NIH consensus statement surveys hepatitis B care.
With its emphasis on long-term clinical outcomes and a call for placebo-controlled trials, the statement may surprise physicians who have been embracing a growing number of practice guidelines and algorithms. These guidelines rely upon intermediate markers, such as serum DNA levels, alanine aminotransferase levels, hepatitis Be antigen (HBeAg) status, and liver histology as a basis for decision making in managing patients.
The NIH draft statement, which is expected to be published in final form in early December, says that these intermediate markers may not improve the likelihood of achieving primary clinical outcomes and that large randomized trials--some of them placebo controlled--are needed to better understand the extent to which therapy affects clinical outcomes in patients with chronic hepatitis B.
"We know that these therapies have positive effects on indicators such as viral load, but further controlled trials are needed to substantiate that these agents prevent disease progression to liver failure and cancer over an extended period of time," said panel and conference chairperson Dr. Michael F. Sorrell, Robert L. Grissom professor of medicine at the University of Nebraska Medical Center in Omaha.
Such studies, along with a multinational, population-based prospective cohort study designed to define the natural history of the disease, could also help to "delineate which patients need immediate therapy and which can be followed," Dr. Sorrell said.
Intermediate markers that measure changes in virologic, histologic, and biochemical parameters have been advanced by investigators as surrogate end points, and were the basis of the Food and Drug Administration's approval, for chronic hepatitis B virus (HBV) infection, of interferon alfa-2b, peginterferon alfa-2a, and five oral nucleoside or nucleotide analogues (lamivudine, adefovir, entecavir, telbivudinc, and tenofovir).
"If the FDA had required that we show we can prevent progression to cirrhosis or mortality, we would never have been able to get a drug approved. ... These outcomes are measured out in decades," Dr. Jules L. Dienstag, dean for medical education and the Carl W. Walter professor of medicine at Harvard Medical School, Boston, told the panel.
There is a "convincing relation" emerging in recent studies--albeit not randomized controlled trials--between sustained high levels of HBV DNA and late clinical outcomes, he said during a presentation on the benefits and risks of nucleoside and nucleotide analogues for hepatitis B.
A prospective cohort study of more than 3,500 untreated hepatitis B-infected patients in Taiwan, for instance, found that progression to cirrhosis was strongly correlated with the level of circulating virus.
"Profound, durable therapeutic HBV DNA suppression can slow and reverse the progression of chronic hepatitis B," Dr. Dienstag told the NIH panel.
In addition, a growing number of studies are now showing, he and others said, that antiviral treatment reverses cirrhosis, reverses decompensation, and allows people to come off" transplant lists. "Ten years ago, the dogma was that cirrhosis wasn't reversible," Dr. Dienstag said.
The NIH panel's focus, however, was relatively narrow. The panel was charged with answering specific questions and with considering a systematic evidence review performed by one of the Agency for Healthcare Research and Quality's Evidence-Based Practice Centers as a "foundation of high-quality evidence" for the conference.
The AHRQ center's review included observational studies to assess the natural history of hepatitis B infection, but only used randomized controlled trials to assess treatment effects. The review concluded that evidence is "insufficient" to assess treatment effect on clinical outcomes, to predict patient response, or to determine "if intermediate measures are reliable surrogates."
The randomized controlled trials that have been conducted in adults with chronic HBV infection were simply not designed to answer such questions, and while "it would seem reasonable that improvement in [intermediate outcomes] would translate to improvement in clinical outcomes," there is "prior precedent" in other clinical areas of such correlations being proven wrong, noted Dr. Timothy Wilt, codirector of the Minnesota AHRQ Evidence-Based Practice Center, after presenting the review.
Still, the panel veered from its focus on long-term randomized controlled trials to conclude that therapy should be given to patients in these categories:
* Patients who have acute liver failure.
* Patients with cirrhosis complications.
* Infants born to hepatitis B surface antigen (HBsAg)-positive women.
* Patients who have reactivation of chronic HBV
* Patients about to receive immunosup pressive therapy or cancer chemotherapy
Panel member Dr. John Inadomi of the University of California, San Francisco, and San Francisco General Hospital said in an interview after the conference that these recommendations cover areas in which high-quality evidence is largely lacking but would be difficult to obtain through further research--and perhaps even unethical to obtain--given the current knowledge base.
