April 2009
Feature Story

Anne Ford

Somehow, despite the fact that “hepatitis” rhymes with countless words (“arthritis,” “laryngitis,” and “gastritis,” just for starters), the music industry has yet to produce a pop song about it. Okay, given the letter designations of some of its associated viruses, you could make a case for the Jackson 5’s “ABC,” but it would be an awfully slim one.

After all, there’s nothing “easy as one, two, three” (as the Jacksons sang) about testing for and treating viruses that can lie dormant in the body for years. Still, perhaps two recent sets of recommendations will make testing protocols simpler and more effective for at least one form of hepatitis: HBV.

The recommendations in question: the National Institutes of Health’s consensus statement on hepatitis B, which appeared in the January issue of the Annals of Internal Medicine, and the Centers for Disease Control and Prevention’s “Recommendations for Identification and Public Health Management of Persons with Chronic Hepatitis B Virus Infection,” released last September.

“There’s really been a consistent progression of guidelines for hepatitis B,” not only across the NIH and the CDC, but also among organizations such as the American Association for the Study of Liver Diseases, says David Hillyard, MD. “I see it as an increased recognition of just how complicated chronic hepatitis B is. That’s clearly reflected in the NIH and CDC guidelines.” Dr. Hillyard is professor of pathology at the University of Utah School of Medicine and director of molecular infectious disease testing at ARUP Laboratories, Salt Lake City.

HBV, of course, isn’t the only hepatitis virus whose testing protocols have needed clarification. Uncertainty surrounds testing for hepatitis C, too, particularly around the question of how well laboratories are heeding the CDC’s 2003 guidelines regarding HCV testing. Those guidelines provided an algorithm designed to streamline the confirmatory test process. Unfortunately, “there are still issues about confirmatory testing,” says D. Robert Dufour, MD, emeritus professor of pathology at George Washington University and consultant in hepatology and pathology at the VA Medical Center, Washington, DC. Some laboratories perform unnecessarily expensive recombinant immunoblot assays in cases where an HCV RNA test would be more appropriate. Others are even still educating clinicians about the importance of confirmatory testing.

At the same time, there are many encouraging HCV-related developments in the works, such as rapid point-of-care tests and new classes of drugs. These advances can’t come too soon, says John Ward, MD, director of the CDC’s Division of Viral Hepatitis: “We have over 3 million persons living with hepatitis C in the United States. Most people have yet to become severely ill with it, and so it’s expected that the serious illness and mortality related to hepatitis C will increase in future years if we don’t do something about it now.”

But first, HBV. One item receiving some attention is the recommendation of the NIH and CDC guidelines that hepatitis B testing be performed on people from countries classified as moderately or highly endemic for the virus, that is, where its general prevalence is two percent or higher (as opposed to the CDC’s previous recommendation of eight percent). Those countries are in Asia and Africa, as well as in Eastern Europe, the Middle East, the South Pacific, the Caribbean, and South America, Dr. Ward says.

“The health burden of hepatitis B is being fueled by changes in the immigration patterns into the United States,” Dr. Ward adds. “Over the last 20 years there has been an increase in immigration from countries where hepatitis B is particularly endemic. People perhaps associate hepatitis B with Asian countries. But also there has been increased immigration from Eastern Europe and from African countries like Somalia.” HBV testing is now also recommended for men who have sex with men, injection drug users, and people with abnormal liver function not explained by other conditions.

In addition, the NIH and CDC statements recommend that patients about to begin chemotherapy or another immunosuppressive therapy undergo HBV testing first. “What we know now is that with people who have had exposure to hepatitis B, the virus is not actually gone,” Dr. Dufour says. “It’s just gone into hiding. When the body’s immune system is suppressed, it can come back. What we’re finding, and what I think a lot of other people are finding too, is that many physicians are not aware of this. We’ve had several cases of patients whose hepatitis B came back, including one who died, who’d never been tested before they were begun on either chemotherapy or immune suppressants.”

Dr. Ward seconds this warning. “This is particularly important for clinical pathologists who work in medical facilities that have large cancer treatment programs,” he says. “For people with markers of past infection, if those persons are placed on certain immunosuppressant drugs for cancer and other conditions, they will reactivate that sleeping infection. They get fulminant hepatitis, causing some to go to complete liver failure. Studies show the mortality can be quite high.”

But will testing a larger number of asymptomatic people for HBV inadvertently result in an unacceptable number of false-positive results? It might, says Miriam J. Alter, PhD, professor of infectious disease epidemiology and director of the infectious disease epidemiology program at the University of Texas Medical Branch at Galveston. Dr. Alter is former associate director of epidemiologic science in the CDC’s Division of Viral Hepatitis.

“I don’t know how many laboratories do hepatitis B surface antigen testing without performing a confirmatory assay,” she says. “Using a single mar­ker alone, without confirmatory testing, is going to be problematic if we widen testing of asymp­tomatic people. Chances are you’re going to get false-positives.” Whet­her and to what extent this will become a problem, of course, remains to be seen.

In addition, the NIH guidelines made changes to the recommended testing for HBV; real-time PCR testing is now emphasized, for example. Dr. Dufour says, “They’ve made a recommendation for monitoring therapy that laboratories use assays with the lowest detection limit possible, which is currently real-time PCR. Those assays have detection limits that are much, much lower than assays that were available 10 years ago.”

The importance of HBV DNA testing is also emphasized, on the grounds that, as Dr. Dufour puts it, “the amount of virus is predictive of the likelihood that the patient’s going to get into trouble down the road”—develop liver cancer, cirrhosis, or other conditions.

