| 
Past Issues
Volume 16, number 2
February 2002
Contents
Quick Test Quagmire
Why the rapid test for HIV has bogged down in the U.S.A.
Rapid-o-graphs
The advantages and disadvantages of 'rapid' versus 'standard' tests
Intellectual...wha?
All about patents and how they're affecting HIV medicine
Disinterested Parties
What independent review is all about
Mothers' Milk
Questions and answers about HIV and breast-feeding
Want a Piece of Me?
When corporations patent your genes, you pay. An opinion.
Rapid Testing Stalled
By Bob Huff
An article in The Los Angeles Times recently reported that
seven babies in the region had acquired HIV at birth. The children
had been infected at varying times during the past few years but
had not been identified sooner because California does not routinely
test newborns for HIV. Not surprisingly, most cases of transmission
involved women who had declined to be tested for HIV during their
pregnancies or had not received prenatal care. Dr. Jonathan Fielding,
Los Angeles County's director of public health confirmed that, "Those
most at risk of not receiving prenatal care — including HIV
tests — include women who are drug addicts, incarcerated, homeless,
non-English speakers, undocumented immigrants, uninsured or teenagers."
It's known that transmission of HIV to infants is largely preventable
with either a course of AZT as a part of prenatal care or with a
single dose of nevirapine administered prior to or during labor.
Even a single nevirapine dose to the baby if given within 24 hours
of birth may prevent infection from taking hold. Antiretroviral
therapy can reduce the newborn infection rate from as much as 50
percent to less than 8 percent (what happens next is a different
problem: See HIV & Breastfeeding in this issue). In parts of the
world with high HIV prevalence and limited resources for prenatal
care and testing, some have proposed offering nevirapine to every
mother as she enters labor since the drug is cheaper than the test.
But in areas with low rates of HIV incidence, knowing the HIV test
result prior to delivery is essential to identify everyone who can
be helped by treatment.
In Los Angeles, at least one of the HIV-positive infants was not
treated because test results were not received in time to alert
the medical staff. With conventional tests, a lag of up to four
days between the time blood is drawn to when the results are known
leaves the door open for preventable infections to slip through.
Dr. Andrea Kovacs, chief of the Los Angeles County-USC Medical Center's
program for HIV-positive women, children and adolescents was quoted
in The Times article as saying rapid testing could have provided
results within an hour. "We would have treated the baby if we knew
the mom was HIV-positive."
Rapid tests for HIV perform the same job that standard laboratory-based
HIV tests do — but faster. Currently, before a definite diagnosis
of HIV infection can be given, an initial positive result with either
the rapid or conventional test must be confirmed with another type
of laboratory-based HIV test called the "Western Blot." But in situations
when labor has already begun and there is no time for laboratory
confirmation, a positive rapid test result may justify offering
the mother and child nevirapine treatment. The convenience of rapid
testing, however, does not preclude the need for pre-test informed
consent and post-test counseling.
There are more than a dozen rapid HIV tests on the market throughout
the world and simple one-step tests are the norm in regions without
expensive laboratory resources. But in a strange twist on the usual
story of the Haves and Have Nots, no easy-to-use rapid HIV tests
have been approved by the FDA for use at the point of care in U.S.
hospitals, clinics and testing centers. The single one-hour test
that has been approved still depends on laboratory processing and
expert interpretation.
The potential demand for a rapid HIV test in the United States
is huge. Rapid tests cost no more than conventional tests and the
FDA has recently indicated that confirmation of a positive rapid
result with another type of rapid test may be an acceptable substitute
for confirmation by Western Blot. (See Rapid
New World for how this problem is handled elsewhere in the world.)
Providers of HIV counseling, testing and referral services are also
anxiously waiting for point-of-care rapid testing. Statistics show
that up to a third of people who have a sample taken for conventional
testing never return to get their results. Point of care testing
promises to be far more cost effective than conventional testing
because fewer tests will be wasted on no-shows. In addition, prevention
experts are eager to find ways to reach those most at risk for slipping
through the cracks of existing counseling and testing services that
require follow-up appointments.
So why are rapid HIV tests that are available in Japan, France
and Thailand unobtainable in the U.S.? The answer seems to be because
the big companies that make the conventional tests don't want the
competition. And because of a complicated web of patents and intellectual
property agreements, these corporations have the clout to keep rapid
testing out of the established $200 million per year U.S. market
for laboratory-based tests.
According to a recent article in The Wall Street Journal,
the problem stems not from testing for HIV-1, the most common HIV
infection in the world, but with patents that cover testing for
HIV-2, an AIDS-causing virus most prevalent in West Africa. Although
HIV-2 infections have been reported in areas with large immigrant
populations such as New York, overall, infections with the "other"
HIV are rare in the U.S. When a test for HIV-2 became available
in 1990, the Centers for Disease Control, the federal agency responsible
for the safety of the national blood supply, recommended that HIV
blood-screening tests should be able to detect both types of HIV.
Although the FDA requires that blood-screening tests check for HIV-2,
the agency does not ask the same of tests used to diagnose HIV in
individuals. Yet producers of HIV diagnostic assays have voluntarily
adopted the standard that an HIV test should be able to test for
all forms of HIV prevalent in the world.
