rock%lighthouse%pyrdc%wubios@uunet.UU.NET (Roger Rock Rosner) (10/29/89)
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EDUCATION - Table of Contents August 1989 - Vol 1, No 3
Stemming the spread of AIDS
The Speckled Band
Updates from the Fifth International Conference on AIDS
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STEMMING THE SPREAD OF AIDS
HIV Infection and the Intravenous Drug User
by Sally Breul
At the end of May, 1989, the Centers for Disease Control (CDC) reported
97,193 cases of AIDS nationwide. Almost half of the 97,193 persons with
AIDS are in the States of New York (23.4 percent) and California (19.9
percent). The District of Columbia reported 1733 or 1.8 percent of the
total. As of January 1, 1989, 30 percent of all reported AIDS cases
occurred in IV drug abusers, of whom about 80 percent are heterosexual and
the remainder are male homosexual/bisexuals. In the heterosexual IV drug
user group, minorities have been hardest hit, representing 80 percent of the
total, with Blacks at 38 percent and Hispanics at 40 percent. Seven percent
are White and the remainder are Asian, American Indian or Alaskan
natives.[1]
Since nearly one third of all cases of AIDS are now attributed to people who
use illegal drugs intravenously, often living in the inner cities of the
large urban centers, there is major concern as to how best to reach this
population with messages that will alter behaviors that contribute to the
spread of the HIV virus.
In general, AIDS prevention and education efforts have focused on changing
sexual behavior and, for the IV drug abuser, stopping the use of drugs
completely, arresting needle sharing, and cleaning syringes and needles
before use.
Changing human behavior is one of the most complex and little understood
phenomena confronting social scientists. Nevertheless, behavioral change
does occur. Cigarette smoking, which is also addictive, has declined
precipitously as a result of massive educational campaigns showing that
tobacco smoking is a major cause of mortality from lung cancer and heart
disease. That sexual practices can be changed has been demonstrated in some
places, such as the well-organized gay communities in large cities like San
Francisco, where major reductions in anal intercourse without condoms have
been reported.[2]
------------------------------
NEEDLE SHARING
Needle sharing among intravenous drug users is endemic in many places where
illegal drugs are procured and injected. To share "works" with a fellow
user fosters a trust relationship between those engaged in such high risk
illegal activity. Moreover, since possession of hypodermic syringes is
illegal in some localities, supply is limited and arrest for possession can
lead to lengthy jail terms. Yet sharing needles contaminated with drops of
blood harboring HIV appears to be a quite effective way of transmitting the
infectious agent.
In efforts to stem the use of contaminated needles and reach the "forgotten"
men and women in our large cities, a variety of outreach programs are being
tried. Trial programs have been proposed that would distribute free
needles, sometimes in exchange for used ones. However, a large majority of
states have laws restricting the use of hypodermic needles and syringes for
injection of illegal drugs.[3] Free needle distribution has also been
opposed by some in Congress who see needle distribution as certain to
increase drug abuse and, thus, exacerbate rather than alleviate the spread
of AIDS. Debate over this issue is likely to continue.
Programs launched in major metropolitan centers, similar to those that have
been carried out for the past few years by the Whitman Walker Clinic in
Washington, D.C., are aimed at halting the needle sharing behavior so common
among drug addicts, or at least at providing means for cleaning needles and
syringes during use. Through the Sunnye Sherman Outreach Project (formerly
A.O.R.T.A.), the Clinic has organized carefully structured programs aimed at
the alienated people using drugs on the streets of the city. These programs
recruit workers, often recovered addicts, from the community and focus on
the commercial sex industry (prostitutes and pimps); street IV drug dealers
and users; staff, residents, and out-patients in drug treatment programs;
jail and prison inmates; the homeless; and runaways.
The success of such efforts has been reported in other parts of the country,
where intravenous drug addicts, notoriously impervious to health messages,
have adopted the ritual of rinsing contaminated equipment with
bleach--indeed, there are shooting galleries where the use of bleach is
enforced.
------------------------------
SEXUAL PRACTICES
In double jeopardy for contracting and transmitting AIDS, the IV drug user
must modify both drug-taking behavior by learning to clean "works" before
sharing a needle, and alter sexual practices by disciplined use of condoms.
In the decades since the advent of the "pill," contraceptive use has been
considered the responsibility of women, and only relatively recently have
men begun to share in this obligation. Furthermore, many people continue to
believe that AIDS affects only gay, white, middle-class men, not Black or
Hispanic men who consider themselves heterosexual. Many men do not think
having sex with another man is a homosexual act,[2] especially in sexually
segregated environments like jails and prisons.
Compounding the problem of sexual transmission is the reluctance of many men
to use condoms with their wives or lovers, placing their partners at
particular risk for HIV infection, especially if their partner is an
infected IV drug abuser. Furthermore, women who become infected by their
sexual partners can then transmit the disease to their babies. An
increasing number of infected babies are now being born in our hospitals.
Prostitutes, similarly infected, are considered to be crucial links in the
chain for heterosexual transmission of the virus, particularly if they abuse
intravenous drugs. They can transmit the virus to their clients who then
return to their homes and families, where the infection can again
proliferate.
------------------------------
SOLVING THE PROBLEM
Attempts to reach the IV drug-using segment of the population with AIDS
education and prevention messages are fraught with difficulty. Many drug
abusers, already threatened by law enforcement authorities because of their
use of illegal substances, living in urban ghettos, jobless, often poorly
nourished and housed, are suspicious and unwilling to trust outreach workers
trying to persuade them to enter drug treatment facilities, or at least to
change their needle sharing and sexual behaviors.
Although IV drug users have no well-developed network of social support
systems like those that have contributed so much to the successful reduction
of high risk behavior in the gay community, a study in Chicago has found
that as addicts learn more about the causes of AIDS, a strong sense of
social responsibility does develop which can lead to successful prevention
advocacy.[4]
Drug abuse treatment remains one of the most viable alternatives to
continued proliferation of the AIDS virus, but current drug abuse treatment
facilities and qualified personnel to staff them are woefully inadequate.
Long waiting lists exist for admission to those programs that are available,
especially in large urban areas.
Nevertheless, treatment has been shown to reduce drug use dramatically, and
recent studies of large numbers of opiate addicts in methadone treatment
programs throughout the country indicate that as many as 75 percent of
addicts who stay in treatment for more than one year have substantially
reduced their opiate use, or are drug free.[5] However, an additional
problem has appeared among IV drug abusers who shoot cocaine, sometimes with
heroin, since methadone is powerless to control the effects of cocaine.
The drug abuse prevention legislation passed at the end of 1988 contains
funding for establishment of more treatment centers where addicts may also
receive HIV testing and counseling in AIDS prevention. Surprisingly, a
study of addicts entering drug abuse treatment in Baltimore showed that they
responded positively when asked if they wished to be tested for HIV
antibodies, and they were subsequently counseled about prevention techniques
and strategies for informing their sexual partners. They also expressed the
need for testing and counseling programs in other drug treatment
facilities.[6]
Clearly, no drug user is going to wait drug-free for his or her turn to come
up for treatment, so drug use and needle sharing continue, as does the
dangerous spread of the virus by these people to their sexual partners and
the larger population.
