       TreatmentUpdate60 - Volume 7, No. 6 - June 1995
       ***********************************************
       Community AIDS Treatment Information Exchange,
       420 - 512 College St, Toronto, Ontario, Canada,
       M6G 4A2
       ***********************************************

       I  ANTI-HIV AGENTS

       A. 3TC (Lamivudine)--early results

       * BACKGROUND

       Developed in Montral, 3TC is a chemical 'related' to AZT.
Experiments on HIV-infected humans using this drug are underway in
North America and in the European Union. In this article we report
results from 2 studies looking at safety and anti-HIV effects, as
well as the development of viruses resistant to 3TC. Detailed
results from a study testing a combination of 3TC and AZT had not
been released as we went to press.

       * STUDY DETAILS

       All 114 subjects were male and had less than 401 CD4+ cells.
Researchers randomly assigned 15 subjects to one of 6 groups, each
group taking a different dose of 3TC. After each dose, researchers
looked for side effects of 3TC. When subjects did not experience
toxicity, the researchers increased their dose of 3TC. Subjects took
3TC in "two equal doses every 12 hours". The doses of 3TC used were
1/2 or 1, 2, 4, 8, 12 or 20 mg/kg of body weight/day. Six months
after entering the study, subjects taking lower doses were allowed
to increase their dose to 8 mg/kg/day, which is about 300 mg/day.

       * TOXICITY

       The researchers claimed that "3TC was well tolerated" at all
doses. Common side effects included:

       - diarrhea               69% of subjects
       - fatigue                56%
       - headache               49%
       - coughing               39%
       - problems sleeping      30%
       - muscle pain            25%
       - nausea/vomiting        19%

       The researchers stated that many of these symptoms were
temporary and "mild". Less than 5% of subjects developed low blood
levels of white blood cells and platelets. Others developed high
blood levels of liver enzymes. According to the researchers, all
these changes were temporary.

       * DEATHS, DISEASES AND DROPOUTS

       Fourteen subjects stopped taking 3TC mostly "because of
[falling] CD4+ cell counts." Five of 11 subjects who developed
life-threatening infections or cancers left the study. One subject
left because of headaches and 2 subjects died. There were no
significant differences between dose groups when researchers looked
at who developed AIDS.

       * COUNTING CD4+ CELLS AND OTHER LAB TESTS

       Before potential subjects received 3TC, doctors made sure
that at least 2 CD4+ cell counts were done. They found that
statistically significant increases occurred even before subjects
received 3TC. In half of the subjects the increase was about 17
cells. CD4+ cell counts reached their highest level during the first
2 months of the study. Half of the subjects had their CD4+ counts
return to their pre-study level after receiving 3TC for 12 weeks.
Despite using different ways of analyzing data, researchers could
not find a link between the dose of 3TC and an increased CD4+ cell
count. Researchers also measured production of virus, levels of
beta2- microglobulin and neopterin, but again there were no
statistically significant links between doses of 3TC and changes in
those laboratory measurements.

       * HIV RESISTANCE AGAINST 3TC

       In other developments, researchers in the laboratory of
virologist Mark Wainberg (Montral) and elsewhere have been studying
the long term effect of 3TC on HIV in 39 subjects with less than 301
CD4+ cells. Subjects received various doses of 3TC (as listed
earlier). Technicians found HIV resistant to 3TC in blood samples
from 13 subjects. Resistance developed in subjects taking low doses
(1/2, 1 or 4 mg/kg/day) as well as in subjects taking high doses
(8, 12 and 20 mg/ kg/day). Resistance appeared as early as 4 months
in some subjects, while in others it appeared in the 10th month of
using 3TC. The researchers could not find any link between the dose
of 3TC used and the development of resistance. As well there was no
connection between the development of HIV resistant to 3TC and
declining CD4+ cell counts and the development of life-threatening
infections. A number of studies of 3TC are underway. There is an
'open-label' trial where subjects can get 3TC taken orally.
Subjects will be randomly assigned to receive either a low dose (150
mg/day) in two divided doses, or 300 mg day, again in a divided
dose. Subjects taking the 150 mg dose may also take AZT. Physicians
in Canada and the USA interested in enrolling their patients in the
open label programme may call 1-800-248-9757 (personal
communication, D. Donaldson, Glaxo-Wellcome and D. Maclean).

       REFERENCES:

              1. van Leeuwen R, Katlama C, Kitchen V, et al.
       Evaluation of safety and efficacy of 3TC (lamivudine) in
       patients with asymptomatic or mildly symptomatic Human
       Immunodeficiency Virus infection: a phase I/II study. Journal
       of Infectious Diseases 1995;171:1166-1171.

              2. Wainberg MA, Solomon H, Gu Z, et al. Development of
       HIV-I resistance to (-)2'-deoxy-3'-thiacytidine in patients
       with AIDS and advanced AIDS-related complex. AIDS
       1995;9(4):351-357.

       B. AZT and L-697,661

       * BACKGROUND

       AZT and related drugs (ddC, ddI, 3TC, d4T--nucleoside
analogues) are supposed to have anti-HIV activity by affecting a key
viral enzyme RT (reverse transcriptase). There is also a different
group of anti-HIV agents call non-nucleoside drugs that can affect
RT, these drugs include nevirapine and L-697,661 (L-697). In
laboratory experiments with cells and HIV, the virus becomes quickly
resistant to drugs such as nevirapine and L-697. In experiments on
HIV-infected humans, researchers confirmed similar results. We now
report results from a study where researchers tested combinations of
AZT and L-697.

       * STUDY DETAILS

       Researchers in Frankfurt enrolled 119 subjects (109 men, 10
women) for a study where some subjects received combinations of AZT
and L-697. Subjects had CD4+ cell counts ranging between 200 and 500
CD4+ cells, with the average count at about 350 CD4+ cells. No
subject used AZT before entering this study nor did any have AIDS.
Researchers randomly assigned subjects to one of four groups or
'arms' of the study:

       - group 1: L-697 200 mg/8 hours
       - group 2: L-697 100 mg/8 hours and AZT 100 mg/day (low dose
                  combination)
       - group 3: L-697 200 mg/8 hours and AZT 100 mg/8 hour (high
                  dose combination)
       - group 4: AZT 100 mg/8 hours

Each group had 30 subjects, except for the AZT only arm which had
29. Researchers conducted the study for about 1 year. During this
time neither doctors nor their subjects were supposed to know which
drug or combinations of drugs they received. The researchers could
unblind the study after 6 months and subjects who remained in the
study could receive the high dose combination (as in group 3) if
they wished.

       * RESULTS-CD4+ CELLS

       Note: the researchers only released data on CD4+ cell counts
for the first 6 months of the study.