The patent for the HIV-1 test is controlled by the U.S. National
Institutes of Health (NIH). The NIH has freely issued permission
to use the patent in exchange for modest royalty payments which
are shared with the French Institut Pasteur, a co-discoverer of
HIV-1. Several years after the first test for HIV-1 became available,
researchers at the Institut Pasteur learned that HIV-2 could also
cause disease and that the existing HIV test could not reliably
detect it. The Institut Pasteur received a comprehensive U.S. patent
for HIV-2, which was then licensed to a spin-off, for-profit corporation.
In a complicated series of business transactions, effective control
of the U.S. patent was subsequently traded among the big-three makers
of conventional diagnostics, including Abbott Laboratories, the
largest supplier of HIV tests. The result: anyone who wants to market
an HIV test that detects both HIV-1 and HIV-2 in the U.S. needs
the permission of Abbott and the others.
Several makers of rapid assays that detect both HIVs have tested
the waters for U.S. approval. Most have received positive signals
about their chances. Yet in every case, failure to come to terms
over the HIV-2 patent has sunk efforts to bring these tests to market.
According to The Wall Street Journal, one company, Universal
Healthwatch, attempted to license HIV-2 but was stonewalled by the
patent holder. The company, afraid to risk a lawsuit over an alternative
method for detecting HIV-2 and unwilling to offer a product that
only tested for HIV-1, abandoned the campaign. Until recently, a
rapid test called OraQuick that had been successfully used by the
CDC on an experimental basis seemed poised for FDA approval. When
the company realized it would not be able to obtain a license to
use the HIV-2 patent in the U.S., it tried a different tack. Abbott
was approached about distributing OraQuick under their license for
HIV-2, yet the diagnostic giant would not agree to guarantee minimum
yearly sales of the test. According to The Journal, the OraQuick
executives feared that Abbott was only interested in obtaining the
rights to their product as a ploy to keep it off the market.
In 1999 ownership of the HIV-2 patent with all of its encumbrances
passed to Bio-Rad Laboratories, a California corporation. Bio-Rad
claims that it has since entered into HIV-2 licensing agreements
with numerous companies, yet suggests that, when it comes to the
U.S. market, its hands are tied by the inherited obligations to
Abbott and the others. In a letter to GMHC, David Schwartz, president
of Bio-Rad said, "We evaluate each request on a case-by-case basis
and enter into licensing agreements based on a variety of criteria,
some of which we are obligated to maintain as a result of our acquisition
of ... the HIV-2 patent."
The frustration over the deadlock is evident in a statement quoted
by The Journal from Bernard Branson, who heads the CDC's
HIV diagnostics program. "I'd call it restraint of trade. It's a
travesty to stand by and allow these tests to languish." Reportedly,
the CDC has asked the Justice Department to investigate if BioRad
and its partners have violated antitrust laws.
Faced with this stalemate and with clamor from the prevention community
for rapid testing, the FDA last year finally gave a clear signal
that diagnostic products that tested for HIV-1 alone would receive
a favorable review as long as trial data demonstrated performance
comparable to lab-based assays. Reportedly, this has unlocked the
gates and several rapid test makers have submitted applications
to the agency. It's possible that an approval could be seen later
this year. As for HIV-2, the patent expires in 2010.
| Rapid
Test in Use |
| Independently evaluated rapid HIV
tests with promising performance. |
| Easiest to use: May be suitable for point of
care. |
| Determine HIV-1/2/O |
Abbott |
| OraQuick |
Epitope, Inc. |
| Hema-Strip HIV-1/2 |
Saliva Diagnostic Systems |
| UniGold HIV-1/2 |
Bray |
| Requires additional laboratory processing:
Suitable for clinics. |
| Retrocell HIV-1/2 |
Abbott Laboratories |
| SUDS HIV-1 |
Abbott Laboratories |
| SimpliRED HIV-1/2 |
Agen Biomed |
| MicroRED HIV-1/2 |
Agen Biomed |
| Bionor HIV-1/2 |
Bionor A/S |
| Genie II HIV-1/2 |
BioRad Laboratories |
| Multispot HIV-1/2 |
BioRad Laboratories |
| Red Dot HIV-1/2 |
Cal Test Diagnostics |
| Serodia HIV-1/2 |
Fujerebio |
| HIV SPOT-1/2 |
Genelabs Technologies, Inc. |
| HIV SAV-1/2 |
Sayvon Diagnostics, Ltd. |
| Entebe HIV Dipstick |
Hepatika Laboratories |
| Dipstick HIV-/2 |
Immunochemical Laboratories |
| HIV Tri-Dot |
J. Mitra & Co. |
| MedMira HIV-1/2 |
MedMira Laboratories |
| DoubleCheck HIV-1/2 |
Orogencis Ltd. |
| HIVCHECK HIV-1/2 |
Saliva Diagnostics Systems |
| Sero-Strip HIV-1/2 |
Saliva Diagnostics Systems |
| CombAIDS HIV-1/2 |
Span Diagnostics |
| Capillus HIV-1/2 |
Trinity Biotech |
| SalivaCard HIV |
Bray |
| SeroCard HIV |
Bray |
| Quix HIV-1/2/O |
Universal Healthwatch |
| DIA HIV-1/2 |
Weiner Labratorios |
| Source: Rapid Tests for HIV Antibody, Bernard
M. Branson; AIDS Reviews 2000;2:76 – 83 |
Rapid New World
By Bob Huff
In the U.S., the gold standard for diagnosing HIV infection has
evolved into a formal process that respects an individual's need
to know the facts about HIV: how the virus is transmitted, how to
limit one's risk, and the meaning of a positive test result. The
process also respects an individual's privacy and strives to provide
appropriate counseling and support if a test result is positive.
