       TreatmentUpdate 53
       ------------------
       Community AIDS Treatment Information Exchange, Vol. 5, No. 4
       October 1994 - ISSN 11817186
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       TABLE OF CONTENTS

       I   ANTI-HIV AGENTS

       A. Cystamine--a new antiviral?

       **********

       I   ANTI-HIV AGENTS

       A.  Cystamine--a new antiviral? 

       Background

       Most anti-HIV drugs (AZT, ddC, ddI, d4T) can block HIV from infecting
uninfected cells. These drugs do not significantly reduce the production of
virus from cells already infected by HIV. Drug companies are testing many
other compounds to find better anti-HIV agents. One potential anti-HIV agent
is cystamine. Researchers in Italy have performed lab experiments using
cystamine, HIV and infected cells. Results from their work suggests that
cystamine can block HIV-infected cells from producing new viruses. 

       Results from the Lab

       Small concentrations of cystamine were able to reduce or block
production of HIV from newly infected cells including T-cells and
macrophages. As well, cystamine also reduced production of HIV from cells
that had been infected for several weeks. 

       An Assembly Line Destroyed

       The research team testing cystamine were not sure why the drug could
stop production of HIV. Cells of the immune system treated with cystamine did
not produce ale natural antiviral substance interferon. Nor did the drug
damage certain enzymes that HIV needs. An infected cell producing HIV is
similar to an assembly line. Different parts are brought together at various
times with lie final product being new HIV ready to infect other cells. By
means of several tests the researchers found that cystamine damaged the virus
assembly line. Instead of producing dangerous virus, lie cystamine-treated
cells produced copies of HIV that were 'defective'.  These copies of lie
virus often had parts missing. In all of the experiments with HIV-infected
cells, cystamine had much greater antiviral effect(s) than AZT. 

       A Drug Given to Children

       Other researchers have used cystamine on mice and rats without causing
toxicity. Perhaps more importantly, researchers gave a compound 'related' to
cystamine, cysteamine, to children with kidney damage without causing
toxicity. These children had cells that could not move/exchange the amino
acid cystine. Levels of cystine then build up forming crystals that damage
the kidney and eventually other organs. Treatment with cysteamine protected
them from kidney damage. 

       Current Use

       The Food and Drug Administration (FDA, USA) has granted a Treatment
IND (Investigational new drug) to Dr. Jes Thoene at the University of
Michigan. This treatment IND is used only for children whose kidneys are
damaged by cystine build up. Sigma Chemical, St. Louis, USA, makes the drug
(in the form of cysteamine hydrochloride). The children receive "50 to 60"
mg per kilogram of body weight every six hours. In the past 7 years patients
could also receive the drug phosphocysteamine made by Medea Labs, Port
Jefferson Station, New York. This other form of cysteamine could be taken in
doses of 1.3 to 1.95 mg per square metre of skin every day. At these doses
the drugs did not cause toxicity in any of the children, but it is not clear
which dose might be best for HIV-infected adults or children until clinical
trials are performed. 

       References: 

       1. Bergamini A, Capozzi M, Ghibelli et al. Cystamine potently
suppresses in vitro HIV replication in acutely and chronically infected human
cells. Journal of Clinical Investigation 1994;93:2251-2257. 

       2. Markello TC, Bernardini M and Gahl WA. Improved renal function in
children with cystinosis treated with cysteamine. New England Journal of
Medicine 1993,328 (16):1157-1162. 

II     INFECTION FIGHTERS

       A. PCP - experimental combinations

       Background

       In North America the life-threatening pneumonia PCP is still a common
cause of death for patients with AIDS. Doctors can choose several antibiotics
with which to treat PCP: 

       * pentamidine (intravenous) 
       * Bactrim/Septra 
       * clindamycin-primaquine 
       * Mepron (atovaquone) 
       * dapsone-trimethoprim
       * trimetrexate-dapsone 

       Side Effects

       These antibiotics can cause side effects in some patients. For some
the side effects are minor and can be ignored but for others side effects can
be severe especially if patients are allergic to sulfa drugs. Drug companies
are testing many antibiotics to find less toxic treatments. Researchers at
Abbott Laboratories (Illinois, USA) have been weakening the immune systems
of rats causing them to develop PCP. The researchers then tested a number of
antibiotics to observe their anti-PCP effects. 

       Erythromycin and Relatives

       In 1989 German doctors reported that 2 to 3 g/day of the antibiotic
erythromycin was an effective therapy for patients (HIV-infected) wit PCP.
Since then two antibiotics 'related' to erythromycin--azithromycin and
clarithromycin have been licensed (for infections other than PCP). Some
doctors treating patients with HIV/AIDS have used these two 'new' antibiotics
in combination with other drugs to treat the life-threatening brain infection
'toxo' (toxoplasmosis) and MAC infection. 

