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HIV Herald, Vol. 5  No. 1, February 1995 

Produced by the National Treatments Project of the Australian Federation of AIDS
Organisations
AFAO
PO Box H274
Australia Square
Sydney, 2000
Ph. 02. 231.2111
Fax. 02.231.2092

National Treatments Officer: Ian McKnight-Smith
Publications Sub-editor: Megan Nicholson



Rifabutin (Mycobutin) made available.

By Ian McKnight-Smith

The Health Minister Dr Carmen Lawrence has returned from her holidays and
approved the drug rifabutin for use as a prophylaxis (preventive treatment). This action
followed a recent meeting in Sydney of people with HIV, clinical specialists and other
members of the HIV affected community, where speakers condemned the delay in
making rifabutin available as prophylaxis for Mycobacterium Avium Complex (MAC).
The drug must now be approved by the Minister for Finance.

MAC is a devastating illness that people develop in the advanced stages of HIV. A
number of studies show that rifabutin is effective in preventing MAC in people with T-
cell or CD4 cell counts less than 100. The chance of developing MAC increases when
a person's T-cell count falls below 100 (the T-cell count gives a rough indication of the
state of the immune system). The prevention of MAC using rifabutin as a prophylaxis
should become routine, as is the prevention of PCP (a type of pneumonia) with the
drug co-trimoxazole. Rifabutin has had dramatic effects, with a significant fall in the
incidence of MAC in the HIV positive population. 

Rifabutin has few side effects; many studies show that people on rifabutin report
similar side effects to those taking the placebo. Side effects include neurological
(nerve) problems and gastric upsets (diarrhoea, nausea,vomiting) and can be reduced
by taking the drug with food. Rifabutin appears to cause fewer side effects than most
other treatments for MAC. The main concern of some clinicians has been the
development of resistant strains of MAC if rifabutin is used alone as prophylaxis. To
date the research has not shown this to be a problem, but the treatment has only
been tried with a relatively small number of people in highly supervised conditions.

In June 1994, rifabutin was approved by Australian Drug Evaluation Committee
(ADEC) for use as a prophylactic treatment. The ADEC recommended that rifabutin
should be included on the section 100 scheme, which would make it available through
hospital pharmacies to people with advanced HIV. The six month delay in ministerial
approval has meant there has been no reimbursement for the expense of the drug.

This has meant that hospitals have had to pick up the cost through its allocation of
pharmaceutical funds or the individual has to pay for it themselves. The latter option
is virtually impossible due to the high cost of the drug. Chemists pay $147 for thirty
150 milligrams capsules. The standard prophylactic dose is two capsules per day.
Therefore, two packs of the drug will be needed each month at a cost of $294 per
month. In addition, dispensing costs mean rifabutin prophylaxis costs more than $300
per month. Hospitals have not been able to cover these cost although some hospitals
have recently been given one-off help with funding from their area health services.
However this is a temporary assistance designed only to cover the situation until the
listing on the Section 100 goes into effect in the next few weeks.

Speakers as the recent meeting were scathing about the delay in ministerial approval.
Professor David Cooper, director of the National Centre for HIV Epidemiology and
Clinical Research, told the meeting that the delays in access to rifabutin are
inexcusable. "Rifabutin was approved last June by the Australian Drug Evaluation
Committee, but the funding arrangements still aren't in place. The Federal Minister,
Dr. Carmen Lawrence, failed to sign the approvals before she went on holidays, so
we are still waiting," Professor Cooper said. "There are significant survival benefits for
people with HIV/AIDS in taking rifabutin as prevention or treatment for MAC infection.
The problem is the dreadful delay in funding".

Tony Keenan, President of the Australian Federation of AIDS Organisations (AFAO)
wrote to Dr Lawrence about delay in funding rifabutin. In the letter he said that
"several hospitals in New South Wales have expressed their reluctance to prescribe
rifabutin for people with HIV/AIDS until these funding agreements are in place. AFAO
finds this withholding of life saving medication intolerable".

Dr Lawrence has responded to these calls, and signed the approval of rifabutin. The
papers have gone to the Minister for Finance for his approval. Let's hope this will be
a very rapid process.