The system is also careful to confirm that a positive result is
truly positive to avoid falsely telling someone they have HIV.
When the healthy immune system is exposed to HIV antigens (antigens
are bits of the protein structure of the virus), it will produce
proteins called antibodies that stick to the viral particles and
help clear them from the body. That HIV ultimately evades this system
is why the disease is so serious. HIV tests use artificially produced
HIV antigens that can capture antibodies if they are present in
a person's blood. If a person has never been exposed to HIV, then
no antibodies will stick to the antigen in the test and it will
read negative. But if the antibody test is positive, it means that
the person has had an immune reaction to HIV in the past and is
probably infected. These tests are called immunoassays.
The usefulness of an HIV antibody test is judged by its sensitivity
and specificity. Sensitivity is the ability of a test to detect
HIV even when present in very small amounts. If a test is not sensitive
enough, some positive samples will slip though the screen. But for
a test to be sensitive enough to detect 99.9 percent of positive
samples, it may sometimes read positive when no HIV is present.
This is called a false positive result. The other measure of a test's
reliability is its specificity. This tells how well the test discriminates
between detecting HIV and other somewhat similar antibodies. There
is usually a tradeoff between sensitivity and specificity, with
highly sensitive tests being more likely to be fooled into giving
a false positive answer by similar but non-HIV antibodies.
The trade-off between sensitivity and specificity is why a positive
result on an initial HIV test must always be confirmed with a second,
more specific, HIV test before telling someone they are positive.
Highly sensitive tests are ideal for jobs such as screening the
blood supply or performing anonymous surveillance of HIV prevalence
in a population. In particular, blood screening is a job where it
is better to be safe than sorry; a few false positives are not of
concern. But a positive HIV diagnosis is of huge concern to the
person who gets one, so the system is careful to be sure the diagnosis
is correct.
Rapid testing brings a new challenge to the established system
of confirming a diagnosis before telling someone his or her results.
If a simple finger prick device can give a result within 15 minutes
(similar to a home pregnancy test), how does a test provider deal
with a positive result? One way is to tell individuals that they
have had an inconclusive result then draw more blood to send to
a lab for the conventional test and confirmation process. So while
a single rapid test may be fine for alleviating the anxiety of the
uninfected, it may not be the best solution for someone who really
has HIV.
In parts of the world where conventional laboratory-based tests
are often not available, a number of rapid tests have come into
common use over the past decade. The World Health Organization (WHO)
has developed a set of protocols for using combinations of rapid
tests to deliver reliable, confirmed results, depending on the purpose
and context of the test.
The result is a system capable of providing test results with the
same confidence as laboratory-based testing but at a far lower cost.
In addition, the availability of same-day results means that many
more people learn their HIV status and remain available for counseling
about their health. Studies have shown that people who learn their
diagnosis are more likely to begin practicing risk reduction behaviors
than those who fail to return for their results.
The WHO protocol recommends confirmation with multiple different
rapid tests depending on the objective of the test and the background
prevalence of HIV in the region. A single test may be sufficient
for screening blood or performing surveillance studies in high prevalence
regions. For individuals with symptoms of HIV disease living in
a high prevalence area, a single test may also suffice. In areas
with a lower background prevalence of infection, the proportion
of false positives from too-sensitive tests demands additional confirmatory
testing.
In settings where multiple confirmatory tests are expected, the
first test performed should have very high sensitivity to insure
that all true positives are captured. Since these first pass tests
will tend to report a higher number of false positives, the second,
confirmatory test should be highly specific for HIV. In multiple
test systems, each test should use a different antigen to avoid
overlapping specificity. One drawback to rapid assays is that a
new sample may need to be obtained if an individual requires a confirmatory
test. WHO recommends collecting serum, plasma or dried blood spots
if multiple test strategies are used, to avoid having to collect
multiple samples.
