HIV HERALD
Publication from the National Treatments Project --
Australian Federation of AIDS Organisations
PO Box H274, Australia Square, 
Sydney NSW,  2000 
Australia

Tel : (+612) 231 2111
Fax : (+612) 231 2092


October 1994
Volume 4 No 9


Contents
Bits and Pieces
>Possible Floconazole/Atovaquone Drug Interaction
>Fluconazole for Candidiasis
>L735,524/Merke Protease
>GEM 91
>Cimetidine (Tagamet) - New Study Results
>Oral Ganciclovir Beneficial for Primary 
     Prohylaxis of CMV Disease
>Oral Valciclovir Passes Phase I Trials
>Changing Antibodies to Enter Cells
>Immuno-C, a New Treatment for Cryptosporidiosis
Antiviral News
>Individualised therapy
>Combination Treatments
Womens Issues
>Maternal Transmission of HIV
News
>Management of HIV in Children
>Questions Raised about Nitrite Inhalants 
     "Amyl/Poppers" and Kaposi's Sarcoma
Opportunistic Illnesses
>Liposomal Doxorubicin Submitted to American
     Authorities for Approval --- Trials in
     Australia set to Start
Clincal Trial News
>935U83 - A New Antiviral Drug Trial Now Recruiting
     in Sydney



BITS AND PIECES

By Ian McKnight - Smith

Possible Fluconazole/Atovaquone 
drug interaction
There has been some confusion regarding drug interactions between
atovaquone and fluconazole. After discussions with Burroughs
Wellcome, what they have found is that people who take both
fluconazole and atovaquone seem to have higher levels of
atovaquone in the blood compared to those who take atovaquone
alone.
     Atovaquone  or Mepron is used in the treatment of PCP and
is also entering studies to determine its effectiveness in
preventing the illness in people who are intolerant to sulphur
based drugs like co-trimoxazole.
[Project Inform Sept 12 1994]

Fluconazole for Candidiasis
Preliminary analysis of a Community Research Initiative trial
studying the effect of fluconazole for the prevention of
candidial infections showed that fluconazole was effective in
preventing candidiasis, however there were several people that
developed resistance to fluconazole. Resistance to fluconazole
seemed to develop when the CD4+ count dropped below 50.
[Project Inform September 12 1994]

L 735,524 / Merck Protease:
A meeting with Merck Sharpe and Dohme recently took place to
discuss their protease inhibitor L-735,524. No new data were
presented and the majority of the meeting was spent discussing
how difficult this drug is to manufacture. Merck is planning on
conducting two Phase III (wider access) trials at the beginning
of next year. (It is noted that as far as we can ascertain  MSD
does not appear to have any intentions for trial work in
Australia.... maybe we are considered to be too small a market?) 

One of the US trials will be for people who are antiretroviral
therapy naive (i.e. that is they have not taken antiretrovirals
before.) and the other will be for people who have taken
antiretrovirals. Both studies are expected to enrol 900 people.
A follow up meeting is scheduled for this month when concept
sheets will be presented to Project Inform for further comment.
     Project inform (San Francisco) has been working with Hoffman
La Roche (makers of the protease inhibitor saquinavir) and Merck
in starting an expanded access program for their protease
inhibitors. While both companies are interested in establishing
an expanded access program, drug supply and the difficulty in
manufacturing these compounds will limit the size of such a
program as well as when they might be available in the US. (Of
course this will have an even greater negative impact on the
availability in Australia)
     Hoffman La Roche ran into manufacturing problems with
saquinavir and as a result, the compassionate access program will
now be delayed until 1995 at the earliest. Merck claims to have
difficulty in manufacturing their protease as mentioned
previously, and now is looking to get its drug approval in the
traditional system (i.e. a full approval rather than an
accelerated approval and that way they do not have to instigate
an expanded access program).
     Merck currently manufactures about 30,000 kilos a year of
Vasotec, their billion dollar a year drug for treating high blood
pressure, but they think that they will need to manufacture as
much as a million kilos a year of the L-735,524. In addition they
claim that this is the most complex compound that they have ever
discovered and the manufacturing is more difficult than that for
imipenam which is widely considered to be the most complex
commercial drug to synthesis.
     In a related development, Dr. Kessler, the FDA Commissioner,
is committed to enter into dialogue with Merck and Roche and to
pressure them to develop an expanded access program for their
protease inhibitors. In fact, Dr. Kessler has already spoken to
a representative from Roche. In effect, this will push/encourage
the companies into increasing the production of the drugs in
question (not withstanding their professed inability to do so
without a great deal of trouble.)
[Project Inform Sept 12 and Oct 3rd 1994]

