Treatment-experienced
patients with extensive drug resistance are in need of new therapies that can
effectively suppress HIV viral load. In the July 7, 2007 issue of The Lancet,
researchers reported 24-week results from 2 studies assessing the investigational
NNRTI etravirine (TMC125), in combination with the second-generation protease inhibitor
(PI) darunavir (Prezista,
formerly TMC114), in this population.
Background
Maximum virological suppression, defined as HIV RNA below 50 copies/mL, represents the
current therapeutic goal for both antiretroviral treatment-naive and treatment-experienced
HIV patients[1]. Unfortunately,
toxicity and the development of drug
resistance continue to
limit treatment options for treatment-experienced individuals. A single amino
acid substitution in the HIV-1 reverse transcriptase can lead to broad NNRTI cross-resistance
and thus threaten the use of this entire drug class [2-3].
An important
and as yet unmet medical need is developing new antiretrovirals
that show activity against resistant HIV and have a high genetic barrier to the
development of cross resistance.
In vitro, the experimental
NNRTI etravirine has shown potent
activity against both wild-type and NNRTI-resistant strains of HIV-1 and has a
higher genetic barrier to the development of resistance compared with the currently available NNRTIsefavirenz (Sustiva), nevirapine (Viramune), and delavirdine (Rescriptor)[4-5].
In addition,
in Phase IIb clinical studies, etravirine
has demonstrated activity against HIV resistant to the available NNRTIs in treatment-experienced HIV patients infected with
virus resistant to both NNRTIs and protease inhibitors
(PIs), and has been shown to have a safety and tolerability profile similar that
of to the control groups in these studies [6-8].
The aim of the
DUET-1 and
DUET-2trials is to examine the efficacy, tolerability, and safety of etravirine in treatment-experienced patients.
The DUET-1 Trial
DUET-1 is an
ongoing randomized, double-blind, placebo-controlled Phase III trial, which (in
combination with the DUET-2 trial,
described below) is assessing the long-term efficacy, tolerability, and safety
of etravirine versus placebo up to 96 weeks in treatment-experienced
patients with documented NNRTI-resistant HIV-1 infection. DUET-1 enrolled patients
in Argentina, Brazil, Chile,
France, Mexico, Panama,
Puerto Rico, Thailand,
and the US.
Eligibility requirements
for participation in the trial included the following:
At least 18 years of age;
On stable but failing antiretroviral
therapy;
At least 1 documented NNRTI resistance-associated
mutation;
Presence of primary PI-resistance
mutations;
Plasma HIV RNA (viral load) >
5000 copies/mL.
The following were exclusion
criteria:
Life expectancy of less than 6
months;
Any currently active AIDS-defining
illness;
Acute viral hepatitis or chronic
hepatitis B or C with ALT and AST concentrations > 5 times the upper limit
of normal;
If female, pregnant, breastfeeding,
or of child-bearing potential and not using adequate contraception;
Concurrent use of experimental
drugs (except darunavir) and agents with potential drug
interactions.
Patients were randomly assigned
in a 1:1 fashion to receive either 200 mg etravirine or placebo
twice daily after a meal. Randomization was stratified for use of enfuvirtide (Fuzeon) in the background
regimen (no use, re-use, or de novo use), previous darunavir use (yes or no), and plasma viral load at screening
(< 30,000 or ≥ 30,000 copies/mL).
All patients also received
darunavir with low-dose ritonavir
as part of the background regimen (600 mg darunavir
plus 100 mg ritonavir twice daily). Since darunavir/ritonavir has shown antiviral efficacy in treatment-experienced
HIV patients [9], the use of darunavir/ritonavir
by all patients ensured that the trial population received at least 1 potentially
active agent (other than etravirine) with demonstrated efficacy.
The primary endpoint of
DUET-1 was the proportion of patients achieving a confirmed viral load < 50
copies/mL at week 24 using an intention-to-treat (ITT)
analysis.
Secondary endpoints were
the proportion of patients achieving a viral load < 400 copies/mL, change in viral load from baseline, change in CD4 cell
count from baseline, and safety and tolerability.
