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

have resistance mutations, I would recommend performing genotypic testing
on the first available plasma specimen.
The results could help to define a better
therapeutic strategy. In patients with
long-term, evolving HIV infection, drugresistant variants transmitted during primary infection may be difficult to detect
in the absence of therapy because wildtype strains will have a replication advantage. In patients in whom therapy is failing, several retrospective studies support
the predictive value of genotypic and
phenotypic testing on a subsequent viral
load response to an alternative therapy.
However, these results require validation
through prospective studies. There is evidence from existing data that phenotype
or genotype analyses will have a role in
the clinical management of HIV-infected
patients. It is possible that they will have
different utilities according to the drug
history and the number of previous drug
failures.
37. Given that the plasma HIV
RNA level must currently be
greater than about oo
copies/mL to obtain genotype information, why
would you not genotype
proviral DNA if the plasma
viral load is below ooo
copies/mL?
DR LOVE DAY: There are two aspects to
this question. First, although plasma
viral load should be more than 1000
copies/mL to obtain genotypic information and most approaches have been
quoted as needing this level of plasma
virus, new advances are occurring rapidly
in the genotyping technologies. Since at
least some approaches are asking for 500
copies/mL or even less, matters are likely
to progress rapidly in this area. Second,

we and others have demonstrated that
proviral DNA can be used to determine
information about genotypic changes
associated with resistance, and our experience is that it probably reflects the plasma
picture that existed 2 to 4 weeks previously. To answer the question directly, it is an
approach we frequently use when having
trouble with low plasma viral load.
DR KURITZKES: Unlike plasma HIV-1
RNA, which reflects the actively replicating pool of virus, proviral DNA is largely
constituted by archival viral sequencesthat is, the DNA record of virus that was
actively replicating at some time in the
past. Equilibration of sequences between
plasma and cellular (proviral) compartments is variable, ranging over weeks to
months. The chief concern would be that
failure to observe an expected resistance
mutation in proviral DNA does not guarantee its absence from the actively replicating pool of virus. Personally, I would
prefer to obtain a virus isolate by culture
for sequencing, since there is more rapid
equilibration between plasma HIV-1
RNA and activatable PBMC-associated
virus compared with the total proviral
DNA pool.
38. Given the emergence of
new diagnostic assays (ie,
resistance phenotyping
and genotyping), is there a
need to reexamine the
staging of HIV?
DR RICH MAN: The roles of CD4+ cell
counts and levels of plasma HIV RNA are
well established and will not be displaced
by assays for drug resistance. We know
that risk factors for poor response to
antiretroviral drug treatment include
high plasma HIV RNA level, low CD4+

27

cell count, and drug-resistant virus, in
addition to poor adherence and other
pharmacologic factors that diminish
plasma levels. The very important practical questions are whether assays of drug
resistance will improve therapeutic
results, which assays should be used, and
how should they be used. Once again,
data are being rapidly accumulated in
this rapidly evolving field.
DR HAMMER: In general the "staging"
of HIV disease has become less meaningful over time with the recognition that
the disease process is a complex continuum. A better and more useful term is
"characterization" of where an individual
stands in that continuum. Currently, the
presence or absence of symptoms, the
CD4+ cell count, and the plasma HIV-1
RNA level are used to characterize where
patients stand prognostically. If the question is suggesting that perhaps resistance
testing should be added to the characterization of patients, it is a most intriguing
proposition. The greatest use of these
assays ultimately will be in helping to
choose an appropriate antiretroviral regimen in circumstances such as a newly
diagnosed patient who is at risk for having acquired a drug-resistant strain or in
someone experiencing virologic failure
on a current regimen. In these circumstances, the characterization of the
patient at the start of therapy or when
considering a change in therapy would
be enhanced, thus leading to greater
individualization of treatment, which is
an important goal. Although early studies demonstrated that phenotypic and
genotypic evidence of resistance to
zidovudine were independent predictors
of clinical outcome, whether this is the
case in the more complex environment of
combination therapy and routine viral
load testing is unclear.

VOLUME 6, OCTOBER 1998