GEM 91
Hybridon the makers of Gem 91, have released plans for an
upcoming Phase II study in the United States. Gem 91 is an
antisense drug. Viruses insert their genetic material into
cellular DNA, once infected, the DNA programs the cell to
manufacture the component proteins of the virus (HIV for
example). To produce proteins, the DNA transmits it s information
to a messenger RNA (mRNA) molecule. This m-RNA is known as the
sense strand. Antisense drugs are the opposite or a mirror image
of the sense strand. These drugs attach to m-RNA and block
production of the particular proteins necessary for viral
activity. This is a simplistic description of the antisense
process.
     The new GEM 91 study is designed to detemine the safety and
antiviral activity of the drug. The principal sites for the
research will be in New York and in Alabama. At the same time the
company will be doing another study in France using a 2 hour
infusion formulation of  3 different doses of GEM 91 every other
day in 30 people. Plans are that all of these studies will start
in October or November of this year.
     In the US the study is also to be by infusion. However they
will be looking at people with CD4 counts between 100 and 500 and
who are  clinically stable . Previous antiretroviral use will be
O.K. However a 2 week washout period is required before starting
the active treatments. 2/3 will receive active drug (They are
looking at two groups since they are looking at two different
doses) and 1/3 will be on a placebo. The active drug will be
given by a daily continuous infusion  for the first two weeks and
then every other day infusion for the 2nd 2 weeks. People
receiving placebo for the first two weeks will receive active GEM
91 for the second part of the study. All participants will be
hospitalised for the duration of receiving study drug.
     So far no significant toxicities have been seen with GEM 91.
Antiviral activity of GEM 91 will be measured by branched DNA
(viral load) tests. 
     At this point in time no trials are planned for this drug
in Australia, however it is suggested that if these studies
provide good responses, that broader phase III type studies
should indeed be considered very quickly.
[Project Inform September 26 1994]

Cimetidine (Tagamet)-New study results
A study recently completed by the Community Research Initiative
in New England (US) comparing cimetidine (Tagamet- a commonly
used drug to treat intestinal ulcers) versus placebo showed that
there were no differences in CD4 and CD8 counts / percentages.
This study contradicts a German study which found that cimetidine
was able to stimulate T-cell counts.
[Project Informs September 26 1994]

Oral Ganciclovir beneficial for primary prophylaxis of
cytomegalovirus (CMV) disease.
An independent data safety monitoring board  (DSMB) for Syntex
ICM study 1654 in the USA, evaluating the potential benefit of
oral ganciclovir for prevention of CMV disease has recommended
ending the placebo arm due to a highly statistically significant 
difference in the incidence of and time of development to CMV
disease in the treatment arm. All patients in placebo arm have
been offered active drug. Approximately one half of the enrollers
had completed 10 months of therapy at the interim analysis. The
study was designed as a double blind placebo controlled
multicentre phase III trial that began enrolment in November
1992. Enrolment of 725 participants was completed in December
1993. The entry criteria included HIV seropositivity, CMV
serpositivity and a CD4 lymphocyte count less than 50 /mm3 or
less than 100/mm3 and history of an AIDS defining opportunistic
illness. Two thirds of enrollers were randomised to receive
active drug while the other third received placebo. The treatment
arm dosage was 1,000 mg 3 times a day of oral ganciclovir.
     Follow up has included eye examinations by an opthamologist
every 2 months along with CMV cultures and other laboratory
measurements. The primary endpoint was a diagnosis of CMV
disease, while secondary endpoints included survival and quality
of life. The study will continue with a open-label unblinded
status to monitor the patients for further efficacy and safety.
[Beta September 1994]

Oral Valciclovir passes phase I trials
Seventeen HIV infected people with a mean CD4 lymphocyte count
of 44 /mm3 completed the phase I study of oral valciclovir, 4
times a day with 1000 mg or 2000 mg for a period of one month.
Valciclovir is a "prodrug" of acyclovir, that is to say the
active ingredient is still acyclovir, but the formulation has
been created that the active ingredient is not released until it
has been absorbed into the blood stream. This in turn
significantly increases serum levels of acyclovir. There are few
side effects. With the higher dosage, the serum levels of the
active agent in the blood were five times greater than levels
achieved with the standard form of acyclovir (800 mg five times
a day). 
Such levels hold promise in the prevention and treatment of HIV-
related CMV, varicella zoster virus, herpes simplex, and possibly
herpes 6 virus.
[Jacobson SFO General Hospital 1994]


Changing Antibodies to Enter Cells.  By Alan Strum
Antibodies are proteins produced by the immune system that
recognise and help to eliminate bugs such as viruses from the
blood and surrounding tissues.  The only problem with antibodies
is that they can't enter cells to inhibit viruses that replicate
inside of the cells.
     A new technique has now been developed that changes
antibodies so they can enter into cells to stop or reduce viral
replication that may be taking place inside of the cells.  This
technique involves removing antibodies from people with HIV
(hyperimmune immunoglobulins - HIVIG) and exposing the antibodies
to a chemical called hexamethylenediame.  The result of this is
that the protein structure of the antibodies changes what is
called its iso-electric point and is then called a cationized
antibody.  This is a different balance of positive and negative
electric charges that is made up of the atoms of the antibody. 
When the antibody has a particular electric charge it is able to
attach to the surface of cells and passes through the cell wall
to enter to the inside of the cell where it can start to inhibit
the replication of HIV.  This process is a bit like magnets that
have opposite ends.  One end of a magnet will repel or reject
another end of a magnet that has the same charge, whereas the
ends of a magnet that are of opposite charges will attract and
attach to each other.
     In a test tube experiment with HIV infected immune cells the
changed antibodies (cationized HIVIG) were able to reduce the
production of p24 antigen by 90%, which indicates that HIV
replication had been substantially reduced in infected cells.
Source: AIDS Weekly, October 3, 1994