| WHO
Algorithm for Confirming HIV Diagnosis with Rapid Testing |
|
| Objective |
|
Prevalence |
Strategy |
| Blood Screening |
|
All |
1 |
| Surveillance |
|
>10%
<10% |
1
2 |
| Diagnosis |
With symptoms |
>30%
<30%
|
1
2 |
| Diagnosis |
With symptoms |
>30%
<30% |
2
3 |
| Strategy 1: Single screening assay. Reactive test
is considered positive. |
| Strategy 2: Two screening assays. If initial test
is reactive, test is repeated with second assay. Specimen considered
positive only when both assays are reactive. |
| Strategy 3: Three screening assays. Specimen considered
positive only when all three assays are reactive. |
A
Comparison of HIV Testing Technologies:
Immunoassays and Rapid Tests |
|
| Specimens |
Advantages |
Limitations |
Costa (USD) |
Complexity |
| Conventional EIA |
Serum
Plasma
Dried blood spots
Oral fluids
Urine |
Can be batched: good for >100 specimens at a time
Can be automated
QA/QC done at national and regional laboratories: easier
to control
Cost per test less than cost per rapid test
Identifies seroconverters earlier: highly sensitive, which
reduces nonreactive period |
Not flexible in testing (need minimum numbers filled)
Required skilled, trained technicians to perform and read
test results
Requires >2 hours for results (if need to run two EIAs,
>5 hours)
Requires special equipment
Requires maintenance of equipment
Reagents must be refrigerated |
1 – 2 |
4 |
| Rapid Test |
Serum
Plasma
Whole blood
Oral fluidsc |
Good for testing 1 to 100 specimens at at time
Requires minimal equipment and reagents
Can be performed in a clinic (on-site testing)
Highly skilled staff not required
Very easy to interpret test
Results in >45 minutes
Test kits can be stored at room temperature (increased
stability) |
Not good for testing >100 specimens at at ime
The QA/QC is performed at multiple sites; requires more
control
May cost more per individual test than EIA
Choice of testing strategy may require multiple specimens
Interreader variability may provide inconsistent results
with some assay formats (e.g., particle agglutination) |
1 – 3 |
For test based on:
Immuno- chromatography 1
Dipstick and membrane flowthrough technology2
Agglutination3 |
aThe cost of a testing technology
will be affected by the direct and indirect costs. bUNAIDS/WHO's
four categories of complexity for HIV antibody tests: 1) No
additional equipment or laboratory experience is required;
2) Reagent preparation or a multistep process is required;
3) Specific skills such as diluting are required; and 4) Equipment
and trained laboratory technician are required (UNAIDS/WHO
1998). cRapid tests using oral fluids are under evaluation
in field settings.
EIA=enzyme immunoassay; QA/QC, quality assurance/quality
control.
Source: Guidelines for Using HIV Testing Technologies in
Surveillance: Selection, Evaluation and Implementation. UNAIDS. |
Patent Primer
By Bob Huff
Ideas aren't real estate. But when ideas and technical know-how
are protected by a legal creation known as a patent, they become
a temporary kind of property. Patented ideas are often referred
to as intellectual property, a class that also includes copyrights
and trademarks. Like other forms of property, intellectual property
can be sold, traded, misused and defended in court.
In the world of patent law, new knowledge about how to make or
use some form of matter is called an invention. Individuals who
believe they have invented something useful can ask the government
to decide if their idea is sufficiently different from similar previous
inventions that it should receive patent protection. A patent simply
grants the legal right to stop other people from using the invention
for commercial gain for a period of time — 20 years in the
U.S. If granted a patent, an inventor can market the product or
process for his own profit, sell or assign the right to do so, or
license the right to third parties.
Under U.S. law, a patent gives the inventor the "right of exclusion,"
that is, the right to prohibit others from using their invention.
This is a limited right and doesn't mean that just any invention
can be marketed. For example, someone may invent and patent a new
kind of poison, but the patent gives him no right to make and sell
poison outside of the usual restrictions that apply to the sale
of poisons. The patent only grants a right to try and stop anyone
else from making and selling that poison within the U.S.
The first step to obtaining domestic patent protection for an invention
is to have it evaluated by an examiner from the U.S. Patent and
Trademarks Office. The examiner compares the invention to earlier,
similar, inventions and tries to determine if three tests are met:
The invention must have some kind of use, it must be substantially
new or represent an improvement on earlier inventions, and it must
not be "obvious." A claim on the use of water for human hydration
(drinking) is an example of an obvious use of water and therefore
not patentable.
Since patents are legal grants by the government, they are not
absolute. In the same way that government can take someone's real
estate in order to build a new road or other public amenity, the
rights to an invention can be denied or reassigned in the interests
of national security. For example, no invention pertaining to atomic
weaponry may be granted a patent — it automatically becomes
the property of the government.
Companies that depend on innovation to give them an edge in the
marketplace use patents to help protect their investments. Enterprises
are more confident about spending money to develop new ideas into
products if they are assured that they have a legal right to stop
others from using their inventions. Patents limit the risk of developing
new products by guaranteeing the patent holder a competition-free
head start to recoup costs and hopefully make a profit.
Patents are used to protect investments in all phases of product
development, not simply to reward the discovery of an idea. Although
patents are granted to individual inventors and recognize authorship,
they only take on economic value when a company is willing to launch
a commercial exploitation of the invention. The economic value comes
from the assurance of a guaranteed period of market exclusivity.
Typically, companies that employ researchers and engineers contractually
require their employees to assign any patents they obtain to the
corporation. Often a product will be protected by more than one
patent on more than one of its novel aspects.
Patents are considered particularly crucial to pharmaceutical manufacturers.
Extended periods of protection are sought since it may take several
years after a patent is granted for a new drug to be thoroughly
tested and proven safe and effective enough to sell. Long periods
of market exclusivity after approval allow companies time to recover
development costs for the approved drug, absorb costs for unsuccessful
attempts, support the development and marketing of new drugs, and
generate profits. The costs associated with the discovery of an
invention leading to a patent are typically only a small part of
the expense of bringing a drug product to market.
After a drug patent expires, manufacturers of generic medicines
are free to begin making and selling an approved equivalent version
of the drug — usually at a substantially lower price based
on the actual cost of making and distributing the drug. Although
some kinds of products are able to retain brand identity and market
domination even after patent protection has expired, in the pharmaceutical
industry the potential to generate revenue from an unprotected drug
is cut drastically. Insurance companies, HMOs and other payers often
opt for the cheaper generic version of a medicine as soon as it
becomes available.
