I Anti-HIV Agents
We report below on selected abstracts and posters from the XI International Conference
on AIDS, which took place from July 7-12, 1996, in Vancouver. Most of the anti-HIV
therapies reported here focus on the newer protease inhibitors indinavir, ritonavir and
saquinavir, alone or in combination. All References are from the conference unless
otherwise noted.
A. How long should treatment be continued?
One research team studied the effect of combinations of anti-HIV agents on subjects
newly infected with HIV. They think that these subjects will need at least 1.5 to 3 years
of treatment to eliminate all HIV-infected cells. In a recent issue of the journal
Science, a doctor reported that one of his patients who had been taking anti-HIV
combination therapy for 78 weeks decided to stop therapy when technicians could no longer
detect HIV in his blood or lymph nodes (the doctor did not reveal the names of the drugs
used, but they probably included a protease inhibitor). "Within 1 week, high levels
of virus could be found in his blood."
References:
- Cohen J. Shooting for the moon with drugs. Science 1996;273(5273):302.
B. Ritonavir -- effect on survival
Researchers randomly assigned over 1,000 subjects to receive ritonavir 600 mg twice
daily or fake ritonavir (placebo). All subjects had less than 101 CD4+ cells, the average
ranging from 30 to 35 cells. After 4 months, subjects receiving placebo could switch to
ritonavir if they developed new life-threatening complications or renewed attacks of old
infections, specifically:
- PCP
- ulcers due to herpes viruses
- yeast infections in the mouth and throat
Subjects were allowed to continue taking whatever drugs they were using before entering
this study. Indeed, half the subjects were taking 14 other drugs.
Who survived?
By the 6th month of the study, researchers found that roughly
- 4% of subjects on ritonavir
- 8% of subjects on placebo
had died. This difference was statistically significant; that is, not likely due to
chance alone.
Extracting meaning from numbers
It is difficult to assess the impact of ritonavir over the long term because after 4
months, subjects who developed serious complications were allowed to use ritonavir.
Moreover, another study found that ritonavir improved the ability of T cells to respond to
infections during the first month of therapy. After this time, T cell function declined to
its pre-ritonavir level. Nearly one year into the study researchers reported the following
events:
Event Ritonavir Placebo
Death 27 35
Yeast infections (oral) 18 41
Kaposi's sarcoma 8 20
PCP 10 22
CMV retinitis 18 17
Wasting syndrome 2 8
HIV and CD4+ cell counts
Some subjects who received ritonavir had an increase of at least 50 CD4+ cells that was
sustained for about one year. After receiving ritonavir for 2 weeks, the amount of HIV in
the blood fell to 1/10th its pre-study level.
Toxicity
Subjects receiving ritonavir experienced diarrhea, tingling around the mouth (both inside
and outside) and nausea. Gradually increasing the dose of ritonavir over a period of 10
days, starting with 600 mg/day, may increase patients' tolerance of the drug.
References:
- Cameron DW, Heath-Chiozzi M, Kravick S, et al. Prolongation of life and prevention
of complications in advanced HIV immunodeficiency with ritonavir: update. Mo.B.411.
- Pakker NG, Roos MTL, de Jong M, et al. Analyses of T cell repopulation and
restoration of T cell function during therapy with different antiretrovirals. We.B.291.
C. Indinavir -- with or without AZT and 3TC
Background and Study details
In this study researchers compared the effects of different regimens:
- Indinavir alone
- Indinavir with AZT and 3TC
- AZT and 3TC
The drugs were taken in their standard doses: AZT 600 mg/day, 3TC 300 mg/day and
indinavir 2.4 grams/day. Researchers assigned subjects at random to each group. All 91
subjects were HIV-infected adults (15 female, 76 male), at least half of whom had a CD4+
cell count of 144 cells. No subject was supposed to have used a protease inhibitor before
entering this study. Neither doctors nor subjects were supposed to know which combination
of drugs was used.
Results -- HIV
Those subjects receiving the triple combination had a dramatic reduction in the amount of
HIV in their blood, averaging about 1/100 th their pre-study level, a reduction was
sustained for 44 weeks. Subjects receiving AZT and 3TC had the amount of HIV in their
blood fall by 50%. This reduction was sustained for the rest of the study.
