                               HIV HERALD
                                    
                From The AFAO NATIONAL TREATMENTS PROJECT
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            National Treatments Officer:  IAN McKNIGHT-SMITH
                                    
                              DECEMBER 1994
                              VOL. 4 No. 11



3TC WITH AZT COULD BE A REAL TREATMENT CHOICE

By Ian McKnight-Smith

There is growing agreement that the use of the nucleoside analogue 3TC (lamivudine)
in combination with AZT can provide some benefits against HIV. It is important to point
out, however, that current clinical reports have not demonstrated a clinical benefit in
terms of survival or delay to disease progression. Later in this overview article we will
report the encouraging results from the recent meeting in Glasgow. First, a review of
3TC (lamivudine) and the experience with it to date.

The drug 3TC, now called lamivudine, is a nucleoside analogue. It comes from the
same family as ddC, AZT etc. Clinical experience with the member of this family of
drugs is quite long, with several studies conducted over several years showing it to
be relatively safe with few serious side effects. As a result this drug has been
available through expanded access in the United States and in Canada  for several
months, particularly for people who have CD4 counts of less than 300 and who are
unable to take other drugs in this group.

In earlier trials where 3TC was used as a single drug therapy against HIV, the results
were far from encouraging. It was concluded that when the drug is used alone it has
a very weak antiviral activity, although it was clear it was well tolerated, with fewer
than expected side effects reported.

Then came the news that laboratory tests had shown that when 3TC was used at the
same time as AZT, the two drugs were synergistic in terms of their activity against
HIV. In other words, the two drugs, when used together, work better than would be
expected by adding their separate effects. It was proposed that this effect may be due
to the 3TC acting as a protective agent against the development of resistance to AZT.
That is,  when the virus has the mutation which makes it resistant to AZT, it cannot
exist in the presence of 3TC. Conversely, when the mutant strain to 3TC develops,
this then renders it susceptible to AZT.

Other researchers believe this effect is not the whole story, particularly as the
synergistic effects are seen from the very first time that the two drugs are taken
together. This of course is far too early for the development of resistant mutations to
either of the drugs. AZT alone does not produce the same immediate improvement,
even in people who have not taken AZT before and who would not have resistance.
More work is ongoing to try and determine the true effect.


3TC MAY ALSO BE USEFUL TO TREAT HEPATITIS B IN HIV NEGATIVE PEOPLE

Early reports also suggest that antiviral effects may be broader than the confines of
HIV, and recent results suggest it is effective as a treatment for hepatitis B. In a study
reported at the American Association for the Study of Liver Disease, the viral DNA to
hepatitis decreased to such an extent that it was no longer detectible by the current
testing methods. This occurred in 22 people treated with either 100 or 300 mg per day
of 3TC. However after 12 weeks the treatment was stopped and within a four week
time period the viral DNA levels had returned in 16 of the 22 participants. Interestingly
the other six remained free of virus, of whom five had previously failed interferon
therapy.

The bonus of using 300 mg /day as the standard treatment dose used continuously
for people with HIV will be the provision of sufficient effect against the hepatitis B
virus, should they be exposed to both.


Combined therapy using 3TC with AZT increases antiviral activity over longer time, 
study shows

