PI Perspective #40
January 2006 View PDF En
español
Entry Inhibitors:
A Race to the Finish Line
As reported in PI Perspective
#38, entry inhibitors are a promising new class of anti-HIV
drugs. One of them, enfuvirtide, is already approved and two others
(maraviroc and vicriviroc) are currently being studied. A third
drug was close behind but its development was stopped in October
2005 due to serious side effects. Several others are in early stages
of development.
People are hopeful about entry inhibitors for a couple of reasons.
Most importantly, they suppress HIV in a completely different way
than other classes of anti-HIV drugs, meaning they should be effective
in people with resistance to the older drugs. Because entry inhibitors
work without interfering with what’s going on inside cells
there’s also hope that they will not have some of the troubling
side effects of other drugs, like body composition changes (lipodystrophy).
Recently, some of the excitement about these new drugs has been
tempered by new concerns about unexpected side effects and somewhat
disappointing effectiveness. Early articles hailed them as the leading
edge of a new era in HIV therapy, yet the most recent experiences
may suggest a more modest future for them. As the two most advanced
drugs are studied, researchers should better understand their strengths
and weaknesses and how best to use them.
New entry inhibitors in study
Several companies are rushing to bring entry inhibitors to market.
Each believes it has come up with the best way to block HIV from
entering cells. Currently, there are two frontrunners—drugs
that are able to be taken by mouth in pill form. Each is being developed
by a large company with substantial resources and expertise in drug
development. The drugs are:
• maraviroc (UK-427857) by Pfizer, already in large studies.
• vicriviroc (Schering D and SCH-417690) by Schering-Plough,
recently entered large studies.
GlaxoSmithKline’s entry inhibitor was recently withdrawn
from development due to indications of liver toxicity.
Other entry inhibitors not covered in this article, but show some
promise in early studies, include:
• AMD070, by Anormed
• BMS-488043, by Bristol Myers Squibb
• TNX-355, by Tanox
• PRO 542, by Progenics
Co-receptor blocking drugs
Maraviroc
and vicriviroc interfere with HIV’s attempts to enter a CD4+
cell by binding to a cell receptor called R5 (CCR5). If HIV cannot
bind to R5, it generally cannot fuse to the cell and enter it. HIV
can use several receptors on CD4+ cells, but X4 (CXCR4) is the only
other one that it uses with any frequency. It is unclear whether
HIV will eventually “learn” to use the other receptors
after being blocked at R5. Because HIV must first bind to the CD4+
receptor on the cell, R5 and X4 are called co-receptors. These receptors
have other functions for the cell—not all of which are understood—but
HIV takes advantage of them in order to infect the cell.
All cells in a person’s body produce R5. Some people make
a damaged or non-functional form of it. Researchers began developing
drugs to block R5 after it was found that people whose CD4+ cells
do not make functional R5 rarely become infected with HIV.
For reasons that are not fully understood, HIV has a hard time
establishing a foothold in a person whose cells have no functional
R5. Also, some people have CD4+ cells that carry fewer functional
R5 than normal. These people can still be infected with HIV, but
they seem to carry greater protection against infection than people
with normal amounts of functional R5. When they do get infected,
the course of their disease is generally slower.
These facts alone are reason enough to explore therapies that block
HIV from using R5. However, another reason was learning that people
without functional R5 appear to suffer no negative health effects.
This is significant and hopeful, as studies have found that there
may be severe consequences to blocking other co-receptors from HIV.
Drugs that block R5—are there risks?
The immune system is complex and controlling it with drugs is tricky.
Researchers simply don’t know whether giving someone a drug
to block R5 will provide the same protection from HIV as that seen
in people who are genetically unable or less able of making functional
R5. Also, using drugs to block R5 may be harmful in ways that are
not apparent in people who naturally do not make functional R5.
One of the most serious, though theoretical, risks has to do with
how changes in receptor use by HIV may hasten disease progression.
At least half of all people with HIV eventually have measurable
changes in the type of HIV found in their blood. Instead of using
R5, HIV begins to use another receptor called X4. This change seems
to correlate with a rapid decline of CD4+ cell counts and the onset
of opportunistic infections. Other research suggests that nearly
everyone with HIV, at some time during their disease, may experience
this shift—but about half may revert back to R5 virus.
