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Illinois
residents to get needles from the pharmacy
Fulfilling a campaign promise,
Illinois governor Rod Blagojevich in July signed into law
legislation allowing adults to buy and possess syringes without
a prescription. The AIDS Foundation of Chicago (AFC) worked
long and hard with legislators for the change. State Senators
Donne Trotter (D-Chicago) and Steven Rauschenberger (R-Elgin)
and State Representative Sara Feigenholtz (D-Chicago) sponsored
the bill. AFC reported that, “The governor’s action
culminates a four-year campaign to expand access to sterile
syringes and represents one of the most significant victories
for AIDS advocates in Illinois.” New syringes will still
be available for free through needle exchange programs, including
the one here at Test Positive Aware Network, run in collaboration
with the Chicago Recovery Alliance. Illinois was one of the
few states left that did not allow syringe purchase without
a prescription.
The
First Year—HIV
The “essential guide
for the newly diagnosed,” in which “a patient-expert
walks you through everything you need to know and do,”
is just that. Fresh on the bookshelves, HIV: An Essential
Guide for the Newly Diagnosed (Marlowe & Company)
is from the series of books The First Year (following diagnosis).
The writing is easy-to-read, with a tone that’s friendly
and down-to-earth. It’s like a good support group in
a book, with quotes from the author’s personal experiences
and that of other people living with HIV. Chapters are only
three to five pages in length. Technical matters, such as
resistance testing, are put in easy-to-understand terms. Even
people way past the first year will find it useful.
Author Brett Grodeck is a
former editor of Positively Aware who did much to professionalize
the magazine and make it more reader-friendly. Brett was all
about people having knowledge, dare I say it?—being aware.
Dr. Dan Berger, a columnist for Positively Aware (see “The
Buzz”), contributed greatly to the book and wrote
the foreword. In addition to medical issues, the book covers
topics such as disclosure, depression and where to go if you’ve
been discriminated against.
ADAP
relief
In August, Bristol-Myers
Squibb (BMS) announced it had reached an agreement with the
state-administered AIDS Drug Assistance Programs (ADAPs) to
provide interim emergency relief in order to help address
the funding crisis facing the programs. The new agreement
is estimated to provide up to $35 million in relief to ADAPs
over the next 20 months by making the company’s complete
line of HIV medications, including the new protease inhibitor
Reyataz (atazanavir) and the non-nucleoside reverse transcriptase
inhibitor Sustiva (efavirenz), available at a reduced cost.
Under this agreement BMS has agreed to provide its entire
portfolio of HIV medications at a reduced cost to ADAPs through
March 31, 2005, when the Ryan White CARE Act will be up for
reauthorization by Congress.—Charles E. Clifton
IAS:
Drug news from Paris
The International AIDS Society
(IAS) held its second Conference on HIV Pathogenesis and Treatment
in Paris in July. IAS also organizes the International AIDS
Conference. Earlier in the epidemic, when advancements were
slow in coming, IAS changed the international conference to
every other year instead of annually. More recently, with
so many advancements such as potent drug combinations and
monitoring tests, IAS added the Pathogenesis conference during
the “off” years of the international conference.
The first one took place two years ago in Buenos Aries. Following
are some highlights from this year’s IAS conference.
(Look also for more IAS reports and ICAAC, the Interscience
Conference on Antimicrobial Agents and Chemotherapy in the
Nov./Dec. issue of Positively Aware.)
Viread
and Ziagen—watch out
New drugs tend to be stronger
and have improvements over older drugs. Because HIV drugs
must be taken in combination, it’s hoped that taking
newer ones together would make for a better combination.
So it was disappointing to
see that Viread and Ziagen (in combination with Epivir), two
of the newest nucleoside analogs on the market, don’t
work so well together. They’re not toxic when taken in
combination. They’re just not as effective as you would
expect. However, Ziagen was taken in an experimental dose
of once-a-day (the standard dose is one pill twice a day).
“The reasons for
failure are not clear and are probably not related to the
once-daily [Ziagen], but rather a unique resistance issue
when these drugs are used together, or a previously unrecognized
drug-drug interaction. No one knows which yet,” said
Dr. Stephen L. Becker of the University of California, San
Francisco and Pacific Horizon Medical Group.
An unsuccessful small pilot
study was reported at IAS. But there were also negative early
results from a large pharmaceutical company trial that did
not make it onto the agenda of IAS. One staff member of GlaxoSmithKline,
the maker of Ziagen, said the company has “lots of data”
that the drug taken once-a-day is as potent as the standard
dose. At least one HIV researcher scoffed at the claim.
Fortunately, Positively
Aware columnist and medical advisory board member Dr.
Daniel Berger was one of the doctors conducting that study.
For his insider’s tale on this tangled web, see “The
Buzz”.
