(Isentress) Activity Is Durable at 96 Weeks; Switch from Lopinavir/ritonavir
Results in More Viral Breakthrough but Better Lipid Profiles
At 96 weeks, the integrase inhibitor raltegravir
(Isentress) in combination with optimized background
therapy (OBT) continued to demonstrate superior antiviral
efficacy compared with OBT alone in highly treatment-experienced
patients in the BENCHMRK trials. In the SWITCHMRK trials,
however, people who switched from lopinavir/ritonavir
(Kaletra) to raltegravir were more like to experience
virological failure, though they also had improved blood
and -2 were identical double-blind Phase 3 trials evaluating the
safety and efficacy of raltegravir in people with extensively
drug-resistant HIV. BENCHMRK-1
(Merck protocol MK-0518) was conducted in Europe, Asia, Australia,
and Peru, while BENCHMRK-2
(MK-0518) was conducted in North and South America.
the 2 studies combined, 699 participants with triple-class-resistant
HIV and prior antiretroviral
therapy (ART) failure were randomly assigned to receive 400
mg twice-daily raltegravir or placebo (2:1 ratio) in combination
with OBT for 48 weeks. Most were white man and more than 90% had
a current or past AIDS diagnosis.
previously reported in the July
24, 2008 New England Journal of Medicine, raltegravir
plus OBT provided significantly better viral suppression than
placebo plus OBT at 48 weeks, with 62% in the raltegravir arms
compared with 33% in the placebo arms achieving HIV RNA < 50
copies/mL. Mean CD4 cell gains were 109 versus 45 cells/mm3, respectively.
in the January
19, 2010 advance online issue of Clinical Infectious Diseases,
the BENCHMRK Study Teams have published 96 week follow-up data
from the 2 trials.
From study weeks 16 to 48, virological failure was defined as
< 1 log10 decrease in HIV RNA levels from baseline, confirmed
> 1 log10 increase in HIV RNA from nadir (lowest-ever level),
or 2 consecutive HIV RNA measurements >400 copies/mL
after a prior result < 400 copies/mL. After week 48, it was
defined as confirmed HIV RNA level >50 copies/mL (2
consecutive measurements at least 1 week apart).
Participants who experienced virological failure at any time after
week 16 were given the choice to exit the double?blind study and
enter an open?label phase to receive raltegravir, remain in the
blinded study, or withdraw altogether; 65% of raltegravir recipients
and 29% of placebo recipients opted to stay in the double-blind
and immunological responses were consistent between the 2
BENCHMRK studies at week 96.
the combined studies, 57% of raltegravir recipients had sustained
HIV RNA < 50 copies/mL at week 96, compared with 26% of
placebo recipients (P < 0.001).
of raltegravir recipients and 62% of placebo recipients experienced
virological failure by week 96.
mean change in viral load from baseline to week 96 was significantly
greater in the raltegravir arm than in the placebo group (-1.5
vs -0.6 log10 copies/mL, respectively; P < 0.001).
mean CD4 cell increase was also larger in the raltegravir
arm (123 vs 49 cells/mm3, respectively; P < 0.001).
was a non-significant trend toward lower rates of AIDS?defining
illness and mortality in the raltegravir arms.
the 192 patients who entered the open?label phase after virological
failure, 15% of those originally randomized to receive raltegravir
and 43% originally assigned to placebo achieved HCV RNA <
testing revealed that virus from 65% of patients with treatment
failure had integrase resistance mutations
of drug-related clinical adverse events (33% in the raltegravir
arms vs 52% in the placebo arms) and grade 3-4 laboratory
abnormalities were statistically similar between the 2 groups.
kinase elevations were slightly more common in the raltegravir
arms, but were not associated with clinical muscle damage.
Based on these findings, the BENCHMRK investigators concluded,
"At week 96 (combined data), raltegravir (400 mg twice daily)
plus optimized background therapy was generally well tolerated,
with superior and durable antiretroviral and immunological efficacy,
compared with optimized background therapy alone."
