Improving the Management of HIV Disease Vol. 6, no. 5 [World Conference on AIDS (12th: 1998: Geneva)]

QUESTIONS TO THE ANTIRETROVIRAL THERAPY AND RESISTANCE TESTING PANELS
Ill.1DOINGIDMIIS'A *O

15. Is there a rationale for not
using 2 NNRTIs together?
DR HAMMER: The rationale thus far for
not using NNRTIs together has been that
they, for the most part, bind to the same
region on the reverse transcriptase
enzyme and thus would theoretically
compete with one another. Further, there
is the theoretical concern that combining
these drugs clinically might enhance
their toxicity profiles, particularly with
respect to rash. There are, however, no
data to speak to this at this time. This
being said, it should be noted that some
in vitro studies suggest that NNRTIs can
be additive or synergistic when used
together and there are some early reports
of using 2 NNRTIs together as part of 6-,
7-, and 8-drug regimens in a salvage situation, an approach that has been termed
"mega-HAART." Whether potency is
truly enhanced by this approach is uncertain, and the class cross-resistance that is
known to be a problem for the NNRTIs
may not be circumvented. NNRTIs individually are quite potent and the success
ful use of these drugs is directly linked to
the strength of the rest of the antiretroviral combination employed in order to try
to limit virus replication and the emergence of mutants that are resistant to the
NNRTIs and other drugs.
DR CONWAY: This is clearly an issue
that needs to be addressed in clinical
research. Potential problems of combination NNRTI therapy would include synergistic toxicity (particularly an increased
incidence of rash if delavirdine and nevirapine are used) and some deleterious
pharmacokinetic interactions, as
efavirenz and nevirapine are net
inducers of the hepatic cytochrome
system (CYP3A4) and delavirdine is a
net inhibitor of this metabolic pathway.
It is not known whether a combination
of 2 NNRTIs would enhance the potency
of a given maximally suppressive antiretroviral therapy regimen. In theory,
there could be a benefit in terms of such
a combination, as certain isolates that
are resistant to delavirdine may retain
some degree of susceptibility to efavirenz
and may be resensitized to nevirapine (if
they had become resistant to this drug),

leading to prolonged efficacy of the
NNRTI component of a regimen after the
first resistance mutations have begun to
emerge. If preliminary pharmacokinetic
studies support the feasibility of combining NNRTIs while maintaining appropriate therapeutic blood levels, the approach
should be evaluated within the context of
a well-designed clinical trial.
16. Are there any data about
twice-daily dosing of nelfinavir and saquinavir hard
gel capsules?
DR VELLA: A twice-daily dosing ofnelfinavir is being explored in clinical trials.
Preliminary results seem favorable but
should be confirmed in larger studies.
Twice-daily dosing of saquinavir hard gel
formulation is possible only when
the drug is used in combination with
other drugs (eg, ritonavir) that improve
pharmacokinetics.

IV CHANGING/CONTINUING THERAPY

DR D'AOUILA: The most current data
continue to indicate that plasma HIV
RNA rebound should be the main trigger
for when to change therapy. Testing for
either genotypic or phenotypic evidence
of resistance is less likely to yield a result
with any of the current methods if plasma HIV RNA is less than about 1000
copies/mL. There were several retrospective studies presented in Geneva and at
the recent Drug Resistance Workshop
that suggested that resistance testing
may help in a different way: to choose
19

which drugs not to use in the next regimen. Each of these studies found that
detection of baseline genotypic or
phenotypic evidence of resistance to one
or more drugs in a salvage regimen was
a reliable predictor of failure of that
salvage regimen.
DR RICH MAN: The reemergence of
detectable plasma HIV RNA defines therapeutic failure. This is not sufficient,
however, to trigger a change in therapy.
Before changing, it is important to ascerVOLUME 6, OCTOBER 1998