Results -- CD4+ cell counts
Subjects who received AZT and 3TC had an average increase of 40 CD4+ cells compared with
their pre-study levels. Those subjects receiving indinavir alone or in combination had
their CD4+ cell counts rise by 100 cells. This increase was maintained for 9 months.
Readers should note that as the trial progressed, more subjects began to leave.
Toxicity
Four subjects in the AZT/3TC group and 2 others developed:
- low levels of certain white blood cells called neutrophils.
Twenty-two produced higher-than-normal levels of :
Eight subjects receiving indinavir and one on AZT/3TC developed
References:
- Gulick RM, Mellors J, Havlir D, et al. Potent and sustained antiretroviral
activity of indinavir, zidovudine and lamivudine. Th.B.931
D. Indinavir -- which dose is best?
In this study researchers tested three doses of indinavir:
- 2.4 g/day
- 3 g/day
- 3.2 g/day
Doctors reported results on 63 subjects who had been using indinavir for about 1 year.
By the 6th month of the study, the amount of HIV in the blood of subjects had decreased to
at least 1/100th of its pre-study level. Half the subjects had an increase of between
"80 to 145 CD4+ cells." By the 12th month of the study, production of HIV
remained as low as it had been 6 months earlier and subjects had 85 extra CD4+ cells than
when they started. Technicians were not able to detect HIV in "54%" of subjects.
Readers should note this does not mean that no virus was present, but simply that the
equipment was not sensitive enough to detect it. Doses of indinavir greater than 2.4 g/day
do not appear to provide any benefit beyond that seen with 2.4 g/day.
Toxicity
About 50% of subjects had higher than normal levels of bilirubin. This was detected in lab
tests only, as subjects did not have any signs/symptoms associated with this. Kidney
stones did develop in the following proportion of subjects:
- 2.4 g -- 10%
- 3.0 g -- 16%
- 3.2 g -- 12%
References:
- Steigbel R, Berry P, Teppler H, et al. Extended follow-up of patientsin a study of
indinavir at 800 mg every 8 hours (2.4 g/day) and 800 mg every 6 hours (3.2 g/day).
Mo.B.412
E. Hydroxyurea -- one year later
Doctors in Italy recruited 60 HIV-infected subjects who had more than 250 CD4+ cells.
Twenty subjects received ddI 400 mg/day and 40 received the same dose of ddI as well as
hydroxyurea 1 g/day. Doctors monitored the subjects for up to 6 months.
Results -- combination
Once subjects started to receive both drugs the amount of virus in their blood fell by
over 90% compared to their pre-study level. Of the 40 subjects on combination therapy, 18
remained in the study until the 6th month. Production of virus remained low and CD4+ cell
counts remained stable.
Result -- ddi alone
Use of ddI also caused a dramatic decrease in production of HIV during the first 2 weeks
of the study, but after that it began to rise. By the 6th month of the study the average
amount of HIV in the blood of these subjects had risen to 50% of its pre-study level. In
25% of subjects on ddI alone, levels of HIV in the blood returned to pre-study levels by
the 6th month of the study.
Results -- 7 subjects
The researchers also did experiments on 7 other subjects, 3 of whom had AIDS. All subjects
saw the amount of HIV in their blood fall to 1/10th its pre-study level. The researchers
did not report any further information.
Reference:
- Lori F, Foli A, Viale P, et al. Sustained absence of viral rebound consistently
observed in patients treated with combination of hydroxyurea and didanosine. Th.B.942,
programme supplement.
F. Saquinavir and d4T
Doctors in Switzerland gave 14 subjects d4T 80 mg/day and saquinavir 1800 mg/day.
Before entering this study, half of the subjects had used ddI for about 3 months. Twelve
of the subjects had survived at least one life-threatening infection. At the time they
entered the study half the subjects had a CD4+ cell count of 33 cells and a CD8+ cell
count of 449. None of these subject improved on other older anti-HIV drugs.
Results
One month after entering the study half the subjects saw their CD4+ cell count climb to 65
cells and by the second month, it had reached 90 cells. Similarly, their CD8+ cell count
increased to 599 cells during the first month, and in the second it rose to 696 cells. Yet
these increases were not statistically significant. During the first month, blood levels
of HIV fell to 1/100th their pre-study level, but returned to 1/10th their pre-study level
by the end of the second month. This difference was statistically significant.