Immuno-C, a new treatment 
for cryptosporidiosis.   By Alan Strum
Cryptosporidiosis is a parasitic infection of the gut responsible
for diarrhoea, malabsorption and wasting.  To date, over 70 drugs
have been tested against this infection with only limited
success.  Biommune Systems Inc., have developed a new passive
immune (antibody based) treatment which appears to inhibit the
development of this bug between the second and fifth days of it's
developmental life cycle.  The company developed a new cell
culture (test tube) technique to test the new treatment.  This
new test will also aid in testing new drugs against
cryptosporidiosis in the future.  Immuno-C will enter phase I
trials later this year in healthy people to evaluate the safety
of the treatment.Source: AIDS Weekly, October 3, 1994



Antivirals News

INDIVIDUALISED THERAPY  By Ian McKnight-Smith

Today, just a handful of physicians are already offering to their
patients components of a treatment strategy that has been termed
 individualised therapy . Within 6-12  months it is estimated
that many more community physicians will adopt elements of this
approach to therapy for HIV. As access increases to powerful new
diagnostic technologies and to more effective treatments regimens
the picture of HIV patient management is going to change
significantly.
     By the end of 1995, the majority of people with HIV cared
for by the mainstream HIV physicians will likely have access to
the primary ingredients of this new treatments strategy.
     
There are five key components of Individualised therapy:

I. Wider access to HIV RNA testing, a new technology that
provides an accurate measure of HIV load in the blood plasma of
the person with HIV or AIDS.

II. Tailoring anti retroviral treatments to each individual
person, based primarily upon periodic measurement of viral load
and the responses seen with the introduction of a particular
treatment.

III. Accelerated approval of, and a wider access to the new
generation of treatments, including protease inhibitors, non
nucleoside reverse transcriptase inhibitors, etc that show
particular promise when used in combination with the nucleoside
analogues.

IV. More widespread use of 3 or 4 drug regimens that combine
different classes of drugs. This cocktail being specifically
designed to the responses that are observed with viral load
testing.

V. Early initiation of drug treatments, while the immune system
is relatively intact and capable of a strong response to HIV
infection.

Combination treatments  By Ian McKnight-Smith

Three drug combinations hold the most promise for effective
sustained control of viral activity. Historically, 3 or 4 drug
combinations have been necessary for the effective treatment of
certain chronic infections and other diseases. For example, state
of the art treatment of TB calls for early initial treatment with
4 or 5 different drugs. In therapy for various cancers treatment
with cocktails of 3 or more chemotherapeutic agents is commonly
the standard of care.
     In HIV disease, laboratory studies of certain 3 drug
combinations of AZT+ddI+3TC and AZT+ddC+Nevirapine produce a
synergistic effect that resources HIV activity to near zero,
according to reports from Wellcome. While in test tube data may
not translate into clinical benefit, the fact that these triple
antiretroviral combinations can completely suppress viral
activity in laboratory cultures suggests that 3 drug combinations
hold promise for providing people with a significant clinical
advantage over the monotherapy  or double drug treatment that is
currently being used. It is also important to note that the drugs
that constitute these promising combinations are already being
used clinically through trials, which should and could be
expanded into broad scale combination access evaluations. This
would quickly indicate which combinations were most effective in
which groups of people etc.
     In the near future the combinations most likely will be
comprised of the following:

Nuclesoside analogue reverse transcriptase inhibitors (NARTIs)
...... AZT, ddI , ddC, d4T, and 3TC. 
Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs):
....Nevirapine, BHAPs such as ateviridine and delaviridine, alpha
APA, 
Protease Inhibitors ... Abbott 77003/74704/80987,  Merck, 735524,
Roche 31-8959, Dupont/Merck q8045 and q8050, Nikko KNI227, KNI272
and many others in earlier stages of development.

While three drug combinations using protease inhibitors plus
reverse transcriptase inhibitors are currently the best hope for
sustained clincial benefits. Over the next 24-36 months people
with HIV may have increased access to other types of
antiretroviral treatments. These may include immunomodulating
therapies such as the therapeutic vaccines and autologous CD8+
cell infusion, passive hyperimmune therapy and interleukin 2, as
well as other novel approaches now in the research pipeline.

