The Arsenal Files 8/The Arsenal Files Collection #8 (Arsenal Computer) (1996).ISO/health/cate71.txt

Text File | 1996-11-11 | 16KB | 411 lines

       TreatmentUpdate 71
       By Sean Hosein
       Volume 8, no 7
       October 1996

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

       Table of Contents

       I ANTI-HIV AGENTS

         A. AZT with and without indinavir

         B. AZT -- resistance may depend on dose

         C. DMP 266

         D. Effect of 3TC and loviride on survival

         E. Indinavir and IL-2 -- one year later

         F. Ritonavir and saquinavir

         G. Saquinavir and indinavir -- some problems

         H. A new protease inhibitor -- 141W94

    A word to readers

       In this issue we present results from the 35th 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. Promising results were seen in 2 combination studies: DMP 266
with indinavir, and ritonavir with saquinavir. The impact of these
combinations on the development of new infections and survival was not
discussed at the conference.

       I ANTI-HIV AGENTS

       A. AZT with and without indinavir

       Study details

       Doctors in Brazil, Canada and the US have enrolled 490
HIV-infected volunteers for this study. No subject was supposed to
have used AZT or protease inhibitors before entering this study.
Subjects had between 50 and 500 CD4+ cells and received either AZT 600
mg/day, or indinavir 800 mg/8 hours or a combination of both drugs.

       Results -- CD4+ cell counts

       At the 6th month of the study, researchers found that subjects
in the following groups had increased numbers of CD4+ cells compared
to their pre-study levels:

        AZT - 28 cells

        indinavir - 91 cells

        combination - 85 cells

       The larger increase in the in CD4+ cell counts in the indinavir
group compared to the AZT group was [statistically] significant. This
means that use of indinavir was responsible for the greatest increase
- not luck or chance.

       Results -- amount of virus

       When technicians measured changes in the amount of HIV in the
blood they found the following changes:

        AZT group -- a slight increase

        indinavir -- a decrease in viral load to 1/8 times the pre-study level

        combination -- a decrease to about 1 /11th  the pre-study level

       The greater decrease in viral load in subjects receiving
indinavir (alone or in combination) compared to that seen in the
subjects receiving AZT was [statistically] significant, that is; not
likely due to chance alone.

       Summary

       Use of indinavir alone or together with AZT caused an increase
of at least 80 CD4+ cells and reduced production of HIV to 1/11th of
its pre-study level.

       REFERENCES:

            1. Leavitt R, Massari F, Nessly M, et al . Antiviral
       activity of indinavir plus AZT compared to indinavir or AZT
       alone in antiretroviral naive patients. Abstract I109.

       B. AZT -- resistance may depend on dose

       Study details

       Although people living with HIV/AIDS using AZT are usually
prescribed 500 or 600 mg/day, anecdoctal reports suggest that people
may be taking 300 or 400 mg/day. This dose reduction may reduce side
effects and the cost of the drug. Doctors in Mexico city conducted a
small study to find out the effect of different doses of AZT on the
development of drug-resistant virus. Doctors recruited 15 HIV-infected
subjects who had between 200 and 500 CD4+ cells. Subjects were
assigned to the following groups:

         AZT 500 mg/day

         AZT 300 mg/day

         no AZT (or any other anti-HIV drugs)

       Blood samples were taken from the subjects for analysis before
they entered the study and at regular intervals.

       Results

       During the course of the study, technicians isolated HIV from
blood samples and exposed the virus to AZT in lab experiments. They
found at the end of the study, HIV from subjects who used the high
dose of AZT required huge quantities (750 times the normal amount) of
the drug to suppress production of HIV in the test tube. Virus taken
from subjects using AZT 300 mg/day needed less drug (93 times the
normal level) to block its activity. Subjects not receiving AZT had
HIV that required even less drug to suppress its production. The
difference between the concentrations of AZT required to suppress the
virus before and after entering the study was [statistically]
significant.

       Interpretation

       Although researchers are not sure which dose of AZT is best,
300 mg/day in combination with other anti-HIV agents may be a
reasonable dose to use. The study could have been a more useful piece
of research had the doctors also measured changes in viral load.

       REFERENCES:

            1. Soto-Ramirez L, Renjifo B, Marlink R, et al .
       Dose-dependent HIV-1 Zidovudine resistance. Abstract I111.

       C. DMP 266

       Background

       Scientists at the Merck pharmaceutical company have made a new
group of drugs that reduce production of HIV in lab experiments. One
of these chemicals is DMP 266 (formerly L743,726) which works by
affecting the viral enzyme RT (reverse transcriptase). The critical
effect of DMP 266 is that it has antiviral activity against HIV that
can resist the effect of delavirdine and nevirapine. In some lab
experiments, DMP 266-treated cells were protected from HIV for up to
10 weeks.