Co-trimoxazole Controversy

By Ian McKnight-Smith

Recently in the United Kingdom, Professor Lacey from Leeds University called for
pharmacies in England to stop supplying co-trimoxazole, also known as Bactrim and
Septrin. He considers co-trimoxazole too dangerous to use as a general antibiotic. He
claims that there have been many thousands of deaths attributed to the use of the
drug, and suggests that these problems have been deliberately concealed by drug
companies and the regulatory authorities in Britain.

Co-trimoxazole is an antibiotic that is made up of two different active agents called
trimethoprim and sulphamethoxazole. It has been widely prescribed for more than
twenty-five years and is particularly effective against a number of infections, including
urinary and respiratory tract infections. More recently, clinical research has clearly
shown that co-trimoxazole is an effective drug to both prevent and treat certain life-
threatening opportunistic illnesses that are associated with AIDS. It is particularly
useful for pneumocystis carinii pneumonia, or PCP, a serious infection of the lungs,
and Toxoplasmosis, a nasty infection of the brain. 

The use of co-trimoxazole has been so effective in treating PCP that there has been
a significant decline in the numbers of people who are reporting this illness as their
first AIDS defining opportunistic illness. Treatment with co-trimoxazole has delayed the
onset of AIDS in many people with HIV. Many clinicians and treatments' advisers
believe that co-trimoxazole is probably the most significant advance in HIV/AIDS
treatments.

Millions of scripts for co-trimoxazole have been written in the last twenty-five years and
the side effects associated with the drug are well known and extensively documented. 
Between fifteen and twenty-five percent of people who take the drug experience side
effects. A skin rash is the most common side effect, indicating an allergic reaction to
the sulphur component of the drug. In most cases, skin rashes subside as soon as the
drug is stopped. If you develop a skin rash, see your doctor to discuss your options.
In very rare cases, mainly among elderly patients, this allergic reaction may be more
severe and can be life-threatening if treatment is continued. This is called the Stevens-
Johnson syndrome.

Recently, a procedure called desensitisation has been introduced to eliminate the
allergy by gradually exposing the patient to sulphur. Once the person is desensitised,
co-trimoxazole therapy can continue. This has been particularly successful for people
with HIV and reports indicate that up to eighty percent of people are able to tolerate
the drug after desensitisation. A complete protocol of desensitisation was included in
the November 1994 HIV Herald, Vol. 4, No.10.

If desensitisation is not successful there are a number of other treatments that can be
considered. These include dapsone with trimethoprim (which contains no sulphur) and
in some cases, pentamidine, clindamycin in combination with primaquine or
pyrimethamine, and possibly atovaquone. These drugs are effective although not as
successful as co-trimoxazole.  

Other side effects of co-trimoxazole are more often seen in the elderly or in people
who have poor kidney or liver function. The latter results in a build up of the drug in
the body which may reach toxic levels. However, there are also reports of the
following side effects: reduced red blood cell numbers or anaemia; reduced white
blood cell numbers; weight loss;nausea and vomiting; and an altered sense of taste.
These side-effects should be discussed with your doctor. 

The National Treatments Project contacted the Therapeutic Goods Administration
(TGA), the government body who document all reports of side effects from around
Australia. The TGA reported forty-four deaths could possibly be attributed to co-
trimoxazole over the twenty-five years it has been in use. In the context the
widespread use of co-trimoxazole, the incidence of death is very low, similar to
paracetamol, a very common analgesic.

In summary, the preventative use of co-trimoxazole and its use in the treatment of
PCP and toxoplasmosis in people with advanced stages of HIV has been shown to
be highly effective. Co-trimoxazole has delayed the onset of AIDS by a significant
period of time for many people. It is acknowledged that some people do exhibit an
allergic rash when starting treatment. Although allergic reactions to co-trimoxazole
occur, these reactions are rarely life-threatening. However, it is clear that the potential
benefits from preventing serious opportunistic illnesses make co-trimoxazole the drug
of choice.







Generic brand of acyclovir available

By Ian McKnight-Smith

The drug acyclovir has been a common treatment for both outbreaks of herpes and
as a prophylaxis against herpes. Recently it has also been approved for use as
treatment against HIV in people with CD4 or T-cell counts of less than 150. 

