The Arsenal Files 8/The Arsenal Files Collection #8 (Arsenal Computer) (1996).ISO/health/cate72.txt

Text File | 1996-11-11 | 27KB | 673 lines

       TreatmentUpdate 72
       By Sean Hosein
       Volume 8, no 8
       October 1996

       A publication of the Community AIDS Treatment Information Exchange (CATIE).

       Table of Contents

         I IMMUNOMODULATORS

           A. At last, a sensible, safe dose of IL-2

        II INFECTION FIGHTERS

           A. Adefovir (GS 840) for hepatitis B

           B. AmBisome(R) for fungal infections in the brain

           C. Low-dose fluconazole to prevent crypto

           D. Lamisil(R) looks good in the lab

           E. Bone marrow stimulant and Humatin(R) for diarrhea

           F. Women using fluconazole

           G. Therapies for CMV

           H. Cidofovir in the eye --- once every 6 weeks

       III TESTING

           A. Absorbing more itraconazole by taking it with food

           B.  Patients in hospitals may not get their medicine

           C. Saquinavir levels reduced by rifabutin

           D. Survival decreases under managed care

       A word to readers

       In this issue, we complete our presentation of results from the
36th ICAAC (Interscience Conference on Antimicrobial Agents and
Chemotherapy). Since much of the information is from abstracts, we may
not be able to provide readers with the details that normally
accompany our reports. Researchers did not release the long-term
results of many of the studies.

       I IMMUNOMODULATORS

       A. At last, a sensible, safe dose of IL-2

       Background

       IL-2 is a chemical produced by the immune system which
stimulates the growth of T cells and helps them fight infections. Most
studies testing IL-2 in PHAs have used large doses -- millions of
units per day. At those doses IL-2 causes side effects including:

        fever

        muscle and bone pain

        tiredness

        headache

       Now a group of American researchers have tested low dose of
IL-2 and we present their results.

Study details

       Doctors at the New York-Cornell Medical Center recruited 16
HIV-infected subjects (the gender of the subjects was not released)
with an average of 347 CD4+ cells. The subjects had been infected with
the virus for an average of 7 years. All subjects had to use at least
one of the following anti-HIV drugs AZT, ddC, ddI, d4T and 3TC for a
minimum of 1 month before receiving IL-2. Researchers gave the
subjects different doses of IL-2 in an attempt to find a nontoxic
dose.

Results -- toxicity and HIV

       The researchers found that the highest range of doses subjects
could tolerate before side effects developed  was 187,500 to 250,000
IU/square metre of skin/day. Moreover, subjects were able to use the
drug for six months, without developing side effects. Production of
HIV was not significantly affected when subjects used IL-2 at or below
this range of doses.

Results: Boosting the immune system

       The type of immune response needed to fight many of the
infections seen in AIDS is called  CMI (cell-mediated immunity). There
are no cheap, sophisticated tests to measure CMI so researchers must
rely on crude skin tests. Small amounts of protein from microbes
(bacteria, fungi and viruses) are injected under the skin. If CMI is
intact, within 48-72 hours swelling and redness develop at the
injection site. This reaction is called DTH (delayed-type
hypersensitivity). In people with weak CMI the reaction is smaller and
sometimes there may be no reaction.

        Low-dose IL-2

       Three of six subjects receiving 125,000 IU/m2/day  or less of
interleukin 2 whose skin did not react to testing before they received
IL-2 , developed DTH reactions to fungi. This indicates that their
immune system detected the fungus and was able to mount a response to
attack it.

        High-dose IL-2

       Among those subjects who could tolerate doses of IL-2 ranging
between 187,500 IU and 250,000 IU/m2/day, four of 10 subjects
developed DTH reactions after 6 months of IL-2. Moreover, the size of
the skin reactions were on average, double the size of pre-IL-2
reactions. This difference was statistically significant, that is; the
increase was likely due to the dose of IL-2 used rather than luck.

