Rescue Regimens:
The Value of PI Boosting
by Sorana Segal-Maurer, M.D.,
and Malte Schütz, M.D.
Looking back over the last
20 years, we have seen a great evolution in the long-term
management of HIV/AIDS. From the initial stages of only one
treatment option to the development of three unique classes
of medication, we have witnessed a great change in the landscape
of this disease. In particular, during the mid 1990s, we began
to see our patients living longer with the discovery of protease
inhibitors and the outlook of AIDS shifted from a deadly and
unmanageable disease to a chronic condition with long-term
options. The current challenge of many physicians in this
specialty and people living with HIV is how to choose the
right therapy for now while still keeping in mind the need
for future options when treatment fails. When you have cycled
through the three classes of HIV drugs and treatment fails,
the next choice of therapy is what we have dubbed “rescue
regimens.”
HAART
In order to fully understand
the concept of rescue regimen therapy, we must first identify
what necessitates rescue therapy: resistance. Achieving long-term
treatment success depends largely upon planned sequential
use of multi-drug combinations called HAART (highly active
antiretroviral therapy). At this point in the evolution of
anti-HIV/AIDS therapies, there are three classes of antiretroviral
drugs approved for the treatment of HIV. The three principal
HIV/AIDS antiretroviral drug classes are: nucleoside reverse
transcriptase inhibitors (nucleosides), Protease inhibitors
(PIs), and non-nucleoside reverse transcriptase inhibitors
(NNRTIs).
Nucleosides were the first
members of the family of HIV drugs. They inhibit the activity
of reverse transcriptase, a portion of HIV needed for the
virus to replicate. Nucleosides are often the basis of multi-drug
combinations. Protease inhibitors are the latest major addition
to the family of HIV/AIDS antiretroviral treatments.
Non-nucleoside reverse transcriptase
inhibitors, like their similarly named drug cousins, interfere
with HIV’s ability to reproduce. NNRTIs are now being used
in combination regimens as antiretroviral therapy to control
HIV and slow the development of resistance. NNRTIs should
be used only in combinations that are designed to maximally
suppress the HIV virus as researchers, clinicians, and patients
have learned that the potential for developing high-level
resistance to NNRTIs can result from a single change in the
HIV virus. Among these, Rescriptor (delavirdine) also has
the important ability to increase or boost the drug levels
of other medications in combination therapy.
Protease—a protein-cutting
enzyme—is a portion of the HIV virus in part responsible for
the ability of the virus to infect healthy cells. Protease
inhibitors block the protease enzyme, causing the HIV to reproduce
itself in a form that cannot invade healthy cells. To develop
resistance to the protease enzymes, HIV must develop many
mutations. Therefore, this family of medications may be used
when viral loads are very high. Table A
lists the medications in each class of HIV drug therapy.
Resistance
The goal of antiretroviral
therapy is to completely suppress viral replication and delay—or
even prevent—drug resistance. Resistance in HIV therapy is
defined as the virus’ failure to respond following treatment
and the subsequent active reproduction of itself. An increasing
viral load is often the first sign that HIV drug resistance
has developed. Below are three major reasons that HIV is able
to develop resistance to a given treatment:
• Weak treatment regimens—If the
drug combination prescribed is not strong enough to block
HIV completely, drug resistance can develop. Higher drug
levels may be required from future therapies to effectively
suppress the virus.
• Inadequate dosage levels—Different
people taking the same dose of the same medicine will often
absorb or break down those medicines differently, which
may result in low drug levels, which in turn may lead to
the development of resistance.
• Poor treatment adherence—Missing
doses, taking them late or not following the food instructions
with medications can lead to resistance, as it often results
in low drug levels. Just a few missed doses of a drug can
cause drug resistance. In such cases, a random mutant virus
can become the dominant virus in the person’s system, causing
the body to develop resistance to that drug.
