By John S. James
AIDS Treatment News
Here are some of the experimental antiretroviral treatments
(not yet approved for general use) that were discussed at the
Retroviruses conference, February 24-28, 2002, in Seattle. We
organized them by drug class.
Non-Nucleoside Reverse
Transcriptase Inhibitors
TMC125
This is a very active antiretroviral of the NNRTI class (non-
nucleoside reverse transcriptase inhibitor -- the same class
as efavirenz, nevirapine, and delavirdine, the three NNRTI
drugs currently approved in the U.S.). But TMC125 was
rationally designed to overcome the main problem of this
class of drugs, the development of viral resistance. This was
accomplished, in part, by making the molecule flexible, so
that it can still fit in the "pocket" (the active site) of
the reverse-transcriptase enzyme, even when HIV mutates to
change the shape of that site.
In patients, TMC125 caused a faster drop in HIV viral load
than has been seen with any other single drug so far (in a
small, 12 patient study) -- an almost 2-log drop in only one
week from this drug alone, in treatment-naïve patients.(1) In
that week the median CD4 increase was 119. No one knows why
the drug worked so well. [Note: short, small clinical trials
like this are used to estimate the antiviral potency, by
measuring how fast the virus disappears from the blood in the
days after the drug is started. This kind of study gives an
idea of the antiviral activity of the new drug by itself,
without giving the virus much time to develop resistance to
it.]
TMC125 also works in patients who are highly resistant to
other NNRTIs. Another small study tested the drug for one
week in patients who were failing either efavirenz or
nevirapine, who had resistant virus with at least 10-fold
reduced sensitivity to the drug they were using (all of these
patients were at least 35-fold less sensitive to nevirapine).
After one week of using TMC125, the median viral load had
decreased 0.9 logs, and was still going down.(2)
These trials used an early phase I formulation of TMC125,
which required the volunteers to take many pills per day. The
formulation has been improved since then, though more work is
needed. Drugs of this class tend to be difficult to dissolve
because of their chemical nature (the molecule needs to bind
to a pocket in the viral enzyme with non-polar bonds), but
this problem can be overcome.
TMC125 was developed by Tibotec-Virco, a company
headquartered in Belgium that uses high-tech methods to
develop new drugs, especially antivirals (including treatment
for hepatitis C). It also offers HIV phenotypic resistance
testing (the Antivirogram) under the name Virco. Many of the
principals in the company have a background in tropical
medicine. On March 22 it was reported that Johnson & Johnson
had bought Tibotec-Virco -- probably good news, as it was
widely believed that Tibotec-Virco did not have enough money
to develop the drug quickly.
But because of the slow pace of drug development generally,
it is unlikely that the company will be able apply for
approval for TM125 before 2004, even if everything works as
well as possible.
DPC-083
This NNRTI is related to efavirenz (Sustiva(R)), but is
active against many viruses that are resistant to efavirenz
and other approved NNRTIs.(3,4) It seems to cause less of a
problem with the mental changes that trouble some patients
when they start efavirenz.
Protease Inhibitors
Tipranavir
Tipranavir, developed by Boehringer Ingelheim
Pharmaceuticals, is the first of a new class of "non-
peptidic" protease inhibitors (PIs) -- giving it a different
resistance profile from the approved PIs. It is active
against HIV that is heavily resistant to the approved drugs.
(As with the protease inhibitor Kaletra, a low dose of
ritonavir has to be used with tipranavir to keep the body
from rapidly destroying the drug.)
Forty one patients who were failing their second protease-
inhibitor regimen, were NNRTI naïve, and had a viral load
over 5,000 were given tipranavir along with other
antiretrovirals (including the NNRTI efavirenz). They had
average viral load reductions of more than 2 logs at 48 weeks
and beyond. Most of them (35 of 41) remained fully
susceptible to tipranavir at 48 weeks. One patient had been
resistant to tipranavir at baseline.(5)
The difference in the resistance profile of tipranavir can be
seen by comparing how resistant these patients were to
various protease inhibitors. For saquinavir, for example, the
average resistance was 17.4 fold (meaning it took about 17
times as much of the drug to suppress this resistant HIV,
compared to HIV that had not developed resistance. By this
measure, the average resistance to saquinavir was 17.4,
nelfinavir 27.8, indinavir 17.1, ritonavir 48.5, amprenavir
3.7, and tipranavir 1.5.
The development of this drug has been seriously delayed in
the past, and patient groups are starting to seek an
expanded-access program as soon as possible for those who
have no other viable option.
Atazanavir
In 48-week data presented at the Retroviruses conference,
this protease inhibitor did not increase blood cholesterol,
LDL cholesterol, or triglycerides in treatment-naive
patients(6) -- suggesting that it may be useful in developing
HAART treatment regimens with fewer side effects.
And in a study of patients who were failing therapy, the
combination of atazanavir and saquinavir worked well at 48
weeks, both in blood lipid levels and in viral load
reduction.(7)
Atazanavir is now in phase III trials. It should soon be
available on expanded access for patients who cannot
construct viable treatment regimens otherwise. It will
probably be the next protease inhibitor approved.