       Antibiotics

       Technicians at Abbott Laboratories gave rats steroids to weaken their
immune systems and then infected them with the microbe that causes PCP. Some
rats received antibiotics while others did not. The researchers used: 

       * Bactrim/Septra 
       * pentamidine 
       * sulfamethoxazole 
       * clarithromycin 

       While each of the antibiotics could reduce the severity of PCP,
combinations of clarithromycin (a drug licensed to Abbott Labs) and
sulfamethoxazole produced better results. Using the drugs together also
seemed to increase the concentration of clarithromycin in the lungs and
blood. 

       From Rats to Humans

       While the scientists tested several doses of sulfamethoxazole, not all
of them can be used in humans. Doctors prescribe clarithromycin in doses of
1 to 2 grams daily when treating MAC infection. Many patients with AIDS
cannot tolerate sulfa drugs so a combination of clarithromycin and sulfa
would not be practical. 

       References: 

       1. Dorlemann A, Reisinger E, Schwander S. et al. Erythromycin in the
treatment of PCP in AIDS patients. V International Conference on AIDS,
Montreal, Canada June 4-9, 1989, abstract TBP 39, page 293. 

       2. Alder J. Mitten, Shipkowitz N. et al. Treatment of experimental
Pneumocystis carinii infection by combination of clarithromycin and
sulfamethoxazole. Journal of Antimicrobial Agents and Chemotherapy
1994;33:253-263. 

       3. Smith GH. Treatment of infections in the patient with Acquired
Immunodeficiency Syndrome. Archives of Internal Medicine 1994;154:949-973. 

       B. Vitamin C and the common cold

       Background

       In Ontario, people with HIV/AIDS who can afford to buy nutritional
supplements often do so (E Mykhalovskiy, personal communication). Some buy
multivitamin/mineral supplements, others may have more detailed regimens and
use extra protein, fatty acids, coenzyme Q10 and carnitine among other
supplements. In a disease where malabsorption, diarrhea and altered energy
cycles (and poor eating habits) may be common, it may not be surprising that
patients buy these products. One common supplement is vitamin C. 

       Vitamin C and HIV

       Several years ago researchers reported that vitamin C could block
production of HIV in laboratory experiments with cells. To achieve this
concentration in the body humans would have to take minimum of 12 g/day of
this vitamin. While many compounds can block HIV infection in the lab, they
do not always provide benefit to patients with HIV/AIDS. Some patients and
doctors who care for them find that extra vitamin C may help them recover
from certain infections faster. One infection where vitamin C has been tested
in humans is the common cold. 

       Vitamin C--Prevention Against The Common Cold? 

       Every year infection from the common cold affects millions of people.
Over 20 research teams have tested vitamin C as a preventative against the
common cold. Overall, the vitamin did not appear to be effective as a
preventative. In one study using Canadian military personnel, the vitamin
clearly protected them from the common cold. It appears that people in these
studies needed at least 3 grams a day to receive benefit. 

       Vitamin C--Reducing Symptoms

       Data from the 21 studies suggest that vitamin C can reduce the
"severity of symptoms", or the amount of time patients had the cold. Twenty
of these studies were double-blind studies (neither patients nor doctors knew
what patients received; vitamin C or a dummy pill) and in some the decrease
in symptoms was statistically significant. 

       Vitamin C Doses

       In analyzing data from the studies it is hard to say which dose of
vitamin C was fee most effective. "Most of the studies [used] 1 g/day
increasing it to 4 grams when symptoms appeared while others took 6 g/day."
One doctor gave patients as much vitamin C as they could tolerate until they
developed 'bowel tolerance' or diarrhea.  Dr. Cathcart found that 'healthy'
patients can get diarrhea when they take between 4 and 15 grams/day of
vitamin C. In comparison sick patients could tolerate up to 30 grams/day
without diarrhea. 

       How It Might Work

       Researchers are not sure how or why high doses of vitamin C could have
reduced symptoms of the common cold. The immune system appears to need more
vitamin C when people have the common cold and additional vitamin C may fill 
this need. The vitamin also protects cells from damage by highly active
compounds called 'free radicals'. While patients have the cold their bodies
may produce higher-than-normal levels of 'free radicals' and vitamin C may
provide some protection. Doctors may wish to keep these results in mind when
treating patients with the common cold. Further details about vitamin C
appear in Treatment Update 13 and 18. 

       References: 

       1. Hemila A. Does vitamin C alleviate the symptoms of the common cold?
A review of current evidence. Scandinavian Journal of Infectious Diseases
1994;26:1-6. 