HIV primarily uses R5 along with the CD4+ receptor to enter cells.
However, it can evolve to use X4. Some strains appear to use both
(dual tropic virus). In test tubes, HIV that uses X4 has been found
to cause CD4+ cells to clump together (syncitia inducing) and die
in a way that R5 virus does not. This, along with the fact that
X4 virus usually has been found in people when they begin to have
rapid disease progression, has led many to label it as more aggressive
and dangerous than R5 virus. However, others point to the fact that
half of people who die from HIV disease mostly have R5 virus. This
may be because the amount of X4 virus in blood can vary.
So, when researchers looked for X4 virus in these people, it may
be that it simply wasn’t measurable at that time, but was
in fact present. Or, it may be that people with R5 virus are also
in danger, whether or not they ever change over to X4 virus. Thus,
the story may be too complex to simply label R5 virus as moderately
bad and X4 virus as really bad. But given that some researchers
may overstate the negative effects of X4 virus, there are some entirely
new risks posed by the studies of R5-blocking drugs.
The greatest potential risk by blocking R5 on CD4+ cells is that
it may give HIV that uses X4 a chance to take over and become the
dominant strain. If X4 virus turns out to be more lethal than R5
virus, using these new entry inhibitors could actually harm people
rather than helping them. This is most likely to happen in those
who already have some measurable degree of X4 virus, are heavily
treatment experienced, and have CD4+ cell counts below 200 (or lowest-ever
counts, nadirs, below 200). This risk is theoretical and no one
can say for sure that it will occur, but it still is a concern.
Evidence of R5 to X4 shift?
Because using drugs to block R5 might increase disease progression,
the earliest studies did not allow people with any trace of X4 virus
to participate. Several people who originally showed no X4 virus
on the screening tests had X4 virus emerge after taking a short
course of the new drugs. When this occurred, other tests were done
on the blood that was originally collected. In most cases, these
other tests found that X4 virus had been present all along but had
been missed. In at least two cases, however, the presence of X4
virus before using the study drug could not be confirmed by using
the standard screening tests.
Researchers followed these two people very closely in the months
after the studies ended and sent samples of their virus for further
evaluation. The results appeared to show that X4 virus had likely
been present before they took the study drug, but that there was
too little present for the standard tests to pick up. In one of
the two, X4 virus disappeared within a few weeks after stopping
the drug. In the other person, X4 virus has remained detectable
more than a year after stopping the drug. So far, neither case has
shown evidence that the shift in virus has caused harm.
Spotlight on the drugs in study
So far there’s a striking similarity between the R5 inhibitors
in terms of their effects on viral load and the degree to which
they remain stuck to R5 receptors for hours (or days) after a person
stops taking the drug. One main difference, so far is the degree
to which the older anti-HIV drugs may increase or decrease the blood
levels of each of the new drugs. Though further data are needed,
scientists have developed virus in the lab that is resistant to
each of the new drugs. Safety problems have already stopped one
R5 drug, and potency problems are being seen in another.
Large studies of maraviroc started in December 2004 while large
studies of vicriviroc started in the summer of 2005. Development
of a third R5 drug, aplaviroc, has stopped due to several cases
of liver-related side effects. AIDS Community Research Initiative
of America (ACRIA) maintains one of the best resources for finding
studies that may be recruiting near you. It can be found online
at www.acria.org.
Another resource by the National Institutes of Health (NIH) is available
online at www.aidsinfo.nih.gov
or by phone at 1-800-448-0440.
Maraviroc (UK-427857)
The first safety studies of maraviroc took place in healthy HIV-negative
people. Various doses were tried, including single doses as high
as 900mg per day and multiple doses of 300mg twice a day, for 28
days. The most frequent side effects were headache and upset stomach.
A more serious side effect in those who took more than 600mg per
day was a feeling of dizziness or faintness from quickly sitting
up or standing (postural hypotension).
Animal studies showed that maraviroc could cause
irregular heartbeats. So far, this has not been found in human studies.
