Clin Ther 2010;32(1):1-10.

Poorolajal J, Mahmoodi M, Majdzadeh R, Nasseri-Moghaddam S, Haghdoost A, Fotouhi A. Long-term protection provided by hepatitis B vaccine and need for booster dose: a meta-analysis. Vaccine 2010;28(3):623-31.

Poorolajal J, Mahmoodi M, Majdzadeh R, Nasseri-Moghaddam S, Haghdoost A, Ghalichi L, Fotouhi A. Seroprotection of hepatitis B vaccine and need for booster dose: a meta-analysis. Hepat Mon 2009;9(4):293-304.

Saab S, Waterman B, Chi AC, Tong MJ. Comparison of different immunoprophylaxis regimens after liver transplantation with hepatitis B core antibody-positive donors: a systematic review. Liver Transpl 2010;16(3):300-7.

- Diagnosis
Reviewed by Graeme Alexander, Consultant Hepatologist, Addenbrooke's Hospital, Cambridge
Smith and Sterling is a fair review of non invasive methods of assessing fibrosis in chronic hepatitis C virus infection. It has many aspects to commend it, including a comprehensive review, fair assessment with fair conclusions and this is an area that is particularly topical at present.


Smith JO, Sterling RK. Systematic review: non-invasive methods of fibrosis analysis in chronic hepatitis C. Aliment Pharmacol Ther 2009;30(6):557-76.

- Treatment Hepatitis B

Reviewed by Steven Ryder, Consultant Physician and Hepatologist, Queen's Medical Centre, Nottingham


NICE has revisited HBV therapies and guidance is available which should be seen in the context of the EASL guidelines for treatment, an excellent and thoughtful document.

Also released this year were revised AASLD guidelines on chronic hepatitis B

Other reviews

There has been a revolution in the therapy of HBV infection with oral agents proving highly effective. Older therapies such as interferon remain an important part of the armoury. In South Asia there have been a number of studies of thymosin alpha. A meta analysis of trials of lamivudine and thymosin (Zhang et al) suggest better outcomes in e antigen positive patients. It is a therapy which we have not seen used in the Western world but the contrast with interferon where combination therapy shows no benefit, is interesting. The effectiveness of interferon alpha treatment in hepatitis B was confirmed and the magnitude of the effect on e antigen seroconversion and surface antigen loss quantified in a meta-analysis of 7 trials (Yang et al), the relative risk of e antigen loss was 0.66 and of surface antigen loss 0.28 over 3-7 years post therapy. A further study confirms that interferon therapy slows progression of hepatic fibrosis (Poynard et al). Another Eastern perspective on HBV is provided by Zhang et al. This summarises the trials of traditional Chinese medicines (TCM) used for HBV as compared to interferon and Lamivudine. The headline was that TCM has greater effect on ALT values than conventional therapies. A health warning concerning the quality of the studies is included but a further view eastwards for effective therapies may be indicated.

Combination therapy seemed the likely best option for long term therapy of hepatitis B with oral agents in the era of relatively weak agents with high resistance rates, the effectiveness of combining adefovir and lamivudine was confirmed in a meta-analysis (Chen et al) but with the newer more potent agents such a strategy may not be so compelling or necessary.

Reactivation of HBV in patients undergoing cancer chemotherapy has been a significant problem, and a meta-analysis suggests that lamivudine prophylaxis reduces the risk of reactivation and showed a trend towards reduced mortality. It gives some concrete figures which are useful in discussions with patients (1/1000 mortality given prophylaxis versus 25/1000 if not).

Children with chronic hepatitis B are frequently in the immunotolerant phase of infection which has limited effectiveness of therapy in the relatively small studies which have been undertaken. A summary of the data is included in a review (Giacchino and Cappelli). There are studies of the more modern oral agents ongoing in adolescents but a limited evidence base for other therapies.

Replicating chronic hepatitis B was a contraindication to liver transplantation 15 years ago but the advances in therapeutics have totally reversed this with HBV now a good indication for transplantation with very low recurrence rates. Zhang, Zhou and Zheng provide a concise summary of the evidence for effectiveness of therapy and the history of improvements in outcomes. A review article summarises the current best practice in prevention of recurrent HBV (Papatheodoridis et al).

Also included in this AEU is a health technology assessment on adefovir dipivoxil and pegylated interferon alpha for chronic hepatitis B by Jones et al.


Chen EQ, Wang LC, Lei J, Xu L, Tang H. Meta-analysis: adefovir dipivoxil in combination with lamivudine in patients with lamivudine-resistant hepatitis B virus. Virol J 2009;6:163.

Giacchino R, Cappelli B. Treatment of viral hepatitis B in children. Expert Opin Pharmacother 2010;11(6):889-903.

Jones J, Shepherd J, Baxter L, Gospodarevskaya E, Hartwell D, Harris P, Price A. Adefovir dipivoxil and pegylated interferon alpha for the treatment of chronic hepatitis B: an updated systematic review and economic evaluation. Health Technol Assess 2009;13(35):1-172, iii.

Papatheodoridis GV, Cholongitas E, Archimandritis AJ, Burroughs AK. Current management of hepatitis B virus infection before and after liver transplantation. Liver Int 2009;29(9):1294-305.

