AIDS TREATMENT NEWS Issue #374, November 23, 2001
phone 800-TREAT-1-2, or 215-546-3776

Contents

** Viral Load: Small Change by Sixth Day of Treatment Can
Often Predict Poor Response
It may be possible to detect a failing antiretroviral
regimen, in many cases, after the first six days of
treatment.

** New Resistance Test Combines Phenotype and Genotype
The first resistance testing which combines both phenotypic
and genotypic testing, from the same company on the same
report, is intended especially for difficult treatment
decisions.

** Protease Inhibitors in Children: Combination Therapy
Reduced Death by Two Thirds
A study of over a thousand HIV-infected children from 1996
through 1999 provides more definitive information on the
benefits of improved treatment. The article and an
accompanying editorial also discuss the risks of treatment
in children, prevention of maternal transmission of HIV,
and the status of efforts to prevent and treat pediatric
AIDS in developing countries.

** South Africa: Activists, Physicians Sue Government to
Prevent Maternal Transmission, Ask International Support
After five years of civil society lobbying for widespread
programs to prevent maternal transmission in South Africa,
activists have sued the government, which has been notably
reluctant to move toward widespread access to
antiretroviral treatment.

** HIV Testing 101 (Part 1 of 2)
A look at antibody testing for HIV -- including ELISA and
confirmatory testing with Western blot, the "window period"
between infection and when the body produces antibodies
that can be detected, oral HIV testing, urine testing, and
the rapid test.


***** Viral Load: Small Change by Sixth Day of Treatment
Can Often Predict

Poor Response

by John S. James

A U.S. National Institutes of Health study of 124 pediatric
and adult patients taking protease inhibitors for the first
time found that the change in viral load in the first six
days of the treatment was able to predict many cases of
poor response of the regimen by week 12. Therefore
treatment could be changed quickly in these cases (instead
of at 4 or 8 weeks, as recommended by current U.S.
guidelines), reducing the development of drug resistance by
minimizing the time on an ineffective therapy.

In this study, "reduction in plasma HIV-1 of less than 0.72
log by day 6 after initiation of therapy predicted poor
long-term responses in more than 99% of the patients." For
those with less than a 0.96 log reduction, the chance of
poor response at 12 weeks was 95%. But while very good at
predicting some cases of drug failure, 6-day viral load was
not as good at assuring long-term success. This is because
unpredictable events can occur after day six, such as new
mutations that cause viral resistance.

In clinical practice, some patients will not get their
blood drawn on exactly the sixth day. Presumably the cut-
off value for counting drug failure should be adjusted if
the second blood draw is at, for example, 7 days, although
the paper did not discuss this. However, this study found
that samples taken at day 13 or day 28 were not as
predictive as those taken at day 6 -- probably because of
the more complex factors affecting viral load after the
initial period of rapid decline.

Prediction may be better if there is also a viral load test
on day 3, 4, or 5 -- due to natural fluctuations of viral
levels, and also due to the variability of test results.
The researchers did not seem to think that this extra test
would be necessary in clinical practice.

This research team previously reported that the trough
(lowest) drug concentration in blood plasma at the end of
the first week, but not the dose, correlated with viral
decline, and predicted long-term response. But it would be
hard to measure blood levels of three or more drugs, or to
know how sensitive the virus was to them. The authors
suggest that the much simpler measurement of early viral
load change is good enough.

Comment

Physicians might want to look at viral load decline by day
six of certain new treatments -- in order to quickly change
a clearly ineffective regimen. But the patients and
treatments in this study were often not representative of
what physicians see today. We hope the guidelines
committees will study all the available information, and
decide if a day-six viral load test should now be
recommended for patients starting or changing
antiretroviral therapy -- or if additional studies should
be done first.


***** New Resistance Test Combines Phenotype and Genotype

by John S. James

On November 15 ViroLogic, Inc. announced a new testing
service that combines phenotypic and genotypic resistance
testing on a single report. The new test, named PhenoSense
GT, is expected to be used especially for patients whose
treatment is complicated by difficult or complex HIV
resistance. The company expects to get test results back to
physicians within 14 days.