An independent Data and
Safety Monitoring Board monitored and assessed adverse events and laboratory abnormalities
on a scheduled basis, and regularly reviewed available safety and efficacy data.
Virological failure leading to treatment
discontinuation was defined as a viral load reduction of less than 0.5 log10 copies/mL
from baseline at week 8 or less than 1.0 log10 copies/mL at week 12 or beyond. Loss of virological
response was defined as plasma viral load of more than 0.5 log10 copies/mL
above the nadir (lowest-ever level) on 2 consecutive measurements after a minimum
of 12 weeks.
All analyses were done on
the ITT population (all randomized patients who had received at least 1 dose of
etravirine, irrespective of protocol compliance or ineligibility). The primary efficacy
analysis was done when all patients had reached week 24 or discontinued earlier.
The effect of adding to
antiretroviral therapy was expected to be different between patients who re-used
or did not use enfuvirtide and patients who used the
drug de novo.
DUET-1
Result
1220 patients were screened; of
these, 612 were randomized and treated (304 in the etravirine group,
308 in the placebo group). All had reached week 24 or discontinued earlier at
the time of analysis.
At week 24, confirmed viral load
below 50 copies/mL was achieved
by 170 patients (56%) in the etravirine group and 119
patients (39%) in the placebo group.
125 patients (68%) with baseline
viral load under 100,000 copies/mL and 45 patients (38%)
with baseline viral load of 100,000 copies/mL or greater achieved the primary endpoint in the etravirine group, compared
with 85 (47%) with baseline viral load under 100,000 copies/mL and 34 (27%) with baseline viral load of 100,000 copies/mL or greater in the placebo group.
At week 24, a confirmed viral
load of less than 400 copies/mL
was achieved by 224 patients (74%) in the etravirine
group and 158 patients (51%) in the placebo group.
Larger proportions of patients
in the etravirine group achieved viral loads below 50
copies/mL and less than 400 copies/mL than in the placebo group, irrespective of the number
of active background agents.
A viral load below 50 copies/mL was achieved by 21 (47%) of the 45 patients in the
etravirine group with no active agents in their background
regimen, compared with four (9%) of
46 such patients in the placebo group.
CDC category C AIDS-defining illnesses
or death were reported in 8 patients (3%) in the etravirine group and 21 patients (7%) in the placebo
group.
CDC category C AIDS-defining illnesses
alone were reported in 5 patients (2%) in the etravirine group and 20 (7%) in the placebo group.
Any AIDS-defining illnesses were
reported in 3 patients (1%) in the etravirine group
and 17 (7%) in the placebo group.
There were 4 (1%) deaths in the
etravirine group and 8 (3%) in the placebo group.
A statistically significant interaction
effect was identified between etravirine and enfuvirtide
use. Further statistical analyses comparing
efficacy between the etravirine and placebo groups were
therefore based on 2 enfuvirtide subgroups: patients
who re-used or did not use enfuvirtide, and patients
who used enfuvirtidede novo.
Of the patients re-using or not
using enfuvirtide, more patients in the etravirine group (126 patients [55%]) reached the primary
endpoint thanin
the placebo group (75 patients [33%]).
Of the patients who used enfuvirtidede novo, the primary endpoint was
reached by 44 patients (59%) in the etravirine group
and 44 (56%) in the placebo group.
The proportion of patients achieving
a viral load below 50 copies/mL was generally greater in the etravirine group than in the placebo group, irrespective
of the baseline number of NNRTI resistance-associated mutations.
More patients re-using or not
using enfuvirtide in the etravirine
group achieved a viral load below 50 copies/mL, irrespective of baseline darunavir
use, than did those in the placebo group.
In the subgroup of patients that
re-used or did not use enfuvirtide, AIDS-defining illnesses
or deaths were recorded in 5 patients (2%) in the etravirine group and 18 (8%) in the placebo group (P
= 0.0081 in a logistic regression analysis).
The frequencies of adverse events
were comparable between the etravirine
and placebo groups, and were mostly grade 1 or 2 (mild to moderate) in severity.
The frequencies of individual
grade 3 or 4 (severe) adverse events, irrespective of causality, in the etravirine
group were comparable to those in the
placebo group.