       - L-697: compared to their pre-study values, subjects
         receiving L-697 alone had declining CD4+ cell counts. By
         the 6th month of the study, subjects in this group had lost
         at least 57 CD4+ cells.
       - Low dose combination: For the first 3 months, the average
         CD4+ cell count rose as high as 79 cells, after which it
         fell and was no longer statistically significant.
       - High dose combination: half the subjects had an increase of
         55 CD4+ cells by the 3rd month of the study. After that
         point, the increase was no longer statistically
         significant.
       - AZT: these subjects had statistically significant increases
         in their CD4+ cell counts during the first 4 months of the
         study with half of the subjects maintaining an increase of
         84 cells. By the 6th month of this study the increase was
         no longer statistically significant.

       * RESULTS-TOXICITY

       Subjects in this study experienced a number of side effects.
The following differences in side effects among the groups were
statistically significant:

       - nausea: subjects receiving AZT or combinations of AZT were
         2 to 3 times more likely to have nausea than subjects
         receiving L-697 alone
       - irritability: 3 subjects taking AZT developed this problem
         while other subjects did not
       - 'sleeping problems': 4 subjects in the high dose
         combination group had this side effect while no other
         subjects did
       - rash: 6 subjects in the L-697 group and 3 others in the
         high dose group reported this side effect

The researchers did note that six serious events occurred in the
study, and in brackets we note in which arm of the study they
enrolled:

       - 2 subjects committed suicide (1 each in the L-697 and AZT
         groups)
       - 1 'developed' lymphoma (AZT arm)
       - 1 developed an abscess near his rectum (low dose
         combination)
       - 1 had life-threatening inflammation of his appendix (low
         dose combination)
       - 1 subject developed Kaposi's sarcoma (group missing)

       * RESISTANCE TO L-697

       Researchers tested blood samples taken during the study to
check for HIV that had become resistant to L-697. At the start of
the study, all HIV infected cells reduced virus production when
treated with L-697. By the 2nd month, technicians found that
HIV-infected cells had become resistant to L-697. Subjects who
received combination therapy (AZT and L-697) had virus that did not
become resistant until some time between the 4th and 8th month of
the study. Blood samples from subjects receiving AZT alone always
had virus that was affected by L-697. Researchers did not check for
HIV resistant to AZT.

       * BEYOND RESISTANCE

       The researchers conducting this study performed sophisticated
analyses of viral resistance and tried to understand this event. It
appeared that subjects receiving L-697 alone had virus that was 100
times more resistant to the drug than when they entered the study.
While that event is interesting, this study did not show that
combination therapy reduced the risk of developing life-threatening
infections/cancers that are the hallmark of AIDS. L-697,661 is made
by Merck, West Point, Pennsylvania, USA.

       REFERENCES:

              1. Staszewski S, Massari FE, Kober A, et al.
       Combination therapy with Zidovudine prevents selection of
       Human Immunodeficiency Virus type 1 variants expressing
       high-level resistance to L-697,661 a nonnucleoside reverse
       transcriptase inhibitor. Journal of Infectious Diseases
       1995;171:1159-1165.

       II INFECTION FIGHTERS

       A. Who gets PCP despite prophylaxis?

       * BACKGROUND

       Although a number of drugs are available to treat and prevent
the life-threatening pneumonia PCP, some HIV-infected patients
still develop PCP. Researchers in the USA are beginning to
investigate these cases of PCP despite use of preventative
antibiotics (called PCP prophylaxis).

       * STUDY DETAILS

       Researchers used data from 473 men who had less than 200 CD4+
cells "within 6 months before they began [taking preventative doses
of antibiotics] and 3 other men who had [less than 200 CD4+ cells]
within 12 months before they began to use PCP prophylaxis." Thus
researchers used data on a total of 476 men. Seventy-seven percent
of subjects had never had an attack of PCP before entering this
study; their use of preventative antibiotics is called primary
prophylaxis. The remaining 23% of subjects had an episode of PCP
before entering this study; their use of PCP prevention is called
secondary prophylaxis. Drugs used to prevent PCP were
Bactrim(R)/Septras (B/S), dapsone and/or aerosol pentamidine (A/P).

       * RESULTS-SWITCHING DRUGS

       The study began in 1989 with about 20% of subjects using
B/S,73% using AP and 7% dapsone. According to the study doctors,
"use of [B/S] doubled" during the study. This change happened to the
same extent in subjects who had had or who had never had PCP before
entering this study.

       * RESULTS-PCP

       Eventually 19% of subjects developed PCP. Doctors diagnosed
PCP in one of two ways:

       - analyzing samples from the lungs 73%
       - improvement in subjects treated with anti-PCP drugs 27%

       Half of the subjects who had never had PCP before entering
this study developed PCP within 12 months into this study. This
group survived for about 2 years.

       Half of subjects who had had an episode of PCP before
entering this study developed PCP roughly 8 months after entering
this study. This group survived for about 1.2 years. This difference
in survival between the 2 groups was statistically significant; that
is, not likely due to chance alone. Changing the drug used for
prevention did not appear to cause PCP. The type of PCP prophylaxis
did not affect survival.

       Whichever drug subjects used when they first entered the
study did not affect survival (in a statistically significant
manner). Subjects having relatively high CD4+ cell counts (defined
by researchers as 100 or more CD4+ cells) were more likely to stop
using anti-PCP drugs than those with lower CD4+ cell counts. This
event was statistically significant.

       * A DETAILED REVIEW

       Reviewing their data and making adjustments for changes over
time, researchers found "that the most important independent factor
for developing PCP [despite use of preventative drugs] was [a very
low CD4+ cell count]."

       As well, the following factors appeared to provide protection
from PCP:

       - use of B/S
       - cigarette smoking

       In their more sophisticated analysis, AZT was not linked to
preventing PCP because, after "[CD4+] cell counts were considered,
non-users [of AZT] had higher CD4+ cell counts than previous users
who had lower cell counts." That cigarette smoking affected which
subjects developed PCP is interesting. In earlier studies subjects
who smoked cigarettes were more likely to develop PCP than those who
didn't. The researchers warn that their results should not be used
to encourage patients with HIV/AIDS to smoke as that causes lung
problems. According to the researchers, the following proportion of
subjects developed PCP at the cell counts listed:

       - 85%: who had less than 75 CD4+ cells
       - 75%: who had less than 50 CD4+ cells

       The study doctors decided that the microbe that causes PCP
did not become resistant to any of the drugs used by subjects as
prophylaxis. Indeed, subjects who used B/S as prophylaxis recovered
from PCP when treated with the same drug. Finally the doctors stated
that "more effective [regimens against the microbe that causes PCP
need to be developed]."