       Study details

       Doctors in the US enrolled 16 HIV-infected subjects (3 females,
13 males) who had an average of 221 CD4+ cells and a viral load
averaging 131,000 copies (each copy represents 1 virus). Thirteen of
the 16 subjects had used anti-HIV drugs before entering this study.
During the first 2 weeks of the study, 5 subjects received either fake
DMP 266 (placebo) or "DMP 266, 200 mg/day." In the third week all
subjects received indinavir 800 mg/8 hours. Those subjects who were
receiving DMP 266 during the previous two weeks continued to do so.

       Results

       Two weeks' use of DMP 266 resulted in a 98% decrease in the
amount of HIV in the blood and an increase of 96 CD4+ cells. Subjects
receiving fake DMP 266 had no changes in viral load or CD4+ cell
counts. After 12 weeks of a combination of both antiviral agents,
technicians found the amount of HIV had decreased to less than 1/1,000
of its pre-study level. Common side effects reported included
"headache, dizziness, rash and diarrhea." On average, subjects had
increases of 100 CD4+ cells. Use of DMP 266 may decrease levels of
indinavir by 37%. Further studies of this promising combination are
underway.

       REFERENCES:

            1. Mayers D, Riddler S, Stein D, et al . A double-blind
       study to evaluate the antiviral activity, tolerability and
       pharmacokinetics of DMP 266 alone and in combination with
       indinavir. Abstract LB 08A.

       D. Effect of 3TC and loviride on survival

       Background

       In the CAESAR (Canada, Australia, Europe and South Africa)
study doctors gave subjects fake 3TC (placebo), 3TC or a combination
of 3TC and loviride in addition to whichever antiviral drugs they were
already using. Thus, before entering the study subjects were using
either AZT, AZT and ddC or AZT and ddI. The dose of 3TC used was 150
mg twice daily and that of loviride was 100 mg three times daily.
Nearly 1900 subjects entered the study and had between 25 and 250 CD4+
cells at the start of the trial.

       Results -- Survival

       The following proportion of subjects in each group died:

        placebo - 17%

        3TC - 9%

        3TC and loviride - 8%

       The researchers did not release information on changes in the
amount of HIV in the blood of subjects. That subjects who received 3TC
and/or loviride were less likely to:

         die

         develop life-threatening infections

was [statistically] significant. In a regimen of 'nukes' (nucleoside
analogues; AZT, ddC, ddI, d4T), taking 3TC and/or loviride is likely
to decrease the risk of death or developing AIDS.

       REFERENCES:

            1. Montaner J, Cooper DA, Katlama C, et al . CAESAR:
       confirmation of the clinical benefit of 3TC (Epivir) in HIV-1
       disease: preliminary results. Abstract LB06.

       E. Indinavir and IL-2 -- one year later

       Interleukin-2 (IL-2) is a chemical produced by the immune
system that can have a number of effects, one of which is helping T
cells grow. IL-2 can also increase production of HIV by infected
cells, so in experiments on HIV-infected subjects, researchers always
use anti-HIV drugs with IL-2.

       In this experiment researchers recruited 36 HIV-infected
subjects who had less than 300 CD4+ cells or 20% CD4+ cells. The
subjects were then divided into three groups:

        Group A: 13 subjects received by injection IL-2 up to 12
         million units (12 MU) per day for "5 days every 2 months" and
         indinavir 600 mg every 6 hours.

        Group B: 11 subjects received the same dose and schedule of
         IL-2 as group A. As well, they received indinavir 600 mg/6
         hours only for 10 days every 2 months before, during and
         after they received IL-2.

        Group C: 12 subjects received indinavir 800 mg every 8 hours
         for the duration of the study.