Adverse events leading to permanent
treatment discontinuation were seen in 16 patients (5%) in both the etravirine
and the placebo group.
Rash of any type was seen in 61
patients (20%) in the etravirine group and 30 (10%) in
the placebo group.
In the etravirine group,
most cases of rash were grade 1 or 2 in severity.
Grade 3 rash was recorded in 4
(1%) patients; no grade 4 rashes were reported.
One patient (0.3%) in the etravirine
group and 9 (3%) in the placebo group experienced a grade 3 neuropsychiatric adverse event; no grade 4 cases were recorded.
Individual nervous system adverse
events and psychiatric adverse events in the etravirinegroup were mostly mild
or moderate in severity and were no different from placebo in frequency.
The incidence of grade 3 and 4
laboratory abnormalities (including lipid, hepatic, and pancreatic) was comparable between the treatment groups.
4 patients (1%) in the etravirine
group and 8 (3%) in the placebo group died due to adverse events that began during
the treatment period; none of these deaths was deemed related to etravirine.
DUET-1
Discussion
According to the authors,
at week 24, the primary efficacy endpoint of confirmed viral load below 50 copies/mL was achieved by
a significantly greater proportion of treatment-experienced patients receiving
etravirine than those receiving placebo. The authors also
noted that, “additional benefits of etravirine over placebo were seen for
secondary endpoints including viral load below 400 copies/mL, change in viral load from baseline, and change
in CD4 cell count from baseline.”
The occurrence of AIDS-defining
illnesses and deaths at week 24 was not significantly different between the etravirine and placebo groups in the overall population, “but
did reach significance in the subgroup of patients that re-used or did not use
enfuvirtide,” according to the authors.
Most treatment-emergent
adverse events were mild or moderate in severity, and
the occurrence of serious or grade 3 or 4 events, and of events leading to discontinuation,
was similar in both groups. The authors commented,
“Although rash (any type) occurred more frequently in the etravirinegroup than in the placebo
group, cases were generally mild to moderate in severity, infrequently led to
discontinuation, and generally resolved with continued treatment.”
“Additionally,” noted the
authors, “the nature, frequency, and severity of hepatic, neuropsychiatric,
and lipid-related adverse events did not differ between the etravirine and placebo
groups in the present trial.”
According to the authors,
“The results of this trial show that, at 24 weeks, etravirine has antiviral
activity in patients with NNRTI resistance. The findings are consistent with the
in-vitro activity of etravirine against
NNRTI-resistant HIV strains”
The virological
responses noted in the etravirine group were better
than those of the placebo group, despite all patients having at least 1 documented
NNRTI resistance-associated mutation and an extensive treatment history.
“Etravirine therefore
offers a new treatment option within the NNRTI class,” wrote the authors, “with
the results of the trial also indicating that sequential use of etravirine,
i.e., use of etravirine after another NNRTI -- is probably effective even
in the presence of NNRTI resistance. The results of this trial are also lent support
by the findings of the DUET-2 trial” (discussed below).
The addition of de-novoenfuvirtide seemed to increase virological
response in patients with some degree of resistance to darunavir,
underscoring the need for at least 2 active agents to be included in a regimen.
“Further studies are needed to identify which subgroups of patients require three
or more active drugs in a regimen and whether this would reduce the risk of viral
rebound,” the authors wrote.
One of the limitations of
the trial noted by the authors is that the PI component
of the background regimen was fixed with darunavir/ritonavir.
“Since etravirine
cannot be coadministered with the PI tipranavir,” they wrote, “darunavir
was considered the best PI option for this population with extensive PI resistance”
[11].
In conclusion, the authors
stated, “Longer-term results from the ongoing DUET studies will continue to establish
the role and provide further guidance for the use of etravirine
in this patient population.”
The
DUET-2 Trial
The ongoing DUET-2 trial
is being conducted at 103 medical centers in 12 countries:
Australia, Belgium, Canada,
France, Germany, Italy,
Netherlands, Poland, Portugal,
Spain, the UK, and the US. The trial consists of a 6-week
screening period, a 48-week treatment phase, and a 4-week follow-up period.
Eligibility requirements
and exclusion criteria were the same as those listed for the DUET-1 trial, above.