       REFERENCES

              1. Saah AJ, Hoover DR, Peng Y, et al. Predictors for
       failure of pneumocystis carinii pneumonia prophylaxis.
       Journal of the American Medical Association
       1995;273(15):1197-1202.

       B. Experimental combinations for PCP and toxo

       * BACKGROUND

       Although drugs such as Bactrim/Septra and intravenous
pentamidine are effective against the life-threatening lung
infection PCP, they have side effects which some patients cannot
tolerate. Researchers are testing a number of antibiotics by
themselves or in combination to find alternatives to standard
therapy. Scientists working for Glaxo-Wellcome have been testing
several combinations of anti-PCP drugs in mice, and we report their
results below.

       * MICE WITH PCP

       Researchers used mice with weakened immune systems who were
infected with the microbe that causes PCP. They found that the drugs
Mepron(R) (atovaquone, Wellvone(R)) and dapsone had anti-PCP
activity when used by themselves. The following combinations had
increased anti-PCP activity when used together rather than when used
by themselves:

       - Mepron and azithromycin
       - Mepron and clarithromycin

       While the antibiotic rifabutin (Mycobutin(R)) had no anti-PCP
activity by itself, in combination with Mepron, rifabutin had
significantly increased anti-PCP effect. The researchers noted that
none of the following drugs weakened the anti-PCP effect of Mepron-
azithromycin, B/S, clarithromycin or dapsone.

       * Toxo

       In other developments, researchers in military biomedical
centres and elsewhere in the USA have been testing various compounds
for their anti-parasite activity. Results from their work suggest
that extracts of the Chinese herb A. annua (quinghaosu) and another
antimalarial drug, cycloquanil, can have anti-toxo effects in
experiments with cells and parasites. That antimalarial drugs might
be useful against the microbes that cause PCP/toxo is not
surprising. The drug Mepron was being developed as an antimalarial
until its anti-toxo/PCP effects were discovered. Fansidar is
another antimalarial that some doctors prescribe to prevent toxo. In
the next article we provide details about quinghaosu as an
antimalarial drug and its use in the USA for treating PCP.

       REFERENCES:

              1. Comley JCW and Sterling . Effect of atovaquone and
       atovaquone drug combinations on prophylaxis for Pneumocystis
       carinii pneumonia in SCID mice. Antimicrobial Agents and
       Chemotherapy 1995;39(4):806-81 1.

              2. Holfels E, McAuley J, Mack D, et al. In vitro
       effects of artemisinin ether, cycloquanil hydrochloride
       (alone and in combination with sulfadiazine), quinine
       sulphate, mefloquine, pyrimethamine phosphate,
       trifluoperazine and verampil on Toxoplasmosis gondii. Anti-
       microbial Agents and Chemotherapy 1994;38(6):1392-1396.


       C. Certain drugs may weaken the anti-toxo effects of
          clarithromycin

       * BACKGROUND

       (For information on the symptoms and treatment of the
life-threatening brain infection toxo, please read TreatmentUpdate
59.) One of the problems faced by doctors is that some patients with
toxo may not be able to tolerate standard therapy--a combination of
the antibiotic pyrimethamine and a sulpha drug (such as
sulphadiazine). Doctors may sometimes substitute clindamycin in
place of sulpha drugs. In the EU, some doctors have been
experimenting with the antibiotic clarithromycin to prevent or treat
toxo. As some of their patients at risk for toxo developed that
infection despite use of clarithromycin, they began an investigation
to try and understand what happened.

       * STUDY DETAILS

       Over a period of 20 months, doctors in France treated 21
subjects who had life-threatening MAC infection with a combination
of antibiotics that included clarithromycin, which they took for 3
months. Thirteen subjects had anti-toxo antibodies in their blood,
suggesting that they had been infected with the parasite that causes
toxo (T. gondii). Before being treated for MAC, 1 subject had toxo
but had completely recovered. During the 20 months, 4 subjects
developed toxo after an average of 4 months of treatment with
clarithromycin. None of the other 9 subjects with anti-toxo
antibodies developed toxo.

       * RESULTS

       The researchers tried to find out why some subjects developed
toxo. None of the following differences between the two groups of
subjects was statistically significant:

       - CD4+ cell counts
       - length of time they had AIDS
       - chronic diarrhea
       - weight
       - use of other anti-toxo drugs

       The doctors did find that a difference in drug combinations
between the 2 groups was statistically significant. Subjects who
developed toxo were more likely to have been using Cipro,
ethambutol, ddI and rifampin.

       * EXPLANATION

       As many people with HIV/AIDS can be using several drugs for
different reasons, it is not surprising that these drugs might
interact with each other. The researchers think that ddI might have
reduced the absorption of clarithromyin while rifampin could have
reduced blood levels of clarithromycin. The researchers note that
they only had a small number of subjects in their study and that
another study with more subjects should be conducted to investigate
possible drug interactions.

       * WARNING

       The researchers warn that clarithromycin should not be given
for prevention of toxo/MAC to patients who are also using rifampin.
Patients using such a combination may also develop signs/symptoms of
toxo.

       REFERENCES:

              1. Raffi F, Struillou L, Ninin E, et al. Breakthrough
       cerebral toxoplasmosis in patients with AIDS who are being
       treated with clarithromycin. Clinical Infectious Diseases
       1995;20:1075-1077.

       D. QHS (artemisinin)--experience with malaria

       * BACKGROUND

       Malaria kills between 1 and 2 million people each year.
Although there are several antimalarial drugs available, the
parasite that causes malaria is becoming increasingly resistant to
them. In Asia, where malaria is a serious problem, researchers are
continually trying to find and test new antimalarial compounds.

       * TARRAGON AND SAGEBRUSH

       In the past, practitioners of traditional Chinese medicine
used the bark sweet wormwood (A. annua) to treat hemorrhoids and
about 1700 years ago they documented its ability to "reduce fevers".
More importantly, about 400 years ago, Chinese doctors documented
its antimalarial activity. In the 1970s, Chinese researchers
'rediscovered' the antimalarial activity of A. annua and extracted
the chemical QHS (quinghaosu or artemisinin). The weed A. annua is
'related' to plants such as sagebrush and tarragon. Plant scientists
think that A. annua came from Asia. The weed can be found along the
bank of the Potomac river in Washington, DC. The concentration of
QHS in A. annua is low and researchers have only been able to
extract about "2% of dry plant weight". A. annua growing in Sichuan
province, China, is supposed to have the highest concentration of
QHS.

       * QHS

       Pure QHS or artemisinin looks like "fine, colourless needles"
and does not dissolve in water but can be mixed with oil forming a
'suspension'. Chinese researchers have made drugs 'related' to QHS
and they are:

       - artemether
       - arteeher
       - artelinic acid

       * QHS AND MALARIA

       QHS and related compounds, used in China and Vietnam since
the late 1970s, are potential treatments for malaria and up to 1
million humans with malaria have received QHS or its 'relatives'.
Some researchers think that QHS causes the release of highly active
molecules called 'free radicals', which damage the parasite that
causes malaria.

