In
the first study, Joseph Gathe, MD, and colleagues compared once- versus twice-daily
lopinavir/ritonavir (Kaletra)
(abstract 775).
A smaller prior study of treatment-naive patients found that once-daily dosing
of Kaletra soft-gel capsules was not inferior to twice-daily dosing when co-administered
with a nucleoside/nucleotide
reverse transcriptase inhibitor (NRTI) backbone, though diarrhea was more
frequent in the once-daily arm.
In the present trial, Study M05-730, the
investigators evaluated 800/200 mg once-daily versus 400/100 mg twice-daily administration
of lopinavir/ritonavir using the new tablet formulation of Kaletra, which tends
to cause less gastrointestinal upset. Unlike the gel formulation, the tablets
can be taken with or without food and do not require refrigeration.
A total
of 664 antiretroviral-naive participants (78% men; 75% white) were randomly assigned
to 1 of 4 groups, receiving Kaletra as either once- or twice-daily soft gel capsules
or once- or twice-daily tablets, for 8 weeks. In addition, all patients received
once-daily tenofovir + emtricitabine (Truvada).
At week 8, participants taking the capsule formulation switched to tablets, maintaining
their once- or twice-daily dosing schedule. Baseline characteristics were similar
across groups, with a mean HIV viral load of about 100,000 copies/mL and a mean
CD4 cell count of 215 cells/mm3.
The study is scheduled to last for up
to 96 weeks. Results of the primary week 48 analysis were presented at CROI. The
pre-defined non-inferiority margin was 12% for the comparison of once-daily versus
twice-daily Kaletra in an intent-to-treat, non-completer = failure (ITT NC=F)
analysis of the proportion of patients with HIV RNA < 50 copies/mL.
Results
•
At week 48, 77% in the once-daily arm and
76% in the twice-daily arm achieved HIV RNA < 50 copies/mL, a non-significant
difference (P = 0.65).
•
The 95% confidence interval for the difference
in response rates confirmed the non-inferiority of the once-daily regimen.
•
Virological response rates were similar regardless
of baseline viral load (< 50 or > copies/mL) or CD4 cell count (<50,
50-200, or > 200 cells/mm3), with no differences between once-daily
and twice-daily Kaletra administration in any group.
•
Mean increases in CD4 cell count at week 48
were 186 cells/mm3 in the once-daily and 197 cells/mm3 in the twice-daily arms,
also a non-significant difference.
•
Adverse event (AE) rates, including gastrointestinal
symptoms, were similar in the once-daily and twice-daily arms.
•
Moderate-to-severe diarrhea was reported by
17% of patients in the once-daily arms and 15% in the twice-daily arms, again
a non-significant difference.
•
Serious laboratory AEs, including abnormal
liver enzyme and blood lipid levels, were uncommon and of similar frequency in
the once- and twice-daily arms.
•
However, the twice-daily group had a slight
but statistically significant larger increase in total cholesterol.
•
Through 48 weeks, 15% of patients in the once-daily
arms and 17% in the twice-daily arms discontinued treatment prematurely.
•
Discontinuation due to adverse events occurred
in 4.5% of once-daily patients and 2.4% of twice-daily subjects, which did not
reach statistical significance (P = 0.202).
•
Among subjects with viral rebound genotype
data available, no new protease inhibitor (PI) mutations were observed; however
2 of 8 in the once-daily and 1 of 5 in the twice-daily arms evidenced the M184I/V
mutation.
Based
on these findings, the researchers concluded, "Through 48 weeks, lopinavir/ritonavir
once-daily was not inferior to twice-daily when co-administered with tenofovir
+ [emtricitabine] in antiretroviral-naive subjects. Efficacy was similar regardless
of baseline HIV-1 RNA or CD4 cell count."
They added that, "Once-daily
dosing of lopinavir/ritonavir tablets was similarly well tolerated when compared
to twice-daily dosing of lopinavir/ritonavir tablets. Consistent with prior lopinavir/ritonavir
trials in antiretroviral-naive subjects, no new PI mutations were detected upon
virologic rebound."