Following enrollment, all patients received background antiretroviral
therapy that consisted of the darunavir plus low-dose
ritonavir (600/100 mg twice daily), plus at least 2
investigator-selected approved antiretroviral drugs chosen from nucleoside/nucleotide
reverse transcriptase inhibitors (NRTIs), and optional
enfuvirtide.
No additional NNRTIs or PIs were allowed. Etravirine
can be given with darunavir- ritonavir
without dose adjustment [1]. Since
darunavir/ritonavir has demonstrated significant antiviral
activity in treatment-experienced HIV patients, this PI was fixed in the antiretroviral
treatment background to increase the possibility of patients receiving at least
2 active drugs.
The primary endpoint was
the proportion of patients achieving a plasma viral load of
less than 50 copies/mL at week 24. Secondary
endpoints were antiviral efficacy at all time points (including change from baseline
in viral load and proportion of patients achieving viral load of < 400 copies/mL,
or ≥ 1 log10 viral load reduction), changes in CD4 cell count,
and safety and tolerability.
The trial was designed to
have 95% power to detect a significant difference in the primary endpoint between
treatment groups. All analyses used the intention-to-treat (ITT) population, defined
as all randomized patients receiving at least 1 dose of trial medication, irrespective
of compliance with the protocol.
DUET-2
Results
954 patients were screened and
593 were randomized and treated (304 in
the etravirine group, 308 in the placebo group).
All analyses include the 591 patients
who started treatment, irrespective of their eligibility or compliance with the protocol (ITT population),
and data were collected when all patients had either received at least 24 weeks
of treatment or discontinued.
All
patients used darunavir, with 23 (4%) re-using this
drug.
Enfuvirtide use was well balanced
between treatment groups; overall, 148 patients (25%) re-used enfuvirtide (73 [25%] in the etravirine group
and 75 [25%] in the placebo group); 283 (48%) did not use the drug (143 [49%]
in the etravirine group and 140 [47%] in the placebo group),
and 160 (27%) used the drug de novo (79 [27%] in the etravirine
group and 81 [27%] in the placebo group).
The number and specific NRTIs used were similar between treatment groups.
The median treatment
duration was 33.1 weeks in the etravirine group
and 32.2 weeks in the placebo group.
51 patients (17%) in the etravirine
group and 73 (25%) in the placebo group discontinued prematurely, mainly because
of virological failure.
Viral load below 400 copies/mL at week 24 was achieved by 153 patients (71%) in the
etravirine
group, compared with 96 (45%) in the
corresponding placebo group.
At week 24, 170 patients (56%) in the etravirine
group and 119 (39%) in the placebo group achieved a confirmed viral load of less
than 50 copies/mL.
A statistical interaction was
found between enfuvirtide use and treatment outcome.
Of the individuals who re-used
or did not use enfuvirtide, 125 (58%) in the etravirine
group achieved a viral load below 50 copies/mL at week
24, compared with 74 (34%) in the corresponding
placebo group (P < 0.0001).
Most adverse events were mild or moderate in severity.
The most common
adverse events were diarrhea, nausea, rash (any type),
injection site reaction (related to enfuvirtide administration),
headache, and fatigue.
The type and incidence of all adverse events, including neuropsychiatric events, seen with etravirine
were generally comparable to those
seen with placebo, with the exception of rash and diarrhea.
The
frequency and type of serious adverse events, and the overall rate of discontinuation
due to any adverse event, were similar between the etravirine and placebo
groups.
Rash was reported for 41 patients
(14%) in the etravirine group and 27 (9%) in
the placebo group.
Most rashes were described as
erythematous or maculopapular
and were of mild or moderate severity.
No grade 4 skin events were reported,
while grade 3 skin events were reported for 4 patients (1%) in the etravirinegroup and one
(0%) in the placebo group.
Nervous system and psychiatric
adverse events were reported with a similar nature, frequency, and severity in
the etravirine and placebo groups.
Events
were generally mild or moderate in severity; no grade 4 nervous system or psychiatric
adverse events were reported in the etravirinegroup, and
grade 3 neuropsychiatric adverse events were reported
with similar low frequency in both treatment groups (1 patient in the etravirine group
and 3 in the placebo group).