        NK cells

       Use of IL-2 did not cause increases in the level of CD8+,
neutrophils and other cells with the exception of NK  (natural killer)
and, in some subjects, CD4+ cells. NK cells attack tumours and
virus-infected cells. Subjects receiving the high dose IL-2 had their
level of NK cells increase to 6 times higher than their pre-study
level.

        CD4+ cells

       Those subjects receiving 125,000 IU/day had their CD4+ count
fall to an average of 276 cells which is about a loss of  28 CD4+
cells/month. Among subjects receiving up to 250,000 IU/m2 the average
CD4+ cell count rose to an average of 543 cells or an increase of 28
cells/month. The differences in changes in CD4+ cell counts between
the high and low dose groups was statistically significant.

What's next?

       Large studies are needed to find out if the daily doses of IL-2
used in this study can:

        delay the appearance of AIDS

        decrease the risk of death

when used in combination with other anti-HIV agents such as indinavir,
nelfinavir, ritonavir, saquinavir and VX-478.

       REFERENCES:

            1. Jacobsen EL, Pilaro F and Smith KA. Rational
       interleukin-2 therapy for HIV-positive individuals: daily low
       doses enhance immune function without toxicity. Proceedings of
       the National Academy of Sciences 1996;10405-10410.

       II    INFECTION FIGHTERS

       A. Adefovir (GS 840) for hepatitis B

       Background

       Gilead Sciences which makes the anti-CMV drug cidofovir is also
developing a treatment called adefovir (Bis-POM PMEA) for hepatitis B
infection. Although most people quickly recover from HBV (hepatitis B
virus) infection, a few develop continuous (chronic), low-level HBV
infection in the liver. Over time HBV infects more liver cells and the
damage slowly spreads through  the entire organ. Eventually the liver
damage is so severe that some people die and others get liver cancer.
Doctors rely on interferon alpha to treat HBV infection but this drug
is not always useful.

       Study details

       Doctors enrolled 20 subjects with chronic HBV infection into
this study. Sixty-five percent of them also had HIV infection.
Doctors randomly selected 15 subjects and gave each, one tablet of
adefovir (125 mg) daily and 5 other subjects fake adefovir, both for 1
month.

       Results

       Levels of HBV fell by 97% compared to their pre-study level in
subjects receiving adefovir. Subjects receiving fake adefovir had
their level of HBV rise by 7% during the study. This difference in HBV
levels between the two groups of subjects was statistically
significant. This means that the changes in HBV levels were likely due
to the use of adefovir and not a chance event.

       Toxicity

       Two subjects using adefovir had nausea while three had higher
than normal levels of liver enzymes in their blood ; which indicated
mild liver damage. HBV infection can also cause increases in liver
enzyme levels. In other studies, nearly 200 HBV-infected people have
used adefovir 125 mg/day for  up to 14 months "without any sign of
toxicity." In the US, adefovir is also being  tested with AZT and
related drugs as well as protease inhibitors as a treatment for HIV
infection.

       REFERENCES:

              1. Gilson RI, Chopra K, Murray-Lyon I, et al . Adefovir
       dipivoxil (Bis-POM PMEA) treatment for chronic hepatitis B
       infection; a placebo-controlled phase I/II study. Abstract
       LB01.

            2. Anonymous. Gilead Sciences announces statistically
       significant antiviral activity against hepatitis B virus. Press
       release 16 September, 1996.

       B. AmBisome(R) for fungal infections in the brain

       Background

       One of the life-threatening brain infections PHAs can develop
is 'crypto' (Cryptococcal meningitis). Standard treatment is iv AmB
(amphotericin B) followed by oral fluconazole as maintenance. AmB can
be toxic for the kidneys so researchers have been developing new forms
of AmB one of which is called AmBisomer.  This product consists of
tiny balls of fat called liposomes containing amphotericin B. In
theory these liposomes should penetrate the areas infected with the
fungus and release the amphotericin there rather than expose the whole
body to the drug.

       Study details

       Doctors in Amsterdam enrolled 28 HIV-infected subjects who had
crypto into their study to compare the effects of AmB against that of
Ambisome. Fifteen subjects received AmBisome 4 mg/kg of body weight
per day for 3 weeks while 13 received AmB 0.7 mg/kg/day also for 3
weeks. After this both groups received oral fluconazole 400 mg/day for
7 days.

