Putting some teeth
of the CDC’s new guidelines for hepatitis C virus testing sound
a bit like politicos when they speak on the topic. The thrust of
their observations could fit smoothly into campaign slogans: Spend
more to save more. Put the testing burden back where it belongs.
End false-positives—and false hopes.
empty political rhetoric and certain fuzzy economic proposals, the
new guidelines have some meat on them.
good sense; it’s medical good sense," says James Versalovic, MD,
PhD, who helped draft the guidelines. "There are really no major
disadvantages to this."
"It’s an important
development," he adds. "But it’s one that could be easy to overlook."
basis for such concern. By and large, most agree, HCV simply doesn’t
draw the same interest or serious level of discussion as HIV. Add
to that persistent misunderstandings about the value of and need
for confirmatory testing, and HCV antibody testing arrives at its
The new guidelines,
which appear in the Feb. 7 issue of "MMRW Recommendations and
Reports" [52 (RR03); 1-16] (also available online at www.cdc.gov/mmwr/PDF/rr/rr5203.pdf),
take clear aim at that muddle.At their core lies a recommendation
that anti-HCV testing include reflex supplemental testing by RIBA
or nucleic acid testing, and, to reduce costs, that this testing
be based on screening-test-positive signal-to-cutoff (s/co) ratios.
For the two currently licensed anti-HCV enzyme immunoassays, the
guidelines say that supplemental testing needs to be performed only
for EIA-positive samples with ratios less than 3.8. By using these
ratios, laboratories should be able to keep the need for supplemental
testing to a minimum while making reported test results more reliable.
This option could
substantially change laboratory testing practices, says Miriam Alter,
PhD, the lead author of the guidelines and by some accounts the
primary force behind their genesis. "Only a minority of laboratories
provide any routine supplemental testing for anti-HCV," says Dr.
Alter, associate director for science at the CDC’s Division of Viral
Hepatitis. "These guidelines, we hope, will encourage laboratories
that don’t do supplemental testing to adopt this alternative use
of signal-to-cutoff ratios to improve the interpretation of the
That, of course,
implies there is a problem with results interpretation—an
implication with a fair amount of truth to it, says Dr. Versalovic,
director of microbiology laboratories, Texas Children’s Hospital,
and assistant professor of pathology, Baylor College of Medicine,
Houston. The overall goal of the guidelines, he says, is to reduce
the number of false-positive HCV test results being reported. The
problem stems from the testing method. An initial HCV test is done
using a simple ELISA method to screen for the presence of antibodies,
says Dr. Versalovic, who is a member of both the CAP Microbiology
Resource and Molecular Pathology committees.
"The problem is
that many laboratories are reporting the screening result as positive
or negative." By their very nature, however, screening tests are
"very sensitive, but they’re not as specific as we’d like them to
be. The problem then becomes, many people may get a positive test
result but not have the virus."
the screening assays were developed without a so-called gray, or
buffer zone, says Frederick Nolte, PhD, professor of pathology and
laboratory medicine, Emory University, Atlanta, and director of
the clinical microbiology and molecular diagnostics laboratories
for Emory Medical Labs. This zone, which encompasses weakly positive
results, isn’t acknowledged in package inserts. "So labs are left
on their own on how to proceed," says Dr. Nolte. "It’s a simple
matter, but a problem nonetheless."
makes the inevitable comparison to HIV to explore the screening
ELISA’s limitations. While an ELISA is also used to screen for antibodies
to HIV-1, it’s rarely the last word. "As a rule, because HIV is
such a sensitive issue, patients who are positive by the screening
test have a followup immunoblot. No result is released without that,"
HCV is different,
though it shouldn’t be. "It’s an important problem, and in terms
of numbers is a much greater problem than HIV-1," says Dr. Versalovic.
"And of course long-term there’s the risk of cirrhosis and liver
cancer." Yet followup testing is uncommon.
Chalk it up, in
part, to attitude. "I have participated in many discussions in which
comments were made that getting a false-positive test for hepatitis
C isn’t serious, or isn’t as serious as getting one for HIV," Dr.
