Full text of DOI:10.1016/S1055-3290(06)60243-4

Treatment Review Column
JBAuNrkAleC/VDorlu.g13R,eNsios.ta1n,cJeananudarSy/eFqeubernucairnyg2002
Antiretroviral Therapy for HIV:
Drug Resistance and Sequencing
Wayne S. Burkle, PharmD
or her initial antiretroviral regimen has the best chance
Background
of maintaining long-term drug benefit because he or
she would not have a large number of preexisting
mutations from prior therapy. However, because of
incomplete adherence or other factors, the initial drug
regimen may fail. As a result, providers must select an
initial drug regimen that will preserve the patient’s
ability to take additional drugs or types (classes) of
drugs in the future should the current regimen fail.
There are currently 18 Food and Drug Administra-
tion–approved antiretroviral drugs available to treat
patients with HIV, the virus that causes AIDS. These
drugs fall into three classes: protease inhibitors (PIs),
nucleoside reverse transcriptase inhibitors (NRTIs),
and non-nucleoside reverse transcriptase inhibitors
(NNRTIs). Treatment regimens with combinations of
these agents are designed to reduce the patient’s level
of HIV (viral load) and increase the number of CD4
lymphocytes, a type of T-cell that is normally present
in the body to fight off viruses, fungi, mycobacteria,
and other disease-causing agents.
Resistance
What Is Resistance?
Resistance is the ability of the virus to replicate in
the presence of drugs. One of the challenges with HIV
is that it mutates constantly. The HIV in any one indi-
vidual is a mix of viral strains. The predominant strain
is called wild-type HIV and is sensitive to drugs. How-
ever, other strains carry mutations that may be resistant
to drugs. Anti-AIDS drugs do not cause resistance, but
if a drug regimen fails to keep viral loads low enough,
preexisting HIV mutations that are less susceptible to
the drug therapy will be able to grow in increasing
numbers (MacArthur, 2000).
In some cases, mutant viruses can become resistant
to more than one drug or even to entire classes of drugs
(Hertogs et al., 1998), which is called cross-resistance.
Cross-resistance can occur even though a patient has
not been exposed to the other drugs in the class.
Despite the number of drugs available and the many
drug combinations possible, some regimens are
unable to maintain low viral loads and high T-cell
counts adequately in some patients. In some cases, the
HIV virus mutates, causing the drugs to become inef-
fective. In this case, physicians must prescribe a new,
more powerful regimen.
Many HIV-positive patients face increasing viral
loads after 1 to 2 years of therapy, indicating that the
virus is becoming resistant to at least one antiretroviral
agent in their regimen and that their regimen might be
failing and alternatives need to be considered. When
resistance occurs, providers must determine which
new drugs to prescribe that will continue to adequately
suppress the virus and raise T-cell counts. The order in
which antiretroviral drugs are prescribed—the
sequencing—is vitally important to the long-term suc-
cess of therapy.
HIV is a chronic condition, which usually requires
that drug therapy, once begun, continue over the
patient’s lifetime. A patient who strictly adheres to his
Wayne S. Burkle, PharmD, works in the Medical Informa-
tion Department of GlaxoSmithKline.
JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE, Vol. 13, No. 1, January/February 2002, 76-80
Copyright © 2002 Association of Nurses in AIDS Care

Burkle / Drug Resistance and Sequencing 77
Why Is Resistance a Problem?
•
•
Viral load increases significantly.
T-cells drop or the patient develops an opportu-
nistic infection while the patient is on
antiretroviral therapy.
Resistance reduces the effectiveness of drugs. Fur-
thermore, cross-resistance reduces the number of
treatment options available to providers and their
patients. If cross-resistance becomes extensive
enough, there may be no drugs left to suppress the
growth of the virus.
How Might Providers or Patients
Address HIV Drug Resistance?