Social scientists in the poorly understood field of human behavior seem to
agree that change occurs when community standards change so that it becomes
"socially unacceptable for an addict to pass a colleague a dirty needle, or
for two strangers to have sex without a condom."[2] As more people contract
AIDS, fewer in high risk groups like drug abusers will be insulated from the
realities of the devastation caused by the epidemic, and although it will be
too late for many, behavior will change.
------------------------------
References
1. AIDS Weekly Surveillance Report, US AIDS Program, Centers for Disease
Control, February 6, 1989, and June, 1989
2. Science, 242:2 Dec, 1988, 1237-38. Booth, William "Social Engineers
Confront AIDS"
3. National Institute on Drug Abuse Research Monograph Series 1988:80,
119-36. Pascal, C.B. "Intravenous Drug Abuse and AIDS Transmission: Federal
and State Laws Regulating Needle Availability"
4. National Institute on Drug Abuse Research Monograph Series 1988:80,
137-150. Wiebel, W.W. "Combining Ethnographic and Epidemiologic Methods in
Targeting AIDS Interventions: The Chicago Model"
5. University of Maryland, Ball, J.C. "Report from Methadone Maintenance
Programs in Three Cities, 1985 and 1986"
6. Journal of Substance Abuse Treatment, 1988:5:145-49. Weddington,
W.W.Jr. and Brown, B.S. "Acceptance of HIV-Antibody Testing by Persons
Seeking Outpatient Treatment for Cocaine Abuse"
------------------------------
Sally Bruel is a retired pharmacologist who is a consultant with the
National Institute on Drug Abuse.
============================================================================
Cases Per Year
1983 1984 1985 1986 1987 1988
------ ------ ------ ------ ------- -------
Gay 2187 3354 5972 7297 13328 18187
IV 528 789 1367 2219 3608 7640
Gay/IV 0* 0* 0* 2238 1488 2148
Other 349 402 771 1254 2364 3928
Percentages:
1983 1984 1985 1986 1987 1988
------ ------ ------ ------ ------- -------
Gay 71.4 73.8 73.6 56.1 64.1 57.0
IV 17.2 17.4 16.9 17.1 17.4 23.9
Gay/IV 0* 0* 0* 17.2 7.2 6.7
Other 11.4 8.8 9.5 9.6 11.4 12.3
* NOTE: PEOPLE WHO WERE BOTH GAY AND IV DRUG ABUSERS WERE INCLUDED IN THE
"GAY" CATEGORY UNTIL 1986, WHEN THEY WERE BROKEN OUT SEPARATELY.
By Race
1983 1984 1985 1986 1987 1988
------ ------ ------ ------ ------- -------
White 1270 2710 4987 7905 12861 17389
Black 611 1161 2056 3268 5374 9283
Hispanic 327 694 1142 1920 2720 5530
Other 13 70 64 96 173 108
Percentages:
1983 1984 1985 1986 1987 1988
------ ------ ------ ------ ------- -------
White 57.2 58.5 60.5 59.9 60.9 53.8
Black 27.5 25.0 24.9 24.8 25.4 28.7
Hispanic 14.7 15.0 13.8 14.6 12.9 17.1
Other 0.6 1.5 0.8 0.7 0.8 0.3
Graphics by Bryan Harrison; Source: Centers for Disease Control AIDS
Quarterly Reports 1982-1989
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THE SPECKLED BAND
The following article is an account of one person's encounters with the
uncertainties still present in the arenas of HIV testing, diagnosis, and
treatment. The individual involved wishes to remain anonymous.
"...As I bent over her she suddenly shrieked out in
a voice which I shall never forget, `Oh, my God!
Helen! It was the band! The speckled band!' "
from "The Adventure of the Speckled Band"
in The Adventures of Sherlock Holmes,
by Sir Arthur Conan Doyle
I was young and idealistic. I had seen close-up the devastation caused by
HIV. I wanted to help save the world before more people died. I had a true
belief in the scientific method, and was willing to use my own body as a
"test tube with skin" to help increase mankind's knowledge in the fight
against HIV. And, most important of all, I seemed to be the kind of person
they were looking for. So, in June of 1988 I applied for a protocol at NIH
testing an experimental vaccine against HIV called gp-160.
The vaccine protocol required that participants be male and HIV-negative.
The protocol was to certify that the participants were not HIV-infected at
the start of the study using the ELISA, the Western Blot, and other blood
tests. The volunteers would then be inoculated with gp-160, which is a
precursor to two proteins, gp-120 and gp-41, which are proteins on the
envelope (exterior) of HIV.
The hope was that the body would react to the gp-160, and produce antibodies
to it in the blood. The theory was that if the volunteer was later exposed
to real HIV, complete with gp-120 on its surface, the vaccinated volunteer's
body would already have antibodies on the lookout for the HIV, and would
detect it and destroy it before it had a chance to take hold.
One of the projected side-effects of all this is that the volunteers,
because their blood would have antibodies to HIV, might "seroconvert" (have
their blood change) to show positive on an ELISA test. The Western Blot,
however, would show that they were not actually infected with HIV, just with
gp-160. Note that the vaccine was (and still is) made from genetically-
copied gp-160 (spliced into moth cells, of all things), NOT from HIV, so
there was ZERO chance of contracting HIV or AIDS from the vaccine. There
were other possible side effects (some mild, some horrific--like triggering
an auto-immune reaction, where your body attacks itself), but HIV infection
was definitely not one of them.
The effectiveness of the vaccine would be judged by drawing blood from the
protocol participants, and seeing how it reacted to HIV and some other
substances in the test tube. (By the way, NIH is still recruiting
volunteers for the protocol. See the description in the Treatment section
of this issue, or call Margaret Easter at (301) 496-7196.)
Well, I went for the initial screening, at which time a lot of blood was
drawn, and I was told that I would be called back to the Clinical Center in
a month if my tests were satisfactory. My blood tests were basically fine,
my ELISA was negative, and my Western Blot was clear (negative).
I went back a month later for the final screening, which included more blood
work, an EKG, a chest x-ray, and a physical. I was told to come back the
next morning to actually get inoculated. Later that day, however, I got a
phone call that my Western Blot was slightly abnormal. It was nothing to
worry about, I was told, and they suspected that it could have been due to
problems in the lab. They were going to re-run the test, and they would
call me the next day.
The next day, the results were still strange. The researchers were going to
try a Western Blot test from a different manufacturer. They would call me
the next day. They did. The results were still strange. They tried one
last time, and my Western Blot still came out as "High Background." At this
point, I was told, "You'd better come in so we can discuss your test
results." Thus started my "Adventure of the Speckled Band."