In the past, only the brand called Zovirax was available, supplied by the
pharmaceutical company Wellcome. The company has decided to supply acycolvir to
the manufacturers of generic brands, although the product patent has not expired. This
means acyclovir will be available under a number of trade names.

The first such product has the trade name Zyclir and is supplied by Amrad
Pharmaceuticals. There will be a second brand shortly, supplied by another Australian
company Alphapharm.

At this stage, there will be no change in the price of acyclovir for the consumer. The
cost of acyclovir to the pharmacy has decreased marginally, which will help the
pharmacies meet their costs in a market where they are struggling. Australian-based
production will mean the dollars are kept in this country.

The 200 milligram Zyclir tablets are identical to Zovirax in terms of the ingredients. The
difference is that Zyclir are round, rather than octagonal shape of the Wellcome
tablets. This may provide some advantages for people who have problems swallowing
the Zovirax tablets. 

Back to Basics Column

WHAT IS THE DIFFERENCE BETWEEN A "NUCLEOSIDE ANALOGUE" AND A
"PROTEASE INHIBITOR"


By Ian McKnight-Smith

A few years ago, anti-viral treatments against HIV was relatively simple. However,
things are changing, and there are a number of new classes of drugs being introduced
into clinical use, such as protease inhibitors. With the recent good news from the
Second International Congress on HIV treatments in Glasgow, we are going to hear
a lot more about new treatments and drugs.

How do anti-viral drugs differ? Why can some be used together while others can not?
This article discusses two main classes of drugs; nucleoside analogues and protease
inhibitors. The nucleoside analogues include the well-known drugs such as AZT, ddI
and ddC. Recently, two new members of this group have been introduced and they
are d4T and 3TC. The protease inhibitors include drugs such as saquinavir and the
Abbott protease inhibitor, ABT538.


NUCLEOSIDE ANALOGUES

Nucleoside analogues are also referred to as reverse transcriptase inhibitors. This is
a broad grouping which includes many anti-virals that work on inhibiting the process
of reverse transcription where the genetic information of the HIV is inserted into the
human DNA. Another group of reverse transcriptase inhibitors are also known as non
nucleoside reverse transcriptase inhibitors or NNRTIs and these drugs work in a
slightly different way to the nucleoside analogues.

What are nucleoside analogues and how do they work?

When the virus enters the T-cell or CD4 cell (the immune cell which HIV infects), it
injects a strand of a substance called RNA. This is the basic unit of genetic
information that is needed to reproduce the various components of the virus, such as
the nucleus, the outside coat and the enzymes (small proteins) that drive the activities
of the virus. 

RNA must be converted into a form that is compatible with the genetic material, or
DNA, of the T-cell. As audio tape stores music, RNA and DNA store human genetic
codes. These codes are made up of small units called nucleosides. As the viral RNA
code is read within the T-cell, a chain of DNA is created. This process involves an
enzyme, called reverse transcriptase, which makes the process occur.  The reverse
transcriptase facilitates the conversion of RNA to DNA.

Where do the nucleoside analogue drugs fit into this picture? The word analogue
means that it is a "look alike". These drugs look like the building blocks that are used
to make up the chain of DNA.  When the nucleoside analogue is picked up and put
into this chain, the process of building the viral DNA is disrupted, because the next
unit is unable to join the DNA chain.

Ideally, the infection of this cell is stopped and hence the cell does not go on and
become a factory for producing new viruses. The nucleoside analogues reduce the
amount of virus in the body and reduce the number of new cells being infected and
damaged. There is evidence that these drugs slow the progress of the disease and
give people a longer period of being well. Unfortunately, after a period of time, the
virus is able to get around this point in the transcription and hence is able to complete
transcription. 

While the nucleoside analogues do work, they are only useful for a period of time. You
may need to consider swapping or adding treatments after a you have been on one
drug for an extended period of time. Certainly you should monitor how you are going;
if there are signs that the drug is no longer being effective, then you should consider
alternatives.