Conclusion
Individualised therapy is an emerging new treatment strategy for
HIV, that differs from the current cookbook approach which relies
almost entirely upon CD4 cell counts and clinical symptoms to
dictate the treatment decisions. The essential elements of
individualised therapy include the use of  powerful tests for (1)
measuring HIV viral load to determine disease stage as well as
treatment efficacy, (2) evaluating treatment regimens and (3)
guiding the timing and choice of changing antiviral treatments.

The concept of early antiretroviral treatment in HIV disease,
also a component of individualised therapy, is supported by the
finding that, after the initial immune response to acute
infection, 25% of CD4 T lymphocytes in the lymph node are
infected with HIV. Furthermore, it is now well established that
HIV is actively replicating in the lymph nodes and other lymphoid
tissue throughout the asymptomatic period of the illness. Since
monotherapy with AZT in early disease appears to have only
limited effect on HIV load in the lymph nodes, earlier treatment
with double and triple combination regimens using nucleoside
analogue reverse transcriptase inhibitors plus a protease
inhibitor potentially offer  the possibility of producing
prolonged suppression of the viral replication and therefore
improved clinical benefits.
     Before individualised therapy can be put into widespread
practice, the following ongoing developments need to be
completed:

1) Clinical trials now in progress must be completed and new ones
must be designed and implemented to show conclusively that  viral
load measurement using quantitative PCR and/or branched chain DNA
assays (The two systems being developed to measure viral load)
correlates with clinical outcomes.

2) Standardised kits of these two assays must be developed and
approved by the regulatory authorities to ensure consistent
results when the tests are run in different laboratories.

3) New drugs currently in the research pipeline most notably the
protease inhibitors, and the NNRTIs  must become available as
soon as possible for use in widespread 3 and 4 drug combination
access studies.

4)ADEC (The Australian Drug Evaluation Committee) must maintain
the current standards for rapid evaluation and approval of
promising new AIDS drugs namely that these drugs demonstrate
 reasonable  safety and efficacy.

     
Women's Issues

Maternal Transmission of HIV.  By Alan Strum

Caesarean sections may reduce maternal HIV transmission by 4.6%
NB : This study may not be applicable to Australian conditions.

A study published in the American Journal of Public Health has
indicated that there is enough statistically significant evidence
to suggest that children can catch HIV during the birthing
process and that reducing the risks of exposure to HIV at birth
can reduce the numbers of paediatric HIV/AIDS in the United
States.  Generally approximately 25 - 30% of children born to
mothers with HIV will eventually show signs of HIV infection, but
these statistics vary between different countries.
     The study suggests we know that some children are born
without HIV being detectable in their blood at birth, by testing
directly for HIV genetic material (PCR).  Approximately half of
the infants with HIV can be detected at this early stage, but
half go on to develop detectable levels of HIV over a period of
time.  This suggests that these children may be exposed to HIV
at birth.  A further reason to believe that children are exposed
to HIV at birth is that the first born of twins often develops
HIV infection while the second born twin does not.  This suggests
that the first born is exposed to higher levels of HIV during the
initial birthing process, whereas the second birth is usually a
faster birthing process not exposing the child to as much HIV in
the birth canal.
     This particular study looks at the events that took place
during the birth of 632 children with HIV/AIDS and compares the
events that took place at birth to that of births in children
without HIV.  The results of this study suggest that there is a
less chance of mother to child transmission of HIV if the child
is born by caesarean section, followed by natural birth without
complications, caesarean section with complications and natural
birth with complications respectively.  The statistics indicate
that a problem free caesarean birth could reduce the rate of HIV
births by 4.6%.
     The down side of this study is that it makes many
assumptions based on the lifestyles and health of the mothers of
which many may not be applicable to situations in Australia. 
Firstly, it was noted that there was a high percentage of mothers
in this study who were from low socio-economic groups, had
limited health care available to them in the USA, a high
proportion of mothers were using drugs and there was a much
higher incidence of sexually transmitted diseases.  All or any
of these parameters could effect the results and make it
difficult to say that the same statistics would apply to
Australian conditions.  Not to mention that these statistics do
not account for the most recent information about the use of AZT
reducing the rates of HIV births by about 70%.  However, this
information could help to indicate when the most appropriate time
might be to use antivirals like AZT to prevent transmission at
birth.  Source : American Journal of Public Health, July 1994,
Vol. 84. No.7