* * *
To make a Western Blot test, ground-up pieces of HIV are placed in a gel-
like material, and then forced to distribute themselves through the gel in
different groups according to their charge, which is related to the weight
of the molecules involved, using a process called electrophoresis (figure
1). The lighter proteins like p17 go towards one end of the polyacrylamide
gel slab, and the heavier ones like gp-160 stay at the other. (The numbers,
like 17 in p17 and 160 in gp-160 are the molecular weight of the protein in
kilodaltons.) The different bands of fragments of HIV then get transferred
from the gel slab to a thin strip of cellulose that forms the actual Western
Blot (figure 2).
The cellulose strip is then incubated with your blood serum. This provides
an opportunity for the different antibodies in your blood serum that respond
to different pieces of HIV to find their corresponding piece of HIV on the
strip, and bind to it (figure 3). Another chemical is then added that binds
to the antibodies, and yet another chemical is added that reacts with the
first chemical and makes it turn the strip dark (figure 4). The result is
that you have a cellulose strip which is dark in regions corresponding to
HIV proteins to which antibodies are present in the serum, and light
elsewhere.
Each of the proteins in HIV has a specific function: gp160 is part of the
outer envelope of HIV, and it breaks down into gp120 and gp41. p55 is the
precursor of the two core proteins p24 and p17. Some of the proteins
involved in HIV reproduction (including the infamous "Reverse
Transcriptase") are p66, p51, and p31.
In order to be classed as "positive" (according to criteria given with the
FDA-licensed Immunoblot Test Kit made by Biotech/Du Pont), a Western Blot
needs to have a band at p24, p31, AND either gp41 or gp160 (figure 5). In
other words, you have to have a core protein, a reproduction protein, and
one of the envelope proteins in order to be considered positive. If the
blot does not show any bands, it is considered "negative." All the rest are
considered "indeterminate."
* * *
My first Western Blot (figure 6) was completely clear. This is normal for
someone who is HIV-negative. It means that the strip did not react to the
presence of any HIV-related proteins in my blood. My next Western Blots
were "high background" (figure 7). I was somehow staining the strip dark
even in places where that shouldn't have been possible. None of the
researchers at the National Institutes of Health could even hazard a guess
at what it meant. (I discounted a friend's semi-facetious suggestion that
it was because of my junk-food diet. Besides, pizza IS good for you.)
How my blood was able to do this is somewhat of a mystery, although some of
the scientific literature about Western Blots says that "because the viral
antigen preparation used for immunoblots contain nonviral cellular proteins,
not all bands appearing on an immunoblot are necessarily HIV specific." In
other words, something else in my blood besides HIV could somehow be
triggering the Western Blot.
Because I was applying for health insurance, I had occasion to get a
complete physical, including blood drawn, just before Thanksgiving. I had
remained in contact with the research staff at NIH, and they suggested I
bring them some more blood to test. So I had my doctor draw more blood, and
dropped it off at NIH.
Three days before Christmas, I got the results. My Western Blots were now
showing some of the bands for HIV (similar to figure 8), specifically p17
and a possible p66 band, so I was now officially classed as "indeterminate."
So what does being "indeterminate" mean? Well, initially no one was exactly
sure. The literature on the subject said "...because of the many
uncertainties in resolving indeterminate immunoblot test results, it is
prudent to assume that all indeterminate immunoblot test results are
potentially indicative of early seroconversion." It is also worth noting,
however, that the Western Blot is normally used only to CONFIRM blood serum
that has tested positive TWICE on the ELISA.
All tests have two measurements of effectiveness: SENSITIVITY and
SPECIFICITY. Sensitivity is the probability that the test will correctly
read positive blood serum as positive. Specificity is the probability that
a positive test result is actually positive. While these may seem to be the
same, they aren't. If a test has a sensitivity of 99.9%, it means that only
one sample out of a thousand that is actually positive will read incorrectly
as negative. If a test has a specificity of 99.7%, it means that of 1,000
samples that test positive, 997 of them will actually be positive, and that
3 will have falsely read as positive.
The ELISA test has a very high sensitivity (close to 100%), so that almost
all the samples infected with HIV will read positive. However, it has a
relatively low specificity, meaning that many of the positive results will
be false positives. (This is the trade-off you want for a test that is
protecting the nation's blood supply. You want very few units of infected
blood to get through the screening, and if you throw out some blood that
isn't infected along with the blood that is, that's an acceptable price to
pay.) The Western Blot test, on the other hand, has a lower sensitivity (so
it might miss some HIV-infected samples), but it has a higher specificity.
This is why blood serum samples that test positive on the ELISA get
confirmed by the Western Blot. The combination of the sensitivity of the
ELISA and the specificity of the Western Blot mean that the false-positive
rate of the two combined will be less than one person per 100,000 tested.
This method of combined testing is also why, because my blood is negative on
the ELISA and indeterminate on the Western Blot, the researchers had even
less idea of what the implications were, since normally a negative ELISA
would prevent my blood from ever getting a Western Blot test.
In posters at the Fifth International Conference on AIDS in Montreal, data
was presented which seems to indicate that the Western Blot is capable of
generating bands even for people who do not appear, based on our current
knowledge, to be HIV-infected. A poster (Th.B.P.179) from NIH and
Georgetown University reported on "high risk HIV/ELISA negative individuals"
who were part of a AIDS vaccine study, and who showed various indeterminant
patterns on Western Blots. Seventy-eight out of 214 individuals (36%) had a
variety of band patterns, with bands at p55 and p24 being the most common.
The scientists followed 20 of the 78 for a one-year follow-up, and none of
the twenty went from an indeterminant to a positive Western blot. There
was, however, evidence that seven of the 20 individuals showed some reaction
on the more sensitive polymerase chain reaction (PCR) test. Another report
(T.B.P.123) from NIAID, Johns Hopkins, and Georgetown found similar results
from volunteers for another vaccine study, with 32% of 158 individuals
showing an indeterminant Western blot.
* * *
With the recent evidence of people who are negative on the ELISA and Western
Blot but who still appear to be HIV-infected, and with the uncertainties I
encountered with testing, we get yet another reminder that we still have
much to learn about HIV, both stopping it and testing for it. For myself, I
will continue doing what I should do anyway, namely monitoring my health,
and hope that--for everyone--either time or research will provide a clearer
answer to the mysteries encountered in the Adventure of the Speckled Band.
------------------------------
References
AIDS: Etiology, Diagnosis, Treatment, and Prevention (Second Edition).
Vincent T. DeVita, Jr., Samuel Hellman, and Steven A Rosenberg, Editors.
J.B. Lippincott Company, Philadelphia, Pennsylvania. 1988. Pages 127-131,
423-425, 457-458.