Because patent protection is a legal device, it is dependent on
governments to grant, adjudicate and enforce. Worldwide, patent
laws have varied considerably, with some countries respecting U.S.
and European patents explicitly, others limiting what kind of inventions
can be patented or for how long they should be protected, and other
countries offering no protection at all. Often a company will not
seek patent protection in a country in which it perceives no market
potential. Recently, in an effort to stabilize the worldwide business
climate, proposed new international trade agreements have insisted
that all participating countries establish patent laws in conformity
with those in the U.S. and Europe. One consequence of this has meant
that some countries are faced with adopting unfamiliar legal concepts
of property, which may result in the disruption of certain evolved
business practices particular to weak economies. Yet signatories
to the international agreements are given little leeway — they
must accept international corporate conventions or face exclusion
from the world economy.
Some countries with longstanding systems of patent protection for
most inventions treat pharmaceutical products as a special category.
In India, for example, foreign drug makers have not historically
been offered market exclusivity for their medicines themselves —
only for the methods of making them. This exception has allowed
a vigorous market to flourish for domestically produced generic
versions of drugs that had been developed and patented elsewhere.
For a poor, highly populous country with ambitions of economic independence
such as India, this accommodation has supported development of technical
infrastructure, provided jobs and supplied medicines that would
have been otherwise unaffordable.
Patent protections may be lacking altogether in other, less developed,
countries. In the case of pharmaceuticals, though, since there may
be no domestic capacity to produce drugs and few individuals affluent
enough to afford them, the absence of protection in these countries
has had little consequence for patent holders doing business elsewhere
in the world.
Independent Review
By Carlton Hogan
There are certain minimum protections designed to help assure the
integrity of research data that one should look for when evaluating
reports of clinical trial results. There should always be several
layers of review evident that not only evaluate the final result,
but monitor the trial from initial design all the way through publication.
In each of these, independent review is perhaps the most important
common thread.
Institutional review boards
One of the first levels of review evaluates a research plan before
it is implemented. Institutional Review Boards (or IRBs) exist at
the actual sites in the communities where trials are undertaken.
A typical IRB would include physicians, ethicists, members of the
clergy, and patient representatives who assure that a trial will
be appropriate and ethical within the culture of that particular
community, and that limited resources are expended on questions
that are relevant to that community.
Community advisory boards (CAB)
CABs are patient advisory groups drawn from the communities in
which the trials will be conducted. They give the patient's perspective
on whether a trial offers ethical, reasonable approaches to the
issues that are relevant to that community. The federally-funded
clinical trial networks such as the CPCRA or the AACTG are mandated
to establish CABs. Each local CAB also elects one or several members
to serve on a network-wide Community Constituency Group (CCG). This
system of representation tries to insure that the medical and administrative
leadership of the national networks will hear the concerns of community
members that their research is supposed to benefit.
It was not always this way. Up until the late eighties, meetings
of federally-funded AIDS research groups were closed affairs —
patient representatives were not even welcome as observers. Courageous
and brash activists crashed the group meetings of the AACTG (then
called simply the ACTG) and demanded not only to observe the meetings,
but also to participate in decision-making. Fortunately, some investigators
were wise enough to see that community input could only help to
create more relevant and attractive trials. It is now mandated in
grants and cooperative agreements that federally-funded AIDS research
groups not only have functional CCGs, but that patient representatives
and other advocates be full members of key committees and protocol
teams. Frequently the CCG representative will be listed among the
group's research paper authors, thus helping assure responsible
oversight from a patient perspective.
Data and safety monitoring boards
Every trial in the U.S. is overseen by what is called a Data and
Safety Monitoring Board or DSMB. These are physicians, researchers
and ethicists who have ongoing access to the trial data and are
empowered to make important suggestions to modify, prolong, or even
terminate a study, depending on what occurs in the course of that
trial. If it becomes absolutely clear that one treatment is superior
to another, the DSMB can choose to end the trial, so as to reduce
the amount of time patients remain on the "loser" therapy. Alternatively,
if they decide that a trial has no possibility of ever achieving
a meaningful answer, they may decide to halt the study and stop
wasting resources and participants' time. Or they may modify a trial
to improve its scientific integrity or assure patient safety. A
good example of this was an early AIDS trial of a drug called pyremethamine
that depleted B vitamins. A DSMB decided that a special form of
B vitamin called leucovorin needed to be added to the protocol to
protect patients.
In general, while a trial is ongoing, very few people have access
to the data. Usually only the statistician(s) and DSMB get full
summaries of key endpoint data. Even the principal investigator
is unable to review the data in midstream. This is to ensure that
no one jumps to conclusions about trends seen in a trial that are
not yet statistically significant (like trying to figure out the
average number of coin tosses after only three flips) Otherwise
there is a risk that the investigators or others could consciously
or subconsciously alter their behavior, and affect the trial's outcome.
The investigators are said to be "blinded" to the endpoint data.