       C. Protecting eyes from CMV

       Background

       The sight-threatening eye infection CMV retinitis is a common problem
for people wit AIDS in North America. Patients with AIDS who may be at high
risk for this complication are those with less than 100 CD4+ cells,
particularly those with less than 50 CD4+ cells. Usually there are no early
wag signs of retinitis and patients may not suspect that they have it until
some damage has occurred. Regular eye exams by an ophthalmologist are the
only way retinitis can be detected if the patent has no symptoms or normal
vision. Some patients may notice 'floaters' or cotton wool spots across their
eyes. Having floaters alone does not necessarily mean that the patient has
retinitis. 

       Treatment

       Ganciclovir (Cytovene, DHPG) is often the drug that doctors first
prescribe for CMV-retinitis. Initially patients may receive: 

       * 5 mg/kg of body weight/12 hours for 10 to 14 days

Once the infection has stopped spreading patients receive maintenance
therapy: 

       * 5 mg/kg/day for between 5 and 7 days. Some doctors may use a
         Monday, Wednesday, Friday schedule. 

Ganciclovir does not destroy CMV; the drug stops CMV-infected cells from
producing virus. Eventually CMV becomes resistant to the effects of
ganciclovir and the retinitis worsens and patients can lose their vision. 

       Foscarnet (Foscavir(R), Sodium Phosphonoformate)
 
       Doctors may switch patients from ganciclovir to foscarnet. In one
controlled study, 234 subjects received either ganciclovir or foscarnet.
Subjects who received foscarnet lived, on average, 4 months longer than
subjects receiving ganciclovir. This difference was statistically
significant. Subjects receiving foscarnet who had kidneys that were not
working normally did not have extended survival. Initially, doctors often
prescribe foscarnet 60 mg/kg for 1 hour every 8 hours for 2 or 3 weeks. As
well, some doctors suggest that an infusion of salt solution (1 litre) during
therapy reduces the toxicity of foscarnet to the kidneys. For maintenance
therapy doctors may prescribe 90 to 120 mg/kg/day. Some doctors are
experimenting with different schedules such as Monday, Wednesday, Friday;
others recommend Monday through Friday. 

       Few Choices
 
       Eventually the protection of foscarnet will fade. Some researchers
think that not enough foscarnet or ganciclovir enters the eye and this is why
the virus quickly becomes resistant to those drugs. To preserve vision some
doctors and their patients are experimenting with different regimens, drugs,
and new ways to deliver drugs to the eyes. Here are some examples: 

       * combination therapy with ganciclovir and foscarnet 
       * alternating treatment with ganciclovir or foscarnet 
       * pellets of slow-release ganciclovir in the eye 
       * gene therapy 
       * new antiviral drugs such as HPWC 
       * new foams of old drugs such as Valaciclovir 

In this issue of TreatmentUpdate/TraitementSida we report on some of these
drugs and over reports on potential CMV therapies will appear in future
issues. As we go to press we do not have details about the effectiveness of
gene therapy. 

       References: 

       1. Smith GH. Treatment of infections in the patent with Acquired
Immunodeficiency Syndrome. Archives of Internal Medicine 1994;154:949-972 

       2. Kupperman B, Quiceno JL, Flores-Aguilar M, et al.  Intravitreal
ganciclovir concentrations after intravenous administration in patients with
cytomegalovirus-retinitis; implications for therapy. Journal of Infectious
Diseases 1993;168:1506-1509. 

       3. Polis M, De Smet M, Baird BE, et al. Increased Survival in a cohort
of patients with Acquired Immunodeficiency Syndrome and CMV retinitis who
received sodium phosphonoformate. American Journal of Medicine
1993;94:175-180. 

       D. Combination treatment for CMV eye infections 

       Background
 
       Although the drugs ganciclovir and foscarnet can block infection and
damage from CMV, these drugs do not destroy the virus. Eventually
patients treated with these drugs have outbreaks of retinitis. In some
cases patients can have worsening symptoms in as little as 3 months
after starting maintenance therapy. As there are no widely available
alternatives, doctors are experimenting with combinations of both drugs.
 
       Treatment and Maintenance
 
       Doctors at the University of California-Davis recruited 9 subjects (8
males, 1 female) with CMV retinitis into their study. At first these
subjects received ganciclovir intravenously 5 mg/kg/12 hours for
between 2 and 4 weeks until they had reduced symptoms (3 of the
subjects also received oral ganciclovir but doctors did not provide
further details). Alternatively, doctors prescribed foscarnet for some
patients 60 mg three times daily for between 2 and 4 weeks until
symptoms resolved. At that point doctors then gave them maintenance
therapy. Subjects on foscarnet maintenance therapy received either 90
or 120 mg/kg/ day. Subjects on ganciclovir maintenance therapy
received 5 mg/kg/day of that drug. 