+--------+ kD
|xxxxxxxx|
|xxxxxxxx| 160
| |
|xxxxxxxx|
|xxxxxxxx| 120
| |
|xxxxxxxx| 66 Figure 1. HIV is divided up
| | into its component parts,
|xxxxxxxx| 55 which are then spread
| | throughout a polyacrylamide
|xxxxxxxx| 51 gel, and get positioned into
| | bands of differing molecular
|xxxxxxxx| weight by a process called
|xxxxxxxx| 41 electrophoresis.
| |
|xxxxxxxx| 31
| |
|xxxxxxxx| 24
| |
|xxxxxxxx| 17
+--------+
||
gp160 ||>
||
gp120 ||>
||
p66 ||> Figure 2. The bands of
p55 ||> components of HIV then get
p51 ||> transferred to a thin
|| cellulose strip by
gp41 ||> electroblotting.
||
p31 ||>
||
p24 ||>
||
p17 ||>
||
||
gp160 ||>
||
gp120 ||>
||
p66 ||> Figure 3. When exposed to
p55 ||> blood, antibodies in the blood
p51 ||> attach themselves to their
|| corresponding pieces of HIV on
gp41 ||> >>-- ANTI-gp41 the Western Blot test strip.
||
p31 ||> >>-- ANTI-p31
||
p24 ||> >>-- ANTI-p24
||
p17 ||>
||
+-----+
|| | |
gp160 ||> | |
|| | |
gp120 ||> | | Figure 4. Another chemical is
|| | | added which binds to the HIV
p66 ||> | | antibodies and stains the
p55 ||> | | strip dark, thus giving the
p51 ||> | | characteristic dark bands
|| | | where you have corresponding
gp41 ||> >>-- ]-O )] |XXXXX| antibodies, and light
|| | | elsewhere.
p31 ||> >>-- ]-O )] |XXXXX|
|| | |
p24 ||> >>-- ]-O )] |XXXXX|
|| | |
p17 ||> | |
|| | |
+-----+
p17 p24 p31 gp41 p55 p66 gp120 gp160
| | | | | | | |
| | | | | | | | Figure 5.
+-----------------------------------------------------------+ A typical
| I II I II I I II II XXXXXXXX| positive
| I II I II I I II II XXXXXXXX| Western
+-----------------------------------------------------------+ Blot.
| | | | | | | |
| | | | | | | |
| | | | | | | | Figure 6.
+-----------------------------------------------------------+ A typical
| XXXXXXXX| negative
| XXXXXXXX| Western
+-----------------------------------------------------------+ Blot.
| | | | | | | |
| | | | | | | |
| | | | | | | | Figure 7.
+-----------------------------------------------------------+ A Western
|I|.:.|I|..:|.!.III|:..!|II.:.||...!II||II!:...||::!XXXXXXXX| Blot with
|:.||...!II||II!:...||::!I|.:.|I|..:|.!.III!!:..I.::XXXXXXXX| high
+-----------------------------------------------------------+ background.
| | | | | | | |
| | | | | | | |
| | | | | | | | Figure 8.
+-----------------------------------------------------------+ An indeter-
| II I XXXXXXXX| minate
| II I XXXXXXXX| Western
+-----------------------------------------------------------+ Blot.
***************************************************************************
UPDATES FROM THE MONTREAL FIFTH INTERNATIONAL CONFERENCE ON AIDS, JUNE 1989
by Basil Vareldzis
The Fifth International Conference on AIDS was a very optimistic meeting
with very encouraging results. Several papers were presented dealing with
the natural history of this disease. We have learned that HIV causes a
chronic progressive illness that lasts over ten years if untreated and
longer with treatment. We also learned that several surrogate markers can
be used to differentiate those who are more likely to progress in disease
from those who will remain asymptomatic. These markers include elevated
beta-2 microglobulin, decreased CD4 count and presence of p24 antigen.
These have significant implications for patient management in that patients
who are more likely to progress in disease should receive more aggressive
anti-retroviral therapy (AZT or ddC or ddI or AZDU or D4T or CD4 etc.).
In terms of treatment of the primary viral infection with HIV, significant
advances in our treatment armamentarium have occurred. We now know that
Zidovudine (AZT) prolongs life and has a transient effect on CD4 cells.
This effect is most dramatic in the first year, but continues on to the
second and third years of treatment. Survival of AIDS (CDC Class IV)
patients receiving AZT was over 85% for one year and 58% at 21 months. ARC
(CDC Class IV.A and IV.C.2) patients receiving AZT did even better with 94%
surviving one year, and 81% 21 months. This compares to survival of only
39% at 9 months for AIDS patients initially treated with placebo.
We also learned that the combination of AZT with Granulocyte Macrophage-
Colony Stimulating Factor (GM-CSF) enhances the antiviral efficacy of AZT
while at the same time decreasing the neutropenic side-effects of therapy.
A worrisome trend was noted by several researchers who reported that HIV is
becoming resistant to AZT after six to 18 months of therapy. The clinical
implications are not yet clear, since patients who have resistant viral
isolates continue to respond to therapy. All is not lost however, as
several researchers demonstrated that this viral resistance to AZT does not
cross over to the other anti-retrovirals such as ddC and ddI since they have
a slightly different mechanism of action using different nucleoside
analogues such as cytosine and inosine. These different mechanisms of
actions also yield the advantage of different side effect profiles for these
agents so that patients who cannot tolerate AZT because of its toxicity can
tolerate ddI or ddC.
More progress was made in the treatment of opportunistic infections. We now
have a better understanding of managing patients with Toxoplasmosis, CMV
Retinitis, pneumocystis pneumonia, tuberculosis and others.
Major papers were presented dealing with prophylaxis against pneumocystis
pneumonia. There was a clear consensus that prophylaxis should be used by
all persons following a diagnosis of PCP as well as for those with CD4
counts below 200 or percent CD4 below 20.
Three agents were shown to be effective in preventing PCP: they are
Aerosolized Pentamidine, Trimethoprim-Sulfamethoxazole (Septra or Bactrim),
and Dapsone.
Aerosol Pentamidine offers the advantages of convenient once-a-month dosing,
few side effects, and good efficacy. The disadvantage is the high cost
($120 to $350 per month), and the lack of systemic efficacy (extrapulmonary
pneumocystis is not prevented). This agent is now FDA approved as of June
14, 1989, so insurance companies should be reimbursing for it.
Trimethoprim-Sulfamethoxazole is given in pill form once or twice a day. It
is equally effective to Aerosol Pentamidine in preventing PCP, and has the
added advantages of low cost (about $30 per month) and systemic efficacy.
The major disadvantage is the high rate of side effects including fever and
rash that require stopping this medication in up to 50% of patients. This
is a very good therapy for those patients that can tolerate it. Leucovorin
5 mg per day is recommended to reduce the side effects. This is very
expensive, however, costing over $200 per month for 30 tablets.
The third agent that is effective is Dapsone. This drug has been used for
years in the treatment of leprosy. It is very inexpensive ($2-3 per month)
and usually well tolerated at the dose of 50-100 mg per day. It has
systemic efficacy, better tolerance than trimethoprim-sulfamethoxazole, and
has the added advantage of being effective against Toxoplasmosis as well as
PCP. The major toxicity is a severe anemia that can occur in persons who
are G-6-PD deficient (predominantly those of African ancestry). All persons
planning to start on this medication should first be screened for G-6-PD
deficiency.
This is but a brief overview of the clinical advances presented in Montreal
this past June. Further updates will be presented in the next issue.
----------------------------
Basil Vareldzis, M.D., is the Clinical Director of the Whitman-Walker
Clinic.