       * EFFECTIVENESS AGAINST MALARIA

       Several forms of QHS have been tested and the total dose
given over 3 to 5 days is:

       - tablets: 3g (50 mg/kg) or
       - injection (same dose) into muscle (QHS in oil or water).

       Most subjects with malaria recovered within 2 days. Relapse
was more likely among subjects who received tablets than among those
who received injections. In other studies, QHS-treated subjects
recovered faster than others given chloroquine, quinine or
mefloquine. In one study, 21% of subjects receiving QHS relapsed 1
month after treatment, while no relapse occurred among subjects
given quinine during that time.

       QHS has also been made into suppositories and tested in at
least 600 subjects. Giving adults 2800 mg over 3 days (50 mg/kg)
produced "the best results". In trials comparing QHS or related
compounds to standard therapy, preliminary results indicated that
fewer subjects on QHS died.

       * TOXICITY

       In experiments with animals, QHS and related drugs "are
considerably less toxic than [standard therapy]." Large doses of
artemisinin compounds do cause side effects in 'large animals'.
Symptoms of toxicity in dogs include "loss of spinal and pain
responses, restlessness, tremors and incoordination...[problems
breathing and standing], convulsions and [death]."

       According to one team of reviewers, there "have been
remarkably few adverse effects in [humans]" caused by QHS or related
drugs. In summarizing test results, they noted that "there has been
no evidence of significant toxicity in over 4,000 [human] subjects
entered into clinical studies." One research team warns that "for
now, it is best to avoid use of [QHS] compounds in pregnant women
with uncomplicated malaria...".

       * VERY RARE SIDE EFFECTS

       1 of 82 subjects receiving artesunate and 3 of 39 [subjects]
receiving artemether temporarily had a first-degree heart block".
This seemed to have no further toxicity or cause any damage to
subjects. Some subjects receiving more than 4 mg/kg of artemether
had decreased red blood cell counts 4 days after receiving the drug.
One week later they returned to normal. One subject who received
"120 mg/kg" of artemesinin suppositories had temporarily increased
blood levels of liver enzymes. In phase III studies in China, 6% of
subjects using artemisinin suppositories had gastrointestinal
problems such as nausea/vomiting, intestinal pain and diarrhea. As
many as 25% of subjects using QHS and related compounds have
temporary bouts of fever.

       * FUTURE USE

       The cost of developing QHS compounds to meet standards set by
the US Food and Drug Administration (FDA) is high. As well, some
researchers suggest that pharmaceutical companies do not make huge
profits on "antimalarials and do not have an incentive to develop
them".

       * AVAILABILITY

       In some Asian countries--China and Vietnam--QHS containing
compounds are sold for the treatment of malaria in the form of
tablets, suppositories or mixed with oil for injection. Some
researchers think that longer courses of treatment--between 5 and 7
days--may provide better results than shorter courses. In our next
article we report on the potential of QHS as a treatment for
PCP/toxo.

       REFERENCES:

              1. Klayman Dl. Quinghaosu (artemisinin): an
       antimalarial drug from China. Science 1985;228:1049-1055.

              2. Hien TT and White NJ. Quinghaosu. Lancet
       1993;341:603- 608.

              3. Wesche DL, DeCoster MA, Tortella FC and Brewer TG.
       Neurotoxicity of artemisinin analogues in vitro. Antimicrobial
       Agents and Chemotherapy 1994;38(8):1813-1819.

       E. QHS-Chinese herb for PCP?

       * STUDY DETAILS

       At an HIV/AIDS conference in San Francisco last summer,
acupuncturist Susan Paul presented preliminary information on her
use of QHS-related compounds in the treatment of "very early" PCP.
Ms. Paul describes early PCP as "fatigue, lack of appetite and rapid
[breathing] with a sense of chest constriction. At this stage there
is no cough, and chest X-ray and sputum cultures will be negative."
She has treated 13 subjects with PCP who could not tolerate standard
anti-PCP therapy and who developed "very early" PCP. She prescribed
the Seven Forests brand of Bellamoconda 15 (3 tablets, 3 times a
day) and the Brion brand of QHS (2 grams, 3 times/daily) using
loose, single granules. According to her regimen, "therapy is
continued until the patient has been totally cleared of all symptoms
for 7 to 10 days."

       * RESULTS

       She has not found any side effects with this therapy, noting
that no patient experienced diarrhea. Ms Paul is currently
monitoring 6 additional subjects who cannot tolerate standard
anti-PCP prevention. These subjects have an average of 96 CD4+ cell
counts and over a 3-month period have not developed PCP or toxo. Ms
Paul notes that QHS also appears to prevent oral fungal infections.

       * LONG TERM OBSERVATION

       When questioned at the conference about long term results
from her original group of 13 patients, Ms Paul said that 4 subjects
no longer use the herb. One subject developed dementia and is dying;
another developed the life-threatening brain infection 'crypto'
(Cryptococcal meningitis); a third developed severe rectal warts,
seizures and Kaposi's sarcoma. She has not been able to locate the
4th subject. One of her subjects took 20 times the normal dose and
developed nerve damage.

       * QUALITY CONTROL

       We cannot verify the purity of the product used by Ms. Paul's
subjects. Moreover, even doctors in Southeast Asia concede that
factories manufacturing QHS may not produce a highly pure product.
There are also some problems with her definition of PCP, as subjects
could have been infected with other microbes.

       * PROBLEMS

       One possible problem with QHS is the way it is supposed to
work. In treating patients with malaria, QHS causes the release of
highly active molecules called free radicals. As patients with
HIV/AIDS may have weakened defences against free radicals, chronic
therapy with QHS may pose some risk. In experiments on mice with
malaria, removing vitamin E (an antioxidant) from their diet
increased the antimalarial activity of QHS. Trials with short
courses or intermittent use of QHS may be one way to test this idea.

       According to Chinese research, QHS appears to boost CMI
(cell-mediated immunity)--one part of the immune system that is
weakened by HIV infection. This may be useful because many of the
infections seen in AIDS can only be kept in check by CMI.

       Clearly, better studies need to be designed to test QHS'
potential for some of the infections seen in AIDS. The quality of
QHS used in Southeast Asia seems good enough for treating malaria,
and perhaps researchers might consider this when making decisions
about which form of the drug to use.

       REFERENCES:

              1. Saah AJ, Hoover DR, Peng Y, et al. Predictors for
       failure of Pneumocystis carinii pneumonia prophylaxis.
       Journal of the American Medical Association
       1995;273(15):1197-1202.


