Although the widespread use of HAART
has significantly reduced mortality and morbidity among HIV positive individuals,
there is a continuing need for the development of new anti-HIV drugs that are
safe, provide sustained virological suppression, and
exhibit a favorable resistance profile.
The HIV protease inhibitor (PI) darunavir (Prezista) was developed by Tibotec
Therapeutics to meet these needs. The U.S. Food and Drug Administration (FDA)
granted “fast track” (accelerated) approval to darunavir
in June 2006 for use in combination
with other antiretroviral agents for the treatment of HIV infection in adults.
Published in the July 7, 2007 issue
of The Lancet, the current study, called
TITAN (TMC114/r In Treatment-experienced
pAtientsNaive to lopinavir)
[1], evaluated the efficacy and safety
of ritonavir-boosted darunavir
in HIV patients naive to lopinavir who -- although not
antiretroviral treatment-naive -- were not heavily treatment-experienced.
The objective of TITAN was to evaluate
darunavir/ritonavir in a broad range of treatment-experienced
HIV patients that reflect a “real-life” clinical population, and that also included
patients undergoing treatment interruption.
“Our main aim,” wrote the study authors,
“was to show non-inferiority of darunavir/ritonavir
600/100 mg twice daily compared with
lopinavir/ritonavir (Kaletra)
400/100 mg twice daily, in terms of virological response,
with both agents given in addition to an individually optimized background regimen”.
The authors noted that they chose to compare darunavir/ritonavir
with lopinavir/ritonavir “because of [Kaletra’s] efficacy and safety in protease inhibitor-experienced
patients in several randomized controlled trials” [2-5].
Study Design and Patient Profile
TITAN is an ongoing, international,
randomized, controlled, open-label, 96-week Phase III
trial that is being conducted at 159 medical centers in 26 countries.
The trial included lopinavir-naive, treatment-experienced (defined as being on
HAART for at least 12 weeks) patients at least 18 years of age with HIV viral
loads above 1000 copies/mL. Patients coinfected with chronic hepatitis B or C were
allowed to enter the trial if their condition was clinically stable and if they
were not expected to receive hepatitis treatment during the 96-week study period.
Exclusion criteria were as follows:
active AIDS-defining illness
(except stable Kaposi’s sarcoma or
HIV-related wasting syndrome), any clinically important disease, and clinical
or laboratory evidence of significantly decreased hepatic function at screening.
Patients with previous or current use of lopinavir,
darunavir, tipranavir
(Aptivus), or enfuvirtide
(Fuzeon), therapy for hepatitis B or C, or current
use of any investigational antiretroviral drugs were also excluded.
The trial was designed to reflect guidelines
established by the FDA and the European Agency for the Evaluation of Medicinal
Products (EMEA). The primary goal of this trial was to generate longer-term safety
and efficacy data on the FDA- and EMEA-approved dose of darunavir/ritonavir (600/100 mg twice daily) in a broad range of treatment-experienced patients
[emphasis added-Ed].
Of note, the study protocol was amended
to allow patients randomized to lopinavir/ritonavir
to switch from 133.3/33.3 mg capsules to the new 200/50 mg tablet formulation
as soon as it was approved by local regulatory authorities.
Patients also received an investigator-selected
optimized background regimen (OBR) that included at least 2 nucleoside reverse
transcriptase inhibitors (NRTIs) with or without NNRTIs,
based on screening resistance test and antiretroviral treatment history. As stated
above, enfuvirtide, tipranavir,
and experimental antiretroviral drugs (except tenofovir
and emtricitabine,
which are still investigational in some of the participating countries) were disallowed
in theOBR.
Endpoints
The primary efficacy outcome was the proportion of patients with plasma HIV
RNA less than 400 copies/mL
at week 48.
Secondary efficacy outcomes included the following:
Proportion of patients with plasma HIV RNA less
than 50 copies/mL (now regarded as the virological target for all treatment-experienced patients);
Proportion of patients with at least a 1.0 log10
reduction from baseline in plasma HIV RNA;
Mean log10 change in HIV RNA at all
time points;
Median change in CD4 count.
A non-completer
considered as failure (NC=F) analysis was used to assess mean change in log10
HIV RNA and immunological response. An independent Data and Safety Monitoring
Board (DSMB) reviewed the incidence and severity of adverse events and laboratory
abnormalities.
According to the study authors, approximately
250 patients in each treatment arm were needed to provide adequate statistical
power to ascertain whether darunavir/ritonavir was non-inferior
to lopinavir/ritonavir, and 80% power to detect the
difference.
If non-inferiority was established,
a secondary endpoint would be to ascertain whether darunavir/ritonavir
was superior to lopinavir/ritonavir, or vice versa.
