[e-med] Les gros labos offrent une nouvelle association à doses fixes d'ARV

["remed" <remed@remed.org>]

[remerciements à CR pour la traduction partielle de ce message publié par 
e-drug et druginfo.CB]

Les gros labos offrent une nouvelle association à doses fixes d'ARV
------------------------------------------------

[Gilead et MSD ont mis au point ensemble une association à doses fixes d'ARV
de prise quotidienne unique: tenofovir + emtricitabine + efavirenz, et elle
marche mieux que le "classique" zidovudine + lamivudine + efavirenz dans une
étude clinique publiée dans le New England Journal of Medicine NEJM
(abstract disponible plus bas); c'est une bonne nouvelle pour les malades du
SIDA. On remercie les deux labos pour leur collaboration dans l'intérêt des
patients!

GSK avait déjà une ssociation à doses fixes avec zidovudine + lamivudine +
abacavir, mais elle était plutôt chère (1241 dollars US par an) et abacavir
n'a pas toujours eu les honneurs de la presse.

Quelqu'un connaît-il le prix de cette nouvelle association? MSF dans sa
dernière édition de "entangling the web" parlait du prix de 362 dollars US
pour l'association emtricitabine + tenofovir et de 347 dollars US pour
efavirenz 600. Soit 709 dollars US pour l'ensemble par an. Ce qui est bien
sûr bien loin des 182 dollars US pour l'association la plus couramment
utilisée en Afrique STV+LMV+NVP FDC

Le message ci-dessous est disponible sur DRUGINFO, il inclut les excellents
commentaires de son modérateur Andy Gray.W.Bannenberg, modérateur de e-drug]

----- Message d'origine ----- 
De : "E-Drug" <e-drug@healthnet.org>
À : "E-drug" <e-drug@healthnet.org>
Envoyé : samedi 21 janvier 2006 10:26
Objet : [e-drug] A new once-a-day ARV FDC from big farma


E-DRUG: A new once-a-day ARV FDC from big farma
------------------------------------------------
[Gilead and MSD have together developed a once-a-day ARV FDC: tenofovir +
emtricitabine + efavirenz, and it has done better than the "standard"
zidovudine + lamivudine + efavirenz in a clinical trial published in the
NEJM (abstract below); this is good news for AIDS patients. Compliments for
both companies that they have collaborated in the interest of AIDS patients!

GSK already had an FDC with zidovudine + lamivudine + abacavir, but that was
quite expensive (USD 1241 per year) and abacavir has not always had such
good reviews.

Anyone knows what the likely price of this FDC is going to be? The latest
"Entangling the web" of MSF had an African cost of USD 362 for emtricitabine
+ tenofovir comb, and USD 347 for Efavirenz 600. Together USD 709 per person
per year. This is of course still much more than the USD 182 for the generic
STV+LMV+NVP FDC which is currently the most widely used FDC in Africa.

Message below crossposted from DRUGINFO, including the excellent comments
from its moderator, Andy Gray. Copied as fair use. WB]

Hi all

Here's more on the TDF+FTC+EFV combination, from the WP as "fair use", with
the NEJM abstract below.

Some points on the study design: "'Noninferiority' is a relatively new term
that has not been universally adopted, and in the past noninferiority and
equivalence trials, which have an important distinction, have both been
referred to as 'equivalence trials'. To make the confusion even worse, both
of these terms are somewhat misleading. It is fundamentally impossible to
prove that two treatments have exactly equivalent effects. Equivalence
trials, therefore, aim to show that the effects differ by no more than a
specific amount. This tolerance is known as the equivalence margin, and is
often denoted by the symbol *. In an equivalence trial, if the effects of
the two treatments differ by more than the equivalence margin in either
direction, then equivalence does not hold. Noninferiority trials, on the
other hand, aim to show that an experimental treatment is not worse than an
active control by more than the equivalence margin. An improvement of any
size fits within the definition of noninferiority. Bioequivalence trials are
true equivalence trials, but it is difficult to imagine any trial comparing
the clinical effects of an experimental treatment and active control that
would not more appropriately be termed a noninferiority trial." (Steven M
Snapinn. Noninferiority trials. Current Controlled Trials in Cardiovascular
Medicine 2000, 1:19-21  doi:10.1186/cvm-1-1-019 -
http://www.trialsjournal.com/content/1/1/19)

