[procaare] Strategies for Third Line Therapy

[ProCAARE <procaare@usa.healthnet.org>]

"Strategies for Third Line Therapy"
********************

Project Inform Perspective (03.02) No. 34; P. 8-9
Source: [AEGiS] CDC HIV/STD/TB Prevention News Update 04/09/02

One area of HIV therapy research that has been inadequately
addressed is strategies around third line therapy regimens. Third
line therapy is usually defined as a regimen for an individual
who has developed resistance to at least one drug in all three
classes of HIV therapies [nucleoside analogue reverse
transcriptase inhibitors (NRTIs), non-nucleoside reverse
transcriptase inhibitors (NNRTIs) and protease inhibitors] or has
failed two treatment regimens. Third line regimens are also
termed by some as mega-HAART, giga-HAART, salvage therapy and
multi-drug rescue therapy.

Most third line regimens consist of four or more drugs, the
theory being that not all of the virus in a patient is going to
be resistant to all of the drugs. By using many drugs with
different mechanisms of blocking HIV reproduction, it may be
possible to achieve a potent therapy. Multi-drug regimens also
increase the risk of side effects and make it more difficult to
manage drug interactions. The use of therapeutic monitoring,
using an experimental diagnostic test that measures the amount of
drugs in the blood, may ensure adequate drug levels are achieved
and mitigate side effects associated with higher blood drug
levels.

The most obvious third line option includes several new
drugs that may be active against multi-drug resistant HIV that
are FDA-approved or are still in early development. These
include: fusion inhibitors T-20 (pentafuside) and T-1249;
nucleotide analogue tenofovir, which, in general, can be
considered an NRTI as it shares some of the same resistance
patterns; new protease inhibitors including atazanavir (Zrivada),
tipranavir and TMC 114; existing protease inhibitors enhanced by
the addition of small doses of ritonavir, which increases their
ability to overcome partially resistant virus; new NRTIs
including DAPD, alovudine and ACH-126,443; new NNRTIs including
capravirine, TMC125 and DPC961; CCR5 inhibitors including
Schering C (SCH 351125) and UK-427,857; entry inhibitors
including PRO 367; attachment inhibitors including PRO 542; and
integrase inhibitors including S1360.

It is probably advisable for people considering a third line
regimen to get a resistance test. For most of these drugs, the
only method of access is by participating in clinical trials,
while some provide drugs to people through expanded access
programs. Currently, there is a very limited expanded access
program for T-20 and one planned for atazanavir by the end of the
first quarter 2002.

There is still much debate about the role of structured
treatment interruptions (STIs) as part of a third line regimen.
Several studies have shown STI in third line situations do
trigger a reversal of resistance when using standard resistance
tests, but drug resistant HIV can be detected using a more
sensitive test. Still, there is often a period of renewed
activity from drugs that had previously failed. It is unclear how
long the benefits last once therapy is restarted after an STI.
One major concern with STIs is that there is often a rapid drop
in CD4+ cell counts and an increase in viral load, both of which
can be very significant after stopping therapy. Furthermore,
after restarting therapy there is a slow increase in CD4+ cells,
with some people never returning to their pre-STI cell counts.

Immune-based therapies have not adequately been studied as
part of third line regimens. There are some data showing that the
use of GM-CSF (granulocyte colony stimulating factor, Leukine)
may have some benefit.

Several studies report that even when regimens appear to
"fail" -  defined as a return of measurable viral load despite
treatment -  there is usually still a lasting benefit for people
who remain on treatment. It is likely that viral load tests do
not tell the whole story of how the body responds to HIV drugs.
Early results of research into the "fitness" of the virus suggest
that HIV is not able to replicate as well after it becomes
resistant to certain drugs. Thus, one reasonable choice might
simply be to stay on whatever regimen patients have been using.
As long as patients remain clinically well and don't suffer a
rapid further decline of CD4+ cells, it might be wise to not worry
excessively about drug "failure."

The article concluded, "There is a definite need to evaluate
the optimal strategy in putting together a third line regimen and
the various clinical trial networks and pharmaceutical companies
need to make this issue a priority."

Source: [AEGiS] CDC HIV/STD/TB Prevention News Update 04/09/02
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