       Results

       Three subjects in each group did not recover during the first 3
weeks of the study. By the end of the 3rd week of the study
technicians could not find any fungus in 10 of 15 subjects on AmBisome
and in 3 of 8 subjects on AmB. This difference between the two groups
was statistically significant, that is, likely due to the effects of
the drugs rather than luck. Two subjects receiving AmB had to be
withdrawn from the study because of kidney damage. Although the
overall effects of AmBisome sound promising, more details are needed
about the subjects in the study and their survival over the long term.

       REFERENCES:

            1. Leenders ACAP, Reiss P, Portegies P, et al . A
       randomized trial of liposomal amphotericin B (AmBisome) 4 mg/kg
       versus amphotericin B 0.7 mg/kg for cryptococcal meningitis in
       HIV-infected patients. Abstract L035.

       C. Low-dose fluconazole to prevent crypto

       Study details

       Doctors in the US recruited 231 HIV-infected subjects, half of
whom had 40 CD4+ cells, to test the ability of fluconazole to prevent
the life-threatening brain infection crypto. Although none of the
subjects had crypto in the past, 60% had experienced other
life-threatening infections before entering this study. Subjects were
supposed to take fluconazole 200 mg, three times daily, each week.
Half the subjects were monitored for one year.

       Results

       During this time only 1 person developed crypto and 20% had yeast
infections appear in the mouth or throat. The researchers interviewed
subjects and found that the yeast infections were more likely to occur
in subjects who did not take fluconazole as instructed. Among those
subjects who did take fluconazole according to schedule, those that
developed yeast infections had a "low" CD4+ cell count (the
researchers did not release a figure). Only about 3% of subjects
reported side effects -- "nausea [and] skin rash."

       REFERENCES:

            1. Singh N, Barnish MJ, Berman S, et al . Low dose
       fluconazole  for primary prophylaxis of cryptococcal  infection
       confined to AIDS patients with less than 101 CD4+ cells:
       demonstration of efficacy in a prospective, multicentre trial.
       Abstract I173.

       D. Lamisil(R) looks good in the lab

       Background

       Lamisil (terbinafine) is a new antifungal drug licensed for
treating fungal infections of the nails. As more reports of fungal
infections resistant to fluconazole or itraconazole appear, doctors
are beginning to consider combination antifungal therapy . In lab
experiments, terbinafine used with fluconazole had greater antifungal
activity than either drug alone in 50% of tests using yeast resistant
to fluconazole. Even greater antifungal activity was seen in 90% of
tests using itraconazole and terbinafine. Now experiments on
HIV-infected people are needed to find out if the combination is safe
and effective.

       REFERENCES:

              1. Fothergill AW, Leitner I, Meingasser JG, et al .
       Combination antifungal susceptibility testing of terbinafine
       and the triazoles fluconaozle and itraconazole abstract E053.

       E. Bone marrow stimulant and Humatin(R)for diarrhea

       Background

       Infection with the parasite C. parvum can cause
life-threatening diarrhea in  PHAs. Doctors have tried many drugs to
treat people infected with this parasite, including azithromycin,
garlic enemas, paramomycin (Humatin) but use of these drugs do not
work in every PHA. There have been a number of reports about the drug
nitazoxanide but the details have not been published (see
TreatmentUpdate 70). As well, none of these drugs deal with the
underlying problem -- a weakened immune system.

       GM-CSF

       The chemical GM-CSF (granulocyte macrophage-colony-stimulating
factor, also called Leukine(R)or Prokine(R)) is produced by the body
and can stimulate the bone marrow to produce more white blood cells.
It is used to treat people who have low levels of white blood cells
because of chemotherapy, AZT or ganciclovir. It is possible that this
bone marrow stimulant may also enhance the infection-fighting
abilities of white blood cells.