Alter reports. "That’s appalling. I think it’s appalling that anyone
would have that attitude toward giving a patient a false-positive
result, and then subjecting them to not only the psychological stress
but also the expense of additional evaluation when it isn’t necessary."
new guidelines could do much to quell such attitudes.
have roots in the blood bank community, according Dufour, MD, chief
of pathology and laboratory medicine service at the VA Medical Center,
Washington, DC, and professor of pathology, The George Washington
University Medical Center. Blood bankers first reported the implications
of weakly positive anti-HCV test results; namely, those with weakly
positive results tend not to be HCV RNA positive or positive on
a recombinant immunoblot assay, or RIBA.
were largely ignored in the clinical setting, says Dr. Dufour, who
helped write the CDC guidelines. "Probably the first time anyone
paid any attention to this was at our institution, when my predecessor
published an abstract in 1994 indicating that even in the clinical
setting, those with weakly positive antibodies were typically negative
when further testing was done.
"But even after
that, nobody paid much attention to it," he says ruefully.
In the late 1990s,
Dr. Dufour continues, the blood banks provided CDC with data showing
that s/co ratios could be used to predict supplemental test results.
In response, the CDC began assembling samples from various populations,
including high-risk and low-risk individuals to evaluate the use
of s/co ratios in other settings.
At about the same
time—October 2000, to be exact—Dr. Dufour and his colleagues
also began routine confirmation testing of all weakly positive results.
They found that the vast majority-approximately 86 to 88 percent-of
patients with weakly positive antibodies were negative on all confirmatory
testing. (Their study is published in the March issue of Clinical
Chemistry. 2003; 49: 479-486.)
Following up weakly
positive anti-HCV results in this manner put Dr. Dufour’s laboratory
in the minority. As the guidelines report, two 2002 surveys on anti-HCV
testing practices—one of public health laboratories, one of
VA medical centers—revealed the practice of confirmatory testing
is rare. "Very, very few laboratories are doing confirmatory testing,"
Dr. Dufour says. "I would venture to say that in hospital laboratories,
it’s even less common."
The CDC guidelines
note that the majority of public and private-sector laboratories
rely primarily on requesting physicians to order the appropriate
tests and correctly interpret their results. The guidelines also
suggest such reliance is not wise.
It’s a view shared
by Dr. Nolte. "Labs, in a cost-conscious environment, are abdicating
some of their responsibility for producing reliable results, in
the false hope that the ordering physician will be knowledgeable
about the test’s performance characteristics. And that may be true
of hepatologists, but it certainly [isn’t] true of primary care
physicians and other people who may be doing the screening," he
in fact, may be among the few subsets of physicians who understand
the nuances of anti-HCV testing well enough to argue that the CDC’s
guidelines are unnecessary. "Gastroenterologists and liver disease
specialists have a certain perspective on this," says Dr. Nolte,
"and that perspective is, in a high-risk patient population, RIBA
testing doesn’t add very much, because almost every time they see
a patient who is EIA positive, the RIBA’s positive." This group
of physicians, he says, will likely find the CDC guidelines "not
"But that’s not
the point," he continues. "The point is, there’s a lot of testing
that goes on in other settings. When you have 1.8 percent of the
U.S. population seropositive, some 2 million to 4 million people,
you realize there’s a lot of testing that goes on for hepatitis
C outside of the liver disease clinic." And, as the CDC guidelines
point out, laboratories don’t know, on an individual patient basis,
who is high risk and who is low risk. "The way the guidelines are
constructed, they allow you to target the supplemental test to that
group of specimens that would benefit from having the supplemental
test done, regardless of the pre-existing risk factors or disease
prevalence of the population you’re testing," Dr. Nolte says.
developers of the guidelines assessed how they would work in
various populations, with different disease prevalence. They also
covered virtually every possible testing algorithm. "We didn’t want
to launch a surprise, or issue recommendations in a vacuum. So we
did a lot of work with everybody we could think of before we even
drafted the guidelines, to deal with potential barriers," Dr. Alter
recalls. "The last thing I wanted to find out after publication
was that there was some barrier that couldn’t be overcome for some
"But we didn’t
find one," she continues. "We found difficult ones, but not insurmountable
ones." The two biggest barriers were (1) reprogramming laboratory
software to generate an appropriate s/co ratio, and (2) reimbursement.
