       TreatmentUpdate 69
       By Sean Hosein
       Volume 8, no 5
       July 1996

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

       Table of Contents
        I ANTI-HIV AGENTS

           A. Triple therapy - loviride with 3TC and  AZT
           B. Nevirapine plus
           C. Viracept  and d4T
           D. 3TC - not with ddC


       II IMMUNOMODULATORS

           A. Neupogen  boosts T cell counts


      III INFECTION FIGHTERS

           A. Oral ganciclovir to prevent CMV
           B. Oral cidofovir?

       I ANTI-HIV AGENTS

       A. Triple therapy - loviride with 3TC and AZT

       Background

       To reduce production of HIV and help the immune system resist
HIV infection, researchers are testing combinations of anti-HIV drugs.
Loviride is a drug that affects an essential viral enzyme called RT
(reverse transcriptase) but that drug is not 'related' to AZT or
similar drugs. Drugs such as loviride reduce production of HIV and are
not as toxic as AZT. The problem with loviride and related drugs such
as nevirapine is that HIV quickly becomes resistant to their effects.
This is why combination therapy is essential when using these drugs.

       Study details

       Researchers in Germany enrolled 20 HIV-infected subjects (2
female, 18 male) for their study. Their CD4+ cell counts ranged
between 12 and 464 cells. Before entering this study, 15 subjects had
used anti-HIV agents including AZT and ddI. At the time they entered
the trial none of the subjects had any life-threatening infections.
Ten subjects received a combination of 2 drugs; 600 mg/day of AZT and
300 mg/day of loviride. The other ten received both AZT and loviride
in the same dose as used above but they also received 3TC 300 mg/day.
Subjects received the drugs for 6 months. After this time subjects
could receive the triple combination for 12 months if they wished.

       Results - CD4+ cells

       At least half the subjects receiving the 3 drug combination had
their CD4+ cell counts increase by 78% by the 12th week of the study
compared to their pre-study values. By the 6th month of the study this
figure had decreased to 45%. At least half of the subjects receiving
the double combination had an increase in their CD4+ cell count of
roughly 25% by the 4th week of the study. By the 6th month of the
study, however, the CD4+ cell counts fell to their pre-study levels.

       Results - HIV

       Subjects receiving triple combination had dramatic decreases in
the amount of HIV in their blood. After the 8th week the amount of HIV
detected rose slowly but remained below the pre-study level. In
contrast, subjects receiving the double combination had production of
HIV return to their pre-study level by the 24th week.

       Toxicity

       Five subjects on double combination and 6 on triple combination
had side effects which included:

        tiredness
        fever
        headache
        diarrhea

The researchers concluded that the combinations were "well tolerated."
Other studies with loviride are underway in several countries.
Loviride is made by Janssen Research.

       REFERENCES:

       1. Staszewski S, Miller V, Rehmet S, et al. Virological and
          immunological analysis of a triple combination pilot study
          with loviride, lamivudine and zidovudine in HIV-1 infected
          patients. AIDS 1996;10:F1-F7.

       B. Nevirapine plus

       Study details

       Researchers in the European Union and Australia compared the
effects of a combination of two anti-HIV drugs, namely AZT and
nevirapine, versus AZT alone. All subjects were supposed to have used
between 500 and 600 mg/day AZT for "at least 6 months" before entering
this study. Researchers recruited 49 subjects (13 female, 36 male) at
least half of whom were free from symptoms of HIV infection.
Researchers randomly assigned 24 subjects to receive continued AZT and
25 others to receive nevirapine and AZT (combination group). The
average CD4+ cell count of subjects in the AZT only group was 210
cells and in the combination group it was 195 cells. This difference
was not statistically significant.

       All subjects received AZT at either 500 or 600 mg/day. In the
combination group doctors gave the subjects "200 mg/day nevirapine for
two weeks followed by 400 mg/day for 26 weeks." By the 28th week,
subjects who had been assigned to receive only AZT could receive the
combination if they wished. During the study subjects in the AZT only
group who had increasing levels of HIV in their blood could also
receive nevirapine.

       Results - CD4+ cells

       Subjects in the combination group had an increase of 34 cells
by the 4th week of the study, which was statistically significant;
that is, not likely due to chance alone. By the 28th week their
average CD4+ cell count fell 40 cells below their pre-study level.
Subjects who received AZT alone had, on average, about 10 less CD4+
cells than when they started. The average CD4+ cell count remained at
this level by the 28th week.

       Results - infections

       Although 63% of subjects in the AZT only group and 40% of
subjects in the combination group developed worsening symptoms of HIV
infection, this difference was not statistically significant. Indeed,
20% of subjects on combination developed AIDS as did 13% of the AZT
group, but this difference was also not statistically significant.

       Results - HIV

       By the 6th week, subjects on the combination had a dramatic
decrease in the amount of HIV in their blood -- 8 times less than
their pre-study levels, a statistically significant event. By the 12th
week levels of HIV rose to their pre-study levels. Subjects on AZT
alone had increasing levels of HIV in their blood.

