HAART interruption may control HIV long-term
Large amount of HIV produced after infection
The interruption of highly active antiretroviral therapy (HAART) may be a means of long-term control of HIV in AIDS patients, said Anthony S. Fauci, MD, at the XIII International AIDS Conference in Durban, South Africa.
"Unfortunately, prolonged courses of continuous HAART are not an option for most HIV-infected individuals because of the short- and long-term problems associated with a variety of regimens," said Fauci, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health in Bethesda, MD. "With current drugs, it is almost certainly not feasible to have people on therapy for an indefinite period of time. Therefore, new approaches have to be undertaken."
Studies prompt review of long-term therapy
The re-thinking of the philosophy of therapeutic approaches to long-term treatment of HIV is based on a number of studies, including one by the National Institute of Allergy and Infectious Diseases, that have found that a reservoir of HIV is established soon after primary infection.
"The reservoir consists at least in part of resting, latently infected CD4+ T-cells distributed in various lymphoid organs throughout the body. The presence of latently infected CD4+ T-cells is relevant to previous projections regarding the possibility of eradicating HIV infection," Fauci said.
He referred to an earlier model of viral dynamics demonstrating that a considerable proportion — 93% to 99% — of plasma virus emanated from recently infected, rapidly turning over, productively infected CD4+ T-cells. The model, developed in part by David Ho, MD, head of Aaron Diamond AIDS Research Center in New York City, had a lesser amount — 1% to 7% — of plasma virus that came from long-lived cell populations.
"An immeasurably small proportion of the plasma virus comes from latently infected CD4+ T-cells," Fauci said.
While the presence of those cells was not particularly relevant during the period of uncontrolled bursts of viremia, he said, it was relevant during the aviremic state induced by HAART in many individuals.
Studies have shown that despite what had seemed to be the adequate control of the virus by HAART, virus replication was likely ongoing and possibly contributed to the maintenance or reconstitution of the latently infected pool of resting CD4+ T-cells.
"When individuals are receiving HAART, viral spread is contained, and hence an aviremic state persists," he said. "However, when individuals are taken off HAART, within a couple of weeks, high levels of virus expression are seen in the lymphoid tissue."
Jury out on impact of repeated interruptions
Fauci said interrupting therapy had been used to determine whether HIV had been eliminated. "It was clear we had to deal seriously with the existence of a persistent pool of latently infected, resting CD4+ T-cells in HIV-infected individuals, even those who had been effectively treated with HAART."
The approach of interrupting therapy for variable periods of time is a subject of intense investigation worldwide, Fauci said. "There are several approaches to this. One is the single interruption of therapy without cycling. Another falls under the rubric of strategic or structured therapy interruptions [STIs]; one such approach resumes therapy after interruption only when plasma viremia reaches a predetermined level, while another is to discontinue and resume therapy at predetermined times to do cyclic interruptions."
Initial studies had shown that with a single discontinuation of therapy, the virus came back with a vengeance within four weeks in most patients, but only rarely within the first seven days off therapy, Fauci said. Based on that, he looked at what happened if therapy was interrupted every other week. He found that the virus did, in fact, come back after discontinuation of therapy, but in no individual did it go above several hundred copies per mm3.
"Over a seven-cycle or eight-cycle regimen, we found striking differences between individuals who had HAART interrupted every other week, compared to those who had therapy interrupted every two months," he said.
Plasma viremia rebounded in virtually all HAART-treated patients in whom therapy was interrupted, and levels of HIV-specific CD8+ T-cells also rebounded in parallel with the return of plasma viremia.
Repeated interruptions of HAART could lead to prolonged intervals before viral rebound and or lower peaks of rebound due to residual HIV specific CD8+ T-cells or other immune responses left over from previous viral-induced stimulations, he said. "This delay in rebound of plasma viremia may allow for significant periods of time off therapy."
However, he said it was doubtful whether a specific percentage of patients who originally had progressed prior to therapy would be able to have HAART discontinued for prolonged periods of time following repeated interruptions.
Fauci concluded by saying that the precise role and mechanisms of the HIV-specific immune control of HIV during repeated interruptions of therapy had not yet been delineated. He also said the long-term effect of interruptions of HAART on the emergence of resistance mutations and the ultimate clinical course of patients remained to be determined.
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