The DSMB also tries to strike a balance between closely watching
the trial, and not looking too frequently. The reason for this is
actually pretty simple: every time anyone takes a look at the data,
they increase the risk of prematurely declaring a winner, when in
fact, not enough data (or "coin flips") have accumulated to really
be certain. So when the sample size (the number of patients) is
calculated for a trial, it is adjusted upward for each time the
DSMB is expected to take a peek.
Because the DSMB is privy to such sensitive information, it is
absolutely imperative they be as independent as possible. If premature
"hints" about how a trial is going leak into the community it could
cause people to make up their minds even though the data are not
yet reliable. So an independent DSMB is an absolute necessity for
credible research
Disclosing financial ties
In all of these cases — IRBs, CABs, CCGs and DSMBs —
the essential characteristic is that they be independent of the
company making the drug and the organization conducting the trial.
Independent reviewers must have no personal financial, ideological,
or ego investment in the outcome of the trials they oversee.
These independent review mechanisms also protect investigators
who often do have financial and other ties to corporations keenly
interested in the outcome of the research they conduct. For better
or worse, these financial relationships are now so common as to
seem unavoidable. Therefore it is crucial that investigators disclose
these relationships whenever writing or speaking about their research
or offering their expert opinion on matters that could affect the
business of their patrons.
Marcia Resnick, the former editor of the New England Journal
of Medicine, perhaps the most prestigious medical journal in
the world, was among the first to speak out strongly about the risks
of conflict of interest and requiring the routine disclosure of
the investigators' financial ties along with publication. This was
an important first step. After all, if you want to critically evaluate
a research article, it's reasonable to want to know if the investigator
had a financial stake in the outcome. Sadly, while everybody seems
to agree with Dr. Resnick in principle, not all journals have taken
such a firm stand on the right of the reader to consider possible
conflicts-of-interest just as carefully as a study's methodology.
Happily, this seems to be an area the National Institutes of Health
is showing leadership in at this time, and some of the federally-funded
research groups are already drafting, or putting in place, much
stronger conflict of interest disclosure policies.
HIV & Breast Feeding: What's a
Mother to Do? By Rebecca
Denison
Reprinted from WORLD, October 2001
Contact Rebecca Denison at WORLD by e-mail: rdenison@womenhiv.org
What's the background?
Most babies born to HIV-positive mothers will not get HIV. But
some will. A baby can get HIV from its mother:
During pregnancy (before birth);
- During delivery (the most common way babies get infected);
- Through breast-feeding.
Breast-feeding can increase the risk of HIV transmission.
Prolonged breast-feeding increases the risk of a woman giving HIV
to her baby by about 14 percent. Here are what two studies of babies
born to HIV-positive women show:
- Nairobi, Kenya — At 24 months, 20 percent of formula-fed
babies became infected with HIV, compared to 36 percent of breast
fed babies.
- South Africa — HIV transmission was 12 percent higher in
breast-fed babies than in formula- fed ones at 15 months.
Formula feeding also has risks.
There is no HIV in baby formula, but formula that is not given
safely can make a baby very sick. Making formula with dirty water,
or serving it in a bottle or cup that isn't totally clean, can expose
the baby to dangerous bacteria. According to the World Health Organization
(WHO), babies in developing countries who are fed on formula are
up to six times more likely to die from diseases like diarrhea and
respiratory infections than breast-fed babies are.
Mixed feeding (breast + formula) is most dangerous.
Mixed feeding is the most dangerous method, because formula feeding
can irritate the lining of the baby's stomach, making it easier
for the HIV in breast milk to get in and cause an infection. In
a South African study of HIV-positive women and their babies, 36
percent of babies who received mixed feeding were reported infected
compared to about 25 percent of those who were exclusively breast-fed
and 19.5 percent of formula-fed babies.
What's an HIV-positive mother to do?
In the United States and other developed nations, HIV-positive
women are advised to not breast-feed and to use formula instead.
This is because most women in these regions have easy access to
formula, clean water for mixing and washing, and refrigeration.
Women in developed regions can usually get health care if the baby
becomes sick to prevent a case of diarrhea from becoming fatal.
While formula feeding may be the most obvious choice for preventing
HIV transmission, it's still not easy to use.
During the first years of the epidemic, in developing countries
where many people do not have access to clean water, HIV-positive
women were often advised to breast feed their babies to protect
them from the health problems related to formula feeding. Today,
some people still feel that's the best advice, while others feel
that women should have more information, more choices and better
access to affordable formula. Whichever method a woman chooses,
there are some things she can do to make it safer.
Breast-feeding exclusively for 6 months or less is less risky.
Researchers agree exclusive breast-feeding (where no other foods
or liquids are given) is safer than mixed feeding. However, they
disagree about whether women will realistically be able to do so.
A study from South Africa showed that after an educational campaign,
72 percent of participants were able to breast feed exclusively.
However, a study in Uganda reported that, of 60 women who used breast-feeding,
only six actually breast-fed exclusively. As more people learn about
the benefits of exclusive breast-feeding, the number of women who
do it will likely rise. But, as several Ugandan women at a recent
conference said, it would still be hard for most women to do without
exception.
The risk of a baby getting HIV from breast-feeding increases the
longer the baby is exposed to HIV in the breast milk. When breast-feeding
is stopped at six months, the risk of transmission is reduced —
some say to as little as 5 percent (compared to 14 percent with
longer periods of breast-feeding).
What about women who don't know their HIV status?