       Study details

       Doctors in Milan have tested different drugs to try and help 2
PHAs with less than 50 CD4+ cells recover from diarrhea caused by C.
parvum. The two had been treated with Humatin 4.3 grams/day for "at
least 10 days" but their diarrhea did not resolve. The doctors then
gave them GM-CSF -- 300 micrograms/day injected under the skin, for 14
days. They continued to receive paramomycin and AZT 500 mg/day.

       Results

       Recovery from diarrhea occurred in two days after the PHAs
received GM-CSF. When the doctors stopped giving them GM-CSF the
diarrhea returned and required several courses of GM-CSF (each course
consisted of GM-CSF 300 mcg/day for 14 days). In one subject diarrhea
disappeared and he has not had to use GM-CSF and Humatin for  6
months. The other subject's diarrhea decreased but never cleared. His
condition gradually grew worse and he died 9 months after he began to
use GM-CSF. Although these are only 2 cases, there is no effective
treatment for  the diarrhea caused by C. parvum and perhaps a pilot
study with GM-CSF in other people with the same infection may confirm
the drug's benefit or that of the related chemical G-CSF (granulocyte
colony-stimulating factor).

       REFERENCES:

              1. Capetti A, Bonfanti P, Rizzardini G, et al . Can
       rHu-GM-CSF help in treating drug-resistant cryptosporidiosis in
       AIDS? Abstract G033.

              2. Barsig J, Bundschuh DS, Hartung T, et al . Control of
       fecal peritoneal infection in mice by colony-stimulating
       factors. Journal of Infectious Diseases 1996;174(4):790-799.

              3. Lejeune M, Sariban E, Cantinieux B, et al . Defective
       polymorphonuclear function in children receiving chemotherapy
       for cancer are partially restored by recombinant human
       granulocyte-colony stimulating factor in vitro. Journal of
       Infectious Diseases 1996;174(4):800-805.

       F. Women using fluconazole

       Study details

       Doctors in the US recruited 323 HIV-infected women who had less
than 300 CD4+ cells for this study.  One hundred and  sixty-two
received fluconazole 200 mg/week and  161 received fake fluconazole
(placebo). Researchers monitored 50% of subjects for 2 and a half
years.

       Results

       Thirteen subjects developed yeast infections; 6 in the
fluconazole group and 7 in the placebo group.

       REFERENCES:

              1. Vasquez JA, Steel-Moore L, Schuman P, et al .
       Antifungal susceptibility among Candida species recovered from
       HIV-positive women receiving fluconazole prophylaxis. Abstract
       LB10.

       G. Therapies for CMV

       Who will get CMV retinitis?

       In North America, PHAs who have less than 50 CD4+ cells are at
high risk for the development of CMV retinitis but not everyone with
such a low cell count gets retinitis. Several research teams are
developing tests to detect CMV in the blood of PHAs. Just as
increasing levels of HIV in the blood (HIV viral load) is linked to
wakened immunity, some doctors think that increasing levels of CMV in
the blood may occur before signs of retinitis appear. Unfortunately
reliable, accurate and rapid results from test kits for CMV viral load
are not yet available.

       What the eyes see

       CMV can infect the light-sensing part of the eye called the
retina, causing it to become swollen. People with HIV/AIDS who have
CMV retinitis may  see:

        floaters

        flashes of light

        blurred or distorted vision

        blind spots

       Some people "often describe their vision loss as a curtain
coming down over the eye." If left untreated, CMV retinitis results in
blindness.

       Therapies for CMV

       Standard treatment for CMV retinitis is iv (intravenous)
ganciclovir or foscarnet. In some cases where CMV becomes resistant to
these drugs doctors may use both of them in combination. These drugs
have side effects and must be taken frequently. Recently the new
anti-CMV drug cidofovir (Vistide(R), HPMPC) has been licensed in the
US and is available in Canada through the EDRP (emergency drug release
program). Previous reports on cidofovir have appeared in
TreatmentUpdate 60.

