Being Alive 1998 Mar 5: 2
On the last day of the Conference Dr. Scott Hammer of the
Harvard Medical School presented an excellent talk called "New
Agents on the Horizon" in which he summarized what we can
expect to see emerging from the new drug development pipeline
in the near and distant future.
These new weapons in the anti-HIV arsenal will include drugs in
all three of the familiar antiretroviral classes-protease
inhibitors (PIs), and both nucleoside and non-nucleoside
reverse transcriptase inhibitors (NRTIs and NNRTIs).
Some of these drugs will become FDA-approved and widely
available fairly soon, and are already available through
various clinical trials (the PI amprenavir, the NRTIs abacavir
and adefovir, and the NNRTI efavirenz). Others are in the
earliest stages of development, still undergoing laboratory
appraisals, and safety tests in animals and in humans.
Dr. Hammer also described some compounds, under investigation
but still far from practical use, which aim to attack HIV in
ways different from the drugs we already have, and therefore
could be effective against antiviral-resistant strains of the
virus. Chemokine receptor antagonists, fusion inhibitors, and
drugs that target "zinc fingers": just some of the singular
ways scientists hope to interfere with and interrupt the
replication cycle of the virus.
Earlier in the Conference Dr. W. Gary Tarpley of Pharmacia and
Upjohn urgently called for bold and resolute focus on the
development of new agents to attack HIV. "With a pathogen like
HIV," he stated, "which has established itself throughout the
world, which initiates a chronic and permanent infection and
which has tremendous replicating potential if unleashed by
incomplete suppression, I think we must prepare for a future
scenario in which, over time, this virus will learn to evade
all the current drugs we have."
Many of these new drugs will play a crucial role in "salvage
therapy," presenting additional options to people who have
already been through all of the currently-available antivirals
and whose viral loads are rebounding. Several trials are
underway to assess the effectiveness of various combinations in
people who have experienced viral rebound while on the various
regimens of HAART. We should be hearing more about this through
the coming year.
(Hydroxyurea, an inexpensive generic drug that has been in use
more than 30 years, is currently getting a lot of attention.
Several studies are showing it to be especially effective
against HIV in combination with other antiretrovirals. For a
discussion of hydroxyurea, click here.)
The following is a summary of what we can look forward to in
1998 and beyond, as described in Dr. Hammer's talk and in other
Conference sessions and posters.
Fortovase (saquinavir soft-gel, Hoffman-La Roche). Strictly
speaking, this reformulation of saquinavir is not exactly a
"new" drug, but it is an improvement over the original hard-gel
version of the drug. Taken at twice the dose of the older
Invirase, Fortovase is more efficiently metabolized, permitting
a total drug exposure in the body that is eight times greater
than before. Simply put, a lot more of the drug makes it into
the blood stream. The relative weakness of Invirase compared to
other protease inhibitors is overcome with Fortovase, which is
as potent as the other available PIs. Fortovase is now
FDA-approved and available from U.S. pharmacies.
For some time now, Invirase (hard-gel saquinavir) has been used
by some people in combination with ritonavir. Hoffman-La Roche
has indicated that Invirase will be phased out, leaving only
Fortovase on the market. People who have been doing well on the
ritonavir/saquinavir combination understandably do not want to
make any change, and have logged protests with the company. In
a meeting at the Conference, a company spokesperson stated that
Invirase will be made available to these people, although not
necessarily through pharmacies.
Fortovase is also being used currently in combination with
Agouron's nelfinavir (Viracept), with encouraging reports of
significantly lowered viral load. Amprenavir (formerly known as
141W94, Glaxo Wellcome). Like nelfinavir, amprenavir is an
adaptation of the basic, highly effective and HIV-specific
molecular structure of saquinavir, altered to achieve greater
availability in the body and to less resemble the molecular
shape of saquinavir so as to better avoid viral resistance.
Several reports at the Conference dealt with amprenavir in
combination with other antiretrovirals. Results showed that
amprenavir in combination with either indinavir, nelfinavir or
saquinavir produced impressive decreases in viremia (viral
activity). Another study showed that when amprenavir was used
as monotherapy resistance formed quickly. Amprenavir in
combination with the NRTI abacavir (see below) proved effective
in a very limited and small pilot study of seven patients over
four weeks, resulting in a median 2-log drop in viral load and
an increase of CD4s of 114. But another study of people who
were highly experienced with antiretrovirals and PIs proved
disappointing, showing viral rebound within three months.
Most common side effects of this two-drug combination were
diarrhea, nausea, headache and rash, not dissimilar to other PI
side effects. It is unclear at this time whether amprenavir
will indeed prove effective against PI-resistant viruses. Its
role in salvage therapy (treating people whose viral load is
rebounding despite the use of HAART) is currently being
New Protease Inhibitors With Novel Mechanisms
ABT-378 (Abbott Labs). This promises to be one of the most
powerful protease inhibitors developed so far. At this time it
has been tested only in vitro (in test tube) and in rats; in
those tests it has proven to be ten times more potent than
ritonavir (Norvir). Abbott says it has a synergistic effect
when used with ritonavir. Resistance profiles suggest that
people with extensive exposure to previous PIs should remain at
least partially sensitive to ABT-378, and people previously
treated with saquinavir should remain wholly sensitive.