***************************************************************************
Copyright (C) 1988,1989 by Washington HIV News, all rights reserved.
Permission is granted for non-commercial use only.phil@wubios.WUstl.EDU (J. Philip Miller) (11/20/89)
Forwarded message: >From pyrdc!lighthouse!rock@uunet.UU.NET Tue Oct 24 19:16:47 1989 Date: Tue, 24 Oct 89 18:56:39 GMT-0500 From: pyrdc!lighthouse!rock@uunet.UU.NET (Roger Rock Rosner) Message-Id: <8910242356.AA01266@ lighthouse > To: phil@wubios, ddodell@stjhmc.fidonet.org Subject: Washington HIV News: V1N3, 2/3 *************************************************************************** EDUCATION - Table of Contents August 1989 - Vol 1, No 3 Stemming the spread of AIDS The Speckled Band Updates from the Fifth International Conference on AIDS *************************************************************************** STEMMING THE SPREAD OF AIDS HIV Infection and the Intravenous Drug User by Sally Breul At the end of May, 1989, the Centers for Disease Control (CDC) reported 97,193 cases of AIDS nationwide. Almost half of the 97,193 persons with AIDS are in the States of New York (23.4 percent) and California (19.9 percent). The District of Columbia reported 1733 or 1.8 percent of the total. As of January 1, 1989, 30 percent of all reported AIDS cases occurred in IV drug abusers, of whom about 80 percent are heterosexual and the remainder are male homosexual/bisexuals. In the heterosexual IV drug user group, minorities have been hardest hit, representing 80 percent of the total, with Blacks at 38 percent and Hispanics at 40 percent. Seven percent are White and the remainder are Asian, American Indian or Alaskan natives.[1] Since nearly one third of all cases of AIDS are now attributed to people who use illegal drugs intravenously, often living in the inner cities of the large urban centers, there is major concern as to how best to reach this population with messages that will alter behaviors that contribute to the spread of the HIV virus. In general, AIDS prevention and education efforts have focused on changing sexual behavior and, for the IV drug abuser, stopping the use of drugs completely, arresting needle sharing, and cleaning syringes and needles before use. Changing human behavior is one of the most complex and little understood phenomena confronting social scientists. Nevertheless, behavioral change does occur. Cigarette smoking, which is also addictive, has declined precipitously as a result of massive educational campaigns showing that tobacco smoking is a major cause of mortality from lung cancer and heart disease. That sexual practices can be changed has been demonstrated in some places, such as the well-organized gay communities in large cities like San Francisco, where major reductions in anal intercourse without condoms have been reported.[2] ------------------------------ NEEDLE SHARING Needle sharing among intravenous drug users is endemic in many places where illegal drugs are procured and injected. To share "works" with a fellow user fosters a trust relationship between those engaged in such high risk illegal activity. Moreover, since possession of hypodermic syringes is illegal in some localities, supply is limited and arrest for possession can lead to lengthy jail terms. Yet sharing needles contaminated with drops of blood harboring HIV appears to be a quite effective way of transmitting the infectious agent. In efforts to stem the use of contaminated needles and reach the "forgotten" men and women in our large cities, a variety of outreach programs are being tried. Trial programs have been proposed that would distribute free needles, sometimes in exchange for used ones. However, a large majority of states have laws restricting the use of hypodermic needles and syringes for injection of illegal drugs.[3] Free needle distribution has also been opposed by some in Congress who see needle distribution as certain to increase drug abuse and, thus, exacerbate rather than alleviate the spread of AIDS. Debate over this issue is likely to continue. Programs launched in major metropolitan centers, similar to those that have been carried out for the past few years by the Whitman Walker Clinic in Washington, D.C., are aimed at halting the needle sharing behavior so common among drug addicts, or at least at providing means for cleaning needles and syringes during use. Through the Sunnye Sherman Outreach Project (formerly A.O.R.T.A.), the Clinic has organized carefully structured programs aimed at the alienated people using drugs on the streets of the city. These programs recruit workers, often recovered addicts, from the community and focus on the commercial sex industry (prostitutes and pimps); street IV drug dealers and users; staff, residents, and out-patients in drug treatment programs; jail and prison inmates; the homeless; and runaways. The success of such efforts has been reported in other parts of the country, where intravenous drug addicts, notoriously impervious to health messages, have adopted the ritual of rinsing contaminated equipment with bleach--indeed, there are shooting galleries where the use of bleach is enforced. ------------------------------ SEXUAL PRACTICES In double jeopardy for contracting and transmitting AIDS, the IV drug user must modify both drug-taking behavior by learning to clean "works" before sharing a needle, and alter sexual practices by disciplined use of condoms. In the decades since the advent of the "pill," contraceptive use has been considered the responsibility of women, and only relatively recently have men begun to share in this obligation. Furthermore, many people continue to believe that AIDS affects only gay, white, middle-class men, not Black or Hispanic men who consider themselves heterosexual. Many men do not think having sex with another man is a homosexual act,[2] especially in sexually segregated environments like jails and prisons. Compounding the problem of sexual transmission is the reluctance of many men to use condoms with their wives or lovers, placing their partners at particular risk for HIV infection, especially if their partner is an infected IV drug abuser. Furthermore, women who become infected by their sexual partners can then transmit the disease to their babies. An increasing number of infected babies are now being born in our hospitals. Prostitutes, similarly infected, are considered to be crucial links in the chain for heterosexual transmission of the virus, particularly if they abuse intravenous drugs. They can transmit the virus to their clients who then return to their homes and families, where the infection can again proliferate. ------------------------------ SOLVING THE PROBLEM Attempts to reach the IV drug-using segment of the population with AIDS education and prevention messages are fraught with difficulty. Many drug abusers, already threatened by law enforcement authorities because of their use of illegal substances, living in urban ghettos, jobless, often poorly nourished and housed, are suspicious and unwilling to trust outreach workers trying to persuade them to enter drug treatment facilities, or at least to change their needle sharing and sexual behaviors. Although IV drug users have no well-developed network of social support systems like those that have contributed so much to the successful reduction of high risk behavior in the gay community, a study in Chicago has found that as addicts learn more about the causes of AIDS, a strong sense of social responsibility does develop which can lead to successful prevention advocacy.[4] Drug abuse treatment remains one of the most viable alternatives to continued proliferation of the AIDS virus, but current drug abuse treatment facilities and qualified personnel to staff them are woefully inadequate. Long waiting lists exist for admission to those programs that are available, especially in large urban areas. Nevertheless, treatment has been shown to reduce drug use dramatically, and recent studies of large numbers of opiate addicts in methadone treatment programs throughout the country indicate that as many as 75 percent of addicts who stay in treatment for more than one year have substantially reduced their opiate use, or are drug free.