Phenotypic resistance testing uses part of the patient's
virus to construct a new virus that is then grown in the
lab and tested with varying concentrations of the approved
anti-HIV drugs, using automated equipment (it would be
difficult to grow the unchanged patient's virus in a
laboratory). Genotypic testing looks for mutations known to
be associated with resistance to the various drugs; it is
usually less expensive than phenotypic testing, but more
difficult to interpret. While the results are often
similar, the two kinds of tests can give different
information in some cases.

The PhenoSense GT assay includes resistance testing for the
newly approved drug tenofovir.

The number to call for ordering this test is 1-800-777-
0177. Unfortunately the price is $1210.

New information on HIV resistance will be presented at the
ICAAC conference in Chicago in mid December.

Comment

We believe that offering the two tests on one integrated
report, by a single company that applies compatible
standards and quality assurance throughout, opens
opportunities to provide better information to physicians.
How well it is accepted in practice remains to be seen.

As with other resistance testing, a major challenge will be
giving physicians the help that they need to get the most
out of the test. HIV physicians must keep up with many
things, and cannot all be expected to be drug-resistance
experts. At this time we do not know what information the
company plans to provide to help physicians interpret the
report.

What we would like to see eventually is a semi-automated
system that would compare patterns in the reported data
with a database of past experience, and add to the report
any one or more of perhaps thousands of pre-written notes,
calling the physician's attention to significant
information that might otherwise be overlooked. Ideally,
artificial-intelligence software would make the first
selection of these interpretive notes. Then an HIV-
resistance expert or panel of experts would look at every
report that was not clearly routine, changing the selection
or text of the notes when there is a good reason to do so
(these experts could work online from anywhere). Any
improvements by the human expert(s) would go to the
physician, and also be used to improve the software for the
future.


***** Protease Inhibitors in Children: Combination Therapy
Reduced Death by Two Thirds

by John S. James

A November 22 article in the NEW ENGLAND JOURNAL OF
MEDICINE reported on a cohort of 1028 HIV-infected children
studied from 1996 through 1999(1). After statistical
analysis to adjust for the fact that those starting
treatment tended to be sicker, the study found that
introduction of an antiretroviral regimen including a
protease inhibitor was associated with a two-thirds
reduction in risk of death (hazard ratio 0.33). The total
reduction in death -- reflecting many treatment advances,
not just antiretroviral therapy -- was more impressive:
5.3% mortality in 1996, 2.1% in 1997, 0.9% in 1998, and
0.7% in 1999. Both findings were highly statistically
significant, p<0.001.

This study could not compare combinations including a
protease inhibitor with combinations including an NNRTI
(efavirenz, nevirapine, or delavirdine) because too few of
the children were on NNRTI combinations -- only 3% in the
last year of the study, 1999 -- compared to 73% on
protease-inhibitor combinations, and 24% receiving only
nucleoside analogs. But an accompanying editorial(2) noted
that combination therapy with NNRTI drugs can achieve the
same result. All the children were on antiretroviral
therapy of some kind by 1999.

African American and Hispanic children were found to start
therapy later. After statistical adjustment for severity of
illness, this effect became less, and was no longer
statistically significant. However, the authors suggested
continued vigilance to ensure equitable access to
treatment.

The authors also urged continued vigilance about the long-
term risks of today's antiretroviral drugs when started in
childhood; serious metabolic and other side effects have
been seen in children as well as adults. This cohort study
(PACTG 219) is continuing, and will be able to provide more
information about long-term outcome and risk vs. benefit.