Poynard T, Massard J, Rudler M, Varaud A, Lebray P, Moussalli J, Munteanu M, Ngo Y, Thabut D, Benhamou Y, Ratziu V. Impact of interferon-alpha treatment on liver fibrosis in patients with chronic hepatitis B: an overview of published trials. Gastroenterol Clin Biol 2009;33(10-11):916-22.

Yang YF, Zhao W, Xia HM, Zhong YD, Huang P, Wen J. Long-term efficacy of interferon alpha therapy on hepatitis B viral replication in patients with chronic hepatitis B: a meta-analysis. Antiviral Res 2010;85(2):361-5.

Zhang J, Zhou L, Zheng SS. Clinical management of hepatitis B virus infection correlated with liver transplantation. Hepatobiliary Pancreat Dis Int 2010;9(1):15-21.

Zhang L, Wang G, Hou W, Li P, Dulin A, Bonkovsky HL. Contemporary clinical research of traditional Chinese medicines for chronic hepatitis B in China: an analytical review. Hepatology 2010;51(2):690-8.

Zhang YY, Chen EQ, Yang J, Duan YR, Tang H. Treatment with lamivudine versus lamivudine and thymosin alpha-1 for e antigen-positive chronic hepatitis B patients: a meta-analysis. Virol J 2009;6:63.

Ziakas PD, Karsaliakos P, Mylonakis E. Effect of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in lymphoma: a meta-analysis of published clinical trials and a decision tree addressing prolonged prophylaxis and maintenance. Haematologica 2009;94(7):998-1005.

- Treatment Hepatitis C


The following guidelines were published this year:

Diagnosis, management, and treatment of hepatitis C: an update (American Association for the Study of Liver Diseases)

British HIV Association guidelines for the management of coinfection with HIV-1 and hepatitis B or C virus 2010

Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program

Cochrane reviews

The following Cochrane reviews were released or updated this year:

Brok J, Gluud LL, Gluud C. Ribavirin monotherapy for chronic hepatitis C. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD005527. DOI: 10.1002/14651858.CD005527.pub2.

Brok J, Gluud LL, Gluud C. Ribavirin plus interferon versus interferon for chronic hepatitis C. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD005445. DOI: 10.1002/14651858.CD005445.pub2.

Gurusamy KS, Tsochatzis E, Xirouchakis E, Burroughs AK, Davidson BR. Antiviral therapy for recurrent liver graft infection with hepatitis C virus. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD006803. DOI: 10.1002/14651858.CD006803.pub3.

Iorio A, Marchesini E, Awad T, Gluud LL. Antiviral treatment for chronic hepatitis C in patients with human immunodeficiency virus. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD004888. DOI: 10.1002/14651858.CD004888.pub2.
Other reviews

Reviewed by Jane Collier, Consultant Hepatologist, John Radcliffe Hospital, Oxford and Jan Freeman, Consultant Hepatologist and Lead Clinician for Gastroenterology and Hepatology, Royal Derby Hospital

Jane Collier: The current recommended treatment of hepatitis C is pegylated interferon and ribavirin, but very few Chinese patients were included in the large phase 3 trials of this. Zhao et al have reviewed 7 studies, including a total of 398 Chinese patients, comparing this with standard interferon and ribavirin, confirming that the former is superior to the standard combination, with a relative risk of 1.76 (95% confidence interval 1.21 to 2.56).

A recent randomised trial has shown no difference between the efficacy of pegylated interferon 2a and pegylated interferon 2b. In a meta-analysis by Awad et al, 12 studies comparing these 2 drugs were pooled. Although pegylated interferon 2a was superior with a sustained virological response (SVR) experienced by 47% of participants, compared with 41% in pegylated interferon 2b, with a risk ratio (RR) of 1.11, the studies included were heterogeneous: different genotypes were included and not all patients were naïve or given weight based ribavirin. There were also not enough adverse events recorded to conclude a difference between the two drugs. The length of current treatment is dependent on genotype and viral kinetics, and as these drugs are expensive, recent research has been aimed at individualising length of treatment. A recent large study (ACCELERATE) in genotype 2 and 3 patients showed significant lower SVR with 16 weeks versus the conventional 24 weeks of therapy, even in those patients with a rapid virological response (RVR) (i.e. those who were HCV PCR negative at 4 weeks). The meta-analysis by Slavenburg et al looked at 8 studies comparing 24 weeks with 16 weeks treatment. 3 studies were randomised at the start of treatment (as per ACCELERATE) and 5 randomised at 4 weeks in those achieving a RVR. Although SVR were higher in those randomised to 2 weeks at baseline, RR 0.8, the SVR was similar in those patients who were HCV negative at 4 weeks and given 16 weeks compared to 24 weeks (82% versus 83%; RR 1.00). Patients who are not tolerating treatment at 16 weeks with an RVR could stop treatment with a good chance of an SVR. The role of a favourable interferon lambda genotype in identifying which of those with a RVR will achieve at SVR is currently unknown.