An intention-to-treat (ITT) population was used to assess superiority as defined
by current guidelines [6-8].
Results
595 patients
(of 785 screened) were randomized and treated (298 with darunavir/ritonavir
and 297 with lopinavir/ritonavir) and were included
in the ITT analysis.
At week 48, significantly
more patients in the darunavir/ritonavir than in the
lopinavir/ritonavir arm achieved HIV RNA levels less
than 400 copies/mL (77% vs68%; estimated difference 9%).
Compared with those receiving
lopinavir/ritonavir, fewer patients with virological
failure treated with darunavir/ritonavir developed primary PI mutations (21%
[n=6] vs36% [n=20]) or NRTI-associated mutations
(14% [n=4] vs27% [n=15]).
The median change from baseline in CD4 cell count
at week 48 was similar in the 2 groups (NC=F): 88 cells/mm3
with darunavir/ritonavir and 81 cells/mm3
with lopinavir/ritonavir.
More patients withdrew from the
lopinavir/ritonavir arm than the darunavir/ritonavir group.
11% of patients in the lopinavir/ritonavir group discontinued treatment due
to virological failure, compared
with 1% in the darunavir/ritonavir group.
Safety data were generally
similar between the groups.
Grade 3 or 4 adverse
events occurred in 80 patients (27%) in the darunavir/ritonavir
group and 89 (30%) in the lopinavir/ritonavir group.
As with the primary efficacy endpoint, significantly
more patients in the darunavir/ritonavir group achieved
plasma HIV RNA less than 50 copies/mL at week 48 in
an ITT-TLOVR analysis (71% [n=211] vs60% [n=179]).
Authors’ Conclusions
In conclusion, the study authors wrote,
“The results of this large Phase III trial in lopinavir-naive,
HIV-infected, treatment-experienced patients showed that darunavir/ritonavir
was non-inferior to lopinavir/ritonavir, as determined
by the primary endpoint of less than 400 copies/mL of
HIV RNA at week 48.”
Furthermore, the authors stated, “Results
of a secondary analysis showed that darunavir/ritonavir
was superior to lopinavir/ritonavir at this time point
[48 weeks].”
“Importantly,” they continued, “the
population was specifically selected to include patients with less advanced disease
than those studied in the POWER 1 and 2 trials, in which darunavir had already shown superiority to lopinavir and other available protease inhibitors” [9-11].
Commentary
A commentary
on the TITAN study by Bernard Hirschel, MD, and Thomas
Perneger, MD, of GenevaHospital in Switzerland
accompanied the Lancet article.
Drs. Hirschel and Pernager
wrote, “It is unlikely these results will generate a large-scale switch from lopinavir
to darunavir....because darunavir's
superior efficacy would be difficult to show in drug-naive patients, in whom pre-existing
resistance to lopinavir is not the rule, [and because]
darunavir/ritonavir is more expensive, particularly
in the USA, than lopinavir/ritonavir."
The commentators
also suggested that the patients in the lopinavir/ritonavir
arm of the TITAN study might have experienced fewer side effects had they been
using the new formulation Kaletra tablets throughout
the trial: “What would have been TITAN’s results if
[the new Kaletra] tablets had been used throughout?
We can venture a guess: the difference in efficacy may have been the same, but
the difference in gastrointestinal side effects might be absent or smaller.”
Discussion
The majority of adverse events (64%)
seen in this study were mild or moderate (Grade 1 or 2), and discontinuations
due to adverse events were infrequent: 20 (7%) in the darunavir/ritonavir
group and 21 (7%) in the lopinavir/ritonavir group.
Discontinuations due to diarrhea or liver-related or lipid laboratory abnormalities
were more frequent in the lopinavir/ritonavir group
compared with the darunavir/ritonavir group.
The study authors noted that their
findings “confirm the observation from the POWER studies that darunavir/ritonavir has a high barrier to resistance” [9-11]. In the present study, darunavir/ritonavir
was associated with a low rate of additional mutations conferring resistance to
PIs and NRTIs, which can help preserve future treatment
options. Furthermore, they noted, “The benefit of darunavir/ritonavir
was shown in patients who had viruses that were fully sensitive (FC < 10) and
in those with reduced susceptibility (FC > 10) to lopinavir,
showing that the results were not only driven by reduced susceptibility to lopinavir.”
The results of the Phase IIb POWER studies demonstrated the antiviral and immunological
benefits of darunavir/ritonavir in adults with extensive
prior PI resistance. By contrast, the patients in the present study had less advanced
disease, less treatment experience, and were naive to lopinavir,
darunavir, tipranavir, and
enfuvirtide.
