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restoration of drug susceptibility allowing for antiretroviral drugs' recycling.
Unfortunately, the reversion to the wild type is frequently seen in plasma virus,
but not in cell-associated virus, whereas a marked increase in viral ®tness occurs
during therapy interruption Finally, the heavy decrease in CD4 cell count and
the long period of time required for their recovery, possibly associated with a
high incidence of new clinical events, cast serious doubts on the advantage of
performing STI in persons with advanced HIV disease.
STI in fully suppressed persons follows a quite di¨erent philosophy. Though
eradication of HIV does not seem to be a feasible goal even with the most po-
tent and timely interventions in use today, evidence that a speci®c and e¨ective
cellular immune response to HIV occurs in infected subjects has led to the ex-
ploration of alternative approaches to therapy that would aim at enhancing the
host immune response. The hope is that short treatment interruptions may be
able to augment the length and strength of host immune responses to HIV and
increase immunologic control of the infection (Haslett et al., 2000; Lori et al.,
2000; Rosemberg et al., 2000). Therapeutical holidays may also help in pre-
venting or reducing side e¨ects. Results from a few uncontrolled studies are
available and the majority of persons seem to experience a rapid rebound of
plasma HIV RNA during treatment interruptions as well as a rapid decline in
CD4 counts, so that the possibility of boosting the HIV-speci®c immune re-
sponses through this approach therefore remains controversial and should be
clari®ed by controlled studies ( Ruiz et al., 2000). However, the following con-
clusions can be drawn from the limited experience so far: STI appear to be safe,
as shown by the prompt reduction in HIV RNA and increase in CD4 that fol-
low the reinstitution of treatment and by the conserved pro®le of drug suscep-
tibility of the rebound virus. In a variable proportion of individuals, the in-
crease in HIV-speci®c CD4 lymphoproliferative activity and some favorable
e¨ects on breadth and magnitude of cytoxic T lymphocyle response has been
observed. In a few cases, a reduced virological setpoint has been seen after re-
peated STI, although we do not know whether the observed reduction in viro-
logical setpoint is really due to STI or whether it is just a casual event (such as
normally seen in wide cohorts of HIV individuals) and for how long will spe-
ci®c immune responses induced by STI persist.
Another possibility stands behind the need to carefully test, in the appropri-
ately controlled trial setting, the strategy of structured treatment interruptions.
Because it became evident that HIV/AIDS care in the third millenium implies
long-term management of a chronic disease, with limited pharmacological op-
tions, the logical consequence is the need for durable therapeutic strategies,
keeping in mind that adherence and quality of life issues strongly limit the long-
term use of currently available antiretroviral regimens.
The current paradigm is that treatment of HIV must be continuous and for
life. This is based on present knowledge of HIV dynamics under therapy. The
perception is that cessation of treatment would lead to immediate reversion to
pretreatment clinical status and be detrimental to the patient. However, ``un-
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