One recent study in Hartford,
Connecticut looked at 40 inner-city clinic patients using
MEMS caps (computerized medication bottle caps that record
each time the container is opened) to measure adherence. Researchers
found that as the percentage of doses missed increased, the
percentage of viral load increased as well. Specifically,
when the percentage of dosage taken fell below 80 percent,
the treatment success rate failed to be suppressed in one
half of patients. For example, if a group of people are taking
medicines twice a day (60 doses per month), and they each
miss six days of the medicine in one month, half of them would
be unable to suppress their viral load. Less than one third
of patients taking less than 70 percent of their dosage had
undetectable viral loads.1 Common causes of non-adherence
include forgetting to take medication (57 percent), negative
side effects (39 percent), feeling well/not feeling a need
for therapy (22 percent), and suspecting that therapy is not
working (20 percent).2
One of the results of resistance,
which should be considered in planning your HIV therapy, is
cross-resistance. Research has shown that some drugs share
similar mutation patterns which confer cross-resistance to
other drugs within their class. Because of cross-resistance,
you can get resistant to medications which you have actually
never taken. Despite the large number of approved HIV medications,
the number of sequential treatment options that will be effective
for an individual patient is sharply limited by cross-resistance.
Although each class of drug combats HIV in a different way,
cross-resistance should be considered an important factor
in selecting each treatment regimen. Knowing which options
will exist for future regimens is critical in the long-term
management of HIV.
Resistance Testing
Once you have experienced
a viral load rebounding after HIV treatment, future treatment
options may become more limited. The best way to determine
which combinations will be effective at this point is through
resistance testing. Two methods of testing currently exist:
genotype testing and phenotype testing. Genotyping maps out
the reverse transcriptase and protease inhibitor genes to
determine resistance mutations to specific drugs. By doing
this, you are able to assess HIV drug resistance based on
genetic indicators, or letters of the code, which have mutated.
Phenotyping more directly measures resistance by examining
the ability of HIV to grow in the presence of each of the
available drugs. Phenotype testing is conducted by growing
recombinant HIV virus with the patient’s resistance pattern
in a test tube in the lab. These tests then measure resistance
by adding antiretrovirals to the culture medium to determine
which are susceptible to the virus.
Both of these tests have
many pluses and minuses. Phenotyping, for instance, offers
a direct measurement of HIV drug susceptibility and results,
which can be easier to understand than genotyping results.
However, these particular tests are expensive, slow, insensitive
for minor virus populations and extremely difficult to conduct;
in fact, phenotype tests are so difficult to conduct that
they are considered an art form. Genotype tests, while quicker
to perform and less expensive than phenotype tests, have their
own limitations. Primarily, given the fact that more than
100 resistance mutations have been described, genotypic data
does not always offer straightforward interpretations and
may require the physician to have a lot of knowledge on how
to interpret the findings. Despite their limitations, both
of these tests can be extremely helpful in evaluating which
drugs the virus has become resistant to and considering what
future drugs might be effective and if higher drug levels
will be beneficial. They also allow us to judge if a new drug
class should be introduced.
Rescue Regimens and PI
Boosting
Rescue regimen is a
term used for therapy alternatives following a viral load
rebound from all three classes of antiretrovirals. What to
choose as a rescue regimen can be challenging. As the previous
section has outlined, resistance mutations limit these options
significantly. The addition of a new class, when available,
is a unique opportunity to suppress the virus, but currently
only three classes are available. [See “News
Briefs” in this issue for new drug]. In addition,
higher drug levels are a strong consideration in a rescue
regimen, as these higher drug levels may help to overcome
resistance. Furthermore, boosting agents can help simplify
the dosing of protease inhibitors, such as fewer doses of
Crixivan (indinavir) when it is combined with Norvir (ritonavir)
or Rescriptor (delavirdine).
To further explain boosting
agents’ utility in rescue regimens, it is helpful to first
understand the way in which all protease inhibitors and NNRTIs
are metabolized, or broken down and removed from the blood.
Most PIs and NNRTIs are metabolized by the same system, or
pathway, in the liver: cytochrome P-450. Some HIV medications
slow down the liver enzymes, like a plug might stop the water
from going through the drain in a bathtub. This function allows
the drugs using those enzymes to be broken down more slowly,
boosting the level of these drugs within the body and allowing
them to remain in the body longer.
Two antiretroviral drugs—Norvir
and Rescriptor—possess this unique ability of inhibiting cytochrome
P-450 and, in turn, boosting the levels of other drugs. Norvir
has the greatest degree of success as a boosting agent among
the PIs; it is an effective agent at boosting the levels of
Invirase, Fortovase (saquinavir soft-gel), Crixivan, Agenerase
(amprenavir) and Viracept (nelfinavir). Kaletra contains a
small dose of Norvir right in the capsule and is also considered
a boosted combination. Among the NNRTIs, Rescriptor is the
most successful boosting agent with select PIs; it is a valuable
boosting agent when used in conjunction with Crixivan, Viracept,
Agenerase, Invirase or Fortovase. Rescriptor is the only NNRTI
effective in this role, as both Sustiva and Viramune do not
boost the levels of PIs.