[5] However, an additional problem has appeared among IV drug abusers who shoot cocaine, sometimes with heroin, since methadone is powerless to control the effects of cocaine. The drug abuse prevention legislation passed at the end of 1988 contains funding for establishment of more treatment centers where addicts may also receive HIV testing and counseling in AIDS prevention. Surprisingly, a study of addicts entering drug abuse treatment in Baltimore showed that they responded positively when asked if they wished to be tested for HIV antibodies, and they were subsequently counseled about prevention techniques and strategies for informing their sexual partners. They also expressed the need for testing and counseling programs in other drug treatment facilities.[6] Clearly, no drug user is going to wait drug-free for his or her turn to come up for treatment, so drug use and needle sharing continue, as does the dangerous spread of the virus by these people to their sexual partners and the larger population. Social scientists in the poorly understood field of human behavior seem to agree that change occurs when community standards change so that it becomes "socially unacceptable for an addict to pass a colleague a dirty needle, or for two strangers to have sex without a condom."[2] As more people contract AIDS, fewer in high risk groups like drug abusers will be insulated from the realities of the devastation caused by the epidemic, and although it will be too late for many, behavior will change. ------------------------------ References 1. AIDS Weekly Surveillance Report, US AIDS Program, Centers for Disease Control, February 6, 1989, and June, 1989 2. Science, 242:2 Dec, 1988, 1237-38. Booth, William "Social Engineers Confront AIDS" 3. National Institute on Drug Abuse Research Monograph Series 1988:80, 119-36. Pascal, C.B. "Intravenous Drug Abuse and AIDS Transmission: Federal and State Laws Regulating Needle Availability" 4. National Institute on Drug Abuse Research Monograph Series 1988:80, 137-150. Wiebel, W.W. "Combining Ethnographic and Epidemiologic Methods in Targeting AIDS Interventions: The Chicago Model" 5. University of Maryland, Ball, J.C. "Report from Methadone Maintenance Programs in Three Cities, 1985 and 1986" 6. Journal of Substance Abuse Treatment, 1988:5:145-49. Weddington, W.W.Jr. and Brown, B.S. "Acceptance of HIV-Antibody Testing by Persons Seeking Outpatient Treatment for Cocaine Abuse" ------------------------------ Sally Bruel is a retired pharmacologist who is a consultant with the National Institute on Drug Abuse. ============================================================================ Cases Per Year 1983 1984 1985 1986 1987 1988 ------ ------ ------ ------ ------- ------- Gay 2187 3354 5972 7297 13328 18187 IV 528 789 1367 2219 3608 7640 Gay/IV 0* 0* 0* 2238 1488 2148 Other 349 402 771 1254 2364 3928 Percentages: 1983 1984 1985 1986 1987 1988 ------ ------ ------ ------ ------- ------- Gay 71.4 73.8 73.6 56.1 64.1 57.0 IV 17.2 17.4 16.9 17.1 17.4 23.9 Gay/IV 0* 0* 0* 17.2 7.2 6.7 Other 11.4 8.8 9.5 9.6 11.4 12.3 * NOTE: PEOPLE WHO WERE BOTH GAY AND IV DRUG ABUSERS WERE INCLUDED IN THE "GAY" CATEGORY UNTIL 1986, WHEN THEY WERE BROKEN OUT SEPARATELY. By Race 1983 1984 1985 1986 1987 1988 ------ ------ ------ ------ ------- ------- White 1270 2710 4987 7905 12861 17389 Black 611 1161 2056 3268 5374 9283 Hispanic 327 694 1142 1920 2720 5530 Other 13 70 64 96 173 108 Percentages: 1983 1984 1985 1986 1987 1988 ------ ------ ------ ------ ------- ------- White 57.2 58.5 60.5 59.9 60.9 53.8 Black 27.5 25.0 24.9 24.8 25.4 28.7 Hispanic 14.7 15.0 13.8 14.6 12.9 17.1 Other 0.6 1.5 0.8 0.7 0.8 0.3 Graphics by Bryan Harrison; Source: Centers for Disease Control AIDS Quarterly Reports 1982-1989 *************************************************************************** THE SPECKLED BAND The following article is an account of one person's encounters with the uncertainties still present in the arenas of HIV testing, diagnosis, and treatment. The individual involved wishes to remain anonymous. "...As I bent over her she suddenly shrieked out in a voice which I shall never forget, `Oh, my God! Helen! It was the band! The speckled band!' " from "The Adventure of the Speckled Band" in The Adventures of Sherlock Holmes, by Sir Arthur Conan Doyle I was young and idealistic. I had seen close-up the devastation caused by HIV. I wanted to help save the world before more people died. I had a true belief in the scientific method, and was willing to use my own body as a "test tube with skin" to help increase mankind's knowledge in the fight against HIV. And, most important of all, I seemed to be the kind of person they were looking for. So, in June of 1988 I applied for a protocol at NIH testing an experimental vaccine against HIV called gp-160. The vaccine protocol required that participants be male and HIV-negative. The protocol was to certify that the participants were not HIV-infected at the start of the study using the ELISA, the Western Blot, and other blood tests. The volunteers would then be inoculated with gp-160, which is a precursor to two proteins, gp-120 and gp-41, which are proteins on the envelope (exterior) of HIV. The hope was that the body would react to the gp-160, and produce antibodies to it in the blood. The theory was that if the volunteer was later exposed to real HIV, complete with gp-120 on its surface, the vaccinated volunteer's body would already have antibodies on the lookout for the HIV, and would detect it and destroy it before it had a chance to take hold. One of the projected side-effects of all this is that the volunteers, because their blood would have antibodies to HIV, might "seroconvert" (have their blood change) to show positive on an ELISA test. The Western Blot, however, would show that they were not actually infected with HIV, just with gp-160. Note that the vaccine was (and still is) made from genetically- copied gp-160 (spliced into moth cells, of all things), NOT from HIV, so there was ZERO chance of contracting HIV or AIDS from the vaccine. There were other possible side effects (some mild, some horrific--like triggering an auto-immune reaction, where your body attacks itself), but HIV infection was definitely not one of them. The effectiveness of the vaccine would be judged by drawing blood from the protocol participants, and seeing how it reacted to HIV and some other substances in the test tube. (By the way, NIH is still recruiting volunteers for the protocol. See the description in the Treatment section of this issue, or call Margaret Easter at (301) 496-7196.) Well, I went for the initial screening, at which time a lot of blood was drawn, and I was told that I would be called back to the Clinical Center in a month if my tests were satisfactory. My blood tests were basically fine, my ELISA was negative, and my Western Blot was clear (negative). I went back a month later for the final screening, which included more blood work, an EKG, a chest x-ray, and a physical. I was told to come back the next morning to actually get inoculated. Later that day, however, I got a phone call that my Western Blot was slightly abnormal. It was nothing to worry about, I was told, and they suspected that it could have been due to problems in the lab. They were going to re-run the test, and they would call me the next day. The next day, the results were still strange. The researchers were going to try a Western Blot test from a different manufacturer. They would call me the next day. They did. The results were still strange. They tried one last time, and my Western Blot still came out as "High Background." At this