Reference:
- Rutschmann O, Kaiser L, Gabriel V, et al. Adding saquinavir to d4T in advanced
HIV-1 infection. Th.B.945.
G. Saquinavir -- 2 or 4 times the normal dose
Why increase the dose?
Although saquinavir can reduce production of HIV in laboratory experiments, when taken
orally more than 90% of the drug is not absorbed or processed, which drastically reduces
the amount of drug that gets into the blood. As a result, researchers have been testing
between 2 and 4 times the licensed dose of saquinavir (1800 mg/day) to see if absorption
can be increased.
Study details
Researchers enrolled 40 HIV-infected subjects (1 female, 39 male) with CD4+ cell counts
ranging between 188 to 527 cells, the average being 346. Sixteen subjects in each group
had less than 3 months of exposure to AZT and "related" drugs. Half the subjects
received "low-dose" saquinavir, that is, 3,200 mg/d. The other half received
"high-dose" saquinavir, that is, 7,200 mg/day. The drug was supplied in 200 mg
capsules, so some subjects "needed to take 36 [capsules] each day."
Results -- low dose saquinavir
Subjects in the low-dose group had an increase of 72 cells by the 4th week of the
study. By the 6th month of the study, this figure had fallen to 31 cells. The increased
cell count was statistically significant until the 4th month.
The amount of HIV in the blood fell to 1/12th its pre-study level by the 2nd week of
the study. After that it began to increase until by the 6th month, it had returned to near
its pre-study level.
Results -- High dose saquinavir
The average CD4+ cell count rose by 121 cells when subjects started using saquinavir. Six
months later the average increase was 82 cells. These changes were statistically
significant. Readers should note that all subjects in this group had an increase of at
least 50 CD4+ cells. The difference in the increased CD4+ cell counts between the
high-dose and low-dose groups was statistically significant in the 3rd and 5th months of
the study.
In the high-dose group, production of HIV fell to 1/22nd its pre-study level. After
this, it began to increase slowly but still remained below its pre-study level by the 6th
month. This difference between the level of HIV in the 6th month and the pre-saquinavir
level was statistically significant.
Toxicity -- low-dose group
Common signs/symptoms included:
- fatigue
- headache
- muscle pain
- diarrhea
- low-blood sugar
Toxicity -- the high-dose group
Common signs/symptoms included:
- headache
- muscle pain
- diarrhea
- low levels of magnesium in the blood
According to the researchers, all subjects recovered from all of these effects once
they stopped taking the drug. They added, "Most gastro-intestinal [problems happened
during] the first 1 - 2 weeks [of the study] and decreased or disappeared.... without
[need to reduce the dose]." Since subjects could tolerate the doses of drugs used in
this study, the researchers think that further experiments with these doses of saquinavir
and other antiviral drugs should be conducted. The company that makes saquinavir is also
testing a new form of the drug in soft gel capsules. Researchers think that use of this
product should result in much higher levels of saquinavir in the blood. In Canada that
study in question is being coordinated at Sunnybrook Hospital (Toronto). Reference:
- Schapiro JM, Winters MA, Stewart F, et al. The effect of high-dose saqunavir on
viral load and CD4+ T cell counts in HIV-infected patients. Annals of Internal Medicine
1996;124(12):1039-1050.
H. A cocktail of 5 anti-HIV drugs
Researchers used 6 subjects who had become infected within the past 6 months. Subjects
received standard doses of AZT, ddC, ddI and interferon-alpha with or without 3TC. In some
subjects, the use of combination anti-HIV therapy caused a dramatic decrease in the amount
of HIV detected in their blood. Viral load (HIV RNA) fell to 1/1,000th its pre-treatment
level. One subject had a normal CD4+ cell count and the amount of HIV RNA in his blood was
less than 12 copies/ml.
Reference:
- Saget BM, Elbiek T, Guthries J, et al. Dramatic suppression of HIV-1 plasma RNA
using a combination of zidovudine, didanosine, zalcitabine, epivir, and interferon-alpha
in subjects with recent HIV-1 infection. We.B.533
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