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National Institute of Allergy and
Infectious Diseases (NIAID)
http://www.niaid.nih.gov

FOR IMMEDIATE RELEASE
Tuesday, July 11, 2000
3:00 a.m. Eastern Time

Media Contact:
Greg Folkers
(301) 402-1663

niaidnews@niaid.nih.gov

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Fauci Presents New Data on Structured Intermittent Therapy at XIIIth World AIDS Conference in Durban, South Africa

For some HIV-infected patients whose plasma levels of virus have fallen to undetectable levels while on highly active antiretroviral therapy (HAART), it may prove feasible to move from a continuous HAART regimen to intermittent therapy in which an individual discontinues, then resumes HAART in a pre-planned, cyclic fashion, according to preliminary results from two studies at the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, USA.

This cyclic approach to treatment — known as "structured intermittent therapy" — might, with further refinement, enable an HIV-infected person to have regular HAART-free periods while maintaining a minimal viral load and adequate levels of CD4+ T cells. CD4+ T cells are the crucial immune system cells typically depleted during HIV disease.

"Structured intermittent therapy may prove to be an important treatment option, particularly in settings where continuous HAART is financially untenable," says Anthony S. Fauci, M.D., director of NIAID and chief of the NIAID Laboratory of Immunoregulation (LIR). He and his team speculate that this strategy could potentially reduce total time on HAART in any given period by as much as 30 to 50 percent, thereby reducing HAART-related toxicities and costs while improving patients' adherence to therapy. They stress, however, that many questions remain to be answered before structured intermittent therapy can be recommended to individual patients who are not enrolled in closely monitored clinical trials.

Dr. Fauci will present his laboratory's latest findings on structured intermittent therapy -- and the scientific rationale for this approach — at the XIIIth International AIDS Conference in Durban, South Africa on Tuesday, July 11, at 9:00 a.m. (3:00 a.m. Eastern Time). LIR staff clinician Mark Dybul, M.D., will present additional data on Thursday, July 13, at 3:45 p.m. (9:45 a.m. Eastern Time).

Most researchers agree that HIV is unlikely to be eradicated with currently available drugs. HIV-infected individuals face the prospect of many years — or a lifetime — of continuous highly active antiretroviral therapy.

"This is not a reasonable scenario for most individuals because continuous HAART, although effective in many patients, can be toxic, difficult to adhere to, and, in many settings, prohibitive in cost," says Dr. Fauci.

Therefore, researchers around the world are pursuing approaches toward the long-term control of HIV infection that may reduce a patient's reliance on HAART. Examples of such strategies include enhancing HIV-specific immunity by vaccinating with HIV antigens, broadly expanding the immune response with immune-stimulating molecules such as interleukin-2, and strategically interrupting therapy. A number of approaches to therapy interruptions are being examined: for example, one strategy resumes therapy after interruption only when virus levels in a patient's blood rise to pre-determined levels. The NIAID researchers are assessing a somewhat different approach, in which patients discontinue and resume therapy at pre-determined times.

In Durban, Dr. Fauci will discuss data from two ongoing NIAID studies enrolling HIV-infected patients on long-term HAART whose plasma viral loads had been driven to undetectable levels (less than 50 copies per milliliter [mL] of blood).

In the first study, which will ultimately enroll a total of 70 HIV-infected individuals, 31 patients have been randomly assigned to receive either continuous HAART, or repeated cycles of eight weeks on HAART followed by four weeks off HAART. The patients' lowest lifetime CD4+ T-cell counts range from 22 to 693 cells per cubic millimeter (mm3) (mean, 366). Upon entry into the NIAID study (following successful treatment with HAART), the patients all had CD4+ T-cell counts greater than 300 cells/mm3, with a mean of 740 cells/mm3.

Data on nine patients receiving intermittent therapy (two months on, one month off) will be presented. Among these individuals, HIV levels rebounded to varying degrees when HAART was discontinued. Scientists have suggested that rebounding virus comes from hiding places in the body known as viral reservoirs, which are established soon after a person is infected with HIV. These hiding places include certain HIV-infected lymphocytes known as resting CD4+ T cells, where low levels of viral replication likely persist. Dr. Fauci and his colleagues have shown that normal stimulatory molecules of the immune system may induce HIV replication and viral rebound when HAART is no longer present to keep the virus in check.

Upon resuming therapy, HIV levels in the nine patients again dropped to undetectable levels. In four of nine patients, peak levels of plasma virus following discontinuation of therapy fell by a mean of 1.2 log from the first cycle off HAART to the second cycle off HAART. In four patients, there was no significant change from cycle one to cycle two; in one patient, a 1.2 log increase from cycle one to cycle two was observed.

Previous studies have shown that when a patient's viral load becomes undetectable on long-term HAART, levels of CD8+ T cells, thought to be necessary for the long-term immunologic control of HIV, fall dramatically. If HAART is interrupted, rebounding virus induces a transient increase in HIV-specific CD8+ T cells, but when HAART is reinstated and the virus is again driven down to an undetectable level, CD8+ T-cell levels also again fall.

"Our current data suggest that repeated interruptions of HAART may lead to prolonged intervals before viral rebound and /or lower peaks of rebound, possibly due to residual HIV-specific CD8+ T cells or other immune responses left over from previous viral-induced stimulations," says Dr. Fauci. "The delay in rebound of plasma viremia may allow for significant periods of time-off therapy." In Durban, Dr. Fauci also will present data from a smaller study in which patients receive HAART in short, repeated cycles of seven days followed by seven days off HAART.

"Our previous studies of a single discontinuation of therapy taught us that the virus comes back with a vengeance within four weeks in most patients, but only rarely within the first seven days off therapy," he explains. "Therefore, we looked at what would happen if we interrupted therapy every other week."

Among five patients receiving HAART on a seven-day-on, seven-day-off schedule, small blips of rebounding virus were observed when patients came off therapy, but only infrequently and at levels that have not exceeded several hundred copies. In this study, patients' lowest lifetime CD4+ T-cell counts ranged from 262 to 510 cells/mm3 (mean, 350); at study entry, the patients had CD4+ T-cell counts that ranged from 428 to 1331 (mean, 940). Encouraging results among the patients receiving the seven-day-on, seven-day-off HAART regimen have prompted Dr. Fauci, Dr. Dybul and their team to enroll more individuals in this study.

Dr. Fauci concludes: "Our preliminary data suggest that structured intermittent therapy may decrease the total time that patients receive anti-HIV medications, thereby reducing toxicities and cost, and enhancing adherence. I would stress, however, that many questions remain to be answered, including whether drug resistance will develop, and what the ultimate clinical course of patients receiving structured intermittent therapy will be.

"It is essential that these and other issues related to treatment interruptions be addressed before intermittent HAART can be recommended to an individual patient outside the setting of a controlled clinical trial," he adds.


NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at www.niaid.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Last Updated July 11, 2000