Volume XXIII Number 4 Winter 2009

Editor’s Note:
In the spring 2003 issue of this with systemic or local inflammation.
In this Issue publication, the editor’s note was Vascular inflammation is associated with
headlined “Beyond Cholesterol.” In significantly lower levels of CRP than
Editor’s Note . . . . . . . . . . . . . . . . .1 that issue, we reported and discussed those seen in systemic inflammation.
the recently released (2003) American Assays for hs-CRP are more sensitive
By JUPITER! . . . . . . . . . . . . . . . . .2 Heart Association/Centers for Disease and reported in mg/L versus CRP that
Control and Prevention (AHA/CDC) is reported in mg/dL. Therefore, it is
Chronic Hepatitis B Virus – scientific statement from the workshop important to order hs-CRP when testing
Updated Recommendations from on inflammatory markers and for vascular inflammation associated
CDC . . . . . . . . . . . . . . . . . . . . . . . .4 cardiovascular disease (CVD). with CVD. Quest Diagnostics uses the
proprietary name of Cardio CRP™
The concept of atherosclerosis as an
(CCRP) for hs-CRP to differentiate
inflammatory process was still relatively
between tests for vascular and systemic
new at that time, and the body of
inflammation. In the following article
evidence in support of the clinical
titled “By JUPITER!” we will refer to
use of inflammatory biomarkers was
hs-CRP as CCRP.
modest. The AHA/CDC statement
made Level II recommendations on The above-noted studies published
the use of high-sensitivity C-reactive since the release of the 2003 AHA/CDC
protein (hs-CRP) for stratifying risk statement have provided a growing
for cardiovascular disease. A Level II body of evidence that measurement of
recommendation indicated that the hs-CRP in a primary prevention setting
weight of evidence was favorable, but adds predictive power to traditional risk
Herman Hurwitz, M.D., F.C.A.P.
more data were needed before general scores for some intermediate risk
Senior Medical Director
Quest Diagnostics Philadelphia consensus could be reached. individuals. Additionally, it has been
Medical Director, Western Region noted that hs-CRP levels could assist in
Since 2003, considerable data have
identifying individuals at increased risk
been published on the use of hs-CRP
who could benefit from lifestyle
to improve assessment of cardiovascular
modification and pharmacologic
risk for patients in primary prevention
preventive therapies such as the use
programs. A recent comprehensive
of statin drugs.
review noted that at least 20 prospective
studies of distinct cohorts demonstrated The use of hs-CRP as a patient
elevated hs-CRP levels, which were education and motivational tool, which
Our Values associated with future risk for coronary is recommended in the AHA/CDC
heart disease (CHD) even after statement, also has been shown to be
Quality adjustment for traditional risk factors, useful in practice. Although less robust,
Integrity including the Framingham risk score data support the use of hs-CRP results
and/or diabetes and obesity. to guide treatment in the secondary
Innovation prevention situation such as in the
To refresh the reader’s memory, tests
Accountability for hs-CRP associated with vascular
acute coronary syndrome.
Collaboration inflammation measure the same
molecule as tests for CRP associated continued on page 2
Leadership
Editor’s Note
continued from page 1
One of the nagging questions about infection. In the past, HBsAg testing evaluation and management for
the use of hs-CRP has been—Does the has been recommended previously by chronically infected individuals and
presence of an elevated hs-CRP level in the CDC for pregnant women, infants their contacts. Routine testing for
the absence of hyperlipidemia signal born to HBsAg-positive mothers, HBsAg now is recommended for
an increased CVD risk that should be household contacts and sex partners of additional groups. The recommenda-
treated with drugs to lower hs-CRP? HBV-infected individuals, persons born tions now include populations with an
That question has recently been in countries with an HBsAg prevalence HBsAg prevalence of >2%, persons
answered by the results of the of >8%, persons who are the source born in areas with an HBsAg prevalence
Justification for the Use of Statins of blood or body fluid exposures of >2%, men who have sex with men,
in Prevention: an Intervention Trial that might warrant postexposure and injection-drug users.
Evaluating Rosuvastatin (JUPITER) prophylaxis (e.g., needlestick injury to
In this issue, we will review the
trial. The answer now is in and, a healthcare worker or sexual assault),
progression of serologic events that
according to most cardiologists, the and persons infected with the human
occur in uncomplicated and chronic
answer appears to be a resounding yes! immunodeficiency virus (HIV).
HBV infection, as well as discuss the
Serologic testing for hepatitis B surface A recent report from the CDC updates interpretation of various serologic
antigen (HBsAg) is the primary and expands the previous guidelines markers of HBV infection.
laboratory tool used to identify persons for HBsAg testing and includes new
with chronic hepatitis B virus (HBV) recommendations for public health

and high risk (>3.0 mg/L)