The accompanying editorial looked at treatment in
developing countries. In the United States, the rate of HIV
transmission from infected pregnant women to their children
went from 25% to 1.4% with standard antiretroviral therapy;
in those children who do get infected, beginning treatment
in the first three months of life can stop viral
replication completely and preserve normal immune function,
provided proper treatment is continued. However,
infrastructure in the developing world is just beginning to
be created -- the United Nations AIDS Summit this year set
a goal of only a 20% reduction in mother-to-child
transmission by 2005. "Our efforts must focus on devising
simple, relatively inexpensive, triple-combination regimens
for the treatment of all HIV-1-infected pregnant women and
all HIV-1-infected children. Such a regimen could be
provided for $5 per day and would have a substantial effect
on the prevention and treatment of HIV-1 disease in the
developing world. These efforts would represent an
important step toward changing the face of pediatric HIV-1
infection for the many millions who are affected by it
around the world."(2)

References

1. Gortmaker SL, Hughes M, Cervia J, and others. Effect of
combination therapy including protease inhibitors on
mortality among children and adolescents infected with HIV-
1. THE NEW ENGLAND JOURNAL OF MEDICINE November 22, 2001;
volume 345, number 21, pages 1522-1528.

2. Sullivan JL and Luzuriaga K. The Changing Face of
Pediatric HIV-1 Infection. THE NEW ENGLAND JOURNAL OF
MEDICINE November 22, 2001; volume 345, number 21, pages
1568-1569.

Note: The abstract is available online to anyone at:
http://content.nejm.org/cgi/content/short/345/21/1522
The abstract has links to the full text and the editorial -
- but these are only available to subscribers to the
Journal.


***** South Africa: Activists, Physicians Sue Government to
Prevent Maternal Transmission, Ask International Support

by John S. James

On November 26 South Africa's Treatment Action Campaign
(TAC), supported by about 200 doctors, sued the South
African government, asking for wider use of nevirapine to
prevent mother-to-infant transmission of HIV. About 70,000
infants every year are born with HIV in South Africa, and
about half of these infections at birth could be prevented
by a single tablet of nevirapine given to the mother, and a
single dose to the infant. This lawsuit follows five years
of lobbying by civil-society organizations.

The government is currently running a pilot program that
offers testing, counseling, and nevirapine if needed to
about 10% of pregnant women. It argues that it needs time
to evaluate this program before expanding it; TAC says that
the current program will not allow any expansion beyond the
18 current sites until at least April 2003. The government
also says that it cannot afford antiretrovirals, because it
has only $207 million a year to spend on public-sector
medicines for the country of over 40 million people.

How you can support TAC in this case? At this time TAC is
asking for letters to be sent to South Africa, and also for
individuals and organizations to sign the Bredell Consensus
Statement -- a statement on HIV treatment in South Africa,
endorsed by participants of the Bredell Conference, which
took place October 18 and 19. Since the situation will
change over time, check their Web site,
http://www.tac.org.za. This site also includes court papers
and other background on the case.

Comment

It is widely believed that the real issue for the
government is not the cost of the nevirapine for preventing
maternal-infant transmission (which the drug's manufacturer
Boehringer Ingelheim has offered free, although the cost of
so little nevirapine would not be a barrier in any case),
but that once the government provides the drug routinely to
HIV-positive pregnant women, there will certainly be more
pressure to also treat the mothers, fathers, and others.
Antiretrovirals are heavily patented and expensive in South
Africa. While generic nevirapine is available from India,
which has different patent laws, the South African
government is afraid to use compulsory licensing or other
means to override patents and obtain drugs it can afford,
due to fear of economic retaliation. While South Africa is
considered a middle-income country, so much of its
population is infected that it could not pay for widespread
access at the high prices set by the manufacturers.

A related problem is that South Africa's President Mbeki
personally has a hard time backing down from a position
once he has taken it. In this case, he picked up conspiracy
theories over a year ago from AIDS denialists who argued
that antiretrovirals are inappropriate because HIV does not
cause AIDS -- or because AIDS in Africa does not exist, and
the deaths are due to other illnesses and to poverty
instead. So officials under him are constrained in what
they can do.

The result is that South Africa is not successfully making
the plans, building the infrastructure, and getting the
experience to deal with one of the highest rates of HIV
infection in the world.


***** HIV Testing 101 (Part 1 of 2)

by Bruce Mirken

[Note: On November 9, 2001, the U.S. Centers for Disease
Control and Prevention issued two revised guidelines
encouraging health care providers to routinely offer HIV
testing more often. The goal is to increase the number of
people who know their HIV status. These guidelines are
available at:
http://www.cdc.gov/hiv/ctr, or by calling 1-800-458-5231.