       Results

       The first part of this study lasted for 14 weeks. Below are the
average CD4+ cell counts before subjects began to use the study drugs,
followed by the counts at the 14th week:

         Group A -- 205 and 363 cells

         Group B -- 191 and 246 cells

         Group C -- 144 and 230 cells

       We list below the decrease in HIV levels in the blood of
subjects by the 14th week:

        Group A -- 1.5 times less HIV

        Group B -- 1.2 times less HIV

        Group C -- 5 times less HIV

       After the 14th week subjects were allowed to add other anti-HIV
drugs to their regimens and subjects in group C could also use IL-2.
About one year after entering the study fewer subjects remained and
only 8 subjects in each group were receiving IL-2. By this time the
average CD4+ cell counts were:

        Group A -- 536 cells, 9 subjects

        Group B -- 386 cells, 8 subjects

        Group C -- 302 cells, 12 subjects

       Toxicity and lack of effect

       Subjects experienced "typical" side effects from use of IL-2
(fever, headache, muscle/joint pain, fatigue), and at least 2 subjects
developed kidney stones. During the first year of the study no
subjects died. In the 2nd year one subject developed PCP and 1 subject
not receiving IL-2 developed dementia. Four subjects in group A, 2 in
group B and 2 in group C stopped using IL-2 because it did not
increase their CD4+ cell counts.

       Interpretation

       The use of indinavir and IL-2 caused a small decrease in the
viral load and also increased CD4+ cell counts. Use of combination
anti-HIV therapy together with IL-2 may be useful in the long term.

       REFERENCES:

            1. Falloon J, Owen C, Metcalf C, et al . Indinavir and
       IL-2 in HIV: one year follow up. Abstract I108.

       F. Ritonavir and saquinavir

       Study details

       Researchers in the US and Canada have enrolled at least 136
subjects with CD4+ cell counts between 100 and 500 cells who had never
used protease inhibitors. Before entering this study subjects were not
improving despite use of AZT and related drugs. Subjects were randomly
assigned to receive one of three regimens:

         ritonavir 800 mg/day and saquinavir 800 mg/day

         ritonavir 1200 mg/day and saquinavir 800 mg/day

         ritonavir 1200 mg/day and saquinavir 1200 mg/day

       Results

       After 3 months in the study, levels of HIV in the blood fell by
over 99% in half the subjects and CD4+ cell counts rose by more than
100 cells. Nine subjects have left the study, 7 in the first dose
group. Side effects included " diarrhea, fatigue, nausea and tingling
around the mouth." No information on the effect of the combination on
the development of infections or survival has been released.

       REFERENCES:

            1. Cohen C, Sun E, Cameron W, et al . Ritonavir-saquinavir
       combination treatment in HIV-infected patients. Abstract LB
       07B.

       G. Saquinavir and indinavir -- some problems

       In an attempt to increase the anti-HIV activity of protease
inhibitors researchers are testing several drug combinations in lab
experiments. At low concentrations, indinavir used with saquinavir
have increased anti-HIV activity than either drug used alone. At
higher concentrations the anti-HIV effects of the drugs are reduced.
When technicians tested the combination against HIV that was resistant
to AZT, every concentration of the 2 drugs had reduced anti-HIV
activity than when each  was used alone.

       REFERENCES:

            1. Merril DR, Manion DJ, Chou T-C, et al . Protease
       inhibitor combination regimens against HIV-1 in vitro. Abstract
       I002.

       H. A new protease inhibitor -- 141W94

       141W94

       To study the effects of this drug 141W94 researchers recruited
42 adult (7 females, 35 males) HIV-infected subjects. Ninety-two
percent were either free from symptoms or had mild symptoms of HIV
infection. None were supposed to have used protease inhibitors before
entering this study. Researchers divided the subjects into 4 groups
and gave them several doses of 141W96; 600 mg/day, 900 mg/day, 1800
mg/day and 2400 mg/day for 4 weeks.

       Results -- amount of virus

       At the start of the study subjects had relatively high levels
of HIV in their blood. As well, half the subjects had at least 254
CD4+ cells. The greater the dose of 141W94 used, the greater the
decrease in viral load. Subjects receiving 900 mg/day or more of the
protease inhibitor had their viral load fall to 1/10th of its
pre-study level. Those subjects receiving 2,400 mg of the study drug
had their viral load decrease to 1/100th of its prestudy level.

       Results -- changes in CD4+ cell counts

       The changes in CD4+ cell counts did not mirror the trends in
viral load. Half the subjects in the groups below had the following
increases in CD4+ cell count:

          600 mg/day -- 64 cells

          900 mg/day -- 85 cells

        1,800 mg/day -- 35 cells

        2,400 mg/day -- 110 cells

       Toxicity

       Common side effects included "diarrhea, loose stools, rash and
headache." Three subjects left the study early because of rash (2
subjects) and "worsening [intestinal inflammation]."

       REFERENCES:

            1. The 141W94 International Study group. Preliminary data
       on the safety and antiviral efficacy of the novel protease
       inhibitor 141W94 in HIV-infected patients with 150 to 400 CD4+
       cells/mm3. Abstract LB 07A.

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