The CDC worked closely with anti-HCV test manufacturers on the former
issue, and contacted the Centers for Medicare and Medicaid Services
to explore reimbursement possibilities.
explain that documenting physician ordering of the reflex supplemental
testing—on which reimbursement may hinge—can be done
via a printed requisition form that clearly identifies the level
of screening-test results that will trigger supplemental testing,
and what type of testing that will be. The guidelines also recommend
that each of the supplemental tests offered (RIBA or nucleic acid
testing) be listed separately, enabling clinicians to order them
Thanks to this
advance work, the guidelines have been met with no resistance so
far, Dr. Alter reports. "I’m hoping it’s because we did include
everybody we needed to include, and that we gave them a lot of time
to think this over." She and others are getting the word out via
teleconferences and at annual meetings, and the guidelines are being
widely distributed via mail and the Internet.
Dr. Nolte’s laboratory
has already begun applying the guidelines. "We were one of the few
laboratories that were confirming all of the positive screening
tests with RIBA," he says. This gave them an opportunity to do a
lookback study to assess the CDC’s s/co ratios. They looked at 1,000
test results, in a population with a 7.5 percent seroprevalence
rate. Of the 75 positive EIAs, 65 had a signal-to-cutoff ratio of
greater than 3.8; of those, 64 (98.5 percent) were RIBA positive.
Of the 10 positive specimens with an s/co value of less than 3.8,
30 percent were RIBA positive.
Based on those
results, Dr. Nolte’s laboratory adopted the guidelines and now performs
RIBA testing only on samples with low signal-to-cutoff ratios. "As
you can see, that substantially decreases the amount of RIBA testing
that we’re doing. That’s a tremendous cost savings for the laboratory,
and it doesn’t compromise our antibody results at all."
report informs physicians that if a result has an s/co of greater
than 3.8, it’s strongly positive for antibody to HCV. The laboratory
doesn’t report the actual s/co ratio. It does note that greater
than 98 percent of strongly positive samples are also positive on
the supplemental RIBA. Strongly positive samples are followed up
with a qualitative HCV RNA test, ordered reflexively, to distinguish
active from resolved infection.
Samples that are
weakly positive for HCV antibody are sent for supplemental RIBA.
The laboratory informs clinicians that a qualitative HCV RNA test
is recommended for all confirmed antibody-positive samples to distinguish
active from resolved infection, but that such tests must be ordered
separately. "If the RIBA comes back positive on that weakly positive
screening test, we don’t automatically reflex to PCR—it’s
too complicated to keep track of that in the laboratory to make
sure it gets done effectively," Dr. Nolte says.
In Dr. Nolte’s
laboratory, the s/co is determined manually. "It’s not a difficult
calculation, and it’s not something that will present a problem
for most laboratories. Remember, you’re only doing it for samples
that are positive." Positivity rates rarely run higher than 20 percent,
and more frequently they fall into the one to five percent range,
The s/co can also
be calculated automatically (depending on the instrument used) with
either of the two enzyme immunoassays (Abbott HCV EIA 2.0, Abbott
Laboratories; Ortho HCV version 3.0 ELISA, Ortho-Clinical Diagnostics).
It is automatically calculated on the enhanced chemiluminescence
immunoassay (Vitros anti-HCV assay, Ortho-Clinical Diagnostics).
The CDC guidelines indicate that for the licensed EIAs, an s/co
of greater than or equal to 3.8 would be highly predictive of the
true anti-HCV status. For the CIA test, an s/co of greater than
or equal to 8 was recommended.
The beauty of
using s/co ratios is that it makes the process more efficient, says
Dr. Versalovic. "What you’ve effectively done is increased the value
of confirmatory testing. That s/co, if it’s high enough, is sufficient
for confirmation without additional testing. Only the low positives
are submitted for confirmatory serologic testing." The net result,
he says, is an approach that doesn’t necessarily add another test,
but rather improves the accuracy of current testing.
the spend more-save more theory comes into play. By increasing the
efficiency and value of confirmatory testing, the guidelines should
help curb or stabilize costs. "And the costs of unnecessary followup
testing will drop," Dr. Versalovic says.
Dr. Alter sounds
equally realistic as well as upbeat. She doesn’t expect the guidelines
will be an overnight success. "But I’m hoping within six months
to a year, it will really have taken hold," she says.n Karen Titus
is CAP TODAY contributing editor and co-managing editor.
Karen Titus is CAP TODAY contributing editor and co-managing editor.