[We had asked previously asked Bruce Mirken to write an
introduction to HIV testing, including reliability of the
tests today, oral HIV tests, rapid HIV tests, anonymous
testing, the home test kit (which makes anonymous testing
available in all states), and viral load testing to detect
HIV in the "window period" before the immune system has
produced antibodies, which standard HIV tests detect. JSJ]

* * * * *

HIV antibody testing has been with us since 1985. Testing
technology has evolved considerably over the years, with a
variety of new and improved tests coming into use, both in
research and daily practice. Since determining one's HIV
status is the first step in treatment decisions, it is
important to understand the tests being used today,
including their limitations.

The Basic Testing Procedure

"The primary purpose of the test in 1985 was to screen the
blood supply," recalls Steve Morin, director of the
University of California San Francisco's AIDS Policy
Research Center. At the time there were no treatments
available for HIV infection, and no one knew how likely it
was that an HIV-infected person would get AIDS or how
quickly it might happen. The only medical interventions
available dealt with the opportunistic diseases that
appeared once the immune system was weakened, so there was
no pressing need for people to find out their HIV status.

Still, it was clear that some who believed themselves at
risk would want to know.

And that, Morin notes, led to "a fear that people who
wanted to know whether they were infected or not would go
to donate blood in order to find out." To head off this
possible threat to the blood supply, federal and state
governments set up alternative test sites, where people
could be tested without giving blood. Back then, the main
public health value of HIV testing was "as a prevention
tool," Morin says, "to counsel people... about not
transmitting the virus to anyone else."

That changed with the advent of antiretroviral therapy and
prophylaxis (preventive treatment) aimed at preventing
opportunistic infections. Over time, HIV testing became a
gateway to treatment, as well as a prevention tool.

Although there have been technological changes, HIV testing
in the U.S. still follows the same basic testing procedure
as in 1985: HIV infection is only considered confirmed
after two tests have been done, a screening test and a
confirmatory test. In a recent article for the University
of California San Francisco's HIV InSite
(http://hivinsite.ucsf.edu), University of Maryland
researcher Niel Constantine explains that "screening tests
possess a high degree of sensitivity, whereas confirmatory
assays have a high specificity. Tests with high sensitivity
produce few false-negative results, whereas tests with high
specificity produce few false-positive results." Because
the screening tests can produce false positives, a second
screening test is typically run on the same sample - in
duplicate - with the confirmatory tests only run on samples
that are repeatedly positive ("reactive" in lab parlance).

The combination of the two types of tests produces results
that are "highly accurate," Constantine notes, but
technical errors are possible, and biological factors can
occasionally produce problems.

The most common screening test is the enzyme-linked
immunosorbent assay (ELISA), sometimes called enzyme
immunoassay (EIA). The most often used confirmatory test is
the Western blot. Identical technology is used in tests for
numerous illnesses, including Lyme disease, Constantine
explains. Indeed, the immunological methods underlying
these tests are so fundamental that Sally Liska, head of
the city of San Francisco's Public Health Laboratory, calls
it "serology 101."

The ELISA is used for initial screening because of both its
high sensitivity and its practical advantages, Liska adds:
"It's a lot easier to do many specimens on an ELISA. It's
smaller volume, it's less handling, it's more automated."

Over 40 different ELISA HIV test kits are available from
various manufacturers, though only a fraction of these are
licensed by the FDA - a requirement if they are to be used
in the U.S. (a few tests are approved for research only).
These tests use artificial HIV proteins that are able to
capture antibodies to the virus. Once those antibodies are
caught, Constantine explains, they "can be detected using
other reagents that are usually coupled to an indicator
such as a dye or enzyme that can produce color." The change
in color is read by a machine.

The Western blot is somewhat similar, but uses an
electrical field that separates out the various components
by their molecular weight. This allows identification of
antibodies to specific viral antigens, which show up as
identifiable "bands" on a strip of test paper.