In a meta-analysis looking at the cost-effectiveness of 24 weeks of treatment for genotype 2/3 and 48 weeks for genotype 1, Sroczynski et al showed treatment to be cost effective as defined by a 84700 Euro/QALY with a 3-4 year life, excluding patients with mild disease (normal LFTs). This study did not assess if costs could be reduced by individualising treatment, which was done by Siebert et al. They looked at the cost-effectiveness of German guidelines, which include 24 weeks treatment for genotype 2/3 and stopping treatment at 12 weeks in patients with genotype 1 who had < 2 log drop, and use weight based ribavirin dosing. Pegylated interferon and ribavirin increased undiscounted life expectancy by 5 life-years and individualisation of treatment dose was cheaper with a cost saving of 17000 Euros/per QALY. Similar studies will need to be performed when the protease inhibitors become licensed as they are likely to be significantly more costly. A meta-analysis by Singal et al has confirmed improved survival in patients with advanced fibrosis following a SVR with less liver related mortality (RR 0.23). None of the above studies were able to assess reduced liver related mortality in non-cirrhotics with a SVR due to lack of sufficient long-term follow-up data in patients with and without a SVR.

Ribavirin is associated with haemolysis and dose reduction. Ribavirin dose reduction may not lead to poorer outcomes as a recent trial comparing ribavirin with the prodrug taribavirin which, although causing less anaemia, did not lead to a increased SVR. Chan, Partovi and Ensom looked at whether therapeutic drug monitoring (TDM) for ribavirin is warranted in clinical practice. In a review of literature showed not clear that good relationship between drug levels and degree of anaemia, In 53 small studies, 12 in HIV infection and 5 in renal failure, there was no clear relationship between ribavirin concentration and virological response. There are no studies comparing ribavirin TDM versus dose reduction using Hb on SVR. Overall, there is no clear evidence for use of TDM.

Adherence to therapy (compliance) is important in HCV treatment and will continue to be once direct antiviral therapy, i.e. protease inhibitors, are licensed, as poor compliance may lead to drug resistance. Weiss et al identified 8 studies assessing adherence with interferon/ribavirin combinations. 5 studies with pegylated interferon reported missed doses with adherence rates between 74%-92% in the first 12 weeks, falling towards end of treatment, with only 1 reporting effect on SVR. Three further studies, which combined adherence with dose reductions for medical reasons, showed that taking at least 80% of the initial prescribed dose of interferon/ribavirin for 80% of the recommended duration of treatment was associated with increased SVR. Thus these studies show non-adherence is common, but the effects on SVR for PEG-IFN/ribavirin are unknown.

Gentile et al have reviewed the phase 2 data on the protease inhibitor telepravir combined with pegylated interferon and ribavirin for naïve genotype 1 patients and this together with the phase 2 study in treatment experienced patients both show improved SVR over current standard therapy (ie peg-interferon and ribavirin). Telepravir was given at different time points and different length during treatment and the ongoing phase 3 study will dictate the optimum dosing regimen and confirm efficacy data.

Jan Freeman: Camma et al address the issue of retreatment in non-responders, giving good advice on who to select for retreatment rather than indiscriminate treatment of all non-responders. Modest efficacy (16% SVR) of retreatment is achieved in genotype 2 or 3, in the non-obese, and by use of a 24 week stopping rule in those who fail to seroconvert.

Fabrizi et al show that the use of Pegylated interferon does not add any benefit to standard interferon mono-therapy in patients undergoing dialysis.

Gluud, Marchesini and Iorio confirm the utility of PEG interferon and ribavirin in co-infected patients although the study shows that adverse events are more common.

Gordon et al demonstrate factors which give more favourable outcomes in Hepatitis C patients undergoing dialysis – these include the use of larger doses of interferon (greater than 3 million units thrice weekly), treatment completion rates, female gender and early virological negativity.

Hellard, Sacks-Davis and Gold support the active treatment of patients who continue to abuse drugs intravenously as comparable treatment outcomes can be achieved to those who are former IV drug users.

Moreno et al's meta-analysis shows that only HCV-1 patients with a low base line HCV-RNA (less than 50IU/ml) at 4 weeks of therapy do not lose a chance of a sustained virological response if they are treated for 24 weeks - all others should be given 48 weeks of therapy.

In Singal et al, pooled data shows a reduced risk of hepatocellular carcinoma in HCV treated patients (RR 0.43) who achieved a sustained virological response, but maintenance interferon therapy in those who failed to achieve a SVR did not reduce the risk of HCC.

Zanini and Lanzini is a good review of strategies to prevent HCV infection and disease progression, attitude and access to therapy amongst IV drug abusers.


Awad T, Thorlund K, Hauser G, Stimac D, Mabrouk M, Gluud C. Peginterferon alpha-2a is associated with higher sustained virological response than peginterferon alfa-2b in chronic hepatitis C: systematic review of randomized trials. Hepatology 2010;51(4):1176-84.

Cammà C, Cabibbo G, Bronte F, Enea M, Licata A, Attanasio M, Andriulli A, Craxì A. Retreatment with pegylated interferon plus ribavirin of chronic hepatitis C non-responders to interferon plus ribavirin: a meta-analysis. J Hepatol 2009;51(4):675-81.

Chan AH, Partovi N, Ensom MH. The utility of therapeutic drug monitoring for ribavirin in patients with chronic hepatitis C--a critical review. Ann Pharmacother 2009;43(12):2044-63.

Fabrizi F, Dixit V, Messa P, Martin P. Pegylated interferon monotherapy of chronic hepatitis C in dialysis patients: Meta-analysis of clinical trials. J Med Virol 2010;82(5):768-75.