Using a combination of AZT (Zidovudine) and 3TC (Lamivudine) increases the drugs'
ability to fight the virus and allows them to remain effective for longer, researchers
reported at the Second International Congress on Drug Therapy in HIV Infection.
A trial of the two drugs enrolled 129 people who had not taken AZT before, and who
had CD4 cell counts of between 100 and 400. Participants were randomly divided into
two groups -- one group received AZT at a dose of 600mg/day, while the second
received a combination of 600mg AZT and 600mg 3TC every day.  They were then
followed over six months.  
At the end of the trial, all participants were offered open label 3TC for a further 24
weeks.
The group receiving combination treatment showed a mean CD4 cell increase of 85
after between four and eight weeks of treatment.  This was in contrast to the group
receiving only AZT which showed an increase of 34 cells.  
Of greater interest, however, was the finding that the rise in CD4 cells in people
receiving only AZT was quickly lost, with their CD4 cells returning to their original level
before the study started.  In fact, there was a mean fall of seven cells by week 24. 
This decay of CD4 cells was not seen in the group receiving combination therapy. In
this group, CD4 levels remained significantly above baseline for the whole of the six
months after being offered the open label 3TC. In some people, the levels remained
high after 11 months. 
When viral load was measured in these groups, it was found that people given the
combination treatment had a substantial drop in virus (as detected by the PCR test). 
More importantly, this drop in viral load (below 1 log) was maintained for the entire 48
weeks that they were followed.  However, in those who were only treated with AZT,
the viral load dropped by only 0.6 log, and these levels slowly returned to the starting
point by the end of the 24 week period.
The people who had been taking AZT only, and who started to take 3TC in
combination at the end of the 24 weeks, showed a median increase of 40 CD4 cells
and their viral load was reduced similarly to those who had been on 3TC and AZT
from day one.
The side effects reported by the group receiving both AZT and 3TC were not
significantly different than those reported by the group taking AZT alone.  Certainly the
well known problems of neutropenia and anaemia (reduced blood cell counts) were
not seen in any greater numbers in the combination group.
A paper presented on the first day of the conference may shed some light on why this
combination is working so well.  It showed that 3TC added to AZT may not  cause an
increased antiviral effect on its own, but rather appears to strengthen the effects of
AZT.  In particular, it appears to prevent the development of strains of the virus that
are highly resistant to AZT, which in turn are able to slowly weaken the effects of AZT
treatment alone.
So what does this mean to the person who is considering treatment with drugs like
AZT?  Clearly the use of the combination of AZT and 3TC may have a better effect
than using AZT alone. If this effect is seen you should be able to stay on the treatment
for a considerably longer period of time before resistance eventually develops. 
However, it's important to stress that from the results of studies looking at the effects
of one year of treatment, it's not possible to say how long it will be before resistance
develops. In addition it would appear that you would not be putting yourself at greater
risk of side effects than if you were to use AZT alone.
Of course it is still too early to say whether this will translate into greater delays of
disease progression with survival benefits.  Longer and bigger studies are needed to
answer these questions.
There is also good news for people who have already been using AZT for up to two
years.  A second study, similar in design to the one described above, was presented
at the conference. There were three groups in this study -- one remained on AZT;
another was given AZT and 3TC at 300mg per day; and another was given AZT and
3TC at 600 mg per day.
Preliminary results from this study showed that the combination groups had increases
in CD4 cell counts and decreases in viral load, despite the fact that they had already
been taking AZT previously.  
Interestingly, there were no significant differences between the two doses of 3TC,
suggesting that the 300mg dose may be just as effective as the 600mg dose.  Again
the responses to the drugs were sustained over the full 24 weeks of the study. The
number of reported side effects was no higher in the combination group than in those
who remained on AZT.
Unfortunately there is no data to show whether the same kind of effects can be seen
if ddI or ddC is used in combination with 3TC. However, there seems to be a
consensus that the answer would be 'no', given the rational behind how 3TC works
as a protector against AZT resistance.
While people in Canada, Europe and the USA can now access 3TC through clinical
trials or expanded access programs, it is not possible, at the time of going to press,
to get the drug in Australia.
These results show that the use of this combination of drugs offers benefits to both
people who are starting treatment for the first time and to people who have already
been taking AZT. It is a matter of extreme urgency that Glaxo, the manufacturers of
3TC, immediately starts making this drug available to people with HIV in Australia.
It has been suggested that the prospect of further trials looking at three drug
combinations -- AZT, 3TC and other antiretroviral drugs -- has led to 3TC being held
back. These trials are very important and they should be done.  But not at the
expense of people who can derive real clinical benefits now, as has been clearly
demonstrated in the three reports presented at the Glasgow conference. 



3TC to be made available in Australia

 With the release of the results in Glasgow there has been an immediate need to
make the drug available to PLWHA in Australia. As a result the Glaxo company,
manufacturers of 3TC, has moved quickly to provide two ways that  people may
access the drug. However it must be emphasised that the effective use of 3TC is
dependant upon your ability to take AZT, as there is little or no effect when taken
alone. As a result, if you cannot take AZT due to side effects or any other reason,
then 3TC will not be for you.

The immediate actions proposed for making 3TC available are two fold:

     * The rapid commencement of a wide ranging  phase III trial in Australia

       * The rapid introduction of a special access program for 3TC for those who
       would not be eligible to participate in the study.

The trial will be a collaborative effort between the National Centre for HIV
Epidemiology and Clinical Research (NCHECR) and The Community HIV/AIDS Trial
Network (CHATN). Access to the study will be wide and will include most major cities
throughout Australia. At the time of going to press, this will definitely include Sydney,
Melbourne, Adelaide, Perth, Brisbane, Nambour, Cairns and the Gold Coast. Other
sites are still being considered.

This large International study is planned to start enrolling early in the new year
(February) and will have at least 300 places available in Australia. Half of these will
be given AZT and 3TC, a quarter will be given AZT and 3TC and another new antiviral
agent called alpha APA (loviride). The remaining 25 per cent of trial participants will
continue with their current antiviral treatment, which has to include AZT.

To be eligible you should have a CD4 (T) cell count of between 25 and 250. Beyond
that the restrictions are few, with people who have successfully used  AZT before, and
those who have never used the drug, being able to obtain a place in the trial.

The National Treatments Project encourages people who are eligible to participate in
the study to do so, since the early results are so encouraging. However, we still need
to find out how good this combination is slowing the progress of the disease and
whether it can provide a significant survival benefit.

The trial will be conducted over a 12 month period and on conclusion, all participants
will be offered any of the treatment combinations available in the study at no charge. 

A special access scheme is also to commence very early in 1995 and this scheme will
have two initial components:

       * Immediate access to 3TC free of any charge, for anyone who has a CD4
       count that is less than 25.
       