A limitation of the TITAN study, addressed
by the authors, is that immunological responses at week 48 were similar for both
treatment groups, with about half the patients in each arm achieving a median
CD4 count of greater than 350 cells/mm3. This
similarity, despite the difference in virological efficacy
between the groups, could be explained by the fact that CD4 count is a less sensitive
marker of efficacy than undetectable HIV RNA [13].
The darunavir-ritonavir
development program is currently evaluating a once-daily dose of 800 mg darunavir plus 100 mg ritonavir
in treatment-naive patients compared
with lopinavir/ritonavir (the ARTEMIS study). According
to the authors, “Results from ARTEMIS will improve understanding of any role of
ritonavir 100 mg twice daily in raising lipid concentrations
and assess whether the once-daily dosing with only 100 mg of ritonavir
will lead to an improved lipid profile compared with that of lopinavir/ritonavir.”
In conclusion, the study authors wrote,
“In view of the lower incidence of treatment failure and lower emergence of mutations
seen in patients on darunavir/ritonavir, our findings
show that darunavir/ritonavir provides highly effective
therapy across the range of treatment-experienced patients.”
More Details from the TITAN Safety Data
During the study, 4 patients in the
darunavir/ritonavir group and 1 in the lopinavir/ritonavir
group developed AIDS-defining illnesses, which were reported as adverse events.
Of the 4 patients in the darunavir/ritonavir group,
1 developed Kaposi’s sarcoma and 3
developed infections (1 case each of esophageal candidiasis,
progressive multifocalleukoencephalopathy,
and pulmonary tuberculosis). In the lopinavir/ritonavir
group, 1 patient developed AIDS-related encephalopathy.
Two patients died in the darunavir/ritonavir group and 3 in the lopinavir/ritonavir
group. The causes of death were as follows:
For the 2 patients in the darunavir/ritonavir
group, respiratory failure secondary to Kaposi’s sarcoma
and septic shock caused by lobar pneumonia;
For 2 in the lopinavir/ritonavir group, cardio-respiratory
arrest secondary to bronchopneumonia and cardio-respiratory arrest.
For the third patient in the lopinavir/ritonavir
group the cause of death was unknown at the time of the report.
All deaths were considered to be unrelated
to study treatment.
Among patients receiving darunavir/ritonavir, the most frequently reported adverse
events (incidence of 10% or greater), regardless of severity and cause, were diarrhea
(32%), nausea (18%), nasopharyngitis (12%), headache
(11%), and upper respiratory tract infection (10%). Among patients receiving lopinavir/ritonavir,
the most frequently reported adverse events were diarrhea (42%), nausea (21%),
and nasopharyngitis (11%).
When adverse events were assessed according
to severity, Grade 2-4 events that were at least possibly related to study treatment
and occurred in 2% or more of patients, the rate of Grade 2 diarrhea in the lopinavir/ritonavir
group was twice that in the darunavir/ritonavir group.
Rash-related events (regardless of severity or cause) were seen in 16% of patients
(n=48) in the darunavir/ritonavir group and 7% (n=20)
in the lopinavir/ritonavir arm.
Members of the TITAN Study Group and Study Sites
Treinamento DST/AIDS, Mariana-São Paulo,
Brazil (J V Madruga MD); Northstar Medical
Center, Chicago, IL (D Berger, MD); University of Sydney, Australia (M McMurchie, MD); OspedaliRiunitidi Bergamo, Italy (F Suter, MD); SzentLásló Hospital, Budapest, Hungary (D Banhegyi, MD); HIVNAT, Thai Red Cross AIDS Research Centre
and Chulalongkorn University, Bangkok, Thailand (K Ruxrungtham, MD);Comprehensive
Research Institute, Tampa, FL (D Norris, MD); Janssen-Cilag, Tilburg, Netherlands (E Lefebvre, MD); Tibotec, Mechelen, Belgium (M-P de Béthune,
PhD; M De Pauw, PharmD; T
VangeneugdenMSc; S Spinosa-Guzman, MD); Tibotec, Yardley, PA (F Tomaka, MD).
1. J V Madruga, D Berger, MMcMurchie,
and others (TITAN study group).Efficacy
and safety of darunavir-ritonavircompared with that of lopinavir-ritonavir
at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. The Lancet 370 (9581): 49-58. July 7, 2007.
12. B Hirschel and T Perneger. No patient
left behind -- better treatments for resistant HIV infection [Commentary]. The
Lancet370 (9581): 3-5. July 7, 2007.
References
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13. A CozziLepri, T L Katzenstein, H
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September 10, 1998.
Index
of All HIV and AIDS Articles by Topic ( A to Z)