point, I was told, "You'd better come in so we can discuss your test results." Thus started my "Adventure of the Speckled Band." * * * To make a Western Blot test, ground-up pieces of HIV are placed in a gel- like material, and then forced to distribute themselves through the gel in different groups according to their charge, which is related to the weight of the molecules involved, using a process called electrophoresis (figure 1). The lighter proteins like p17 go towards one end of the polyacrylamide gel slab, and the heavier ones like gp-160 stay at the other. (The numbers, like 17 in p17 and 160 in gp-160 are the molecular weight of the protein in kilodaltons.) The different bands of fragments of HIV then get transferred from the gel slab to a thin strip of cellulose that forms the actual Western Blot (figure 2). The cellulose strip is then incubated with your blood serum. This provides an opportunity for the different antibodies in your blood serum that respond to different pieces of HIV to find their corresponding piece of HIV on the strip, and bind to it (figure 3). Another chemical is then added that binds to the antibodies, and yet another chemical is added that reacts with the first chemical and makes it turn the strip dark (figure 4). The result is that you have a cellulose strip which is dark in regions corresponding to HIV proteins to which antibodies are present in the serum, and light elsewhere. Each of the proteins in HIV has a specific function: gp160 is part of the outer envelope of HIV, and it breaks down into gp120 and gp41. p55 is the precursor of the two core proteins p24 and p17. Some of the proteins involved in HIV reproduction (including the infamous "Reverse Transcriptase") are p66, p51, and p31. In order to be classed as "positive" (according to criteria given with the FDA-licensed Immunoblot Test Kit made by Biotech/Du Pont), a Western Blot needs to have a band at p24, p31, AND either gp41 or gp160 (figure 5). In other words, you have to have a core protein, a reproduction protein, and one of the envelope proteins in order to be considered positive. If the blot does not show any bands, it is considered "negative." All the rest are considered "indeterminate." * * * My first Western Blot (figure 6) was completely clear. This is normal for someone who is HIV-negative. It means that the strip did not react to the presence of any HIV-related proteins in my blood. My next Western Blots were "high background" (figure 7). I was somehow staining the strip dark even in places where that shouldn't have been possible. None of the researchers at the National Institutes of Health could even hazard a guess at what it meant. (I discounted a friend's semi-facetious suggestion that it was because of my junk-food diet. Besides, pizza IS good for you.) How my blood was able to do this is somewhat of a mystery, although some of the scientific literature about Western Blots says that "because the viral antigen preparation used for immunoblots contain nonviral cellular proteins, not all bands appearing on an immunoblot are necessarily HIV specific." In other words, something else in my blood besides HIV could somehow be triggering the Western Blot. Because I was applying for health insurance, I had occasion to get a complete physical, including blood drawn, just before Thanksgiving. I had remained in contact with the research staff at NIH, and they suggested I bring them some more blood to test. So I had my doctor draw more blood, and dropped it off at NIH. Three days before Christmas, I got the results. My Western Blots were now showing some of the bands for HIV (similar to figure 8), specifically p17 and a possible p66 band, so I was now officially classed as "indeterminate." So what does being "indeterminate" mean? Well, initially no one was exactly sure. The literature on the subject said "...because of the many uncertainties in resolving indeterminate immunoblot test results, it is prudent to assume that all indeterminate immunoblot test results are potentially indicative of early seroconversion." It is also worth noting, however, that the Western Blot is normally used only to CONFIRM blood serum that has tested positive TWICE on the ELISA. All tests have two measurements of effectiveness: SENSITIVITY and SPECIFICITY. Sensitivity is the probability that the test will correctly read positive blood serum as positive. Specificity is the probability that a positive test result is actually positive. While these may seem to be the same, they aren't. If a test has a sensitivity of 99.9%, it means that only one sample out of a thousand that is actually positive will read incorrectly as negative. If a test has a specificity of 99.7%, it means that of 1,000 samples that test positive, 997 of them will actually be positive, and that 3 will have falsely read as positive. The ELISA test has a very high sensitivity (close to 100%), so that almost all the samples infected with HIV will read positive. However, it has a relatively low specificity, meaning that many of the positive results will be false positives. (This is the trade-off you want for a test that is protecting the nation's blood supply. You want very few units of infected blood to get through the screening, and if you throw out some blood that isn't infected along with the blood that is, that's an acceptable price to pay.) The Western Blot test, on the other hand, has a lower sensitivity (so it might miss some HIV-infected samples), but it has a higher specificity. This is why blood serum samples that test positive on the ELISA get confirmed by the Western Blot. The combination of the sensitivity of the ELISA and the specificity of the Western Blot mean that the false-positive rate of the two combined will be less than one person per 100,000 tested. This method of combined testing is also why, because my blood is negative on the ELISA and indeterminate on the Western Blot, the researchers had even less idea of what the implications were, since normally a negative ELISA would prevent my blood from ever getting a Western Blot test. In posters at the Fifth International Conference on AIDS in Montreal, data was presented which seems to indicate that the Western Blot is capable of generating bands even for people who do not appear, based on our current knowledge, to be HIV-infected. A poster (Th.B.P.179) from NIH and Georgetown University reported on "high risk HIV/ELISA negative individuals" who were part of a AIDS vaccine study, and who showed various indeterminant patterns on Western Blots. Seventy-eight out of 214 individuals (36%) had a variety of band patterns, with bands at p55 and p24 being the most common. The scientists followed 20 of the 78 for a one-year follow-up, and none of the twenty went from an indeterminant to a positive Western blot. There was, however, evidence that seven of the 20 individuals showed some reaction on the more sensitive polymerase chain reaction (PCR) test. Another report (T.B.P.123) from NIAID, Johns Hopkins, and Georgetown found similar results from volunteers for another vaccine study, with 32% of 158 individuals showing an indeterminant Western blot. * * * With the recent evidence of people who are negative on the ELISA and Western Blot but who still appear to be HIV-infected, and with the uncertainties I encountered with testing, we get yet another reminder that we still have much to learn about HIV, both stopping it and testing for it. For myself, I will continue doing what I should do anyway, namely monitoring my health, and hope that--for everyone--either time or research will provide a clearer answer to the mysteries encountered in the Adventure of the Speckled Band. ------------------------------ References AIDS: Etiology, Diagnosis, Treatment, and Prevention (Second Edition). Vincent T. DeVita, Jr., Samuel Hellman, and Steven A Rosenberg, Editors. J.B. Lippincott Company, Philadelphia, Pennsylvania. 