It is difficult for women to make informed choices when they do
not know their HIV status. Some don't know because they are afraid
to be tested. In many places, women don't have access to voluntary
counseling and testing. Steps are needed to make testing available
and to reduce discrimination against those who test positive.
It took years of public health campaigns to teach people that "breast
is best." (Of course, if the mother is HIV-negative, breast-feeding
is still the best choice.) When these campaigns began no one predicted
the AIDS epidemic. Now some believe that every effort should be
made to obtain free formula for those who want it — including
changing laws enacted that prohibit formula makers from giving away
free product as a marketing strategy. Others think breast-feeding
should still be actively promoted for HIV-positive women, fearing
that if women with HIV start using formula, there may be a "spill
over effect" in which women who are not HIV-positive or don't know
their status opt for formula too.
What about the mother's health?
Much of the breast-feeding debate has focused on the baby, however
a study in Kenya suggested that women who breast-fed got sicker,
faster than those who used formula. This may be because a breast-feeding
woman needs the extra calories, nutrient and fluids for her own
body's health.
What about HIV drugs?
HIV drugs can reduce the risk of a baby getting infected from breast
milk by reducing the viral load in the mother and her milk and by
improving the mother's health. However, HIV transmission can still
occur through breast-feeding and, in the U.S., HIV-positive women
on therapy are encouraged to formula feed. Most women in developing
countries do not have access to HIV drugs. Some studies are looking
at giving HIV drugs to the mother (or the baby) throughout the breast-feeding
period to reduce the chances of HIV transmission to infants. Broader
campaigns are working to make HIV drugs available to all HIV-positive
people — adults, children and babies — worldwide.
More options and strategies:
Modifying cow's milk.
Cow's milk has too much protein and salt for a baby's kidneys to
process, and not enough calories. However, full fat cow's milk can
be modified. For example, for a 1–3 month old infant: mix
2 parts milk + 1 part clean water + sugar to taste, then boil.
Whatever baby doesn't drink should be thrown out.
Heat treatment (pasteurization):
Breast milk should not be boiled, but it can be heat treated to
inactivate the HIV in it by placing a jar of expressed milk in a
pot of boiling water, removing the pot from the heat and leaving
the jar in the pot for 60 minutes.
Another strategy is to leave expressed breast milk at room temperature.
Unlike formula, which spoils after an hour, breast milk can be left
out for several hours before it begins to go bad. Although leaving
breast milk to stand won't eliminate the HIV, it may reduce the
amount of virus in the milk.
Alternative breast milk sources.
It may be possible to have another woman breast feed the baby or
to get breast milk from another woman or from a milk bank. However,
this assumes that the woman has tested HIV-negative, is still negative,
and that she will not become infected with HIV for as long as she
is providing milk. Naturally, this is not an easy thing to guarantee.
For women in the U.S. and wealthier countries
Although HIV-infected women in the U.S. and other developed countries
usually have access to clean water and formula The decision not
to breastfeed is not always easy.
Breast-feeding is the norm in most developed countries, and women
who bottle-feed may fear questions about why they don't use their
breast milk. Birthing classes, WIC, and other programs directed
at pregnant women and new mothers actively promote breast-feeding.
Many HIV-positive women have had to lie or disclose their status
to get counselors, teachers or social workers to stop pressuring
them to breast-feed. Often these activities take place in a group,
which can cause a woman to become concerned about her confidentiality
being violated, or about feeling social isolation when everyone
else is having a different experience.
An HIV-positive woman who breast-feeds and discloses that choice
could possibly face a legal threat of having her children removed
by authorities. Since most people who know of an HIV-positive woman's
status believe she has made the safest choice for her child when
she formula feeds, they may overlook giving her an opportunity to
express her anger or sadness about not being able to breast feed
her child.
What should the message be?
There has been great debate about what women who have HIV, or those
who live in high-risk areas, should be told about HIV and breast-feeding.
Some argue that HIV-positive women should be given all the information
and be encouraged to make the best decision they can based on the
realities of their own situations. Others worry that people are
getting mixed messages and that the confusion is dangerous. People
on all sides of the debate want to do what's best — but there
are still disagreements on what that is.
Breast feeding Versus Formula: Risks and Benefits
Exclusive breast-feeding
Exclusive breast-feeding is giving the baby breast milk only.
Risks:
Breast-feeding increases the risk of a baby getting HIV by up to
14 percent. A baby will be at greater risk of getting HIV through
breast feeding if the mother:
- Breast feeds her baby for a long time (this is why many suggest
weaning by 6 months if the mother is HIV-positive);
- Gets infected with HIV while breast feeding;
- Gets cracked or bleeding nipples;
- Gets mastitis (a breast infection);
- Is very sick, or has a high viral load or a low CD4+ count,
or has a lot of virus in her breast milk.
Breast-feeding is hard on a woman's body. To maintain her health
and milk flow, she needs extra calories and fluids.
Benefits:
- Breast milk is very nutritious and helps protect a baby from
diseases;
- Breast-feeding can help a mother and baby bond (although a formula-fed
baby and mom can bond just as well);
- Breast-feeding may help a baby that is born infected stay healthy
and avoid germs from formula feeding;
- A woman is less likely to get pregnant while exclusively breast
feeding, helping her to space her children.