News

Management of HIV in Children  By Alan Strum

The U.S. Department of Health and Human Services has released a
clinical guide for evaluating and managing HIV in children in the
Unites States.  The guide stresses the importance of early
detection of HIV in children as they can tend to progress to AIDS
quickly.
     In adults, generally, antibody tests will detect the
presence of HIV within 3 months of exposure to the virus.  In new
born babies of HIV positive mothers, the antibody test is
inappropriate as the baby initially carries the mothers
antibodies to HIV up until 18 months of age.  Thus it is
necessary to carry out viral culture tests or tests to detect HIV
genetic material (PCR tests) one month after the baby is born. 
If these tests are not available, p24 antigen tests can be used
to determine whether HIV is present.  If the tests are negative,
they should then be repeated between 3 - 6 months of age.  If at
6 months of age the tests are still negative, then they should
have antibody tests at 15 and 18 months to further try to
determine the HIV status of the child.
     During this time, CD4 cell counts should be obtained at 1,
3 and 6 months followed by every 3 months until the HIV status
of the child is known.  If the child does have HIV then a CD4
count should be done every 3 - 6 months.
     Monitoring the CD4 cell count can bring to the attention of
the doctor any problems that might occur due to immune
suppression and will also indicate when to consider prophylaxis
against PCP (pneumocystis carinii pneumonia) or if antiviral
therapy should be considered as shown by the CD4 cell counts for
children in table 1.  It is a bit confusing to look at this table
if comparing CD4 counts of children to those of adults.  In
general, very young children have a much higher CD4 count than
adults.  However, opportunistic illnesses occur in children at
much higher counts than they do in adults.  Table 2 shows
conditions that children may develop as a result of HIV disease.

<Table 1 ----- not available on bulletin board>

     A particular issue is a range of neurological disorders that
occurs in up to 19% of infants and young children.  This figure
may be as high as 90% in older children showing
neurodevelopmental (eg co-ordination) delays or regression and
neuropsycological (eg. intelligence, personality, and brain
function) deficits.  To monitor for these effects it is necessary
to perform age related development assessments every 3 months up
until 24 months, and then every 6 months.  If HIV is affecting
the nervous system/development, measures can be taken to lessen
the impact of the virus' effects on the child's development. 
These measures could include nutritional supplementation,
physical therapy, speech therapy, and early intervention
programs.  A baseline CT scan or MRI scan of the brain may be
considered at the time of diagnosis so that a comparison can be
made if neurological problems develop later in life.
Source: The AIDS Reader, July/August 1994, Vol.4 No.4.

Table 2: HIV-Associated Conditions in Children with HIV.

*    Failure to thrive
*    Generalised lymphadenopathy - swollen glands
*    Hepatomegaly - large liver
*    Spleenomegaly - large spleen
*    Persistant oral candidiasis - thrush
*    Parotitis - inflammation around the bones
*    Recurrent or chronich diarrhoea
*    Encephalopathy - any disease of the brain
*    Lymphoid interstitial pneumonitis - inflammation 
     of the lungs
*    Hepatitis - inflammation of the liver
*    Cardiomyopathy - disease of the heart
*    Nephropathy - disease of the kidneys
*    Recurrent bacterial infections
*    Opportunistic infections
*    Malignancies (lymphoma) - cancer of the lymph tissue


Questions raised about Nitrite Inhalants 
"Amyl/Poppers" and KS  By Ian McKnight-Smith

Over the last twelve to fifteen years that we have been
diagnosing people with HIV and AIDS, one of the lingering
controversies is the possible effect that using nitrite inhalants
(poppers) has on the progress of the disease. In particular many
have suggested that there is a direct association between using
nitrite inhalants and the development of Kaposi's Sarcoma (KS).
     In the United States the sale of these substances has been
banned since 1989, and it would now appear that similar moves are
being considered in the United Kingdom. 
     In May of this year the US National Institute of Drug Abuse
convened a meeting to discuss the evidence surrounding the impact
of poppers on KS and HIV progression. The result of this
conference was that there was no clear result. However, the
Scientists all agreed that this is still a very important
question and that  there should be active research to provide
answers once and for all about the product.

