rs (CD4+ cell
count, viral load, or clinical manifesta-
tions). In any situation when antiretrovi-
ral therapy is going to be changed, and
in many situations when therapy is to
be started, I would order a resistance
test. There is no other way in which to
know whether a patient has a fully wild-
type drug-susceptible virus or to gauge
the magnitude and type of drug-resis-
tant virus predominating in that patient
at that time. We no longer prescribe
what should work best for most patients
who are in certain circumstances. We
can now prescribe the best choices for
each individual patient at any point in
the course of his or her disease.
Resistance testing is one of the tools
that can help us to do that, and I use it
whenever a patient has access to it.
Question 2: In the setting of geno-
typic testing showing only minor
mutations, would you change the
drug regimen?
Dr Conway:
No, if the level of viremia
and CD4+ cell count suggests continu-
ing therapy, I would not change only on
the basis of minor mutations being pre-
sent. I would follow the level of virolog-
ic suppression that is being maintained,
ensure adherence to the regimen is opti-
mal, and have a low threshold for
repeating resistance testing if progres-
sive virologic breakthrough is observed.
If changes in viral load or CD4+ cell
count suggest a change in the regimen
is indicated, I would select the most
effective combination that would also
favor patient adherence, taking all the
resistance mutations into consideration
(even the minor ones) that are present
at that time.
Question 3: A patients 3-drug regi-
men is starting to fail. Resistance
testing results show mutations
associated with resistance to only 1
of the 3 drugs. Would you replace
just the 1 drug?
Dr Mellors:
I would not change just one
drug in a failing regimen as the only
alteration in patient management. I
would try to determine why the regi-
men failed. Without this understand-
ing, the next regimen might fail also.
Was the reason inadequate regimen
potency, advanced disease (low CD4+
cell count and high HIV-1 RNA levels),
incomplete regimen adherence, drug
intolerance, pre-existing resistance, or
inadequate drug exposure from malab-
sorption or negative drug-drug interac-
tions? I would probably increase the
potency of the regimen as well as its
convenience. There is no set formula
for managing drug failure, and therapy
changes must be individualized.
Question 4: Is there a point in time
after which resistance testing in
drug-naive patients may not be
useful (ie, time after seroconver-
sion)?
Dr Conway:
Probably after 18 to 24
months. After this time, it is likely that
resistance mutations that may have
been present initially have been out-
competed by wild-type isolates in the
absence of drug pressure. In such
patients, I would favor performing a
resistance test if appropriate virologic
suppression is not achieved in the first
4 to 6 weeks of therapy. This is enough
Special Contribution
Questions to and Answers from the International AIDS
SocietyUSA Resistance Testing Guidelines Panel
In 1996 the International AIDS SocietyUSA convened
an international panel of experts in HIV drug resis-
tance and clinical management to develop guidelines
for the clinical use and limitations of resistance test-
ing. Since then the International AIDS SocietyUSA
Resistance Testing Guidelines Panel has developed
and regularly published its recommendations. The
latest panel recommendations appear in the July 1
issue of Clinical Infectious Diseases.
We periodically pose questions to the panel relat-
ing to clinical elements of resistance testing that have
been collected from HIV practitioners across the
nation. We are happy to feature the latest edition in
this issue of Topics in HIV Medicine. It is our hope that
addressing these issues will help guide your treat-
ment strategy decisions regarding resistance testing.
The International AIDS SocietyUSA Resistance
Testing Guidelines Panel consists of Martin S. Hirsch,
MD; Françoise Brun-Vézinet, MD, PhD; Bonaventura
Clotet, MD, PhD; Brian Conway, MD; Daniel R.
Kuritzkes, MD; Richard T. DAquila, MD; Lisa M.
Demeter, MD; Scott M. Hammer, MD; Victoria A.
Johnson, MD; Clive Loveday, MD, PhD; John W.
Mellors, MD; and Douglas D. Richman, MD.
On a related note, the International AIDS
SocietyUSA Drug Resistance Mutations Group will
publish its update later this year in Topics in HIV
Medicine. The current version is available at
www.iasusa.org. time to allow for the selection of a
minority species of resistant viruses
that could have been present in the
baseline viral swarm.
