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What’s New with Drug Regimens?
by Charles E. Clifton
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Since researchers unveiled
protease inhibitor drugs at the 1996 world AIDS conference,
researchers and treatment activists alike have come to each
of the international gatherings hungry for the latest information
on how to make these cumbersome but life saving medications
more user friendly.
For patients who have never
taken antiretroviral drugs, the selection of an initial regimen
is crucial to long-term preservation of the body’s immune
system. Studies have shown that in order to successfully suppress
HIV in the body, very high levels of adherence to an antiretroviral
regimen is required. But lifetime adherence to HIV drug regimens
is no easy task.
Pills must be taken as much
as four times a day. Some require food with each dose; others
need to be taken on an empty stomach. Many of the drugs cause
painful side effects. Some of those side effects, like diarrhea,
are immediate while others, such as liver damage and increased
cholesterol levels, are long-term. Perhaps most visibly dramatic,
some meds cause changes in the shape and size of the body
by redistributing fat (a condition known as lipodystrophy).
Finally, many of the side effects worsen conditions that already
plague African Americans, such as heart disease and high blood
pressure.
Several presenters at the
Barcelona conference have reported studies on new strategies
to initiate treatment in HIV-positive people who have never
taken antiretroviral drugs. Following are some highlights
of studies comparing the effectiveness of regimens that spare
HIV-positive patients from using the punch-packing protease
inhibitors in their initial treatment regimen. (Visit www.aids2002.com
for more information.)
Viramune
vs. Viracept
J. Mallolas presented data
comparing the effectiveness of two different regimens in “treatment
naïve” HIV-positive clients—or people who have not previously
received medication to combat their infections. One group
of participants was given a regimen consisting of two nucleoside
reverse transcriptase inhibitors (Videx [ddI] and Zerit [d4T])
plus one protease inhibitor (Viracept [nelfinavir]). A second
group was given two NRTIs (Retrovir [AZT] and Epivir [3TC])
and one NNRTI (Viramune [nevirapine]). The aim of this study
was to determine whether individuals with fewer CD4 T-cells,
in this case less than 500, could be treated successfully
with a regimen that spared the use of protease inhibitors.
The results of the 18-month study indicate that the regimen
consisting of Retrovir, Epivir and Viramune was as effective
and tolerable in this group of treatment naïve HIV-positive
participants.
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Sustiva
beats dual PIs
J.R. Arribas discussed data
comparing the effectiveness of a regimen using Sustiva (efavirenz)
from the NNRTI class against regimens using protease inhibitors.
In this study of 214 participants with immune systems that
were severely impacted by HIV, each participant had fewer
than 100 CD4 T-cells. The participants were randomly divided
into six different study groups. In the five groups using
protease inhibitors, 47 participants were given regimens that
included Crixivan (indinavir) in addition to drugs from the
NRTI class, 47 were taking Viracept (nelfinavir), 25 with
Norvir (ritonavir), three with Crixivan combined with Norvir,
and three with Fortovase (saquinavir soft-gel) combined with
Norvir. Ninety-two participants were taking Sustiva in addition
to drugs from the NRTI class. Following 12 months of close
study, the researchers determined that there was no difference
between the Sustiva or the PI-based use of HAART in the initial
treatment of HIV-positive individuals with severely suppressed
immune systems, suggesting that Sustiva is an effective drug
to use in initial regimen options.
A final study presented by
O. Kirk examined data seeking to determine the effectiveness
of a triple class HAART regimen, and the potential for greater
levels of toxicity. Again treatment naïve HIV-positive participants
were randomized into two study groups. One group of 118 participants
was taking Viracept and Viramune plus two NRTIs, the second
group of 115 individuals was taking Norvir and Fortovase plus
two other NRTIs. After 48 weeks of study, researchers determined
that a regimen of nelfinavir and nevirapine plus two NRTIs
was well tolerated and was effective at suppressing HIV when
compared to a regimen containing the Norvir and Fortovase
(both protease inhibitors) plus two NRTIs.
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A few highlights in antiretroviral
therapy issues in the treatment experienced individuals
Switching
PIs
Can you simplify your PI
treatment by switching to Sustiva, Viramune or Ziagen? In
a simplification study, researchers from Spain looked at the
response of participants who switched from a HAART regimen
containing a protease inhibitor to a regimen containing either
Viramune or Sustiva, both non-nucleoside analogue reverse
transcriptase inhibitors (NNRTIs), or to a regimen containing
the nucleoside analogue reverse transcriptase inhibitor (NRTI)
Ziagen (abacavir). To date head-to-head studies comparing
these three drugs have not been reported.
Researchers found that people
were more likely to have detectable viral load with Ziagen.
However, they were significantly more likely to discontinue
Sustiva or Viramune because of side effects.
A total of 400 adult participants,
on a regimen containing at least one protease inhibitor plus
two NRTIs and with viral load less than 200 copies/mL were
randomly switched from the PI to either of the three study
drugs (Viramune 155, Sustiva 156, Ziagen 149). The goal was
to maintain viral load below 200 copies/mL for 12 months following
the switch. After 12 months, 94% (Viramune), 94% (Sustiva),
and 87% (Ziagen) of participants remained below the 200 count.
