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Conference
"Treatment Interruptions" Dr. Jose Gatell (biography) English - 2002-04-14 - 38 minutes
Summary : In order to achieve a sustained suppression of the HIV-1 replication is necessary a high level of compliance (probably above 90-95% of the prescribed medications) with a combination (usually three or more drugs) of antiretroviral agents. Moreover the clinical benefits of HAART have also been very well documented. Yet, interruptions of antiretroviral therapy have gained wide acceptance and popularity not only among patients and non-governamental organizations but also among treating physicians despite lack of controlled data. Structured, supervised, or strategic treatment interruptions (STIs) have been considered in very different situations: following aggressive therapy of acute HIV syndrome, following suppressive antiretroviral therapy of established infection, to facilitate salvage after therapy has failed. The rationales for interruption of therapy in these three setting are very different.
The goal of STIs following successful treatment of acute HIV-1 infection is to avoid loosing the specific immunological response against HIV-1 and/or further boost host HIV-specific immune responses, with the hope that maintained and boosted responses will suppress virus replication sufficiently to eventually reduce of obviate the need for further antiretroviral treatment at least during transient period of time. Data from preliminary uncontrolled trials from small numbers of acutely infected patients suggest that this may be possible.
Treatment interruptions in the setting of chronic established infection and suppressed viral load are aimed at reducing long-term toxicity and cost by limiting drug exposure. Boosting HIV-specific immune responses occurs less frequently in this setting but have been demonstrated in a limited percentage of patients. Following treatment interruption, a very quick virus rebound is observed, with pre-therapy setpoint reached in a few days or weeks together with a progressive decrease in CD4+ cell counts. A few instances of recurrence of acute HIV syndromes also have been observed following treatment interruptions in chronically infected patients in whom virus was maximally suppressed.
Treatment interruptions following failed therapy have been proposed as an approach to enhance the reemergence of wild-type virus in the circulating pool, thereby increasing antiretroviral options for subsequent treatment regimens. This approach is associated with considerable risk, including precipitous reductions in CD4+ cell counts eventually leading to development of opportunistic infections. Moreover, archived resistant virus can typically still be detected in peripheral blood lymphocytes once therapy is reinstituted. These approach seems to be justified exclusively in case of unmanageable toxicity to antiretroviral agents.
Finally, treatment discontinuation has also been proposed as a strategy for individuals who on appropriate antiretroviral regimens have achieved CD4+ cell counts above and plasma HIV RNA levels below those currently recommended for instituting therapy. There are no long-term studies assessing the validity of this approach. One report suggests that individuals in whom this is attempted return to the CD4+ cell count and HIV RNA setpoints they had before therapy was instituted at a median time of 24 weeks with more rapid decline in those with a low CD4+ cell count nadir. Thus, until more data are available, the recommendation is that treatment discontinuation should not be recommended. Definitely should not be recommended for individuals who prior to therapy, were symptomatic, had low CD4+ cell counts or high plasma HIV RNA levels or who had been receiving suboptimal therapies in the past.
The best sequencing for drug discontinuation has not been defined, particularly when using regimens containing drugs with widely differing half-lives. In this case stopping simultaneously all drugs may expose the patient to monotherapies eventually leading to selection of mutant strains. Once STI is attempted, patients must be monitored closely for symptoms, CD4+ cell decline, viral rebound, and the emergence of drug resistance virus. No information is available on the optimal time after initiation of aggressive therapy to attempt STI, or if and when to restart treatment once STI has been attempted. Given the paucity of available data and the potential risk, STIs (as differentiated from unplanned treatment interruptions associated with toxicity) cannot be recommended for current clinical practice, and should exclusively be attempted in the context of cohort studies of clinical trials.
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