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,
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 presented 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 at
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 discussed 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
Data on nine patients receiving intermittent therapy (two
months on, one month off) was 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 presented 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
Dr. Fauci concluded: "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 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).