       * Free access to 3TC for anyone who has a CD4 count below 250. However,
       this will not commence until the clinical trial is fully enrolled. It is our belief that
       this study will recruit very quickly and therefore we anticipate that this
       component will be activated before mid-1995.
       
Initial discussions with Glaxo appear to be very open and the company is keen to work
closely with the community. In particular it is open to change as more information
comes to hand, or if the conditions in the community were to change significantly. 

Finally Glaxo hopes to deliver its marketing submission to the Australian Drug
Evaluation Committee in early- to mid-1996, but much of this is dependent on
obtaining meaningful results from the current trial program.


BETTER UNDERSTANDING OF COMBINATION TREATMENTS CHOICES 

By Ian McKnight-Smith

It is becoming clear that single drug therapy using the current antiviral agents is going
to lead to resistant forms of the virus. In some cases this resistance can develop very
quickly, making the use of the drug alone impossible.

We would hope that if we can reduce viral replication by using more than one
treatment at a time, then we would be able to reduce the emergence of resistance.
However this is still very much up in the air. The questions that still remain of course
are what combinations we should choose, and when should such drugs be used in the
course of  illness?

Dr Brendan Larder from the UK presented an interesting overview of the effect that
two drug combinations have on the understanding of drug resistance and hence the
way that decisions about treatments may be made.

Apart from selecting combinations based upon our knowledge of side effects --  one
of the objectives of selecting and increasing drug numbers is to keep the levels of side
effects to a minimum -- we can get some information from looking at the effects of
putting the two drugs together in the test tube, particularly in terms of whether there
is an increase in the overall effects of the two drugs on the virus (this is called
synergy) and to avoid a situation where the two drugs antagonise each other. 

Much can also be gained from understanding the ways that resistance develops when
the two drugs are used together. For example it is not a good idea that when two
drugs are used together they develop cross resistance to each other. Ideally
combinations would be more useful where there is difficulty for the virus to develop
resistance to both of the drugs at the same time.

If we consider cross resistance for example, we know that AZT does not readily
develop cross resistance with most of the other nucleoside analogues that are being
used. That is to say it does not readily develop cross resistance to ddI, ddC, 3TC etc.
Therefore this makes AZT a good candidate for combination with these antivirals. In
terms of ddI and ddC they are closer related, particularly in terms of the sites where
the resistance patterns develop, and indeed we now know that there is a high potential
for cross resistance between these drugs. Therefore it would not be a wise move to
use these two drugs in combination.

The information included here will concentrate on the combinations of AZT and the
other nucleoside drugs ddC, ddI and 3TC. Firstly a Wellcome study looked at the
development of viral resistance in 180 people with CD4 counts below 300 who were
given either the combination of AZT and ddC, or AZT and ddI. This was compared to
the use of AZT alone as the "placebo".

When looking at the effect of treatment on CD4 counts there was some advantages
seen with the use of the combinations when compared with the AZT alone group.
Interestingly there was no difference in the development of specific AZT mutations
between any of the three groups. However there was a considerable difference in the
levels of viral load. The AZT and ddI, and AZT and ddC, combinations showed a
considerably greater decrease in the levels of virus as compared to the AZT alone
group. Interestingly there was no statistical difference between the two combinations
and in both cases there was a gradual increase in the viral levels by week 48 of the
study, although they remained below the levels at the start of the study. In contrast the
use of AZT alone resulted in levels returning to baseline during this time. When
investigated further, evidence was still found of resistance to AZT, but there did
appear to be suppression of the development of resistance to ddI or ddC, which
probably translated into the sustained change in the blood markers.

In the case of 3TC it was clear that the development of strong resistance to this drug,
when used as monotherapy is very rapid. However when 3TC is introduced into an
environment where there is highly AZT resistant virus, this resistance to AZT appears
to be strongly suppressed even to the original wild type. The way this may occur is a
greater ability of the virus to become resistant to 3TC, but if and when this occurs this
mutant form of the virus is sensitive to AZT. In addition it appears that the
development of co-resistance to 3TC and AZT at the same time is quite difficult.

When a clinical trial was conducted to see the effects of using monotherapy and all
three combinations in people with HIV and counts of between 100 and 400, the results
clearly show that the best suppression of viral load was observed in the group given
AZT and 3TC in combination. Again in this study when researchers looked at the
types of resistance that was present at week 24, there was significant resistance to
3TC but either very low level or no resistance was present for AZT. However in the
case of AZT and ddC, and AZT and ddI, the resistance to AZT was present but only
low levels of resistance to the ddC or ddI. 

In summary, it would appear from this very early data that the AZT and 3TC
combination may provide a longer lasting and more effective therapy against HIV, due
to its ability to suppress and protect AZT from high levels of resistance by the virus.
Clearly this needs to be tested in terms of clinical effects.


SEXUAL TRANSMISSION OF AZT RESISTANT STRAINS

By Ian McKnight-Smith

Professor David Cooper of the National Centre for HIV Epidemiology and Clinical
Research  presented a paper on the isolation of AZT resistant strains of HIV in people
who were examined during the seroconversion phase of HIV infection.