SOME OF THE ARGUMENTS IN THE DEBATE

At the extreme of course is Peter Duesberg who claims that the
nitrites are one of the principal causes of AIDS. His suggestions
are that HIV is not the principal component in the epidemic and
only acts as a co-factor. Many disagree with him, and now he
plans to put his theories to the test with animal experiments.
He plans to follow groups of mice who have been exposed to
nitrites alone, nitrites plus HIV and HIV alone. However the
problem with this approach is the inability of HIV to impact on
mice in the same way that it does in humans.
     Some of the studies that have tried to look at the effects
of poppers on groups of people with KS, in terms of their sexual
and drug use history, have come up with very mixed and
inconclusive results. In some cases the only factor which was
shared by the people with KS was the use of poppers. Other
studies have shown that only rimming (oral-anal contact) or a
history of parasitic gut infections have been the only common
factor.
     Research in animals have shown that nitrites can cause
mutations, cancer development and deformities in the foetus.
However there has been no research to indicate if this is also
true in humans. However, there is some evidence to suggest that
the use of poppers does have a suppressive effect on both animal
and human immune system functions. Further it has been
established that poppers can cause the depletion (even though in
most cases temporarily) of chemicals that are of key importance
to the functioning of the immune system. One such chemical is
glutathione.
     Some researchers have suggested that the effects are
directly linked to the frequency of use. This is very much in
line with effects seen with cigarette use. So the person who is
using poppers heavily and over a long period of time will be at
far greater risk of immune damage and the development of KS than
the person who uses only occasionally.
     Many researchers are sceptical of any direct association
between poppers and KS. They argue that the evidence suggests
that the more plausible data is that KS is caused by an as yet
unknown sexually transmitted pathogen.Some of the evidence that
supports this idea has been the development of KS by women
partners of bisexual men with KS and in some cases with very
similar forms of the illness. Further there have also been a
number of cases of HIV negative gay men who have developed KS,
and only in a very small proportion of these people had they been
heavy users of poppers.
     One theory that has been proposed to support the
transmission of a pathogen, is by Prof Don Abrams of San
Francisco General Hospital. He suggests that the incidence of KS
in HIV could be linked to the epidemic of gay bowel syndrome that
was seen to peak between 1978 and 1982 in the larger US cities.
San Francisco City Clinic Cohort has shown a history of
amoebiasis as the only significant factor that can be linked to
KS in their study cohort. A British study was able to demonstrate
very similar relationships between the practices of rimming and
faecal contact to the incidence of KS in a group of AIDS patients
that they investigated.
     In addition the incidence of KS is not confined to gay men,
but is seen extensively in certain communities in Africa. In
these communities the incidence is the same in both males and
females, and occurs in the complete absence of poppers. While Dr.
Robert Gallo argues that the KS we see in people with HIV is very
different to that seen in the populations of Africa, the symptoms
are not that removed to suggest that it is being caused by a very
different causative agent. Further more there is a considerable
amount of evidence that has shown KS to occur in people who have
never or only on rare occasions used poppers.
     Arguments have also been made that the incidence of KS would
have moved outside of the gay male community into other
communities that are affected with AIDS if it is directly related
to a sexually transmitted pathogen. (e.g. the hispanic or black
populations etc.) This has not largely been the case and
therefore they suggest that this weakens the pathogenic theory.
However others suggest that the sexual practices are different
and indeed the practice of rimming etc. is more likely to be a
gay activity. Further other infectious diseases have indeed
tended to be confined to specific target populations such as
Hepatitis B in gay men.

DOES THE INHALATION OF NITRITES SUPPRESS 
THE IMMUNE SYSTEM ?
Several studies have now been conducted to look at the effects
of nitrites on the immune system of animals and humans.
     The first animal study of nitrites was reported in 1983, and
dismissed their effects as insignificant. Critics of the study
say this result was hardly surprising given the doses used, doses
which one would expect to encounter if one left an open bottle
of poppers in the room, rather than inhaling them directly from
the bottle. Even though the mice were receiving comparatively low
doses, they developed a yellowish skin tone and their white blood
cell counts (cells in the immune system) went down.
     Later studies used larger doses and found correspondingly
greater impairment of immune function. Researchers at the
University of Arkansas found that mice exposed to nitrites for
45 minutes daily for 14 days in a row suffered serious impairment
of their T-cell functions and the ability of their macrophages
to control the development of potential tumours. Critics of this
study point out that the mice were exposed to massive amounts of
the nitrites and that it may well be toxic as would be the case
with many other substances that we ingest.
     The only study to have taken place in humans gave normal
doses of nitrites to HIV negative men three times a day for one
week and then intermittently for a further one and a half weeks.
By the end of this period the main defect in the immune function
was in the levels of natural killer cells (NK), which recognise
and destroy a wide range of infected body cells or tumour
(cancer) cells. Levels of T-lymphocytes were not seriously
affected and there was no selective effect on any of the sub-
groups of T-cells. However researchers concluded that their
evidence suggested that "chronic exposure to inhaled nitrites,
even at relatively infrequent intervals, is sufficient to produce
longer lasting alteration in lymphocyte functions... In humans,
inhalation of volatile nitrites causes cycles of modest
immunosuppression, particularly in natural killer cell activity,
followed by a gradual recovery when the drug is not inhaled over
several days...Nitrite induced suppression of natural killer cell
may play a role in KS pathogenesis."
     While these studies can provide suggestive evidence, it is
important to remember that they are far from conclusive. We don't
know whether such changes in immune cell levels actually have any
harmful effects. No studies to date have yet demonstrated that
alterations to the NK levels correlate with any of the different
patterns of illness, with the possible exception of KS. Even if
poppers do cause immune suppression, this would not necessarily
automatically result in the development of KS. In the absence of
conclusive evidence, most experts feel that it is too early to
make any hard and fast recommendations on the use of poppers.

RESEARCH IS NEEDED
A number of key issues need to be resolved through controlled
research..

*To look at the incidence of KS in outlying cases, such as women,
drug users and haemophiliacs and other subcommunities where
HIV/AIDS is prevalent and to determine if there are any direct
relationships between the use of poppers and the development of
KS. At the same time it would be important to eliminate as many
of the other variables as possible. In particular if there are
any direct relationships of the sexual practices of the community
and the development of KS.