CDC category C AIDS-defining illness
or death was reported for 14 patients (5%) in the etravirine
group, compared with 20 (7%) in the
placebo group.
No deaths were deemed to be related
to trial medication.
DUET-2
Discussion
At week 24 in the DUET-2
trial, a significantly higher proportion of patients who received etravirine with background antiretrovirals
achieved a confirmed viral load of less than 50 copies/mL than did those who received placebo with background
antiretrovirals. According to the study authors, this
occurred, “irrespective of the baseline viral load or presence of several NNRTI
resistance-associated mutations. Furthermore, etravirine had a tolerability
profile much the same as placebo, with few clinically relevant differences.”
The DUET trials evaluated
2 experimental drugs (etravirine and darunavir, which was not approved when the study began) that
both show activity in patients with HIV resistant to NNRTIs
and PIs. “These findings support the concept of using more than one experimental
drug in clinical trials of treatment-experienced HIV patients,” wrote the authors.
Differences in virological response between the etravirine
and placebo groups were most apparent in patients with no active background antiretrovirals (44% in the etravirine
group vs7% in the placebo group achieved viral
load < 50 copies/mL). In patients receiving 2 or
more active drugs in the background regimen, the difference was smaller, noted
the authors. “In support of current treatment guidelines [2,3], we report an incremental increase
in virological response rate when 1 or 2 active background
antiretrovirals were used in addition to etravirine,”
the authors noted.
According to the authors,
the results of DUET-2 suggest that, “the sequential use of etravirine, i.e.,
after virological failure on current NNRTI-based treatment,
is now possible.”
The limitations of the trial
included fixing the PI component of
the background regimen as darunavir-ritonavir, since
although more patients were sensitive to darunavir/ritonavir
than any other PI, some individuals might have been more sensitive to another
PI. However, because co-administration of etravirine and tipranavir is not recommended
[4], “darunavir-ritonavir was the PI component that was thought to offer the best potential
for response in the trial patients,” according to the authors.
In conclusion, the authors
stated, “There is currently an unmet clinical need to expand the NNRTI class for
treatment-experienced patients, including those with NNRTI resistance. The magnitude
of the results seen with etravirine in DUET-1
and DUET-2 (56% and 62% of patients achieved undetectable viral loads at week
24), and the similarity of the responses across both trials done in different
countries, indicate that the higher genetic barrier to resistance of etravirinecompared with currently available NNRTIs and its activity against NNRTI-resistant virus are
central to the ability of etravirine, given as part of an antiretroviral
regimen, to produce significantly better virological
responses than the placebo group in treatment-experienced patients.”
Finally, they concluded,
“The maintenance of the response to 24 weeks without additional clinically relevant
tolerability concerns further suggests that etravirineis an encouraging new
agent in this antiretroviral class.”
Commentary
on Both Trials
In an accompanying commentary,
Bernard Hirschel, MD, and Thomas Perneger,
MD of GenevaHospital
in Switzerland
argued that important questions have been left unanswered by the DUET-1 and DUET-2
trials, including “quality-of-life measurements, and
detailed correlations between resistant genotype and treatment success which may
help gauge etravirine’s prospects in individual patients.”
Drs. Hirschel
and Perneger also lamented that the study authors did
not write a pooled analysis of DUET-1 and DUET-2, which they claim would have
provided more clarity to readers. In addition, they write, “A combined analysis of the DUET studies would have allowed
the investigators to claim as of today a clinically important benefit for etravirine.
It is a shame to see this opportunity delayed.”
07/13/07
Sources
J V Madruga, P Cahn, B Grinsztejn, and others (on
behalf of the DUET-1 study group).Efficacy
and safety of TMC125 (etravirine) in treatment-experienced
HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind,
placebo-controlled trial. The Lancet 370(9581): 29-38. July 7, 2007.
A Lazzarin, T Campbell,
B Clotet, and others (on behalf of the DUET-2 study
group).Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients
in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled
trial. The Lancet 370(9581): 39-48.
July 7, 2007.
