The Buzz: Structured Treatment
Interruption and Immune Reconstitution
by Daniel S. Berger, MD
Drug holidays, treatment
interruptions, and strategic or structured treatment interruptions:
many names, many questions but only a few answers. Structured
treatment interruptions (STI) were originally investigated
due to the hypothesis that stimulation of the immune system
would occur with intermittent exposure of the blood to virus.
Patients who maintained undetectable viral loads with treatment
were thought to have too small a quantity of virus in the
blood for the immune system to react to HIV. Immunologic improvements
would occur while interrupting treatment due to a cytotoxic
T-cell immune response to HIV. In other words, the scheduling
of treatments with regular interruptions would provide intermittent
exposure to virus and thus repeated stimulation of the immune
response (meaning the immune system would attack and keep
the virus at bay on its own without the need of antivirals).
It was theorized that possible results from these repeated
interruptions could lead to eventual discontinuation of antiviral
therapy completely. However, several structured treatment
interruption studies have failed to demonstrate evidence of
this possibility becoming a reality. While treatment of HIV-positive
patients with highly active antiretroviral therapy (HAART)
has shown to reduce HIV viral loads to below detection in
the blood, the significant degrees of immune restoration that
followed did not result in eradication of the virus.
At the 41st Interscience
Conference on Antimicrobial Agents and Chemotherapy (ICAAC)
held in December of 2001, several studies were presented and
several lessons were learned. Data from an 18-month observational
study by K. Wolfe, et al., described the outcome of 115 patients
with treatment interruptions compared to 186 individuals who
did not interrupt therapy. At the start of study, the average
CD4 T cell counts were in the 400-500 range and viral loads
were less than 50 in 52% of participants undergoing treatment
interruption, compared to 43% of the on-treatment control
group (not undergoing treatment interruptions). The average
length of the first interruption in treatment was 5.4 weeks
and interestingly 29% of the participants had more than one
interruption. As expected with an interruption of treatment,
CD4 count decreased by an average of 72 cells and viral load
increased 2.1 logs. However, cholesterol and triglycerides
decreased significantly. The significance is that not everyone
who underwent interruption had undetectble viral loads.
After 18 months of observation,
the patients undergoing treatment interrutions showed no significant
change in their CD4 count. Seventy-six percent vs. 47% changed
their antiviral regimen, but viral loads remained less than
50 in 66% vs. 73%. Of the remaining patients whose viral loads
did not end up under 50, they still had an eventual decrease
in viral RNA: -.6 log vs. -.3 log (regimen change and no change
respectively).
In another study, Dr. Anthony
Fauci from the National Institute of Allergy and Infectious
Disease presented results of 10 patients who underwent 32
cycles of seven days on and seven days off treatment (64 weeks).
These individuals were on Norvir (ritonavir) + Crixivan (indinavir)
+ Epivir (3TC) + Zerit (d4T). There was no change in plasma
(blood), cellular (within the cells), proviral HIV RNA (building
blocks of the virus) or latently infected CD4 cells. There
was no evidence of HIV resistance by either genotype nor phenotype
testing, and lymph node biopsies done on some of the participants
showed no negative changes. Also, there was no change in patients’
CD4 T cell counts nor CD4 percentages. However, cholesterol
and triglycerides improved steadily during the course of the
study, which is ongoing.
Results from STI studies
presented at the 13th International AIDS Conference noted
the development of resistance in a few patients, but more
notably when non-nucleosides were included in their regimen.
This can be explained by the fact that non-nukes, especially
Sustiva (efavirenz), have long “half-lives,” meaning they
remain in the blood much longer than the other antiviral agents.
Thus when interrupting treatment, unlike most other antivirals
which are cleared from the blood faster, non-nukes remain
present. Because the drug is acting against the virus alone,
the virus can more easily circumvent the effect of non-nukes
and develop resistance to this class of antivirals. Thus we
can infer that traditional treatment interruptions should
be avoided for those patients on the non-nucleoside class
as a backbone for their antiviral regimen.
Interruption situations are
found to be useful for patients who have been highly exposed
to antiviral agents and resulting multi-drug resistance. These
individuals may have little viable options for treatment.
Wild type virus, the typical viral population present during
initial infection and susceptible to the effects of antiviral
drugs, is stronger and domineering over the presence of resistant
virus. To invoke the emergence of wild type virus, HIV drug
therapy is interrupted for several months. As wild type virus
begins to emerge and replicate it suppresses resistant strains,
thereby allowing drug treatment to become effective again.
This approach is investigative, but is increasingly getting
more attention from clinicians and researchers.
At the present time we still
do not know enough to boast of a clear understanding about
how to best structure treatment interruptions, which patients
will benefit most, and what intervals are most optimum. There
is the valid concern that patients will stop treatment on
their own with little supervision. Due to the risks of the
development of resistance and possible opportunistic complications,
an STI should not be undertaken without the guidance and care
of a trained physician.
However, several essential
facts can be abstracted from the valuable studies already
done. Firstly, interruptions probably can be performed safely
in certain patients within several parameters. Secondly, certain
and substantial numbers of patients who have taken treatment
holidays for up to a median of five months have had their
CD4 T=cells restored and viral loads decrease to undetectable
within three months of resumption of treatment (JF Braun,
et al., 41st ICAAC). Finally, most studies have shown benefits
regarding blood lipids: cholesterol and triglycerides decreased
significantly during interruption of therapy.
The fact remains that patients
can not be expected to consume fists full of pills forever.
As lives are extended, the toxicities of medications have
become rather obvious, and pill fatigue has set in. Attention
must now focus on dealing with HIV infection in the long-term.
Structured treatment interruptions need to be investigated
for the good of our patients. Perhaps as the risks of developing
lipodystrophy and metabolic abnormalities are minimized, patients
may be less likely to develop treatment fatigue and non-compliance.
Treatment interruptions can also result in large cost savings.
While STIs remain a new avenue for research and hope, it is
important to recognize that more studies are needed to examine
the many issues discussed in this article. We will continue
to explore this approach, patiently.
Daniel S. Berger, M.D.
is Medical Director for NorthStar Healthcenter and Clinical
Assistant Professor of Medicine at the University of Illinois
at Chicago. He is editor of AIDS Infosource (www.aidsinfosource.com)
and also serves as medical consultant and columnist for Positively
Aware. For further inquiries Dr. Berger can be reached
at DSBergerMD@aol.com
or (773) 296-2400.
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