There are a number of nucleoside analogues that are currently available to people
with HIV in Australia. The most well-known and commonly used is AZT (zidovudine
with the brand name of Retrovir). Two other drugs are currently licensed: ddI
(didanosine with the brand name Videx) and ddC (zalcitabine with the brand name
Hivid). The drugs d4T (stavudine) and 3TC (lamivudine) are also available through
trials or special access programs. In Australia, most people begin treatment for HIV
with this group of anti-viral drugs; in particular, treatment often begins with AZT at a
dose of about 500 to 600 milligrams per day. 

There is increasing evidence that two or more drugs may be the most effective
treatment available. The virus finds it more difficult to get around two drugs than one,
which slows the progress of the virus for longer periods. Common combinations of
nucleoside analogues include AZT+ddI, or AZT+ddC and most recently AZT+3TC.
Early reports suggest that AZT and 3TC may be the most effective anti-viral treatment.

There are also many studies looking at combining one or more of the nucleoside
analogues with other anti-viral drugs that work at different points in the reproduction
cycle of the virus. The next section will discuss the class of drugs called protease
inhibitors and how they work.

PROTEASE INHIBITORS

The protease inhibitors are also anti-viral drugs that attack the effects of HIV. However
they work at a different point in the reproductive cycle of the virus in the T-cell.

What are protease inhibitors and how do they work?

Once the virus has converted the RNA into the DNA, the viral DNA is inserted into the
main DNA of the human cell. The cell then becomes a 'factory' for producing new HIV.

The codes on the DNA dictate the production of the components of the new virus. A
long chain of protein is constructed. This chain of protein is then chopped up and
assembled as parts of the new virus. The process of cutting up the protein is
controlled by an enzyme called protease. Interfering with the protease enzyme will
hopefully disrupt the process of new viral construction, which in turn may slow the
progress of the illness.

There are a number of compounds that have been designed to interfere with the
enzyme protease. In the last year, early trials with a number of the new protease
inhibitors have been completed. The results look very promising, however some
protease inhibitors are difficult for blood to absorb. In some trials, only small amounts
of the protease inhibitors are getting into the T-cell.  When the compounds reach the
protease target, they are highly effective in stopping the production of new HIV. 

However, as with nucleoside analogues, the virus is able to get around the effects of
the protease inhibitors. Over a period of time the virus can become resistant to this
group of drugs. Therefore researchers think that protease inhibitors will probably not
be used as single drug treatments. Instead they will be used in combination with other
types of anti-HIV treatment. For example, one nucleoside analogue may be taken in
combination with a protease inhibitor. Clinical trials are under way around the world
to see if this is a more effective treatment. At this stage there is insufficient information
to say how long the combinations of drugs will be effective and to what degree the
progress of the illness will be delayed. 

It is too early to know the side effects of protease inhibitors. In the early trial with the
Abbott protease inhibitor ABT 538, the only side effects reported were an increase in
triglycerides (a form of cholesterol that indicate some viral activity) and some local
numbness. However, larger studies are needed to provide more information on the
side effects of ABT 538. Saquinavir is another protease inhibitor being trialed and
again there are few side effects being reported. There is evidence that the body has
trouble absorbing saquinavir which raises doubts about its effectiveness.

Conclusion

There are now two different approaches to preventing HIV reproduction in the human
T-cells. The nucleoside analogues are designed to prevent the conversion and
integration of the viral RNA into the human DNA. The aim is to stop the cell from
producing new viruses that go on to infect other T-cells.

The protease inhibitors work at a later stage in the cycle, once viral DNA is inserted
into the cell's DNA. Protease is the enzyme that builds the new virus from protein.
When this enzyme is inhibited, the process is stopped or slowed and therefore new
virus can not be made in that cell.

Neither of the anti-viral treatments are perfect. The only work for a period of time
before the virus is able adapt and no longer be affected by the drug. This is called
resistance. The use of single drugs does not provide long term benefit. It is hoped that
studies looking at the use of anti-virals in combination will be more effective in fighting
the HIV infection.  