1988. Pages 127-131, 423-425, 457-458. +--------+ kD |xxxxxxxx| |xxxxxxxx| 160 | | |xxxxxxxx| |xxxxxxxx| 120 | | |xxxxxxxx| 66 Figure 1. HIV is divided up | | into its component parts, |xxxxxxxx| 55 which are then spread | | throughout a polyacrylamide |xxxxxxxx| 51 gel, and get positioned into | | bands of differing molecular |xxxxxxxx| weight by a process called |xxxxxxxx| 41 electrophoresis. | | |xxxxxxxx| 31 | | |xxxxxxxx| 24 | | |xxxxxxxx| 17 +--------+ || gp160 ||> || gp120 ||> || p66 ||> Figure 2. The bands of p55 ||> components of HIV then get p51 ||> transferred to a thin || cellulose strip by gp41 ||> electroblotting. || p31 ||> || p24 ||> || p17 ||> || || gp160 ||> || gp120 ||> || p66 ||> Figure 3. When exposed to p55 ||> blood, antibodies in the blood p51 ||> attach themselves to their || corresponding pieces of HIV on gp41 ||> >>-- ANTI-gp41 the Western Blot test strip. || p31 ||> >>-- ANTI-p31 || p24 ||> >>-- ANTI-p24 || p17 ||> || +-----+ || | | gp160 ||> | | || | | gp120 ||> | | Figure 4. Another chemical is || | | added which binds to the HIV p66 ||> | | antibodies and stains the p55 ||> | | strip dark, thus giving the p51 ||> | | characteristic dark bands || | | where you have corresponding gp41 ||> >>-- ]-O )] |XXXXX| antibodies, and light || | | elsewhere. p31 ||> >>-- ]-O )] |XXXXX| || | | p24 ||> >>-- ]-O )] |XXXXX| || | | p17 ||> | | || | | +-----+ p17 p24 p31 gp41 p55 p66 gp120 gp160 | | | | | | | | | | | | | | | | Figure 5. +-----------------------------------------------------------+ A typical | I II I II I I II II XXXXXXXX| positive | I II I II I I II II XXXXXXXX| Western +-----------------------------------------------------------+ Blot. | | | | | | | | | | | | | | | | | | | | | | | | Figure 6. +-----------------------------------------------------------+ A typical | XXXXXXXX| negative | XXXXXXXX| Western +-----------------------------------------------------------+ Blot. | | | | | | | | | | | | | | | | | | | | | | | | Figure 7. +-----------------------------------------------------------+ A Western |I|.:.|I|..:|.!.III|:..!|II.:.||...!II||II!:...||::!XXXXXXXX| Blot with |:.||...!II||II!:...||::!I|.:.|I|..:|.!.III!!:..I.::XXXXXXXX| high +-----------------------------------------------------------+ background. | | | | | | | | | | | | | | | | | | | | | | | | Figure 8. +-----------------------------------------------------------+ An indeter- | II I XXXXXXXX| minate | II I XXXXXXXX| Western +-----------------------------------------------------------+ Blot. *************************************************************************** UPDATES FROM THE MONTREAL FIFTH INTERNATIONAL CONFERENCE ON AIDS, JUNE 1989 by Basil Vareldzis The Fifth International Conference on AIDS was a very optimistic meeting with very encouraging results. Several papers were presented dealing with the natural history of this disease. We have learned that HIV causes a chronic progressive illness that lasts over ten years if untreated and longer with treatment. We also learned that several surrogate markers can be used to differentiate those who are more likely to progress in disease from those who will remain asymptomatic. These markers include elevated beta-2 microglobulin, decreased CD4 count and presence of p24 antigen. These have significant implications for patient management in that patients who are more likely to progress in disease should receive more aggressive anti-retroviral therapy (AZT or ddC or ddI or AZDU or D4T or CD4 etc.). In terms of treatment of the primary viral infection with HIV, significant advances in our treatment armamentarium have occurred. We now know that Zidovudine (AZT) prolongs life and has a transient effect on CD4 cells. This effect is most dramatic in the first year, but continues on to the second and third years of treatment. Survival of AIDS (CDC Class IV) patients receiving AZT was over 85% for one year and 58% at 21 months. ARC (CDC Class IV.A and IV.C.2) patients receiving AZT did even better with 94% surviving one year, and 81% 21 months. This compares to survival of only 39% at 9 months for AIDS patients initially treated with placebo. We also learned that the combination of AZT with Granulocyte Macrophage- Colony Stimulating Factor (GM-CSF) enhances the antiviral efficacy of AZT while at the same time decreasing the neutropenic side-effects of therapy. A worrisome trend was noted by several researchers who reported that HIV is becoming resistant to AZT after six to 18 months of therapy. The clinical implications are not yet clear, since patients who have resistant viral isolates continue to respond to therapy. All is not lost however, as several researchers demonstrated that this viral resistance to AZT does not cross over to the other anti-retrovirals such as ddC and ddI since they have a slightly different mechanism of action using different nucleoside analogues such as cytosine and inosine. These different mechanisms of actions also yield the advantage of different side effect profiles for these agents so that patients who cannot tolerate AZT because of its toxicity can tolerate ddI or ddC. More progress was made in the treatment of opportunistic infections. We now have a better understanding of managing patients with Toxoplasmosis, CMV Retinitis, pneumocystis pneumonia, tuberculosis and others. Major papers were presented dealing with prophylaxis against pneumocystis pneumonia. There was a clear consensus that prophylaxis should be used by all persons following a diagnosis of PCP as well as for those with CD4 counts below 200 or percent CD4 below 20. Three agents were shown to be effective in preventing PCP: they are Aerosolized Pentamidine, Trimethoprim-Sulfamethoxazole (Septra or Bactrim), and Dapsone. Aerosol Pentamidine offers the advantages of convenient once-a-month dosing, few side effects, and good efficacy. The disadvantage is the high cost ($120 to $350 per month), and the lack of systemic efficacy (extrapulmonary pneumocystis is not prevented). This agent is now FDA approved as of June 14, 1989, so insurance companies should be reimbursing for it. Trimethoprim-Sulfamethoxazole is given in pill form once or twice a day. It is equally effective to Aerosol Pentamidine in preventing PCP, and has the added advantages of low cost (about $30 per month) and systemic efficacy. The major disadvantage is the high rate of side effects including fever and rash that require stopping this medication in up to 50% of patients. This is a very good therapy for those patients that can tolerate it. Leucovorin 5 mg per day is recommended to reduce the side effects. This is very expensive, however, costing over $200 per month for 30 tablets. The third agent that is effective is Dapsone. This drug has been used for years in the treatment of leprosy. It is very inexpensive ($2-3 per month) and usually well tolerated at the dose of 50-100 mg per day. It has systemic efficacy, better tolerance than trimethoprim-sulfamethoxazole, and has the added advantage of being effective against Toxoplasmosis as well as PCP. The major toxicity is a severe anemia that can occur in persons who are G-6-PD deficient (predominantly those of African ancestry). All persons planning to start on this medication should first be screened for G-6-PD deficiency. This is but a brief overview of the clinical advances presented in Montreal this past June. Further updates will be presented in the next issue. ---------------------------- Basil Vareldzis, M.D., is the Clinical Director of the Whitman-Walker Clinic. *************************************************************************** Copyright (C) 1988,1989 by Washington HIV News, all rights reserved. Permission is granted for non-commercial use only. -- J. Philip Miller, Professor, Division of Biostatistics, Box 8067 Washington University Medical School, St. Louis MO 63110 phil@wubios.WUstl.edu - Internet (314) 362-3617 phil@wubios.wustl - bitnet uunet!wucs1!wubios!phil - UUCP C90562JM@WUVMD - alternate bitnet