Gentile I, Carleo MA, Borgia F, Castaldo G, Borgia G. The efficacy and safety of telaprevir - a new protease inhibitor against hepatitis C virus. Expert Opin Investig Drugs 2010;19(1):151-9.

Gluud LL, Marchesini E, Iorio A. Peginterferon plus ribavirin for chronic hepatitis C in patients with human immunodeficiency virus. Am J Gastroenterol 2009;104(9):2335-41.

Gordon CE, Uhlig K, Lau J, Schmid CH, Levey AS, Wong JB. Interferon for hepatitis C virus in hemodialysis--an individual patient meta-analysis of factors associated with sustained virological response. Clin J Am Soc Nephrol 2009;4(9):1449-58.

Hellard M, Sacks-Davis R, Gold J. Hepatitis C treatment for injection drug users: a review of the available evidence. Clin Infect Dis 2009;49(4):561-73.

Moreno C, Deltenre P, Pawlotsky JM, Henrion J, Adler M, Mathurin P. Shortened treatment duration in treatment-naive genotype 1 HCV patients with rapid virological response: a meta-analysis. J Hepatol 2010;52(1):25-31.

Siebert U, Sroczynski G, Aidelsburger P, Rossol S, Wasem J, Manns MP, McHutchison JG, Wong JB. Clinical effectiveness and cost effectiveness of tailoring chronic hepatitis C treatment with peginterferon alpha-2b plus ribavirin to HCV genotype and early viral response: a decision analysis based on German guidelines. Pharmacoeconomics 2009;27(4):341-54.

Singal AG, Volk ML, Jensen D, Di Bisceglie AM, Schoenfeld PS. A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus. Clin Gastroenterol Hepatol 2010;8(3):280-8.

Singal AK, Singh A, Jaganmohan S, Guturu P, Mummadi R, Kuo YF, Sood GK. Antiviral therapy reduces risk of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis. Clin Gastroenterol Hepatol 2010;8(2):192-9.

Slavenburg S, Weggelaar I, van Oijen MG, Drenth JP. Optimal length of antiviral therapy in patients with hepatitis C virus genotypes 2 and 3: a meta-analysis. Antivir Ther 2009;14(8):1139-48.

Sroczynski G, Esteban E, Conrads-Frank A, Schwarzer R, Mühlberger N, Wright D, Zeuzem S, Siebert U. Long-term effectiveness and cost-effectiveness of antiviral treatment in hepatitis. C. J Viral Hepat 2010;17(1):34-50.

Weiss JJ, Bräu N, Stivala A, Swan T, Fishbein D. Review article: adherence to medication for chronic hepatitis C - building on the model of human immunodeficiency virus antiretroviral adherence research. Aliment Pharmacol Ther 2009;30(1):14-27.

Zanini B, Lanzini A. Antiviral treatment for chronic hepatitis C in illicit drug users: a systematic review. Antivir Ther 2009;14(4):467-79.

Zhao SH, Chu YL, Cheng DX, Waqar AB, Yu Q, Yang PH, Xue X, Yang HJ, Liu EQ. Treatment with peginterferon plus ribavirin vs. interferon plus ribavirin for 48 weeks in Chinese patients with chronic hepatitis C. Int J Clin Pract 2009;63(9):1334-9.

- Adverse effects
Reviewed by Janice Main, Reader in Infectious Diseases and General Medicine, Imperial College at St Mary's Hospital, London
Frankel et al published a consensus document on treatment issues in patients with psoriasis and hepatitis C virus (HCV) infection. Interferon alpha can exacerbate psoriasis and there are concerns that immunomodulatory therapy used for more severe cases of psoriasis may cause more rapid disease progression of hepatitis C. There are additional issues with drugs such as methotrexate which can cause hepatotoxicity. The authors conclude that data are limited and, where possible, topical therapy should be used.

Slavenburg, Heijdra and Drenth describe a case of pneumonitis in a patient with HCV receiving peginterferon and ribavirin and then review the relevant literature. Although pneumonitis is a very rare side effect of therapy it is important that this is recognized quickly as it can be fatal. Cessation of antiviral therapy is advised and steroid therapy is recommended.

Thyroiditis is a much more common side effect of interferon based therapy and Tran et al describe their experience with 11 patients. All patients subsequently had a sustained virological response (SVR). However larger studies have not demonstrated such a high SVR in these patients. The authors conclude that with this side effect it is reasonable to treat the thyroiditis and to continue with antiviral therapy.

Hepatitis B vaccination generally appears very safe but Fraunfelder, Suhler and Fraunfelder highlight 32 case reports of uveitis and possible links to HBV vaccination.


Frankel AJ, Van Voorhees AS, Hsu S, Korman NJ, Lebwohl MG, Bebo BF Jr, Gottlieb AB, National Psoriasis Foundation. Treatment of psoriasis in patients with hepatitis C: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol 2009;61(6):1044-55.

Fraunfelder FW, Suhler EB, Fraunfelder FT. Hepatitis B vaccine and uveitis: an emerging hypothesis suggested by review of 32 case reports. Cutan Ocul Toxicol 2010;29(1):26-9.