*To further investigate the effects of nitrites on the immune
system. Are there different responses in people who are HIV
positive etc.

*Ongoing research into the other potential factors that may
contribute to the development of KS. Is it an infectious agent
that is passed on through certain sexual contact. More intensive
study of KS occurrence in people who are HIV negative may also
shed more light on this question.


Our thanks to NAM Publications for allowing us to use some of the
text from AIDS Treatment Update.

Terms used in this article: 
Poppers:       A slang term for amyl nitrite and related volatile
               chemicals that are often used as a "dance drug" or to
               increase the intensity of sexual pleasure. When inhaled it
               causes a dilation of the blood vessels, increased heart
               rate and a feeling of being "high".
Pathogenesis:       The mechanism by which an organism causes illness.
Rimming:       Oral to anal sexual contact.
Natural Killer Cells:    Immune cells which can recognise and destroy a wide
                         range of infected blood cells, or tumour cells.
Lymphocyte:         A kind of white blood cell that is involved in immune
                    function.
Volatile:      Able to evaporate into a gas or vapour at room
               temperature.
               
Opportunistic
Illnesses

LIPOSOMAL DOXORUBICIN SUBMITTED TO AMERICAN
AUTHORITIES FOR APPROVAL -- 
TRIALS IN AUSTRALIA SET TO START  
By Ian McKnight - Smith

The liposomal formulation of doxorubicin (DOX-SL) has been
submitted to the regulatory authorities in the US (FDA) for
general approval as a treatment for Kaposi's Sarcoma.
     Liposomal Technology filed a new drug application, as a
chemotherapy to treat symptomatic Kaposi's Sarcoma. DOX-SL is a
liposome (fat) encapsulated formulation of doxorubicin
(Adriamycin). This formulation helps the drug stay in the body
longer and is supposed to reach its target, namely KS, in greater
concentrations by using less drug and therefore with fewer side
effects than the non-liposomal form of the drug. However unlike
most conventional liposomes, it is composed of tiny spheres
composed of durable and primarily biodegradable lipid (fat)
membranes.
     DOX-SL is a trademark "Stealth" liposome that is surrounded
by long chains of a substance called polyethylene glycol (PEG).
These coated chains alter the surface of the liposomes and in
doing so shield them from engulfment by the "phagocytes" in the
human immune system.
     Thus the "stealth" liposomes are able to travel through the
blood stream for longer periods of time and hence deliver their
contents directly to the sites of the disease. It is therefore
hoped that this form of the drug will deliver active ingredients
more effectively.
     Results from phase I and II trials demonstrate that the drug
is relatively safe and yields significantly higher response rates
than those reported with standard doxorubicin.
     Northfelt and others (1993) showed that in their phase I
study that DOX-SL has a half life in the blood of over 40 hours
compared to free doxorubicin which has a reported half life of
about 5 minutes.
     Further the active ingredient was detected in the KS lesions
at a concentration that was between 5 and 11 times greater than
the peak levels seen with standard doxorubicin.
     Side effects appear to be milder but include alopecia (hair
falling out), neutropenia (low white blood cell count) and
anaemia (low red blood cell counts). G-CSF is often used to avoid
the problem of neutropenia. The cardiac (heart) problems that
have been associated with the use of high dose doxorubicin have
not been reported with the liposomal forms.
     Most recently, preliminary results on 48 patients on an
early study in people with advanced KS showed a 66.7% (2/3)
partial response rate (Thommes 1994). The average duration of the
response before disease progression seen was in the order of 83
days. It is generally believed that if the drug is introduced
earlier in the course of the illness the better the response will
be, however this has yet to be seen in a clinical trial.
     Further many of the US studies with this drug now appear to
have closed to recruitment to some of its trials. The only
remaining studies are:

i) An open access study where people can get DOX-SL if they have
undergone a minimum of 2 cycles of systemic chemotherapy and have
then progressed or have had to stop therapy due to toxicity.

ii) There is also a comparative trial of DOX-SL versus a
combination of bleomycin and vincristine.

iii) It is also proposed that when DOX-SL is approved that a
further study will be conducted to look at the effects of DOX-SL
in combination with other drug groups such as vincristine and
bleomycin

After two years of protracted negotiations with Liposomal
technologies International an agreement has been made on the
protocol for an open trial to be conducted with DOX-SL in
Australia. The study will be for treatment of moderate to severe
AIDS related KS.
     People who will be eligible to enter this study are those
who have AIDS related KS of an extent that is measurable and a
severity that requires systemic chemotherapy. 

You will not be able to enter the trial if:

     *You are pregnant or breast feeding.
     *Had radiotherapy, electron beam therapy, cytotoxic
     chemotherapy, or interferon within the preceding three
     weeks. No previous radiotherapy or intralesional therapy to
     indicator lesions allowed.
     *Previous treatment with DOX-SL or other anthracycline drug
     of greater than 60 mg/m2 cumulative dose.
     *Have other neoplasms (cancer) treated with extensive
     chemotherapy.
     *Have significant cardiac disease, or active opportunistic
     illnesses.

