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Emtriva
Emtriva (FTC/emtricitabine)
is the new nucleoside analog on the block approved this July
based on 48 weeks of data. This drug is almost identical to
Epivir (3TC), with a similar resistance and toxicity profile,
so it doesn’t offer much for people who have developed
Epivir resistance. In pre-clinical studies it’s activity
against HIV was 4–10 fold greater that Epivir. But two
clinical trials comparing it to Zerit and Epivir showed it
to be “non-inferior,” which is a safe way to say
it is no better and no worse. Another one-pill, once-daily
drug, it has a long half-life and stays in cells up to 39
hours. But because there is less safety information about
Emtriva due to the company’s decision to not have an
expanded access program, we will undoubtedly learn more about
side effects as time goes by. People considering Emtriva as
a new drug should first be tested for resistance to Epivir.
Plans are underway to study
Emtriva as a combination pill with Viread (tenofovir), the
fastest selling new AIDS drug. When you take the two drugs
together levels of Emtriva are increased by about 20%. Gilead
Sciences, the manufacturer of both drugs, may have a safe,
potent and useful once-a-day therapy with this combination—but
not until 2005.
Trizivir
Trizivir is an approved anti-HIV
drug not showing to be the breakthrough its maker, GlaxoSmithKline
(GSK) had hoped. The drug is a combination of three drugs
from the same class—AZT, Epivir and Ziagen, all nucleoside
analogs. The standard of care had been to use three drugs
from two different classes, known as HAART (Highly Active
Antiretroviral Therapy), so it was surprising when GSK came
up with Trizivir, only targeting the reverse transcriptase
phase of HIV.
At the IAS meeting a large
study from the AIDS Clinical Trials Group here in the U.S.
showed this “single class” drug to not be as effective
compared to two other treatment arms used in the study (Combivir
+ Sustiva and Trizivir + Sustiva). The Trizivir-only arm was
considered “demonstrably inferior” and was discontinued.
Concern over the results were so significant that on March
10th, the National Institutes of Health issued a clinical
warning because of the study’s early results (see “We
Want Our Trizivir”).
Another study of 500 people
who had never been on AZT, Epivir or Ziagen compared Trizivir
to Crixivan plus AZT and Epivir for one year. There was no
difference between the two arms in reducing viral load to
undetectable levels. However, those with higher viral loads
did better in the Crixivan arm. GSK had hopes that Trizivir
was a better drug, in fact it was approved based on effectiveness.
There were high hopes in this drug as a simple 3-in-1 drug,
but it turns out it probably should only be used with a protease
inhibitor or non-nucleoside analog.
Ziagen
Another surprise stirring
up the HIV treatment world is the poor showing of once-daily
Ziagen, now approved as a twice-daily nucleoside analog. In
two separate studies, once-daily Ziagen or “fixed dose”
in combination with Viread and Epivir is proving to be a disaster
in terms of controlling HIV. The studies showed a high rate
of virologic failure in those who were using the experimental
once daily Ziagen in combination with Viread and Epivir. GSK,
the maker of Ziagen, issued an Important Health Warning to
doctors because of the results of the studies. The letter
warns not to use the three-drug combination by itself for
those who may be considering it; that anyone currently being
controlled on the regimen should be closely monitored and
consider other options; and that those using the triple-drug
regimen with other anti-HIV drugs should be closely monitored.
So far there have been no clinical setbacks because of once-daily
Ziagen. But once again, as more information is gained we are
learning that new and simpler is not always what its cracked
up to be (see “The Buzz”).
Fuzeon
Probably the one new drug
that is showing the most promise is Fuzeon, a new drug that
was approved in March of this year from an entirely new class
of antiretrovirals, fusion inhibitors. Fuzeon may extend the
lives of those who have fewer treatment options. It is the
most welcomed new drug because it is from an entirely new
drug class and is needed for those who have failed other drug
classes.
One study from the IAS meeting
showed longer-term durability and a sustained effect from
48 weeks of Fuzeon use. However, one important distinction
is that the drug was most effective in conjunction with an
“optimized background regimen” (a combination of
drugs that work best according to prior usage and resistance
testing) for those who have less than 100,000 viral load and
greater than 100 CD4 cells. Until now people had thought Fuzeon
was a drug of last resort.
Fuzeon is the most expensive
AIDS drug ever, and has magnified the crisis with ADAP and
Medicaid programs, already strapped for cash. Also, since
it is given by twice-daily injections, causing painful injection
site reactions, it is not at all an easy drug to take. So,
the favorable treatment aspects are clouded with access, pricing
and side effect issues. And now we have longer-term data that
tells us an even more select group of people will benefit
from the drug. Bottom line is that few people with AIDS will
probably end up using and benefiting from Fuzeon.
Buyer Beware
Often in HIV, follow-up studies
and real world usage will provide more information on the
benefits of a therapy in different treatment strategies and
over longer periods of time. However, people with HIV need
to be aware that sometimes in these follow-up studies an old
drug can prove to be ineffective, or less than it appeared
to be when it was approved. We have to remember that these
new anti-HIV drugs are not like new designer jeans to try
just because they are new. As with drugs used for other illnesses
and conditions, fancy pharmaceutical ad campaigns and the
marketing spin of just “being new” get a lot of
attention and sometimes cause drugs to be misused. Health
care providers and people with HIV must weigh all the intrinsic
characteristics of each drug carefully before using them,
and remember that individualized care must take precedence.
It is impressive that so
many drugs are available today to treat HIV. The good news
is that there are many options. The bad news is cross-resistance.
According to the newly published U.S. Guidelines for the Use
of Antiretroviral Agents, virologic failure is seen in 63%
of patients in population-based studies. This most certainly
has to do with adherence, but it also has to do with the biology
of HIV resistance and the fact that most of the drugs we have
today are cross-resistant.
As a result, treating HIV
has proven to be extremely complex and confusing and will
become more so as time goes by. Many of the new formulations
and new drugs are mere copies of older ones with similar mutation
patterns. Others are proving to not work in simpler doses.
So, although there are lots of options, there are a limited
number of effective regimens and there are lots of variables
that throw a wrench in this positive treatment era. There
must be easier ways to take these drugs, but they must also
work! The drug companies should work to study new ways to
fight HIV with new drug classes and work less on making “me
too” drugs. There are several new drugs from new classes
being studied, but it will be some time before we know how
well they work. Stay tuned…
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