"In the last decade, we have seen a shift
from simply treating and helping extend life for those infected with HIV to creating
therapies that also offer improved convenience for patients," Scott Brun,
MD, of Abbott's Global Pharmaceutical Research and Development said in a press
statement. "The tablet formulation of Kaletra dosed as once-daily combination
therapy is a real advantage for therapy-naive patients and physicians, offering
a convenient and effective HIV treatment option, as indicated by the results of
this study."
Therapeutic
Concepts, Houston, TX; Abbott Labs, Abbott Park, IL; Maple Leaf Med Clin, Toronto,
Canada; Hosp Univ de Bellvitge, Barcelona, Spain; Hosp 12 de Octubre, Madrid,
Spain.
In
the second study, Alexandra Calmy, MD, and colleagues with the Swiss HIV Study
and the Dutch ATHENA Cohort presented data on once- versus twice-daily use of
nevirapine (Viramune) (abstract
786).
Though 200 mg twice-daily was the initially approved nevirapine
dose, the drug is often prescribed once-daily in clinical practice; however, some
prior studies have cast doubt on whether once-daily dosing is equally effective.
The
present analysis included 5244 HIV positive patients in the Swiss and Dutch cohorts
who had previously used nevirapine-based combination HAART: 4471 twice-daily and
629 once-daily. The investigators analyzed 3 groups with available viral load
and CD4 count data: 853 treatment-naive patients, 1700 previously treated patients
starting nevirapine with an undetectable viral load, and 2054 treatment-experienced
individuals with detectable HIV RNA.
Time to reach an undetectable viral
load (< 50 copies/mL) and time to loss of virological response (TLOVR) were
performed using Kaplan-Meier survival analysis. Results
•
Among treatment-naive patients, 82% of those
on a twice-daily regimen achieved undetectable HIV RNA at 96 weeks, compared with
84% of those starting a once-daily regimen, a non-significant difference (P =
0.67).
•
However, treatment-naive patients taking once-daily
nevirapine took longer to reach an undetectable level than those on twice-daily
nevirapine (log rank 0.04).
•
Among treatment-experienced patients with
undetectable HIV RNA, there was no observed difference in time to loss of virological
response between the once-daily and twice-daily groups through week 96 (log rank
0.084).
•
In treatment-experienced patients with detectable
viral load, once-daily nevirapine was associated with significantly better virological
outcomes at week 96 compared with the twice-daily dosing schedule (50% vs 69%;
P <0.0001).
•
In this same group, time to viral load suppression
was significantly shorter in patients on a once-daily regimen (log rank 0.001).
•
In this patient population, CD4 cell count
gains at 96 weeks were significantly higher in the once-daily nevirapine group
(80 vs 110 cells/mm3; P = 0.0009).
"These
data suggest that nevirapine once daily in clinical practice is at least as efficient
as nevirapine prescribed twice daily," the researchers concluded.
"For
patients with detectable HIV RNA who have been exposed to other antiretroviral
drugs and commencing a regimen including nevirapine," they continued, "nevirapine
once daily is associated with better and faster virological suppression, as well
as a stronger immune restoration."
As
reported in the last issue, Boehringer Ingelheim recently announced that recruitment
has started for an 18-country randomized clinical trial, called VERXVE, that will
assess the safety and efficacy of once-daily nevirapine.
Univ Hosp Geneva,
Switzerland; Ctr for Poverty-Related Communicable Diseases, Academic Med Ctr,
Amsterdam, Netherlands; Univ Hosp Basel, Switzerland; HIV Monitoring Fndn, Amsterdam,
Netherlands.
2/19/08
Sources
Abbott.
Clinical Study Demonstrates Similar Effectiveness Of Once-Daily vs. Twice-Daily
Dosing of Abbott's Kaletra (lopinavir/ritonavir) Tablet in HIV-Infected Patients
New to Antiretroviral Therapy. Press release. February 8, 2008.
Once-daily
Lopinavir/ritonavir (Kaletra) and Nevirapine (Viramune) Appear as Effective as
Twice-daily
Many
Results