DRUG RESISTANCE

By Ian McKnight-Smith
(adapted from article by Edward King/AIDS Treatment Update) 

Most reports about antiviral treatments against HIV include discussions about the
development of HIV strains that are resistant to these treatments. Resistance seems
to occur due to a kind of 'natural selection'. When someone starts taking an antiviral
drug against HIV, such as AZT, the virus that is highly sensitive to the drug is rapidly
killed. This leaves behind strains of HIV that are naturally less susceptible to AZT. 

When HIV reproduces, the new viruses often have small changes or mutations in their
structure. Some of these mutations occur in the HIV enzymes, such as the reverse
transcriptase and the protease enzymes, that are targeted by the antiviral drugs (see
article in this issue of HIV Herald). Particular mutations can result in virus strains that
are less susceptible to the effects of antiviral drugs. That is, antiviral drugs do not
effectively inhibit the reproduction of the mutated or resistant HIV virus.

Over a period of time, the 'pool' or amount of viruses that are sensitive to the
treatment decreases and this leaves only strains of virus that can survive and grow
in the presence of the antiviral being taken. A new pool of resistant viruses is created.
Tests can now identify the presence of the HIV mutations that provide resistance to
antivirals. Researchers can artificially produce HIV particles that have specific drug
resistant mutations, allowing them to study their effects and interactions.

There is now a growing body of information indicating that the development of HIV
strains that are resistant to AZT may have a significant and negative impact on the
survival time of the person who has this resistant form of HIV. Some research
suggests that the development of high level AZT resistance is linked to an increased
risk of disease progression even in people who switch to antivirals such as ddI or ddC.

The development of resistance is not confined to the antivirals used against HIV; it
occurs with many of the drugs that are used to treat the opportunistic illnesses
associated with HIV. A number of antibiotics and antifungals see resistance develop
relatively quickly if used as a single drug therapy. For example, resistance to many
antibacterial agents used against tuberculosis has been documented.

Cross Resistance
At the Second International Congress on Drug Therapy on HIV in Glasgow, researcher
Dr. Brendan Larder reported that some mutations caused by anti-HIV drugs can make
the virus resistant to drugs which the individual may never have taken. This
phenomenon is called cross resistance.

The mutations caused by AZT do not appear to be cross resistant to other anti-HIV
drugs. However there does appear to be cross resistance between ddI, ddC and 3TC,
so HIV strains that are resistant to one of these drugs also have reduced susceptibility
to the others. Research presented in Glasgow raised questions about the possibility
that cross resistance may also occur between the members of the group  of drugs
called protease inhibitors (see article in this issue ).


Consequently, current drug treatment may affect the benefits of other drugs in the
future. This is particularly true of drugs such as AZT, ddI and ddC. However, there are
benefits to be had from the current treatments and delaying use may adversely affect
a person's prognosis or quality of life.

Cross resistance is caused by a mutation which confers resistance to several drugs.
This is different to multi-drug resistance in which a single strain of HIV develops
several mutations which create resistance to a specific drug. Multi-drug resistant
strains can develop in people who have taken several anti-HIV drugs at one time.

 
Using Resistance For Benefit
In 1992 researchers in Boston reported that by exposing HIV to three drugs
simultaneously, HIV developed mutations, which made it unable to reproduce or go
on to infect other cells. There was considerable interest in encouraging the virus to
mutate into a form that was not able to live or reproduce. 

However, it soon became clear that the experiments had been flawed. Researchers
found that HIV could develop resistance to several drugs and still be able to infect and
kill cells.

Nevertheless, research presented in Glasgow suggested that there may be still a role
for exploring virus mutation. One explanation for the promising results seen with the
combination of AZT and 3TC is that the combination prevents the development of AZT
resistant strains of HIV, or makes them susceptible to treatments again.  The pressure
to mutate may have been toward forming resistant strains to 3TC that were in turn
sensitive to the effects of AZT. Dr. Larder further reported that in the test tube, it had
been impossible to produce strains of HIV that were resistant to both AZT and 3TC.





New CMV Retinitis Treatment

By Ian McKnight-Smith

A study conducted by the National Eye Institute (NEI) in the United States has
reported that the use of ganciclovir implant pellets are effective in treating CMV
retinitis, a sight threatening illness that affects a high proportion of people with HIV.