Studies also found that while maraviroc blood levels were reduced
by almost half with food, there was very little difference in viral
suppression between people taking it with or without food.
Interactions are expected between maraviroc and
other drugs. Ritonavir, even at low doses, and saquinavir greatly
increase blood levels of maraviroc—by up to four times. On
the other hand, drugs like efavirenz and rifampin can greatly lower
its blood levels. Pfizer provides information on adjusting the dose
of maraviroc when taking it with these drugs. Drug interaction studies
are ongoing.
Studies examining the effect of maraviroc on viral
load in people with HIV were reported in 2004. It was found that
doses of 100mg to 300mg taken twice a day for ten days (without
other anti-HIV drugs) resulted in viral load decreases of up to
1.6 logs.
Several studies (phase II/III) started in December
2004. One study of 1,071 people who had never taken anti-HIV therapy
is comparing one of two doses (300mg once or twice daily) of maraviroc
+ 3TC + AZT to efavirenz + 3TC + AZT. All will be screened for X4
virus and anyone who has it will not participate.
A US study is recruiting people who are heavily
treatment experienced. They plan to enroll 500 volunteers to determine
whether one of two doses (150mg once or twice daily) of maraviroc
added to an optimized regimen of approved drugs (based on resistance
testing and treatment history) will suppress a person’s HIV
better than by using the optimized regimen alone.
Eligible volunteers must have known resistance to
at least one drug in each of the three older classes of anti-HIV
drugs. They will be screened for X4 virus. If it is found, these
people will not be eligible but may be allowed to enroll in another
study limited to those with X4 virus. Other studies are looking
at maraviroc in people with X4-only virus and R5/X4 (dual tropic)
virus.
Vicriviroc (Schering D)
Schering-Plough has presented data on a 14-day dose finding study
of 48 people living with HIV. Volunteers had CD4+ cell counts above
200 and were off all anti-HIV drugs for at least eight weeks before
starting the study. People were randomized to take one of three
doses (10mg, 25mg or 50mg) of vicriviroc once a day or a placebo.
All who took vicriviroc had a major reduction in viral load by day
14, at which point they were scheduled to stop taking the drug.
Viral load results from phase I dose-finding study
| Regimen |
Viral
load at day 14 (last day on drug) |
Viral
load at day 16 (2 days off drug) |
Viral
load at day 28 (14 days off drug) |
| vicriviroc
10mg |
-
0.9 log |
-
1.0 log |
-
0.2 log |
| vicriviroc
25mg |
-
1.5 log |
-
1.4 log |
+
0.1 log |
| vicriviroc
50mg |
-
1.6 log |
-
1.5 log |
-
0.3 log |
| placebo |
+
0.2 log |
+
0.3 log |
+
0.2 log |
Of note, the decreased viral load was sustained for at least 48
hours after they stopped the drug, and it did not return to its
original (baseline) level until two weeks after the drugs were stopped.
A larger ongoing study is comparing three different
once-daily doses of vicriviroc given together with a ritonavir boost.
To enter the study people must be failing on a ritonavir-boosted
protease inhibitor regimen and have viral loads above 5,000. A total
of 120 people will receive one of three doses (5mg, 10mg or 15mg)
of vicriviroc or a placebo, added to their failing regimen for the
first two weeks. The ritonavir dose will be the same as the one
used in the failing regimen. Then, people will switch to a new optimized
regimen (with input from drug resistance tests) and continue taking
the original dose of vicriviroc or a placebo, together with the
new regimen and a ritonavir boost, for 46 weeks. The study results
will not likely be available until Spring 2006.
An ongoing phase II trail of vicriviroc was recently
stopped because of treatment failure. It compared vicriviroc plus
AZT/3TC to efavirenz plus AZT/3TC in people who had never taken
anti-HIV drugs. An independent group (called a Data and Safety Monitoring
Board) evaluating results from the trial recommended that it be
stopped when too many people taking vicriviroc were having increases
in viral load. This was a somewhat surprising outcome as most people
had expected a regimen using vicriviroc to work about as well as
a standard three-drug combination. It did not. Studies of the drug
in treatment-experienced patients, so far, will go ahead as planned.