              2. Holfels E, McAuley J, Mack D, et al. In
       vitro effects of artemisin ether, cycloguanil hydrochloride
       (alone and in combination with sulfadiazine), quinine
       sulfate, mefloquine, primaquine phosphate, trifluoperazine
       hydrochloride and, veridical on toxoplasmosis gondii.
       Antimicrobial Agents and Chemotherapy 1994;38(6): 1392-1396.

              3. Paul S. Herbal prophylaxis for PCP. Presenters
       handbook HIV/AIDS and Chinese Medicine II, San Francisco,
       July 22-24, 1994.

              4. Levander DA, Ager Al, Morris VC and May RG.
       Quinghaosu, dietary vitamin E, selenium, and cod-liver oil:
       effect on the susceptibility of mice to the malarial parasite
       Plasmodium yoeli. American Journal of Clinical Nutrition
       1989;50:346-352.

              5. Meshnick SR, Yang Y-Z, Lima V, et al.
       Iron-dependent free radical generation from the antimalarial
       agent artemisinin (quinghaosu). Antimicrobial Agents and
       Chemotherapy 1993;37(5):1108-1114.

              6. Weinberg GA. Iron chelators as therapeutic agents
       against Pneumocystis carinii pneumonia. Antimicrobial Agents
       and Chemotherapy 1994;38(5):997-1003.

              7. Haque S, Khan I, Haque A and Kasper L. Impairment
       of cellular immune response in acute murine toxoplasmosis:
       regulation of interleukin 2 production and macrophage-
       mediated inhibitory effects. Infection and Immunity
       1994;62(7):2908-2916.

              8. Hien TT and White NJ. Quinghaosu. Lancet
       1993;341:603-608.

       F. Oral ganciclovir, eye implants and other therapies for CMV

       * BACKGROUND

       As doctors in North America have gained experience treating
and preventing some of the infections seen in AIDS, patients are
living longer than when the epidemic first appeared. As patients
survive longer with "very low CD4+ cell counts", they can develop
infections that were not commonly seen at the start of the
epidermic. The sight-threatening infection CMV retinitis is
increasingly being diagnosed in North American patients with AIDS.
That virus can also cause ulcers in the throat and intestines, as
well as infecting nerve cells inside and outside the brain. In a few
patients CMV can cause pneumonia. Standard treatment for CMV is
intravenous ganciclovir or foscarnet. These drugs have side effects
and CMV can become resistant to them. Details about standard therapy
for CMV infection appear in TreatmentUpdate 56. We now report on new
options for managing CMV infection.

       * ORAL GANCICLOVIR

       Researchers in the USA treated subjects who had CMV retinitis
with a 2 or 3 week course of intravenous ganciclovir. As
maintenance, some subjects received oral ganciclovir 1 g three times
daily. On average, subjects given oral ganciclovir had worsening
retinitis "5 to 12 days earlier than [subjects] who received
[intravenous] ganciclovir." (In this trial doctors made decisions
about the effectiveness of the therapy by looking at photographs of
the part of the eye damaged by CMV: the retina. Researchers consider
decisions made by judging photographs to be more 'objective' than
finding out what patients can or cannot see on eye charts). The
difference between the 2 groups in the amount of time for retinitis
to develop was not statistically significant. 50% of patients were
protected from worsening retinitis for between "32 and 45 days" when
treated with intravenous ganciclovir or foscarnet. In the USA, the
FDA has approved the use of 1 g oral ganciclovir 3 times daily as
"maintenance treatment" for CMV retinitis once patients have first
received treatment with intravenous ganciclovir or foscarnet. In a
future issue of TreatmentUpdate we will present data from a study of
oral ganciclovir in the EU.

       * ORAL GANCICLOVIR-PREVENTION FOR SOME

       In other experiments, researchers in the USA found that some
subjects with less than 100 CD4+ cells given oral ganciclovir were
less likely to develop CMV disease than others given placebo (an
inactive therapy). The following subjects developed CMV disease:

       - 31% on placebo
       - 17% on oral ganciclovir

       Thus despite receiving oral ganciclovir, a large proportion
of subjects (nearly 60%) developed CMV disease (mostly retinitis)
anyway. Researchers think that the high rate of breakthrough may be
due to:

       - poor absorption of oral ganciclovir
       - virus became resistant to the drug
       - subjects may not have taken their drug as directed.

       Side effects seen in subjects receiving oral ganciclovir
included bone marrow damage and low blood levels of certain white
blood cells and platelets. In the USA, the use of oral ganciclovir
to prevent symptoms of CMV infection will cost at least $39/day US.
At this time we do not have data on quality of life and survival
from subjects in this study.

       * EYE IMPLANTS-RISKS AND BENEFITS

       In TreatmentUpdate 56 we report results from a study of slow
release pellets of ganciclovir placed inside a device (commonly
called implants) in the eyes of subjects. The advantages of the
implant over standard therapy can include:

       - high concentrations of drugs in the eye
       - no bone marrow or kidney damage
       - less risk of bacterial infections
       - less frequent blood work
       - possible improved quality of life

       Against these advantages there are potential disadvantages:

       - $5,000 per implant every 6 months
       - complications from surgery

       Indeed one researcher warns that "[eye surgeons] with less
surgical skill or experience may have higher complication rates, and
it must be recognized that these complications can have a disastrous
impact on vision".

       * EYE IMPLANTS AND SURVIVAL

       As one researcher notes, "there are no data directly
comparing survival of subjects receiving the [eye implant] with
others receiving intravenous therapy for CMV retinitis". In the
study on the eye implant, 50% of subjects survived for about 10
months. In another study where subjects received "intravenous
maintenance ganciclovir", half of them survived for about 9 months.
In another study, 50% of subjects receiving intravenous foscarnet
survived for between 13 and 14 months.

       * CIDOFOVIR-INTRAVENOUS

       Preliminary results from trials of intravenous cidofovir
(HPMPC; Vistide(tm)) suggest that "5 mg/kg given weekly for 2 weeks,
then once every 2 weeks" appears to stop further damage to the eye.

       * CIDOFOVIR-LIPOSOMES

       Researchers in the USA have made tiny spheres of fat (called
liposomes) containing high concentrations of HPMPC (1 mg). Injected
into the eyes of rabbits infected with a herpes virus, the liposomes
provided prolonged protection from eye damage, lasting between 5 and
8 months. The doctors who made the liposomes were not working for
Gilead Sciences which has a monopoly on the use of HPMPC for
treating CMV infections in humans. See this issue of Treatment
Update for an article on eye injections of HPMPC.

       * ANTIBODIES AGAINST CMV

       Giving subjects who receive transplanted organs (who also
receive immunosuppressive drugs) high doses of intravenous anti-CMV
antibodies seems to reduce the incidence of CMV disease. In subjects
with AIDS these antibodies have not yet provided benefit.

