Februray 19, 2001
Dr. Anthony Fauci discussed issues of HIV control over the long term and the role of HIV reservoirs of infection in this effort.
He reviewed the mathematical models of HIV eradication proposed following the introduction of protease inhibitor-based therapies. These models, cause for much optimism following the Vancouver conference of 1996, have been based on two assumptions which have since been proven false. The first assumption is that there are no reservoirs of virus shielded from antiviral therapy or from the body's immune defenses. Indeed, several different body compartments that serve as havens, where the virus is able to evade the antiviral therapy as well as the body's immune defenses, have been documented time and again in recent years, and pose a tremendous barrier to the eradication of HIV. Reservoirs are established early in acute infection, and for the entire course of infection pose a formidable barrier to viral eradication by their very nature. The second assumption is that HAART completely blocks HIV replication, and this too has also been proven false. Individuals with consistently undetectable HIV RNA over three and three and a half years have been shown in studies done at the National Institutes of Health to harbor replicating virus in resting cells. In related studies, interleukin-2 was given intermittently to patients in an effort to stimulate these resting cells into releasing their virus into the hostile environment of the ART-laden bloodstream. Although theoretically attractive, study results have been disappointing despite promising early findings.
It is against this background that the more realistic concept of long-term HIV control was born, and strategies to achieve this devised. As it becomes increasingly clear that prolonged courses of HAART are probably not options for most patients, this effort has grown in acceptance and popularity. Long-term control may be achieved by enhancing HIV-specific immunity through vaccination, by stimulating the immune response globally with interleukin-2 or cytokines, or through structured treatment interruptions.
Structured treatment interruptions (STIs) are currently used in specific settings:
New approaches involve Structured Intermittent Treatment (SIT), with interruption of therapy at predetermined times instead of at a predetermined level of viremia as with STI. Long cycles of SIT involve cycles of two months on therapy followed by one month off, while short-cycle SIT involves one-week cycles on and off therapy.
In a trial on long-cycle SIT, results were disappointing. Of 24 subjects on SIT, all were shown to have viral load rebound off HAART, with return to undetectable levels with reinstitution of therapy. Longer term RNA trends were mixed. Theoretical risks of decreased viral susceptibility to ART and increased risk of transmission raise the question of the practical utility of long-cycle SIT.
To date, data on short-cycle SIT are more promising. In ten subjects with CD4 >300 and RNA <50 on stavudine, lamivudine, indinavir, and ritonavir therapy, now 48 weeks into the trial, no viral blips were noted except in two subjects who stayed off therapy for more than the planned seven days. There were no adverse effects on CD4 counts, no genotypic or phenotypic resistance, no change in proviral DNA, no change in replication-competent virus, and no change in lymph node biopsies. Although long-term clinical effects remain to be determined, short-cycle SIT is a promising strategy for achieving virologic control.
Asked whether cycling affected compliance, Dr. Fauci replied that although the numbers of subjects in SIT studies are too small to support any such conclusions to date, his own impression was of improved adherence.
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