The implant consists of a small pellet measuring four millimetres in diameter, which
contains a sustained release formulation of the drug ganciclovir. This pellet is inserted
directly into the inside of the eye, where it releases a small but steady amount of the
drug over a period of several months. When the drug supply is exhausted a new pellet
will be inserted.

The study results show CMV is slowed or halted in people recently diagnosed with the
illness. The average period of remission was approximately eight months. In the
control group, who received no immediate treatment, the retinitis was seen to be
significantly worse within fifteen days of entering the study. "The findings provide
strong scientific evidence that this experimental device can help to improve treatment
and potentially the quality of life for thousands of AIDS patients worldwide," said Dr
Kupfer, one of the principal researchers.

Currently CMV retinitis is treated with the use of intravenous infusions of ganciclovir
or foscarnet. While these treatments can be effective in slowing progression of the
illness, they are also invasive because the recipient undergoes daily intravenous
infusions throughout his or her life. This has prompted investigations into a better way
of taking the drugs. 

The eye implants will require people with CMV to have minor surgery to insert the
device. The procedure is performed quickly under local anaesthetic, taking less than
one hour to perform in an outpatients setting.

The American Federal Drug Administration has not yet approved the ganciclovir
implant, however the results from this study may accelerate the approval process, and
the subsequent approval of ganciclovir for use in Australia. Pharmaceutical company
takeovers may further delay the use of ganciclovir in this country. Roche has taken
over Syntex, and Syntex was negotiating the licensing of the implant formulation of
ganciclovir with the manufacturers. Negotiations were not completed and this process
appears to be back at square one.

The study evaluated the safety and efficacy of the ganciclovir implant as the first line
of treatment for the newly diagnosed people with AIDS and peripheral CMV retinitis.
Twenty-six people were studied; thirty eyes were randomly assigned to either
immediate treatment with the pellets (within 48 hours of entry into the study) or
deferred treatment (when there were indications of progression of the illness).

The study found that in the people who received immediate treatment, the ganciclovir
implants eliminated all signs of active CMV for an average of 226 days, or about eight
months in total. In the deferred group this time to progression was reduced to 15 days.

The optimal time to replace the implants still has to be determined, but researchers
suggested that the life of the implant would around thirty-two weeks to ensure that the
risk of relapse was minimised. The researchers commented, "we found that the
implants released the drug into the eye at variable rates, making it hard to know when
the device actually needed to be replaced."

The researchers further reported that the participants enjoyed good vision with the
implant. By the final follow up eye examination, thirty-four or the thirty-nine eyes
treated with the implant had nearly perfect vision. However most patients reported
blurred vision immediately after receiving the ganciclovir implant; normal vision took
about four weeks to return.

A number of other difficulties emerged during the study. Detachment of the retina, a
common problem for people with CMV retinitis, occurred in eighteen percent of the
eyes in the study. The researchers said that they were unclear as to whether the
detachments were due to the implants or to the CMV illness itself. Because the
implant releases ganciclovir into one eye, the researchers are concerned  that such
an approach may result in one eye being protected against retinitis and the other then
being free to develop symptoms, and possibly at an accelerated rate. In addition, eight
of the participants in the study developed CMV infections in other parts of the body.
These people then had to be treated with the conventional forms of intravenous
ganciclovir or foscarnet.

Further studies are being conducted overseas to expand the experience with this form
of treatment. In Australia, a few people have had experience with the treatment when
the parent company offered the National Centre of HIV Epidemiology and Clinical
Research some sample kits to use with selected patients. The  HIV Herald does not
know of any plans to market the product.


Hepatitis C infection does not influence survival in AIDS
By Ian McKnight-Smith
Hepatitis C and HIV co-infection does not appear to have a significant impact on the
survival of gay men with HIV/AIDS, according to a report from San Francisco.
Researchers compared co-infection in a group of gay men who were not intravenous
drug-users, and a control group of general blood donors. They found that unprotected
gay sex may be a means of transmitting hepatitis C.

Both hepatitis C (also known as HCV) and HIV are known to be transmitted by
injection (parenteral), and co-infection with these two viruses is common among
people with a history of unsafe intravenous drug use or transfusion. Researchers
commented, "It is less clear whether hepatitis C, like HIV is sexually transmitted; and
there is  limited information available about the prevalence of hepatitis C and HIV co-
infection among gay and bisexual HIV-infected patients without a history of
intravenous drug use".