In addition, when using PI
boosters such as Norvir and Rescriptor, certain facts must
be considered. First, Norvir is a PI and Rescriptor is an
NNRTI. Norvir has been associated with the following side
effects: nausea, diarrhea, liver toxicity, high cholesterol
and high triglycerides. Rescriptor, while only more recently
observed for use in PI- boosting, appears to have a better
side effect profile; it is free of significant gastrointestinal
side effects, liver toxicity or cholesterol elevation but
has been associated with an occasional rash.
One recent study, ACTG 3593,
evaluated Rescriptor’s effect on the drug levels of several
protease inhibitor combinations, including Viracept (NFV),
Fortovase (SQV), and Norvir (RTV). The following combinations
were studied both with and without Rescriptor: NFV + SQV;
NFV + SQV + Adefovir; RTV + SQV; RTV + SQV + ADV. In this
study, Rescriptor is shown to have significantly increased
the drug levels of each combination. The percentage of patients
with a viral load less than or equal to 500 who maintained
a virologic response at 16 weeks was more than 10 percent
higher across the board than those patients not receiving
Rescriptor in their combination. At 48 weeks, the trend continued,
showing that in the specific case of patients on the combination
of NFV + SQV + ADV, the percentage of patients maintaining
a viral load of 500 or less more than doubled with the addition
of Rescriptor.
Both Norvir and Rescriptor
can greatly enhance drug levels in a rescue regimen, with
the effect of Norvir being somewhat more pronounced. Knowing
when to select which one of these boosting agents can be the
real challenge. Table B helps to simplify
this decision with recommendations for when to use Norvir
and when to use Rescriptor in PI boosting.
Hypersusceptibility
Hypersusceptibility
can be another reason for the addition of an NNRTI in a rescue
regimen. Hypersusceptibility occurs when the virus has become
extremely susceptible, or vulnerable, to a medication. Often,
a patient who has experienced resistance to nucleosides and
protease inhibitors may respond well, in terms of HIV suppression,
to the addition of an NNRTI in rescue therapy. Several studies
lead us to believe that it is nucleoside-resistant mutations
in the reverse transcriptase gene which may confer hypersusceptibility
to NNRTIs. One such study is CCTG 575, which indicated that
patients who had at least six months experience on antiretroviral
therapy, including at least one non-nucleoside, showed hypersusceptibility
to the introduction of an NNRTI in phenotypic testing.4 In
the specific case of Sustiva, those with Sustiva-hypersusceptible
virus receiving Sustiva had significantly lower viral loads
by month two when compared with those without the Sustiva-hypersusceptible
virus. Furthermore, by month four, there were also markedly
higher increases in CD4 cells for hypersusceptible patients.
This study suggests that
NRTI-resistance mutations may sensitize viral isolates to
NNRTIs, making NNRTIs a sound choice for rescue therapy. It
also supports the use of phenotypic resistance testing in
nucleoside-experienced patients, as it may uncover hypersusceptibility
for future therapy choices.
Where do we go from here?
PI boosters such as Norvir
and Rescriptor can play a significant role in rescue therapy
since higher drug levels can help in overcoming resistance.
Long-term planning can have an immense impact on future therapy
options, which can become critical as resistance mutations
limit the choice of medications available in rescue therapy.
You should speak with your physician about which treatment
strategy and rescue regimens will prove most tolerable and
effective.
Sorana Segal-Maurer, M.D.,
New York Hospital Queens, Division Infectious Diseases Flushing,
New York and Malte Schütz, M.D., Triad Health Practice, Advocate
Illinois Masonic Medical Center, Chicago, Illinois
1 K. Abriola, XIII World
AIDS Conference, Durban, South Africa.
2 Ohmit S, et al. XII World
AIDS Conference, Geneva, Switzerland, 1998, Abstract No. 32347.
3 Gulick. 7th CROI, 2000,
San Francisco, Abstract 235.
4 Haubrich. Antivir Ther
2000; 5(suppl3): 69.
|