Trizivir
maintenance
ESS400013 looked at Trizivir
and Sustiva in what’s called induction/maintenance. Participants
took Trizivir/Sustiva for a year, then half of them dropped
the Sustiva for the second year. (Only people with less than
50 viral load at the end of the year could have their regimen
simplified to Trizivir alone.) Results from only the first
year were reported.
The year went well—61%
of the participants were under 50 viral load when using a
strict intent-to-treat (ITT) analysis. Missing data was counted
as failure. When looking at only those people who actually
stayed on the drugs, 90% had less than 50. T-cells went up
by 305. Participants were treatment naïve.
Seven percent of participants
had a hypersensitivity (allergic) reaction to the Ziagen in
Trizivir. That’s higher than the 3 to 5 percent listed
in registration trials that brought the drug to market.
Eleven percent of the 448
people in this large trial dropped out due to side effects.
Six percent dropped out for virologic failure. (For 22 of
the 28 participants with failing therapy, 46% had the Epivir
mutation of M184V and 41% had the Sustiva signature mutation
of K103N. The most common reason for developing mutations,
that in turn lead to treatment failure, is taking the medicine
incorrectly.)
Previous studies have shown
that the higher a person’s viral load is, the longer
it takes them to get to undetectable. Sure enough, it took
a median of 35 weeks for people who started with more than
750,000 viral load to get to undetectable. This compared to
less than half of that, 16 weeks, for the people who began
the study with less than 100,000. Time to undetectable was
only 17 weeks for the people in between.
Presenter Dr. Martin Markovitz,
of Aaron Diamond AIDS Research Center in New York City, was
asked if he had concerns about the use of Trizivir by itself,
given the results from the ACTG (AIDS Clinical Trials Group)
5095 study (see "We Want
Our Trizivir!"). Dr. Markovitz said the question
was difficult to answer. Was Trizivir failing because of chronic
infection? Higher viral load to start with? Low T-cell counts?
Complex quasispecies in their virus?
He pointed out that the long
induction phase of a year allowed people to achieve virological
success. Otherwise, those people who started out with the
highest viral load would not have been able to move into the
maintenance part of the trial. Dr. Markovitz said he felt
that 24 weeks is too early to begin simplifying a regimen
into a maintenance phase.
Is
something broken with the triple nukes?
The question arises with
both ACTG 5095 (see "We
Want Our Trizivir!") and the Viread/Ziagen combination—is
there something broken with the use of three nukes? If so,
what is it and can it be fixed? The race is on to find the
answer.
Researchers are looking at
two main areas. First, is there some kind of pharmacokinetic
effect among the nukes that cripples them when used together?
That is, what are the drug interactions—primarily, how
are they affecting each other’s blood levels. Secondly,
are they influencing each other’s mutation patterns for
the worse? Drugs exert a so-called “selective pressure”
on HIV which makes the virus mutate. Most HIV mutations make
it stronger in the face of the drug therapy being used.
“We have signals
here that three nukes don’t work for many people, despite
their potency,” said Dr. Becker.
This is disappointing because
people on a successful nucleoside-only regimen could save
the three other classes of HIV drugs for later, if necessary.
Expanding the available regimens is simply necessary in HIV.
The protease inhibitors,
for example, are generally inconvenient to take and can increase
blood lipid levels. Kaletra in specific is a popular protease
inhibitor to use, but can greatly increase levels of triglycerides.
“We’re scared of 1,500 triglycerides,” says
Dr. Becker. “It’s rare, but it happens. Will we
trade potency for simplicity? Who will three nukes work for?
Not work for?” Once again, HIV research gets a curve
ball.
“It is important
to point out that the Trizivir regimen studied in 5095 did
not do as well as the Sustiva-based regimen. If the goal of
treatment is full viral suppression [viral load below 50 or
400], than a triple [nucleoside] regimen is not as good as
one with Sustiva,” Dr. Becker explained. “That said,
for many patients who have co-morbid conditions [other illnesses]
or financial, social or psychological constraints, the simplicity
of Trizivir is important and may make it an acceptable regimen.
Seventy-four percent of patients on Trizivir in 5095 achieved
viral suppression.”
Kaletra/Sustiva
Just as ACTG 5095 looked
at sparing the protease inhibitors, the BIKS study looked
at sparing the nukes. “BIKS” stands for “bi-therapy
initiation with Kaletra/Sustiva,” even though in Europe
Sustiva is called Stocrin.
French researchers reported
that, “[Nukes] are associated with significant long-term
toxicities and cross-resistance. [Nuke]-sparing regimens need
to be assessed as alternative HAART regimens.” (HAART
stands for Highly Active Antiretroviral Therapy.) Early 24
weeks results were reported.