"Although the BENCHMRK studies were not powered to show statistically
significant effects within subgroups, efficacy analyses by baseline
prognostic factors continued to demonstrate a consistent treatment
advantage of raltegravir over placebo, even in patients with high
baseline HIV RNA levels or low baseline CD4 cell counts,"
they elaborated in their discussion.
"Raltegravir also demonstrated superior efficacy, compared
with placebo, in patients who received OBT and had genotypic and/or
phenotypic sensitivity scores of 0 -- generally regarded as the
most challenging treatment scenario," they continued. "Among
patients who received new, active antiretroviral therapy in their
OBT, up to 79% of raltegravir recipients had undetectable HIV
RNA levels at week 96."
Overall, they summarized, "these data demonstrate that raltegravir
has a potent antiviral effect in most patients with few or no
remaining treatment options and has even greater efficacy when
used in combination with other active antiretroviral agents."
BENCHMRK showed that raltegravir has superior efficacy compared
with placebo in heavily treatment-experienced patients, a more
challenging -- and clinically relevant -- comparison is whether
it works as well as the standard of care or best currently approved
people who are doing well on their current regimen may wish to
switch to something new, for example to improve convenience or
reduce side effects. The SWITCHMRK
studies looked at maintenance of virological suppression among
patients who substituted raltegravir for lopinavir/ritonavir,
which can cause blood lipid abnormalities associated with increased
cardiovascular risk. (Darunavir
[Prezista] was not yet widely used when SWITCHMRK was designed.)
1 and 2 were again identical double-blind Phase 3 trials. SWITCHMRK
1 (Merck protocol 032) included participants in North America,
Europe, and Australia, while SWITCHMRK 2 (protocol 033) included
participants from these same industrialized areas as well as Latin
America, Africa, and Southeast Asia. About 80% of participants
in both studies were men; about 17% in SWITCHMRK 1 and about 52%
in SWITCHMRK 2 were of non-white race/ethnicity.
participants had maintained viral suppression < 50 copies/mL
for at least 3 months on a stable ART regimen containing lopinavir/ritonavir.
Overall, they had mild immune deficiency, with a median CD4 count
of about 475 cells.mm3. Past treatment failures were permitted.
total of 707 participants were randomly assigned (1:1 ratio) to
either remain on the same regimen or to replace 400/100 mg twice-daily
lopinavir/ritonavir with 400 mg twice-daily raltegravir; 702 patients
received at least 1 dose and were include in the combined analysis.
Participants stayed on the same background therapy, which included
at least 2 nucleoside/nucleotide reverse transcriptase inhibitors
(NRTIs) (i.e., the background regimen was not optimized at the
time of randomization).
previously reported at the 2009 Conference on Retroviruses
and Opportunistic Infections, the trials were halted at 24 weeks
after data showed that raltegravir did not demonstrate non-inferiority
compared with lopinavir/ritonavir. Complete study findings have
now been published in the January
13, 2010 advance online issue of The Lancet.
week 24 in a non-completer=failure analysis, 84% of patients
in the raltegravir arms maintained HIV RNA < 50 copies/mL,
compared with 91% in the lopinavir/ritonavir arms.
treatment difference of -6.2% did not meet the pre-set non-inferiority
threshold of -12%.
in an unplanned post hoc analysis that excluded patients with
a history of treatment failure (about one-third in both treatment
groups), efficacy was similar in raltegravir and lopinavir/ritonavir
arms (89% vs 90%).
in lipid levels from baseline to week 12 were significantly
more favorable in the raltegravir arms than in the lopinavir/ritonavir
arms (P < 0.0001):
cholesterol: -12.6% vs +1.0%, respectively;
("bad") cholesterol: -15.0% vs +2.6%, respectively;
-42.2% vs +6.2%, respectively.
