Long-Term Efficacy and Safety of Raltegravir Combined with Optimized Background Therapy in Treatment-Experienced Patients with Drug-Resistant HIV Infection: Week 96 Results of the BENCHMRK 1 and 2 Phase III Trials
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Received 12 June 2009; accepted 2 October 2009; electronically published 19 January 2010
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Members of the study group are listed at the end of the text.
1000, UG3D-56, North Wales, PA 19454-1099
BENCHMRK-1 and -2 are ongoing double-blind phase III studies of raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus infection. At week 96 (combined data), raltegravir (400 mg twice daily) plus optimized background therapy was generally well tolerated, with superior and durable antiretroviral and immunological efficacy, compared with optimized background therapy alone.
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tidrug-resistant HIV-1 in vitro [1, 2]. In phase II clinical trials,
raltegravir demonstrated potent and durable antiretroviral
activity for up to 96 weeks when given with optimized
background therapy (OBT) in treatment-experienced patients [3]
or with tenofovir and lamivudine in treatment-naive patients
[4]. Week 48 results of the BENCHMRK phase III studies
confirmed the efficacy of raltegravir in treatment-experienced
patients infected with multidrug-resistant HIV-1 [5, 6]. This
report presents follow-up results through week 96 of the ongoing
BENCHMRK studies.
Methods. BENCHMRK-1 (protocol 018; NCT 00293267)
and BENCHMRK-2 (protocol 019; NCT 00293254) are
doubleblind, randomized, phase III studies with identical study
designs, as described elsewhere [5]. This report presents efficacy
results through study week 96 and all available safety data from
the double-blind phase through 29 August 2008 (week 96
database lock). From study weeks 1648, virologic failure was
defined as !1 log10 decrease in HIV RNA levels from baseline,
confirmed 11 log10 increase in HIV RNA level from the nadir,
or 2 consecutive HIV RNA level measurements 400 copies/
mL after a prior result of !400 copies/mL. To be consistent
with the recently updated recommended target for viral
suppression [7], virologic failure after week 48 was defined as
confirmed HIV RNA level 50 copies/mL (2 consecutive
measurements at least 1 week apart). Patients with virologic failure
at any time after week 16 could (1) exit the double-blind study
and enter an open-label phase to receive raltegravir as part of
a new regimen, (2) remain in the blinded study, or (3) withdraw
from the study. The potential emergence of resistance to
raltegravir was investigated in patients with virologic failure by
genotyping the integrase coding sequence according to standard
methods [6] and by comparison with pretreatment genotypes.
The following predefined end points were examined at week
96: proportion of patients with HIV RNA levels !50 copies/
mL, proportion of patients with HIV RNA levels !400 copies/
mL, change from baseline in log10 HIV RNA level (copies/mL),
and change from baseline in CD4 cell count (cells/mm3). For
the proportions over time analysis, a worst-case approach as
used that counted all patients who did not complete the study
as treatment failures; missing HIV RNA level measurements
were imputed as failures unless the values flanking the missing
value were both successes, in which case the absent value was
left as missing. For the change from baseline analyses, an
observed failure approach was used: patients who discontinued
treatment for lack of efficacy were assumed to have returned
to their baseline value at subsequent times, but no other missing
values were imputed. Data from patients who discontinued
Table 1. Patient Disposition
Variable
Treated
No. (%) of patients
Raltegravir and OBT
Placebo and OBT
NOTE. OBT, optimized background therapy; OLPVF, open-label postvirologic failure.
a Patients completed original 48-week protocol but did not continue into extension.
b Including patients who moved or relocated, or the clinical trial was terminated at the site.
treatment for other reasons were censored at discontinuation.
The observed failure approach was also used for exploratory
subgroup analyses by potential prognostic factors and for the
assessment of treatment effect homogeneity across
subpopulations. Suspected AIDS-defining events were reviewed by an
independent adjudicator, and blinded safety and efficacy results
were periodically reviewed by an independent Data and Safety
Monitoring Board. Additional details of the statistical analyses
and the adjudication of AIDS-defining events are described
elsewhere [5].
Results. Baseline characteristics were generally balanced
between treatment groups [5]. Most enrolled patients were highly
treatment-experienced white male individuals with AIDS.
Duration of double-blind follow-up was longer in the raltegravir
group (median, 110.4 weeks; range, 3.0127.4 weeks) than in
the placebo group (median, 37.6 weeks; range, 5.6126.4 weeks)
because of more frequent discontinuations for virologic failure
among placebo recipients (Table 1).
Virologic and immunologic responses were consistent
be
Variable
Death
No. of patients/PYR at risk
(rate, cases per 100 PYR)
Raltegravir (...truncated)