An NRTI-sparing initial regimen of raltegravir (Isentress) plus boosted darunavir (Prezista) worked as well as traditional
antiretroviral therapy containing tenofovir/emtricitabine (the drugs in Truvada), according to findings from the
NEAT 001 study reported at the 21st Conference on Retroviruses and
Opportunistic Infections (CROI) this week in Boston.
treatment guidelines have historically recommended combination antiretroviral
therapy (ART) consisting of a pair of nucleoside/nucleotide reverse
transcriptase inhibitors (NRTIs) plus a third drug from a different class, such
as a non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease
inhibitor. NRTIs cause side-effects and toxicities in some patients, however,
and the advent of novel antiretroviral classes allows more flexibility to
create NRTI-free regimens.
François Raffi of University Hospital in Nantes,
presented findings from NEAT 001/ANRS 143, a randomised clinical trial
comparing two different types of first-line ART regimen.
This multicentre, open-label phase 3 study included 805 people living with HIV who had not previously taken HIV treatment, at 78 sites in 15 countries in Europe. Most (88%) were men, 82% were white, 13% were
black and the median age was 38 years. Participants were required to have a CD4 cell count of at least 500 cells/mm3 (median about 330 cells/mm3)
and no major drug-resistance mutations. Only 4% had hepatitis
Study participants were randomly assigned (1:1) to receive either 400mg
raltegravir taken twice daily or the Truvada
tenofovir/emtricitabine co-formulation taken once daily, both with 800/100mg
Participants were followed for at least 96 weeks. More than 90% of
participants in both arms of the study completed 96 weeks of treatment, and most of the
remainder were lost to follow-up.
The primary study endpoint was time to treatment failure, using a
composite measure of three virological criteria (switching therapy before week
32 due to insufficient virological response, or HIV RNA >50 copies/ml
at week 32 or at any time thereafter) and three clinical criteria (death due to
any cause, any new or recurring AIDS-defining event or any serious non-AIDS
At 96 weeks, the probability of meeting one of the specified criteria for
treatment failure was 17% for people taking raltegravir vs 14% for people taking Truvada. This difference fell
within the pre-set 9% margin, indicating that raltegravir was non-inferior to Truvada overall.
In most cases this was due to viral load >50 copies/ml at week
32 or after. In addition, there were four deaths (three in the raltegravir arm
and one in the Truvada arm), eight
AIDS-defining events (five and three, respectively) and 14 non-AIDS events
(seven in each arm).
Raltegravir was also non-inferior to Truvada
when looking only at virological failure (15 vs 12%) or at the primary
endpoint plus discontinuation of any drug in the randomised regimen (23 vs
20%). Similar proportions of patients in the raltegravir and Truvada arms achieved HIV RNA <50
copies/ml (89 vs 93%). CD4 cell gains were also equivalent (+197 vs +193 at 48
weeks, +267 vs +266 at 96 weeks).
The researchers also did a planned sub-analysis looking at the effects
of baseline viral load and CD4 cell count. Among people with high viral load (>100,000
copies/ml) at study entry, treatment failure rates were 36% with raltegravir
and 27% with Truvada. Among those
with low CD4 counts (<200 cells/mm3), failure rates were 39 vs
Raffi explained that the CD4 cell count difference was significant (p = 0.02),
meaning that raltegravir was inferior to Truvada
for people with low baseline CD4 cell counts. People with high baseline viral load
also did not do as well on raltegravir, but the difference did not reach
statistical significance (p = 0.09) and was largely attributable to patients who
had both high viral load and low CD4 count at study entry.
Among participants with virological failure who underwent genotypic
testing, 5 out of 28 people in the raltegravir arm had evidence of major
resistance mutations (mostly integrase inhibitor resistance) compared with none
in the Truvada arm.
Raltegravir and Truvada were
both generally safe and well-tolerated as part of combination ART, with similar
rates of serious adverse events (89 with raltegravir vs 75 with Truvada), grade 3-4 adverse events (2.1
vs 1.0 per 100 person-years) and adverse events leading to treatment
modification (4.2 per 100 person-years in both arms).
People taking raltegravir had somewhat larger increases in blood fat
levels, but total-to-HDL cholesterol ratios remained stable in both arms.
Looking at kidney function, creatinine clearance – measured as estimated glomerular
filtration rate or eGFR – declined in the Truvada
arm (-3.8 ml/min) while rising in the raltegravir arm (+0.9 ml/min), a
In this well-powered, open-label, randomised study,
the researchers summarised, "Overall twice-daily raltegravir was well
tolerated and had comparable efficacy to once-daily tenofovir/emtricitabine,
when co-administered with once daily darunavir/ritonavir, over 96 weeks in
first-line antiretroviral therapy."
Based on these findings, they concluded that
raltegravir plus darunavir/ritonavir "represents an alternative
option" to tenofovir/emtricitabine plus darunavir/ritonavir for first-line
therapy, particularly for people with CD4 counts above 200 cells/mm3.