Initial reports indicated that HIV accelerates the course of hepatitis C illnesses, in
particular liver disease, however the overall impact on people with both illnesses has
been unknown. This recent study looked at the prevalence of HCV infection in a
population of HIV-positive, non-users to determine if there are any differences in the
course of the HIV illness in the group who were co-infected with HIV and HCV
compared with the general HIV population.

The study included 512 participants, 224 of whom had AIDS, 11.7 percent of the total
group were hepatitis immunoassay positive. This was confirmed by use of more
sensitive tests such as PCR. The finding was in direct contrast to a randomly selected
control group of blood bank donors, where the incidence of hepatitis C was a little
greater than one percent.

The results showed that there was no significant difference in the survival time for the
group shown to be hepatitis C positive and those who were negative. When the
groups were looked at in terms of AIDS defining illnesses, again there was no
difference between those who were co-infected with the two viruses and those who
only had HIV.

"Our study suggests that among patients with HIV infection, HCV infection is
transmitted by homosexual contact; anti-HCV was several times more common
(11.7%) in homosexual or bisexual patients from this HIV positive population (53%)
without acknowledged drug use than in volunteer blood donors (less than 2%)", said
the researchers.

"Epidemiological studies now support the idea that HIV infection may facilitate the
sexual transmission of hepatitis C, although the basis for this apparently increased
transmission is unknown." they said. "Actuarial survival in HIV infected patients with
or without AIDS has been shown to be unaltered by the presence of hepatitis B co-
infection", they continued. "This study indicates that HCV, like hepatitis B, does not
influence the survival time of HIV positive people, whether or not they have clinical
symptoms of AIDS".





Vitamin C and the common cold in people with HIV

Adapted from Treatments Update Canada 
October 1994

Background
Many people with HIV/AIDS in Australia and other developed countries buy nutritional
supplements as part of their treatment programs against illness. Some take multi-
vitamin and mineral supplements, while other people have detailed regimens for each
vitamin. People use a wide range of supplements including extra proteins, fatty acids,
co-enzyme Q10 and carnitine. In illnesses where malabsorption, diarrhoea, altered
energy cycles and poor appetite occur, people may look to other ways to maintain
health and nutrition. Vitamin C may be a common supplement.

Vitamin C and HIV
Several years ago researchers reported that vitamin C could block the production of
HIV in the test tube. To achieve a concentration of the vitamin in the body equivalent
to that used in the test tube, it was estimated that a person would have to take a
minimum of twelve grams per day, which is more than six times the normal dose.
Subsequently, some studies have suggested that the use of these very high doses
may cause more harm than good, however the results were conflicting. While many
compounds can block HIV in the test tube, they do not always provide the same
benefit to people with HIV/AIDS. Nevertheless, some doctors and therapists who care
for people with HIV have found that extra vitamin C can accelerate recovery from
illnesses such as the common cold.

Prevention against the common cold
Every year infection from the common cold affects millions of people. Over twenty
research studies have tested vitamin C as a preventative against infection. Overall the
vitamin did not appear to be effective as a preventative agent, although one study did
show the vitamin was protective against infection. The dose needed to achieve
protection against the cold was in the order of three grams or higher.

Reducing symptoms
Information from twenty-one studies suggests that the use of vitamin C can reduce the
severity and the duration of symptoms. Twenty of these studies were double blind
studies, where neither the doctor nor the patient knew whether they were getting the
vitamin or a placebo. In fourteen of these studies the differences reached statistical
significance, and other studies indicated trends in favour of the people taking the
vitamin.

Doses 
These studies do not provide recommendations on the best dosage. Most studies
used a starting dose of one gram which was then increased to four grams when the
symptoms appeared. The highest doses reached six grams per day. Some side
effects, such as diarrhoea, were associated with high doses of vitamin C. However,
as a person becomes sicker, the chance of diarrhoea was reduced in people taking
large doses of vitamin C, such as thirty grams per day.