The initial standard dose of DOX-SL will be 20 mg/m2 administered
intravenously. The dose will be decreased to 10 mg/m2 according
to the toxicity and responses to the treatments. The treatment
will be administered every six weeks until six cycles are
completed beyond the best response measured in that person. A
maximum of 40 cycles or an accumulative dose of 400 mg/m2 has
been set as an upper limit of the treatment schedule.
     We understand that the protocol has now been prepared for
submission to the ethics committee and then with this approval
will start recruiting shortly there after. It is our estimate
that this will be at the earliest in December and more likely in
the beginning of the New Year.

Refs:     Northfelt D.W. et al Proc Am Soc.Clin Oncol 12:51 (8A)
          1993.
          Thommes et.al.Proc Am Soc.Clin Oncol 13:55 (24) 1994.
     
     

Clinical Trial News


935U83 - A New Antiviral Drug Trial 
Now Recruiting in Sydney.  By Alan Strum

935U83, a Wellcome drug, is a new nucleoside analogue similar to
AZT, ddI and ddC but targets a different part of the HIV reverse
transcriptase enzyme.  The 935U83 is different from the current
nucleoside analogues as it is based on a different nucleotide
(building block of DNA) called guanine.  This means that this
drug interferes with a different part of the HIV genetic material
as the reverse transcriptase tries to convert the HIV into
proviral DNA (the part of HIV that inserts itself into human
DNA).  As such, it is possible that this drug will have an
entirely different side effect and viral resistance profile to
the antivirals currently being used against HIV.  Thus,  if
someone has HIV that is already resistant to AZT, ddI or ddC,
this drug may still be able to inhibit the replication of these
resistant strains.
     Laboratory tests in test tubes have shown that 935U83 does
in fact inhibit HIV that is resistant to AZT or ddI.  In the USA
and Australia some trial participants have been taking 935U83 for
up to 30 weeks with no particular side effects that can be
attributed to the use of the drug.  There have been 2 isolated
incidents, one who has had an elevated liver enzyme result and
one who has had an inflammation of the eye, but at this early
stage it is difficult to tell if these incidents are related to
the use of the new drug.  The general feeling of this drug so far
is that it does not have any significant side effects (unlike AZT
with anaemia or ddI and ddC with neuropathy or pancreatitis), but
it is still too early to tell.  Early results of p24 antigen and
HIV RNA polymerase chain reaction tests, to indicate the amount
of virus in the blood, look promising, suggesting that the drug
does inhibit HIV in humans, but more time is required to confirm
these preliminary indicators.
     The trial itself is a Phase I safety and efficacy multi-
national trial with 40 places available around the world, 10 of
which are in Sydney.  Of these places, only 5 are now still open
for people who are interested in entering the trial in Sydney. 
The trial will run for an initial period of 12 weeks with an
option to continue the trial for and additional 24 weeks (36
weeks all up).  The 935U83 is to be taken in combination with ddI
during the trial.  It is possible that the drug may be made
freely available to the trial participants at the end of the
trial depending on whether the treatment is considered to be safe
and effective.  Conditions of entry to the trial are as follows
; -

Main Inclusion Criteria
*CD4 count between 100 and 500mm3.
*No AIDS defining conditions including Kaposi's Sarcoma.
*Must have tolerated and be currently using ddI for at least 3
months.

Main Exclusion Criteria
*Must not have had AZT or ddC for at least 3 months.
*Must not be currently taking any other experimental drugs.

People entering the trial will be randomised to different dosing
regimes.  Either ; -
100mg 3 x per day + 400mg ddI
200mg 3 x per day + 400mg ddI
300mg 3 x per day + 400mg ddI
500mg 3 x per day + 400mg ddI

After entry to the trial all participant will be expected to
attend a full days examination at day 3.  A simpler examination
and blood tests will be carried out every 2 weeks for the first
12 weeks.  This will be followed by a blood test every 2 weeks
with an examination every 4 weeks until week 24.  After week 24
blood tests and examinations will take place every 4 weeks until
week 36.  All examinations and blood tests will be at the trial
clinic at St. Vincent's hospital so it is not expected that
participant will have to wait around for a long period of time
ie:- the process is meant to be over and done with very quickly. 
     There is, however, one small catch.  There will be a
randomisation of the 40 participants world wide for which some
people will be expected to attend the clinic for 3 full
consecutive days of tests.  There is no telling how many, if any,
people in Sydney will be randomised into this group.  If
randomised into this group, the drug company will reimburse the
participant for any expected loss in wages over this time.
     For further information contact the trial investigator, Dr.
David Austin - pager # 6807, or the trial nurse, Robyn Beckerleg
- pager # 6419 at St. Vincent's Hospital on 339-1111.