Background

Information that the transmission of AZT-resistant strains of HIV was occurring was
first published in the New England Journal of Medicine, which documented a single
case of transmission that was directly attributable to a person who was already
resistant to AZT. The very same resistance profile was observed in the person who
had become infected and the host partner. Further, this resistant form was seen to
persist beyond the seroconversion phase.

A further study demonstrated very similar results after looking at 26 people who were
seroconverting. In this group three people who had received AZT resistant forms of
the virus at the time of infection were identified.  Researchers also managed to track
the virus to the resistance profile of the sexual partner who had been the source of
infection.

In another case that looked at two children, one was infected by perinatal contact and
subsequently developed AZT resistance after treatment. This was then transmitted via
bodily fluids to a second child in the same household. The second child demonstrated
the same AZT resistant strain as the first even though the child had not been treated
with AZT. Furthermore, this resistance persisted beyond the seroconversion phase.

A further study looked at an injecting drug user who had been treated with AZT and
who subsequently infected his female partner with an identical form of the virus.

The Australian Study

A total of 52 isolates were studied for people who had seroconverted between 1987
and 1994. In all cases the mode of infection could be identified. In most, the isolates
have come from young gay men who were infected by sexual transmission and who
were then followed through the period of the seroconversion illness. The average time
to seroconversion was 22 days after the onset of the symptoms.

Five people in the group were identified as having resistant isolates to AZT. The
source of infection could be identified in all five. In one case there was the same
resistant strain in the infecting partner and who had a history of taking AZT for a
period of 25 months prior to this event.

In five cases, both of the sexual partners had been well documented. In all cases the
isolates were identified as being non-syncytia forming virus, and were the same in
each pair of partners examined.

In one case, a follow up study showed that although he had resistant virus at the time
immediately after seroconversion, this changed with time and by one year the
resistance had been lost and the person was again fully sensitive to AZT. This
suggests that resistance may not persist in all cases and this may be due to the
immune system having sufficient strength at this stage of the illness to provide some
protection against the mutant forms of the virus.

Professor Cooper went on to give some indication as to how common AZT resistant
transmission is within the overall incidence of HIV infection.

Assumptions made were as follows:

In a population of people with HIV and AIDS taking AZT the levels of resistance in that
group are :

               with HIV       with AIDS

1 year    30 per cent              90 per cent

2 years   50 per cent              95 per cent

3 years   70 per cent              >95 per cent
  

 
In a number of studies around the world, evidence is mounting of an increase in the
levels of AZT resistant virus being transmitted, and the kinds of levels suggested and
supported by the Australian experience are of the order shown below:

1988-91   3 per cent

1992      8 per cent

1993-4   19 per cent

Clearly this is an increasing problem that may well translate into some people in the
community having persistent AZT resistant strains and who may develop HIV disease
that is more difficult to manage. As a result, these people may progress more rapidly
than those who are sensitive to AZT therapy.


First trial of Abbott protease inhibitor shows 'promising' early results

By Ian McKnight-Smith

The first trial results for the Abbott protease inhibitor, ABT-538, were presented at the
Second International Congress on Therapeutic Drugs in HIV Infection. 
A protease inhibitor is a drug that works by blocking an enzyme responsible for HIV
replication in infected cells. The study (a phase I/II trial) was designed to look at the
safety and efficacy of this new drug in people with HIV. Participants were randomly
divided into two groups, one of which received a placebo. It also tested for different
doses of the drug (300, 400, 500, and 600mg given twice daily), and was conducted
in Spain and Australia.
All participants had stopped all antiviral treatments for at least three weeks before
starting the trial.  The people in the study were male, with CD4 (T-cell) counts above
50. The average CD4 cell count on entry to the trial was 130. Previous use of
protease inhibitors was not allowed. The study measured CD4 counts, p24 antigen
levels (a part of the virus in the blood) and viral load (amount of genetic material free
in the blood stream).
The results showed that the 400mg dose had a dramatic antiviral effect. A slightly less
antiviral effect was seen with the 300mg dose.  There was some evidence of a dose-
related effect, with the higher doses giving the greatest effects.
The average increase in CD4 cells was 100-150 cells/mm3 above baseline.  In the
higher doses, this was greater than 200 cells/mm3.  The increase was sustained for
the full four weeks of the treatment.  When treatment was stopped, there was a
general decline back to baseline.  
All people in the trial were given the opportunity to continue treatment on an open
label basis for a further eight weeks.  The increases of CD4 cell counts in people who
continued treatment remained sustained.  The median increase of CD4 cell counts
during this period from baseline was greater than 200 cells/mm3.  The good responses
in CD4 cell counts was seen in people with low or high cell counts on entry into the
trial.
The measurements of viral load, as gauged by branched chain DNA tests, also
showed a dramatic fall in the levels of detectable virus. The average reduction was as
great as 100 per cent at the higher doses, which reduced the viral load to levels too
low for the test to be able to detect the virus.  
There were few side effects. The only reports that were directly attributable to the drug
were rises in trigylcerides (fats in the blood) and some reports of people's tongues
becoming numb up to two hours after taking the drug (anaesthesia of the tongue).
In patients who continued to take the protease inhibitor in the maintenance phase,
huge increases in CD4 counts were maintained for the 12 week period.  In some
cases the increases were quite dramatic, with one person increasing from 200 cells
to 700 cells/mm3. In many cases with this group, the viral load remained undetectable. 
However, at the lower doses (300/400mg), there was evidence in some people of viral
load increases after five and six weeks.  This viral load increase was not evident in
the higher doses (500 - 600mg).