By JUPITER! correspond to approximate tertiles
of CCRP in the adult population.
The high-risk tertile has
approximately a twofold increased
In 1998, the AHA convened Prevention white blood cell count, fibrinogen, relative risk compared to the low-risk
Conference V to study strategies for and ESR. tertile. Patients with results >10
identifying patients at high risk for mg/L should be investigated for the
The comparison of the various
CVD and in need of primary disease possibility of systemic infection or
inflammatory markers favored CCRP as
prevention. At that time, the conference inflammation.
the analyte of choice because of sample
concluded that inflammatory markers
stability, accuracy, precision availability, • CCRP can be used to identify
were not yet considered applicable for
and existing proficiency testing among patients without known CVD who
routine risk assessment.
other reasons. The following may be at higher absolute risk than
In 2001, the National Cholesterol recommendations were published in estimated by major risk factors; i.e.,
Education Program Adult Treatment Circulation in 2003: a Framingham risk score of 10-20%
Panel III Guidelines identified • Current evidence supports the use over 10 years (intermediate risk
inflammatory markers as emerging of CCRP as the analyte of choice to score).
factors, which could be used as an assess cardiovascular inflammation.
optional risk factor measurement to • At this time, CCRP is not
adjust estimates of absolute risk • CCRP should be measured in recommended for general
obtained using standard risk factors. metabolically stable individuals population screening nor should
without obvious inflammation or it be used as an alternative to
In March 2002, a workshop titled infections. evaluation of the major risk factors.
“CDC/AHA Workshop on
Inflammatory Markers and • To minimize intra-individual • CCRP measurement may be
Cardiovascular Disease: Applications variation, results of two separate considered in order to motivate
to Clinical and Public Health Practice” assays, two or more weeks apart, patients with moderate to high-risk
was held. The purpose of the workshop should be averaged to provide a levels to improve their lifestyle and
was to determine which tests were most more stable estimate of that comply with drug therapy.
useful to assess cardiovascular risk; what individual’s level.
• CCRP may be useful in estimating
results should be used to define high • Results should be expressed in the prognosis in patients with stable
risk; and which patients should be mg/L. coronary artery disease or acute
tested. The workshop participants coronary syndromes.
reviewed several inflammatory markers, • The cut points of low risk (<1.0
including CCRP, serum amyloid A, mg/L), average risk (1.0-3.0 mg/L),
continued on page 3
Page 2
By JUPITER
continued from page 2
In the spring 2003 issue of this The study, originally designed as a 4- This finding was described by one
publication, which discussed the above year trial, was stopped after 1.9 years of cardiologist as “our most impressive
recommendations, the reader was follow-up, based on recommendations data in women in the
advised to “Stay tuned!” This is a of the drug manufacturer and an primary-prevention setting.”
continuation and update for the reader. independent data monitoring board.
A subgroup analysis showed no
The decision to terminate was based
Tune in to the AHA Scientific Sessions heterogeneity in any of the results,
on unequivocal evidence of a reduction
held in November 2008. New results including an analysis based on age,
in cardiovascular morbidity and
from three studies presented at the race, or ethnic group, as well as
mortality among patients treated with
AHA 2008 Scientific Sessions and baseline LDL-cholesterol and CCRP
rosuvastatin compared with the
published in scientific journals provide levels. The investigators reported that
placebo group. The study took into
strong evidence that CCRP is a useful even patients considered being at very
account the size and precision of the