       Combinations for Relapse
 
       When subjects had worsening symptoms doctors gave them combination
 treatment: 

       * ganciclovir 5 mg/kg twice daily and foscarnet 60 mg/kg 3 times daily
         for between 2 and 4 weeks. Once the infection was stopped then
         doctors prescribed one of two combination maintenance regimens: 
       * low-dose; ganciclovir 5 mg/kg/day and foscarnet 90 mg/kg/day 
       * high-dose; ganciclovir 5 mg/kg twice daily and foscarnet 120
         mg/kg/day 

       Did It Work?

       Recovery from eye damage varied. Seven subjects had "complete healing
in both eyes", while others had complete healing in one eye and partial
healing in the other. The 2 subjects with partial healing did not take
their drugs as directed by the doctors. 

       Doses and Recovery

       All 14 subjects who had 'complete' healing in their eyes received
high-dose treatment and maintenance therapy. According to the study doctors,
subjects did not have serious side effects. As well, subjects did not receive
an infusion of one drug immediately after the other because of potential
toxicity. 

       Survival and Persistence

       Eventually most subjects died. About 1/2 the subjects lived for 1 year
after doctors diagnosed CMV retinitis; the study lasted for about 1 year.
According to be study doctors, "[subjects]...must be [very committed] to this
[therapy because of the time involved--5 hours daily initially and then 3
hours during maintenance. Larger studies looking at combination treatment and
maintenance therapy are underway in the USA. 

       References: 

       1. Kupperman BD, Flores-Aguilar M, Quiceno JL at al. Combination
ganciclovir and foscarnet in the treatment of clinically resistant
cytomegalovirus retinitis in patients with Acquired Immunodeficiency
Syndrome. Archives of Ophthalmology 1993;1 11:1359-1366. 

       E. Alternating treatments for CMV to avoid resistance 

       Background

       Infection of the eye by CMV (cytomegalovirus) can cause a variety of
problems including the sight-threatening problem, CMV retinitis.
Although ganciclovir and foscarnet can, for a time, stop further eye
damage, they do not destroy the virus but simply block infected cells
from producing more virus. Eventually the virus can tolerate the effects
of these drugs and eyesight is threatened. There are few alternatives
left for patients to use. To reduce the chances of CMV becoming
resistant to ganciclovir and foscarnet doctors in Berlin are
experimenting with a new schedule for maintenance therapy. 

       Maintenance

       Doctors in Berlin enrolled 11 male subjects with AIDS in their pilot
study. All subjects had CMV infection in various places, including the
stomach, eyes, brain and throat. At least half of the subjects had a
CD4+ cell count of 20 cells. Researchers did not provide details on CD8+
cell counts. Six subjects received a combination of ganciclovir 5 mg/kg
"twice daily" as well as 60 mg/kg of foscarnet "3 times daily" for 3
weeks. The remaining 5 subjects received ganciclovir 5 mg/kg/day. All
subjects received "maintenance therapy": "ganciclovir 5 mg/kg every other day
alternating with foscarnet 120 mg/kg every other day." At least half of the
subjects received maintenance therapy for 5 months. 

       Results--Symptoms, Survival and Toxicity
 
       Half of the subjects did not have any worsening symptoms of CMV
infection for 15 weeks once they started maintenance therapy. During
maintenance therapy common side effects included "nausea and
vomiting." The researchers think that these side effects were caused
by foscarnet. By the 5th month of therapy 1/2 the subjects died and
later a total of 9 subjects were dead. Four subjects died from
complications due to CMV. One subject tolerated maintenance therapy
for nearly 1 year and 3 others for more than 6 months. According to
the researchers, larger trials of this combination should provide
answers about the effectiveness of combination therapy versus 1-drug
therapy (mono-therapy) for maintenance therapy. 

       REFERENCES: 

       1. Peters M, Schrmann D, Bergmann F. et al. Safety of alternating
ganciclovir and foscarnet maintenance therapy in Human
Immunodeficiency Virus (HIV) -related cytomegalovirus infection: an
open-label pilot study. Scandinavian Journal of Infectious Diseases
1994;26:49-54. 

       F. Acyclovir plus

       Background 

       Herpes viruses are a group of viruses including: 

       * HSV-1 and -2 herpes simplex virus 1 and 2) 

       These viruses can causes lesions/sores, eye and brain infection. 

       * CMV (cytomegalovirus) 

This virus call cause the sight-threatening infection CMV retinitis,
infection of the brain, bone marrow and intestine. 

       * EBV (Epstein-Barr virus) 
       * VZV (varicella Zoster virus) 

These virus can cause shingles and patients may have fever, chills,
fatigue, muscle and joint pain. 