       Toxicity

       Eight subjects receiving nevirapine developed "rash and fever".
For 7 subjects the rash occurred within the first 4 weeks of the
study. In 3 subjects the rash was mild and cleared within 1 week
despite continued use of nevirapine. Once doctors stopped giving the
remaining 5 subjects nevirapine, the rash and fever cleared.

       In this study, use of nevirapine did not appear to provide any
"significant" protection from the development of AIDS. In another
study cited by this research team, use of AZT with ddI and nevirapine
in subjects who used AZT before entering that study, did not provide
any greater protection against the onset of symptoms of HIV infection
than the combination of AZT and ddI.

       REFERENCES:

       1. Carr A, Vella S, de Jong MD, et al. A controlled trial of
          nevirapine plus Zidovudine versus Zidovudine alone in p24
          antigenaemic HIV-infected patients. AIDS 1996;10(6):635-641.

       C. Viracept  and d4T

       Viracept  and d4T

       Researchers in San Francisco have been testing the anti-HIV
drug Viraceptr (nelfinavir), a drug that affects the essential viral
enzyme HIV proteinase (or protease). Doctors recruited 63 HIV-infected
subjects (the number of females and males along with other detailed
information was not released) who had at least 200 CD4+ cells and
divided the subjects into two groups. One group with 30 subjects
received Viracept at one of several doses; 1.5 g/day, 2.25 g/day or 3
g/day. The remaining 33 subjects received d4T alone or in combination
with Viracept in the same doses used in the first group.

       Results

       During the first 4 weeks at least half the subjects on
combination had the amount of HIV in their blood fall to 1/100 th of
their pre-study level. For subjects receiving d4T alone, about half of
them had the amount of HIV in their blood fall to 1/10th of their
pre-study level. Common side effects included "loose stool and mild to
moderate diarrhea."

       REFERENCES:

       1. Peterkin J, Champman S, Conant M, et al. Randomized phase II
          studies of Viracept, an HIV protease inhibitor, given as
          monotherapy and in combination with Stavudine (d4T). Program
          and abstracts of Ninth International Conference on Antiviral
          Research, Japan 1996, abstract 9.

       D. 3TC - not with ddC

       Background

       Drugs such as AZT and the 'related' chemicals 3TC, d4T, ddC and
ddI need to be converted to their antiviral form inside cells if they
are to work. If these drug are not converted they have no anti-HIV
activity. As treatment with combinations of anti-HIV drugs becomes the
standard of care, some researchers are concerned that cells will not
be able to convert all of these drugs into their anti-HIV form.

       Results

       Researchers in England have been conducting experiments with
cells and several drugs including AZT, 3TC and ddC. They found that
when cells were given 3TC and ddC they were unable to convert ddC into
its anti-HIV form. 3TC did not affect the conversion of AZT. The
researchers suggested that combination treatment with 3TC and ddC may
not be useful.

       REFERENCES:

       1. Veal GJ, Hoggard PG, Barry MG, Koo S and other nucleoside
          analogues for intracellular phosphorylation.  AIDS
          1996;10(5):546-548.

       II IMMUNOMODULATORS

       A. Neupogen  boosts T cell counts

       Background

       Certain drugs such as:

            amphotericin B
            Bactrim/Septra
            flucytosine
            ganciclovir

and anti-cancer drugs may be toxic for bone marrow. Use of these drugs
may reduce levels of white blood cells including CD4+ and CD8+ cells
and may make patients less resistant to infections. Drugs such as
G-CSF (granulocyte colony-stimulating factor, Neupogen) stimulate the
bone marrow causing levels of white blood cells to increase. One
research team in San Francisco was treating six subjects with G-CSF
and found some interesting results.

       Study details

       All subjects had AIDS and an average CD4+ cell count of 20
cells. Their bone marrow was not producing normal levels of white
blood cells because some subjects had certain infections, cancer or
the drugs they were using were toxic to the bone marrow (see list
above). Subjects received injections of G-CSF between 3 and 5 ug/kg of
body weight under the skin three times weekly for 2 weeks, or until
their "[white blood cell] count reached the normal range."

       Results

       On average, levels of white blood cells increased by 200 %. The
average CD4+ cell count rose from 20 cells to 32 cells. The average
CD8+ cell count rose from 288 to 494 cells. These changes were
statistically significant. The most dramatic change was seen in levels
of natural killer (NK) cells which rose from an average of 36 cells to
85 cells, an increase of 136%.

       Important results

       The researchers think that the increase in CD4+ cells was too
small to have any impact on the health of the six subjects. CD8+ and
NK cells (CD56+) play an important role in fighting HIV infection.
Researchers do not know the impact of long-term G-CSF therapy on cell
counts. Other studies need to be done to find out what effect
increased CD8+ and NK cell counts might have on the immune systems of
people with HIV/AIDS. One concern is that use of G-CSF may cause
increased production of HIV. However, most experiments with cells and
on other HIV-infected subjects have shown that production of HIV does
not increase when G-CSF is used. This may be due to the increased
numbers of CD8+ and NK cells, which suppress replication of HIV.