Observational studies indicate, for instance, that HBV patients who receive immunosuppression or cancer chemotherapy for other medical conditions are at high risk of developing an exacerbation of hepatitis (including those in the inactive HBsAg carrier phase and those with resolved hepatitis).
"The risk of severe reactivation in these patients is so high that, even though good evidence is lacking, [treatment] seems reasonable," Dr. Inadomi said.
With respect to cirrhosis with complications, a placebo-controlled randomized trial showed a clinically relevant improvement in the Child-Turcotte-Pugh score and a borderline significant reduction in the incidence of liver cancer with oral antiviral therapy. The study was halted for benefit, and a secondary analysis showed that the reduction in cancer reached statistical significance.
The NIH panel also concluded that therapy "may be indicated" in patients in the immune active phase of disease. (This phase, also referred to as the immune clearance phase, is characterized by the presence of HBeAg with elevated HBV DNA levels and evidence of active liver inflammation.)
The risk of developing complications from chronic HBV infection increases in patients around age 40, the consensus statement says. Younger HBeAg-positive patients may undergo spontaneous HBeAg seroconversion, so it is reasonable to monitor this group without therapy. If spontaneous seroconversion does not occur by the late 30s or early 40s, and active inflammation is present, therapy may be indicated.
Therapy is not indicated in patients who are in the immune tolerant phase, patients who are in the inactive carrier/low replicative phase, and patients who have occult HBV infection (HBV DNA without HBsAg), the statement says.
While not endorsing HBV DNA as a reliable surrogate end point for long-term clinical outcomes, the panel did conclude that elevated HBV DNA is the "most important predictor" of cirrhosis or hepatocellular carcinoma in patients with chronic HBV infection. Other risk factors include older age, male sex, a family history of liver cancer, coinfection with hepatitis C or HIV and infection with HBV genotype C, the panel said.
About 1.25 million people in the United States are chronically infected with the hepatitis B virus, resulting in 3,000-5,000 deaths a year. Although the incidence of infection has decreased dramatically among U.S. residents since the mid-1980s, largely because of the widespread immunization of infants and high-risk populations, the prevalence of chronic HBV infection remains high and may be increasing.
The NIH held conferences on the management of hepatitis B in 2000 and 2006, but this conference was the first one convened through the NIH consensus development program. In 2002, the NIH held a consensus development conference on hepatitis C and published a report that gave more detailed clinical direction.
The new report on hepatitis B is valuable, Dr. Inadomi noted, in that it "gives us the chance to step back and ask, how much of our practice is based on high-quality evidence, and what additional research is necessary to ensure that we are helping our patients?"
The panel's research recommendations will probably inform the agenda of a Hepatitis B Clinical Research Network, to be launched by the National Institute of Diabetes and Digestive and Kidney Diseases to promote translational research on the condition.
In the meantime, new data on the natural history and treatment of chronic hepatitis B since 2005 have spurred a new round of guidelines and algorithms. The American Association for the Study of Liver Diseases recently published updated practice guidelines for chronic hepatitis B (Hepatology 2007;45:507-39), and at press time, new guidelines from the European Association for the Study of the Liver are slated for publication in the Journal of Hepatology in the next few months.
Dr. Emmet B. Keeffe and his associates have also revised their treatment algorithm for managing chronic hepatitis B to reflect what they say are numerous developments, from the availability of more-sensitive molecular diagnostic tests to a better understanding of the advantages and disadvantages of new treatments. At press time, a report on the algorithm was scheduled for publication in the December 2008 issue of Clinical Gastroenterology and Hepatology.
"In contrast to published guidelines, the NIH document did not suggest preferred drugs for use in the indications for which treatment was recommended. Society guidelines and algorithms suggest that oral drugs with high potency and a low rate of resistance are the best options when treatment is initiated," said Dr. Keeffe, professor emeritus of medicine, Stanford University Medical Center, Palo Alto, Calif., in an interview. The NIH consensus statement may be accessed through http://consensus.nih.gov.
BY CHRISTINE KILGORE
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|Title Annotation:||News; National Institutes of Health|
|Publication:||Internal Medicine News|
|Date:||Dec 1, 2008|
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