In many cases, modifying drug regimens is the best
way to manage resistance (Hertogs et al., 1998). Using
resistance-testing technologies, providers can deter-
mine which drugs are most likely to suppress mutant
viruses that have become resistant to other drugs.
What Factors Contribute
to Drug Resistance?
There are a number of factors that contribute to drug
resistance, including the following:
How Can Resistance Be Prevented?
•
Failure to adhere to drug regimens. Skipping
drug doses, even occasionally, can allow viral
loads to increase or rebound. When this occurs,
mutations that may be resistant to one or more
drugs in the regimen can become the predomi-
nant HIV strain infecting the patient (Molla
et al., 1996).
In some cases, the body metabolizes drugs too
quickly for them to have an effect, and drug lev-
els may not be high enough to suppress the HIV
virus.
Antiretroviral drugs may have a negative inter-
action with other medications, which can
decrease their effectiveness.
Some antiretroviral drug regimens are not
strong enough to stop the virus from replicat-
ing. This is especially likely if the patient is tak-
ing only one or two drugs to suppress HIV or if
the patient has a high baseline viral load in his
or her blood.
Resistance may not be preventable, but it can be
delayed. The trend has been for physicians to tailor a
drug regimen for the individual patient in hopes that
thisindividualized approach will be less likelytoresult
in resistance. This includes not only selecting the right
drugs but also taking into account the patient’s ability
to adhere to the regimen and to tolerate any adverse
side effects that the regimen might cause. In addition,
potential drug interactions should be considered because
they may result in there being suboptimal levels of
HIV drugs in the body to fight the virus (Hirsch et al.,
2000). Providers should also consider what future reg-
imens would be available if the first regimen fails.
•
•
•
Drug Sequencing
Once HIV has become resistant to one or more
antiretroviral agents in the patient’s regimen, it
becomes increasingly difficult to control the patient’s
viral load. The more regimens a patient fails, the
harder it is for additional regimens to control HIV.
When patients develop resistance to three or four
antiretroviral regimens, switching to another regimen
adequately suppresses the HIV virus in only a minority
of patients (Mayers et al., 1998). This difficulty is usu-
ally attributed to cross-resistance to agents within one
or more of the three available classes of antiretrovirals
(PIs, NRTIs, NNRTIs). Cross-resistance limits the
effectiveness and durability of subsequent anti-
retroviral regimens.
What Are the Possible
Signs of Resistance?
•
•
Viral load does not decrease by 90% after 8
weeks of therapy.
Viral load does not become undetectable after 4
to 6 months of antiretroviral combination
therapy.
A formerly undetectable viral load becomes
detectable.
•

78 JANAC Vol. 13, No. 1, January/February 2002
What Is Sequencing?
lar drugs. The results are often difficult to inter-
pret because different mutations interact in
complex ways, all of which are not known (Lar-
der, Kemp & Herrigan, 1995), particularly
when patients have failed multiple HIV regi-
mens; genotypic testing appears to be most use-
ful in patients failing their first or second HIV
regimen.
Phenotypic testing is a technique that exposes
HIV to different levels of antiretroviral agents
in a test tube, rather than in the patient, to deter-
mine which are most effective against the virus
and identify the amount of drugs needed to
inhibit the growth of HIV. Phenotypic testing
does not look at the mutations but tells the phy-
sician if the virus is becoming resistant to cer-
tain drugs. This test takes longer than genotypic
testing and is usually more expensive but
appears to be more useful in patients failing
multiple HIV regimens. Although these tests
can measure a decrease in viral susceptibility to
drugs, few of the drugs have clinically estab-
lished cutoffs or breakpoints for when they lose
significant efficacy.
The process of selecting the right drugs or drug
combinations for a patient throughout his or her life-
time is called sequencing. Proper sequencing is essen-
tial to limit or delay resistance and to preserve as many
drug options as possible for future use by the patient.
