Signals

From Signals, Fall 1995
PHYSICIAN INVOLVEMENT KEY
TO VIRAL LOAD REIMBURSEMENT
When physicians get involved on their patients' behalf, they dramatically
increase the likelihood that insurance companies will reimburse for viral load
testing. That was the message from a recent interview with John Mclannahan, coordinator of the Chiron Reimbursement Service.
According to Mclannahan, "The single most important factor in successfully obtaining reimbursement is the physician's involvement. When a physician
describes the clinical situation of a specific patient to a health plan medical
director or case manager and explains how he intends to use viral load in managing the patient's therapy, we are much more successful than when the
patient is trying to convince the insurance company alone."
McClannahan later added, "I really can't overemphasize how important it
is for the physician to get involved. One of the most effective things the doctor can do is write a Letter of Medical Necessity. This is an easy way for
them to dramatically improve their patients' chances of getting coverage."
The Chiron Reimbursement Service can assist physicians by providing them
with information that can be incorporated into their "Letter of Medical Necessity." The service will fax to physicians, upon request, material that supports the
case for reimbursement.
Chiron established the reimbursement service to help patients secure
coverage for viral load testing from their insurance companies. The service is
helpful because a number of insurance companies have not yet established
coverage policies, and many are still dealing with reimbursement requests on
an ad hoc basis.
The service offers assistance to patients, physicians, and laboratories to
Verify benefits
Establish pre-authorization of coverage
Appeal denied or suspended claims
Provide insurance payment and policy information
While the Chiron Reimbursement Service has been successful at expediting claims and obtaining coverage for a number of patients, use of the service
does not guarantee that a claim will be paid.
The service can be reached by calling 1-800-775-7533, and it is free-ofcharge for patients and physicians who are measuring viral load using the services of the Chiron Reference Testing Laboratory.
Chiron Reimbursement Service 1-800-775-7533
Suggested reading:
Keller. Getting your insurer to rover new HIV treatments: a rrash course. AIDS Treatment News 1996;238
HOW TO ORDER VIRAL LOAD
To order bDNA viral load testing for your patients, follow these simple steps:
* Request HIV-1 RNA quantification by bDNA
* You must specify the bDNA testing method because results from other viral load
quantification methods are not interchangeable with bDNA results
* For quickest results, send specimens directly to SmithKline Beecham Clinical
Laboratories, Corning Nichols Institute, or Corning Clinical Laboratories
Contact Information:

SmithKline Client Response Center
- order test code 29273 1-800-877-7003
Corning Clinical Laboratories/Corning Nichols Institute Client Services
- order test code 3690 except in NY
- state of NY 11179 1-800-553-5445
Specimen handling requirements for bONA
Sample: 5.0 mL" EDTA Plasma
Draw two 7 mL or three 5 mL lavender top EDTA tubes
Maintain whole blood at room temperature
Within 4 hours of sample collection, separate the plasma from the cell layers by
centrifugation (1000-1200xg for 10-15 minutes)
Transfer 5.0 mL* of plasma to a sterile, plastic screw-capped tube. Do not use
glass tubes. Do not aliquot the specimen
Freeze specimen at -20~ C or colder immediately after separation
Ship frozen plasma on dry ice. DO NOT THAW

Patients
want to know...what is considered a significant change in viral load?
Published studies report that viral load (unlike CD4+ cell counts) does not fluctuate widely in clinically
stable patients. Studies have also shown that current antiviral drugs, when effective, reduce viral load
from a half log to a log or more. Assay reproducibility is important in order to determine whether
changes in viral load are a result of real changes or the variability of the test. The bDNA assay performed
at the Chiron Reference Testing Laboratory (CRTL) has been shown to be very reproducible and capable
of detecting much less than a half log change in viral load....what is the normal range for viral load?
There is no normal range for viral load. That is why many labs record CRTL values in the abnormal or out
of range columns on their report forms. The Mellors paper gives us some indication of the prognostic
value of specific numbers. He reported that patients with bDNA levels >100 KEq/mL* progressed
10-11 times more rapidly to AIDS than patients with viral burdens <10 KEq/mL. And patients with
bDNA levels between 10-100 KEq/mL progressed 2 times more rapidly....can bDNA values be interchanged with PCR results for trending viral load?
No. Results from these methods cannot be directly interchanged. While bDNA and PCR methods measure the same thing (HIV-1 RNA), they do so by using different technology with different standards and
performance characteristics. If you switch between methods without establishing a new baseline, you will
not know if a change in viral load is due to a change in the method or a real change in the level of virus....how is viral load reported, and what do the numbers mean?
Viral load using the bDNA method is reported as Kilo Equivalents per milliliter of plasma (KEq/mL). One
Kilo Equivalent is approximately 1,000 molecules of HIV-1 RNA. Reports by Drs. Ho (NEJM and Mellors (Annals of Internal Medicine) indicate that high levels of virus (>1 00 KEq/mL) are seen in patients
who progress to AIDS whereas low levels of virus (<1 0 KEq/mL) are seen in non-progressors. Studies
such as ACTG 116 and the VA Cohort showed that when levels of virus decreased by 2-fold or more,
HIV disease progressed more slowly, and patients had a better prognosis.....how often should I measure my bDNA? Can I stop having CD4+ cell counts done?
Since bONA measures viral load and the 004+ cell count measures the immune system's response to
the virus, physicians can derive more information about the status of HIV disease and a patient's
response by measuring both markers. Generally, CD4+ cell counts correlate inversely to viral load (when
viral load decreases, 004+ cell count increases, and vice versa). Since viral load shows a rapid change
within 2-6 weeks after initiation of antiviral therapy, more physicians are ordering a baseline bONA and
004+ cell count before starting therapy. They order another bONA 4-6 weeks after starting or changing therapy and then monitor 004+ cell counts and bONA every 3-4 months while the patient is on
therapy. The frequency of testing is tailored to meet the individual response to antiviral drugs and disease status. For patients not on therapy, viral load testing is often done at the same intervals as 004+