However, there’s no reason to expect the drug to work better
in experienced patients than those just starting treatment, so any
further studies will be watched very carefully.
The similarity in the design of this study and the
ongoing trial of maraviroc raises some concern. After all, the two
drugs have shown similar strength in earlier trials and the two
studies use the same additional drugs (AZT+3TC). It is important
to note that similar problems haven’t been reported for maraviroc,
though the study is far from complete.
A large study of vicriviroc in treatment-experienced
patients is scheduled to begin in 2005. Those interested in learning
more about it can call Project Inform’s Hotline or call or
visit the ACRIA or NIH websites as noted earlier. Vicriviroc has
not been used long enough to know what side effects it may have.
However, some drug interactions are expected given the way that
it is broken down by the body and because it must be used with ritonavir.
Schering-Plough will provide recommendations for study doctors and
volunteers about adjusting the dose of vicriviroc or the other drugs.
Other drug interactions studies are ongoing.
Aplaviroc
GlaxoSmithKline’s (GSK) R5 drug, aplaviroc, ran into problems
and its development has been stopped. The first problems were seen
in studies of people who had never taken anti-HIV drugs (naïves),
when two volunteers developed serious liver problems. In both cases
the problems got better when they stopped taking aplaviroc. This
led GSK to halt all studies of aplaviroc in naïve people while
researchers try to determine the cause and severity of the problems.
Initially the company said it would proceed cautiously with studies
of aplaviroc in people who have taken other anti-HIV drugs. However,
the same problem was later seen in the study of people who had taken
anti-HIV drugs before. This wasn’t surprising as here has
never been a side effect of an anti-HIV drug that only affected
people beginning therapy for the first time while not affecting
people who have use treatment before. In general, people who have
used treatment for longer periods tend to have more, not fewer,
drug side effects.
Putting R5 blockers into place
After a year when only one new anti-HIV drug (tipranavir)
came to market, it is gratifying and hopeful to have several drugs
of an entirely new class making it into larger studies. Because
these drugs work so differently than the older drugs and so little
is known about how treatment-experienced people will respond to
them, it is wise to proceed cautiously.
For instance, people who wish to volunteer for any of these studies
should fully understand the potential risks and benefits. As Project
Inform has stated since its inception, it is vital to make informed
treatment decisions. This is particularly true when a person considers
volunteering for a study. The newest experimental drug is not always
the best choice for one’s treatment, especially when there
are so many proven therapies already available.
It may also be that wide-scale access to these drugs may be slow
to arrive or may be limited, compared to most drugs that have been
approved in the past several years. This is because of safety concerns
and the other studies that may be needed. Fortunately, as promising
as these drugs are, they are by no means the only or even the best
drugs currently being studied in HIV. At least two other anti-HIV
drugs have shown viral load results superior to all three R5 blockers
discussed above. Most are covered in
more detail here. With so many new anti-HIV drugs in development,
there are an equal number of reasons to be hopeful that they will
result in the next major advance in treating HIV.
| Testing for the
R5/X4 Virus
Wise use of the newest entry inhibitors may hinge upon knowing
whether a person has R5 or X4 virus. If there’s one
thing that has become clearer through these early studies,
it is that the test used to determine the type of virus in
a person’s blood has major limitations. In fact, the
test (by Monogram Bioscience, formerly Virologic) is reliable
only 90% of the time. This means that out of every ten tests
done on a sample of HIV, one will miss the X4 virus. Small
labs can run similar tests, but none are currently any more
effective than Monogram’s. Also, none of these labs
has anything near the resources or expertise that Monogram
has to test thousands of samples.
Clearly, advocacy is needed to improve this test,
and Project Inform is working with other groups on this issue.
It is also possible that the results of the studies described
here will show that the R5-blocking drugs will work (at least
together with other anti-HIV drugs) whether or not X4 virus
is present. Thus, the only way to know whether the risks outlined
here will prove true is through the current studies or those
about to begin. Anyone who wishes to enroll in these studies
should be aware of both the potential risks and benefits. |
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