Jose Gatell, from Hospital Clinic Barcelona,
and colleagues evaluated the safety and effectiveness of raltegravir amongst
282 study participants on a stable antiretroviral regimen containing a protease
inhibitor boosted with ritonavir (Norvir), who had HIV RNA suppressed to
less than 50 copies/ml. Patients had to have had an undetectable viral load for at
least six months, but the median duration was much longer, closer to six years.
Participants were randomly assigned either
to continue on their boosted protease inhibitor regimen or to switch to raltegravir,
whilst staying on the same NRTI 'backbone'. The most common protease inhibitors
at enrolment were lopinavir/ritonavir (Kaletra) and atazanavir (Reyataz),
the latter of which causes fewer blood lipid abnormalities than other drugs in
About three-quarters of participants were men
and the median age was about 45 years. The current median CD4 T-cell count was
high, at around 500 cells/mm3, but about one-third of patients had
received an AIDS diagnosis. Nearly 40% had a history of prior treatment
The researchers determined how many people
maintained undetectable virus 48 weeks after switching to raltegravir, using an
intent-to-treat analysis that counted participants who dropped out as treatment
The study also looked at changes in levels of
cholesterol and triglycerides. Protease inhibitors as a class are associated
with changes in blood lipid profiles
– elevated total and LDL 'bad'
cholesterol plus decreased HDL 'good' cholesterol
– that have been
linked to increased cardiovascular risk.
The earlier SWITCHMRK studies
found that, while people who switched from a protease inhibitor to raltegravir
saw improved lipid levels, they were more likely to experience viral rebound.
After these findings were reported, the SPIRAL Data and Safety Monitoring Board
re-evaluated the study and recommended that it continue.
At week 48, the likelihood of
remaining free of treatment failure (defined as two consecutive detectable
viral loads, disease progression or study discontinuation) was high and similar
in the two groups, 89% amongst participants who switched to raltegravir and 87%
amongst those who stayed on a protease inhibitor.
Looking at proportions of
patients free of virological rebound, the rates were even higher, 97% and 95%,
respectively. The differences between the two arms were smaller than the
pre-defined threshold, leading the researchers to conclude that raltegravir was
non-inferior to boosted protease inhibitors.
Differences were larger, in
favour of raltegravir, amongst participants with previous virological failure,
use of prior suboptimal therapy (for example, NRTI monotherapy) and
pre-existing drug-resistance mutations.
About 10% of participants
assigned to either arm discontinued treatment prematurely for reasons including
adverse events and virological failure. The types and frequencies of
side-effects were similar in both groups, including 4% in both groups with
severe adverse events.
As expected, participants who
switched to raltegravir showed improved lipid profiles. The average
triglyceride level fell by 23% in the raltegravir arm whilst rising by 5% in
the protease inhibitor continuation arm. Total and LDL cholesterol decreased
more than HDL amongst switchers, producing a more favourable total-to-LDL
Gatell noted that these blood
fat improvements could have some clinical significance since fewer raltegravir
recipients required lipid-lowering drugs.
With regard to the conflicting
SWITCHMRK findings, he explained that whilst protease inhibitors performed
about equally well in SWITCHMRK and SPIRAL, raltegravir did better in SPIRAL.
One possible explanation is that SPIRAL participants were required to have
longer minimum and medium durations of viral suppression, and longer
suppression has been linked to better outcomes.
Nevertheless, he added, response rates in SPIRAL were very good in both
arms, "among the highest ever seen in a switch study".