Replacement/formula feeding
Risks:
Some common problems related to formula feeding include:
- Infections from germs in water used to mix formula or spoiled
formula can be extremely dangerous;
- Formula-fed babies miss out on the health benefits of colostrum
and many of the nutrients in breast milk;
- People may wonder why a woman isn't breast feeding and ask if
it is because she has HIV;
- Mixing too little formula (watered down) or too much formula
can make a baby sick;
- It takes work to boil water and keep all utensils clean every
time baby is fed;
- Formula is expensive. Paying for it means less money is available
to pay for other basic needs;
- A woman who does not breast-feed will get periods and become
fertile sooner. If she does not want to get pregnant right away,
she'll need contraception immediately.
Benefits:
- There is no HIV in formula. A baby born HIV-negative can stay
HIV-negative;
- Others can help feed the baby if the mother needs a rest, gets
sick, or has to go away for work or other reasons.
Mixed breast-feeding
Giving the baby breast milk and other drinks, such as formula,
glucose water, gripe water or traditional medicines, is called mixed
feeding. Mixed feeding is very common; however it is much riskier
than exclusive breast or formula feeding. When possible, an HIV-positive
mother should try to pick one method and do only that.
Risks:
Giving foods, formula or drinks to your baby can damage the lining
of the stomach and intestines, making it easier for HIV in breast
milk to infect the baby.
If it is so risky, why is it so common?
In many places, mixed feeding is the social norm. Women who choose
to formula feed sometimes breast feed due to social pressure, fear
of relatives discovering their HIV status, or not having enough
money for formula.
Women who choose to breast feed sometimes use formula because they
get sick, they have to leave the baby with someone to go to work,
or they can't produce enough breast milk to adequately nourish the
baby.
WORLD: Women Organized to Respond to Life-threatening Disease
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Web site: http://www.womenhiv.org
Opinion: You Don't Own Me
By Gregg Gonsalves
For the past several years, I have become increasingly worried
about how patents could affect our response to the AIDS epidemic.
Many of us are familiar with the international debates about patents
on AIDS drugs and the fight to use cheaper, generic, equivalents
in the developing world. However, my particular concern is about
a kind of intellectual property that is more insidious: the patenting
of human genes and other kinds of genetic material, particularly
HIV itself.
Two years ago, Human Genome Sciences (HGS) of Maryland was granted
a patent on the gene for CCR5, one of the cellular receptors that
HIV uses to infect cells. HGS didn't discover this receptor's role
in HIV infection; they simply sequenced large swaths of the human
genome and claimed patents for everything they collected. They only
found out that CCR5 was a lucky catch when William Paxton, Richard
Koup, John Moore, Daniel Littman, Nathaniel Landau and other leading
researchers did the hard work to pinpoint this protein's critical
importance in AIDS.
The U.S. Patent and Trademark Office (USPTO) subsequently made
it more difficult to patent genetic material without accompanying
knowledge of a specific, substantial, and credible use for a given
gene and its proteins. But over 6,000 gene patents had already been
granted under the old criteria and at least 20,000 more were pending
approval when the guidelines changed. Scientists trying to develop
new drugs for HIV based on CCR5 or any other protected gene —
human or retroviral — may have to negotiate a thicket of patents,
perhaps paying licensing fees to more than one party. This could
unduly hold up the development of novel therapeutics for HIV. As
HGS CEO William Haseltine said in 2000, "If someone in a company
wants to use the CCR5 cloned gene, they may need two licenses: our
license for composition of matter and a license [from NIH research
by Edward Berger] to practice HIV inhibition."
My concerns around the patent on CCR5 are theoretical as far as
I know. However, there have been some real and devastating consequences
from the patenting of HIV itself, in particular, the patent on HIV-2,
owned by Bio-Rad Laboratories, Inc. Bio-Rad has refused to grant
U.S. licensing rights for HIV-2 to several small companies with
proven rapid diagnostic tests for HIV-1/HIV-2. These tests have
revolutionized HIV testing outside of this country by providing
reliable results within minutes. But the three companies with U.S.
licenses from Bio-Rad, Abbott Laboratories, Johnson and Johnson
and Chiron Corporation, either make their own rapid tests —
though not for sale in the U.S. — or have no interest in developing
these tests, perhaps because of lucrative franchises involving the
more expensive, slower laboratory-based assays that dominate the
market here in the 50 states.
Each year in the U.S. over 700,000 people come in for HIV testing
but do not return for their test results according to the CDC. How
many people have missed receiving an HIV diagnosis because of the
intransigence of Bio-Rad and their secret licensing agreements that
seem to be keeping rapid tests out of the U.S.? How many more HIV
tests could be done with the resources saved by using these cheaper
testing alternatives? The incidence of HIV infection in the African-American
and Latino communities in the U.S., especially among young gay men,
has skyrocketed over the past few years, with rates rivaling those
of some countries in sub-Saharan Africa. Making HIV testing simpler
and more accessible for hard-to-reach populations is a key part
of improving our HIV prevention efforts in the communities hardest
hit by the epidemic. Rapid tests would be an important new tool
in our fight against HIV here in the U.S. According to Bio-Rad,
they'll be submitting an application to the FDA sometime soon for
approval of their own rapid test kit. I don't think we have the
time to wait when there are dozens of different rapid tests already
in use across the globe.
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