and laboratory adverse events occurred with statistically
similar frequencies in the raltegravir and lopinavir/ritonavir
only moderate-to-severe drug-related adverse event reported
by 1% of either treatment group was diarrhea (no raltegravir
recipients vs 3% of lopinavir/ritonavir recipients).
results led the SWITCHMRK investigators to conclude, "Although
switching to raltegravir was associated with greater reductions
in serum lipid concentrations than was continuation of lopinavir-ritonavir,
efficacy results did not establish non-inferiority of raltegravir
"Our finding that substitution of lopinavir/ritonavir for
raltegravir did not achieve non-inferiority compared with continuation
of lopinavir/ritonavir underscores the complex considerations
involved in providing the best possible treatment regimens for
individual patients," they continued in their discussion.
"In practice, clinicians need to gather all available background
information, including past resistance tests and treatment outcomes,
when contemplating the potential risks and benefits of modifying
a suppressive antiretroviral regimen."
an accompanying editorial, J. Michael Kirby from the Medical University
of South Carolina noted that SWITCHMRK offers "a reminder
that whenever possible, to assure sustained dependable activity,
even our most promising antiretroviral agents should be used in
combination with two or more fully active drugs."
BENCHMRK: State University of New York at Stony Brook; Aaron
Diamond Research Center, Rockefeller University, New York, NY;
Merck Research Laboratories, North Wales, PA; University of North
Carolina, Chapel Hill; Georgetown University Medical Center, Washington,
DC; Emory University School of Medicine, Atlanta, GA; National
Centre in HIV Epidemiology and Clinical Research, University of
New South Wales, Sydney, Australia; Hospital Clinic-IDIBAPS, University
of Barcelona; Hospital Germans Trias i Pujol, Fundación
Irsicaixa, UAB, Barcelona, Spain; Department of Medicine I, University
of Bonn, Bonn, Germany; Universidade Federal do Rio de Janeiro,
Rio de Janeiro, Brazil; Hospital Pitié Salpêtrière,
Université Pierre et Marie Curie; Hospital Bichat-Claude
Bernard, Paris, France; University of Toronto, Ontario, Canada;
San Raffaele Scientific Institute, Milan, Italy.
SWITCHMRK: University of North Carolina School of Medicine,
Chapel Hill, NC; Denver Infectious Disease Consultants, Denver,
CO; National Centre in HIV Epidemiology and Clinical Research,
University of New South Wales, Sydney, NSW, Australia; Garrett
Anderson Ward Royal Free Hospital, London, UK; Orlando Immunology
Center, Orlando, FL; Antiguo Hospital Civil de Guadalajara, Guadalajara,
Mexico; AIDS Research Initiative, Darlinghurst, NSW, Australia;
Projeto Praça Onze, Universidade Federal do Rio de Janeiro,
Rio de Janeiro, Brazil; Department of Internal Medicine, University
of Cologne, Cologne, Germany; Northstar Medical Center, University
of Illinois at Chicago, Chicago, IL; Georgetown University Medical
Center, Washington, DC; Merck Research Laboratories, North Wales,
Steigbigel, DA Cooper, H Teppler, and others. Long-term efficacy
and safety of raltegravir combined with optimized background therapy
in treatment-experienced patients with drug-resistant HIV infection:
week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clinical
Infectious Diseases (Abstract).
January 19, 2010 (Epub ahead of print).
Eron, B Young, DA Cooper, and others. Switch to a raltegravir-based
regimen versus continuation of a lopinavir-ritonavir-based regimen
in stable HIV-infected patients with suppressed viraemia (SWITCHMRK
1 and 2): two multicentre, double-blind, randomised controlled
trials. The Lancet (Abstract).
January 13, 2010 (Epub ahead of print).
JM Kilby. Switching HIV therapies: competing host and viral factors
(Editorial comment). The Lancet. January 13, 2010 (Epub
ahead of print).