       Doctors can prescribe the anti-herpes drug acyclovir (Zovirax(R)) to
treat sores caused by HSV. Once the patient recovers, they may take
lower doses of acyclovir to suppress the appearance of sores. The
problem with taking continuous doses of the drug is that the virus will
become resistant to acyclovir. At first doctors may raise the dose of
acyclovir and this will probably help patients. Eventually the virus
becomes resistant to even high doses of acyclovir (4,000 mg/day). At
this point doctors may prescribe any one of the following drugs
intravenously: 

       * acyclovir S to 10 mg/kg/day 
       * foscarnet 60 mg/kg once or more daily 
       * ganciclovir S mg/kg/day 
       * vindarabine 15 mg/kg/day 

       In cases where the lesions are on the skin sometimes covering the skin
 with gauze wet with trifluridine (Viroptic(R)) can help. 

       Note: For women with sores on their external genitals, Viroptic may
not be as effective as in men. 

       Unfortunately doctors are reporting more cases of herpes infections
 that are not only resistant to oral ganciclovir but to foscarnet and
 other drugs. 

       Acyclovir

       When swallowed, only about 20% of acyclovir gets absorbed. To increase
blood levels of acyclovir physicians may order intravenous acyclovir.
This is not convenient for patients and eventually the virus may
become resistant to even this. Some Patients with AIDS are taking up to
4 grams/day of acyclovir to delay the sight-threatening infection CMV
retinitis. Researchers have not proven that this dose of oral acyclovir
can delay this complication. Some researchers think that increasing the
concentration of acyclovir inside the body may delay serious herpes
virus infections. One way to increase blood levels of acyclovir (other
than intravenous acyclovir) may be to take the related compound
valaciclovir. 

       REFERENCES: 

       1. Safrin S. Kemmerly S. Plotkin B. et al. Foscarnet-resistant herpes
 simplex virus infection in patients with AIDS. Journal of Infectious 
 Diseases 1994;169;193-196. 

       2. Smith GH. Treatment of infections in the patient with Acquired
 Immunodeficiency Syndrome. Archives of Internal Medicine
 1994;154:949-972. 

       3. Balfur HH, Benson C, Braun J. et al. Management of
 acyclovir resistant herpes simplex and varicella-Zoster vans infections.
 Journal of Acquired Immunodeficiency Syndromes 1994;7:254260. 

       G. Varicella-zoster(R) for herpes viruses? 

       Background

       In North America and Australia some patients with AIDS are using high
 doses (3.2 to 4 g/day) acyclovir to suppress or delay the appearance
 of: 

       * lesions caused by HSV 
       * the sight-threatening complication CMV retinitis 

       Only about 20% of oral acyclovir gets absorbed when patients swallow
the drug. Although intravenous acyclovir can increase blood levels of
acyclovir higher than oral acyclovir, it is not convenient.  One way to
get greater concentrations of acyclovir in the body is to take a closely
related product, valaciclovir (Varicella-zoster, BW256U87). 

       Study Details

       Researchers in the USA enrolled 14 men and 3 women with AIDS into
this study of Varicella-zoster. No subject had any life-threatening 
infection/cancer and half of them had a CD4+ cell count of 44 cells.
Subjects were not supposed to enter the study if they had "severe or
persistent nausea or diarrhea". Researchers gave subjects one of 2
daily doses of valaciclovir; 1,000 or 2,000 mg, both four times daily for
30 days. The drug came in 250 mg white capsules. 

       Results--Absorption/Concentration

       The researchers found that subjects absorbed valaciclovir rapidly. The
liver and intestines quickly converted valaciclovir into acyclovir. Within
15 minutes after swallowing a dose of the drug, technicians could detect
acyclovir from blood samples. Subjects taking the 2,000 mg 4 times
daily had higher blood levels of acyclovir than did subjects taking 1,000
mg 4 times daily. According to the researchers, blood levels of
acyclovir were "5 tunes greater than those [seen] after [high-dose]
acyclovir (4,000 mg/day)." For the subjects in the high-dose Varicella-zoster
group, blood levels of acyclovir were similar to those seen in subjects
receiving 5 mg/ kg every 8 hours. This is important because in one
study researchers found that intravenous acyclovir seemed to delay
the spread of CMV-retinitis. 

       Toxicity

       About 1/3 of subjects had one or more of: 

       * nausea 
       * vomiting 
       * diarrhea 

       At high doses (2,000 mg/4 times daily) valaciclovir may affect the
bone marrow reducing levels of white blood cells called neutrophils. These
cells play an important role in defending the body from infections.
Subjects whose blood levels of neutrophils fell while taking Valtex had
them return to normal once they stopped taking the drug. 

       But Will It Work?

