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). Information regarding the conference is available
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
"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
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
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,"
NIAID is a component of the National Institutes of Health (NIH). NIAID
conducts and supports research to prevent, diagnose and treat illnesses such
as HIV disease and other sexually transmitted diseases, tuberculosis,
malaria, asthma and allergies. NIH is an agency of the U.S. Department of
Health and Human Services (DHHS).
Press releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.
The National Institute of Allergy and Infectious Diseases is a component of
the National Institutes of Health, U.S. Department of Health and Human