cell counts....what happens if my viral load drops considerably but my CD4+ cell count does not improve?
Drops in viral load may not follow the same time course as changes in CD4+ cell counts. Viral load
shows a more immediate response to antivirals and tells you quicklywhether a drug regimen is having
an effect. What you are looking for are trends. In response to antiviral therapy, viral load changes may
be seen within weeks, whereas changes in CD4+ cell counts may be seen over months. Some patients
who successfully sustain lower levels of virus may not see the anticipated rise in CD4+ cell counts but
instead may see an absence of further decline.

INTERPRETING CHANCES IN VIRAL LOAD, FROM PAGE 5

in viral load." 58
Holodniy states, "As the flu
season approaches, it is important
to be aware of the transient
changes in viral load caused by
immune stimulation and to look
for longer-term trends in virus
levels before making decisions to
initiate or change therapy"
Another factor that can have a
dramatic effect on the measurement
of viral load is specimen handling.
Improper handling can result in
acute degradation of the HIV-1 RNA
in the sample. To ensure accurate
measurement of viral load, all
bDNA specimens must be collected
in EDTA anti-coagulant, and the
plasma must be separated and

frozen within 4 hours after collection.9 The section above provides
the collection and processing
requirements for the Chiron bDNA
assay
Understanding the factors that
produce both transient and longterm changes in viral load enables
physicians to best utilize the bDNA
assay to individualize therapy As
Holodniy stated, "Viral load quantification can be considered another piece of crucial information
when making treatment decisions.
However, physicians must assess
the whole clinical picture when
deciding to initiate or change therapy to avoid making changes based
on viral fluctuations that are tran
sient, due to normal variability for
that patient, or caused by improper specimen handling. Incorporating all external factors allows
physicians using bDNA to make
informed decisions for their
patients."
References:
1 Cao Y et al. Clinical evaluation of bDNA signal
amplification for quantifying HIV type 1in
human plasma. AIDS Research and Human Retroviruses 1995;11: 353-361
2 Dewer R et al. Application of bDNA signal amplification to monitor human immunodeficiency virus
Type 1 burden in human plasma. JID 1994;170:
1172-1179
3 Todd et al. Performance characteristics for the
quantification of plasma HIV-1 RNA using
branched DNA signal amplification technology. J
Acquir Immune Defic Syndr Hum Retrovirol
1995;10:535-S44
4 O'Brien WA et al. Human immunodeficiency
virus-type 1 replication can be increased in

peripheral blood of seropositive patients after
influenza vaccination. Blood 86(3): 1082-1089
5 Staprans SI et al. Activation of virus replication following vaccination of HIV-1 infected individuals.
Journal of Experimental Medicine (in press December,
1995)
6 Janoff EN et al. Increased HIV-1 burden with
immune activation following immunization with
pneumococcal vaccine. Abstract #1237 from ICAAC
1005
7 Shacker T et al. Reactivation of HSV-2 in HIV infected persons is associated with increased levels of
plasma HIV RNA. Abstract #1235 from ICAAC
1995
8 Mole L et al. Plasma HIV RNA levels are increased
during active Herpes Simplex virus infection.
Abstract #239 from ICAAC 1995
Holodniy M et al. Comparative stabilities of quantitative human immunodeficiency virus RNA in plasma from samples collected in VACUTAINER CPT,
VACUTAINER PPT, and standard VACUTAINER
Tubes. Journal of Clinical Microbiology June, 1995:
1562-1566

SIGNALS STAFF
Co-Editors David Chernoff, MD
Patrick Joseph, MD
Contributing Editor Judith Wilber, PhD
Signals presents news and information focusing on the latest developments in viral load quantification by
branched DNA technology. It is distr'ibuted free-of-charge to qualified
members of the professional healthcare community.
Signals is a publication of the Chiron
Reference Testing Laboratory. Copyright ~ 1996 Chiron Reference Testing Laboratory.
Inventory # HI96SIG03-O
CH IRON

Signals page 6

*HIV-1 RNA kilo equivalents/milliliter of plasma as measured by branched DNA (bDNA) direct quantification. A kilo equivalent - 1,000 molecules of HIV-1 RNA.