Slavenburg S, Heijdra YF, Drenth JP. Pneumonitis as a consequence of (peg)interferon-ribavirin combination therapy for hepatitis C: a review of the literature. Dig Dis Sci 2010;55(3):579-85.

Tran HA, Malcolm Reeves GE, Gibson R, Attia JR. Development of thyroid diseases in the treatment of chronic hepatitis C with alpha-interferon may be a good prognosticator in achieving a sustained virological response: a meta-analysis. J Gastroenterol Hepatol 2009;24(7):1163-8.

- Risk factors
Reviewed by Graeme Alexander, Consultant Hepatologist, Addenbrooke's Hospital, Cambridge, and Martin James, Consultant Hepatologist and Gastroenterologist, Queen's Medical Centre, Nottingham
Graeme Alexander: Chen et al is a solid meta-analysis of 37 studies, with well selected patients from two different eras which demonstrate clearly that hepatitis C co-infection with HIV increases mortality. There is not much more that a meta-analysis can conclude but the message here is clear.

Martin James: The link between HBV infection and the development of hepatocellular carcinoma has been well established previously with studies such as the REVEAL cohort study conducted in Taiwan (JAMA 2006), but the proportion of HCC cases related to chronic viral hepatitis (HBV or HCV) elsewhere in the world varies considerably

Franchesci and Raza conducted a meta-analysis of 90 studies including nearly 28,000 cases of HCC from 36 countries to study the worldwide variation in attributable risk of viral hepatitis in causation of HCC. In addition, they attempted to examine and describe the implementation and impact of HBV vaccination programmes and on HCC development.

As expected, most HCC cases (66%) were from Asia and the rest from the Americas (15%), Europe (12%) with relatively few from Africa (7%; over half of these patients originated from Egypt), probably due to difficulties in accurate recording and publication. There was substantial variation in HBVsAg and anti-HCV antibodies in HCC cases across and within different continents. The highest rates of HBV positivity (over 50%) was in Taiwan, China, Korea, Thailand, Vietnam and Turkey. Conversely, the countries with a higher proportion of HCV positivity in HCC cases were Japan (68%), Pakistan (45%) and Mongolia (40%).

In Europe, all countries apart from Greece had a higher proportion of HCC cases positive for HCV (approximately 45%) than for HBV. In Greece, 56% had HBVsAg positivity. HBV/HCV co-infection was relatively uncommon (3%), whereas absence of any chronic viral hepatitis in some northern European countries was common (80% in the study from Sweden). The majority of American studies came from the US, with 22% anti-HCV positive and only 9% positive for HBVsAg. The relatively low level of viral positivity in Western countries suggests that other aetiologies, principally alcoholic liver disease, are likely to be the cause of cirrhosis and predisposition for HCC, although these data were not presented directly.

HBV vaccines were first licensed in 1981 and are now mostly produced by recombinant DNA technology. HBV vaccination programmes were introduced into highly endemic areas such as Taiwan in 1984; this resulted in a substantial fall in HCC in the following two decades and other studies in Gambia and Qidong China are due to report soon. The debate continues in the UK and other low HBV endemic countries whether universal vaccination should be introduced or to continue with targeting high risk individuals. However, with increased immigration from highly endemic areas, the falling price of HBV vaccines and the serious consequences and high cost of treating HCC, the balance may have shifted enough to reconsider this approach to favour universal vaccination.

Liu et al performed a meta-analysis of the association between different HBV mutations and the risk of HCC using 43 studies mostly from East Asia, including over 11,000 patients with HBV infection, and 2800 with HCC. HBV PreS mutations (C1653T, T1753V) and A1762T/G1764A were associated with an increased risk of developing HCC (summary odds ratio of approximately 3-4). These mutations also became more prevalent with increasing duration of infection and were proposed as potential biomarkers for subsequent HCC development. This raises the potential for confounding of duration of infection and presumably the likelihood of increasing liver fibrosis. In addition, not all patients included in the studies had HBV mutation analysis, which may introduce selection bias for those with higher HBV DNA levels, which has been demonstrated to be an important independent risk for future HCC development (REVEAL; JAMA 2006). The precore mutations G1896A and C1858T were not associated with HCC risk in this meta-analysis.


Chen TY, Ding EL, Seage Iii GR, Kim AY. Meta-analysis: increased mortality associated with hepatitis C in HIV-infected persons is unrelated to HIV disease progression. Clin Infect Dis 2009;49(10):1605-15.

Franceschi S, Raza SA. Epidemiology and prevention of hepatocellular carcinoma. Cancer Lett 2009;286(1):5-8.

Liu S, Zhang H, Gu C, Yin J, He Y, Xie J, Cao G. Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis. J Natl Cancer Inst 2009;101(15):1066-82.

