Date: Fri, 19 Mar 2004 09:41:29 -0800
From: vanessa@...
Subject: [AEGiS] New and different drugs tested in people

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ANTI-HIV AGENTS: New and different drugs tested in people

TreatmentUpdate 141 - 2004 March; Volume 16 Issue 2
Hosein SR

ENGLISH: http://www.aegis.org/pubs/catie/2004/cate14102.html
FRENCH:  http://www.aegis.org/pubs/catie/2004/catf14102.html
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In some countries, as many as 20 drugs are licensed for the
treatment of HIV infection. For the most part, these drugs can be
divided into three classes:

nukes (nucleoside analogues)
non-nukes (NNRTIs, non-nucleoside reverse transcriptase
inhibitors)
protease inhibitors

Because of the development of cross-resistance among drugs within
each class, treatment options may be restricted, particularly for
people with HIV/AIDS (PHAs) with many years of exposure to drug
therapy. New drugs that work against HIV in ways different from
currently licensed therapies are urgently needed.

At the recent CROI, data on new potential therapies were
presented and several appear promising. Most of these drugs are
still in early stages of testing (Phase I or II clinical trials),
where the chief focus is safety and preliminary effectiveness. As
a result, usually the drug in question is taken by subjects on
its own and not as part of combination therapy.

Reverset (D-d4FC)
This drug works in a similar way to the drugs AZT (zidovudine,
Retrovir), 3TC (lamivudine, Epivir), tenofovir (Viread) and other
reverse transcriptase inhibitors. Once-daily dosing results in
high antiviral concentrations inside cells.

In a placebo-controlled Phase I study, 30 HIV positive subjects
(6 women, 24 men) received different doses of Reverset only, for
10 days. At a dose of 200 mg once daily, significant suppression
of HIV occurred=97viral loads fell by nearly 2 logs=97compared to
placebo. During this time, CD4+ cell counts did not rise
appreciably in subjects on Reverset. Some subjects exposed to
this drug developed mild symptoms of the common cold, but this
needs to be confirmed in a larger study. Studies in rats and dogs
suggest that very high doses of Reverset can cause damage to the
bone marrow and intestines. Also, the skin on the noses of some
female dogs lost its colour after exposure to high doses of the
drug. Future research will include treatment-experienced PHAs.
Reverset is being developed by the Incyte Corporation.

GW 140
This drug (its official code name is GW873140, but at CROI it was
simply referred to as GW 140) works by blocking a co-receptor
called CCR5 found on the surface of immune cells. By blocking
this receptor, the drug stops HIV from entering and infecting a
cell.

A double-blind, placebo-controlled study with GW 140 was done in
70 subjects (13 women and 57 men) for up to one week. The results
of the study suggest that twice-daily dosing is possible.
Although the drug did not cause heart damage (a possibility with
co-receptor inhibitors), it did cause diarrhea, intestinal cramps
and loose stools. No antiviral effects were mentioned, nor did
the drug affect CD4+ counts. Further studies are planned by the
developer, GlaxoSmithKline.

SCH-D
This drug is also a CCR5 receptor blocker. Results from a study
with 48 subjects suggest that a dose of 25 or 50 mg twice daily
for two weeks can significantly suppress viral load by up to 1.5
logs. The drug was well tolerated with one case of fever being
the only side effect. A potential drawback of CCR5 inhibitors is
that over time HIV can adapt, change and begin to use other
co-receptors to infect cells. These variants may be more
efficient at helping to destroy immune cells. The developer of
SCH-D is the Schering-Plough Corporation.

BMS-488043
This drug is a small molecule that can prevent HIV from attaching
to CD4+ cells and infecting them. In tests with HIV positive
people, researchers used BMS-488043 at doses of 800 or 1,800 mg
twice daily or placebo for one week. Viral load fell to its
lowest level nine days after subjects began the study, decreasing
by 1.2 logs in the 1,800-mg group and by just over 1 log in the
lower-dose group. Fatigue and headache were more common in
recipients of this drug compared to placebo. Future studies are
planned by the drug's developer, Bristol-Myers Squibb.

REFERENCES

1. Murphy RL, Sch=FCrmann D, Beard A, et al. Tolerance and potent
anti-HIV-1 activity of Reverset following 10 days of mono-therapy
in treatment-na=EFve individuals. Conf Retroviruses Opportunistic
Infect. 2004 Feb 8-11;11th: Abstract No.=20
<http://www.retroconference.org/2004/cd/Abstract/137.htm>Abstract 137.


2. Demarest J, Adkinson K, Sparks S, et al. Single and multiple
dose escalation study to investigate the safety, pharmacokinetics
and receptor binding of GW873140, a novel CCR5 receptor
antagonist in healthy subjects. Conf Retroviruses Opportunistic
Infect. 2004 Feb 8-11;11th: Abstract No.=20
<http://www.retroconference.org/2004/cd/Abstract/139.htm>Abstract 139.


3. Sch=FCrmann D, Rouzier R, Nougarede R, et al. SCH-D: antiviral
activity of a CCR5 receptor antagonist. Abstract 140LB.Conf
Retroviruses Opportunistic Infect. 2004 Feb 8-11;11th: Abstract
No. <http://www.retroconference.org/2004/cd/Abstract/140lb.htm>Abstract=
140LB.


4. Hanna G, Lalezari J, Hellinger J, et al. Antiviral activity,
safety, and tolerability of a novel, oral small molecule HIV-1
attachment inhibitor, BMS-488043, in HIV-1-infected subjects.
Conf Retroviruses Opportunistic Infect. 2004 Feb 8-11;11th:
Abstract No.=20
<http://www.retroconference.org/2004/cd/Abstract/141.htm>Abstract<http://w
.retroconference.org/2004/cd/Abstract/141.htm>=20
141.


20040110
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