SMART
STUDY Strategies
for Management
of Anti-Retroviral
Therapies
In
an effort to reduce the side effects, inconvenience, and cost of antiretroviral
therapy, researchers have explored structure
treatment interruption (STI), in which patients stop therapy periodically
either according to a fixed schedule or based on CD4 cell count. But this strategy
has been shown to be risky in several studies, including the large Strategies
for Management of Anti-Retroviral Therapy (SMART) trial.
SMART
included 5472 mostly treatment-experienced participants with a CD4
cell count above 350 cells/mm3 at baseline. Most (73%) were men, 29% were
black, the median age was 43 years, and the median CD4 count was 597 cells/mm3.
Subjects
were randomly assigned to 2 treatment strategy arms. Patients in the "drug
conservation" (treatment interruption) arm stayed off antiretroviral therapy
when their CD4 count was above 350 cells/mm3 and resumed when it fell back to
250 cells/mm3. Participants in the "viral suppression" (continuous therapy)
arm remained on HAART throughout
the study.
As
previously reported, the study was halted in January 2006 after it became
apparent that participants in the treatment interruption arm had higher rates
of morbidity and mortality than those receiving continuous therapy. Not only were
patients in the treatment interruption arm more likely to experience AIDS-related
opportunistic illnesses or death due to any cause, they also had unexpectedly
higher rates of serious non-opportunistic heart, liver, and kidney events.
At
the 15th Conference on Retroviruses and Opportunistic Infections
this week in Boston, Wafaa El-Sadr reported final results from SMART, looking
at outcomes among patients in the treatment interruption arm after they resumed
therapy -- as all were encouraged to do based on the interim results.
Hazard
ratios (HR) for major clinical outcomes were estimated using Cox models for 2
time periods: from randomization through January 11, 2006 (when the trial was
halted) and from January 11, 2006 through July 11, 2007 (when study follow-up
was completed).
Results
•
At the time of study modification, 36% in
the treatment interruption arm were currently on treatment, compared with 94%
in the continuous therapy arm.
•
35% and 82%, respectively, had HIV RNA <
400 copies/mL.
•
Median CD4 counts at the time of modification
were 425 and 625 cells/mm3, respectively.
•
Before January 2006, patients in the treatment
interruption arm spent 34% of follow-up time on antiretroviral therapy, compared
with 94% in the continuous therapy arm.
•
After January 2006, patients in the treatment
interruption arm spent 71% of follow-up time on therapy, compared with 91% in
the continuous therapy arm.
•
At study completion, 83% of patients in the
interruption arm and 95% in the continuous arm were on treatment.
•
The percentage of follow-up time spent with
a CD4 cell count < 350 cells/mm3 decreased from 31% before January 2006 to
23% after January 2006 in the treatment interruption arm, and from 8% to 7%, respectively,
in the continuous therapy arm.
•
Before January 2006, rates of opportunistic
disease or death, death due to any cause, and a composite outcome of serious cardiovascular,
kidney, and liver events were significantly greater in the treatment interruption
arm:
•
Opportunistic disease or death: 172 events;
3.4 vs 1.4 per 100 person-years (PY) in the treatment interruption and continuous
therapy arms, respectivley; HR 2.5.
•
Death from any cause: 85 events; 1.5 vs 0.8
per 100 PY; HR 1.8;
•
Cardiovascular, kidney, and liver events:
104 events; 1.8 vs 1.1 per 100 PY; HR 1.7.
•
After January 2006, rates for all 3 outcomes
declined in the treatment interruption arm, but remained stable in the continuous
therapy arm:
•
Opportunistic disease or death: 131 events;
2.1 vs 1.4 per 100 PY; HR 1.4; •
Death from any cause: 82 events; 1.3 vs 0.9
per 100 PY; HR 1.4; •
Cardiovascular, kidney, and liver events:
76 events; 1.1 vs 0.9 per 100 PY; HR 1.1.
•
Patients who experienced a non-fatal opportunistic
disease or a serious cardiovascular, kidney, or liver event before January 2006
(113 in the treatment interruption arm, 50 in the continuous therapy arm) remained
at a 5.8-fold increased risk of death after study modification (P < 0.0001).
•
Benefits of treatment re-initiation were most
pronounced among patients who were on therapy for 85% of the total time after
study modification.
Conclusion
Based
on these results, the SMART investigators stated, "Following the recommendation
to re-initiate antiretroviral therapy for patients in the drug conservation [treatment
interruption] group, risk of opportunistic disease or death was significantly
reduced." Though significant, this decrease was "less than complete"
however; "[L]ess than full reversal of risk for drug conservation compared
to viral suppression [continuous therapy] patients for opportunistic disease or
death was noted and non-significant reductions for other major outcomes,"
they said.
They suggested that, "This may be attributed, in part,
to some patients not initiating antiretroviral therapy, lower CD4 counts for drug
conservation patients post-January 2006, and long-term sequellae of morbidity
pre-January 2006."
A notable observation was that there was a delay
in CD4 cell count recovery after resuming therapy in the treatment interruption
arm, even though viral load declined rather rapidly - a finding that may have
contributed to the "excess residual risk."
"These findings
reinforce our recommendation not to interrupt antiretroviral therapy using the
CD4-guided strategy evaluated in SMART and may have implications for other antiretroviral
therapy interruption strategies," the investigator concluded. "Antiretroviral
therapy interruption is associated with long-term consequence beyond the period
of treatment interruption."
Structured treatment interruption has
"lasting adverse effects," Dr. El-Sadr said at a February 3 press conference.
Added to previous results from SMART and other studies, the latest data add to
the evidence that "continuous therapy is the way to go."
2/5/08
Reference W
El-Sadr and others (SMART Study Group). Re-initiation of ART in the CD4-guided
ART Interruption Group in the SMART Study Lowers Risk of Opportunistic Disease
or Death. CROI 2008. Boston, MA. February 3-6, 2008. Abstract 36.
Harms
of Treatment Interruption Lessened, but Not Fully Reversed, after Restarting HAART:
SMART Study