       * OTHER THERAPIES

       Research continues with other drugs such as "anti-sense"
compounds, specially designed anti-CMV antibodies, and eye
injections of ganciclovir, foscarnet or cidofovir (see pages 11-13
of this issue for details on cidofovir).

       REFERENCES:

              1. Polis MA and Masur H. Promising new treatments for
       cytomegalovirus retinitis. Journal of the American Medical
       Association 1995 ;273(18):1457-1459.

              2. Besen G, Flores-Aguilar M, Assil KK, et al. Long
       term therapy for herpes retinitis in an animal model with
       high-concentrated liposome-encapsulated HPMPC. Archives of
       Ophthalmology 1995;1 13:661-668.

       G. Cidofovir (HPMPC) for CMV-safety/toxicity

       * BACKGROUND

       Under development for the past 5 years, cidofovir (HPMPC;
Vistide(tm)) has recently been tested in humans for its toxicity and
anti-CMV effects. This is the first of several reports on this drug.

       * STUDY DETAILS

       Researchers enrolled 31 male adults, all of whom had HIV
infection. Testing of their urine revealed that they were producing
CMV. Half of the subjects had a CD4+ cell count of 61 cells. No
subjects had serious CMV infection in their eyes or other parts of
their body. In this study subjects received various doses and
schedules of cidofovir, ranging from 1/2 mg/kg twice weekly to 10
mg/kg twice weekly. Some subjects also received the drug probenecid
to reduce kidney damage caused by cidofovir.

       * RESULTS

       In general, the higher the dose of cidofovir the more likely
the production of CMV would decline. As no subjects had serious CMV
infection in this study the researchers were not sure which dose was
best. Preliminary results from other experiments suggest that
injection of cidofovir into the eyes of subjects with CMV retinitis
protects them from losing their vision.

       * FOCUS ON KIDNEY DAMAGE

       The most serious problem caused by cidofovir was kidney
damage. Technicians detected increased levels of protein and sugar
in the urine of subjects who had kidney damage. As those subjects
continued to receive cidofovir, kidney damage increased; even
greater amounts of protein and sugar were lost in the urine while
blood levels of important ions (phosphates, bicarbonates) fell. As
well, blood levels of creatinine, produced when kidney cells break
down, increased to over 2 mg/dL. There seemed to be a trend in the
process of kidney damage; protein appears in the urine before sugar.

       Subjects receiving cidofovir 1 mg/kg did not have
"significant [kidney damage]". By that statement, the researchers
meant that blood levels of creatinine did not rise above 2 mg/dL.
Subjects who received doses of cidofovir 3 mg/kg or more had various
degrees of kidney damage. Samples of kidney cells taken from
subjects receiving 3 mg/kg or 10 mg/kg revealed severe damage,
similar to that seen in earlier animal experiments with cidofovir.

       * REDUCING KIDNEY DAMAGE

       To reduce kidney damage researchers gave subjects the drug
less frequently. As well, some subjects received the drug
probenecid. Thus, subjects could tolerate more cidofovir while their
blood levels of creatinine did not rise above 2 mg/dL, nor did their
blood levels of ions fall. Giving subjects extra saline before they
received cidofovir appeared to protect some subjects from kidney
damage.

       * A NOTE ON PROBENECID

       Probenecid is a sulpha drug that doctors sometimes use to
maintain high levels of certain drugs, such as penicillin. In some
studies in the late 1980s, doctors gave their patients probenecid to
keep blood levels of AZT high. Some of those patients were told to
reduce their dose of AZT by as much as 50%. In the experiments with
cidofovir, researchers gave subjects probenecid to protect their
kidneys from damage and in most cases it did.

       * REDUCING THE TOXICITY OF PROBENECID

       Since some people with HIV/AIDS cannot tolerate sulpha drugs,
it is not surprising that some subjects in this study had allergic
reactions when given probenecid including nausea, rashes and
vomiting. To make subjects withstand the allergic reactions, the
study doctors gave some subjects antihistamines. To others, the
doctors first gave small doses of probenecid that were later
increased over three weeks.

       *O DESENSITIZATION

       For the first dose, doctors gave the subjects "10 mg,
increased by 10 mg/kg on days 2 to 5, 20 mg/day on days 6 to 10, 100
mg on day 11 and 250 mg/day on days 12 to 18". To reduce 'upset
stomach', subjects were eventually told to take the drug "after
meals". Use of probenecid "did not appear to [weaken] the anti-CMV
effect of cidofovir". Subjects receiving the 3 mg/kg dose of
cidofovir and who were also taking probenecid had a delay in the
time it took to suppress production of CMV (from 7 to 27 days).

       * SYMPTOMS

       One subject who had a herpes lesion near his rectum which did
not heal despite receiving acyclovir had his lesion heal when he
started to use cidofovir at 5 mg/kg week. Another subject with
'oral hairy leucoplakia' on his tongue had that infection clear
after his first dose of cidofovir also at 5 mg/kg/week. Cidofovir
used in this experiment was supplied by Gilead Sciences, Foster
City, California.

       REFERENCES

              1. Lalezan JP, Drew WL, Glutzer C, et al.
       (S)-1-[3-hydroxy-2-phosphonlmethoxy)propyl] cytosine
       (cidofovir): Results of a phase I/II study of a novel
       antiviral nucleotide analogue. Journal of Infectious Diseases
       1995;171:788-796.

       H. Cidofovir-anti-CMV activity

       * STUDY DETAILS

       In this study, researchers recruited 21 male HIV-infected
subjects, at least half of whom had a CD4+ cell count of 39 cells.
Subjects did not have symptoms of CMV infection but were all
producing CMV, detected in their urine samples. Moreover, blood
samples from 15 subjects also had CMV. As with our earlier report,
subjects received a range of doses and schedules of cidofovir(HPMPC;
Vistide(tm)). To reduce kidney damage, doctors gave some subjects 1
litre of saline before they started to receive cidofovir. All
subjects receiving cidofovir 5 mg/kg/week or more took 2 g
probenecid 3 hours before receiving the cidofovir and 1 g at two and
eight hours after they received cidofovir.

       * RESULTS-TOXICITY

       The most common side effect of HPMPC was kidney damage.
Technicians first detected increased protein and sugar in the urine
samples of subjects; indicating that kidney damage had occurred.
Seventeen subjects had protein detected in their urine samples at
some point during the study. In most subjects, the kidney damage was
temporary. One subject, who also received the anti-HIV drug d4T
(stavudine), developed some heart damage during the study. When he
stopped taking both drugs, he recovered after several months.