marker for CVD. The most eagerly low risk—nonsmokers, not overweight,
observed-treatment benefit, as well as
awaited and widely discussed JUPITER no metabolic syndrome, or had a
effects on the rates of death and other
trial results promoted the most Framingham risk score of <10%—
secondary end points. The investigators
discussion, both in the medical benefited from the statin therapy.
continued the adverse-event reporting
community and the public media, with
in a blinded manner for each Some physicians have urged caution
reports appearing in many newspapers,
participant until each patient’s going forward. An editorial
including the frequently read Health
closeout visit. accompanying the JUPITER study
Sections of both the New York Times
report in the New England Journal of
and the Wall Street Journal. The study authors reported that
Medicine agreed that the AHA/CDC
treatment with rosuvastatin significantly
The New England Journal of Medicine and other guidelines relating to CCRP
reduced the primary composite end
published the results on its Web site are likely to be revisited. There was
point by 44%, compared with the
ahead of print shortly after the findings some disagreement with the study
placebo. The primary end points were
were presented at the AHA Scientific authors regarding the number needed
non-fatal myocardial infarction (MI),
Sessions. Prominent cardiologists to treat in order to prevent hard
non-fatal stroke, hospitalization for
issued comments such as “one of the cardiac events. Additional concern
unstable angina, an arterial revascular-
most important clinical trials in the was expressed regarding the increase
ization procedure, or confirmed death
long history of statin studies” and in glycated hemoglobin levels and
from cardiovascular causes. There was
“It is a true landmark in preventive diabetes mellitus incidence in the
a 55% reduction in non-fatal MI, a 48%
cardiology . . .” rosuvastatin arm. There was no
reduction in the risk of non-fatal
disagreement, however, in the
JUPITER is a large, multinational, stroke, and a 47% reduction in the risk
usefulness of measuring CCRP in
long-term, double-blind, placebo of hard cardiac events—a composite of
asymptomatic individuals who have an
controlled, randomized clinical trial MI, stroke, and death from
intermediate level of risk and whose
that included 17,802 healthy men and cardiovascular events.
treatment might change based on their
women assigned to rosuvastatin 20 mg
In terms of absolute advantage, the CCRP level.
or the placebo. The study was
proportion of patients who had an Editors Note: In the opinion of this editor,
designed to assess whether statin
MI, stroke, revascularization, or individuals with desirable LDL-cholesterol
therapy should be given to apparently
hospitalization for unstable angina or levels and at intermediate risk—now con-
healthy individuals with normal LDL-
died from cardiovascular causes was sidered by many to be 5-20% using the
cholesterol levels but elevated CCRP
1.6% in the rosuvastatin group and Framingham risk score—can be better
(CCRP >2.0 mg/L) values.
2.8% in the placebo arm—an absolute evaluated and managed for CVD risk by
Among patients treated with risk reduction of 1.2%. Likewise, the including CCRP values in the manage-
rosuvastatin, LDL-cholesterol levels proportion of patients with hard ment decision.
were reduced by half, decreasing from cardiac events—MI, stroke, and
a median 108 mg/dL at baseline to 55 cardiovascular death—was 0.9% in the (Circulation 2003; 107:499-511 — NEJM
mg/dL at 12 months. CCRP levels treatment arm, compared with 1.8% 2008; 359 (21):2195-2207, 2280-2282 —
declined 47%, from 4.2 mg/L at in the placebo group—an absolute Nat Clin Pract Cardiovasc Med 2008;
baseline to 2.2 mg/L at 12 months. reduction of 0.9%. 5:621-635 — theheart.org —
Triglyceride levels fell 17% from docguide.com — cardiosmart.org)
Additionally, of the 6,801 women
baseline in the rosuvastatin group.
included in the JUPITER trial,
These effects persisted over the course
rosuvastatin significantly reduced
of the study.
the composite end point by 46%.

