A NRTI-sparing regimen of maraviroc (Celsentri or Selzentry) plus ritonavir-boosted atazanavir (Reyataz) produced good virological suppression and was generally well
tolerated through 96 weeks, according to a study presented Tuesday at the 19th International AIDS Conference (AIDS 2012) in Washington DC.
Standard combination antiretroviral regimens consisting
of two nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs), plus a
third drug from another class, are effective at suppressing HIV, but can cause side-effects
including mitochondrial toxicity. This has led researchers to explore NRTI-sparing
regimens containing two
from other classes.
Anthony Mills reported the latest findings from study A4001078, an exploratory pilot
study evaluating a once-daily, NRTI-sparing, dual regimen containing
the CCR5 blocker maraviroc plus atazanavir/ritonavir for previously untreated
This Phase IIb open-label
trial included 121 treatment-naive participants with CCR5-tropic HIV (virus
that uses the most common co-receptor to enter human cells).
About 90% were
men, three-quarters were white and the median CD4 T-cell count was
approximately 350 cells/mm3. At study entry they had no evidence of
resistance to study drugs.
were randomly assigned to receive either 150mg once-daily maraviroc or
coformulated tenofovir/emtricitabine (Truvada),
both with 300mg atazanavir boosted with 100mg ritonavir.
primary analysis was done at 48 weeks, and the trial was extended to 96 weeks. It
was not powered to show statistically significant differences between the
treatment regimens, meaning observed differences in this small study might be
due to chance.
At 96 weeks, 67.8%
of maraviroc recipients and 82.0% of tenofovir/emtricitabine recipients
suppressed HIV RNA below 50 copies/mL at 96 weeks (p-value not calculated).
Using a less sensitive test, 78.0% and 83.6%, respectively, had viral load
below 400 copies/mL.
Dr Mills noted
that most participants with HIV RNA above 50 copies/mL had transient low-level viral load that fell below 400 copies/mL. People
with viraemia at 96 weeks typically also had detectable HIV RNA at some time point earlier in the follow-up
period, often due to suboptimal adherence.
taking maraviroc and two taking tenofovir/emtricitabine experienced protocol-defined
treatment failure (either failure to achieve viral suppression or confirmed
rebound after suppression).
Median CD4 cell increases were similar in the maraviroc and tenofovir/emtricitabine arms,
at 264 vs 240 cells/mm3, respectively. Earlier studies suggested
maraviroc appeared to produce larger CD4 cell gains soon after starting
treatment, but here increases were similar by 96 weeks.
side-effects, there were more
serious adverse events (22% vs 18%, respectively) and study discontinuations
due to adverse events (two people vs none) in the maraviroc arm than in thetenofovir/emtricitabine arm.
maraviroc group was more likely (17 vs 10%) to develop jaundice due to
elevated bilirubin, a known side-effect of atazanavir. Mills suggested this may
happen because a drug-drug interaction between tenofovir and atazanavir leads
to lower atazanavir concentrations that are less likely to raise bilirubin.
maraviroc showed less decrease in creatinine clearance, an indicator of impaired
kidney function (5.5 vs 18.0 mL/min, respectively). Tenofovir is known to cause
kidney problems in a small proportion of susceptible individuals.
An ad hoc analysis showed that participants
receiving the maraviroc regimen appeared to have more normal levels of bone
formation markers, consistent with previous reports showing that tenofovir is
associated with bone loss. However, bone analysis was not done at baseline in
the study, so it was not possible to compare changes over time.
Among the seven
participants in the maraviroc arm and four in the tenofovir/emtricitabine arm
who underwent viral genetic analysis, none had evidence of genotypic or
phenotypic drug resistance or changes in HIV tropism (switching to use the
CXCR4 co-receptor instead of CCR5).
research suggested maraviroc might have a beneficial effect on inflammation. In
this study, participants taking maraviroc showed a larger reduction in immune
activation on CD4 cells at 48 weeks, but the clinical significance of this
findings is unknown.
"Durable virologic activity of [150mg
once-daily maraviroc] plus atazanavir/ritonavir was demonstrated through 96
weeks, with no differences between the arms in the rates of virologic failure,
no resistance or change in tropism seen, and with most of the treatment
difference due to low-level transient viraemia," the researchers
noted that even people with viral loads up to 400 copies/mL did not develop
resistance, suggesting that it may not be necessary to keep HIV RNA below 50
copies/mL to prevent emergence of resistance mutations.
recommended that the observed differences in immune activation and bone markers
between the two regimens require further investigation in larger and longer
A Phase III trial (study
A4001095) is now underway testing maraviroc with a different protease
inhibitor, darunavir (Prezista), in
about 800 people, which will be powered to allow comparison between regimens.