       Into the eye

       Another approach is to place anti-CMV drugs directly into the
eye. One research team has developed a slow-release form of
ganciclovir, commonly called the "implant", that is inserted into the
eye. They have found that the implant provides about 6 months of
protection for CMV and costs about $5,000. One Canadian team has found
that weekly injections of ganciclovir  into the eyes of people with
CMV retinitis useful. Now a group of American doctors report that
injections of cidofovir need only be injected every six weeks.

       REFERENCES:

            1.     Jabs DA. Acquired Immunodeficiency Syndrome and the
       eye -- 1996. Archives of Ophthalmology 1996;114:863-865.

            2.     Hodge WG, Lalond RG, Samplis J and Deschenes J.
       Once-weekly intra-ocular injections of ganciclovir for
       maintenance therapy of cytomegalovirus retinitis: clinical and
       ocular outcome. Journal of Infectious Diseases
       1996;174:393-396.

            3.     Ward-Able C, Phillips P and Tsoukas CM. The use of
       oral ganciclovir in the treatment of cytomegalovirus retinitis
       in patients with AIDS. Canadian Medical Association Journal
       1996;154(3):363-368.

       H. Cidofovir in the eye --- once every 6 weeks.

       Study details

       Doctors in San Diego recruited 35 volunteers (subjects) with
AIDS who also had CMV-retinitis. These subjects "did not benefit from
or could not tolerate or refused iv (intravenous) ganciclovir or
foscarnet." The study lasted for about 1.5 years and subjects remained
in the study until:

        death 31% (of subjects)

        the study ended 17%

        they developed CMV infection in another part of the
         body 14%

        they developed another serious illness 9%

        they had a detached retina 3%

        they developed complications from the eye
         injections 9%

        they refused to visit the study doctors as
         scheduled 3%.

       There were 34 males and 1 female in the study. Doctors divided
the subjects into  groups, A and B. In group A, "twenty-four eyes in
18 subjects" received injections of cidofovir. This was the first time
they had received anti-CMV drugs. The twenty-nine eyes of the 17
remaining subjects had been previously treated with "ganciclovir,
foscarnet or both."

       Eye injections -- the details

       Before the subjects received cidofovir they took probenecid  2
g orally and eight hours after the injections, 1 g to reduce the
toxicity of cidofovir.  They had their eye(s) and eye-lid(s)
disinfected with Betadine(R) surgical scrub and then a mild anesthetic
was sprayed. The eye(s) was then injected with a stronger anesthetic
(Lidocaine 2%). Another injection containing cidofovir 20 µg
followed. To lower the risk of bacterial infections in the eye,
subjects used Polysporin ointment and  to the reduce swelling and
redness doctors gave them prednisolone eye drops. They received
further injections of cidofovir every 6 weeks. On average subjects
received 5 injections.

       Results

       Group A: "None of the eyes in group A had [retinitis which grew
worse] during the study." Group B: "Four eyes (from two subjects) had
[retinitis which grew worse]" during the study. These eyes belonged to
two subjects who had retinitis which did not improve when previously
treated with iv "ganciclovir or foscarnet." Eventually the damage to
the retina in these two subjects healed.

       Complications -- major

       No intervention such as putting pellets of slow-release
ganciclovir or, injecting eyes with cidofovir is 100% risk-free. Five
eyes had reduced vision due to complications:

        two eyes had reduced pressure inside the eyeball and this
         permanently reduced their vision to "counting fingers."

        one eye could only detect "hand motions...despite rapid
         healing of the retinitis."

        One eye underwent a reduction of vision due to a temporary
         drop in pressure inside the eyeball. "This [person also]
         became ill and  [was] unable to return "[to the study
         clinic]."

       Complications -- minor

       Parts of the eye became swollen because of the injections but
this problem cleared when the subjects used eye-drops containing
prednisolone 1% and other drugs designed to reduce swelling.

       Survival

       Two thirds of subjects in group A died at the end of the study.
Half of these subjects lived for 33 weeks. About 60% of subjects in
group B died by the end of the study, half of whom lived for 47 weeks
but the difference between the groups was not statistically
significant.