- Other
Reviewed by Lynda Greenslade, Clinical Nurse Specialist in Hepatology, Royal Free Hampstead NHS Trust, London
Accessing healthcare is currently an important issue for all health care providers and government who are trying to ensure that the current health service ensures that the general public receive equitable quality care. HCV is a case where it is essential for the health service to identify and offer if appropriate treatment in order to reduce the long term burden of HCV disease on the health service in the future. Treloar and Rhodes look at the lived experience of hepatitis C and its treatment among injecting drug users (IDUs) and has several messages for health care professionals about how to engage with IDUs in order to redesign services and pathways that are inclusive and that uses IDUs own experiences of trying and failing to access healthcare so as to avoid current pitfalls and shortcomings in future patient centred services. This review looked at 25 published articles and generated themes that are uniquely drawing on the perspectives of drug injectors rather than others living with hepatitis C. The analysis of the themes using the thoughts and words of the drug injectors themselves challenges our more traditional health care professional views where past personal adversity such as dealing with drug addiction and withdrawal meant that the drug injector was resilient and able to draw on some of the previously used coping mechanisms to get through their hepatitis C treatment. It shows that often drug injectors felt they were not given enough and appropriate information about treatment and were being hurried through as if to get them out of the system and on to someone deemed to be more worthy. This review is important reading for those of us working with patients with HCV and involved in trying to think out of the box when designing pathways to engage all those who need access to testing and treatment. It also shows that there is a need for more research on the lived experiences of coping with not just HCV but all viral hepatitis.

A second paper by Fabrizi, Messa and Martin looked at health related quality of life (HRQOL) in dialysis patients with hepatitis c infection which is linked to a reduced mortality in patients with end stage renal disease. Interestingly it discussed possible links with HCV infection and depression in patients on dialysis and how this was poorly understood. Depression can be seen in any patients being treated with HCV infection and this paper reminds us that HRQOL screening and assessment for the development of depression throughout treatment for HCV infection remains an important part of the role of HCP looking after patients on treatment.

The paper by Cholongitas, Papatheodoridis and Burroughs also reviews the evidence for using liver grafts from anti-hepatitis B core positive donors, and gives clear guidance that these livers can be safely used and this should be added to any future practice guidelines.

Also included in this AEU are reviews by Hosseini-Moghaddam et al on delta hepatitis in haemodialysis patients, and by Kapp, Tilley and Curtis on the effects of hormonal contraceptives in women with viral hepatitis or cirrhosis.


Cholongitas E, Papatheodoridis GV, Burroughs AK. Liver grafts from anti-hepatitis B core positive donors: a systematic review. J Hepatol 2010;52(2):272-9.

Fabrizi F, Messa P, Martin P. Health-related quality of life in dialysis patients with HCV infection. Int J Artif Organs 2009;32(8):473-481.

Hosseini-Moghaddam SM, Imani AA, Rizzetto M, Alavian SM. Viral hepatitis D among hemodialysis patients: a worldwide underestimated problem. Hepat Mon 2009;9(4):305-9.

Kapp N, Tilley IB, Curtis KM. The effects of hormonal contraceptive use among women with viral hepatitis or cirrhosis of the liver: a systematic review. Contraception 2009;80(4):381-6.

Treloar C, Rhodes T. The lived experience of hepatitis C and its treatment among injecting drug users: qualitative synthesis. Qual Health Res 2009;19(9):1321-34.

- Foreign articles
The following articles were identified by the search as being potentially relevant to the AEU, but were not sent out for appraisal because the full text is in a language other than English. They are included here for interest, and for the sake of completeness.
Almeida AM, Silva DI, Guerra AA Jr, Silva GD, Acurcio Fde A. Efficacy of interferon (conventional, pegylated) and lamivudine for treatment of chronic hepatitis B: a systematic review. Cad Saude Publica 2009;25(8):1667-77.
Language: Spanish

Hu H-B, Xu T, Cheng K, Su N, Tang Y. Lamivudine versus lamivudine-thymosin alpha-1 combination therapy for HBeAg positive chronic hepatitis B: A systematic review. Chin J Evid-based Med 2009;9(8):904-9.
Language: Chinese

Isken LD, Zaaijer HL, van Steenbergen JE. Hepatitis B revaccination not indicated, even for those at increased risk. Ned Tijdschr Geneeskd 2009;153:A415.
Language: Dutch

Qin XK, Han M, Liu JP. Compound Chinese herbal medicines, Chinese herbal drugs and their active extracts for treatment of chronic hepatitis C: a systematic review and meta-analysis of randomized clinical trials. Zhong Xi Yi Jie He Xue Bao 2009;7(10):913-28.
Language: Chinese

Takács IG, Demetrovics Z. The efficacy of needle exchange programs in the prevention of HIV and hepatitis infection among injecting drug users. Psychiatr Hung 2009;24(4):264-81.
Language: Hungarian

Wang Y-F, Wang Y-X, Yu Q-H. Efficacy of peginterferon alpha-2a in HBeAg positive chronic hepatitis B: Meta-analysis study. Chin J Evid-based Med 2009;9(10):1080-6.
Language: Chinese

Zhao SH, Liu EQ, Cheng DX, Xue X, Chu YL. Meta-analysis on peginterferon plus ribavirin in treatment of hepatitis C virus genotype 1 or 4 infection in HIV patients. Zhejiang Da Xue Xue Bao Yi Xue Ban 2009;38(3):315-9.
Language: Chinese

In addition, the following English-language articles were identified by the search but not sent out for review because they were studies of foreign populations:

Alavian SM, Ahmadzad-Asl M, Lankarani KB, Shahbabaie MA, Ahmadi AB, Kabir A. Hepatitis C infection in the general population of Iran: a systematic review. Hepat Mon 2009;9(3):211-23.