       The high concentration of acyclovir in the subjects given
Varicella-zoster is
 encouraging. Doctors in Canada and the USA (ACTG 204) are conducting a
 study testing: 

       * low-dose acyclovir, 1600 mg/day 
       * high-dose acyclovir, 3,200 mg/day versus 
       * Valtex 2,000 mg/4 times daily 

to compare which is best at delaying the sight-threatening infection CMV
retinitis in subjects with less than 100 CD4+ cells. Varicella-zoster is made
by
Burroughs Wellcome. 

       References: 

       1. Jacobsen MA, Gallant J. Wong LH, et al. Phase I trial of
valaciclovir, the L-Valyl ester of acyclovir, in patients with advanced human
immunodeficiency virus disease. Antimicrobial Agents and Chemotherapy
1994;38(7);1543-1540 

       2. Jacobson MA. Valaciclovir (BW256U87): the L-Valyl ester of
acyclovir. Journal of Medical Virology 1993; (supplement 1):150-153. 

       H. Controlling yeast infections naturally

       Background

       Fungal infections by Candida in the skin, mouth and vagina are
common in patients with HIV/AIDS. For some people these infections are
minor, in others, serious. Other fungi attack the brain and lungs.
Guidelines for the treatment of various fungal infections produced by
the British Society for Antifungal Therapy appear in TreatmentUpdate
38. 

       Why Yeasts?

       Yeast infections are common for at least 2 reasons
 
       * a weakened immune system 
       * long-term use of antibiotics 

       Humans have 'friendly' bacteria living in their mouths and intestines.
These 'gut bugs' feed on milk sugar and produce vitamins which we
absorb. Friendly bacteria also physically occupy space in our intestines
This occupation (or colonization) of space by friendly bacteria prevents
other microbes from growing. As well, friendly bacteria make chemicals
which prevent fungi from growing out of control. Under normal conditions
humans also have a small amount of Candida in their intestines. 

       Helping Yeast
 
       The normal balance of microbes in the body can change because of 

       *  stress 
       *  use of antibiotics (they kill friendly bacteria) 
       *  diets high in sugar (which help yeast grow) 
       *  drugs that suppress the immune system (corticosteroids) 
       *  chemicals produced by yeast which suppress the immune system 

       Risks and Benefits
 
       For most people simply using antifungal drugs will stop the fungus
from spreading. Patients with HIV/ AIDS will probably still need to
take antifungal drugs after the infection has been treated so that they
do not 'relapse'. For these patients intermittent (such as Monday,
Wednesday, Friday) or reduced doses of an antifungal drug are a
typical maintenance strategy. Doctors and their patients will need to
weigh the risks of long-term use of antifungals (drug-resistant yeast,
potential toxicity to the immune system) against the benefits (clearance
of infections, improved quality of life). 

       Changes to the Diet
 
       Researchers experimenting on mice with damaged immune systems have
made some interesting discoveries that may help some people with
HIV/AIDS. It appears that sugar encourages the growth of yeasts. As
well, we have heard reports from several doctors and their patients
that eating less sugar has helped them reduce outbreaks of yeast
infections. 

       Substitutes
 
       For some people simply reading the list of ingredients of processed
food that they buy is a good way to begin learning about the sugar in
their diet. Sugar may be 'disguised' from the ordinary shopper as 

       *  corn and maple syrup 
       *  fructose 
       *  glucose 
       *  grape or raisin juice 
       *  invert sugar 
       *  sucrose 

       Some people replace these forms of sugar with
 
       *  barley malt extracts (which have complex carbohydrates but still
          taste sweet) 
       *  concentrated apple and pear juices to sweeten the taste of baked
          foods 
       *  Nutrasweet(R) (aspartame) 

Others add soluble fibre (found in apples, bananas, barley, carrots,
citrus fruits, oats) to their diet. As well, some people eat yogurt and
take capsules of friendly bacteria because yogurt may not have 

       *  friendly bacteria that are alive 
       *  strains of bacteria such as Lactobacillus bifidus or Lactobacillus
          acidophilus that are good at colonizing the intestines 

These patients and their doctors 'save' their antifungal drugs for
when they have an outbreak of oral/vaginal fungal infections or take
them intermittently 1 or 3 days a week. These courses of action may
delay the appearance of drug-resistant fungus. 

       References: 

       1. Vargus SL, Patrick CC, Ayers G and Huges WT. Modulating effect of
dietary carbohydrate supplement on Candida albicans colonization and
invasion in a neutropenic mouse model. Infection and Immunity
1993;61:619-626. 

       2. Muller F. Froland SS, Brandtzaeg P and Fagerhol MK. Oral
candidiasis is associated with low levels of protid calprotectin in
individuals with infection due to human immunodeficiency virus infection.
Clinical Infectious Diseases 1993;16:301. 

       3. Myers CD. HIV and dietary supplements revisited. Brochure July
 1993 (available at CATIE). 

       4. Tavares ]:), Salvador A, Fereira P and Arala-Chaves M.
Immunological activities of a Candida albicans protein which plays an
important role in the Survival of the microorganisms in the host. Infection
and Immunity, 1993;61(5):1881-1888. 