Question 5: Can therapeutic drug
monitoring combined with geno-
typic and phenotypic testing
improve care outcomes? If so, why
is it taking so long to incorporate
therapeutic drug monitoring (TDM)
into practice in the United States,
compared with in Europe?
Dr Demeter:
TDM has been proposed
as potentially useful, primarily to opti-
mize levels of protease inhibitors (PIs).
Retrospective data suggest that having
higher trough levels of PIs is associated
with improved virologic outcome. In
addition, retrospective data correlating
inhibitory quotient (IQ = trough level/
IC
50
) with plasma HIV-1 RNA suppres-
sion indicate that IQ may be a better
predictor of outcome than trough level
or IC
50
alone. However, it is still not clear
whether TDM to increase PI dose and
optimize IQ is a useful prospective strat-
egy for managing treatment-experi-
enced patients. One problem is the vari-
able quality of current TDM laboratories
and insufficiently rigorous standards to
evaluate their performance in measur-
ing antiretroviral drug levels. The sec-
ond problem is that the VIRADAPT trial,
the one prospective study that has eval-
uated TDM in treatment-experienced
patients, showed no benefit of TDM. A
weakness of this trial is that PI drug lev-
els, rather than IQs, were used to adjust
dosing (ie, the targeted drug levels were
not chosen to exceed the IC
50
). TDM
strategies are being evaluated in a num-
ber of clinical trials currently, but cannot
be recommended at this time for rou-
tine clinical use.
Question 6: Should lamivudine be
used even if the M184V mutation is
present, based on the assumption
that this mutation makes the virus
less fit?
Dr Kuritzkes:
To date this remains a
hypothetical rationale for maintaining
lamivudine in a failing regimen. There
are, as yet, no compelling data for or
against this strategy.
Question 7: What is the current
practice in antiretroviral cycling to
decrease the emergence of drug
resistance?
Dr Clotet:
Cycling of drugs is not cur-
rently used as a strategy outside of clin-
ical trials. However, many patients on
highly active antiretroviral therapy
(HAART) who undergo a simplification
or switch for intolerance or side effects
while having plasma HIV-1 RNA levels
below detection limits are in fact expe-
riencing preemptive switching. This
antiretroviral cycling might decrease the
risk of emergence of resistance. The
SWATCH study
1
showed that the virolog-
ic outcome was better with preemptive
switching and drug alternating than
with the current standard of care. In
addition, this approach had similar
adverse events and adherence to that
observed with currently prescribed
fixed HAART. Preemptive switching and
alternating of antiretroviral regimens
with different drug-resistance profiles
theoretically might extend the overall
long-term effectiveness of the first- and
second-line drug options without
adversely affecting either patients
adherence or quality of life, assuming
tolerance and toxicity do not adversely
affect outcome.
Question 8: For a pregnant woman
who emigrated from Africa to the
United States and is infected with
HIV-2, which resistance and HIV-2
quantitative tests should be used
and what is the availability of such
tests in the United States?
Dr Loveday:
HIV-2 originated in West
Africa and is found predominantly in
patients in this region and in countries
that have colonial links to it. Clinically,
HIV-2 appears to be less pathogenic
than HIV-1, with slower progression to
symptomatic disease and death; overall
its numerical contribution to the AIDS
pandemic is minor. Nevertheless, it
does contribute to morbidity and mor-
tality. At present there are approximate-
ly 100 reported cases of HIV-2 in the
United States. Genetically, HIV-2 has
approximately 40% homology with
HIV-1, and this can lead to difficulties in
interpretation of laboratory diagnostic
tests. This is further confounded by the
increasing prevalence of dual HIV-1/HIV-
2 infections in patients originating from
West Africa.
In the case described, the clinical
diagnosis of HIV-2 should first be
reviewed, as the local diagnostic tools
may not be reliable. This is best carried
out using a commercial dual-screening
enzyme immunoassay (EIA) to assess
reactivity and confirmed using an HIV-
2specific EIA or HIV-2 Western blot
assay and polymerase chain reaction
(PCR). The goal is not only to confirm
the diagnosis but also to confirm the
exclusion of dual infection with HIV-1
and HIV-2. The confirmation of dual
infection has major implications for
future management of the patient and
her offspring. For example, dual infec-
tion requires a more aggressive strategy,
selective use of nonnucleoside reverse
transcriptase inhibitors (NNRTIs, which
are not effectiv