Ali SA, Donahue RM, Qureshi H, Vermund SH. Hepatitis B and hepatitis C in Pakistan: prevalence and risk factors. Int J Infect Dis 2009;13(1):9-19.

Batham A, Gupta MA, Rastogi P, Garg S, Sreenivas V, Puliyel JM. Calculating prevalence of hepatitis B in India: using population weights to look for publication bias in conventional meta-analysis. Indian J Pediatr 2009;76(12):1247-57.

Hung HF, Chen TH. Probabilistic cost-effectiveness analysis of the long-term effect of universal hepatitis B vaccination: an experience from Taiwan with high hepatitis B virus infection and Hepatitis B e Antigen positive prevalence. Vaccine 2009;27(48):6770-6.

Jayaraman S, Chalabi Z, Perel P, Guerriero C, Roberts I. The risk of transfusion-transmitted infections in sub-Saharan Africa. Transfusion 2010;50(2):433-42.

Lehman EM, Wilson ML. Epidemic hepatitis C virus infection in Egypt: estimates of past incidence and future morbidity and mortality. J Viral Hepat 2009;16(9):650-8.

Sun J, Yu R, Zhu B, Wu J, Larsen S, Zhao W. Hepatitis C infection and related factors in hemodialysis patients in china: systematic review and meta-analysis. Ren Fail 2009;31(7):610-20.

Tu HA, Woerdenbag HJ, Kane S, Riewpaiboon A, van Hulst M, Postma MJ. Economic evaluations of hepatitis B vaccination for developing countries. Expert Rev Vaccines 2009;8(7):907-20.

Umar M, Khaar HT, Khurram M, Hasan Z. Anti-HCV antibody positivity of various sections of Pakistani patients. J Coll Physicians Surg Pak 2009;19(11):737-41.

Waheed Y, Shafi T, Safi SZ, Qadri I. Hepatitis C virus in Pakistan: a systematic review of prevalence, genotypes and risk factors. World J Gastroenterol 2009;15(45):5647-53.

- Uncertainties
As part of the process of conducting this Annual Evidence Update, we examined the included papers for treatment uncertainties that could be added to the UK Database of Uncertainties about the Effects of Treatments (UK DUETs), a project aimed at creating a central database of such uncertainties. The following list, which has been submitted to the database, is the results of our search. Click on each title for more information.
Antiviral therapy for recurrent liver graft infection with hepatitis C virus
Combined DTP-HBV-HIB vaccine versus separately administered DTP-HBV and HIB vaccine for primary prevention of hepatitis B
Lamivudine or adefovir dipivoxil alone or combined with immunoglobulin for preventing hepatitis B recurrence after liver transplantation
Optimal duration of pegatheron plus ribavirin therapy for chronic hepatitis C in patients with HIV
Optimal ribivirin dose for chronic hepatitis C when taking in combination with pegylated interferon alpha-2a or alpha-2b
Peginterferon plus ribavirin versus no treatment for chronic hepatitis C in patients with HIV
Rate of serious adverse events in antiviral treatment for chronic hepatitis C in patients with HIV
Relationship between treatment and clinical outcomes in antiviral treatment for chronic hepatitis C in patients with HIV
Traditional Chinese medicines for chronic hepatitis B

- Methods for retrieving and evaluating the evidence

The last Annual Evidence Update for Hepatitis B and C was published in September 2009. This AEU serves as an update to that one, and includes articles published in 2009 and 2010. As the Specialist Collection focuses only on secondary information of use to NHS staff and patients, our update was focused on guidelines and systematic reviews written in English. However, foreign language articles were included in the search process. As translations for these articles were not available, the article titles have been listed separately. Our search also recovered a large number of studies of viral hepatitis in foreign populations; as these are of limited relevance to UK practice we did not send these out to our reviewers for appraisal, but we have again listed them separately.

Search strategy

Our search strategy has been updated from last year. The following resources were searched:

•National Library of Guidelines
•NHS Evidence Specialist Collections
•The Cochrane Library
•Database of Abstracts of Reviews of Effects
•NHS Economic Evaluation Database
•HTA Database

The search strategy for MEDLINE, which was modified for the other resources, appears below. We combined this with a modified SIGN systematic review filter in all cases except the searches of the NLG, the Specialist Collections, DARE, NHS EED and HTA (because they consist entirely of the types of publication that we were interested in).

After de-duplication 246 articles were retrieved.

Inclusion and exclusion criteria

Included articles had to meet the following criteria:

•Publication types: systematic review, consensus report, guideline, protocol, care pathway, economic evaluation, health technology assessment
•Published in 2009 or 2010
•Main condition under investigation was hepatitis B or C virus infection

Once the inclusion criteria were applied, 93 articles were left. Of these, 7 were foreign language articles, 7 were Cochrane systematic reviews, 5 were guidelines, and 10 were studies of specific foreign populations.

The Cochrane systematic reviews and guidelines were automatically included in the Evidence Update. The foreign language and foreign population studies were not sent out to reviewers because of translation difficulties and limited relevance to UK practice, but are listed in a separate section of the Evidence Update. This left 64 articles to be sent to our reviewers for appraisal.