Conclusion

ABT-538 is well tolerated and is safe. It causes a significant reduction in viral load
when taken in higher doses that is sustained for 12 weeks, indicating an almost
complete shut down of viral production.
Although these results are encouraging, we must not lose sight of the fact that it is
early days, and questions still need to be answered: how long will the effect be
sustained?  When does resistance develop and how strong is it? Is there cross
resistance with other drugs of the same class? Will this translate into clinical benefit?
Further dose/efficacy studies are ongoing, particularly using doses given three to four
times a day, so that the peak blood levels of the drug can be held at higher
concentrations to possibly combat the virus more effectively.   

SAQUINAVIR RESULTS REPORTED IN GLASGOW 

By Ian McKnight-Smith

A number of papers on early clinical trials of the new protease inhibitor saquinavir
were presented at the Glasgow conference. Protease inhibitors are a relatively new
class of treatments that prevent the assembly of the pieces of the virus once they
have been produced within the cell. This is in contrast to the current antiviral
treatments called nucleoside analogues which try to prevent the integration of the viral
genetic information into the cell so that it can become a factory for producing new
virus.

Initially three early dose ranging trials from France, United Kingdom and Italy were
reported, for a total of 202 patients treated with saquinavir at different stages of their
illness. Some of the studies also looked at combining saquinavir with AZT.

In these studies four doses were used -- 25, 75, 200 and 600mg -- and were given
three times a day. The study period was 16 weeks. The English study evaluated the
effects of these four doses of saquinavir on people who had not taken antivirals and
who had little or no symptoms, but a CD4 count of less than 500. The French study
was performed in 61 previously treated (AZT) people with CD4 counts between 50 and
300. In this study only the three higher doses were used and as single drug therapy.
The Italian study investigated both mono and combination of saquinavir with AZT and
involved 92 (CD4 < 300) people who had not taken antiviral treatment before. In this
trial the participants received one of five treatments: saquinavir 600mg three times a
day alone, AZT 200mg three times a day alone, or  75, 200, or 600mg saquinavir
three times a day in combination with AZT, 200mg given three times a day.

Saquinavir was very well tolerated by all participants in these trials and there were
very few side effects. Many of the participants elected to continue treatment after the
16 week study was completed.

However, the effects of this agent on surrogate markers was disappointing at the
doses used in these trials. Only the highest dose of 600mg when given three times
a day resulted in any significant increases in the CD4 counts. Furthermore this
increase was not sustained beyond six weeks of treatment. However, the researchers
indicated that in many cases the treatments were given at advanced stages of HIV
disease and many had more than a year on AZT prior to this study. The results as
would be expected indicated that the combination of saquinavir and AZT was more
effective than the single drug therapy. Similar trends were seen  when viral load
measurements were made using HIV-DNA and RNA by PCR testing. However, the
overall effects did not appear to be great. It was also clear that resistance develops
by mutations of the virus and a significant number (20 per cent) of the participants had
developed saquinavir resistance by week 20 if the treatment is used alone. Resistance
appears to develop much more slowly when used in combination with AZT.

A further report of the ACTG 229 study was presented by Dr. Michael Saag from the
University of Alabama. This study looked at the safety, tolerance levels and antiviral
activity of saquinavir in combination with AZT and/or ddC. The group recruited had
CD4 counts between 50 and 300 and had already been taking AZT for at least four
months prior to entry into this trial. The treatment duration of this study was 24 weeks.

Among the 302 participants in this trial, 91 per cent were male and had a mean age
of 38 years and a median time of AZT use prior to the study was 25 months. So many
had been using AZT in excess of  two years. 36 per cent of the participants had also
been using AZT and ddC for more than one month prior to entering the trial. The
median CD4 count was 158.

The triple combination of saquinavir,ddC and AZT was seen to give the greater
reductions in viral load and the greatest increases in CD4 count (30 per cent above
baseline at highest point) and were sustained above the starting points over the 24
weeks of the study. There was evidence of decay towards baseline in both the double
and triple drug treatment groups. 

The measures of viral load also indicated that the triple drug user group had the
greatest fall in viral load as compared to the two drug combinations, with 44 per cent
showing greater than one log fall in the former group but only 22 per cent had the
same falls in the two drug groups. This relatively weak reduction may in part be due
to the fact that the group as a whole had already been using nucleoside analogues
(AZT/ddC) for a significant time prior to entry into this trial.