How could it work?
Researchers are not clear how vitamin C works against illness, nor why high doses
have an influence on the symptoms of the common cold. The immune system appears
to need more vitamin C when people have a cold. When a person has a cold, the
body produces more "free radicals", active compounds which damage cells. It is
thought that the vitamin protects cells from "free radicals" . 


Bits and Pieces

By Ian McKnight-Smith

Nevirapine combination study

The American AIDS Clinical Trials Group has conducted a study (ACTG241)
comparing the use of combinations of anti-viral drugs. Researchers compared
AZT+ddI to AZT+ddI+ Nevirapine in people with less than 350 CD4 cells or T-cells
(the immune cells that HIV infects) who have been on AZT for more than 6 months.
The doses used were 200 milligrams of AZT three times a day, 200 milligrams of ddI
twice a day and 200 milligrams of nevirapine twice a day. 

Participants who received the three drug combination had greater increases in T-cell
count after the forty-eight week study, compared to the participants who received the
two drug combination. Additionally, participants who received the three drug
combinations had a greater reduction in viral load (the amount of virus in the blood)
when compared to the group receiving only AZT and ddI. However the disappointing
news was that there was no difference in the rate of progression of illness between
the two study groups.

Source: Gay Men's Health Crisis (GMHC), New York City, Nov. 1994
                                        

Viral Resistance to Protease 

The Merck pharmaceutical company have been testing a new antiviral drug, which is
a type of protease inhibitor. Resistance to L-735,524 the Merck protease inhibitor, has
been shown in recent clinical studies. Initial research showed that some degree of
resistance occurs after 12-16 weeks on the drug, with a corresponding decrease in T-
cells and an increase in viral load. 

Data on a small group of volunteers who continued to take the Merck drug after the
initial trial showed resistance to the protease drug, as well as cross resistance with
other protease inhibitors that are in development. Merck is now exploring higher doses
of this drug as well as combining it with nucleoside analogues such as AZT or ddI to
determine whether these strategies may delay the development of resistance to both
types of anti-virals.

Source: Project Inform, San Francisco Dec. 1994

More Protease Research

Protease inhibitor research is being expanded by the company Upjohn. Upjohn's first
protease inhibitor U 96988 is currently in multi-dose studies in England. A second
drug, U 103107, is being researched on healthy volunteers in the United States. Both
of these drugs are non-peptide based protease inhibitors, and as such are easier and
cheaper to manufacture than peptide derived drugs such as saquinavir. If these drugs
get into general use, they may be about ten times cheaper than other drugs.
Source: Project Inform, San Francisco Dec. 1994


A possible cause of KS

Karposi's Sarcoma (KS), which causes skin lesions in some men with HIV, may be
caused by a virus. Researchers at Columbia University in the United States, have
found evidence of a previously unknown herpes virus in KS lesions of people with
AIDS. People who do not have HIV and KS do not appear to have the new virus. It
is occasionally present in non-KS tissue in people with AIDS.

The association between KS and the virus does not necessarily mean that the virus
causes KS; it could be a normally occurring virus which prefers to grow in KS tissue.
If the virus does cause KS, the finding will be very important in developing treatments,
determining who is at risk, and preventing the spread of the virus. It is not known
whether the new virus is sensitive to any existing drugs. The December 1994 HIV
Herald noted anecodotal patient reports that a drug called foscarnet, which is used to
treat cytomegalovirus (CMV is a type of herpesvirus) had a positive effect on KS.

Researchers have long believed that KS is not a true cancer; KS is thought to be
caused by an infectious agent other than HIV which only becomes a problem in
people who are immune compromised. KS is twenty times more likely to be found in
gay men with AIDS than in haemophiliacs with AIDS and may be transmitted by
unsafe sexual practices.

The new research used an advanced biotechnology technique called representational
differential analysis (RDA). In RDA, two different tissues are taken from the same
person. In this case, samples are taken from a KS lesion and tissue that is not KS
affected. RDA uses gene amplification (PCR) in order to find genetic sequences which
are uniquely present in the tissue of interest. Once such a sequence is identified, more
conventional techniques can be used to identify it in other tissue samples.

Source: AIDS Treatment News, Dec. 23 1994