Critical appraisal process

Before sending out, the articles were divided into categories as follows:

•Adverse effects
•Risk factors

Using these categories as a guide, the papers were divided up and sent to our 8 reviewers. The reviewers then appraised the articles for their validity, relevance and rigour. Following the receipt of their comments, we included in the Evidence Update 49 articles that were deemed to meet the standards.

Publication Date: 26 Jul 2010
Publication Type: Annual Evidence Update
Publisher: NHS Evidence - gastroenterology and liver diseases
Creator: NHS Evidence - gastroenterology and liver diseases
Next Review Date: 23 Jul 2011


Final Notes From Vienna: The Magic of the Global Village, and the Destiny of Change

By Carole Treston July 27, 2010

My intention on my last day in Vienna was to stop in the Global Village for an hour and then cut out and do some sightseeing. Well ... I stayed there four hours and saw a lot. It's great to go to an international AIDS conference -- the energy, the diversity, the solidarity and the possibilities and evidence for change are awesome and the Global Village embodies that. It is a large exhibit hall, adjoining the conference, where people with HIV, affected communities, NGOs, activists and health agencies interact with scientists, physicians, government and civil leaders. It is a place to learn and for many to express themselves, to interact with opinion leaders in a more comfortable space, or there are places to just chill out and catch up. It was great -- there were booths from NGOs from around the globe. (I learned it was free for non-profits -- there is no exhibitor fee -- hope that holds in the United States in 2012.) There were booths from Act-UP Paris to China Youth Network to the International Union of Sex Workers to Housing Works! There were dance performances by Youth ("stomp stomp clap clap -- HIV -- take responsibility") and art work and video showings and special sessions where plenary speakers met with small groups of people for in-depth discussions and spots where you could buy little handmade crafts (mostly from African NGOs) and a little place for tea. It went on and on. It's a space full of life and creativity and diversity.

I sat and watched a documentary The Lazarus Effect produced by HBO about patients in Zambia. First interviewed about their hopes and dreams before ARVs were available and then again when the film makers, Lance Bags and Spike Jonze returned two months later after ARVs. The changes were astounding. Not everyone survived and the stories are still heartbreaking -- but remarkable change happened. To see the video go to www.joinred.com/splash.htm.

Change happens. To me, the most profound moment was during an earlier plenary when Dr. Aaron Motsoaledi, South Africa's Minister of Health spoke about universal access to treatment and scaling up ARV treatment and prevention. It was only a five years ago that the South African government denied HIV caused AIDS and the former Health Minister touted garlic and vitamins as the treatment for AIDS. I was in Johannesburg in 2002 and witnessed the government refusing funds from the Clinton Foundation to buy ARVs to treat HIV positive health care workers. Now, the new South African President and the Minister of Health have a national strategy to test 15 million people and get more than 2 million people on ARVs. Wow.

In the Global Village there is a Youth Pavilion, a networking space that is part of the Youth Programme at AIDS 2010. I listened to groups of young people from around the world talk to each other about common issues, such as access to appropriate services, prevention efforts that work for them and their peers, their reality in condom use and sexual negotiations, and heard the experiences and wisdom of young MSM and young women including transgendered young women living with HIV. I was reminded that too often, youth continue to be left out of planning and delivering interventions that directly affect their lives. I was absolutely reminded that it is essential to engage, encourage and acknowledge youth as assets and leaders in the fight to end HIV both here and globally. I wondered what it will take to make that change happen outside of the conference Global Village.

Post script -- On the plane ride home I re-read the National HIV/AIDS Strategy (and watched three movies). Again, I was impressed by how well written and full of common sense most of it is. It's our plan and I encourage you to read it and use it. BUT there is a big gap -- youth are conspicuously absent. It starts out appropriately on page two "One quarter of new HIV infections occur among adolescents and young adults (13-29)" but then (by my imperfect yellow post-it method of word searching) youth/young people are only referred to 3 more times -- and one doesn't really count as it only points out that 1/3 of youth share common misperceptions about HIV transmission. The role of schools in HIV prevention and comprehensive sex education is weakly noted once as is the role for schools in stigma reduction, and I was specifically searching.

Imagine what a remarkable change might occur in the risk for gay young men and African American youth in acquiring HIV if there was a real investment in them that started with comprehensive sex education, and that included effective HIV prevention in the schools -- real education that included empowerment and skill building for girls and gay youth that would last a lifetime. Imagine youth leading an HIV prevention and care movement for youth. Wow. Youth have already told us what will work for them and their peers for both prevention and access/retention in youth friendly care. You can read some of that at www.aids-alliance.org/youthnhassummary.pdf.

Change will happen when we go beyond convening and listening to youth and take the next step and acknowledge and act on their ideas and suggestions. They are telling us that the same old approaches aren't working for them (25% of new infections). We have a lot of work to do to get that change started -- beginning with making sure that the unique needs of youth in HIV prevention and care are not missed in the implementation of the National HIV/AIDS Strategy.

Founded in 1994, AIDS Alliance for Children, Youth & Families (AACYF) is a national non-profit organization whose mission is to advance the partnership between consumers and providers -- they are the voice of women, children, youth and families living with and affected by HIV/AIDS. AACYF works to enhance and expand access to quality, comprehensive, family-centered care to America's women, children and youth affected by HIV/AIDS. For more information on AIDS Alliance, visit www.aids-alliance.org.