dosing of the integrase inhibitor raltegravir (Isentress)
was found to be inferior to twice-daily dosing for treatment-naive
patients in the QDMRK study, even though most people receiving either
dose were able to suppress HIV to an undetectable level, researchers
reported on Wednesday at the Eighteenth Conference on Retroviruses and Opportunistic Infections (CROI),
taking place this week in Boston.
taken every 12 hours has been shown to be a potent component of
antiretroviral therapy for both treatment-experienced individuals and
those starting therapy for the first time. But twice-daily dosing
makes raltegravir less attractive than some other popular first-line
treatment options. More frequent dosing is less convenient and may
increase the likelihood of poor adherence.
Eron from the University of
North Carolina at Chapel Hill presented findings from QDMRK,
a multi-centre phase 3 clinical trial comparing two raltegravir
study enrolled 770 previously untreated participants. They were
randomly assigned to take raltegravir at doses of either 800mg
once daily or 400mg twice daily, both taken in combination with the
fixed-dose tenofovir/emtricitabine coformulation (Truvada).
characteristics were similar in the two study arms. Most participants
were men and the median age was 38 years. The mean viral load was
approximately 69,000 copies/ml and 40% had HIV RNA levels above
100,000 copies/ml. The average CD4 T-cell count was just under 300
but one-quarter had counts below 200 cells/mm3.
Participants had no documented resistance to tenofovir or
emtricitabine at baseline.
to concerns that once-daily dosing might not be as effective as
twice-daily, eight-week data from a "vanguard" group of
about 150 patients were analysed before enrolling additional
participants. A data safety monitoring committee recommended that the
trial proceed without changes after that interim review and another
at week 24.
an intent-to-treat analysis at week 48, counting participants who
dropped out before this point as treatment failures, 83.2% of
patients in the once-daily raltegravir arm achieved undetectable
viral load below 50 copies/ml, compared with 88.9% in the twice-daily
– among the highest response rates ever seen in a randomised HIV
treatment trial, Eron noted.
similar pattern was seen when looking at viral load below 400
copies/ml, with response rates of 88.5 and 93.5%, respectively. CD4
cell gains were similar in the two arms, at 210 and 196 cells/mm3.
The confidence intervals of the
5.7% estimated difference in proportions of patients with viral suppression
below 50 copies/ml failed to meet a pre-specified margin of 10% (85% confidence intervals
– 10.7 to 0.83),
leading the researchers to conclude that once-daily raltegravir was
not non-inferior to twice-daily dosing. In fact, Eron explained, the
less frequent dose was actually found to be slightly inferior to the
at patient subgroups, the difference in response rates was more
pronounced amongst those with high baseline viral load above 100,000
copies/ml. In group, 74.3% receiving once-daily raltegravir and 84.2%
taking twice-daily raltegravir reached a viral load below 50
copies/ml, a difference of 9.9%. But even amongst people who started
with a lower viral load, twice-daily dosing worked better (89.1 vs
91.9%, respectively), with a difference of 2.7%.
participants experienced virological failure (defined as HIV RNA
above 50 copies/ml at week 24 or viral rebound following suppression)
in the once-daily raltegravir arm compared with twice-daily dosing
(13.9 vs 9.0%, respectively). A time-to-loss-of-virological-response
(TLOVR) analysis also favored the twice-daily schedule.
people who experienced treatment failure in the once-daily group had
evidence of resistance to either raltegravir and emtricitabine or
emtricitabine alone; no patients failing treatment in either arm
showed resistance to tenofovir.
raltegravir dosing schedules were well-tolerated. Very few people in
either arm (less than 1%) experienced severe drug-related adverse
events, and about 1% in both groups dropped out due to adverse
at raltegravir levels in the blood, once-daily dosing produced a
higher overall concentration (area under the curve) and maximum
concentration, but the minimum or trough concentration between doses
fell much lower compared with twice-daily dosing.
on these findings, the data monitoring committee recommended that the
trial be halted at 48 weeks.
once-daily and twice-daily raltegravir in combination with
[tenofovir/emtricitabine] achieved high virologic response rates and
similar immunologic effects," the QDMRK researchers concluded.
"However, once-daily was inferior in virologic efficacy as
compared to twice-daily raltegravir."