“Measurements of HBV DNA have not been widely used in the past,” he notes. That’s partially because earlier generations of HBV DNA tests generally required the presence of very large amounts of virus to yield a positive result. Now that more sensitive tests are available, however, “it’s been recognized that these are the most helpful tests for monitoring treatment. The NIH guidelines have kind of changed the perspective on this, I think, so that viral load is an important factor in deciding whom to consider for treatment.”

Frederick S. Nolte, PhD, agrees. “That, I think, is something that pathologists and laboratory medicine people ought to be aware of, that HBV DNA testing is part of the algorithm now for managing patients that are being treated for chronic hepatitis B,” he says. In his view, the NIH consensus statement represents “a pretty strong endorsement of that.” Dr. Nolte is professor and director of clinical laboratories in the Department of Pathology and Laboratory Medicine at the Medical University of South Carolina, Charleston.

Regarding general trends in HBV testing, Dr. Hillyard says, “The notion that patients who are going to undergo treatment may require some sort of a characterization beyond viral load is certainly gaining steam. While request numbers for genotypic HBV resistance testing are still relatively low, the availability of new antiviral drugs and the well-documented emergence of resistant HBV in patients undergoing therapy set the stage for more widespread genotypic testing. That is a conspicuous development.”

Then, too, he adds, laboratories should be aware of reports that have emerged over the past few years indicating that different hepatitis B genotypes may respond differently to interferon: “If interferon therapy is being considered, it may also be appropriate to guide that decision with genotyping before the start of treatment.”

The last time CAP TODAY reported on hepatitis C testing (“HCV testing swaps high-low for yes-no,” April 2005), reports from the field indicated that some physicians did not appear to be aware of the need to perform confirmatory HCV testing. At the time, for example, Dr. Dufour estimated that only about 15 percent of VA hospitals were reflexively doing confirmatory testing. Since then, “the number that is doing confirmatory testing has gone up, but it still isn’t 100 percent,” he says. That will change soon, he adds: “The VA is actually coming out with a new directive requiring laboratories to do some sort of confirmatory testing on all positive results.”

Another issue as of 2005 was that of RNA versus recombinant immunoblot assay, or RIBA, for confirmatory testing. At the time, not all institutions appeared to be heeding 2003 CDC guidelines that recommended that laboratories perform RNA confirmatory testing on specimens with high signal-to-cutoff ratios and reserve the more expensive RIBA for specimens with low signal-to-cutoff ratios.

Six years after the CDC issued the RNA/RIBA recommendation, it’s clear that it “really does contribute to a clinically proven, cost-effective algorithm for screening and confirmation,” Dr. Hillyard says. “The question is: To what extent is this being well recognized, and is it being adopted? I think the answer is that it really varies from institution to institution.”

In Dr. Dufour’s view, the expense of RIBA is still leading some clinicians to avoid it, even for low-positive specimens. What they might not be realizing, he adds, is that not performing RIBA when indicated can lead to much greater expense down the road.

“We actually tracked one individual patient who had been seen initially at another hospital in the VA system,” he recalls. “He’d gotten a positive result on the initial test, and it had been reported out to the clinicians without saying that it was weakly positive. This turned out to be a false-positive when we did the confirmatory testing in our institution.” The clinicians ordered a measurement of HCV RNA, which was negative, and they referred him to a gastroenterologist. “This patient ended up getting a number of imaging studies for unclear reasons. The first one showed some questionable abnormalities, so he ended up having another one after that, and then another one after that. And then he had another measurement of HCV RNA, and a couple more visits to the gastroenterologist, before they decided he really didn’t have any liver problem.” The calculated downstream cost of the one false-positive test was several thousand dollars. “And I’m sure he’s not the only person this has happened to,” Dr. Dufour says.

The lead author of those 2003 guidelines—Dr. Alter—is similarly skeptical that they’ve achieved widespread adoption. “Anecdotally, I don’t think laboratories have changed their practices,” she says. “Part of the problem is that in order for the confirmatory test to be reimbursed, it has to be under a physician’s order. In response, we suggested that you could change the requisition forms, so that when the physician ordered an antibody test, the form would say that if it was positive, additional testing would be done to confirm it.”

That suggestion, however, “may have gotten lost,” she says. “Independent laboratories, I think, are still doing whatever the request form says. So if it says ‘antibody,’ they’re doing a screening test and not confirming the result and not using signal-to-cutoff ratio to report out results in order to guide the physician.”

In other, more upbeat HCV news, many new classes of drugs for treatment are in development, including nucleoside analogues and protease inhibitors.

“They look very promising,” Dr. Hillyard says. “We’re see­ing a rapid rate of fall of HCV RNA levels with these new drugs in emerging clinical studies.”

Still, he cautions, “Treatment in combi­nation with interferon remains the foundation of therapy. Also, because of this initial rapid rate of HCV viral load fall, even in patients who don’t go on to have sustained therapeutic responses, clinicians using these new drugs may lose the benefit of current stopping algorithms. These algorithms rely on the kinetics of viral load decline to identify patients who are unlikely to have sustained responses to therapy and are important tools for management. Hopefully, new algorithms will be established to better predict patients who will potentially benefit from a full course of the new treatment regimens.”

Also in development are rapid point-of-care tests for HCV diagnosis, which Dr. Ward of the CDC says the FDA may license in the next 18 to 24 months. He expects that their benefits will include the integration of HIV and HCV testing. “We would like to open up a whole new vista of offering tests in a setting where it’s not previously been done,” he says, “and to perhaps present a more powerful message to the person being tested that may lead them to positive behavior change and reduced risk of transmission to others.”