It is interesting to note that there was very little increase in the levels of side effects
experienced with the already established effects of the two drug groups as compared
to the addition of saquinavir as a triple drug treatment.

It may be concluded from these results that saquinavir certainly is active as an
antiviral agent, but at the doses that were used in the studies reported the effects
were weak, even if in combination with other antiviral treatments. The benefit however,
appears to be that the drug has a relatively low level of side effects and that the
addition of the drug to current combinations of treatment does not increase the overall
side effects experienced.

It is known that one of the problems associated with this drug is that the current
formulation is particularly poorly absorbed into the blood stream. Indeed these results
suggest that the doses used  in these studies may be too low to get an adequate
amount of the drug to the sites where it can be effective against the virus. There is
need to study higher doses or ways that higher blood levels can be obtained.

PBAC Removes fluconazole out of hospital reimbursement scheme

By Ian McKnight-Smith

The Pharmaceutical Benefits Advisory Committee (PBAC) has, without notice,
announced that fluconazole (Diflucan) will be taken off the section 100 listing as of
January 1, 1995. This means that the dispensing of this drug through hospital
pharmacies will no longer be reimbursed by the health scheme.

After the National Treatments Project made some enquiries, it found that little or no
consultation has been entered into when making this decision. Certainly the
manufacturer (Pfizer) and the Highly Specialised Drugs Working Party were not
consulted.

To date fluconazole has been reimbursed both through the section 85 (PBS) and
section 100. The PBS allows for dispensing and reimbursement of drugs that are
prescribed by your general practitioner, which you then have filled at your local
chemist shop. Section 100 applies to reimbursement for scripts presented to the
hospital pharmacy. PBAC has indicated that it does not support such dual listing.

However the need for a section 100 listing in addition to the PBS listing for this drug
is based on the fact that serious AIDS illnesses such as cryptococcal meningitis, that
respond to the use of this drug, are more likely to be managed by specialists in
hospital/clinic settings than by the general practitioner. As a result, there is
considerable amounts of dispensing of this drug through outpatients departments in
the larger HIV/AIDS dedicated hospital units.

It is important to note that Fluconazole is still available, as it remains on the PBS.
General practitioners and specialists will be able to prescribe once they receive an
authority approval by the Department of Health.

However, the impact of this change on people living with HIV/AIDS is likely to be
significant, since hospital pharmacies will find it difficult to absorb the cost of
fluconazole. This is due to two reasons. Firstly the drug is usually given at high doses,
and second it is already a relatively expensive drug. Some major centres already
canvassed by NTP have indicated that they will not be able to absorb the cost and will
be sending patients to their general practice.

People with HIV/AIDS who normally attend hospital/specialist clinics will in many
cases have to then see a general practitioner to obtain a script for fluconazole. Some
specialists can prescribe, but this at best will still have to be taken to a retail
pharmacy.

There is also a potential cost impact for the patient. Sharpe's Pharmacy in Sydney,
for example, detailed their charges for fluconazole after being contacted by the NTP.
Standard scripts for one month of  therapy are estimated to cost the patient $16.20.
Health card holders and pensioners will have a cost of $2.60 per script. Those who
have reached health net limit will have no charge. 

In essence this move increases the stress of obtaining essential medication for people
living with HIV and AIDS, both in terms of the physical inconveniences and the further
financial burden on what is already a hard task when trying to make ends meet. The
gains to be made in terms of savings on the overall health care budget are relatively
small and it seems that this decision has been made without a complete
understanding of the situation, and should be reversed.
 
THE ORAL GANCICLOVIR STORY

By Ian McKnight-Smith


Some background Information

Initial presentations on this product compared the ability of the oral  and the
intravenous formulation to establish similar blood levels at the sites where they act in
people with CMV disease.

Unfortunately the bioavailability of the oral formulation of ganciclovir is not high, with
only between six and nine per cent of the administered dose actually getting into the
blood stream. However as would be expected once the drug enters the blood stream
it behaves in a very similar way to that seen with the intravenous formulation. It was
reported that the poor absorption could be improved by up to 20 per cent when the
oral form was taken with food. 

The results of pharmacokinetic studies therefore suggest that if the drug is given in the
presence of food and at a dose of 3000 mg per day, (given either three or six times
a day) the blood levels can reach adequate therapeutic levels and this cleared the way
for use in a clinical setting. 

It was noted that there is a significant interaction between oral ganciclovir and a
number of the antivirals that are used to treat HIV (AZT etc.). However the most
significant and most likely to have a clinical impact was the effect with didanosine
(ddI), which was seen to more than double its serum concentrations when given with
ganciclovir. This of course may well place people at greater risk of experiencing the
side effects that are associated with ddI and hence dose adjustment will need to be
considered. However it was also noted that while the concentrations of ddI went up
the absorbed concentrations of ganciclovir fell by about 20 per cent and this again
may have to be considered since there is already a poor absorption of the drug.