       5. Hilton E, Isenberg HD, Alperskin P. et al. Ingestion of yogurt
containing Lactobacillus acidophilus as prophylaxis for candidal vaginitis.
Annals of Internal Medicine 1992;116(5):353-357. 

       ACKNOWLEDGMENTS: 

       1. We thank CD Myers Ph.D. for helpful advice and comments. 

       I. Living with drug-resistant fungus
 
       Background
 
       As the immune systems of patients with HIV/AIDS degrade they become
at higher risk for various infections. Fungal infections caused by
Candida in the mouth/throat and vagina can be common. Licensed in
the late 1980s in the European Union the antifungal drug fluconazole
(Diflucan(R)) has been used to treat a range of fungal infections in
patients with AIDS. In general, the drug is low in toxicity (although it may
be linked to the death of several patients) and effective against fungi
infecting the mouth/throat and vagina. Once the infection has been contained
patients will need maintenance therapy. Over time the fungus may begin to
tolerate fluconazole. Patients with oral/throat fungal infections may have 
 
       * "altered sense of taste" 
       * "burning" or other pains in the mouth 
       * pain when swallowing 

At this point doctors and their patients have a few options by switching to 

       * ketoconazole 200 to 800 mg/day 
       * higher doses of fluconazole 100 to 800 mg/day 
       * oral amphotericm B--2 g/day 
       * intravenous amphotericin B 50 mg/kg 3 times weekly 
       * itraconazole capsules 200 to 400 mg/day 
       * itraconazole liquid 200 to 400 mg/day 

       Itraconazole capsules versus liquid
 
       Doctors in Britain have been experimenting with a liquid form of
itraconazole (called itraconazole cyclodextrin 10 mg/ml). The researchers
used 43 patients with HIV/AIDS who had fungal infections in their
mouth/throat.  At first these patients were using either ketoconazole,
fluconazole or itraconazole capsules. As the fungi became tolerant of these
drugs patients had more outbreaks of yeast infection.  Doctors then
prescribed the other drugs but the fungi eventually became resistant to them.
Janssen, the manufacturer of itraconazole, produced the itraconazole liquid.
Patients received 200 to 400 mg/day. 

       Itraconazole Liquid
 
       The researchers found that 18 subjects recovered from the infection.
The dose of itraconazole used did not seem to affect who recovered. Once the
infection was stopped patients received either 200 or 400 mg/day as
maintenance therapy. Patients using the 400 mg/day dose did not have another
outbreak of yeast for about 3 months while those receiving the 200 mg/day
doses relapsed about 2 months later. 

       Itraconazole Liquid--Toxicity

       One patient had a rash but this cleared and did not appear when the
patient resumed taking itraconazole. Eight patients had diarrhea but it
is not clear if the liquid caused the diarrhea. One subject who later used
800 mg/day developed low blood levels of potassium. As yet, the best dose of
liquid itraconazole with which to treat patients with drug-resistant fungi
is not clear. Based on results from lab experiments, some researched are
suggesting doses of 400 mg/day or more for such infections. 

       References: 

       1. Sanguineii A, Cschael K, Campbell K. Fluconazole-resistant Candida
albicans after long-term suppressive therapy. Archives of Internal Medicine
1993;153:1122. 

       2. Garber GE. Treatment of oral Candida mucositis infections. Drugs
1994;47(5):736740. 

       3. Baily GG, Perry FM, Denning DW and Mandal BK. Fluconazole resistant
candidosis in an HIV cohorts AIDS 1994;8(6):787-792. 

       4. Menichetti F. Del Favero A, Martino P. et al. Preventing fungal
infection in neutropenic patients with acute leukemia: fluconazole compared
with oral amphotericin B.  Annals of Internal Medicine 1994;120(11):913-918. 

       5 . Cartledge JD, Midgley J. Youle M and Gazzard BG. Itraconazole
cyclodextrin solution effective treatment for HIV-related candidosis
unresponsive to other azole therapy. Journal of Antimicrobial
Chemotherapy 1994;1071-1073. 

       6. Barchiesi F. Colombo AL, McGough DA, et al. In vitro activity of
itraconazole against fluconazole-susceptible and -resistant Candida
albicans isolates from oral cavities of patients infected with human
immunodeficiency virus. Antimicrobial Agents and Chemotherapy
1994;38(7):1530-1538. 

       Toxicity
 
       A. AZT and fluconazole (Diflucan(R))

       Background 

       As the immune systems of people with HIV/AIDS weaken, patients
become at increased risk for various infections. Instead of waiting for
the infection to appear some patients are talking several antibiotics and
antifungal drugs as prevention (prophylaxis). Most of these drugs are
tested in subjects taking just one drug. Moreover, trials with these
drugs often do not take into account the interaction among the various
drugs. Patients talking these drugs may get unexpected side effects. 