       * SERIOUS SIDE EFFECTS

       Two subjects developed skin rashes when given probenecid.
Doctors gave these subjects Tylenol and the antihistamine
Benadryl(R). Despite these measures, one subject had a severe
reaction and went into shock. He later recovered and never again
received probenecid. Another subject had severe nausea when given
probenecid and cidofovir and left the study.

       * ANTI-CMV EFFECTS

       In this study, as the dose of cidofovir increased, production
of CMV fell. Three subjects who received 5 mg/kg twice weekly "did
not have detectable CMV after 3 weeks". Production of CMV did not
immediately resume when these subjects stopped taking HPMPC. In
other subjects, CMV could once more be detected in the urine "up to
2 months after the last dose of cidofovir."

       * CMV IN THE BLOOD

       At the start of the study, 15 subjects had blood from which
CMV could be 'grown' or cultured. Despite receiving cidofovir, CMV
could still be cultured from their blood samples. Indeed, 6 subjects
who had 'negative' blood cultures developed 'positive' blood
cultures. One subject who continued to produce CMV in his blood
developed an intestinal infection from that virus 5 weeks after he
stopped receiving cidofovir. Doctors treated him with intravenous
ganciclovir, and 2 weeks later technicians could not culture CMV
from his blood or urine samples. In another subject, CMV could be
cultured from his blood samples despite receiving 7.5 mg/kg of
cidofovir every three weeks. As in the previous case, after a 2-week
course of ganciclovir, technicians could not culture CMV from his
blood or urine.

       * WHAT NEXT?

       Results from this study suggest that cidofovir 5 mg/kg twice
weekly is too toxic, while the same dose once weekly or 7.5 mg/kg
every 3 weeks has potential benefit without some of the more severe
risks. Probenecid can reduce the toxicity of cidofovir. Larger and
longer studies of cidofovir need to be done in subjects with
symptoms of CMV disease so that researchers can show possible
benefits.

       REFERENCES:

              1. Polis MA, Spooner KM, Baird BF, et al.
       Anticytomegalovirus activity and safety of cidofovir in
       patients with Human Immunodeficiency Virus infection and
       cytomegalovirus viuria. Antimicrobial Agents and Chemotherapy
       1995;39(4):882-886.

       I. Eye injections-cidofovir for CMV

       * STUDY DETAILS

       All 16 subjects in this study were adults (15 males, 1
female) with AIDS, and had 'active' CMV infection in the eye despite
treatment with intravenous ganciclovir and/or foscarnet. Some
potential subjects with complications including eye inflammation,
infection of the eye with other microbes or detached retinae were
not allowed to enter the study. There were 2 stages in this study.
In the first part doctors enrolled 9 subjects and used them to look
for toxic effects from the eye injections while giving them
intravenous ganciclovir. In the 2nd part of the study, doctors were
trying to find out about the anti-CMV effects of cidofovir.

       As with the studies of intravenous HPMPC, most subjects in
this trial received 2 g of probenecid 3 hours before having their
eye injections and later, "1 g orally each at 2 and 8 hours after
cidofovir injections." To inject the drug doctors used a "30 gauge
needle attached to a tuberculin syringe."

       * RESULTS-PART 1

       In the first part of the study, 9 subjects received various
doses of cidofovir ranging from 10 to 100 microgrammes. Half of
these subjects were monitored for about 76 days and doctors examined
their eyes weekly. Three subjects had complications-"[inflamed eyes,
changes of the pressure inside the eyeball]". By the end of the
study, over 90% of untreated eyes had worsening damage from CMV
despite continued intravenous ganciclovir.

       * RESULTS-PART 2

       For this experiment doctors injected cidofovir into 8 eyes.
About half of subjects receiving an injection of cidofovir 20 pg
(microgrammes) had worsening eye damage from CMV 64 days later. No
serious complications as a result of the injections occurred.

       * RECOMMENDED DOSE AND WARNINGS

       The researchers stated that in "every [subject] treated with
cidofovir alone", eye damage by CMV was blocked. They "recommend and
use a dose of 20 pg cidofovir" when treating their patients with CMV
retinitis. They are not sure that probenecid provided any protection
against eye damage caused by cidofovir. As well, while complications
from eye injections were few, the researchers warn that:

       "[complications from eye injections] may not be entirely
       preventable despite [very careful and skillfill] technique,
       [the risk of this happening] must be [carefully explained] to
       any patient [thinking about eye injection] therapy for CMV
       retinitis."

       * PROBLEMS GETTING HPMPC

       Although originally found in plants, chemists can now make
HPMPC in their labs. In the USA the company Gilead Sciences (Foster
City, California) is developing cidofovir as an intravenous therapy
for CMV. The HPMPC used in this study was made by researchers in
Belgium because Gilead refused to supply it for the experiments with
eye injections. An investigation by Jon Cohen for the journal
Science suggests that Gilead refused to supply the drug because
"...it wouldn't make much profit from the small, infrequent doses
used in the [eye injections]." One American treatment activist said
that "[a]ny effort to move forward on intravitreal treatment has
been completely stonewalled by the company." A senior staff person at
Gilead denies that this is the case. Gilead hopes that the FDA will
approve the use of IV cidofovir for the treatment of CMV infection.
The company also plans to conduct a study of injecting HPMPC into
the eyes of subjects to confirm the data from this independent
study.

       ACKNOWLEDGEMENTS:

       1. We thank B. Goldberg for rapid access to this research.

       REFERENCES:

              1. Kisch LS, Arevalo JF, De Clercq E, et al. Phase
       I/II study of intraviteal cidofovir for the treatment of
       cytomegalovirus retinitis in patients with the Acquired
       Immunodeficiency Syndrome. American Journal of Ophthalmology
       1995;119(4):466-476.

              2. Cohen J. AIDS drug: experiencing local delays.
       Science 1995;268:369.

       J. Recovery from MAC infection

       * BACKGROUND

       As the immune system weakens, people with AIDS become at risk
for developing many life-threatening infections including those
caused by MAC (Mycobacterium avium complex). One American doctor
recently reported 1 case in the USA where his patient apparently
recovered from MAC.

       * SYMPTOMS AND TREATMENT

       On his first visit to the doctor the patient had a fungal
infection in the throat and 40 CD4+ cells. He then began to take AZT
500 mg/day. Two months later he was coughing and had to have some
X-ray pictures of his chest taken. At first the doctor thought he
had tuberculosis and prescribed anti-TB therapy, a combination of
isoniazid, rifampin and pyrazinamide. Despite this treatment, he did
not improve. A sample of fluid/tissue taken from a lymph node
revealed that he was infected with MAC. His prescription was changed
to: Cipro 750 mg/day, clofazimine 100 mg/day, ethambutol 15
mg/kg/day "and amikacin 10 mg/kg/day for 2 weeks." He continued to
use rifampin 600 mg/day.

