The Buzz
The Importance of Sequencing
in Treatment Options
by Daniel
S. Berger, MD
Physicians should constantly
consider the sequence for which they use antiviral drugs in
their patients (sequencing therapies). HIV positive individuals
are living longer with the help of effective treatment, but
an increasing number of patients are developing resistance
to their regimen. If a patient develops resistance to his
or her regimen, the next regimen, one that is not cross resistant
and allows for further options, should be well thought out.
Thus, the raison d’être for properly sequencing HIV drug treatment
allows for the maximum number of options and alternatives
to be available for the long term. With the probability of
keeping patients on treatment for 20 or more years, antiretroviral
drugs must be properly sequenced.
Physicians may need to change
a patient’s therapy perhaps as early as 18 months into treatment.
While newer drugs become available, sequencing should encompass
the specific resistance characteristics of all antiviral agents.
For example, patients who have had long experience to the
nucleoside class (nukes, or NRTI) and whose virus in resistant
to, for example, 3TC may have resistance to other nukes, such
as abacavir or Ziagen. Those with high resistance to this
class of drug may alternatively be very susceptible to the
non-nuke class (NNRTI) or have increased susceptibility to
tenofovir (an experimental drug). However, individuals developing
resistance to their new NNRTI will likely have cross-resistance
to other NNRTIs. Likewise, various protease inhibitors bear
cross resistance within their family of drugs. However, using
them in a particular order may allow for further use in salvage
regimens and in various dual protease inhibitor regimens (two
protease inhibitors in the same drug regimen).
For these reasons, changing
therapy should be well thought out, not done haphazardly.
For highly experienced patients newer drugs should be reserved
whenever possible. A basis for changing to another regimen
includes treatment failure, but toxicities or intolerance
to the current antiviral regimen are also grounds for switching
an existing regimen. Pharmaceutical companies are attempting
to develop newer drugs, acutely aware of the urgency and marketability
of drugs effective against resistant virus. A new protease
inhibitor recently approved, Kaletra, is being used in salvage
regimens. Three other agents from differing drug classes are
in development and key in on resistant virus; they include
tenofovir DF, T-20 and DPC-083. These significantly improve
our options for patients who need alternatives.
Kaletra
(lopinavir/ritonavir or ABT-378/ritonavir) has only been available
and on the market for a relatively short period of time. It
has been studied in naïve and protease-experienced patients
in combination with non-nucleosides. The data holds up regarding
the advantages of using this protease inhibitor in certain
situations. Being new, Kaletra has not been studied as extensively
as other drugs, and regarding sequencing protease inhibitors,
it is not quite clear as to where Kaletra should fit in with
the overall treatment scheme of individual patients. Questions
regarding its appropriate use as first line treatment, and
the proper sequencing of this drug because of cross-resistance
to other protease inhibitors have been raised. However, it
is well tolerated and has become a useful addition to the
antiviral armamentarium. Like most new drugs coming to market,
the reported studies were designed to get the drug FDA approved.
Later studies and further clinical experience will add to
our understanding.
Abbott Labs has promoted
Kaletra and a post-marketing switch protocol (FDA approved)
called PLATO. A switch study generally denotes discontinuing
an existing drug therapy and changing to the promoted product.
This particular study involves switching patients who are
intolerant to other therapies to Kaletra. During the study,
Abbott provides Kaletra free-of-charge to the patient, afterwards
it becomes the patient’s responsibility to pay for the drug.
While observed for a period
of only eight weeks, patients are evaluated for quality-of-life
changes. While touted as a “quality-of-life” study, PLATO
disregards side effects impacting this very issue, such as
lipodystrophy and metabolic complications. While lipodystrophy
changes usually arise later, when they do occur, they can
have huge quality-of-life consequences. Studies of Kaletra
have shown that the drug is associated with hyperlipidemia
(increased cholesterol and triglycerides) which are often
associated with lipodystrophy. Other symptoms can appear later
than eight-weeks of treatment which may affect quality-of-life.