B Hirschel and T Perneger.No patient left behind—better treatments for resistant
HIV infection (Comment). The Lancet
370(9581): 3-5. July 7, 2007.
Additional
References for DUET-1 Report
1.
S M Hammer, M S Saag,
M Schechter, and others. Treatment for adult HIV infection:
2006 recommendations of the International
AIDS Society-USA panel. JAMA 296:827–43. 2006.
2.
L Bacheler, S Jeffrey, G Hanna, and others. Genotypic
correlates of phenotypic resistance to efavirenz in
virus isolates from patients failing nonnucleoside reverse
transcriptase inhibitor therapy. Journal of Virology 75:4999–5008.
2001.
3.
C Delaugerre, R Rohban, A
Simon, and others. Resistance profile and cross-resistance of HIV-1 among patients
failing a non-nucleoside reverse transcriptase inhibitor-containing regimen. Journal
of Medical Virology 65:445–48.
4.
K Andries, H Azijn, and T
Thielemans. TMC125, a novel next-generation
onnucleoside reverse transcriptase inhibitor active
against nonnucleoside reverse transcriptase inhibitor-resistant
human immunodeficiency virus type 1.Antimicrob Agents and Chemotherapy 48:4680–86.
2004.
5.
J Vingerhoets, H Azijn, E Fransen, and others. TMC125
displays a high genetic barrier to the development of resistance: evidence from
in vitro selection experiments. Journal of Virology 79:12773–82.
2005.
6. C Cohen, C R Steinhart,
D J Ward, and others. Efficacy and safety results at 48 weeks with the novel NNRTI,
TMC125, and impact of baseline resistance on the virologic response in study TMC125-C223. 16th International
AIDS Conference; Toronto,
Canada; Aug 13–18,
2006. Abstract TUPE0061.
7. TMC125-C223 Writing Group;
J P Nadler, D S Berger, G Blick, and others. Efficacy
and safety of etravirine (TMC125) in patients with highly
resistant HIV-1: primary 24-week analysis. AIDS 21:F1–10. 2007.
8. J Montaner,
P Domingo and P Junod. Safety and tolerability of TMC125
in 3-class-experienced HIV-infected patients: 24-week primary analysis of trial
TMC125-C203. 10th European AIDS Conference; Dublin, Ireland;
Nov 17–20, 2005. Abstract LBPS3/7B.
9. B Clotet,
N Bellos, J M Molina,
and others. Efficacy and safety of darunavir-ritonavir
at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and
2: a pooled subgroup analysis of data from two randomised trials. Lancet 369:1169–78. 2007.
10. Lazzarin A, Campbell T, Clotet B,
et al. Efficacy
and safety of TMC125 (etravirine) in treatment-experienced
HIV-1 infected patients in DUET-2: 24 week results from a randomised, double-blind,
placebo-controlled trial. Lancet 370:39–48.
2007.
11. M Schöller,
M Kraft, R Hoetelmans, and others, Significant
decrease in TMC125 exposures when co-administered with tipranavir
boosted with ritonavir in healthy subjects. 13th Conference
on Retroviruses and Opportunistic Infections; Denver, CO, USA; Feb 5–8, 2006. Abstract 583.
Additional
references for DUET-2 report
1. M Schöller-Gyüre, T N Kakuda,
V Sekar, and others. Pharmacokinetics of darunavir/ritonavir and TMC125 alone and co-administered in
HIV-negative volunteers. Antiviral Therapy (in press).
2. B Gazzard, A J Bernard, M Boffito, and others,.British HIV Association (BHIVA) guidelines for the treatment of HIV-infected
adults with antiretroviral therapy (2006).HIV Medicine 7: 487–503.
2006.
3. S M Hammer, M S Saag,
M Schechter, and others. Treatment for adult HIV infection:
2006 recommendations of the International
AIDS Society-USA panel. JAMA 296:827–43. 2006.
4. D McColl, N Margot,
B Lu, and others. Lack of resistance to tenofovir
at week 48 and impact of baseline resistance mutations on treatment response in
study 934.3rd International AIDS Conference on HIV Pathogenesis
and Treatment; Rio de Janeiro,
Brazil; July 24–27,
2005.Abstract TuPp0305.