       REFERENCES:

       1. Stricker RB and Goldberg B. Increase in lymphocyte subsets
          following treatment of HIV-associated neutropenia with
          granulocyte colony-stimulating factor. Clinical Immunology
          and Immunopathology 1996;79(2):194-196.

       III INFECTION FIGHTERS

       A. Oral ganciclovir to prevent CMV

       Background

       CMV causes the sight-threatening eye infection CMV retinitis in
some people with AIDS, often those with less than 50 CD4+ cells. CMV
also attacks the brain, intestines (called CMV colitis) and lungs.
Although the anti-CMV drugs foscarnet and ganciclovir are effective,
short-term treatment, patients must have a tube installed in their
veins as these drugs have to be taken frequently, in some cases daily.
This places them at an increased risk for bacterial infections and
also reduces quality of life. Researchers have made a form of
ganciclovir that can be taken by mouth as capsules and these may be
more convenient. To delay and/or prevent the appearance of CMV disease
(retinitis, colitis) doctors have tested oral ganciclovir in people
with AIDS who were at risk of developing CMV disease.

       Study details

       All subjects (8 female, 717 male) had less than 100 CD4+ cells,
the average being about 27 cells. Roughly 54% of subjects had had a
life-threatening infection before entering the study and 94% had used
anti-HIV drugs. All subjects had CMV infection but none had
signs/symptoms when they entered the study. Researchers randomly
assigned 486 subjects to receive ganciclovir 1 gram three times daily,
and 239 others to receive fake drug (placebo). At least half the
subjects remained in the study for 1 year.

       Results

       Over a period of 12 months the researchers found that:

         26% of subjects on placebo
         14% of subjects on ganciclovir

developed CMV disease - largely retinitis and a few cases of CMV
colitis. Looking at retinitis alone the researchers found that:

         24% of subjects on placebo
         12% of subjects on ganciclovir

developed CMV retinitis after 1 year. Thus, oral ganciclovir reduced
the development of CMV retinitis by 50%. This result was statistically
significant, that is; not likely due to chance alone.

       Other infections

       Use of anti-HIV drugs and the anti-herpes drug acyclovir did
not appear to affect the protection provided by ganciclovir. Subjects
who received ganciclovir were less likely to develop signs/symptoms of
other herpes virus infections.

       Survival

       By the 12th month, 26% of subjects receiving placebo and 21%
receiving ganciclovir had died. This difference was not statistically
significant.

       Toxicity

       About 16% of subjects on placebo and 19% on ganciclovir stopped
taking their drugs because of side effects. Interestingly, 74% of
subjects on placebo reported symptoms such as

         diarrhea
         nausea
         vomiting
         loss of appetite.

Seventy-seven percent of subjects receiving ganciclovir reported
similar symptoms. Subjects given ganciclovir were more likely to have
less than normal levels of a type of white blood cell called
neutrophils than subjects on placebo, a difference that was
statistically significant. Doctors were more likely to prescribe bone
marrow stimulants (G-CSF) for subjects receiving ganciclovir than
those on placebo.

       Based on these results, people with AIDS with less than 100
CD4+ cells, particularly those with less than 50 CD4+ cells and who
had CMV infection were able to delay the appearance of symptoms of CMV
disease by using oral ganciclovir. In this study, samples of blood and
urine were analysed for CMV. Those samples in which the virus was
detected indicated CMV infection. So the critical decision for doctors
is to identify which of their patients are at high risk of CMV disease
(CMV isolated from fluid samples) and thus those who might benefit
from oral ganciclovir.

       REFERENCES:

       1. Spector SA, McKinley GF, Lalezari JP, et al. Oral
          ganciclovir for the prevention of cytomegalovirus disease in
          persons with AIDS. New England Journal of Medicine
          1996;334(23):1491-1497.

       B. Oral cidofovir?

       Experiments are underway with the new anti-CMV drug cidofovir
(VistideTM) to find out the best dose and schedule for treating and
suppressing CMV infection. As that drug has to be given intravenously
or by direct injection into the eye, researchers are testing oral
cidofovir. At doses of 10 mg/kg of body weight, less than 5% of
cidofovir was absorbed. It is not clear if this is will be useful as
treatment or prevention of CMV disease. In the case of oral
ganciclovir, only 2% to 5% is absorbed, but that is enough to benefit
to people with CD4+ cell counts below 50. Perhaps further reports on
oral cidofovir will emerge at the International AIDS Conference in
Vancouver in July.

       REFERENCES:

       1. Spector SA, Busch DF, Follansbee S, et al. Pharmacokinetic,
          safety, and antiviral profiles of oral ganciclovir in
          persons infected with Human Immunodeficiency Virus: a phase
          I/II study. Journal of Infectious Diseases
          1995;171:1431-1437.

       2. Wachsman M, Petty BG, Cundy KC, et al. Pharmacokinetics,
          safety and bioavailablity of HPMPC (cidofovir) in Human
          Immunodeficiency Virus-infected subjects. Antiviral Research
          1996;29(2,3):153-161.

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