The European Experience of Oral treatment for Maintenance Treatment

Two European researchers (from Paris and Amsterdam) presented information about
two trials that have looked at the efficacy of oral ganciclovir in the treatment of CMV
retinitis. Some of this work was conducted here in Australia. A 20 week study looked
at the effectiveness and side effects of using 3000mg/day of oral ganciclovir as
compared to the standard maintenance regimen of 5mg/kg/day given intravenously.
It is important to note that this is a trial of people who have already completed
induction therapy and have entered the maintenance phase of treatment. A total of
112 people were given the oral preparation while 47 received the intravenous
formulation.

Two techniques were used to assess if there was any change in the progression of
the retinitis, firstly by physical examination of the eye by the clinician (funduscopy) and
secondly by use of photographic techniques.

There appeared to be little difference in the progression of the disease when
comparing the two groups by either technique used. However, the photographic
assessment showed a clear trend to providing more accurate and quicker diagnosis
of changes to the disease status.

By assessment of photographs, CMV retinitis progressed in 72 per cent of people who
were taking oral ganciclovir and 76 per cent of those using the intravenous
formulation. These two figures were not significantly different. 

The average (mean) time to progression starting in people using the oral ganciclovir
was 51 days from the time of starting treatment, while it was 62 days in the group
given the intravenous formulation. Again this was not significantly different at the 0.05
level.

When these results were compared to the direct examinations made by the clinician
(funduscopy), CMV retinitis progressed in 59 per cent of people on oral ganciclovir and
43 per cent if given the intravenous form. Interestingly the time to progression was 86
days in the case of the oral form and this was significantly different (at 0.02 level) to
the intravenous group with 109 days before detecting progression.

It was interesting to note that the study also looked at people who were antiviral
treatment naive as against those who had had experience with treatment previously.
There was some trend to longer time to progression in the naive group as compared
to those who had treatment previously, but this did not reach statistical significance.

In terms of side effects being reported the conclusion made by the researchers was
that both formulations were well tolerated. The oral formulation however reported
significantly lower levels of sepsis -- three per cent in the oral group versus eight per
cent in the intravenous  (toxic infections often at the site of intravenous) -- and
neutropenia, with 14 per cent in the oral group versus 23 per cent in the intravenous
group (a decrease in a particular form of white blood cell called a neutrophil). In
contrast, there appeared to be a trend towards higher levels of diarrhoea in the oral
treatment group. Increases in reports of rashes were also reported in the orally treated
group.

It can be concluded that the use of the oral treatment appears to be effective in terms
of slowing the progression of  CMV retinitis in a group of AIDS patients. In addition the
oral formulation is well tolerated, and may therefore provide an effective alternative to
the inconvenient and often traumatic use of intravenous ganciclovir therapy.

Confirmation from the other side of the Atlantic

Kathleen Squires from the United States presented results from two similar studies
(1653 and 1774). One trial looked at people who were newly diagnosed with CMV
retinitis, while a second study looked at people who had already had CMV treatment
before the trial entry. There were 123 participants in the newly diagnosed group,
therefore all went through a standard regimen of 21 days of induction onto treatment
with intravenous ganciclovir. In contrast there were 237 participants in the previously
treated group. As with the European studies, they looked at the time that lapsed
before there was evidence of progression of the CMV, i.e. where the treatment no
longer appeared able to keep the disease under control. Participants were randomised
to either standard intravenous ganciclovir or one of two groups that received 3000mg
of oral ganciclovir. The only difference between the latter groups was how often they
had to take the treatment.

Time to progression and the differences in times to disease progression between the
intravenous and the oral groups were similar in both studies as shown in the table
below:



                    STUDY 1653          STUDY 1774
                    Newly diagnosed     Previously treated
Intravenous 
Time to Prog.       62 days             66 days

ORAL
Time To Prog.       57 days             54 days

Differences         5 days              12 days

Again there is a trend towards a shorter disease free period for the oral group, but
they were not statistically different to the intravenous groups. 

Again as in the European studies there was a lower incidence of neutropenia in the
orally treated group (see table below). Again as expected the incidence of sepsis was
lower.

                    I.V Treated              Orally Treated
     
Neutropenia         25 per cent              18 per cent    


Conclusions

*Oral ganciclovir is an effective alternative to the intravenous formulation to treat CMV
retinitis in people with AIDS.
*Oral ganciclovir may have a more rapid progression to treatment failure and disease
progression than the intravenous formulation.
*Oral preparations appear to have lower levels of the side effects of neutropenia and
sepsis.

What about the use of oral ganciclovir as prophylaxis against CMV retinitis?

A late breaker paper was presented by Dr. Squires about some preliminary data about
the use of oral ganciclovir as a means of preventing (prophylaxis) the development of
CMV retinitis. This trial looked at primary prevention, i.e stopping the onset of the first
attack of CMV disease in a group of people who had not had symptoms of illness
previously, However this group had a CD4 count (less than 50 or up to 100 if the
person had experienced another AIDS illness) that would put them at increased risk
of developing the illness. All participants were identified as being CMV positive -- that
is, they had been exposed to the virus at some point in the past. 