Using a strict intent-to-treat
(ITT) analysis, 78% of participants achieved less than 400
viral load. For under 50 viral load, the number was 65% (75
people). The average increase in T-cells was 162. These results
were especially good considering that 42% of participants
started out with more than 100,000 viral load, although that’s
to be expected since both Kaletra and Sustiva regimens have
great success in this group. Most of the participants (65)
were treatment-naïve and the other 21 were treatment
experienced.
There were significant (Grade
3 or 4) side effects in 34 people (40%). These included the
central nervous system (CNS) problems associated with Sustiva
(17 people), diarrhea (11) and rash (4). The lipid problems
seen with Kaletra were also found in Grade 3 or 4 lab abnormalities.
Thirteen people had high triglycerides and 29 had high cholesterol.
However, Sustiva is also known to raise cholesterol levels.
There were 14 discontinuations
(16%); three for CNS side effects, three for rash, one for
hyperlipidemia and three were lost to follow-up. Most of these
discontinuations occurred early in the trial. Of four people
with virologic failure (insufficient control of viral load),
two had a blip above 400 before regaining virologic control,
one did not take the medications correctly (was non-adherent)
and only one had confirmed failure.
The French researchers concluded
that a Kaletra/Sustiva regimen is as safe as a nucleoside-based
regimen with similar effectiveness. Final results from 48
weeks are to come.
Kaletra/Fortovase
How about a two-class sparing
regimen that consists solely of two protease inhibitors? Doctors
at IAS were still talking about a study presented in February
that looked at a combination of Kaletra and Fortovase (soft-gel
saquinavir). Results weren’t so great. However, the doctors
believed this was due to an incorrect dose of Fortovase, 1,200
mg. They said 1,600 mg should have been used. In fact, Dr.
Dan Berger said his patients have great success with the standard
dose of Kaletra and 2,000 mg of Fortovase (1,000 mg twice
a day).
For those patients not tolerating
Fortovase, primarily due to diarrhea, he switches to Invirase,
at the same dose of 1,000 mg twice daily in combination with
standard Kaletra dosing. Additionally, Dr. Berger invokes
the study presented in Barcelona at the 2002 International
AIDS Conference, presented by Dr. Staszewski from Germany,
of patients failing other regimens, many with protease inhibitor
resistance and many with nucleoside-related toxicity or side
effects (neuropathy, lipodystrophy, etc). After a strategic
treatment interruption (mean duration was 12 weeks), patients
were placed on the combination of Kaletra plus saquinavir
at the same dose Dr. Berger discussed (or uses). Dr. Staszewksi
observed HIV viral load drops of 3.5 logs and CD4+ T-cell
gains of 159 cells. After 29 weeks, 73% of his patients were
still on therapy.
Dr. Becker noted that Abbott,
the manufacturer of Kaletra, has launched a study comparing
Kaletra with Invirase (a form of Fortovase) against Kaletra
with Combivir in people taking HIV drugs for the first time.
“It’s a pilot study with lots of PK (pharmacokinetic
analysis) to help determine the best dosage.”
Emtriva,
Sustiva and Videx
Emtriva is the newest anti-HIV
drug on the market. It’s a once-a-day nucleoside that
is a lot like Epivir. Here, French researchers looked to see
if Emtriva, Sustiva and Videx, all once-a-day drugs, could
maintain viral load control after people switched from protease
inhibitors. They could, out to 48 weeks.
The study enrolled 355 participants,
most of whom were taking either Crixivan or Viracept. They
all had less than 400 viral load, and none had taken a non-nucleoside
analog before (the class of medication to which Sustiva belongs).
At the end of the year, the
people who were switched to the once-a-day regimen had the
same viral load suppression under 400 as did the people who
stayed on their protease inhibitor—about 90% using ITT,
or 96% looking at people actually on treatment.
However, for the ultra-sensitive
viral load test of under 50, people on the once-daily drugs
actually did statistically better. The numbers were 95% (once-a-day
regimen) vs. 87% (protease inhibitor regimen), for the people
still on treatment.
The average T-cell increase
was only 13 for the control group and 21 for the once-a-day
group. However, participants started out with an average of
540 T-cells. Treatment discontinuation was 12% and 10% respectively,
not statistically different. Study participants had an average
of 35 months on protease inhibitor therapy, and half of them
had nucleoside-only therapy before then. Therefore, this was
a highly treatment-experienced group, making the results extra
good news.
Special thanks to Dr. Stephen
Becker of the University of California, San Francisco and
Pacific Horizon Medical Group, for his review of this material.
Thanks also to the Breakfast Study Group of Rush-Presbyterian
St. Luke in Chicago, hosted by Dr. Harold Kessler, and sponsored
by GlaxoSmithKline at IAS.
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