Until recently, providers tended to sequence drugs
using a fairly standard approach for most or all of their
patients. These standard regimens were determined
through researchtoworkbestfor theaveragepatient.
Today, tests are available that allow providers to
analyze the resistance profile of individual patients
before they start their first antiretroviral drugs and
again each time a virus becomes resistant to a drug reg-
imen. These tests enable providers to better character-
ize the virus and make sequencing decisions that are
tailored to the individual.
•
How Is Sequencing Accomplished?
Sequencing strategies are based on the observation
that all drugs are not created equal. Even drugs within
a class have varying effects. Ongoing research is more
clearly defining the different mutational and cross-
resistance patterns that arise after the virus is exposed
to particular drugs. Providers are able to more closely
individualize therapy when prescribing for particular
patients.
Decisions on sequencing are being aided by
genotypic and phenotypic tests, which are used to
determine a patient’s resistance profile when a regi-
men fails. The tests also are occasionally used to make
treatment decisions for patients who are starting their
first treatment regimen, but this practice is currently
not recommended in treatment guidelines unless there
is a significant chance that the patient was recently
infected with resistant virus (U.S. Department of
Health and Human Services [DHHS], 2001). Informa-
tion from these tests is, however, becoming the most
important factor in determining the next step for
patients who have failed a treatment regimen.
What Are the
Limitations of Testing?
Both genotypic and phenotypic testing have limita-
tions. They are expensive and complicated to interpret.
Both tests can take from 2 to 4 weeks to complete,
which makes them impractical in many clinical set-
tings. The tests also are not reliable for patients with
lower viral loads of 50 to 1,000 copies because there is
less virus to work with. To maximize their benefit to
clinicians, further work is needed to provide standard-
ization and clinical validation of these testing
methods.
How Do Physicians Decide What
Regimen to Start and When to Change
a Regimen That Is Starting to Fail?
•
Genotypic testing, the older of the two technol-
ogies, looks at the genes of the virus to find
mutations associated with resistance to particu-
There are a number of factors that must be taken
into consideration before starting or changing a drug
regimen, including the following:

Burkle / Drug Resistance and Sequencing 79
some advanced patients with significant resistance
(Montaner et al., 1998). It is unlikely that any one virus
in the body will be resistant to all of the drugs in this
regimen. However, complex multidrug regimens are
likely to be associated with higher rates of side effects
and adherence problems.
If a patient’s virus is resistant to an entire class of
drugs but the viral load is low (although not undetect-
able) and the T-cell count is high, some providers may
recommend continuing the treatment if there are no
other treatment options available. This approach, how-
ever, is highly controversial (DHHS, 2001).
New combinations of drugs are constantly being
tested, and new agents in clinical trials will offer pro-
viders more and better options. In addition, the value
and optimal use of resistance testing assays are still
being evaluated.
•
•
•
T-cell and viral loads should be measured. Clin-
ical trials are under way to help providers deter-
mine the effectiveness of new regimens in
patients with varying viral loads and different
resistance patterns.
In the face of a rising viral load, the decision to
switch to a new antiretroviral regimen should
be made only when it has been determined that
the patient has been adherent to the current regi-
men (Hirsch et al., 2000; Molla et al., 1996).
The patient must be psychologically ready to
start the regimen, educated on and prepared for
potential side effects, and willing to adhere to
the prescribed regimen.
What Are the Preferred
Sequencing Regimens?
References
DHHS and the International AIDS Society recom-
mend treatment standards and periodically revise their
recommendations as research continues to find better
ways to treat people with HIV/AIDS. Currently,
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a failing regimen and recommends that at least two
new drugs or an entirely new drug combination be
used. If, however, resistance testing shows that viral
mutations are resistant to only one drug, it may be pos-
sible to replace that one drug, but this approach remains
controversial.
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antiretrovirals with the addition of another drug to
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willing to take the drugs. This process is called
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80 JANAC Vol. 13, No. 1, January/February 2002
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