Page 3
 Chronic Hepatitis B Virus —
Updated Recommendations from CDC
Chronic infection with hepatitis B virus infants born to HBsAg-positive suspected HBV infection. These
(HBV) is a common cause of death mothers, household contacts and sex markers are varied and complex.
associated with cirrhosis, liver failure, partners of HBV-infected individuals, Antigens and antibodies associated with
and hepatocellular cancer (HCC). persons born in countries with an HBV infection include the following:
Worldwide, approximately 350 million HBsAg prevalence of >8%, persons • HBsAg
persons have chronic HBV infection, who are the source of blood or body • anti-HBs (antibody to HBsAg)
and an estimated 620,000 people die fluid exposures that might warrant • anti-HBc (antibody to hepatitis B
annually from HBV-related liver postexposure prophylaxis (e.g., core antigen)
disease. In the United States, needlestick injury to a healthcare • HBeAg (hepatitis Be antigen)
approximately 800,000 to 1.4 million worker or sexual assault), and • anti-HBe (antibody to HBeAg)
persons were estimated to be living persons infected with HIV.
with chronic HBV infection in 2006. At least one serologic marker is present
A recent report from the CDC updates during HBV infection that either
Additionally, chronic HBV infection is
and expands the previous CDC progresses to recovery or develops
the underlying cause of an estimated
guidelines for HBsAg testing and into a chronic, persisting illness. The
2,000-4,000 deaths annually in the
includes new recommendations for following figures and charts from the
United States.
public health evaluation and CDC publication graphically illustrate
Individuals with chronic HBV infection management for chronically infected the serologic findings in uncomplicated
can remain asymptomatic for years and individuals and their contacts. Routine and chronic HBV infection. These
transmit the infection unintentionally testing for HBsAg now is recommended charts are printed separately on page 5
to others, as well as increase their own for additional groups, including for your convenience and future
risk for serious liver disease later in life. populations with an HBsAg prevalence reference.
All persons with chronic HBV infection of >2%, persons born in areas with an
need medical management to monitor HBsAg prevalence of >2%, men who Addendum: The following NIH
the onset and progression of liver have sex with men, and injection drug consensus statements were published
disease and liver cancer. Safe and effec- users. Areas with a prevalence of >2% in the Annals of Internal Medicine on
tive antiviral agents are now available to include much of Eastern Europe, Asia, January 6, 2009:
treat chronic HBV infection. Africa, the Middle East, and the Pacific • “National Institutes of Health
Islands. Consensus Development Conference
Serologic testing for hepatitis B surface
Statement: Management of Hepatitis
antigen (HBsAg) is the primary In this issue, we will graphically review B”
laboratory tool used to identify persons the progression of serologic events,
with chronic HBV infection. In the which occur in uncomplicated and • “Antiviral Therapy for Adults with
past, HBsAg testing has been chronic HBV infection, as well as Chronic Hepatitis B: A Systematic
recommended for pregnant women, discuss the interpretation of various Review for a National Institutes of
combinations of serologic markers in Health Consensus Development
HBV infection. The reader is referred Conference”
News Credits
Herman Hurwitz, M.D., Executive Editor to the cited CDC reference for an Both documents are open access and
Patricia Mellon, Senior Editor in-depth discussion of the subject, available at http://www.annals.org.
Published quarterly by Quest Diagnostics including patient management.
Incorporated. Electronic copies are available at: (MMWR 2008; 57(No. RR-8):1-20 —
www.questdiagnostics.com. All inquiries, I frequently am asked to assist in Ann Intern Med 2009;150(2):104-110,
suggestions,or comments should be addressed to interpreting serologic markers for
Herman Hurwitz, M.D., F.C.A.P., Senior Medical
111-124)
Director, Quest Diagnostics Incorporated, 800
Business Center Drive, Horsham, PA 19044.
Telephone: 215.442.7673
Email: herman.s.hurwitz@questdiagnostics.com
Quest, Quest Diagnostics, the associated logo
and all associated Quest Diagnostics marks are the
trademarks of Quest Diagnostics. Copyright © 2009 Quest
Diagnostics Incorporated. All rights reserved. www.quest-
diagnostics.com

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property of their respective owners.
This newsletter is published quarterly by Quest
Diagnostics as a service to the Medical Community.
Lake Serena, Winter 2005 Scottsdale, Arizona

Page 4
Serologic Markers For HBV Infection

Serologic Course of Acute HBV Infection with Recovery

Serologic Course of Acute HBV Infection with Progression to Chronic HBV Infection

Interpretation of Serologic Test Results for HBV Infection