A total of 725 participants were randomised to receive either oral ganciclovir or
placebo, the absolute numbers are shown in the table below. The active treatment
given was 1000 mg a day given in three doses over the day. 

The study was conducted on an intent to treat basis and these are but  interim results
of an ongoing study.


                         Ganciclovir         Placebo

Numbers                  486            239  
Mean CD4 count            21             23

Time on study                 361 days       340 days
Average time of treatment     304 days       251 days*

*This being due to the increased number of AIDS events

All incidents
for drug discontinuation 56 (12 per cent)         58 (24 per cent)

Incidence of CMV disease 76 (16 per cent)         73 (30 per cent)    **

Incidence of CMV retinitis    52 (11 per cent)         47 (20 per cent)    **

Survival.                There is a trend toward better survival times in the
                         ganciclovir group, but it is yet to reach a statistical
                         difference.

(**statistically difference at p 0.05)

Pancreatitis                  2 per cent               1 per cent

As would be expected there was a higher incidence of side effects in the ganciclovir
treated group. In particular there was an increase in the incidence of leucopoenia and
anaemia. There was some suggestion that there may be some negative effects on the
kidney and liver functions (see above re pancreatitis), but this needs to be more
closely studied. 

Conclusions:

*Oral ganciclovir prophylaxis reduces the incidence of CMV disease in people with low
CD4 counts.
*Oral ganciclovir also delays the development of CMV disease.
*Oral ganciclovir may increase the time of survival in people with HIV who are CMV
positive and have low CD4 counts.
* Oral ganciclovir is relatively well tolerated but is associated with increased levels of
side effects such as leucopoenia and anaemia. There is some concerns about
creatinine clearance that warrants further investigation.

From this study it may also be concluded that rapid development of broader access
programs needs to be considered for people who fit these criteria in Australia. Like the
conditions set with the use of Glaxo's antiviral drug 3TC, this may be best achieved
with a new and wider ranging clinical trial that is started as soon as possible, and the
concurrent development of a special access program for those who cannot participate
in the trial. There is a meeting of the Syntex Advisory Board on the 20th of February
1995 where it is anticipated that these issues will be raised.

 SOME CURIOUS RESPONSES USING FOSCARNET FOR
KAPOSI'S SARCOMA

By Ian McKnight-Smith

A late entry into the proceedings was a presentation by Dr. Linda Morefield, from New
York, who reported her findings on the use of foscarnet in treating people who had
advanced KS disease. The report was only for five patients and was in open label
uncontrolled conditions.

Each patient was described individually and will be summarised below:

Patient #1
Person with advanced KS who had also been treated for PCP. He was treated with
standard doses of foscarnet for a period of 10 days. All lesions exhibited regression
with time and in some cases they resolved almost completely. They remained in
remission for a period of 10-12 months when the lesion numbers and size returned.

Patient # 2
The patient had experienced an episode of active TB and when this was resolved he
was then treated with foscarnet. As in the first case he exhibited significant reduction
in the size and intensity of the lesions associated with his advanced stages of KS.
Nineteen months after treatment he still was considered to have significant regression
of the KS.

Patient #3
This patient had not experienced any other opportunistic illnesses apart from the
development of KS. Again he was given a standard 10 day course of foscarnet. As
was the case in the other patients he exhibited a significant slowing of his KS with no
new lesions being reported and in some cases evidence of regression. Eight months
after the initial treatment he was given a further course of foscarnet and has remained
in remission for a period of 18 months.

Patients #4 and #5 
There was little evidence of change in the progress of the KS. However the author
pointed out that they were both severely immuno-compromised and had a history of
opportunistic illnesses which continued.

Clearly we cannot draw any firm conclusions from what is essentially anecdotal
information. However it is interesting enough to suggest that more work should be
done and under conditions that allow easier clinical evaluation. Maybe this is the
starting point for a clinical trial, which could very easily be conducted either by the
National Centre or probably more appropriately at the community level by the
Community HIV AIDS Trials Network.

It would also be of interest to hear any similar reports that might have occurred here
in Australia -- for example, in association with the use of foscarnet to treat CMV and
where an individual concurrently witnessed a decline in KS. If you have such
experiences we would very much like to hear about them at the National Treatments
Project.

You can subscribe to all of the publications produced by the National
Treatments Project. Just send your name and address to:

The National Treatments Project
c/o Australian Federation of AIDS Organisations
P.O. Box H274, Australia Square
Sydney   NSW  2000
Australia.







Apart from the HIV Herald we also produce:

HIV Briefs.....A comprehensive coverage of individual treatments issues
HIV Brief, Fact Sheets...A  summary of a drug or illnesses associated                                                                                                                                                                                            
with HIV.
Booklets... Dealing with broader topics such as entering clinical trials and
the development of a working relationship with your general practitioner.
Australian Trials Directory...A summary of HIV/AIDS trials in Australia

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