       Study Details
 
       Researchers in Ottawa enrolled 12 HIV-infected men with less than 500
 CD4+ cells for this study. Subjects continued to use AZT 200 mg three
 times daily while in the study. Subjects received AZT and fluconazole
 and had blood samples taken at various times to check for blood levels
 of both drugs. 

       Results

       Taking AZT and fluconazole caused subjects to have higher blood levels
of AZT than when they did not take both drugs. This difference
was statistically significant. The researchers are not sure precisely why
this happened. 

       What To Do?

       In another trial where some subjects received fluconazole (100 to 200
mg/day) to prevent a brain infection, subjects receiving fluconazole
and AZT appeared more likely to have some bone marrow damage resulting
in reduced levels of red and white blood cells. The Ottawa researchers
suggest that patients receiving both AZT and fluconazole "should be
monitored for [AZT toxicity]." 

       References
 
       1. Sahel J. Gallicano K, Pakuts A and Cameron DW. Effect of
fluconazole on Zidovudine pharmacokinetics in patients infected with HIV.
Journal of Infectious Diseases 1994;169(5):1103. 

       B. Questions about gp160 vaccines
 
       Background
 
       In the mid-1980s, researchers had a relatively primitive model of
HIV/AIDS. Some researchers thought that getting the body to produce
antibodies against HIV might protect non-HIV-infected people from the
virus and also delay the decline of the immune systems of people with
HIV/AIDS. Information from the cutting edge of HIV/AIDS research
suggests a more sophisticated model of HIV/AIDS. In this model, there
is a complex interplay between the immune system and the virus. It is
now clear that producing antibodies against HIV will not prevent the
decline of the immune system. Indeed, some research suggests that
producing antibodies against the virus may not be the best response 
by the immune system against HIV. Details on this appear in
TreatmentUpdate 38 and 43. As well, the first generation of HIV
vaccines using gp120 and gp160 has not protected uninfected people
from HIV. The data reported about this research used information from
subjects with HIV infection. 

       Autoimmunity

       Shorty after AIDS appeared, researchers began to find clues that the
immune system of patients with HIV/AIDS was attacking itself (a
condition called autoimmunity). It appears that certain parts of HIV
resemble key parts of the immune system. Antibodies cannot tell the
difference between the virus and the immune system and simply attack
whatever 'looks' like the virus. Some researchers think that autoimmunity
plays an important role in weakening the immune system. 

       Vaccines
 
       Now some researchers think that vaccines based on the HIV protein
gp160 may cause the immune system to malice antibodies that attack
itself. An Italian research team used blood samples from subjects who
received certain vaccines: 

       * rgp160 (VaxSyn2' by MicroGeneSys) 
       * rgp120 HIVAC (Vacc-env by Bristol-Myers Squibb) 

       Subjects who received the HIVAC did not make large amounts of
antibodies against HIV. Once these subjects later received VaxSyn they
then made detectable anti-HIV antibodies. Only subjects who received
large doses of rgp160 made antibodies that could attack both the
immune system and HIV. 

       What Do These Results Mean
 
       This researcher found that "about 45% of [subjects] with full-blown
AIDS, but none of the [symptom-free subjects] had antibodies [that
attacked key parts of the immune system]."  Readers should note that
researchers are not certain that these will damage an immune system
already battered by HIV. They do suggest that when scientists are
designing vaccines that they should make ones that do not trigger
autoimmunity. 

       References: 

       1. Mosmann TR. Cytokine patterns during the progression to AIDS.
Science 1994;256(5169):193-194. 

       2. Miedema F. Petit AJC, Terpestra FG, et al. Immunological
abnormalities in human immunodeficiency virus-infected asymptomatic
homosexual men: HIV affects the immune system before CD4+ T helper cell
depletion occurs. Journal of Clinical Investigation 1988;82:1908-1914. 

       3. Katz-Miller S. Too early for vaccine trials say AIDS experts. New
Scientist 25 June 1994, pages 6 to 7. 

       4. De Santis C, Robbioni P. Longhi R. et al. Cross-reactive response
to human immunodeficiency virus type 1 (HIV-1) gp120 and HLA class I heavy
chain induced by receipt of HIV-1-derived envelope vaccines.  Journal of
Infectious Diseases 1993;168:13961403. 

       5. Morow WJW, Isenberg DA, Sobol RE, et al. AIDS virus infection and
autoimmunity: a perspective of tile clinicaL immunological and molecular
origins of tile autoallergic pathologies associated with HIV disease.
Clinical Immunology and Immunopathology 1991;58:163. 

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