The Western blot, Liska says, "is a little more complicated
to do... It's more hands-on." Because it is less sensitive,
she adds, it "should never be run by itself."

Although the Western blot is the most common confirmatory
test, others are sometime used, including the indirect
fluorescent antibody assay (IFA) and the
radioimmunoprecipitation assay (RIPA). "If performed and
interpreted correctly, these extremely specific tests
should not produce biologic false-positive results,"
Constantine writes.

The "Window" Period Just After Infection

One major drawback of antibody tests is the "window"
period: the time it takes the body to produce antibodies
after infection has begun. The standard tests for HIV do
not detect the virus itself, but the antibodies that the
body produces in response. During the period before the
antibodies are produced, a person can be infected with HIV
and can infect others, but still test negative on the HIV
antibody test.

For the first tests licensed, this window period ranged
from six to 12 weeks, but improved technology has allowed
the detection of lower levels of antibodies, making it
possible to identify them earlier. "Currently used tests
can detect HIV infection between three and five weeks in
most individuals," Constantine says. "This is true of just
about all of the ELISAs and the rapid tests [discussed
further below]. Some tests are a little more consistent in
detecting at the three week period, but in general they are
all equivalent." To some degree, he explains, "it also
depends on the individual (who may not produce antibodies
as fast as another)."

Oral HIV Testing

All of the early tests were done on blood. More recently
developed tests look for antibodies in oral fluid or urine.

The oral test, which follows the same
screening/confirmatory protocol as blood tests, has the
advantage of being a noninvasive procedure that can be done
in settings where blood draws would be impractical or
unsafe. Presently just one brand of oral test, called
OraSure, is FDA-approved. It is not a saliva test, but
instead uses a small pad to draw fluid from within the
gums. These fluids are in fact derived from blood,
Constantine explains. "Therefore they include the same
fluid (plasma) that is used for testing with serum-based
tests."

"We're not taking fluid that's already available" in the
mouth, Liska notes. "It's not saliva or spit."

The pad used to draw the fluid is attached to a small
handle resembling a toothbrush. It is placed against the
gum, where it must remain for at least two full minutes to
collect a proper sample.

Because the saliva present in the mouth dilutes the
antibodies obtained, oral tests must be able to detect
weaker concentrations of antibodies than blood tests. In
general oral tests have been found to be just as accurate,
but Liska believes "the oral fluid test may not be as
sensitive for early seroconverters as the blood test."

Urine HIV Testing

Urine tests exist as well, but have not been as popular as
the oral fluid test. This may be because the FDA has not
yet approved a confirmatory urine test, so anyone with a
positive urine test must return for a confirmatory test .

Rapid HIV Testing

Another innovation has been the development of rapid tests.
In conventional tests the sample is collected and sent to a
central laboratory for processing, a procedure that usually
requires the patient to return a week or more later for the
results. Rapid tests (which come in both blood and oral
versions) are done on-site and give a reading within half
an hour. As with the ELISA, a positive reading on a rapid
test requires a second, confirmatory assay such as a
Western blot.

An advantage of rapid tests is that they eliminate the
problem of testers who don't return for their results. Non-
return rates are fairly low in doctors' offices and
anonymous test sites, but can be quite high in other
settings, including STD clinics, whereas many as one third
of patients never come back to get their results.

According to Constantine, rapid tests have "proved to be as
accurate as the ELISA when performed carefully by
experienced personnel. Technical errors are common with
these assays, however, because users become careless with
these simple procedures." To deal with this problem, many
rapid tests now include a built-in control that indicates
whether or not the test was done properly. At present, the
FDA has licensed one rapid test, made by Murex Diagnostics.

* * *

[Part II will include viral load testing for acute
(primary) HIV infection, the "detuned ELISA," accuracy of
HIV tests today and answers to "denialist" claims they are
unreliable, anonymous testing, home testing anonymously,
informed consent for testing, and counseling.]


***** AIDS TREATMENT NEWS

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Editor and Publisher: John S. James
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AIDS Treatment News
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