The mean changes in CD4 T-cells during the 12 months were
+41 (Viramune), +51 (Sustiva), and +51 (Ziagen). A significantly
higher number of participants discontinued therapy from Viramune
(16%) and Sustiva (17%), than on Ziagen (6%). People with
treatment failure (detectable viral load) after one year were
23 (15%) of those on Ziagen compared with eight of those on
Viramune and seven of those on Sustiva (about 5% each). Results
are from 18 months of follow-up.
The Spanish researchers evaluated
460 patients who had less than 200 viral load. Everyone had
a T-cell increase of around 45. Participants had a median
of 30 months on their PI therapy (mostly Crixivan or Viracept)
and had monotherapy before then. Half of them had an AIDS
diagnosis. There was no “evident” change in body fat abnormalities.
(Abstract WeOrB1262)
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Fortovase/Norvir
Researchers lowered the dose
of Norvir and increased the dose of Fortovase to see if side
effects would be less and the twice-daily combination still
effective. Yes and yes. Doctors said the 400/400 twice-a-day
dose was poorly tolerated, and that Norvir significantly increased
levels of cholesterol and triglycerides.
This small U.S. study examined
the clinical benefits of switching 23 treatment experienced
patients with viral loads less than 200 copies/mL to Fortovase
1000 mg/Norvir 100 mg dosed twice daily in a four-drug antiretroviral
therapy. The goal was to examine the occurrence of hyperlipidemia
and adverse side effects associated with the higher dosing
of ritonavir. Previous data on drug level maintenance supports
the use of a lower dose of ritonavir to boost saquinavir 1000
mg, twice daily. Other inclusion requirements were also that
participants had to have been receiving saquinavir 400 mg/ritonavir
400 mg for at least six months prior to entering the study,
and no prior use of more than one other protease inhibitor
for more than three months.
Drug levels were measured
at time of entry to the study, and at months one and six,
fasting lipids (triglyceride and cholesterol) were measured
every three months. Over the course of six months, the lower
dose of ritonavir was tolerated better, fasting triglyceride
levels fell from an average of 635 to 375 mg/dl, and cholesterol
levels fell on an average of 326 to 236 mg/dl, supporting
growing trends toward dose reduction of ritonavir. Some doctors
wondered why the 1,000/100 twice-a-day dosing was being studied,
when 1,600/100 once a day is popular. They concluded that
the drug companies had to show something to the Food and Drug
Administration for lowering the Norvir dose. (Abstract WeOrB1263)
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Crixivan
vs. Fortovase
International researchers
reported on the first head-to-head comparison of ritonavir
boosted PIs Crixivan and Fortovase, in combination with more
than two NRTIs or NNRTIs. The objectives of the study was
to compare virological outcome between 306 participants randomly
divided into two study groups, based on the percentage of
participants whose viral load remained below 400 c/mL thru
48 weeks, the percentage of participants experiencing adverse
side effects, and those who discontinued treatment prematurely.
No clinical, laboratory nor demographic differences were observed
at the beginning of the trial. As of December 2001, while
viral load remained suppressed in the vast majority of study
participants, an evaluated number of participants had difficulties
tolerating both drugs. In the Crixivan group, 56 of 158 participants
(35%) discontinued therapy due to drug toxicity. Fifty participants
(32%) in this group reported grade 3 or 4 adverse events (serious).
Seven were due to abnormal liver function test. In addition,
serious adverse events that required hospitalization or were
life-threatening occurred in 28 participants (18%).
In the Fortovase group, 42
of 148 participants (28%) discontinued therapy due to drug
toxicity. Twenty-nine (20%) in this group reported grade 3
or 4 adverse events, four of which were due to abnormal liver
function test. Serious adverse events occurred in 21 participants
(14%) in this group. Interestingly, a third of each group
had previously taken the protease inhibitor they were given—Crixivan
or Fortovase—but it had not been boosted by Norvir before.
The MaxCmin1 trial took place in the U.S., Latin America and
Europe. This study is ongoing. (Abstract WeOrB1265)
Viread
resistance
Forty-eight week data, from
an international double-blind study, on the potent activity
against wild-type virus and nucleoside resistant HIV of Viread
(tenofovir) was reported. (Double-blind means that neither
the patients nor the medical personnel knew what drug was
being given, a process which helps to eliminate bias in a
study.) A total of 550 treatment experienced participants
with viral load between 400 and 10,000 c/mL were randomized
to received either Viread 300 mg or placebo, with antiretroviral
therapy, for 24 weeks. After week 24, all participants received
Viread 300 mg through 48 weeks. The mean CD4 T-cell was 427,
and prior antiretroviral use was 5.4 years, at the beginning
of the trial. Through 48 weeks, viral load dropped below 400
c/mL in 41% of all participants, and 18% had a drop below
50 c/mL.
A sub-study of 253 randomly
selected participants observed the long term pharmacokinetics
(PK) of Viread. No changes in the PK of Viread was observed
at week 12, 24, 36 or 48, when compared to day one, and no
drug-related renal toxicity was reported. Through 48 weeks,
only eight participants (3%) developed the K65R mutation (Viread
associated drug resistance). (Abstract WeOrB1266)
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