Entry Inhibitors
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Note that there are three different mechanisms of inhibiting
viral entry into cells -- mechanisms that are used by drugs
being developed today. BMS-806 blocks the first step -- the
binding of gp-120 of the virus with the CD4 receptor on the
cell. A later step is the binding with a co-receptor on the
cell (usually CCR5 or CXCR4); this step is the target of SCH-
C, described below. Then the final step is fusion of the
viral and cell membrane, which brings the viral genes into
the cell; this step is targeted by T-20, a drug well advanced
in clinical trials.
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BMS-806
This compound blocks entry by binding to gp-120 on HIV --
preventing the virus from binding to CD4 and then entering
cells.(8,9) It is new and has not yet been tested in
patients.
SCH-C
This drug blocks viral interaction with the CCR5 co-receptor
on the cell. The low dose studied so far produced an average
of about a 0.7 log viral load decline by day 10.(10) Higher
doses will be studied next.
T-20
We plan to cover this important drug in a later issue.
Integrase Inhibitors
S-1360
This integrase inhibitor was synthesized by Shionogi & Co.
Ltd. in Japan, and is being developed in the U.S. in
partnership with GlaxoSmithKline. It is a small molecule that
is orally bioavailable(11) and is now being tested in
patients. Activists and others at the conference were
encouraged that an integrase inhibitor has finally progressed
this far.
Integrase inhibitors (like entry inhibitors) have a different
viral target than any currently approved drug. Therefore all
the viral resistance that has developed so far is unlikely to
affect these new drugs. HIV will be able to become resistant
to them, however, so the new drugs will have to be used
carefully in appropriate combinations. Their importance will
be in providing new kinds of treatment options -- as protease
inhibitors did when they were introduced.
References
1. Sankatsing S, Weverling G, van 't Klooster G, Prins J,
and Lange J. TMC125 monotherapy for 1 week results in a
similar initial rate of decline of HIV-1 RNA as therapy with
a 5-drug regimen. 9th Conference on Retroviruses and
Opportunistic Infections, Seattle, February 24-28, 2002
[abstract # 5].
2. Gazzard B, Pozniak A, Arasteh K and others. TMC125, a
next-generation NNRTI, demonstrates high potency after 7 days
therapy in treatment-experienced HIV-1-infected individuals
with phenotypic NNRTI resistance. 9th Conference on
Retroviruses and Opportunistic Infections, Seattle, February
24-28, 2002 [abstract # 4].
3. Ruiz N, Nusrat N, Lauenroth-Mai E and others. Study DPC
083-203, a phase II comparison of 100 and 200 mg once-daily
DPC 083 and 2 NRTIs in patients failing a NNRTI containing
regimen. 9th Conference on Retroviruses and Opportunistic
Infections, Seattle, February 24-28, 2002 [abstract #6].
4. Ruiz N, Nusrat N, Lazzarin A and others. Study DPC 083-
201: A phase II double-blind (DB) comparison of 3 once daily
doses of the NNRTI DPC 083 vs 600 mg efavirenz (EFV) in
combination with 2 NRTIs in HIV antiretroviral (ARV)
treatment-naïve patients. 9th Conference on Retroviruses and
Opportunistic Infections, Seattle, February 24-28, 2002
[abstract # 7].
5. Schwartz R, Kazanjian P, Slater L and others. Resistance
to tipranavir is uncommon in a randomized trial of
tipranavir/ritonavir (TPV/RTV) in multiple PI-failure
patients (BI 1182.2). 9th Conference on Retroviruses and
Opportunistic Infections, Seattle, February 24-28, 2002
[abstract # 562-T].
6. Piliero PJ, Cahn P, Pantaleo G and others. Atazanavir: A
once-daily protease inhibitor with a superior lipid profile -
- results of clinical trials at week 48. 9th Conference on
Retroviruses and Opportunistic Infections, Seattle, February
24-28, 2002 [abstract # 706-T].
7. Haas D, Zala C, Schrader S, Thiry A, McGovern R and
Schnittman S. Atazanavir plus saquinavir once daily favorably
affects total cholesterol (TC), fasting triglyceride (TG),
and fasting LDL cholesterol (LDL) profiles in patients
failing prior therapy (trial AI424-009, week 48). 9th
Conference on Retroviruses and Opportunistic Infections,
Seattle, February 24-28, 2002 [abstract # 42].
8. Lin P-F, Robinson B, Gong Y-F and others. Identification
and characterization of a novel inhibitor of HIV-1 entry --
I: Virology and resistance. 9th Conference on Retroviruses
and Opportunistic Infections, Seattle, February 22-28, 2002
[abstract #9].
9. Lin P-F, Guo K, Fridell R, Ho H-T, Yamanaka G, and Colonno
R. Identification and characterization of a novel inhibitor
of HIV-1 entry -- II: Mechanism of action. 9th Conference on
Retroviruses and Opportunistic Infections, Seattle, February
24-28, 2002 [abstract # 10].
10. Reynes J, Rouzier R, Kanouni T and others. SCH C: Safety
and antiviral effects of a CCR5 receptor antagonist in HIV-1
infected subjects. 9th Conference on Retroviruses and
Opportunistic Infections, Seattle, February 24-28, 2002
[abstract # 1].
11. Yoshinaga T, Sato A,, Fujishita T, and Fugiwara T. S-
1360: in vitro activity of a new HIV-1 integrase inhibitor in
clinical development. 9th Conference on Retroviruses and
Opportunistic Infections, Seattle, February 24-28, 2002
[abstract #8].
AIDS Treatment
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