But Abbott’s Medical Director of Global Antiviral Marketing
Product Development denies that the study was done as a marketing
vehicle, simply to get people on their drug, claiming there
are “probably cheaper ways to market drugs, such as starter
packs and coupons.” However, it is widely known that starter
samples and coupons are rarely used for HIV prescriptions
of antiviral drug therapy. Many physicians and treatment advocates
believe the scientific value of studies are improved by designing
conventional longer-term projects that seriously delve into
the important issues of quality of life and metabolic complications.
Tenofovir
DF (developed by Gilead Sciences) is part of a new class
of drugs called nucleotide reverse transcriptase inhibitors.
Its active metabolite (duration of drug lasting in the blood
stream) has a half life between 10–30 hours and the intracellular
half life is equal to or greater than 30 hours, therefore
it can be given at convenient once daily dosing. In vitro
(test tube) toxicity studies show tenofovir having little
effects on the mitochondrial enzymes and not limiting the
mitochondrial DNA, predictors of mitochondrial toxicity. Most
current schools of thought believe that it is this toxicity
to mitochondria that causes lipodystrophy complications in
HIV disease.
Also, tenofovir has activity
against HIV with various Retrovir (AZT), Videx (ddI), and
Hivid (ddC)-associated mutations and shows increased activity
against HIV with Epivir (3TC) resistance. Indeed, an earlier
study (study 902) demonstrated antiviral effect of this agent;
94% of the study patients had NTRI resistance mutations prior
to study. The most recently reported study (study 907) enrolled
more than 550 treatment-experienced patients. There was significant
viral load reduction observed in this group, who had tenofovir
added to their existing drug regimen and 45% achieved viral
loads below 400 copies. Thus, once available, tenofovir appears
to be an attractive choice for use in antiviral regimens.
Tenofovir is currently available
on a compassionate program to patients with CD4 T-cells below
100 count who are failing their regimens (two protease inhibitors
or one protease inhibitor and a non-nuke) and for patients
with recent (within 90 days) opportunistic complications,
the CD4 cells can extend to 200 count for eligibility. Gilead
Sciences is on track for submission of its New Drug Application
to the FDA by mid-year.
A second-generation non-nuke,
DPC-083, developed by DuPont Pharmaceuticals,
is continuing in clinical trials. Phase II studies are being
conducted in Europe and at only five sites around the US,
one being here at NorthStar Medical Center in Chicago. This
particular protocol is studying individuals who are failing
their first regimen containing a non-nucleoside and is still
open for enrollment. As a non-nucleoside, DPC-083 has similar
potency to Sustiva (efavirenz) against wild type virus, however
it has other significant advantages: the drug is effective
for virus that is potentially resistant to Sustiva or Viramune
(nevirapine), including against the infamous K103 mutant,
and is two to eleven times more potent than Sustiva against
other potential resistant virus. It has a long half-life,
and is administered once daily. Thus far the drug has been
found to be well tolerated and side effects have been found
to be of minor severity and of short duration.
DuPont Pharmaceuticals is
currently up for sale. We hope that a pharmaceutical company
experienced in HIV drug development acquires DuPont and will
show the same commitment and ability to develop further antiviral
options, and continues to support the HIV community.
T-20
is another novel agent in a new drug class called fusion inhibitors.
T-20 blocks the ability of HIV to combine or fuse with the
CD4 receptor (T-cell). Preliminary studies have shown that
T-20 is effective in patients with resistance to other antiviral
agents. Cross-resistance is unlikely due to the unique mechanism
of action. Because the chemical structure of this agent is
a chain of amino acids, it is easily broken down by stomach
acids. Thus the drug needs to be administered by subcutaneous
injection. The drug, developed by the small biotech company
Trimeris, sold marketing rights to Roche. This larger pharmaceutical
company will definitely aid in its faster development and
production. T-20 will also become available on a limited compassionate
track program (see News Briefs).
New antiviral agents are
being developed with resistance in mind. With more drugs becoming
available and as we expect to see our patients living to old
age, effective drug sequencing becomes even more crucial and
we’ll need to conserve as many options for treatment as wholly
possible.
Daniel S. Berger, MD is
Medical Director for NorthStar Medical Center; Clinical Assistant
Professor of Medicine at the University of Illinois at Chicago
and editor of AIDS infosource (www.aidsinfosource.com).
He also serves as medical consultant for Positively Aware.
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