PI Perspective #34
March 2002 View PDF En
español
Strategies for Third Line Therapy
One area of anti-HIV therapy research that has been inadequately
addressed is strategies around third line therapy regimens. As a
result, there is only a modest amount of data to guide physicians
and patients in making treatment decisions in this setting. 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 anti-HIV therapies [nucleoside analogue reverse transcriptase
inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors
(NNRTIs) and protease inhibitors] or has failed two treatment regimens.
In general, the nucleotide analogue drug, tenofovir (Viread) can
be considered an NRTI as it shares some of the same resistance patterns.
However, just because someone has developed resistance to some drugs
in all three classes of anti-HIV drugs does not mean that they have
no further treatment options. This article will review some of the
options available to people exploring third line regimen choices.
New Drugs and Expanded Access Programs
The most obvious option includes new drugs that are active against
HIV that is resistant to most or all of the currently available
anti-HIV therapies. There are 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 T20 (pentafuside) and T1249;
- Nucleotide analogue tenofovir;
- 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 DPC 961;
- 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.
For most of these drugs, the only method of access is by participating
in clinical trials, while some provide drug to people through expanded
access programs. Currently there is a very limited expanded access
program for T20 and one planned for atazanavir by the end of the
first quarter 2002. The Project Inform's National HIV/AIDS Treatment Hotline will have information
about these and other expanded access programs as they become available.
Mega-drug Regimens
Most third line regimens consist of four or more drugs. More traditional
anti-HIV therapy regimens typically include only three drugs, or
four anti-HIV drugs at the most. A third line regimen, however,
often includes a minimum of four drugs and it’s not uncommon
to see five, six, seven or more drugs used. Different groups have
used different terms for these third line multi-drug regimens including
megaHAART, gigaHAART, salvage therapy and multi-drug rescue therapy.
The theory behind using a larger number of drugs is that not all
of the virus in a person’s body is going to be resistant to
all of the drugs. By using many drugs with different mechanisms
of blocking HIV from reproducing, it may still be possible to achieve
a potent anti-HIV effect.
The use of several drugs of multiple types, however, also increases
the risk of side effects and makes it much more difficult to manage
drug interactions. Another approach, the use of therapeutic drug
monitoring (see below) may help to reduce side effects while ensuring
optimal drug levels are maintained.
Structured Treatment Interruptions (STI)
There is still considerable debate and much research that needs
to be done about the role of STIs as part of a third line regimen.
The goal of an STI here is focused on the potential for at least
partial reversal of drug resistance when all anti-HIV therapies
are stopped for some period of time.
Several studies have shown that the majority of people in a third
line situation who utilize an STI strategy do in fact see a reversion
back to wild type virus (a reversal of resistance), when using the
standard resistance tests, but when using a more sensitive test,
drug resistant HIV can be detected. Still, there is often a period
of renewed activity from drugs that had previously failed. It remains
unclear how long the anti-HIV benefits will last once therapy is
restarted after an STI.
One major concern with STIs in this scenario 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 anti-HIV therapy.
Furthermore, after restarting anti-HIV therapy there is a slow increase
in CD4+ cells with some people never returning to their pre-STI
CD4+ cell counts. On a more positive note, a small French third
line study involving a STI shows promising results.
Immune-Based Therapies
The use of immune-based therapies has not been adequately studied
as part of third line regimens. There are some data suggesting that
the use of GM-CSF (granulocyte colony stimulating factor, Leukine)
may have some benefit. It remains to be seen what the role of immune-based
therapies may be in third line regimens.
Participate in a Study
There have only been a few studies of third line regimen strategies.
One reason is third line regimens require the use of different drugs
from the various pharmaceutical companies and there has been a history
of difficulty in getting them to collaborate in these types of studies.
However, if a study is available it should be considered as an option.
Resistance Testing
It is probably advisable for people considering a third line regimen
to get a resistance test. A phenotypic resistance test may be more
useful in this situation than the genotypic test. Results from the
resistance test will be useful in putting together a treatment regimen.
For more information on HIV resistance tests, call the Project Inform's National HIV/AIDS Treatment Hotline.
Therapeutic Drug Monitoring (TDM)
This is a new experimental diagnostic test that measures the amount
of drug in blood. Given that most third line regimens involve many
anti-HIV drugs, there are many potential drug interactions. Drug
levels that are too low are associated with drug resistance while
high drug levels are associated with excess side effects. Several
studies have now shown that adequate drug levels are essential to
achieve a potent and sustained anti-HIV response. Information from
the TDM test can be used to change the dose of a particular drug
to ensure that adequate drug levels are achieved. For more information
on TDM, read Project Inform's publication, Drug
Levels and HIV.
Continued Benefit from “Failing” Drugs
A number of studies have reported that even after drug 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 seems likely that
simple viral load tests do not tell the whole story of how the body
responds to anti-HIV drugs.
There is much research in this area looking at the “fitness”
of the virus. Early results suggest that HIV is not able to replicate
as well after it becomes resistant to certain drugs. Thus, for some
people who might seem to lack options, one reasonable choice might
simply be to stay on whatever regimen they have been using. As long
as they remain clinically well and don’t suffer a rapid further
decline of CD4+ cells, it might not be wise to worry excessively
about drug “failure.”
Commentary
We are seeing increasing numbers of people in need of third line
regimens or at least better therapy. 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.
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