       * RESULTS

       Two months later he stopped coughing, X-ray scans suggested
that the infection had not spread and blood levels of liver enzymes
fell to near normal levels. The patient also gained 12 lbs. Several
months later his doctor stopped prescribing clofazimine and gave him
clarithromycin 2 g/day. Six months later all signs and symptoms of
MAC infection cleared and he was switched to just azithromycin 500
mg/day. He later developed several parasitic infections while his
chest X-ray scans and liver enzyme levels remained normal. He
eventually died about 6 months after he started using azithromycin.
In a investigation into his cause of death, pathologists could not
find any infection with MAC.

       REFERENCES:

              1. Farber HW. Long-term resolution of disseminated
       Mycobacterium avium complex infection in a patient with AIDS.
       Clinical Infectious Diseases 1995;20:1067-1068.

       K. Antifungal drugs-- warning about combinations

       * BACKGROUND

       The release of newer antifungal drugs-fluconazole and
itraconazole has been welcome because of their generally lower
toxicity (than existing drugs) and ease of use (swallowing tablets
versus getting intravenous therapy). Doctors are reporting more
cases of fungal infections that are resistant to fluconazole and
itraconazole, so some are experimenting with higher doses of those
drugs or using intravenous amphotericin B (AmB). Researchers in the
EU are performing laboratory experiments with fungi and combinations
of antifungal drugs. Results from their work suggest that using
fluconazole with AmB causes the drugs to interact and weakens their
antifungal effect. Other researchers have confirmed their results in
experiments with animals. They suggest that in cases where patients
have widespread candida infection, combination therapy with AmB and
azoles (including fluconazole, itraconazole, ketoconazole) "should
be avoided". Information on the treatment of some fungal infections
appears in the next issue of TreatmentUpdate.

       REFERENCES:

              1. Scheven M and Scheven M-L. Interaction between
       azoles and amphotericin B in the treatment of candidiasis.
       Clinical Infectious Diseases 1995;20:1079.

       III  TOXICITY

       A. Reducing the toxicity of sulpha drugs

       * BACKGROUND

       Doctors can prescribe Bactrim/Septra (B/S) taken daily or 3
days/week for their HIV-infected patients in an attempt to prevent
or delay the life-threatening lung infection PCP. HIV-infected
people seem to develop more side effects to sulpha drugs than
non-HIV-infected people. To reduce side effects some doctors may
give their patients very small doses of sulpha drugs. Over time, the
dose is gradually increased until patients can tolerate standard
doses. This process of gradually giving patients increased doses of
a drug so they can tolerate it is called desensitization.
Researchers in the USA have been reviewing files on subjects who had
tried to reduce their allergic reactions to sulpha drugs.

       * STUDY DETAILS

       The researchers reviewed data on 22 "consecutive" subjects
with AIDS (19 male, 3 female) who entered a desensitization study.
While taking sulpha drugs in the past, these subjects had developed
severe rashes, high fever, liver damage and vomiting, among other
symptoms. Eight of these went into shock within "minutes" after
taking a regular dose of B/S; 5 of them had to go into an intensive
care unit. The average CD4+ cell count of the subjects was about 113
cells. These subjects were supposed to receive aerosolized
pentamidine but were convinced by the researchers to enter into
their study on desensitization. At first subjects received very
small doses of the drugs contained in Bactrim/Septra (trimethoprim
and sulphamethoxazole) 0.004 mg trimethoprim and 0.02 mg
sulphamethoxazole taken with a glass of water. This dose was
increased ten times every hour for 4 hours. By the fifth hour
subjects received a normal dose of 160 mg of trimethoprim and 800 mg
of sulphamethoxazole. Doctors monitored subjects during the process
so they could rescue them in the event of an allergic reaction.

       * RESULTS

       Nineteen of 22 subjects (86%) finished the desensitization
protocol. The 3 remaining subjects began to vomit or have chills
which cleared when treated with the drugs ibuprofen and Gravol. Of
the 19 subjects, only 2 had reactions such as temporary rash and
"low grade fever". One of the 19 subjects died from a bacterial
infection, leaving 18 subjects for long term monitoring.

       * LONG TERM RESULTS

       Three of the 18 subjects developed side effects "within 2
weeks of desensitization". The side effects included fever and/or
[macular] rash, so they stopped taking B/S. According to one of the
study doctors, "the remaining 15 subjects, including 6 of the eight
[subjects] who [went into shock] before undergoing desensitization
and the 2 who had mild reactions during the procedure, successfully
tolerated long term use of [B/S] as [preventative therapy] for PCP".
Of the 15 subjects, "13 had no side effects to [B/S], while 2 others
had [temporary] rashes" one week after desensitization. Over an
average monitoring period of 14 months, no subject developed PCP.
The researchers also noted that during the desensitization process
no subject "required hospitalization, emergency-department care, or
medications other than ibuprofen or [Gravol] for reactions to [B/S]
during or [after] desensitization".

       * OVERALL RESULTS

       According to the study doctors, results from this review show
that "71% of 21 evaluable [subjects] were successfully
desensitized". They also did not try and "re-desensitize" subjects
who had been unable to become desensitized before this study and who
used their desensitization protocol. One of the features of their
protocol is that it is quick--5 hours--and simple, unlike many other
protocols. Future issues of TreatmentUpdate will have other reports
on desensitization.

       REFERENCES:

              1. Gluckstein D and Ruskin J. Rapid oral
       desensitization to trimethoprim-sulphamethoxazole
       (TMP-SMZ):use in prophylaxis for Pneumocystis carinii
       pneumonia in patients with AIDS who were previously
       intolerant to TMP-SMZ. Clinical Infectious Diseases
       1995;20:849-853.

       CORRECTION

       In TreatmentUpdate 57, under the subheadline "AZT: Delivery &
Dose" (page 6, sentence 4), a quote was omitted. The sentence should
read:

       AZT is supposed to work by interfering with the viral enzyme
       RT (reverse transcriptase): "AZT prevents the infection of
       new cells, but not the production of [HIV] from cells already
       infected".

       REFERENCE:

              Nowak, MA, Bornueffer S, Loveday C. et al. EGV results
       in the frame: results confirmed. Nature 1995;375:193.

       CORRECTION:

       The wrong issue number was given in the section titled "A
warning about thalidomine", in TreatmentUpdate 59. Further
information about thalidomine can be found in TreatmentUpdate 32. We
apologize for these errors and any inconvenience they may have
caused.

       Copyright (c) 1995 - CATIE.  Distributed by AEGIS, your
       online gateway to a world of people, knowledge, and
       resources.  714.248.2836 * 8N1/Full Duplex * v.34+