       REFERENCES:

            1. Rahhal FM, Arevalo F, Mungia D, et al . Intravitreal
       cidofovir for the maintenance treatment of cytomegalovirus
       retinitis. Ophthalmology 1996;103:1078-1083.

       III TESTING

       A. Absorbing more itraconazole by taking it with food

       Background

       Absorption of food and certain drugs is reduced in some PHAs
because of intestinal damage caused by HIV or other microbes. As well,
some PHAs don't produce enough acid in their stomachs to properly
digest food. Lower-than-normal levels of stomach acid affects
absorption of the antifungal drug itraconazole (Sporanox(R)). Doctors
in Ann Arbor, Michigan, recruited 20 HIV-infected subjects for their
experiment to find out how itraconazole absorption could be increased.
Some subjects took itraconazole 200 mg:

        on an empty stomach

        with food

        on an empty stomach with a supplement of acid (glutamic
         acid)

        with food and an acid supplement

       Results

       Subjects who took itraconazole with food absorbed significantly
more of the drug than other subjects. Use of the acid supplement did
not increase absorption of itraconazole whether the drug was taken
with or without food.

       REFERENCES:

            1. Welage L and Kauffman C. The effect of food and gastric
       pH on the oral bioavailability of itraconazole in HIV+
       patients. Abstract A031.

       B.  Patients in hospitals may not get their medicine

       Study Details

       Another American team in Chicago conducted a study on 18 PHAs
in the AIDS ward of a hospital to find out if they received their
medicine as prescribed by the hospital's doctors.  The doctors found,
on average, that in 20% of cases:

        some patients received too little medicine

        others received too much

       In cases where intravenous antibiotics, antifungals and
antivirals were prescribed, an average of 26% of patients did not
receive the dose prescribed by their doctors.

       REFERENCES:

            1.     Max BE, Itokazu G, Danziger LH, et al . Do
       hospitalized patients receive their prescribed medications?
       Abstract  N010.

       C. Saquinavir levels reduced by rifabutin

       Study details

       Doctors in Ottawa enrolled 12 HIV-infected men to test the
effect of rifabutin 300 mg/day on the amount of saquinavir that is
absorbed and ends up in the blood. They found that rifabutin reduces
levels of saquinavir in the blood by 40%. So doctors treating PHAs
taking this combination are going to have to increase their dose of
saquinavir, perhaps by 40%.

       REFERENCES:

            1. Sahai J, Stewart F, Swick L, et al . Rifabutin reduces
       saquinavir plasma levels in HIV-infected patients. Abstract
       A027.

       D. Survival decreases under managed care

       Background

       Over the past 5 years doctors in the US have found that
increasing numbers of  their patients have their medical bills paid
for by agencies called HMOs (health maintenance organizations). Today
HMOs are large, covering tens of thousands of patients, are
increasingly influential, and can force doctors to reduce their fees.
This in turn cuts the costs to the HMOs and lowers the income of
doctors.  Some doctors complain about HMOs which don't allow them to
order certain expensive tests, carry out costly procedures or
prescribe high-priced drugs, even if these options are in the best
interests of their patients.  This system of health care run by HMOs
is called managed care. One team of doctors has been monitoring 1,000
men with HIV/AIDS to find out the effect managed care has on their
health.

       Results

       The doctors found that 50% of men who had AIDS at the time they
entered the study or who developed AIDS while in the study lived for
17 months under managed care. The equivalent figure for men who were
in the traditional fee for service system (which exists in Canada) was
30 months. This difference--an increase in survival time of 60% -- was
[statistically] significant, that is; not likely caused by chance
alone.

       REFERENCES:

            1. Palenick J, Graham NMH, Wu A, et al . Poorer survival
       among AIDS patients enrolled in managed care organisations
       versus traditional indemnity insurance. Abstract N024.

       Copyright (c) 1996 - CATIE.  Distributed by AEGIS, your online
       gateway to a world of people, knowledge, and resources.  Direct
       Dial: v.34+: 714.248.2836; v.120/ISDN: 714.248.0433  Internet:
       telnet:aegis.com  www: http://www.aegis.com