PNU-140690 (Pharmacia & Upjohn), Bristol Myers 232632,
Parke-Davis 178390. These three drugs aim to disrupt the HIV
replication process in a way different from the "peptide-class"
of PIs with which we are already familiar (saquinavir,
indinavir, ritonavir and nelfinavir, as well as amprenavir and
ABT-378). Because of their different mechanism for blocking
reproduction, these drugs could prove highly effective against
PI-resistant strains of HIV.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Abacavir (formerly 1592U89, Glaxo Wellcome). Now in Phase
II/III clinical trials, this nucleoside analog has shown
synergy with other RTIs in vitro, and is the only NRTI that
equals AZT's ability to penetrate the central nervous system.
There appears to be no cross-resistance with AZT or d4T, but
resistance to 3TC is likely.
Abacavir is up to three times more active than AZT, and in
monotherapy trials has resulted in significant viral load
reductions of two logs.
As noted in the pages of the Newsletter before, an adverse
reaction to abacavir has been reported in 3% of patients,
characterized by fever, malaise, nausea, vomiting and rash.
These side effects do abate once the drug is discontinued, but
attempts to go back on the drug have resulted in exaggerated
life-threatening reactions, including one death.
Abacavir is now available through an expanded access program.
Further expanded trials of abacavir, in combination with other
antivirals including protease inhibitors, are under way. We
expect soon to learn more about this potentially valuable drug.
Adefovir (formerly PMEA, brand name Preveon, Gilead Sciences).
This nucleoside analog's mechanism is different from other
NRTIs and therefore has the potential for being effective
against HAART-resistant HIV. In lab studies, adefovir is also
effective against many herpes viruses, including herpes simplex
types 1 and 2, CMV and hepatitis B. A major asset of this drug
is that it needs to be taken only once a day.
A Phase II/III trial is now underway, and Gilead has an
expanded access program, available to people who have been
failed by or are intolerant of combination therapy with at
least two commercially available nucleosides and at least one
protease inhibitor. "In addition, the treating physician must
be unable to construct a viable regimen based on current
treatment guidelines and the patient's previous antiretroviral
use." Exceptions to Gilead's current CD4 and viral load
requirements will be favorably considered. For information on
the Adefovir Expanded Access Program call 800.gilead.5.
FTC. This nucleoside analog, now in Phase I/II clinical trials,
resembles 3TC but is ten times more powerful (in the test
tube). It looks to have the same resistance profile as 3TC, and
researchers believe it will work synergistically with AZT, d4T,
indinavir, efavirenz and others.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz (brand name Sustiva, formerly DMP-266, DuPont Merck).
This NNRTI has shown particularly good activity against strains
of HIV resistant to NRTIs and to indinavir, and has shown good
effectiveness against strains resistant to the NNRTIs
nevirapine and delavirdine as well.
Resistance studies reveal that efavirenz, like the other
NNRTIs, should always be used in combination with NRTIs and/or
In combination with indinavir, efavirenz resulted in a mean
decrease in viral load of 4.75 logs; in a 24-week study, 95% of
the participants had viral loads under 500, and their CD4
counts increased by a mean of 199. Limited clinical efficacy
studies suggest that efavirenz is significantly more potent
than either nevirapine or delavirdine.
Side effects include rash and light-headedness, symptoms which
tend to go away in days or sometimes weeks.
DuPont Merck recently made its eligibility requirements more
flexible for the Efavirenz Expanded Access Program, allowing
people who are highly experienced on HAART to have a CD4 count
less than 400 (up from their previous requirement of 50), and a
rebounding viral load. For more information call 800.998.6854.
MKC-442 (Triangle Pharmaceuticals). In early stage of
development. Clinical trials have recently started: preliminary
results show the potential for a 1.4 log decline in viral load.
Way Out There: New Drugs, New Approaches
As can be clearly seen by the above summary, anti-HIV drugs
available now and in the immediate future belong to two
classes: those that target the reverse transcriptase or the
protease enzymes of the virus. New approaches are going to be
necessary to avoid cross-resistant variants of HIV and the
eventual "failure" of currently-available versions of HAART.
Several new approaches are being explored.
For some time we've heard of integrase inhibitors, which would
target a third vital enzyme of the virus's replication
mechanism. These drugs have been slow to evolve, however. It is
not known how effective they will be, but it is unlikely that
there would be any cross-resistance between integrase
inhibitors and the existing classes of antiretrovirals. The
human body does not possess such an enzyme; therefore, it is
expected that inhibition of the HIV integrase would be safe and
not cause adverse effects.
Zinc Finger Inhibitors
HIV contains a structure called "zinc fingers" which cannot
readily change by mutation; that is, the virus would find it
difficult if not impossible to mutate around and form
resistance to a drug which targeted these "zinc fingers." The
hope is that a drug that attacks the virus at this crucial
structure would permanently disable the virus's replication.
Such a drug is now in early human testing.
This genetically engineered peptide is designed to target a
specific step in the process by which HIV attaches to a cell in
the course of infecting that cell. It has already been shown to
substantially reduce viral load, and it is unlikely to have
cross-resistance with our current batch of treatments.
Therefore, T-20 may be highly effective in people who have been
heavily treated with HAART and are experiencing drug failure
and viral rebound. This drug may not be especially practical
for anyone other than those with literally no other options: it
will probably have to be given by continuous intravenous
infusion. In clinical trials it is being administered via a
small computerized pump with a flexible catheter, something
used successfully in diabetes treatment. It is doubtful that
any but the most desperate patients would be interested in
undergoing this kind of therapy.
Two more drugs have gained the attention of researchers,
although little is known about their mechanisms or potential
for effectively fighting HIV. TCN (triciribine) has been shown
to be an inhibitor of HIV, but exactly how it does that is
still under examination. AMD-3100, being developed by Johnson
Murphy, is seen as a potential weapon against the virus's