An NRTI-sparing dual antiretroviral regimen containing maraviroc
(Celsentri) plus ritonavir-boosted
darunavir (Prezista) was found to be
less effective than a standard combination with tenofovir/emtricitabine (the
drugs in Truvada), according to
findings from the MODERN study presented this week at the 20th International
AIDS Conference (AIDS 2014) in Melbourne.
Combination antiretroviral therapy (ART)
typically consists of two nucleoside/nucleotide reverse transcriptase
inhibitors (NRTIs) plus a drug from another class such as an HIV protease
inhibitor, a non-nucleoside reverse transcriptase inhibitor, an entry inhibitor or
an integrase inhibitor. NRTIs are generally an effective 'backbone' for ART, but
their mechanism of action interferes with human cells as well as viruses, and
they can cause a variety of side-effects ranging from mitochondrial toxicity to
bone loss and impaired kidney function.
Jürgen Stellbrink, Eric Le Fevre and fellow investigators with the international
MODERN trial (study A4001095) evaluated the safety and
efficacy of a first-line regimen containing the CCR5 antagonist maraviroc plus
the boosted protease inhibitor darunavir – without NRTIs – for initial antiretroviral
Maraviroc was selected as a second agent in this NRTI-sparing
regimen because of the low risk of resistance and the preservation of future
treatment options. Maraviroc is well-tolerated and has good penetration in the
genital tract, ensuring that the regimen should effectively reduce the risk of sexual transmission.
This double-blind phase 3 study enrolled more than 1400
previously untreated adults in Europe and North America. Most (just over 90%) were
men, about 80% were white and the median age was 36 years. The median CD4 cell count was approximately 350 cells/mm3, one in five had high
baseline viral load (HIV RNA >100,000
copies/ml), and they did not have known resistance to study drugs at
Participants were first tested with one of two assays to
determine whether they had CCR5-tropic HIV, or virus that uses the CCR5 (rather
than CXCR4) co-receptor to enter cells. Because it blocks this receptor,
maraviroc only works against CCR5-using virus. This first part of the study
compared the Siemens genotype assay versus the
Monogram BioSciences Enhanced Sensitivity Trofile Assay for their ability to
identify CCR5-tropic HIV.
The 797 participants who were found to have susceptible
virus were then randomly assigned (1:1) to receive either 150mg maraviroc or
co-formulated tenofovir/emtricitabine, both once daily in combination with
Treatment lasted for 96 weeks and the primary endpoint was the proportion of participants
with undetectable viral load (HIV RNA <50 copies/ml) at 48 weeks according
to the FDA 'snapshot' analysis.
At 48 weeks, 77% of participants in the
maraviroc arm achieved undetectable viral load, compared with 87% in the
tenofovir/emtricitabine arm. Results were similar among people with low
pre-treatment viral load (80 vs 89%, respectively), but
maraviroc did not perform as well among people with high viral load (65 vs
80%, respectively). CD4 cell gains
were also similar in both arms, at about 195 cells/mm3.
The proportion of people who achieved
viral suppression did not differ significantly based on which test was used to
determine viral tropism (81% with the genotype test and 74% with the Trofile assay).
Protocol-defined treatment failure was more
common in the maraviroc compared to the tenofovir/emtricitabine arm (10.1 vs
3.2%, respectively) and more people taking maraviroc stopped early due to lack
of efficacy (8.3 vs 2.0%). Most participants who experienced treatment failure
had low viral load <400 copies/ml.
Both regimens were generally safe and well-tolerated. Serious adverse events and laboratory abnormalities were similar in
the two treatment arms, and similar proportions discontinued treatment due to
adverse events (4.8% with maraviroc vs 4.5% with tenofovir/emtricitabine). The
most common events were diarrhoea, upper respiratory inflammation, rash, nausea
The difference of -9.5 in the primary
endpoint did not meet the -10% criteria for non-inferiority, meaning maraviroc
did not work as well tenofovir/emtricitabine. The trial was therefore stopped
early due to lack of efficacy.
maraviroc in a two-drug regimen "demonstrated statistically lower rates of
viral suppression" in treatment-naive participants when compared to a standard
three-drug regimen of tenofovir/emtricitabine
plus darunavir/ritonavir, the researchers concluded. "There was no treatment-emergent resistance in either arm. There was
comparable safety and no unexpected safety findings."
NRTI-sparing regimen appears less effective than a
NRTI-containing regimen for people starting treatment for the first time –
especially those with high viral load – it may still be an option for people
who wish to switch regimens after achieving stable viral suppression. Maraviroc
plus a boosted protease inhibitor is now under study in the ongoing MARCH