regards
Andy
~~~

http://www.washingtonpost.com/wp-dyn/content/article/2006/01/18/AR2006011802428.html
Once-a-Day AIDS Pill Could Be Ready Soon
By Justin Gillis
Washington Post Staff Writer
Thursday, January 19, 2006; A01

Two drug companies say they've put aside commercial rivalry to achieve a
goal that seemed out of reach for 20 years: a single-pill, once-a-day AIDS
treatment.

The pill is to contain a regimen of three drugs already available on
pharmacy shelves and shown to be effective in multiple studies, including
one coming out today in the New England Journal of Medicine. Barring
last-minute problems in formulating the pill, doctors expect it to be
approved by the end of the year.

If that happened, it would be a milestone in the development of treatments
for the human immunodeficiency virus, which causes AIDS. The virus has
infected 1.1 million people in the United States and more than 40 million
around the world, the vast majority of those in poor countries.

When effective AIDS treatments were first devised in the 1990s, patients
sometimes had to wake up in the middle of the night to take regimens
consisting of 50 or 60 pills administered several times a day with
complicated food restrictions. Back then, a once-a-day pill seemed a distant
mirage, but doctors have long said it would be a big help in getting more
people onto treatment.

Under heavy pressure to simplify treatment regimens, companies have been
combining medicines and reducing pill counts for several years. Yet for
commercial, rather than scientific, reasons, no company has yet managed to
create a single once-a-day pill containing an effective combination of AIDS
drugs. As it happened, no single company owned the rights to all the drugs
necessary for an optimal combination, and the companies were wary of working
together.

Now two companies say they have combined into one salmon-colored pill the
three licensed AIDS drugs that already make up the most-prescribed drug
regimen for newly diagnosed HIV patients. The companies recently announced
data showing the pill can achieve adequate blood levels of all three drugs,
and today's study in the New England Journal of Medicine adds to a large
body of evidence showing the drug combination is effective with relatively
few side effects. The companies are already producing test lots of the pill
at a plant in Ontario.

The Food and Drug Administration readily blesses new, more convenient
formulations of previously licensed drugs, and approval of the new pill,
though it will take several more months, is expected to be routine. The
biggest hurdle at this point is making sure the pills have an adequate shelf
life, a problem the companies say they are confident they can solve.

"I think it's a huge thing these companies are going to do," said Nelson
Vergel, an AIDS treatment activist in Houston. "If they give it at the right
price to developing countries, it's going to become the main treatment in
the world."

The companies involved, Gilead Sciences Inc. and Bristol-Myers Squibb Co.,
say they are indeed committed to providing the treatment to poor people
overseas. But their immediate goal is to get it on the U.S. and European
markets by the end of this year. If the pill, which doesn't have a name yet,
can capture a bigger slice of the market, the potential profit is huge.
While the companies have yet to announce a price, some AIDS regimens can
cost upward of $30,000 per patient per year.

The Gilead-Bristol collaboration required a year of complex negotiations,
with lawyers involved at every step to make sure the erstwhile competitors
didn't run afoul of antitrust laws. And repeated tests were needed to get a
pill with the right formula to achieve good blood levels.

It's the first such collaboration, but it probably won't be the last.

With nearly two dozen AIDS drugs on the market, with many more on the way,
and with the patients taking them expecting to live out normal life spans,
companies say devising convenient regimens has become a make-or-break
problem. Each company's initial strategy was to combine only treatments it
owned, but the firms say commercial pressure is forcing them to cross
company lines.

AIDS treatment activists once marched in the streets and broke windows at
the FDA to demand treatments. Today, they sit on committees advising the
government and the pharmaceutical companies. Listening to them in 2003, a
man named Kevin Trapp, a strategist for New York-based Bristol-Myers Squibb,
realized that a medicine controlled by his company could be combined with
two other drugs controlled by Gilead, of Foster City, Calif. The result
would be the first-ever once-a-day pill.

"They said, 'Companies should be working together,' " Trapp recalled
yesterday from a conference in Paris. "The best thing to do is listen to the
customer."

Gilead has already combined its two drugs into a single pill, so the
three-drug regimen is available today as two pills taken once a day. It
doesn't sound arduous, but even for people taking just two pills, the idea
of a one-pill-a-day treatment holds some kind of symbolic appeal. "I'm
counting the days" until the new pill becomes available, said Lucky Santana,
a medical worker in Atlanta who is already on the two-pill combination.

It isn't just that people hate swallowing pills; they hate swallowing the
co-payments at the pharmacy that go with the pills, and those can run $50 a
month for every prescription. Santana expects to save $30 every time he
fills a prescription when the new pill becomes available. "That's a tank of
gas nowadays," he said.

The regimen in question consists of three drugs sold separately under the
brand names Sustiva, Viread and Emtriva. The three-drug regimen is already
the one most commonly prescribed for new HIV patients starting treatment,
with nearly 20 percent of the market, according to figures from HIV Therapy
Monitor, a data service from Synovate Healthcare Inc., a London research
company. The runner-up regimen commands about 11 percent of the market,
Synovate data show.

A New England Journal of Medicine study being published today, led by Joel
E. Gallant of Johns Hopkins University, shows the three-drug combination to
be slightly more effective than the runner-up regimen. It is clear, however,
that the once-a-day pill won't be right for every patient.

After several years of an AIDS regimen, the virus in a patient's body can
develop resistance. Patients who have been on treatment for years often need
to switch to more complex regimens than the one in the once-a-day pill. The
pill won't be ideal for women of child-bearing age, since it may cause birth
defects. And one of the drugs in the regimen can cause a bizarre side effect
that bothers some people: exceedingly vivid dreams. "It's like you are
there," said Santana, the Atlanta medical worker.

Norbert W. Bischofberger, executive vice president for research and
development at Gilead and the man spearheading the one-a-day project, said
his company was "fully committed" to offering the pill at sharply reduced
prices in developing countries, noting that it could be a boon for patients
without the background to understand a complicated drug regimen.

The new pill, however welcome, won't eliminate pressure to develop even
simpler AIDS regimens.

"Somebody is going to have to try in the future to come up with something
that's once a week," Santana said.

