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New Targets, New Drugs, Failed
Trials and the Need for More Information
by Stephen L. Becker, MD
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This past year has seen the
approval of the first drug directed against a novel HIV target.
This of course is T-20, or enfuvitide. T-20 marks the first
new class since the protease inhibitors were introduced in
late 1995. While T-20 has provided some heavily treatment
experienced patients with the means of constructing an effective
and enduring antiretroviral regimen, its twice daily subcutaneous
injection, cost and limited availability will markedly limit
its widespread use. Nonetheless, it paves the way for a new
generation of virus entry and fusion inhibitors. Many of these
agents will be orally administered and will no doubt provide
the means of interdicting the viral life cycle for many patients.
One can only hope that their eventual cost will remain in
the range of the majority of currently available antiretroviral
agents, and thus be widely affordable for patients receiving
their care in the public as well as private sector.
This year also saw the approval
in the U.S. and Europe of two new protease inhibitors (PI)
and one nucleoside reverse transcriptase inhibitor (NRTI).
Among these agents, the PI
atazanavir (Reyataz) has garnered the most attention. Atazanavir
appears to be effective in both treatment-naïve and,
when boosted with ritonavir, in some treatment-experienced
patients. Atazanavir is dosed once daily, well tolerated,
and has remarkably little effect on serum cholesterol or triglycerides.
Each of these features clearly distinguish it from the majority
of approved PIs. Care must be taken when using atazanavir
with other HIV agents, notably tenofovir. Also, it cannot
be used at present with anti-acid agents (studies are underway),
including proton pump inhibitors such as Prilosec or H2 blockers
such as Pepcid AC, Zantac or Tagamet.
The other PI approved this
year is the pro-drug of amprenavir (Agenerase). Called Lexiva
(fos-amprenavir), this formulation greatly reduces the pill
burden and gastrointestinal side effects of amprenavir. Lexiva
has demonstrated impressive effectiveness in advanced (low
CD4, high viral load) patient populations. Lexiva has been
tested in treatment-naïve and experienced patients, and
can be used either once or twice daily with or without ritonavir
boosting. (All treatment-experienced patients should use it
twice daily and with ritonavir.)
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A new nucleoside analogue
was approved this year as well. Emtriva (FTC or emtricitabine)
is a NRTI much like lamivudine (3TC or Epivir). It has an
identical resistance pattern, safety profile, and like 3TC
can be dosed once daily. It will soon be combined with tenofovir
(Viread) into a combination pill much like Combivir.
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Failed trials
Several important clinical
trials have improved our understanding of the most effective
combinations of antiretroviral therapy. Combinations containing
three NRTIs, so called triple nukes, have been found to be
inferior to three drug combinations using at least two classes
of antiretroviral agents.
In an important study that
was terminated early, the triple nuke combination of AZT,
3TC and abacavir (all in one drug, Trizivir) was found to
be significantly less effective than an efavirenz (Sustiva)-based
regimen in treatment-naïve patients. While Trizivir clearly
still has a place among the drugs used to treat HIV, it is
also clearly not as effective when used as the whole regimen
and not part of anti-HIV therapy.
Two other seemingly potent
triple nuke regimens fared far worse than Trizivir in studies.
Unlike Trizivir, the performance of these combinations was
so dismal that they should never be used as sole treatment.
The combination of tenofovir, abacavir and lamivudine was
dramatically less effective than the combination of efavirenz
with abacavir and lamivudine. Didanosine (ddI or Videx) when
used with tenofovir and lamivudine was effective in only one
of the 30 patients who received this combination. Clearly
more work is needed to understand why these otherwise effective
agents failed so miserably.
Drug of choice
The guidelines for treatment
of HIV infection issued by the Department of Health and Human
Services for the first time listed combinations of agents
to be used in the treatment of naïve patients. This recommendation
was based on the evaluation of these combinations in clinical
trials. Among the preferred combinations are those of
- efavirenz (Sustiva) with Combivir,
or
- efavirenz with stavudine (d4T or Zerit)
and lamivudine
- (3TC or Epivir), or
- efavirenz with tenofovir and lamivudine.
Recommended among the PIs is
- Kaletra with Combivir, or alternatively
- Kaletra with stavudine and lamivudine.
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This is not to
say that other triple drug combinations are not effective, but
rather that these combinations have not shown the same effectiveness,
safety and durability as the preferred combinations. |
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Drugs on the horizon
Several important agents
are in advanced (Phase III) clinical trials. These include
the PIs tipranavir and TMC-114. Both agents are felt to be
effective in those patients harboring significant PI-resistant
virus. If these agents prove effective they should become
available in expanded access in 2004 and 2005.
Clinical trials are of course
the means by which new agents are tested for effectiveness
and safety. It is also the venue for testing against the current
standard of care agents. Participation in clinical trials
is a very important part of the learning and discovery process,
especially for HIV agents.
It is of vital importance
that participants in clinical trials be of a diverse racial/ethnic
and sexual mix. By participating in clinical trials we can
not only speed along the process of drug development and approval,
but learn valuable lessons about how the drugs work in different
patient populations. If a clinical trial meets your particular
needs, consider participation. You can avail yourself of important
treatment options, but also assist all clinicians and researchers
in the HIV field by providing crucial clinical information.
In turn, you’ll be helping people with HIV around the
world.
Dr. Stephen L. Becker is
with Pacific Horizon Medical Group in San Francisco, and on
the faculty of the University of California, San Francisco.
Special thanks to Gilead
Sciences for supporting Dr. Becker’s work on the 8th
Annual HIV Drug Guide.
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