~~~
http://content.nejm.org/cgi/content/short/354/3/251
Volume 354:251-260  January 19, 2006  Number 3

Tenofovir DF, Emtricitabine, and Efavirenz vs. Zidovudine, Lamivudine, and
Efavirenz for HIV

Joel E. Gallant, M.D., M.P.H., Edwin DeJesus, M.D., José R. Arribas, M.D.,
Anton L. Pozniak, M.D., Brian Gazzard, M.D., Rafael E. Campo, M.D., Biao Lu,
Ph.D., Damian McColl, Ph.D., Steven Chuck, M.D., Jeffrey Enejosa, M.D., John
J. Toole, M.D., Ph.D., Andrew K. Cheng, M.D., Ph.D., for the Study 934 Group

ABSTRACT

Background Durable suppression of replication of the human immunodeficiency
virus (HIV) depends on the use of potent, well-tolerated antiretroviral
regimens to which patients can easily adhere.

Methods We conducted an open-label, noninferiority study involving 517
patients with HIV infection who had not previously received antiretroviral
therapy and who were randomly assigned to receive either a regimen of
tenofovir disoproxil fumarate (DF), emtricitabine, and efavirenz once daily
(tenofovir-emtricitabine group) or a regimen of fixed-dose zidovudine and
lamivudine twice daily plus efavirenz once daily (zidovudine-lamivudine
group). The primary end point was the proportion of patients without
baseline resistance to efavirenz in whom the HIV RNA level was less than 400
copies per milliliter at week 48 of the study.

Results Through week 48, significantly more patients in the
tenofovir-emtricitabine group reached and maintained the primary end point
of less than 400 copies of HIV RNA per milliliter than did those in the
zidovudine-lamivudine group (84 percent vs. 73 percent, respectively; 95
percent confidence interval for the difference, 4 to 19 percent; P=0.002).
This difference excludes the inferiority of the tenofovir DF, emtricitabine,
and efavirenz regimen, indicating a significantly greater response with this
regimen. Significant differences were also seen in the proportion of
patients with HIV RNA levels of less than 50 copies per milliliter (80
percent in the tenofovir-emtricitabine group vs. 70 percent in the
zidovudine-lamivudine group; 95 percent confidence interval for the
difference, 2 to 17 percent; P=0.02) and in increases in CD4 cell counts
(190 vs. 158 cells per cubic millimeter, respectively; 95 percent confidence
interval for the difference, 9 to 55; P=0.002). More patients in the
zidovudine-lamivudine group than in the tenofovir-emtricitabine group had
adverse events resulting in discontinuation of the study drugs (9 percent
vs. 4 percent, respectively; P=0.02). In none of the patients did the K65R
mutation develop.

Conclusions Through week 48, the combination of tenofovir DF and
emtricitabine plus efavirenz fulfilled the criteria for noninferiority to a
fixed dose of zidovudine and lamivudine plus efavirenz and proved superior
in terms of virologic suppression, CD4 response, and adverse events
resulting in discontinuation of the study drugs. (ClinicalTrials.gov number,
NCT00112047 [ClinicalTrials.gov] .)

Source Information

>From the Division of Infectious Diseases, Johns Hopkins University School
>of Medicine, Baltimore (J.E.G.); the Orlando Immunology Center, Orlando,
>Fla. (E.D.); Hospital de La Paz, Madrid (J.R.A.); Chelsea and Westminster
>Hospital, London (A.L.P., B.G.); the University of Miami, Miami (R.E.C.);
>and Gilead Sciences, Foster City, Calif. (B.L., D.M., S.C., J.E., J.J.T.,
>A.K.C.).

Address reprint requests to Dr. Gallant at the Division of Infectious
Diseases, Johns Hopkins University School of Medicine, 1830 E. Monument St.,
Rm. 443, Baltimore, MD 21287, or at jgallant@jhmi.edu.